Cosmetic Dermatology: Products and Procedures

Cosmetic Dermatology Products and Procedures

Cosmetic Dermatology Products and Procedures E D I T E D BY

Zoe Diana Draelos MD Consulting Professor Department of Dermatology Duke University School of Medicine Durham, North Carolina USA

A John Wiley & Sons, Ltd., Publication

This edition first published 2010 © by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Cosmetic dermatology : products and procedures / edited by Zoe Diana Draelos. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-8635-3 (hardcover : alk. paper) 1. Skin–Care and hygiene. 2. Cosmetics. 3. Dermatology. I. Draelos, Zoe Kececioglu. [DNLM: 1. Cosmetics. 2. Dermatologic Agents. 3. Cosmetic Techniques. 4. Skin Care– methods. QV 60 C8346 2009] RL87.C68 2009 646.7′2–dc22 2009031482 ISBN: 9781405186353 A catalogue record for this book is available from the British Library. Set in 9 on 12 pt Meridien by Toppan Best-set Premedia Limited Printed and bound in Singapore 1

2010

Contents

Contributors, viii

Section II Hygiene Products, 75

Foreword, xiv Jeffrey S. Dover

Part One Cleansers, 77

Introduction: Definition of Cosmetic Dermatology, xv Zoe D. Draelos

10 Bar cleansers, 77 Anthony W. Johnson and K.P. Ananthapadmanabhan

Section I Basic Concepts, 1 Part One Skin Physiology Pertinent to Cosmetic Dermatology, 3 1 Epidermal barrier, 3 Sreekumar Pillai, Marc Cornell, and Christian Oresajo 2 Photoaging, 13 Murad Alam and Jillian Havey 3 Self-perceived sensitive skin, 22 Olivier de Lacharrière 4 Pigmentation and skin of color, 27 Chesahna Kindred and Rebat M. Halder 5 Sensitive skin and the somatosensory system, 38 Francis McGlone and David Reilly 6 Novel, compelling non-invasive techniques for evaluating cosmetic products, 47 Thomas J. Stephens, Christian Oresajo, Robert Goodman, Margarita Yatskayer, and Paul Kavanaugh 7 Contact dermatitis and topical agents, 55 David E. Cohen and Aieska de Souza Part Two Delivery of Cosmetic Skin Actives, 62

11 Personal cleansers: body washes, 88 Keith Ertel and Heather Focht 12 Facial cleansers and cleansing cloths, 95 Erik Hasenoehrl 13 Non-foaming and low-foaming cleansers, 102 Duncan Aust 14 Liquid hand cleansers and sanitizers, 106 Duane Charbonneau 15 Shampoos for normal scalp hygiene and dandruff, 115 James R. Schwartz, Marcela Valenzuela, and Sanjeev Midha Part Two Moisturizers, 123 16 Facial moisturizers, 123 Yohini Appa 17 Hand and foot moisturizers, 130 Teresa M. Weber, Andrea M. Schoelermann, Ute Breitenbach, Ulrich Scherdin, and Alexandra Kowcz 18 Sunless tanning products, 139 Angelike Galdi, Peter Foltis, and Christian Oresajo 19 Sunscreens, 144 Dominique Moyal, Angelike Galdi, and Christian Oresajo Part Three Personal Care Products, 150

8 Percutaneous delivery of cosmetic actives to the skin, 62 Marc Cornell, Sreekumar Pillai, and Christian Oresajo

20 Antiperspirants and deodorants, 150 Eric S. Abrutyn

9 Creams, lotions, and ointments, 71 Irwin Palefsky

21 Blade shaving, 156 Keith Ertel and Gillian McFeat

Contents

Section III Adornment, 165 Part One Colored Facial Cosmetics, 167

38 Retinoids, 309 Olivier Sorg, Gürkan Kaya, Behrooz Kasraee, and Jean H. Saurat

22 Facial foundation, 167 Sylvie Guichard and Véronique Roulier

39 Topical vitamins, 319 Donald L. Bissett

23 Camouflage techniques, 176 Anne Bouloc

40 Clinical uses of hydroxyacids, 327 Barbara Green, Eugene J. Van Scott, and Ruey Yu

24 Lips and lipsticks, 184 Catherine Heusèle, Hervé Cantin, and Frédéric Bonté

41 The contribution of dietary nutrients and supplements to skin health, 335 Helen Knaggs, Steve Wood, Doug Burke, and Jan Lephart

25 Eye cosmetics, 190 Sarah A. Vickery, Peter Wyatt, and John Gilley Part Two Nail Cosmetics, 197 26 Nail physiology and grooming, 197 Phoebe Rich and Heh Shin R. Kwak 27 Colored nail cosmetics and hardeners, 206 Paul H. Bryson and Sunil J. Sirdesai 28 Cosmetic prostheses as artificial nail enhancements, 215 Douglas Schoon Part Three Hair Cosmetics, 222 29 Hair physiology and grooming, 222 Maria Hordinsky, Ana Paula Avancini Caramori, and Jeff D. Donovan

Part Two Injectable Antiaging Techniques, 342 42 Botulinum toxins, 342 Joel L. Cohen and Scott R. Freeman 43 Hyaluronic acid fillers, 352 Mark S. Nestor 44 Calcium hydroxylapatite for soft tissue augmentation, 356 Stephen Mandy 45 Skin fillers, 361 Neil Sadick, Misbah H. Khan, and Babar K. Rao 46 Polylactic acid fillers, 373 Kenneth R. Beer Part Three Resurfacing Techniques, 377

30 Hair dyes, 227 Frauke Neuser and Harald Schlatter

47 Superficial chemical peels, 377 M. Amanda Jacobs and Randall Roenigk

31 Permanent hair waving, 236 Annette Schwan-Jonczyk and Gerhard Sendelbach

48 Medium depth chemical peels, 384 Gary D. Monheit and Jens J. Thiele

32 Hair straightening, 248 Harold Bryant, Felicia Dixon, Angela Ellington, and Crystal Porter

49 CO2 laser resurfacing: confluent and fractionated, 393 Mitchel P. Goldman

33 Hair styling – technology and formulations, 256 Thomas Krause, Rene Rust, and Dianna C. Kenneally

Section IV Antiaging, 267

50 Non-ablative resurfacing, 409 David J. Goldberg and Katie Rossy 51 Microdermabrasion, 418 Pearl Grimes 52 Dermabrasion, 426 Christopher Harmon and Chad Prather

Part One Cosmeceuticals, 269 34 Botanicals, 269 Carl Thornfeldt 35 Antioxidants and anti-inflammatories, 281 Bryan B. Fuller 36 Peptides and proteins, 292 Karl Lintner 37 Cellular growth factors, 302 Richard E. Fitzpatrick and Rahul C. Mehta

Part Four Skin Modulation Techniques, 432 53 Laser-assisted hair removal, 432 Keyvan Nouri, Voraphol Vejjabhinanta, Nidhi Avashia, and Rawat Charoensawad 54 Radiofrequency devices, 439 Vic Narurkar 55 LED photomodulation for reversal of photoaging and reduction of inflammation, 444 Robert Weiss, Roy Geronemus, David McDaniel, and Corinne Granger

Contents Part Five Skin Contouring Techniques, 450 56 Liposuction: manual, mechanical, and laser assisted, 450 Emily Tierney and C. William Hanke 57 Liposuction of the neck, 463 Kimberly J. Butterwick 58 Hand recontouring with calcium hydroxylapatite, 473 Kenneth L. Edelson Part Six Implementation of Cosmetic Dermatology into Therapeutics, 480

60 Over-the-counter acne treatments, 488 Emmy M. Graber and Diane Thiboutot 61 Rosacea regimens, 495 Joseph Bikowski 62 Eczema regimens, 502 Zoe D. Draelos 63 Psoriasis regimens, 507 Steven R. Feldman and Lindsay C. Strowd Index, 514

59 Antiaging regimens, 480 Karen E. Burke

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Contributors

Eric S. Abrutyn

Donald L. Bissett

MS Founder TPC2 Advisors Ltd. Inc. Chiriqui, Republic of Panama

PhD Beth Jewell-Motz Procter & Gamble Co. Sharon Woods Technical Center Cincinnati, OH, USA

Murad Alam

MD, MSCI Associate Professor of Dermatology and Otolaryngology Chief of Cutaneous and Aesthetic Surgery Department of Dermatology Feinberg School of Medicine Northwestern University Chicago, IL, USA

K.P. Ananthapadmanabhan

PhD

Senior Principal Scientist Unilever HPC R&D Trumbull, CT, USA

Yohini Appa

PhD Senior Director of Scientific Affairs, Johnson & Johnson New Brunswick, NJ, USA

Duncan Aust

PhD Senior Vice President of Research and Development DFB Branded Pharmaceuticals Fort Worth, TX, USA

Nidhi Avashia

MD Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

Kenneth R. Beer

MD, PA Palm Beach Esthetic, Dermatology & Laser Center West Palm Beach, FL, USA and Clinical Voluntary Assistant Professor of Dermatology University of Miami Miami, FL, USA

Frédéric Bonté

PhD Director of Scientific Communication LVMH Recherche Saint Jean de Braye, France

Anne Bouloc

MD, PhD Vichy International Medical Director Cosmetique Active International Asnières, France

Ute Breitenbach

PhD

Beiersdorf AG Hamburg, Germany

Harold Bryant

PhD Assistant Vice President L’Oréal Institute for Ethnic Hair and Skin Research Chicago, IL, USA

Paul H. Bryson

PhD Director of Research and Development OPI Products Inc. North Hollywood Los Angeles, CA, USA

Doug Burke

PhD Senior Scientist Phamanex Global Research and Development Provo, UT, USA

Karen E. Burke

MD, PhD Assistant Clinical Professor, Dermatology The Mount Sinai Medical Center Rivercourt New York, NY, USA

Joseph Bikowski

MD, FAAD Clinical Assistant Professor, Dermatology Ohio State University Columbus, OH, USA and Bikowski Skin Care Center Sewickley, PA, USA

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Kimberly J. Butterwick

MD Dermatology/Cosmetic Laser Associates of La Jolla, Inc. San Diego, CA, USA

Contributors

Hervé Cantin

Zoe D. Draelos

LVMH Recherche Saint Jean de Braye, France

Ana Paula Avancini Caramori

MD Department of Dermatology Complexo Hospitalar Santa Casa de Porto Alegre Porto Alegre, Brazil

Duane Charbonneau

PhD

Global Microbiology Procter & Gamble Co. Health Sciences Institute Mason, OH, USA

Rawat Charoensawad

Director, Rawat Clinic and Clinical Consultant, Biophile Training Center Bangkok, Thailand

David E. Cohen,

MD, MPH Vice Chairman for Clinical Affairs Director of Allergic, Occupational, and Environmental Dermatology New York University School of Medicine Department of Dermatology New York, NY, USA

Joel L. Cohen

MD About Skin Dermatology Englewood, CO, USA and Department of Dermatology University of Colorado Englewood, CO, USA

Marc Cornell Director L’Oréal Research Clark, NJ, USA

Felicia Dixon

PhD Manager L’Oréal Institute for Ethnic Hair and Skin Research Chicago, IL, USA

Jeff C. Donovan

MD, PhD

Division of Dermatology University of Toronto Toronto, Canada

Jeffrey S. Dover

MD, FRCPC, FRCP (Glasgow) Associate Clinical Professor of Dermatology Yale University School of Medicine, Adjunct Professor of Dermatology Dartmouth Medical School, SkinCare Physicians Chestnut Hill, MA, USA

MD Consulting Professor Department of Dermatology Duke University School of Medicine Durham, NC, USA

Kenneth L. Edelson

MD, FAACS Clinical Instructor, Department of Dermatology Mount Sinai School of Medicine Attending Physician, Dermatology, The Mount Sinai Hospital New York, NY, USA and Private Practice Cosmetic, Dermatologic and Laser Surgery New York, NY, USA

Angela Ellington Assistant Vice President L’Oréal Institute for Ethnic Hair and Skin Research Chicago, IL, USA

Keith Ertel

MS, PhD Principal Scientist Procter & Gamble Co. Cincinnati, OH, USA

Steven R. Feldman

MD, PhD Center for Dermatology Research Departments of Dermatology, Pathology, and Public Health Sciences Wake Forest University School of Medicine Winston-Salem, NC, USA

Richard E. Fitzpatrick

MD Founder, Chair, Scientific Advisory Board SkinMedica, Inc. Carlsbad, CA, USA and Associate Clinical Professor Division of Dermatology UCSD School of Medicine San Diego, CA, USA

Heather Focht

Section Head Procter & Gamble Co. Cincinnati, OH, USA

Peter Foltis

MS Director of Scientific Affairs and Skin Care L’Oréal USA Clark, NJ, USA

Scott R. Freeman

MD Dermatology Resident University of Colorado at Denver and Health Sciences Center Denver, CO, USA

Contributors

Bryan B. Fuller

PhD Founder, CEO Therametics and Adjunct Professor of Biochemistry and Molecular Biology University of Oklahoma Health Sciences Center Oklahoma City, OK, USA

Angelike Galdi

L’Oréal USA Clark, NJ, USA

Pearl Grimes

MD Director Vitiligo and Pigmentation Institute of Southern California Los Angeles, CA, USA and Clinical Professor Division of Dermatology David Geffen School of Medicine University of California–Los Angeles Los Angeles, CA, USA

Sylvie Guichard Roy Geronemus

MD Laser & Skin Surgery Center of New York New York, NY, USA and New York University Medical Center New York, NY, USA

John Gilley Principal Researcher Procter & Gamble Cosmetics Hunt Valley, MD, USA

David J. Goldberg

MD Clinical Professor and Director of Laser Research Department of Dermatology at the Mount Sinai School of Medicine New York, NY, USA and Director, Skin Laser & Surgery Specialists of New York and New Jersey New York, NY, USA

Mitchel P. Goldman

MD Volunteer Clinical Professor of Dermatology/Medicine University of California, San Diego and Dermatology/Cosmetic Dermatology Associates of La Jolla, Inc. San Diego, CA, USA

Robert Goodman Thomas J. Stephens & Associates Inc. Dallas Research Center Carrollton, TX, USA

Emmy M. Graber

SkinCare Physicians Chestnut Hill, MA, USA

Corinne Granger MD Director of Instrumental Cosmetics L’Oréal Research Asnières, France

Make Up Scientific Communication Director L’Oréal Recherche Chevilly-Larue, France

Rebat M. Halder

MD Professor and Chair Department of Dermatology Howard University College of Medicine Washington, DC, USA

C. William Hanke

MD, MPH, FACP Professor of Dermatology University of Iowa Carver College of Medicine Iowa City, IA, USA and Clinical Professor of Otolaryngology-Head and Neck Surgery Indiana University School of Medicine Indianapolis, IN, USA

Christopher Harmon

MD Total Skin and Beauty Dermatology Center Birmingham, AL, USA

Erik Hasenoehrl

PhD Procter & Gamble Co. Ivorydale Technical Center Cincinnati, OH, USA

Jillian Havey Department of Dermatology Feinberg School of Medicine Northwestern University Chicago, IL, USA

Catherine Heusèle LVMH Recherche Saint Jean de Braye, France

Maria Hordinsky Barbara A. Green

RPh, MS VP Clinical Affairs, NeoStrata Company, Inc. Princeton, NJ, USA

MD Professor and Chair Department of Dermatology University of Minnesota Minneapolis, MN, USA

M. Amanda Jacobs Senior Associate Consultant Department of Dermatology Mayo Clinic Rochester, MN, USA

Contributors

Anthony W. Johnson

PhD

Jan Lephart

Director, Skin Clinical Science Unilever HPC R&D Trumbull, CT, USA

Senior Director Nu Skin Global Research & Development Provo, UT, USA

Behrooz Kasraee

Karl Lintner

MD Department of Dermatology Geneva University Hospital Geneva, Switzerland

MSc, PhD Technical Advisor Enterprise Technology/Sederma SAS Le Perray en Yvelines Cedex, France

Paul Kavanaugh

MS Thomas J. Stephens & Associates Inc. Dallas Research Center Carrollton, TX, USA

Gürkan Kaya

MD, PhD Department of Dermatology Geneva University Hospital Geneva, Switzerland

Stephen Mandy

MD Volunteer Professor of Dermatology University of Miami Miami, FL, USA and Private Practice Miami Beach, FL, USA

David McDaniel Dianna C. Kenneally

ChE

Principal Scientist Procter & Gamble Co. Mason, OH, USA

Misbah H. Khan

MD Fellow, Procedural Dermatology Northwestern University and Northwestern Memorial Hospital Chicago, IL, USA

Chesahna Kindred

MD Laser Skin & Vein Center of Virginia Virginia Beach, VA, USA and Eastern Virginia Medical School Virginia Beach, VA, USA

Gillian McFeat

PhD Gillette Reading Innovation Centre Procter & Gamble Co. Reading, UK

MD, MBA

Clinical Research Fellow Department of Dermatology Howard University College of Medicine Washington, DC, USA

Francis McGlone

PhD Perception and Behaviour Group Unilever Research & Development Wirral, UK

Rahul C. Mehta Helen Knaggs

PhD

Vice President Nu Skin Global Research and Development Provo, UT, USA

PhD

Senior Scientific Director SkinMedica, Inc. Carlsbad, CA, USA

Sanjeev Midha Alexandra Kowcz

MS, MBA

VP, US R&D Beiersdorf Inc. Wilton, CT, USA

PhD Principal Scientist Procter & Gamble Beauty Science Cincinnati, OH, USA

Gary D. Monheit Thomas Krause

PhD

Polymer Chemist Wella/Procter & Gamble Service GmbH Upstream Design Styling Darmstadt, Germany

Heh Shin R. Kwak

Dominique Moyal

PhD

L’Oréal Recherche Asnières, France

Knott Street Dermatology 301 NW Knott Street Portland, OR, USA

Olivier de Lacharrière

MD Total Skin & Beauty Dermatology Center, PC, and Clinical Associate Professor Departments of Dermatology and Ophthamology University of Alabama at Birmingham Birmingham, AL, USA

MD, PhD

L’Oréal Recherche Clichy, France

Contributors

Vic Narurkar

MD, FAAD Director Bay Area Laser Institute San Francisco, CA, USA and University of California Davis Medical School Sacramento, CA, USA

Babar K. Rao

MD Chair Department of Dermatology University of Medicine and Dentistry New Jersey Robert-Wood Johnson Medical School Somerset, NJ, USA

David Reilly Mark S. Nestor

MD, PhD

Director Center for Cosmetic Enhancement Aventura, FL, USA and Voluntary Associate Professor of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

Frauke Neuser

PhD

Principal Scientist Procter & Gamble Technical Centres Ltd Rusham Park, Whitehall Lane Egham Surrey, UK

Keyvan Nouri

MD Professor of Dermatology and Otolaryngology Director of Mohs, Dermatologic and Laser Surgery Director of Surgical Training Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

PhD

One Discover Colworth Park Sharnbrook Bedford, UK

Phoebe Rich

MD Oregon Dermatology and Research Center Portland, OR, USA

Randall Roenigk

MD Robert H. Kieckhefer Professor, Chair Department of Dermatology Mayo Clinic Rochester, MN, USA

Katie Rossy

MD New York Medical College New York, NY, USA

Véronique Roulier Make Up Development Director L’Oréal Recherche Chevilly-Larue, France

Rene Rust

Assistant Vice President L’Oréal USA Clark, NJ, USA

PhD Senior Scientist, Hair and Scalp Care Wella/Procter & Gamble Service GmbH Darmstadt, Germany

Irwin Palefsky

Neil Sadick

Christian Oresajo

PhD

CEO Cosmetech Laboratories Inc. Fairfield, NJ, USA

Sreekumar Pillai

PhD Associate Principal Scientist L’Oréal Research Clark, NJ, USA

Crystal Porter

PhD Manager L’Oréal Institute for Ethnic Hair and Skin Research Chicago, IL, USA

Chad Prather

MD Total Skin and Beauty Dermatology Center Birmingham, AL, USA

MD, FAAD, FAACS, FACPh Clinical Professor Weill Cornell Medical College New York, NY, USA and Sadick Dermatology New York, NY, USA

Jean H. Saurat

MD Department of Dermatology Geneva University Hospital Geneva, Switzerland

Ulrich Scherdin

PhD

Beiersdorf AG Hamburg, Germany

Andrea M. Schoelermann

PhD

Beiersdorf AG Hamburg, Germany

Harald Schlatter

PhD Principal Toxicologist Procter & Gamble German Innovation Centre Darmstadt, Germany

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Contributors

Douglas Schoon

Emily Tierney

Schoon Scientific and Regulatory Consulting, LLC Dana Point, CA, USA

Annette Schwan-Jonczyk

PhD

Wella/Procter & Gamble Service GmbH Global Hair Methods Darmstadt, Germany

James R. Schwartz

PhD

Research Fellow Procter & Gamble Beauty Science Cincinnati, OH, USA

Gerhard Sendelbach

PhD Wella/Procter & Gamble Service GmbH Global Hair Methods Darmstadt, Germany

PhD Mohr Surgery and Procedural Dermatology Fellow Laser and Skin Surgery Center of Indiana Carmel, IN, USA and Department of Dermatology Boston University School of Medicine Boston, MA, USA

Marcela Valenzuela

PhD Senior Scientist Procter & Gamble Beauty Science Cincinnati, OH, USA

Eugene J. Van Scott

Private Practice Abington, PA, USA

Voraphol Vejjabhinanta Sunil J. Sirdesai

PhD Co-Director of Research and Development OPI Products Inc. North Hollywood Los Angeles, CA, USA

Olivier Sorg

PhD Department of Dermatology Geneva University Hospital Geneva, Switzerland

Aieska de Souza

MD, MSc New York University School of Medicine Department of Dermatology New York, NY, USA

Thomas J. Stephens

PhD Thomas J. Stephens & Associates Inc. Dallas Research Center Carrollton, TX, USA

Lindsay C. Strowd

MD Center for Dermatology Research Department of Dermatology Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC, USA

Diane Thiboutot

MD Pennsylvania State University College of Medicine Milton S. Hershey Medical Center Hershey, PA, USA

Jens J. Thiele

MD, PhD Dermatology Specialist, Inc. Oceanside, CA, USA

Carl Thornfeldt CTDerm, PC Fruitland, ID, USA and Episciences, Inc. Boise, ID, USA

MD Clinical instructor Suphannahong Dermatology Institute Bangkok, Thailand and Mohs, Dermatologic and Laser Surgery Fellow Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

Sarah A. Vickery

PhD Principal Scientist Procter & Gamble Cosmetics Hunt Valley, MD, USA

Teresa M. Weber

PhD Director, Clinical and Scientific Affairs Beiersdorf Inc. Wilton, CT, USA

Robert Weiss

MD Maryland Laser Skin & Vein Institute Hunt Valley, MD, USA and Johns Hopkins University School of Medicine Baltimore, MD, USA

Steve Wood

PhD Director Phamanex Global Research and Development Provo, UT, USA

Peter Wyatt Senior Engineer Procter & Gamble Cosmetics Hunt Valley, MD, USA

Margarita Yatskayer

L’Oréal Research USA Clark, NJ, USA

MD, FAAD

Ruey J. Yu

PhD, OMD Private Practice Chalfont, PA, USA

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Foreword

Dermatology began as a medical specialty but over the last half century it has evolved to combine medical and surgical aspects of skin care. Mohs skin cancer surgery was the catalyst that propelled dermatology to become a more procedurally based specialty. The combination of an aging population, economic prosperity, and technological breakthroughs have revolutionized cosmetic aspects of dermatology in the past few years. Recent minimally invasive approaches have enhanced our ability to prevent and reverse the signs of photoaging in our patients. Dermatologists have pioneered medications, technologies, and devices in the burgeoning field of cosmetic surgery. Cutaneous lasers, light, and energy sources, the use of botulinum exotoxin, soft tissue augmentation, minimally invasive leg vein treatments, chemical peels, hair transplants, and dilute anesthesia liposuction have all been either developed or improved by dermatologists. Many scientific papers, reviews and textbooks have been published to help disseminate this new knowledge. Recently it has become abundantly clear that unless photoaging is treated with effective skin care and photoprotection, cosmetic surgical procedures will not have their optimal outcome. Cosmeceuticals are integral to this process but, while some rigorous studies exist, much of the knowledge surrounding cosmeceuticals is hearsay and non-data based marketing information. Given increasing requests by our patients for guidance on the use of cosmeceuticals, understanding this body of information is essential to the practicing dermatologist. In Cosmetic Dermatology: Products and Procedures, Zoe Draelos has compiled a truly comprehensive book that addresses the broad nature of the subspecialty. Unlike prior texts on the

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subject she has included all the essential topics of skin health. The concept is one that has been long awaited and will be embraced by our dermatologic colleagues and other health care professionals who participate in the diagnosis, and treatment of the skin. No one is better suited to edit a textbook of this scope than Dr. Zoe Draelos. She is an international authority on Cosmetic Dermatology and she has been instrumental in advancing the field of cosmeceuticals by her extensive research, writing, and teachings. This text brings together experts from industry, manufacturing, research, and dermatology and highlights the best from each of these fields. Doctor Draelos has divided the book into four different segments. The book opens with Basic Concepts, which includes physiology pertinent to cosmetic dermatology, and delivery of cosmetic skin actives. This section is followed by Hygiene Products, which include cleansers, moisturizers, and personal care products. The section on Adornment includes colored facial products, nail cosmetics, and hair cosmetics. The book concludes with a section on Antiaging, which includes cosmeceuticals, injectable antiaging techniques, resurfacing techniques, and skin modulation techniques. You will enjoy dipping into individual chapters or sections depending on your desires, but a full read of the book from start to finish will no doubt enhance your knowledge base and prepare you for the full spectrum of cosmetic dermatology patients. Enjoy. Jeffrey S. Dover August 2009

Introduction: Definition of Cosmetic Dermatology

This text is intended to function as a compendium on the field of cosmetic dermatology. Cosmetic dermatology knowledge draws on the insight of the bench researcher, the innovation of the manufacturer, the formulation expertise of the cosmetic chemist, the art of the dermatologic surgeon, and the experience of the clinical dermatologist. These knowledge bases heretofore have been presented in separate textbooks written for specific audiences. This approach to information archival does not provide for the synthesis of knowledge required to advance the science of cosmetic dermatology. The book begins with a discussion of basic concepts relating to skin physiology. The areas of skin physiology that are relevant to cosmetic dermatology include skin barrier, photoaging, sensitive skin, pigmentation issues, and sensory perceptions. All cosmetic products impact the skin barrier, it is to be hoped in a positive manner, to improve skin health. Failure of the skin to function optimally results in photoaging, sensitive skin, and pigmentation abnormalities. Damage to the skin is ultimately perceived as sensory anomalies. Skin damage can be accelerated by products that induce contact dermatitis. While the dermatologist can assess skin health visually, non-invasive methods are valuable to confirm observations or to detect slight changes in skin health that are imperceptible to the human eye. An important part of cosmetic dermatology products is the manner in which they are presented to the skin surface. Delivery systems are key to product efficacy and include creams, ointments, aerosols, powders, and nanoparticles. Once delivered to the skin surface, those substances designed to modify the skin must penetrate with aid of penetration enhancers to ensure percutaneous delivery. The most useful manner to evaluate products used in cosmetic dermatology is by category. The book is organized by product, based on the order in which they are used as part of a daily routine. The first daily activity is cleansing to ensure proper hygiene. A variety of cleansers are available to maintain the biofilm to include bars, liquids, nonfoaming, and antibacterial varieties. They can be applied with the hands or with the aid of an implement. Specialized products to cleanse the hair are shampoos, which may be useful in prevention of scalp disease. Following cleansing, the next step is typically moisturization. There are unique moisturizers for the face, hands, and feet. Extensions of moisturizers that contain other active

ingredients include sunscreens. Other products with a unique hygiene purpose include antiperspirants and shaving products. This completes the list of major products used to hygiene and skincare purposes. The book then turns to colored products for adorning the body. These include colored facial cosmetics, namely facial foundations, lipsticks, and eye cosmetics. It is the artistic use of these cosmetics that can provide camouflaging for skin abnormalities of contour and color. Adornment can also be applied to the nails, in the forms of nail cosmetics and prostheses, and to the hair, in the form of hair dyes, permanent waves, and hair straightening. From adornment, the book addresses the burgeoning category of cosmeceuticals. Cosmeceuticals can be divided into the broad categories of botanicals, antioxidants, antiinflammatories, peptides and proteins, cellular growth factors, retinoids, exfoliants, and nutraceuticals. These agents aim to improve the appearance of aging skin through topical applications, but injectable products for rejuvenation are an equally important category in cosmetic dermatology. Injectables can be categorized as neurotoxins and fillers (hyaluronic acid, hydroxyapatite, collagen, and polylactic acid). Finally, the surgical area of cosmetic dermatology must be address in terms of resurfacing techniques, skin modulation techniques, and skin contouring techniques. Resurfacing can be accomplished chemically with superficial and medium depth chemical peels or physically with microdermabrasion and dermabrasion. The newest area of resurfacing involves the use of lasers, both ablative and non-ablative. Other rejuvenative devices than collagen and pigmentation include intense pulsed light, radiofrequency, and diodes. These techniques can be combined with liposuction of the body and face to recontour the adipose tissue underlying the skin. The book closes with a discussion of how cosmetic dermatology can be implemented as part of a treatment regimen for aging skin, acne, rosacea, psoriasis, and eczema. In order to allow effective synthesis of the wide range of information included in this text, each chapter has been organized with a template to create a standardized presentation. The chapters open with basic concepts pertinent to each area. From these key points, the authors have developed their information to define the topic, discuss unique attributes, advantages and disadvantages, and indications.

Introduction It is my hope that this book will provide a standard textbook for the broad field of cosmetic dermatology. In the past, cosmetic dermatology has been considered a medical and surgical afterthought in dermatology residency programs and continuing medical education sessions. Perhaps this was in part because of the lack of a textbook defining the knowl-

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edge base. This is no longer the case. Cosmetic dermatology has become a field unto itself. Zoe D. Draelos May 2009

Section I Basic Concepts

Part 1: Skin Physiology Pertinent to Cosmetic Dermatology Chapter 1: Epidermal barrier Sreekumar Pillai, Marc Cornell, and Christian Oresajo L’Oréal Research, Clark, NJ, USA

BAS I C CONCEPTS • The outer surface of the skin, the epidermis, along with its outermost layer, the stratum corneum, forms the epidermal barrier. • The stratum corneum is a structurally heterogeneous tissue composed of non-nucleated, flat, protein-enriched corneocytes and lipid-enriched intercellular domains. • The roles of the skin barrier include preventing microbes from entering the skin, protecting from environmental toxins, maintaining skin hydration, and diffusing oxidative stress. • Delivery technologies such as lipid systems, nanoparticles, microcapsules, polymers, and films can improve the barrier properties of the skin.

Introduction Skin is the interface between the body and the environment. There are three major compartments of the skin: the epidermis, the dermis, and the hypodermis. Epidermis is the outermost structure and it is a multilayered, epithelial tissue divided into several layers. The outermost structure of the epidermis is the stratum corneum (SC) which forms the epidermal permeability barrier that prevents the loss of water and electrolytes. Other protective or barrier roles for the epidermis include: immune defense, UV protection, and protection from oxidative damage. Changes in the epidermal barrier caused by environmental factors, age, or other conditions can alter the appearance as well as the functions of the skin. Understanding the structure and function of the SC and the epidermal barrier is vital because it is the key to healthy skin and its associated social ramifications.

Structural components of the epidermal barrier The outer surface of the skin, the epidermis, mostly consists of epidermal cells, known as keratinocytes, which are arranged in several stratified layers – the basal cell layer, the

spinous cell layer and the granular cell layer – whose differentiation eventually produces the SC. Unlike other layers, the SC is made of anucleated cells called corneocytes which are derived from keratinocytes. The SC forms the major protective barrier of the skin, the epidermal permeability barrier. Figure 1.1 shows the different layers of the epidermis and the components that form the epidermal barrier. The SC is a structurally heterogeneous tissue composed of non-nucleated, flat, protein-enriched corneocytes and lipidenriched intercellular domains [1]. The lipids for barrier function are synthesized in the keratinocytes of the nucleated epidermal layers, stored in the lamellar bodies, and extruded into the intercellular spaces during the transition from the stratum granulosum to the SC forming a system of continuous membrane bilayers [1,2]. In addition to the lipids, other components such as melanins, proteins of the SC and epidermis, free amino acids and other small molecules also have important roles in the protective barrier of the skin. A list of the different structural as well as functional components of the SC is shown in Table 1.1.

Corneocytes Corneocytes are formed by the terminal differentiation of the keratinocytes from the granular layer of the epidermis. The epidermis is comprised of 70% water, as are most tissues, yet the SC is comprised of only 15% water. Alongside this change in water content the keratinocyte nuclei and virtually all the subcellular organelles begin to disappear in the granular cell layer leaving a proteineous core containing keratins, other structural proteins, free amino acids and amino acid

BASIC CONCEPTS

Skin Physiology

Keratohyalin and lamellar granules of the stratum granulosum

Stratum corneum Stratum granulosum

Desmosomes Stratum spinosum

Melanocyte Langerhans cell

Stratum basale

Dermis Figure 1.1 Diagram of the epidermis indicating the different layers of the epidermis and other structural components of the epidermal barrier.

Table 1.1 Structural and functional components of the stratum corneum. Components

Function

Location

Protection

Topmost layer of epidermis

Resiliency of SC

Outer surface of the SC

Cornified envelope precursor proteins

Structural proteins that are cross-linked to form CE

Outer surface of SC

Permeability barrier of skin

Granular cells of epidermis

SC interfacial lipids

Permeability barrier of skin

Lipid bilayers between SC

Lipid–protein cross-links

Scaffold for corneocytes

Between SC and lipid bi-layers

Desmosomes and corneodesmosomes

Intercellular adhesion and provide shear resistance

Between keratinocytes and corneocytes

Keratohyalin granules

Formation of keratin “bundles” and NMF precursor proteins

Stratum granulosum

NMF

Water holding capacity of SC

Within SC

pH and calcium gradients

Provides differentiation signals and LG secretion signals

All through epidermis

Specialized enzymes (lipases, glycosidases, proteases)

Processing and maturation of SC lipids, desquamation

Within LG and all through epidermis

Melanin granules and “dust”

UV protection of skin

Produced by melanocytes of basal layer, melanin “dust” in SC

CE, cornified envelope; LG, lamellar granules; NMF, natural moisturizing factor; SC, stratum corneum.

1. Epidermal barrier derivatives, and melanin particles which persist throughout the SC. From an oval or polyhedral shape of the viable cells in the spinous layers, the keratinocyte starts to flatten off in the granular cell layer and then assumes a spindle shape and finally becomes a flat corneocyte. The corneocyte itself develops a tough, chemically resistant protein band at the periphery of the cell, called the cornified cell envelope, formed from cross-linked cytoskeletal proteins [3].

teins. The molecular structure of these components suggests that the glutamine and serine residues of CE envelope proteins such as loricrin and involucrin are covalently linked to the omega hydroxyl ceramides [8]. In addition, other free fatty acids (FFA) and ceramides (Cer), may also form protein cross-links on the extracellular side of the CE, providing the scaffold for the corneocytes to the lipid membrane of the SC.

Proteins of the cornified envelope

Desmosomes and corneodesmosomes

The cornified envelope (CE) contains highly cross-linked proteins formed from special precursor proteins synthesized in the granular cell layer, particularly involucrin, loricrin, and cornifin. In addition to these major protein components, several other minor unique proteins are also cross-linked to the cornified envelope. These include proteins with specific functions such as calcium binding proteins, antimicrobial and immune functional proteins, proteins that provide structural integrity to SC by binding to lipids and desmosomes, and protease inhibitors. The cross-linking is promoted by the enzyme transglutaminase which is detectable histochemically in the granular cell layer and lower segments of the stratum corneum. The γ-glutamyl link that results from transglutaminase activity is extremely chemically resistant and this provides the cohesivity and resiliency to the SC.

Desmosomes are specialized cell structures that provide cell– cell adhesion (Figure 1.1). They help to resist shearing forces and are present in simple and stratified squamous epithelia as in human epidermis. Desmosomes are molecular complexes of cell adhesion proteins and linking proteins that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments proteins. Some of the specialized proteins present in desmosomes are cadherins, calcium binding proteins, desmogleins, and desmocollins. Cross-linking of other additional proteins such as envoplakins and periplakins further stabilizes desmosomes. Corneodesmosomes are remnants of the desmosomal structures that provide the attachment sites between corneocytes and cohesiveness for the corneocytes in the SC. Corneodesmosomes have to be degraded by specialized proteases and glycosidases, mainly serine proteases, for the skin to shed in a process called desquamation [9].

Lamellar granules and inter-corneocyte lipids Lamellar granules or bodies (LG or LB) are specialized lipidcarrying vesicles formed in suprabasal keratinocytes, destined for delivery of the lipids in the interface between the corneocytes. These lipids form the essential component of the epidermal permeability barrier and provide the “mortar” into which the corneocyte “bricks” are laid for the permeability barrier formation. When the granular keratinocytes mature to the SC, specific enzymes within the LB process the lipids, releasing the non-polar epidermal permeability barrier lipids, namely, cholesterol, free fatty acids and ceramides, from their polar precursors – phospholipids, glucosyl ceramides, and cholesteryl sulfate, respectively. These enzymes include: lipases, phospholipases, sphingomyelinases, glucosyl ceramidases, and sterol sulfatases [4,5]. The lipids fuse together in the SC to form a continuous bi-layer. It is these lipids, along with the corneocytes, that constitute the bulk of the water barrier property of the SC [6,7].

Keratohyalin granules Keratohyalin granules are irregularly shaped granules present in the granular cells of the epidermis, thus providing these cells their granular appearance (Figure 1.1). These organelles contains abundant amount of keratins “bundled” together by a variety of other proteins, most important of which is filaggrin (filament aggregating protein). An important role of this protein, in addition to bundling of the major structural protein, keratin of the epidermis, is to provide the natural moisturizing factor (NMF) for the SC. Filaggrin contains all the amino acids that are present in the NMF. Filaggrin, under appropriate conditions, is dephosphorylated and proteolytically digested during the process when granular cells mature into corneocytes. The amino acids from filaggrin are further converted to the NMF components by enzymatic processing and are retained inside the corneocytes as components of NMF [4,9].

Lipid–protein cross-links at the cornified envelope LG are enriched in a specific lipid unique to the keratinizing epithelia such as the human epidermis. This lipid (a ceramide) has a very long chain omega-hydroxy fatty acid moiety with linoleic acid linked to the omega hydroxyl group in ester form. This lipid is processed within the SC to release the omega hydroxyl ceramide that becomes crosslinked to the amino groups of the cornified envelope pro-

Functions of epidermal barrier Water evaporation barrier (epidermal permeability barrier) Perhaps the most studied and the most important function of the SC is the formation of the epidermal permeability barrier [1,4,10]. The SC limits the transcutaneous movement

BASIC CONCEPTS

Skin Physiology

of water and electrolytes, a function that is essential for terrestrial survival. Lipids, particularly ceramides, cholesterol, and FFA, together form lamellar membranes in the extracellular spaces of the SC which limit the loss of water and electrolytes. Corneocytes are embedded in this lipid-enriched matrix, and the cornified envelope, which surrounds corneocytes, provides a scaffold necessary for the organization of the lamellar membranes. Extensive research, mainly by Peter Elias’ group has elucidated the structure, properties, and the regulation of the skin barrier by integrated mechanisms [5,7,11]. Barrier disruption triggers a cascade of biochemical processes leading to rapid repair of the epidermal barrier. These steps include increased keratinocyte proliferation and differentiation, increased production of corneocytes, and production, processing, and secretion of barrier lipids, ultimately leading to the repair of the epidermal permeability barrier. These events are described in more detail in the barrier homeostasis section below. A list of the different functions of human epidermis is shown in Table 1.2.

Mechanical barrier Cornified envelope provides mechanical strength and rigidity to the epidermis, thereby protecting the host from injury. Specialized protein precursors and their modified amino acid cross-links provide the mechanical strength to the SC. One such protein, trichohyalin, is a multifunctional crossbridging protein that forms intra- and inter-protein crosslinks between cell envelope structure and cytoplasmic keratin filament network [12]. Special enzymes called trans-

Table 1.2 Barrier functions of the epidermis. Function

Localization/components involved

Water and electrolyte permeability barrier

SC/corneocyte proteins and extracellular lipids

Mechanical barrier

SC/corneocytes, cornified envelope

Microbial barrier/immune function

SC/lipid components/viable epidermis

Hydration/moisturization

SC/NMF

Protection from environmental toxins/drugs

SC/corneocytes, cornified envelope

Desquamation

SC, epidermis/proteases and glycosidases

UV barrier

SC/melanins of SC/epidermis

Oxidative stress barrier

SC, epidermis/antioxidants

NMF, natural moisturizing factor; SC, stratum corneum.

glutaminases, some present exclusively in the epidermis (transglutaminase 3), catalyze this cross-linking reaction. In addition, adjacent corneocytes are linked by corneodesmosomes, and many of the lipids of the SC barrier are also chemically cross-linked to the cornified envelope. All these chemical links provide the mechanical strength and rigidity to the SC.

Antimicrobial barrier and immune protection The epidermal barrier acts as a physical barrier to pathogenic organisms that attempt to penetrate the skin from the outside environment. Secretions such as sebum and sweat and their acid pH provide antimicrobial properties to skin. Innate immune function of keratinocytes and other immune cells of the epidermis such as Langerhans cells and phagocytes provide additional immune protection in skin. Epidermis also generates a spectrum of antimicrobial lipids, peptides, nucleic acids, proteases, and chemical signals that together forms the antimicrobial barrier (Table 1.3). The antimicrobial peptides are comprised of highly conserved, small, cysteine rich, cationic proteins that are expressed in large amounts in skin. Desquamation, which causes the outward movement of corneocytes and their sloughing off at the surface, also serves as a built-in mechanism inhibiting pathogens from colonizing the skin.

NMF and skin hydration and moisturization NMF is a collection of water-soluble compounds that are found in the stratum corneum (Table 1.4). These compounds compose approximately 20–30% of the dry weight of the

Table 1.3 Antimicrobial components of epidermis and stratum corneum. Component

Class of compound

Localization

Free fatty acids

Lipid

Stratum corneum

Glucosyl ceramides

Lipid

Stratum corneum

Ceramides

Lipid

Stratum corneum

Sphingosine

Lipid

Stratum corneum

Defensins

Peptides

Epidermis

Cathelicidin

Peptides

Epidermis

Psoriasin

Protein

Epidermis

RNAse 7

Nucleic acid

Epidermis

Low pH

Protons

Stratum corneum

“Toll-like” receptors

Protein signaling molecules

Epidermis

Proteases

Proteins

Stratum corneum and epidermis

1. Epidermal barrier

Table 1.4 Approximate composition of skin natural moisturizing factor. Components

Percentage levels

Amino acids and their salts (over a dozen)

30–40

Pyrrolidine carboxylic acid sodium salt, urocanic acid, ornithine, citruline (derived from filaggrin hydrolysis products)

7–12

Urea

5–7

Glycerol

4–5

Glucosamine, creatinine, ammonia, uric acid

1–2

Cations (sodium, calcium, potassium) Anions (phosphates, chlorides)

10–11 6–7

Lactate

10–12

Citrate, formate

0.5–1.0

corneocyte. Many of the components of NMF are derived from the hydrolysis of filaggrin, a histidine- and glutaminerich basic protein of the keratohyalin granule. The SC hydration level controls the protease that hydrolyzes filaggrin and histidase that converts histidine to urocanic acid. As NMF is water soluble and can easily be washed away from the SC, the lipid layer surrounding the corneocyte helps seal the corneocyte to prevent loss of NMF. In addition to preventing water loss from the organism, the SC also acts to provide hydration and moisturization to skin. NMF components absorb and hold water allowing the outermost layers of the SC to stay hydrated despite exposure to the harsh external environment. Glycerol, a major component of the NMF, is an important humectant present in skin which contributes skin hydration. Glycerol is produced locally within the SC by the hydrolysis of triglycerides by lipases, but also taken up into the epidermis from the circulation by specific receptors present in the epidermis called aquaporins [13]. Other humectants in the NMF include urea, sodium and potassium lactates, and pyrrolidine carboxylic acid (PCA) [9].

Protection from environmental toxins and topical drug penetration The SC also has the important task of preventing toxic substances and topically applied drugs from penetrating the skin. The SC acts as a protective wrap because of the highly resilient and cross-linked protein coat of the corneocytes and the lipid-enriched intercellular domains. Pharmacologists and topical or “transdermal” drug developers are interested in increasing SC permeation of drugs into the skin. The multiple route(s) of penetration of drugs into the skin can be via hair follicles, interfollicular sites, or by penetration

through corneocytes and lipid bilayer membranes of the SC [10]. The molecular weight, solubility, and molecular configuration of the toxins and drugs greatly influence the rate of penetration. Different chemical compounds adopt different pathways for skin penetration.

Desquamation and the role of proteolytic enzymes The process by which individual corneocytes are sloughed off from the top of the SC is called desquamation. Normal desquamation is required to maintain the homeostasis of the epidermis. Corneocyte to corneocyte cohesion is controlled by the intercellular lipids as well as the corneodesmosomes that bind the corneocytes together. The presence of specialized proteolytic enzymes and glycosidases in the SC help in cleavage of desmosomal bonds resulting in release of corneocytes [9]. In addition, the SC also contains protease inhibitors that keep these proteases in check and the balance of protease–protease inhibitors have a regulatory role in the control of the desquamatory process. The desquamatory process is also highly regulated by the epidermal barrier function. The SC contains three families of proteases (serine, cysteine, and aspartate proteases), including the epidermalspecific serine proteases (SP), kallikrein-5 (SC tryptic enzyme [SCTE]), and kallikrein-7 (SC chymotryptic enzyme), as well as at least two cysteine proteases, including the SC thiol protease (SCTP), and at least one aspartate protease, cathepsin D. All these proteases have specific roles in the desquamatory process at different layers of the epidermis.

Melanin and the UV barrier Although melanin is not typically considered a functional component of the epidermal barrier, its role in the protection of the skin from UV radiation is indisputable. Melanins are formed in specialized dendritic cells called melanocytes in the basal layers of the epidermis. The melanin produced is transferred into keratinocytes in the basal and spinous layers. There are two types of melanins, depending on the composition and the color. The darker eumelanin is most protective to UV than the lighter, high sulfur-containing pheomelanin. The keratinocytes carry the melanins through the granular layer and into the SC layer of the epidermis. The melanin “dust” present in the SC is structurally different from the organized melanin granules found in the viable deeper layers of the epidermis. The content and composition of melanins also change in SC depending on sun exposure and skin type of the individual. Solar UV radiation is very damaging to proteins, lipids, and nucleic acids and causes oxidative damage to these macromolecules. The SC absorbs some UV energy but it is the melanin particles inside the corneocytes that provide the most protection. Darker skin (higher eumelanin content) is significantly more resistant to the damaging effects of UV on DNA than lighter skin. In addition, UV-induced apoptosis

BASIC CONCEPTS

Skin Physiology

(cell death that results in removal of damaged cells) is significantly greater in darker skin. This combination of decreased DNA damage and more efficient removal of UVdamaged cells plays a critical part in the decreased photocarcinogenesis seen in individuals with darker skin [14]. In addition to melanin, trans-urocanic acid (tUCA), a product of histidine deamination produced in the SC, also acts as an endogenous sunscreen and protects skin from UV damage.

a controlled manner by degradation of desmosomal constituent proteins by the SC proteases. The protease activities are under the control of protease inhibitors which are colocalized with the proteases within the SC. In addition, the activation cascade of the SC proteases is also controlled by the barrier requirement. Lipids and lipid precursors such as cholesterol sulfate also regulate desquamation by controlling the activities of the SC proteases [21].

Corneocyte maturation Oxidative stress barrier The SC has been recognized as the main cutaneous oxidation target of UV and other atmospheric oxidants such as pollutants and cigarette smoke. UVA radiation, in addition to damaging the DNA of fibroblasts, also indirectly causes oxidative stress damage of epidermal keratinocytes. The oxidation of lipids and carbonylation of proteins of the SC lead to disruption of epidermal barrier and poor skin condition [15]. In addition to its effects on SC, UV also initiates and activates a complex cascade of biochemical reactions within the epidermis, causing depletion of cellular antioxidants and antioxidant enzymes such as superoxide dismutase (SOD) and catalase. Acute and chronic exposure to UV has been associated with depletion of SOD and catalase in the skin of hairless mice [16]. This lack of antioxidant protection further causes DNA damage, formation of thymine dimers, activation of proinflammatory cytokines and neuroendocrine mediators, leading to inflammation and free radical generation [17]. Skin naturally uses antioxidants to protect itself from photodamage. UV depletes antioxidants from outer SC. A gradient in the antioxidant levels (alfa-tocopherol, vitamin C, glutathione, and urate) with the lowest concentrations in the outer layers and a steep increase in the deeper layers of the SC protects it from oxidative stress [18]. Depletion of antioxidant protection leads to UV-induced barrier abnormalities. Topical application of antioxidants would support these physiologic mechanisms and restore a healthy skin barrier [19,20].

Regulation of barrier homeostasis The epidermal barrier is constantly challenged by environmental and physiologic factors. Because a fully functional epidermal barrier is required for terrestrial life to exist, barrier homeostasis is tightly regulated by a variety of mechanisms.

Desquamation Integral components of the barrier, corneocytes, and the intercellular lipid bilayers are constantly synthesized and secreted by the keratinocytes during the process of terminal differentiation. The continuous renewal process is balanced by desquamation which removes individual corneocytes in

Terminal differentiation of keratinocytes to mature corneocytes is controlled by calcium, hormonal factors, and by desquamation. High calcium levels in the outer nucleated layers of epidermis stimulate specific protein synthesis and activate the enzymes that induce the formation of corneocytes. A variety of hormones and cytokines control keratinocyte terminal differentiation, thereby regulating barrier formation. Many of the regulators of these hormones are lipids or lipid intermediates which are synthesized by the epidermal keratinocytes for the barrier function, thereby exerting control of barrier homeostasis by affecting the corneocyte maturation. For example, the activators and/or ligands for the nuclear hormone receptors (e.g. peroxisome proliferation activator receptor [PPAR] and vitamin D receptor) that influence keratinocyte terminal differentiation are endogenous lipids synthesized by keratinocytes.

Lipid synthesis Epidermal lipids, the integral components of the permeability barrier, are synthesized and secreted by the keratinocytes in the stratum granulosum after processing and packaging into the LB. Epidermis is a very active site of lipid synthesis under basal conditions and especially under conditions when the barrier is disrupted. Epidermis synthesizes ceramides, cholesterol, and FFA (a major component of phospholipids and ceramides). These three lipid classes are required in equimolar distribution for proper barrier function. The synthesis, processing, and secretion of these lipid classes are under strict control by the permeability barrier requirements. For example, under conditions of barrier disruption, rapid and immediate secretion by already packaged LB occurs as well as transcriptional and translational increases in key enzymes required for new synthesis of these lipids to take place. In addition, many of the hormonal regulators of corneocyte maturation are lipids or lipid intermediates synthesized by the epidermis. SC lipid synthesis and lipid content are also altered with various skin conditions such as inflammation and winter xerosis [22,23].

Environmental and physiologic factors Barrier homeostasis is under control of environmental factors such as humidity variations. High humidity (increased

1. Epidermal barrier SC hydration) downregulates barrier competence (as assessed by barrier recovery after disruption) whereas low humidity enhances barrier homeostasis. Physiologic factors can also have influence on barrier function. High stress (chronic as well as acute) increases corticosteroid levels and causes disruption of barrier homeostasis. Conditions that cause skin inflammation can stimulate the secretion of inflammatory cytokines such as interleukins, induce epidermal hyperplasia, cause impaired differentiation, and disrupt epidermal barrier functions.

Hormones Barrier homeostasis and SC integrity, lipid synthesis is all under the control of different hormones, cytokines, and calcium. Nuclear hormone receptors for both well-known ligands, such as thyroid hormones, retinoic acid, and vitamin D, and “liporeceptors” whose ligands are endogenous lipids control barrier homeostasis. These liporeceptors include peroxisome proliferator activator receptor (PPAR alfa, beta, and gamma) and liver X receptor (LXR). The activators for these receptors are endogenous lipids and lipid intermediates or metabolites such as certain FFA, leukotrienes, prostanoids, and oxygenated sterols. These hormones, mediated by their receptors, control barrier at the level of epidermal cell maturation (corneocyte formation), transcriptional regulation of terminal differentiation proteins and enzymes required for lipid processing, lipid transport, and secretion into LB [5].

pH and calcium Outermost SC pH is maintained in the acidic range, typically in the range 4.5–5.0, by a variety of different mechanisms. This acidity is maintained by formation of FFA from phospholipids; sodium proton exchangers in the SC and by the conversion of histidine of the NMF to urocanic acid by histidase enzyme in the SC. In addition, lactic acid, a major component of the NMF, has a major role in maintaining the acid pH of the SC. Maintenance of an acidic pH in the SC is important for the integrity and cohesion of the SC as well as the maintenance of the normal skin microflora. The growth of normal skin microflora is supported by acidic pH while a more neutral pH supports pathogenic microbes’ invasion of the skin. This acidic pH is optimal for processing of precursor lipids to mature barrier forming lipids and for initiating the desquamatory process. The desquamatory proteases present in the outer SC such as the thiol proteases and cathepsins are more active in the acidic pH, whereas the SCCE and SCTE present in the lower SC are more active at neutral pH. When the pH gradient is disrupted, desquamation is decreased resulting in dry scaly skin and disrupted barrier function. In the normal epidermis, there is a characteristic intraepidermal calcium gradient, with peak concentrations of

calcium in the granular layer and decreasing all the way up to the SC [24]. The calcium gradient regulates barrier properties by controlling the maturation of the corneocytes, regulating the enzymes that process lipids and by modulating the desquamatory process. Calcium stimulates a variety of processes including the formation and secretion of LB, differentiation of keratinocytes, formation of cornified envelope precursor proteins, and cross-linking of these proteins by the calcium inducible enzyme transglutaminase. Specifically, high levels of calcium stimulate the expression of proteins required for keratinocyte differentiation, including key structural proteins of the cornified envelope, such as loricrin, involucrin, and the enzyme, transglutaminase 1, which catalyzes the cross-linking of these proteins into a rigid structure.

Coordinated regulation of multiple barrier functions Co-localization of many of the barrier functions allows regulation of the functions of the epidermal barrier to be coordinated. For example, epidermal permeability barrier, antimicrobial barrier, mechanical protective barrier, and UV barrier are all co-localized in the SC. A disruption of one function can lead to multiple barrier disruptions, and therefore multiple barrier functions are coordinately regulated [5]. Disruption of the permeability barrier leads to activation of the cytokine cascade (increased levels of primary cytokines, interleukin-1, and tumor necrosis factor-alfa) which in turn activates the synthesis of antimicrobial peptides of the SC. Additionally, the cytokines and growth factors released during barrier disruption lead to corneocyte maturation, thereby strengthening the mechanical and protective barrier of the skin. Hydration of the skin itself controls barrier function by regulating the activities of the desquamatory proteases (high humidity decreases barrier function and stimulates desquamation). In addition, humidity levels control filaggrin hydrolysis which releases the free amino acids that form the NMF (histidine, glutamine arginine, and their by-products) and trans-urocanic acid (deamination of histidine) which serves as a UV barrier.

Methods for studying barrier structure and function Physical methods SC integrity and desquamation can be measured using tape stripping methods. Under dry skin conditions, when the barrier is compromised, corneocytes do not separate singly but as “clumps.” This can be quantified by using special tapes and visualizing the corneocytes removed by light microscopy. Another harsher tape-stripping method involves stripping of the SC using cyanoacrylate glue. These physical methods provide a clue to the binding forces that hold the

BASIC CONCEPTS

Skin Physiology

corneocyte together. The efficacy of treatment with skin moisturizers or emollients that improve skin hydration and reduce scaling can be quantitated using these methods.

Instrumental methods The flux of water vapor through the skin (transepidermal water loss [TEWL]) can be determined using an evaporimeter [25]. This instrument contains two water sensors mounted vertically in a chamber one above the other. When placed on the skin in a stable ambient environment the difference in water vapor values between the two sensors is a measure of the flow of water coming from the skin (TEWL). There are several commercially available evaporimeters (e.g. Tewameter® [Courage & Khazaka, Köln, Germany]), which are widely used in clinical practice as well as in investigative skin biology. Recovery of the epidermal barrier (TEWL) after disruption using physical methods (e.g. tape strips) or chemical methods (organic solvent washing) provides valuable information on epidermal barrier properties [26]. Skin hydration can be measured using the Corneometer® (Courage & Khazaka, Köln, Germany). The measurement is based on capacitance of a dielectric medium. Any change in the dielectric constant caused by skin surface hydration variation alters the capacitance of a precision measuring capacitor. The measurement can detect even the slightest changes in hydration level. Another important recent development in skin capacitance methodology is the SkinChip® (L’Oreal, Paris, France). Skin capacitance imaging of skin surface can be obtained using the SkinChip. This method provides information on skin microrelief, level of SC hydration, and sweat gland activity. SkinChip technology can be used to quantify regional variation in skin, skin changes with age, effects of hydrating formulations, surfactant effects on corneocytes, acne, and skin pore characteristics [27]. Several other recently developed methods for measuring epidermal thickness such as confocal microscopy, dermatoechography, and dermatoscopy can provide valuable information on skin morphology and barrier abnormalities [28]. Other more sophisticated (although not easily portable) instrumentation techniques such as ultrasound, optical coherence tomography, and magnetic resonance imaging (MRI) can provide useful information on internal structures of SC and/or epidermis and its improvements with treatment. MRI has been successfully used to evaluate skin hydration and water behavior in aging skin [29].

Biologic methods Ultrastructural details of SC and the intercellular spaces of the SC can be visualized using transmission electron microscopy of thin vertical sections and freeze–fracture replicas, field emission scanning electron microscopy, and immunofluorescence confocal laser scanning microscopy [30]. The ultrastructural details of the lipid bi-layers within the SC can

be visualized by electron microscopy after fixation using ruthenium tetroxide. The existence of corneodesmosomes in the SC, and their importance in desquamation, can be measured by scanning electron microscopy of skin surface replicas. The constituent cells of the SC, the corneocytes, can be visualized and quantitated by scraping the skin surface or by use of a detergent solution. The suspension so obtained can be analyzed by microscopy, biochemical or immunologic techniques. Punch or shaved biopsy techniques can be combined with immunohistochemistry using specific SC and/or epidermis specific antibodies to quantify the SC quality. Specific antibodies for keratinocyte differentiation specific proteins, desmosomal proteins, or specific proteases can provide information on skin barrier properties.

Relevance of skin barrier to cosmetic product development Topical products that influence barrier functions The human skin is constantly exposed to a hostile environment: changes in relative humidity, extremes of temperature, environmental toxins, and daily topically applied products. Daily exposure to soaps and other household chemicals can compromise skin barrier properties and cause unhealthy skin conditions. Prolonged exposure to surfactants removes the epidermal barrier lipids and enhances desquamation leading to impaired barrier properties [4,10]. Allergic reactions to topical products can result in allergic or irritant contact dermatitis, resulting in itchy and scaly skin and skin redness leading to barrier perturbations.

Cosmetics that restore skin barrier properties Water is the most important plasticizer of SC. Cracking and fissuring of skin develops as SC hydration declines below a critical threshold. Skin moisturization is a property of the outer SC (also known as stratum disjunctum) as corneocytes of the lower SC (stratum compactum) are hydrated by the body fluids. “Moisturizers” are substances that when applied to skin add water and/or retains water in the SC. The NMF components present in the outer SC act as humectants, absorb moisture from the atmosphere, and are sensitive to humidity of the atmosphere. The amino acids and their metabolites, along with other inorganic and organic osmolytes such as urea, lactic acid, taurine, and glycerol act as humectants within the outer SC. Secretions from sebaceous glands on the surface of the skin also act as emollients and contribute to skin hydration. A lack of any of these components can contribute to dry scaly skin. Topical application of all of the above components can act as humectants, and can relieve dry skin condition and improve skin moisturization

1. Epidermal barrier and barrier properties. Film-forming polysaccharide materials such as hyaluronic acid binds and retains water and helps to keep skin supple and soft. In addition to humectants, emollients such as petroleum jelly, hydrocarbon oils and waxes, mineral and silicone oils, and paraffin wax provide an occlusive barrier to the skin, preventing excessive moisture loss from the skin surface. Topically applied barrier compatible lipids also contribute to skin moisturization and improved skin conditions. Chronologically aged skin exhibits delayed recovery rates after defined barrier insults, with decreased epidermal lipid synthesis. Application of a mixture of cholesterol, ceramides, and essential/non-essential FFAs in an equimolar ratio was shown to lead to normal barrier recovery, and a 3 : 1 : 1 : 1 ratio of these four ingredients demonstrated accelerated barrier recovery [31]. Topical application of antioxidants and anti-inflammatory agents also protects skin from UV-induced skin damage by providing protection from oxidative damage to skin proteins and lipids [19,20].

Skin irritation from cosmetics Thousands of ingredients are used by the cosmetic industry. These include pure compounds, mixtures, plant extracts, oils and waxes, surfactants, detergents, preservatives, and polymers. Although all the ingredients used by the cosmetic industry are tested for safety, some consumers may still experience reactions to some of them. Most common reactions are irritant contact reactions while allergic contact reactions are less common. Irritant reactions tend to be more rapid and cause mild discomfort and redness and scaling of skin. Allergic reactions can be delayed, more persistent, and sometimes severe. Ingredients previously considered safe can be irritating in a different formulation because of increased penetration into skin. More than 50% of the general population perceives their skin as sensitive. It is believed that the perception of sensitive skin is, at least in part, related to skin barrier function. People with impaired barrier function may experience higher irritation to a particular ingredient because of its increased penetration into deeper layers of the skin.

Conclusions and future trends Major advances have been made in the last several decades in understanding the complexity and functions of the SC. Extensive research by several groups has elucidated the metabolically active role of SC and characterized the major components within it and their importance in providing protection from the external environment. New insights into the molecular control mechanisms of desquamation, lipid processing, barrier function, and antimicrobial protection have been elucidated in the last decade.

Knowledge of other less well-known epithelial organelles such as intercellular junctions, tight junctions, and gap junctions and their role in barrier function in the skin is being elucidated. Intermolecular links that connect intercellular lipids with the corneocytes of the SC and their crucial role for maintaining barrier function is an area being actively researched. New knowledge of the corneocyte envelope structure and the physical state of the intercellular lipid crystallinity and their interrelationship would lead to development of new lipid actives for improving SC moisturization and for treatment of skin barrier disorders. Further research in the cellular signaling events that control the communication between SC and the viable epidermis will shed more light on barrier homeostasis mechanisms. Novel delivery systems have an increasingly important role in the development of effective skin care products. Delivery technologies such as lipid systems, nanoparticles, microcapsules, polymers, and films are being pursued not only as vehicles for delivering cosmetic actives through skin, but also for improving barrier properties of the skin. Undoubtedly, skin care and cosmetic companies will exploit this new knowledge in developing novel and more efficacious products for strengthening the epidermal barrier and to improve and enhance the functional and aesthetic properties of the human skin.

References 1 Elias PM. (1983) Epidermal lipids, barrier function, and desquamation. J Invest Dermatol 80, 44s–9s. 2 Menon GK, Feingold KR, Elias PM. (1992) Lamellar body secretory response to barrier disruption. J Invest Dermatol 98, 279–89. 3 Downing DT. (1992) Lipid and protein structures in the permeability barrier of mammalian epidermis. J Lipid Res 33, 301–13. 4 Rawlings AV, Matts PJ. (2005) Stratum corneum moisturization at the molecular level: an update in relation to the dry skin cycle. J Invest Dermatol 124, 1099–11. 5 Elias PM. (2005) Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125, 183–200. 6 Elias PM. (1996) Stratum corneum architecture, metabolic activity and interactivity with subjacent cell layers. Exp Dermatol 5, 191–201. 7 Elias PM, Feingold KR. (1992) Lipids and the epidermal water barrier: metabolism, regulation, and pathophysiology. Semin Dermatol 11, 176–82. 8 Uchida Y, Holleran WM. (2008) Omega-O-acylceramide, a lipid essential for mammalian survival. J Dermatol Sci 51, 77–87. 9 Harding CR, Watkinson A, Rawlings AV, Scott IR. (2000) Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 22, 21–52. 10 Schaefer H, Redelmeier TE, eds. (1996) Skin Barrier: Principles of Percutaneous Absorption. Karger, Basel. 11 Elias PM, Menon GK. (1991) Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 24, 1–26.

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12 Steinert PM, Parry DA, Marekov LN. (2003) Trichohyalin mechanically strengthens the hair follicle: multiple crossbridging roles in the inner root shealth. J Biol Chem 278, 41409–19. 13 Choi EH, Man M-Q, Wang F, Zhang X, Brown BE, Feingold KR, et al. (2005) Is endogenous glycerol a determinant of stratum corneum hydration in humans? J Invest Dermatol 125, 288–93. 14 Yamaguchi Y, Takahashi K, Zmudzka BZ, Kornhauser A, Miller SA, Tadokoro T, et al. (2006) Human skin responses to UV radiation: pigment in the upper epidermis protects against DNA damage in the lower epidermis and facilitates apoptosis. FASEB J 20, 1486–8. 15 Sander CS, Chang H, Salzmann S, Muller CSL, EkanayakeMudiyanselage S, Elsner P, et al. (2002) Photoaging is associated with protein oxidation in human skin in vivo. J Invest Dermatol 118, 618–25. 16 Pence BC, Naylor MF. (1990) Effects of single-dose UV radiation on skin SOD, catalase and xanthine oxidase in hairless mice. J Invest Dermatol 95, 213–6. 17 Pillai S, Oresajo C, Hayward J. (2005) UV radiation and skin aging: roles of reactive oxygen species, inflammation and protease activation, and strategies for prevention of inflammationinduced matrix degradation. Int J Cosmet Sci 27, 17–34. 18 Weber SU, Thiele JJ, Cross CE, Packer L. (1999) Vitamin C, uric acid, and glutathione gradients in murine stratum corneum and their susceptibility to ozone exposure. J Invest Dermatol 113, 1128–32. 19 Lopez-Torres M, Thiele JJ, Shindo Y, Han D, Packer L. (1998) Topical application of alpha-tocopherol modulates the antioxidant network and diminishes UV-induced oxidative damage in murine skin. Br J Dermatol 138, 207–15. 20 Pinnell SR. (2003) Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 48, 1–19.

21 Madison KC. (2003) Barrier function of the skin: “la raison d’etre” of the epidermis. J Invest Dermatol 121, 231–41. 22 Chatenay F, Corcuff P, Saint-Leger D, Leveque JL. (1990) Alterations in the composition of human stratum corneum lipids induced by inflammation. Photodermatol Photoimmunol Photomed 7, 119–22. 23 Saint-Leger D, Francois AM, Leveque JL, Stoudemayer TJ, Kligman AM, Grove G. (1999) Stratum corneum lipids in skin xerosis. Dermatologica 178, 151–5. 24 Menon GK, Grayson S, Elias PM. (1985) Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ioncapture cytochemistry. J Invest Dermatol 84, 508–12. 25 Nilsson GE. (1977) Measurement of water exchange through the skin. Med Biol Eng Comput 15, 209. 26 Pinnagoda J, Tupker RA. (1995) Measurement of the transepidermal water loss. In: Serup J, Jemec GBE, eds. Handbook of Non-Invasive Methods and the Skin. Boca Raton, FL: CRC Press, pp. 173–8. 27 Leveque JL, Querleux B. (2003) SkinChip, a new tool for investigating the skin surface in vivo. Skin Res Technol 9, 343–7. 28 Corcuff P, Gonnord G, Pierard GE, Leveque JL. (1996) In vivo confocal microsocopy of human skin: a new design for cosmetology and dermatology. Scanning 18, 351–5. 29 Richard S, Querleux B, Bittoun J, Jolivet O, Idy-Peretti I, de Lacharriere O, et al. (1993) Characterization of skin in vivo by high resolution magnetic resonance imaging: water behavior and age-related effects. J Invest Dermatol 100, 705–9. 30 Corcuff P, Fiat F, Minondo AM. (2001) Ultrastructure of human stratum coreum. Skin Pharmacol Appl Skin Physiol 1, 4–9. 31 Zettersten EM, Ghadially R, Feingold KR, Crumrine D, Elias PM. (1997) Optimal ratios of topical stratum corneum lipids improve barrier recovery in chronologically aged skin. J Am Acad Dermatol 37, 403–8.

Chapter 2: Photoaging Murad Alam and Jillian Havey Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

BAS I C CONCEPTS • UV radiation damages human skin connective tissue through several interdependent, but distinct, processes. • The normal dermal matrix is maintained through signaling transduction pathways, transcription factors, cell surface receptors, and enzymatic reactions. • UV radiation produces reactive oxygen species which inhibit procollagen production, degrade collagen, and damage fibroblasts.

Introduction Skin, the largest human organ, is chronically exposed to UV radiation from the sun. Thinning of the ozone layer, which increases UV transmittance to the Earth, has heightened awareness of the potential injurious skin effects of exposure to UV radiation: photoaging, sunburn, immunosuppression, and carcinogenesis. Photoaging, the most common form of skin damage caused by UV exposure, produces damage to connective tissue, melanocytes, and the microvasculture [1]. Recent advances in understanding photoaging in human skin have identified the physical manifestations, histologic characteristics, and molecular mechanisms of UV exposure.

Definition Photoaging is the leading form of skin damage caused by sun exposure, occurring more frequently than skin cancer. Chronic UV exposure results in premature skin aging, termed cutaneous photoaging, which is marked by fine and coarse wrinkling of the skin, dyspigmentation, sallow color, textural changes, loss of elasticity, and premalignant actinic keratoses. Most of these clinical signs are caused by dermal alterations. Pigmentary disorders such as seborrheic keratoses, lentigines, and diffuse hyperpigmentation are characteristic of epidermal changes [2]. These physical characteristics are confirmed histologically by epidermal thinning and disorganization of the dermal connective tissue (see p. 14). Loss of connective tissue inter-

stitial collagen fibrils and accumulation of disorganized connective tissue elastin leads to solar elastosis, a condition characteristic of photoaged skin [3]. Similar alterations in the cellular component and the extracellular matrix of the connective tissue of photoaged skin may affect superficial capillaries, causing surface telangiectasias [4].

Physiology Photoaged versus chronically aged skin Skin, like all other organs, ages over time. Aging can be defined as intrinsic and extrinsic. Intrinsic aging is a hallmark of human chronologic aging and occurs in both sunexposed and non-sun-exposed skin. Extrinsic aging, on the contrary, is affected by exposure to environmental factors such as UV radiation. While sun-protected chronically aged skin and photoaged chronically aged skin share common characteristics, many of the physical characteristics of skin that decline with age show an accelerated decline with photoaging [5]. Compared with photodamaged skin, sunprotected skin is characterized by dryness, fine wrinkles, skin atrophy, hom*ogeneous pigmentation, and seborrheic keratoses [6]. Extrinsically aged skin, on the contrary, is characterized by roughness, dryness, both fine and coarse wrinkles, atrophy, uneven pigmentation, and superficial vascular abnormalities (e.g. telangiectasias) [6]. It is important to note that these attributes are not absolute and can vary according to Fitzpatrick skin type classification and history of sun exposure. While the pathophysiology of photoaged and photoprotected skin differ, the histologic features of these two entities are distinct. In photo-protected skin, a thin epidermis is present with an intact stratum corneum, the dermoepidermal junction and the dermis are flattened, and dermal fibroblasts produce less collagen. In photoaged skin,

BASIC CONCEPTS

Skin Physiology

the thickness of the epidermis can either increase or decrease, corresponding to areas of keratinocyte atypia. The dermoepidermal junction is atrophied in appearance and the basal membrane thickness is increased, reflecting basal keratinocyte damage. Changes in the dermis of photoaged skin can vary based on the amount of acquired UV damage. Solar elastosis is the most prominent histologic feature of photoaged skin. The quantity of elastin in the dermis decreases in chronically aged skin, but in UV-exposed skin, elastin increases in proportion to the amount of UV exposure [7,8]. Accumulated elastic fibers occupy areas in the dermal compartment previously inhabited by collagen fibers [9]. This altered elastin deposition is manifest clinically as wrinkles and yellow discoloration of the skin. Another feature of photoaged skin is collagen fibril disorganization. Mature collagen fibers, which constitute the bulk of the skin’s connective tissue, are degenerated and replaced by collagen with a basophilic appearance, termed basophilic degeneration. Additional photoaged skin characteristics include an increase in the deposition of glycosaminoglycans and dermal extracellular matrix proteins [10,11]. In fact, the overall cell population in photodamaged skin increases, leading to hyperplastic fibroblast proliferation and infiltration of inflammatory substrates that cause chronic inflammation (heliodermatitis) [12]. Changes in the microvasculature also occur, as is clinically manifested in surface telangiectasias and other vascular abnormalities.

UV-B

Photobiology In order to fully understand the molecular mechanisms responsible for photoaging in human skin, an awareness of the UV spectrum is crucial. The UV spectrum is divided into three main components: UVC (270–290 nm), UVB (290– 320 nm), and UVA (320–400 nm). While UVC radiation is filtered by ozone and atmospheric moisture, and consequently never reaches the Earth, UVA and UVB rays do reach the terrestrial surface. Although the ratio of UVA to UVB rays is 20 : 1 [13] and UVB is greatest during the summer months, both forms of radiation have acute and chronic effects on human skin. Photoaging is the superposition of UVA and UVB radiation on intrinsic aging. In order to exert biologic effects on human skin, both categories of UV rays must be absorbed by chromophores in the skin. Depending on the wavelength absorbed, UV light interacts with different skin cells at different depths (Figure 2.1). More specifically, energy from UVB rays is mostly absorbed by the epidermis and affects epidermal cells such as the keratinocytes, whereas energy from UVA rays affects both epidermal keratinocytes and the deeper dermal fibroblasts. The absorbed energy is converted into varying chemical reactions that cause histologic and clinical changes in the skin. UVA absorption by chromophores mostly acts indirectly by transferring energy to oxygen to generate reactive oxygen species (ROS), which subsequently causes several effects such as transcription factor activation, lipid peroxidation, and DNA-strand breaks. On the contrary, UVB has a more direct effect on the absorb-

UV-A

Epidermis

Keratinocytes AP-1 NF-κB

ROS Dermis

Fibroblasts

MMP and mtDNA

Figure 2.1 Ultraviolet light interacts with different skin cells at different depths. More specifically, energy from UVB rays is mostly absorbed by the epidermis and affects epidermal cells such as the keratinocytes. Energy from UVA rays affects both epidermal keratinocytes and the deeper dermal fibroblasts. AP-1, activator protein 1; NF-κB, nuclear factor κB; MMP, matrix metalloproteinase; mtDNA, mitochondrial DNA; ROS, reactive oxygen species. (Reproduced by permission of: Blackwell Publishing. This figure was published in: Berneburg M, Plettenberg H, Krutmann J. (2000) Photoaging in human skin. Photodermatol Photoimmunol Photomed 16, figure 1, p. 240.)

2. Photoaging ing chromophores and causes cross-linking of adjacent DNA pyrimidines and other DNA-related damage [14]. Approximately 50% of UV-induced photodamage is from the formation of free radicals, while mechanisms such as direct cellular injury account for the remainder of UV effects [15].

Cutaneous microvasculature Intrinsically aged skin and photodamaged skin share similar cutaneous vasculature characteristics, such as decreased cutaneous temperature, pallor, decreased cutaneous vessel size, reduced erythema, reduced cutaneous nutritional supply, and reduced cutaneous vascular responsiveness [16– 18]. However, there are also significant differences in the microvasculature of chronologic sun-protected versus photoaged skin. Studies have reported that the blood vessels in photoaged skin are obliterated and the overall horizontal architecture of the vascular plexuses is disrupted [19]. In contrast to photodamaged skin, intrinsically aged skin does not display a greatly disturbed pattern of horizontal vasculature. Additionally, while cutaneous vessel size has been reported to decrease with age in both scenarios, only photoaged skin exhibits a large reduction in the number of dermal vessels. This reduction is especially highlighted in the upper dermal connective tissue, where it is hypothesized that chronic UV-induced degradation of elastic and collagen fibers is no longer able to provide the physical support required for normal cutaneous vessel maintenance [16]. Furthermore, preliminary studies have reported that the effects of exposure to acute UV radiation differ from chronic exposure. Recent studies have implied that a single exposure to UVB radiation induces skin angiogenesis in human skin in vivo [20,21]. The epidermis-derived vascular endothelial growth factor (VEGF) is an angiogenic factor that is significantly upregulated with UV exposure in keratinocytes in vitro and in human skin in vivo. Chung and Eun [16] have demonstrated that, compared to low VEGF expression in non-UV-irradiated control skin, epidermal VEGF expression increased significantly on days 2 and 3 post-UV-irradiation, consequently inducing cutaneous angiogenesis. Therefore, acute UV exposure has been shown to induce angiogenesis. However, chronic UV-exposed photodamaged skin exhibits a significant reduction in the number of cutaneous blood vessels. The reasons for this discrepancy between the effects of acute and chronic UV exposure on angiogenesis in vivo are still under investigation.

damages human skin by at least two interdependent mechanisms: 1 Photochemical generation of ROS; and 2 Activation of cutaneous signal transduction pathways. These molecular processes and their underlying components are described in detail below. Before these processes are highlighted, however, the structure and function of collagen must be understood.

Collagen Type I collagen accounts for greater than 90% of the protein in the human skin, with type III collagen accounting for a smaller fraction (10%). The unique physical characteristics of collagen fibers are essential for providing strength, structural integrity, and resilience to the skin. Dermal fibroblasts synthesize individual collagen polypeptide chains as precursor molecules called procollagen. These procollagen building blocks are assembled into larger collagen fibers through enzymatic cross-linking and form the three-dimensional dermal network mainly made of collagen types I and III. This intermolecular covalant cross-linking step is essential for maintenance and structural integrity of large collagen fibers, especially type I collagen. Natural breakdown of type I collagen is a slow process and occurs through enzymatic degradation [22]. Dermal collagen has a half-life of greater than 1 year [22], and this slow rate of type I collagen turnover allows for disorganization and fragmentation of collagen which impair its functions. In fact, fragmentation and dispersion of collagen fibers is a feature of photodamaged skin that is clinically manifest in the changes associated with photodamaged human skin. The regulation of collagen production is an important mechanism to understand before discussing how this process is impaired. In general, collagen gene expression is regulated by the cytokine, transforming growth factor β (TGF-β), and the transcription factor, activator protein (AP-1), in human skin fibroblasts. When TGF-βs bind to their cell surface receptors (TβRI and TβRII), transcription factors Smad2 and Smad3 are activated, combine with Smad4, and enter the nucleus, where they regulate type I procollagen production. AP-1 has an opposing effect and inhibits collagen gene transcription by either direct suppression of gene transcription or obstructing the Smad complex from binding to the TGF-β target gene (Figure 2.2) [23]. Therefore, in the absence of any inhibiting factors, the TGF-β/Smad signaling pathway results in a net increase in procollagen production.

How does UV irradiation stimulate photoaging?

Molecular mechanisms of photoaging During the last few years substantial progress has been made in exposing the molecular mechanisms accountable for photoaging in human skin. One major theoretical advance that has been elucidated by this work is that UV irradiation

UV irradiation stimulates photoaging through several molecular mechanisms, discussed in detail below.

Reactive oxygen species Approximately 50% of UV-induced photodamage is from the formation of free radicals, while mechanisms such as

BASIC CONCEPTS

Skin Physiology complex. This, in turn, reduces TGF-β target gene expression, such as expression of type I procollagen [27].

TGF-β TGF-β

UV-induced matrix metalloproteinases stimulate collagen degradation

Smad 2,3 Smad 7 TβR I/II

Smad 2,3 Smad 4

Smad 2,3

Smad 4 AP-1

Smad 2,3

Smad 4

TGF-β target gene

Collagen

Figure 2.2 The regulation of procollagen production: the TGF-β/Smad signaling pathway. AP-1, activator protein 1; TβR, TGF-β receptor; TGF-β, transforming growth factor β. (Reproduced by permission of: Elsevier Ltd. This figure was published in: Kang S, Fisher G, Voorhees JJ. (2001) Photoaging pathogenesis, prevention, and treatment. Clin Geriatric Med 17(4), figure 1, p. 645.)

direct cellular injury account for the remainder of UV effects [15]. Proposed in 1954, the free radical theory of aging suggests that aging is a result of reactions caused by excessive amounts of free radicals, which contain one or more unpaired electrons [24]. Generation of ROS occurs during normal chronologic aging and when human skin is exposed to UV light in photoaging [25]. ROS mediate deleterious post-translational effects on aging skin through direct chemical modifications to mitochondrial DNA (mtDNA), cell lipids, deoxyribonucleic acids (DNA), and dermal matrix proteins, including collagens. In fact, a 4977 base-pair deletion of mtDNA was recently found in dermal human fibroblast cells. This deletion is induced by UVA via ROS and is a marker of UVA photodamage [26].

UV radiation inhibits procollagen production: TGF-β/Smad signaling pathway UV light inhibits procollagen production through two signaling pathways: downregulation of TβRII and inhibition of target gene transcription by AP-1. UV radiation has been reported to disrupt the skin collagen matrix through the TGF-β/Smad pathway [1]. More specifically, UV radiation downregulates the TGF-β type II receptor (TβRII) and results in a 90% reduction of TGF-β cell surface binding, consequently reducing downstream activation of the Smad 2, 3, 4 complex and type I procollagen transcription. Additionally, UV radiation activates AP-1, which binds factors that are part of the procollagen type I transcriptional

It has been demonstrated that UV irradiation affects the post-translational modification of dermal matrix proteins (through ROS) and also downregulates the transcription of these same proteins (through the TGF-β/Smad signaling pathway). UVA and UVB light also induces a wide variety of matrix metalloproteinases (MMPs) [28]. As their name suggests, MMPs degrade dermal matrix proteins, specifically collagens, through enzymatic activity. UV-induced MMP-1 initiates cleavage of type I and III dermal collagen, followed by further degradation by MMP-3 and MMP-9. Recall that type I collagen fibrils are stabilized by covalent cross-links. When undergoing degradation by MMPs, collagen molecules can remain cross-linked within the dermal collagen matrix, thereby impairing the structural integrity of the dermis. In the absence of perfect repair mechanisms, MMP-mediated collagen damage can accrue with each UV exposure. This type of collective damage to the dermal matrix collagen is hypothesized to have a direct effect on the physical characteristics of photodamaged skin [14]. In addition to UV induction of MMPs, transcription factors may cause MMP activation. It has been reported that within hours of UV exposure, the transcription factors AP-1 and NF-κB are activated which, in turn, stimulate transcription of MMPs (Figure 2.3) [29].

Fibroblasts regulate their own collagen synthesis Fibroblasts have evolved to regulate their output of extracellular matrix proteins (including collagen) based on internal mechanical tension [30]. Type I collagen fibrils in the dermis serve as mechanical stabilizers and attachment sites for fibroblasts in sun-protected skin. Surface integrins on the fibroblasts attach to collagen and internal actin– myosin microfilaments provide mechanical resistance by pulling on the intact collagen. In response to this created tension, intracellular scaffolding composed of intermediate filaments and microtubules pushes outward to causing fibroblasts to stretch. This stretch is an essential cue for normal collagen and MMP production by fibroblasts (Figure 2.4) [30]. This mechanical tension model is different in photoaged human skin. Fibroblast–integrin attachments are lost, which prevents collagen fragments from binding to fibroblasts. Collagen–fibroblast binding is crucial for maintenance of normal mechanical stability. When mechanical tension is reduced, as in photoaged skin, fibroblasts collapse, which causes decreased procollagen production and increased collagenase (COLase) production [30]. Collagen is continually lost as this cycle repeats itself.

2. Photoaging

FB FB

FB Figure 2.3 Model depicting the effects of UV irradiation on epidermal keratinocytes (KC) and dermal fibroblasts (FB). AP-1, activator protein 1; MMP, matrix metalloproteinase. (Reproduced by permission of: Fisher GJ, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol 2002; 138: figure 1 p. 1463. Copyright 2002, American Medical Association. All Rights reserved.)

Growth factor Cytokine receptors

Signal transduction cascade

AP-1

MMPs

Procollagen MMP promoters promoters nucleus

MMPs

AP-1 MMP promoters

MMPs

Dermal matrix breakdown Imperfect repair

nucleus

Photoaging

Intact collagen Cross-links

Photoprotected or young skin

Integrin

Figure 2.4 Fibroblasts have evolved to regulate their output of collagen based on internal mechanical tension. Model depicting the effects of mechanical tension on procollagen production in (a) sun-protected human skin versus (b) photodamaged human skin. (Reproduced by permission of: Fisher GJ, Varani J, Voorhees, JJ. Looking older. Arch Dermatol 2008; 144(5), figure 2, p. 669. Copyright 2008, American Medical Association. All rights reserved.)

(a) Stretched fibroblast Collagen fragments

Photoaged or aged skin

Cross-links

(b) Collapsed fibroblast

BASIC CONCEPTS

Skin Physiology

Ethnic skin: photoaging All races are susceptible to photoaging. However, people with Fitzpatrick skin phototypes IV–VI are less susceptible to the deleterious effects of UV irradiation than people with a lower Fitzpatrick skin type classification. This phenomenon is most likely a result of the protective role of melanin [31]. Studies reporting ethnic skin photoaging are few and far between. However, for the purposes of this discussion, characteristics of photoaging in different ethnic skin categories are briefly highlighted. In one of the first studies comparing UV absorption amongst different skin types, Kaidbey et al. [32] compared the photoprotective properties of African-American skin with Caucasian skin exposed to UVB irradiation. It was known that only 10% of the total UVB rays penetrated the dermis. However, the mean UVB transmission into the dermis by African-American dermis (5.7%) was found to be significantly less than for Caucasian dermis (29.4%). Similar experiments were performed with UVA irradiation. Although only 50% of the total UVA exposure penetrates into the papillary dermis, UVA transmission into AfricanAmerican dermis was 17.5% compared to 55% for white epidermis [32]. The physiologic reason behind this difference in black and white skin lies at the site of UV filtration. The malpighian layer (basal cell layer) of African-American skin is the main site of UV filtration, while the stratum corneum absorbs most UV rays in white skin. The malpighian layer of African-American skin removes twice as much UVB radiation as the overlying statum corneum, thus mitigating the deleterious effects of UV rays in the underlying dermis [33]. In African-Americans, photoaging may not be clinically apparent until the fifth or sixth decade of life and is more common in individuals with a lighter complexion [34]. The features of photoaging in this ethnic skin group manifest as signs of laxity in the malar fat pads sagging toward the nasolabial folds [35]. In patients of Hispanic and European descent, photoaging occurs in the same frequency as Caucasians and clinical signs are primarily wrinkling rather than pigmentary alterations. The skin of East and South-East Asian patients, on the contrary, mainly exhibits pigmentary alterations (seborrheic keratoses, hyperpigmentation, actinic lentigines, sun-induced melasma) and minimal wrinkling as a result of photoaging [36,37]. Finally, very few studies have reported on the signs of photoaging in South Asian (Pakistanis, Indians) skin. UV-induced hyperpigmentation, dermatosis papulosa nigra, and seborrheic keratosis are noted [38]. Despite all of these differences, it is important to note that the number of melanocytes per unit area of skin does not vary across ethnicities. Instead, it is the relative amount of melanin packaged into melanocytes that accounts for the

physiologic differences between Caucasian skin and ethnic skin [39].

Prevention Although the effects of the sun’s rays appear daunting, there are some ways to avoid the deleterious effects of photoaging. Avoiding photoaging can often prove to be more costeffective than trying to reverse the signs of photoaging after they have manifested.

Primary prevention Sun protection UV rays are especially prevalent during the hours of 10AM– 4PM and sun protection should be encouraged during this time. Sun protection can be offered to patients in the form of sunscreens, sun-protective clothing, and/or sun avoidance. Sun-protective clothing includes any hats, sunglasses, or clothing that would help block the sun’s rays. Photoprotective clothing is given a UV protection factor (UPF) rating, which is a measurement of the amount of irradiation that can be transmitted through a specific type of fabric. A UPF of 40–50 is recommended by most dermatologists, as it transmits less than 2.6% of UV irradiation [5]. Traditionally, sunscreens contain one or more chemical filters – those that physically block, reflect, or scatter specific photons of UV irradiation and those that absorb specific UV photons. UVA sunblocks contain the inorganic particulates titanium dioxide or zinc oxide, while UVA-absorbing suncreens contain terephthalylidene dicamphor sulfonic acid or avobenzene. UVB-absorbing sunscreens can contain salicylates, cinnamates, p-aminobenzoic acid, or a combination of these [40]. The US Food and Drug Administration (FDA) recommended dose of sunscreen application is 2 mg/cm2 [41]. The sun protection factor (SPF) is an international laboratory measure used to assess the efficacy of sunscreens. The SPF can range from 1 to over 80 and indicates the time that a person can be exposed to UVB rays before getting sunburn with sunscreen application relative to the time a person can be exposed without sunscreen. SPF levels are determined by the minimal amount of UV irradiation that can cause UVBstimulated erythema and/or pain. The effectiveness of a particular sunscreen depends on several factors, including the initial amount applied, amount reapplied, skin type of the user, amount of sunscreen the skin has absorbed, and the activities of the user (e.g. swimming, sweating). The sun protection factor is an inadequate determination of skin damage because it does not account for UVA rays. Although UVA rays have an important role in photoaging, their effects are not physically evident as erythema or pain, as are UVB rays. Therefore, it has been suggested that SPF may be an imperfect guide to the ability of a particular sun-

2. Photoaging UV

Skin angiogenesis VEGF TSP

Acute effects

ECM degradation Collagen MMPs

Inflammation Figure 2.5 Model depicting the acute and chronic effects of UV irradiation on skin angiogenesis and extracellular matrix (ECM) degradation in human skin. MMP, matrix metalloproteinase; TSP, thrombospondin-1 (ECM protein; inhibitor of angiogenesis in epithelial tissues); VEGF, vascular endothelial growth factor. (Reproduced by permission of: Blackwell Publishing. This figure was published in: Chung JH, Eun HC. (2007) Angiogenesis in skin aging and photoaging. J Dermatol 34, figure 1, p. 596.)

Worse environment for normal vasculature Photoaged human skin ECM (collagen fibers, elastic fibers) Dermal vasculature

Chronic effects

screen to shield against photoaging [5]. As a result, combination UVA–UVB sunscreens have been developed and are recommended to protect the human skin from both types of irradiation.

Aged and photoaged human skin ECM (collagen fibers, elastic fibers) Dermal vasculature Retinoic acid

Secondary prevention Retinoids A large number of studies have reported that topical application of 0.025–0.1% all-trans retinoic acid (tRA) improves photoaging in human skin [42,43]. Results vary based on treatment duration and applied tRA dose. Although there have been a variety of clinical trials on the topic, the molecular mechanisms by which tRA acts are still waiting to be discovered. Retinoic acids have been used in an ex post facto manner to reverse the signs of photodamage and in a preventative fashion to avoid photoaging. More specifically, tRA has been shown to induce type I and III procollagen gene expression in photoaged skin [44]. It has been observed that topical tRA induces TGF-β in human skin [45], which stimulates the production of type I and III procollagen. In addition, tRA has been used in a preventive fashion to avert UV-induced angiogenesis. Kim et al. [20] demonstrated that topical application of retinoic acid before UV exposure inhibited UV-induced angiogenesis and increases in blood vessel density. In general, extracellular signal-related kinases (ERKs, or classic MAP kinases) positively regulate epidermally derived VEGF. VEGF stimulates angiogenesis upon UV induction. Retinoic acid inhibits ERKs, which can potentially lead to downregulation of VEGF expression, UV-induced angiogenesis, and angiogenesis-associated photoaging (Figures 2.5 and 2.6) [16]. Finally, tRA has been reported to prevent UV-stimulated MMP expression. The transcription factor, c-Jun, is a key

ECM degradation Collagen MMPs

Skin angiogenesis VEGF Vascularization

Better environment for normal vasculature

Improve skin aging Figure 2.6 Model depicting the effect of topical retinoids on photoaged human skin. ECM, extracellular matrix; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor. (Reproduced by permission of: Blackwell Publishing. This figure was published in: Chung J, Eun HC. (2007) Angiogenesis in skin aging and photoaging. J Dermatol 34, figure 5, p. 599.)

component in forming the AP-1 complex. Recall that the AP-1 complex both inhibits types I and III procollagen and stimulates transcription of MMPs. Retinoic acid blocks the accumulation of c-Jun protein, consequently inhibiting the formation of the AP-1 complex and dermal matrixassociated degradation [46].

Antioxidants It is important to highlight briefly the role of antioxidants in the reduction of photoaging. In vitro studies have

BASIC CONCEPTS

Skin Physiology

discovered a large number of antioxidants that either forestall or reverse the clinical signs of photodamage caused by ROS. In vivo studies investigating these same antioxidants are ongoing. One such antioxidant, vitamin C, has been shown to mitigate photodamaged keratinocyte formation and erythema post-UV-irradiation [47].

Inherent defense mechanisms Although science has developed exogenous mechanisms to prevent and reverse the clinical signs of photoaging, the human skin possesses endogenous machinery built to protect the skin from UV-induced damage. These inherent defense mechanisms include, but are not limited to, increased epidermal thickness, melanin distribution, DNA repair mechanisms and apoptosis of sunburned keratinocytes, MMP tissue inhibitors, and antioxidants [5,32,48–50].

Failure of prevention: immunosuppression Although photoaging is the most prevalent form of skin damage, local and systemic immunosuppression, leading to skin carcinoma, can result from overexposure to the sun’s rays. This immunosuppression is mediated by a combination of DNA damage, epidermal Langerhans’ cell depletion, and altered cytokine expression [51,52].

Conclusions The pathophysiology of photoaging derives from the ability of UV irradiation to exploit established molecular mechanisms which have evolved to maintain the internal milieu of human skin connective tissue. Disruption of the normal skin architecture does not occur through one pathway, but rather is the culmination of several interdependent, but distinct, processes that have gone awry. The integrity of the normal dermal matrix is maintained through signaling transduction pathways, transcription factors, cell surface receptors, and enzymatic reactions that are intertangled and communicate with one another. When UV irradiation is introduced into this homeostatic picture, deleterious effects can be implemented. Production of ROS, inhibition of procollagen production, collagen degradation, and fibroblast collapse are only a few known processes amongst the medley of mechanisms still waiting to be discovered that contribute to photoaging. Although human skin is equipped with inherent mechanisms to protect against photoaging and methods of prevention and therapeutics are widely available, these alternatives are not absolute and do not necessarily guarantee a perfect escape from the sun’s UV irradiation. With each passing day, scientists continue to discover

novel cutaneous molecular mechanisms affected by UV irradiation and, consequently, search for new solutions to photodamage.

References 1 Quan T, He T, Kang S, Voorhees JJ, Fisher GJ. (2004) Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling. Am J Pathol 165, 741–51. 2 Gilchrest B, Rogers G. (1993) Photoaging. In: Lim H, Soter N, eds. Clinical Photomedicine. New York: Marcel Dekker, pp. 95–111. 3 Kang S, Fisher GJ, Voorhees JJ. (2001) Photoaging: pathogenesis, prevention, and treatment. Clin Geriatr Med 17, 643–59. 4 Weiss RA, Weiss MA, Beasley KL. (2002) Rejuvenation of photoaged skin: 5 years results with intense pulsed light of the face, neck, and chest. Dermatol Surg 28, 1115–9. 5 Rabe JH et al. (2006) Photoaging: mechanisms and repair. J Am Acad Dermatol 55, 1–19. 6 Rokhsar CK, Lee S, Fitzpatrick RE. (2005) Review of photorejuvenation: devices, cosmeceuticals, or both? Dermatol Surg 31, 1166–78; discussion 1178. 7 Bernstein E, Brown DB, Urbach F, Forbes D, Del Monaco M, Wu M, et al. (1995) Ultraviolet radiation activates the human elastin promoter in transgenic mice: a novel in vivo and in vitro model of cutaneous photoaging. J Invest Dermatol 105, 269–73. 8 Lewis KG, Bercovitch L, Dill SW, Robinson-Bostom L. (2004) Acquired disorders of elastic tissue: part I. Increased elastic tissue and solar elastotic syndromes. J Am Acad Dermatol 51, 1–21. 9 El-Domyati M, Attia S, Saleh F, Brown D, Birk DE, Gasparro F, et al. (2002) Intrinsic aging vs photoaging: a comparative histopathological, immunohistochemical, and ultrastructural study of skin. Exp Dermatol 11, 398–405. 10 Mitchell R. (1967) Chronic solar elastosis: a light and electron microscopic study of the dermis. J Invest Dermatol 48, 203–20. 11 Smith JG Jr, Davidson EA, Sams WM Jr, Clark RD. (1962) Alterations in human dermal connective tissue with age and chronic sun damage. J Invest Dermatol 39, 347–50. 12 Lavker R, Kligman A. (1988) Chronic heliodermatitis: a morphologic evaluation of chronic actinic damage with emphasis on the role of mast cells. J Invest Dermatol 90, 325–30. 13 Urbach F. (1992) Ultraviolet A transmission by modern sunscreens: Is there a real risk? Photodermatol Photoimmunol Photomed 9, 237–41. 14 Fisher G, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. (2002) Mechanisms of photoaging and chronological skin aging. Arch Dermatol 138, 1462–70. 15 Bernstein EF, Brown DB, Schwartz MD, Kaidbey K, Ksenzenko SM. (2004) The polyhydrxy acid gluconolactone protects against ultraviolet radiation in an in vitro model of cutaneous photoaging. Dermatol Surg 30, 189–96. 16 Chung JH, Eun HC. (2007) Angiogenesis in skin aging and photoaging. J Dermatol 34, 593–600. 17 Chung JH, Yano K, Lee MK, Youn CS, Seo JY, Kim KH, et al. (2002) Differential effects of photoaging vs intrinsic aging on the vascularization of human skin. Arch Dermatol 138, 1437–42. 18 Kelly RI, Pearse R, Bull RH, Leveque JL, de Riqal J, Mortimer PS. (1995) The effects of aging on the cutaneous microvasculature. J Am Acad Dermatol 33, 749–56.

2. Photoaging 19 Kligman AM. (1979) Perspectives and problems in cutaneous gerontology. J Invest Dermatol 73, 39–46. 20 Kim MS, Kim YK, Eun HC, Cho KH, Chung JH. (2006) All-trans retinoic acid antagonizes UV-induced VEGF production and angiogenesis via the inhibition of ERK activation in human skin keratinocytes. J Invest Dermatol 126, 2697–706. 21 Yano K, Kadova K, Kajiya K, Hong YK, Detmar M. (2005) Ultraviolet B irradiation of human skin induces an angiogenic switch that is mediated by upregulation of vascular endothelial growth factor and by downregulation of thrombospondin-1. Br J Dermatol 152, 115–21. 22 Verzijl N, DeGroot J, Thorpe S. (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275, 39027–31. 23 Massague J. (1998) TGF-β signal transduction. Annu Rev Biochem 67, 753–91. 24 Herman D. (1998) Expanding functional life span. Exp Geriatr Ontol 33, 95–112. 25 Sohal R, Weindruch R. (1996) Oxidative stress, caloric restriction and aging. Science 273, 59–63. 26 Berneburg M, Plettenberg H, Medve-Konig K, Pfahlberg A, Gers-Barlaq H, Gefeler O, et al. (2004) Induction of the photoaging-associated mitochondrial common deletion in vivo in normal human skin. J Invest Dermatol 122, 1277–83. 27 Karin M, Liu ZG, Zandi E. (1997) AP-1 function and regulation. Curr Opin Cell Biol 9, 240–6. 28 Berneburg M, Plettenberg H, Krutmann J. (2000) Photoaging of human skin. Photodermatol Photoimmunol Photomed 16, 239–44. 29 Fisher G, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ. (1997) Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 337, 1419–28. 30 Fisher GJ, Varani J, Voorhees JJ. (2008) Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol 144, 666–72. 31 Pathak M. (1974) The role of natural photoprotective agents in human skin. In: Fitzpatrick T, Pathak M, eds. Sunlight and Man. Toyko: University of Toyko Press. 32 Kaidbey KH, Agin PP, Sayre RM, Kligman AM. (1979) Photoprotection by melanin: a comparison of black and Caucasian skin. J Am Acad Dermatol 1, 249–60. 33 Munavalli GS, Weiss RA, Halder RM. (2005) Photoaging and nonablative photorejuvenation in ethnic skin. Dermatol Surg 31, 1250–60; discussion 1261. 34 Taylor SC. (2002) Skin of color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol 46 (Suppl 2), S41–62. 35 Matory W. (1998) Skin care. In: Matory W, ed. Ethnic Considerations in Facial Aesthetic Surgery. Philadelphia: LippincottRaven, p. 100. 36 Chung JH, Lee SH, Youn CS, Park BJ, Kim KH, Park KC, et al. (2001) Cutaneous photodamage in Koreans: influence of sex, sun exposure, smoking, and skin color. Arch Dermatol 137, 1043–51. 37 Goh SH. (1990) The treatment of visible signs of senescence: the Asian experience. Br J Dermatol 122 (Suppl 35), 105–9. 38 Valia R, Ed. (1994) Textbook and Atlas of Dermatology. Bombay: Bhalani Publishing House.

39 Szabo G, Gerald AB, Pathak MA, Fitzpatrick TB. (1969) Racial differences in the fate of melanosomes in human epidermis. Nature 222, 1081–2. 40 Seite S, Colige A, Piquemal-Vivenot P, Montastier C, Fourtanier A, Lapiere C, et al. (2000) A full-UV spectrum absorbing daily use cream protects human skin against biological changes occurring in photoaging. Photodermatol Photoimmunol Photomed 16, 147–55. 41 Bowen D. (1998) http://www.fda.gov/ohrms/dockets/dailys/00/ Sep00/090600/c000573_10_Attachment_F.pdf. 42 Griffiths CE, Kang S, Ellis CN, Kim KJ, Finkel LJ, Ortiz-Ferrer LC, et al. (1995) Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation: a double-blind, vehicle-controlled comparison of 0.1% and 0.025% tretinoin creams. Arch Dermatol 131, 1037–44. 43 Kang S, Voorhees JJ. (1998) Photoaging therapy with topical tretinoin: an evidence-based analysis. J Am Acad Dermatol 39, S55–61. 44 Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. (1993) Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 329, 530–5. 45 Kim HJ, Bogdan NJ, D’Agostaro LJ, Gold LI, Bryce GF. (1992) Effect of topical retinoic acids on the levels of collagen mRNA during the repair of UVB-induced dermal damage in the hairless mouse and the possible role of TGF-beta as a mediator. J Invest Dermatol 98, 359–63. 46 Fisher GJ, Talwar HS, Lin J, Lin P, McPhillips F, Wang Z, et al. (1998) Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 101, 1432–40. 47 Lin JY, Selim MA, Shea CR, Grichnik JM, Omar MM, MonteiroRiviere NA, et al. (2003) UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol 48, 866–74. 48 Huang LC, Clarkin KC, Wahl GM. (1996) Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc Natl Acad Sci U S A 93, 4827–32. 49 Oh JH, Chung AS, Steinbrenner H, Sies H, Brenneisen P. (2004) Thioredoxin secreted upon ultraviolet A irradiation modulates activities of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in human dermal fibroblasts. Arch Biochem Biophys 423, 218–26. 50 Soter N. (1995) Sunburn and suntan: immediate manifestations of photodamage. In: Gilchrest B, ed. Photodamage. Cambridge, MA: Blackwell Science, pp. 12–25. 51 Vink AA, Moodycliffe AM, Shreedhar V, Ullrich SE, Roza L, Yarosh DB, et al. (1997) The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimers. Proc Natl Acad Sci U S A 94, 5255–60. 52 Toews GB, Bergstresser PR, Streilein JW. (1980) Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J Immunol 124, 445–53.

Chapter 3: Self-perceived sensitive skin Olivier de Lacharrière L’Oréal Recherche, Clichy, France

BAS I C CONCE P T S • Sensitive skin is a term used by individuals who perceive their skin as being more intolerant or reactive than the general population. • Sensitive skin is clinically characterized by subjective, sensorial signs: facial discomfort with stinging, burning, and itching. • The clinical signs of sensitive skin appear in specific conditions, provoked by reactivity factors: environmental factors: wind, sun, cold weather, fast changes in temperature; topical factors: hard water, cosmetics; internal factors: life stress, menstruation, or spicy or hot foods.

Introduction

Clinical features

Sensitive skin is a clinical syndrome, first described in the 1960s by Thiers [1]. A protocol for clinical evaluation of sensitive skin using lactic acid sting testing was first introduced in the 1970s by Frosch and Kligman [2]. Subsequent to that, interest in the field of sensitive skin exploded based on “subjective discomfort, namely, delayed stinging from topical agents applied to the skin.” In spite of the contrary opinion expressed by Maibach et al. [3] at the end of the 1980s, that “the plausibility of the concept of the sensitive skin evokes discussion and often amusem*nt because of the variance of the number of opinions compared with the amount of data, at least until recently,” significant progress has been made on sensitive skin research in recent years. Based on current opinion, sensitive skin is now well accepted as a clinical syndrome. Based on consumer complaints, it is clear that sensitive skin is a term used by individuals who perceive their skin as being more intolerant or reactive than the general population. Consequently, sensitive skin could be defined as a hyperreactive skin, characterized by exaggerated sensorial reaction to environmental or topical factors, including hard water and cosmetics. Consequently, instead of “sensitive skin,” it is better to call this syndrome “self-perceived sensitive skin” (SPSS). In the last decade, some new understanding on the mechanisms of sensitive skin, involving sensitive epidermal nerves has been emphasized [4].

Clinical signs and provocative factor

Sensitive skin is clinically characterized by subjective, sensorial signs: facial discomfort with stinging, burning, and itching. SPSS is more frequent in young women, and decreases with age. The clinical signs of sensitive skin appear in specific conditions, provoked by reactivity factors: • Environmental factors: wind, sun, cold weather, fast changes in temperature; • Topical factors: hard water, cosmetics; • Internal factors: life stress, menstruation, or spicy or hot foods.

Clinical subgroups Although the distribution of sensitive skin occurs throughout the population, multivariate analysis shows that several subgroups could be defined [4,5], according to the severity of sensitive skin and to the provocative factors: 1 Severe sensitive skin; 2 Sensitive skin to environment; 3 Sensitive skin to topical factors.

Severe sensitive skin Severe sensitive skin demonstrates very high facial skin reactivity to all kinds of factors: topical, environmental including atmospheric pollution and also internal factors such as stress and tiredness. Severe sensitive skin could present as “crisis phases” occurring for several days or weeks. During these phases, known as “status cosmeticus,” the skin becomes intolerant to all applied products, even products that are usually very well tolerated by the consumer [6].

3. Self-perceived sensitive skin

Sensitive skin to topical factors Around 25% of women have sensitive skin to topical factors. In this subgroup of sensitive skin, the provocative factor is the application of a product on the skin. It is important to underline that the intolerance observed appears immediately or in the minutes following application, sometimes from the first application.

Table 3.1 List of tested allergens on self-perceived sensitive skin and non-self-perceived sensitive skin subjects. (From [4] and [9].) Diazolidinyl urea

Hydroquinone

Colophon

Cocamidopropylbetaine

Formaldehyde

Ethylene diamine

Balsam of Peru

Ortho-aminophenol

Sensitive skin to environmental factors Around 15–20% of women have sensitive skin to environmental factors such as heat, rapid changes in temperature, or wind.

Benzoic acid

Glyceryl monothioglycolate

Pyrogallol

Ammonium thioglycolate

Parabens mix

Dowicil

Diathesis factors

Ammonium persulfate

Isothiazolinones

In most cases of sensitive skin, the skin hyperreactivity is constitutional. Thiers [1], who was the first to describe this syndrome, has suggested that diathesis features could exist. We also found that a familiar history of sensitive skin exists. Sensitive skin is more frequently found in subjects with fair complexion, and/or redness on the cheekbones [7,8]. Severe dry skin could be as affected as severe oily skin by skin hyperreactivity. Acquired skin hyperreactivity could mimic the signs observed during sensitive skin syndrome. This acquired “sensitive skin,” characterized by a temporary decrease of the threshold of sensorial reactivity of the skin, could be linked to topical irritants improperly applied such as retinoids or hydroxy-acids. In these cases, it is possible that skin that is usually “non-reactive” becomes “reactive” for a period of time. The presence of active facial dermatitis such as seborrheic dermatitis or rosacea could also lower the threshold of skin reactivity. However, although an outbreak of facial atopic dermatitis increases skin reactivity, it is incorrect to consider all sensitive skin as atopic skin.

p-aminodiphenylamine

Fragance mix

Sensitive skin and immuno-allergologic pattern An important point about sensitive skin comes from controversial opinions that exist regarding allergic status [5,7]. To explore this, skin patch test reactivity was studied in 152 female adult volunteers [9]. Eighty-eight declared themselves as having sensitive skin, and 64 as having nonsensitive skin. A series of 44 different topical ingredients known to be potential allergens were applied to the back under Finn Chambers (Table 3.1). The patches were removed after 47 hours and the reactions read after 1 hour and 2 days. For each ingredient, the incidence of positive reactions was compared between the two populations, using the χ2 test. Positive reactions were recorded for 19 out of the 44 tested compounds. No significant difference in the incidence of positive reactions was found between sensitive and non-sensitive skin subjects for any of the patch-tested ingredients. Currently, sensitive skin must not be considered as a syndrome linked to an immuno-allergologic pattern.

Wool alcohols

Diagnosis Provocative tests The diagnosis of SPSS must be based on clinical signs, which are neurosensorial (i.e. subjective). In fact, facial stinging, burning, and itching are clinical signs directly felt by the subject but not seen by the observer. It corresponds to the concept of “invisible dermatoses” [10], as is also the case for all sensorial signs encountered in dermatology (e.g. itching, pain). Pertinent clinical questionnaires are probably the best tools to diagnose this syndrome. Provocative tests could be of help. The lactic acid stinging test was first described by Frosch and Kligman [2,11]. A solution of 10% lactic acid is applied to a nasolabial fold and the provoked stinging feeling is quantified. Generally, the stinging is measured every minute for 5 minutes on a scale from 0 to 3. The lactic acid reaction is compared with the other nasolabial fold where a control solution (saline solution) is applied. The test discriminates between “stingers” and “non-stingers,” but does not affect the discrimination between sensitive skin and non-sensitive skin subjects [12]. In our opinion, the lactic acid stinging test is of interest to assess efficacy of products, but not for diagnostic purposes. Considering the clinical signs linked to SPSS (stinging, burning, itching), we have hypothesized that the main player is the sensitive epidermal nerve, C-fibers [13]. According to this physiologic hypothesis, we have proposed to test the skin reactivity by using capsaicin [14], an irritant compound extracted from red pepper which acts on vanilloid receptors of the nociceptive C-fibres and provokes the release of neuropeptides as substance P and calcitonin generelated peptide (CGRP) [15,16].

BASIC CONCEPTS

Skin Physiology

Capsaicin cream (0.075%) was applied at the angle of the jaw over an area of 4 cm2. The neurosensorial signs (stinging, burning, and itching [SBI]) were assessed at 3, 5, 10, 15 and 20 minutes according to a scale score (0, 1, 2, 3). The sum of the scores gives the global SBI score. The results we obtained on two groups of subjects clearly showed that the sensitive skin subjects’ (n = 64) reactions were significantly higher than the non-sensitive subjects (n = 88) (Figure 3.1). The capsaicin test allows one to discriminate quite well between SPSS subjects and non-SPSS subjects. On the same population sample, we compared the scores obtained with the capsaicin test with those from the lactic acid stinging test. The results are presented in Table 3.2. With capsaicin, the scores showed a better correlation to the SPSS than those recorded with lactic acid. Furthermore, there is a real relationship between the severity of the sensitive skin and the response to the capsaicin test. The higher the severity of SPSS, the higher the capsaicin score.

Sensitive skin and populations Epidemiologic data The prevalence of SPSS is estimated at 51–56% in Europe, USA, and Japan [8,17–20]. Willis et al. [8] published an epidemiologic study in the UK on sensitive skin where 2058 people (up to 18 years of age) were investigated. Of those who reposonded, 51% of the women and 38% of the men declared themselves to have sensitive skin. In the San Francisco area, the reported prevalence of SPSS in four ethnic groups (African-American, Asian, EuroAmerican, and Hispanic Central American) is 52% [19]. No significant difference of prevalence in each group was found: 52% of African-Americans had sensitive skin, 51% of Asians, 50% of Euro-Americans, and 54% of South Americans. Yang et al. [21] studied the sensitive skin in four cities of China: Beijing and Harbin (northern cities), Chengdu and Suzhou (southern cities). Two thousand Chinese women, aged 18–75 years, were included. The global prevalence of sensitive skin was 36%. The prevalence decreases with age (47% at 21–25 years; 20.8% at 51–55 years).

Global discomfort (stinging + burning + itching) 2.5

Clinical features

Mean score

2.0

Although the comparison of groups living in San Francisco (African-Americans, Asians, Euro-Americans, and Hispanics) gave the same prevalence of sensitive skin (52%), some differences (10) were observed for factors of skin reactivity and, to a lesser extent, its clinical symptoms. EuroAmericans were characterized by higher skin reactivity to the wind and tended to be less reactive to cosmetics. African-Americans presented less skin reactivity to most environmental factors and a lower frequency of recurring facial redness. Asians appeared to have greater skin reactivity to sudden changes in temperature, to the wind, and also to spicy foods. They tended to experience itching more frequently. In addition, the frequency of skin reactivity to alcoholic beverages was significantly lower in the African-

1.5 1.0 0.5 Sensitive skin (n = 88) Non-sensitive skin (n = 64)

0 0

10 5 Time (minutes)

Figure 3.1 Stinging, burning, and itching (SBI) score with capsaicin test on self-perceived sensitive skin and non-self-perceived sensitive skin subjects. Scores are significantly different at each experimental time (p < 0.01). (From [4] and [14].)

Table 3.2 (a) Stinging and itching scores with capsaicin test according to the different selfassessed level of self-perceived sensitive skin. (From [4].) Non-sensitive (n = 64)

Sensitive (n = 88)

Significance

Weak

Medium

Strong

(n = 42)

(n = 39)

(n = 7)

Stinging

2.6 ± 0.6

3 ± 0.6

4.3 ± 0.6

5 ± 0.6

p < 0.02

Itching

0.6 ± 0.4

1.6 ± 0.4

2 ± 0.4

2.9 ± 0.4

p < 0.02

3. Self-perceived sensitive skin

Table 3.2 (b) Stinging scores during lactic acid stinging test according to the different self-assessed level of self-perceived sensitive skin. (From [4].)

skin, suggesting a direct involvement of epidermal sensitive nerves in skin reactivity.

Specific brain activation on sensitive skin subjects Non-sensitive (n = 64)

2 ± 0.3

Sensitive (n = 88)

Significance

Weak

Medium

Strong

(n = 42)

(n = 39)

(n = 7)

2 ± 0.2

3.3 ± 0.3

3 ± 0.3

p < 0.001

p < 0.01

American and Hispanic sensitive groups and higher in the Asian group. In China, Yang et al. [21] have reported that sensitive skin was strongly reactive to environmental factors, but not to cosmetic use. A significantly higher prevalence (55.8%) of sensitive skin was found in Chengdu (Sichuan), where the food is very spicy. By studying the link between chili consumption and sensitive skin prevalence, it has been confirmed that sensitive skin was strongly linked to spicy food intake.

Physiologic mechanisms involved in selfperceived sensitive skin Barrier function and sensitive skin It is currently believed that sensitive skin is linked to the skin barrier alteration which could explain the increase in skin reactivity to physical or chemical factors. In fact, transepidermal water loss (TEWL) has been reported to be increased in subjects with sensitive skin [18]. In addition, an increase in TEWL has also been reported in the “lactic acid stingers” subjects [12]. The alteration of the skin barrier function is certainly involved in the physiology of some patterns of sensitive skin, but it is not unequivocal.

Epidermal sensitive nerves and sensitive skin In the last decade, additional evidence has been discovered implicating the key role for sensitive nerves in the physiologic mechanisms involved in sensitive skin. The neurosensorial signs of the pattern of capsaicin reactivity of sensitive skin suggest a neurogenic origin [14]. Recent data that emphasize the role of C-fibres in the itching process must also be considered [13]. It is observed that there is a decrease with age in the epidermal sensitive nerve density on the face [22]. It should also be noticed that there is a similar decrease in the facial skin reactivity to capsaicin and in the prevalence of sensitive

To investigate the possible involvement of the central nervous system (CNS) in SPSS patterns, we measured cerebral responses to cutaneous provocative tests in sensitive and in non-sensitive skin subjects using functional magnetic resonance imaging (fMRI) [23]. According to their responses to validated clinical questions about their skin reactivity, subjects were divided into two balanced groups: severe SPSS and non-SPSS subjects. Event-related fMRI was used to measure cerebral activation induced by split-face application of lactic acid and of its vehicle (control). In sensitive skin subjects, prefrontal and cingulate activity was significantly higher demonstrating a CNS involvement in sensitive skin physiologic pathways.

Conclusions Sensitive skin is a syndrome observed all over the world. The key clinical features of sensitive skin are neurosensorial signs, mainly provoked by climatic factors, or by topical applications usually well-tolerated on skin. The hypothesis of the neurogenic origin of sensitive skin is becoming more and more predominant. 1 Sensitive skin subjects demonstrate a significantly higher skin hyperreactivity to capsaicin which specifically stimulates the C-fibers. 2 With age, as sensitive skin is decreasing, facial sensitive epidermal nerve density is also decreasing. 3 Spicy food (rich in capsaicin) increases the prevalence of sensitive skin. 4 The results obtained with fMRI show that sensitive skin subjects demonstrate a specific pattern on cerebral activation, with a higher brain activity for sensitive skin subjects in prefrontal and cingulated areas.

References 1 Thiers H. (1986) Peau sensible. In: H. Thiers. Les Cosmétiques, 2nd edn. Paris: Masson, pp. 266–8. 2 Frosch PJ, Kligman AM. (1977) A method of appraising the stinging capacity of topically applied substances. J Soc Cosmet Chem 28, 197–209. 3 Maibach HI, Lammintausta K, Berardesca E, Freeman S. (1989) Tendancy to irritation: sensitive skin. J Am Acad Dermatol 21, 833–5. 4 De Lacharrière O. (2006) Sensitive skin: a neurological perspective. 24th IFSCC, Osaka, October 2006. 5 Francomano M, Bertoni L, Seidenari S. (2000) Sensitive skin as a subclinical expression of contact allergy to nickel sulfate. Contact Dermatitis 42, 169–70. 6 Fisher AA. (1990) Part I: “Status cosmeticus”: a cosmetic intolerance syndrome. Cutis 46, 109–11016.

BASIC CONCEPTS

Skin Physiology

7 De Lacharriere O, Jourdain R, Bastien P, Garrigue JL. (2001) Sensitive skin is not a subclinical expression of contact allergy. Contact Dermatitis 44, 131–2. 8 Willis CM, Shaw S, De Lacharriere O, Baverel M, Reiche L, Jourdain R, et al. (2001) Sensitive skin: an epidemiological study. Br J Dermatol 145, 258–63. 9 Jourdain R, De Lacharrière O, Shaw S, Reiche L, Willis C, Bastien P, et al. (2002) Does allergy to cosmetics explain sensitive skin? Ann Dermatol Venereol 129, 1S11–77. 10 Kligman AM. (1991) The invisible dermatoses. Arch Dermatol 127, 1375–82. 11 Frosch P, Kligman AM. (1996) An improved procedure for conducting lactic acid stinging test on facial skin. J Soc Cosmet Chem 47, 1–11. 12 Seidenari S, Francomano M, Mantovani L. (1998) Baseline biophysical parameters in subjects with sensitive skin. Contact Dermatitis 38, 311–5. 13 Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE. (1997) Specific C-receptors for itch in human skin. J Neurosci 17, 8003–8. 14 de Lacharrière O, Reiche L, Montastier C, et al. (1997) Skin reaction to capsaicin: a new way for the understanding of sensitive skin. Australas J Dermatol 38(Suppl 2), 288. 15 Magnusson BM, Koskinen LO. (1996) Effects of topical application of capsaicin to human skin: a comparison of effects evaluated by visual assessment, sensation registration, skin blood flow

18 19

and cutaneous impedance measurements. Acta Derm Venereol 76, 29–32. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–24. Johnson AW, Page DJ. (1995) Making sense of sensitive skin. Proceedings of the 18th IFSCC Congress, Yokohama, Japan 1995. Morizot F, Le Fur I, Tschachler E. (1998) Sensitive skin: definition, prevalence and possible causes. Cosm Toil 113, 59–66. Jourdain R, De Lacharriere O, Bastien P, Maibach HI. (2002) Ethnic variations in self-perceived sensitive skin: epidemiological survey. Contact Dermatitis 46, 162–9. Morizot F, Le Fur I, Numagami K, Guinot C, Lopez S, Tagami H, et al., eds. Self-reported sensitive skin: a study on 120 healthy Japanese women. 22nd IFSCC, Edinburgh, September 2002. Yang FZ, De Lacharriere O, Lian S, Yang ZL, Li L, Zhou W, et al. (2002) Sensitive skin: specific features in Chinese skin: a clinical study on 2,000 Chinese women. Ann Dermatol Venereol 129, 1S11–77. Besne I, Descombes C, Breton L. (2002) Effect of age and anatomical site on density innervation in human epidermis. Arch Dermatol 138, 1445–50. Querleux B, Dauchot K, Jourdain R, Bastien P, Bittoun J, Anton JL, et al. (2008) Neural basis of sensitive skin: an fRMI study. Skin Res Technol 1, 1–8.

Chapter 4: Pigmentation and skin of color Chesahna Kindred and Rebat M. Halder Howard University College of Medicine, Washington, DC, USA

BAS I C CONCEPTS • Differences in the structure, function, and physiology of the hair and skin in individuals of skin of color are important in understanding the structural and physiologic variations that exist and influence disease presentations. • Melanin, the major determinant of skin color, absorbs UV light and blocks free radical generation, protecting the skin from sun damage and aging. • UV irradiation of keratinocytes induces pigmentation by the upregulation of melanogenic enzymes, DNA damage that induces melanogenesis, increased melanosome transfer to keratinocytes, and increased melanocyte dendricity. • Racial differences in hair include the hair type, shape, and bulb.

Introduction The demographics of the USA reflect a dynamic mixture of people of various ethnic and racial groups. Currently, one in three residents in the USA is a person of skin of color [1]. Persons of skin of color include Africans, African-Americans, Afro-Caribbeans, Asians, Latinos (Hispanics), Native Americans, Middle Easterners, and Mediterraneans. The term “black” as in black skin refers to individuals with African ancestry, including Africans, African-Americans, and Afro-Caribbeans. Subgroups exist within each ethnoracial group. The differences in the structure, function, and physiology of the hair and skin in individuals of skin of color are important in understanding the structural and physiologic variations that exist and influence disease presentations. Pigmentation is especially important in patients of skin of color because pigmentary disorder is the most common reason for a visit to a dermatologist in this group [2].

Melanocytes Melanin, the major determinant of skin color, absorbs UV light and blocks free radical generation, protecting the skin from sun damage and aging. Melanocytes, the cells that produce melanin, synthesize melanin in special organelles, melanosomes. Melanin-filled melanosomes are transferred from one melanocyte to 30–35 adjacent keratinocytes in the basal layer [3]. The number of melanocytes also decreases with age. Cosmetic Dermatology: Products and Procedures. Edited by Z.D. Draelos. ©2010 Blackwell Publishing.

There is more than one type of melanin: eumelanin, a dark brown–black pigment; and pheomelanin, a yellow– reddish pigment. Eumelanin is deposited in ellipsoidal melanosomes which contain a fibrillar internal structure. Synthesis of eumelanin increases after UV exposure (tanning). Pheomelanin has a higher sulfur content than eumelanin because of the sulfur-containing amino acid cysteine. Pheomelanin is synthesized in spherical melanosomes and is associated with microvesicles [4]. Although not obvious to the naked eye, most melanin pigments of the hair, skin and, eyes are combinations of eumelanin and pheomelanin [5]. It is generally believed that genetics determine the constitutive levels of pheomelanin and eumelanin. Eumelanin is more important in determining the degree of pigmentation than pheomelanin. Eumelanin, and not pheomelanin, increases with visual pigmentation [5]. Lighter melanocytes have higher pheomelanin content than dark melanocytes. In one study [5], white persons had the least amount of eumelanin, Asian Indians had more, and AfricanAmericans had the highest. Of note, adult melanocytes contain significantly more pheomelanin than cultured neonatal melanocytes. Melanosomes also differ among different races. In black persons they are mostly in the basal layer, but those of white persons are mostly in the stratum corneum. This is evident in the site of UV filtration: the basal and spinous layers in blacks and the stratum corneum in white persons. Of note, the epidermis of black skin rarely shows atrophied areas [6]. In black skin, melanocytes contain more than 200 melanosomes. The melanosomes are 0.5–0.8 mm in diameter, do not have a limiting membrane, are stuck closely together, and are individually distributed throughout the epidermis. In white skin, the melanocytes contain less than 20 melanosomes. The melanosomes are 0.3–0.5 mm in

BASIC CONCEPTS

Skin Physiology

diameter, associated with a limiting membrane, and distributed in clusters with spaces between them. The melanosomes of lighter skin degrade faster than that of dark skin. As a result, there is less melanin content in the upper layers of the stratum corneum. Thus, the melanocytes in black skin are larger, more active in making melanin, and the melanosomes are packaged, distributed, and broken down differently from in white skin. There is also a difference in melanosomes between individuals within the same race but with varying degrees of pigmentation. Despite greater melanin content in darker skins, there is no evidence of major differences in the number of melanocytes [7]. Also, dark Caucasian skin resembles the melanosome distribution observed in black skin [8]. Black persons with dark skin have large, nonaggregated melanosomes and those with lighter skin have a combination of large non-aggregated and smaller aggregated melanosomes [9]. White persons with darker skin have non-aggregated melanosomes when exposed to sunlight and white persons with lighter skin have aggregated melanosomes when not exposed to sunlight [7,8,10]. The steps of melanogenesis are as follows. The enzyme tyrosinase hydroxylates tyrosine to dihydroxyphenylalanin (DOPA) and oxidizes DOPA to dopaquinone. Dopaquinone then undergoes one of two pathways. If dopaquinone binds to cysteine, the oxidation of cysteinyldopa produces pheomelanin. In the absence of cysteine, dopaquinone spontaneously converts to dopachrome. Dopachrome is then decarboxylated or tautomerized to eventually yield eumelanin. Melanosomal P-protein is involved in the acidification of the melanosome in melanogenesis [11]. Finally, the tyrosinase activity (not simply the amount of the tyrosinase protein) and cysteine concentration determine the eumelanin–pheomelanin content [5]. Tyrosinase and tyrosinase-related proteins 1 and 2 (TRP-1 and TRP-2) are upregulated when α-melanocyte-stimulating hormone (α-MSH) or adrenocorticotropin binds to melanocortin-1 receptor (MC1R), a transmembrane receptor located on melanocytes [11–14]. The MC1R loss-offunction mutation increases sensitivity to UV-induced DNA damage. Gene expression of tyrosinase is similar between black and white persons, but other related genes are expressed differently. The MSH cell surface receptor gene for melanosomal P-protein is expressed differently between races. This gene may regulate tyrosinase, TRP-1, and TRP-2 [5]. In addition to the MC1R, protease-activated receptor 2 (PAR-2) is another important receptor that regulates epidermal cells and affect pigmentation [15]. PAR-2 is expressed on many cells and several different organs. Accordingly, the receptor is involved in several physiologic processes, including growth and development, mitogenesis, injury responses, and cutaneous pigmentation. In the skin, PAR-2 is expressed

in the keratinocytes of the basal, spinous, and granular layers of the epidermis, endothelial cells, hair follicles, myeoepithelial cells of sweat glands, and dermal dendritic-like cells [16,17]. PAR-2 is a seven transmembrane domain G-protein-coupled receptor which undergoes activation via proteolytic cleavage of the NH2 terminus which acts as a tethered ligand which then activates the receptor (autoactivation). PAR-2 activating protease (PAR-2-AP), endothelial cellreleased trypsin, mast cell-released trypsin and chymase, and SLIGKV all irreversibly activate PAR-2 while serine protease inhibitors interferes with the activation of the receptor [18–20]. SLIGKV and trypsin activate PAR-2 to use a Rhodependent signaling pathway to induce melanosomal phagocytosis by keratinocytes. The result is an increase in pigmentation to the same degree as UV radiation [17–21]. Serine proteases are regulatory proteins involved in tumor growth, inflammation, tissue repair, and apoptosis in various tissues [17]. In the skin, serine protease inhibitors prevent the keratinocytes from phagocytosing melanosomes from the presenting dendritic tip of the melanocyte. This leads to a dose-dependent depigmentation without irritation or adverse events. PAR-2 also has a proinflammatory affect in the skin [17]. The activation of PAR-2 expressed on endothelial cells by tryptase, trypsin, or PAR-2-AP leads to an increase in proinflammatory cytokines interleukin 6 (IL-6) and IL-8 and also stimulates NF-κB, an intracellular proinflammatory regulator [18]. Mast cells interact with endothelial cells to regulate inflammatory responses, angiogenesis, and wound healing, and PAR-2 has a regulatory role in this cell–cell interaction [17,18]. UV irradiation of keratinocytes induces pigmentation in several ways: upregulation of melanogenic enzymes, DNA damage that induces melanogenesis, increased melanosome transfer to keratinocytes and increased melanocyte dendricity. UV radiation (UVR) increases the secretion of proteases by keratinocytes in a dose-dependent manner. Specifically, UVR directly increases the expression of PAR-2 de novo, upregulates proteases that activate PAR-2, and activates dermal mast cell degranulation [21]. Data on whether PAR-2 is expressed differently in skin of color compared to white skin are needed. One study did find differences in skin phototypes I, II, and III [21]. UVR increases the expression of PAR-2 in the skin and activated PAR-2 stimulates pigmentation. This study found that the response of PAR-2 to UVR is an important determinant of one’s ability to tan. In the non-irradiated skin, PAR-2 expression was confined to the basal layer and just above the basal layer. Irradiated skin showed de novo PAR-2 expression in the entire epidermis or upper twothirds of the epidermis. Skin phototype I had a delayed upregulation of PAR-2 expression compared to phototypes II and III.

4. Pigmentation and skin of color

Dyspigmentation After cutaneous trauma or inflammation, melanocytes can react with normal, increased, or decreased melanin production; all of which are normal biologic responses. Increased and decreased production results in postinflammatory hyperpigmentation or hypopigmentation. Postinflammatory hyperpigmentation (PIH) is an increase in melanin production and/or an abnormal distribution of melanin resulting from inflammatory cutaneous disorders or irritation from topical medications [22,23]. Examples include acne, allergic contact dermatitis, lichen planus, bullous pemphigoid, herpes zoster, and treatment with topical retinoids. Often, the PIH resulting from acne is more distressing to darker skinned individuals than the initial acute lesion. The color of the hyperpigmentation in PIH depends on the location of the melanin. Melanin in the epidermis appears brown, while melanin in the dermis appears blue-gray. Wood’s lamp examination distinguishes the location of the melanin: the epidermal component is enhanced and the dermal component becomes unapparent [24]. Postinflammatory hypopigmentation shares the same triggers as PIH but instead results from decreased melanin production with clinically apparent light areas [23]. The Wood’s lamp examination does not accentuate hypopigmentation in postinflammatory hypopigmentation; it is useful for depigmented disorders such as vitiligo and piebaldism. The pathogenesis of PIH and postinflammatory hypopigmentation are unknown. It is likely that an inflammatory process in the skin stimulates keratinocytes, melanocytes, and inflammatory cells to release cytokines and inflammatory mediators that lead to the hyperpigmentation or hypopigmentation. The cytokines and inflammatory mediators include leukotriene (LT), prostaglandins (PG), and thromboxane (TXB) [25]. Specifically for PIH, in vitro studies revealed that LT-C4, LT-D4, PG-E2, and TXB-2 stimulate human melanocyte enlargement and dendrocyte proliferation. LT-C4 also increases tyrosinase activity and mitogenic activity of melanocytes. Transforming growth factor-α and LT-C4 stimulate movement of melanocytes. In postinflammatory hypopigmentation, the pathogenesis likely involves inflammatory mediators inducing melanocyte cell-surface expression of intercellular adhesion molecule 1 (ICAM-1) which may lead to leukocyte–melanocyte attachments that inadvertently destroy melanocytes. These inflammatory mediators include interferon-gamma, tumor necrosis factor α (TNF-α), TNF-β, IL-6, and IL-7.

Natural sun protective factor in skin of color It is clear that those who fall within Fitzpatrick skin phototypes IV–VI are less susceptible to photoaging; this is most

likely due to of the photoprotective role of melanin [26,27]. The epidermis of black skin has a protective factor (PF) for UVB of 13.4 and that of white skin is 3.4 [28]. The mean UVB transmission by black epidermis is 5.7% compared to 29.4% for white epidermis. The PF for UVA in black epidermis is 5.7 and in white epidermis is 1.8 [28]. The mean UVA transmission by black epidermis is 17.5% and 55.5% for white epidermis. Hence, 3–4 times more UVA reaches the upper dermis of white persons than that of black persons. The main site of UV filtration in white skin is the stratum corneum, whereas in black skin it is the basal layer [28]. The malphigian layer of black skin removes twice as much UVB radiation as the stratum corneum [29]. It is possible that even greater removal of UVA occurs in black skin basal layers [29]. While the above characteristics of natural sun protective factor were studied in black skin, they can probably be extrapolated to most persons of skin photoypes IV–VI.

Skin of color Epidermis The epidermal layer of skin is made up of five different layers: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The stratum basale (also termed the basal layer) is the germinative layer of the epidermis. The time required for a cell to transition from the basal layer through the other epidermal layers to the stratum corneum is 24–40 days. The morphology and structure of the epidermis is very similar among different races, although a few differences do exist.

Stratum corneum The stratum corneum, the most superficial layer, is the layer responsible for preventing water loss and providing mechanical protection. The cells of the stratum corneum, the corneocytes, are flat cells measuring 50 μm across and 1 μm thick. The corneocytes are arranged in layers; the number of layers varies with anatomic site and race. There are no differences between races in corneocyte surface area, which has a mean size of 900 μm [2,30]. The stratum corneum of black skin is more compact than that of white skin. While the mean thickness of the stratum corneum is the same in black and white skin, black skin contains 20 cell layers while white skin contains 16. The answer to whether or not there are racial differences in spontaneous desquamation is inconclusive [29–31]. Parameters for skin barrier function (stratum corneum hydration, sebum secretion, erythema, and laser Doppler flowmetry) are similar, even after an objective epicutaneous test with sodium lauryl sulfate [32].

BASIC CONCEPTS

Skin Physiology

Transepidermal water loss Transepidermal water loss (TEWL) is the amount of water vapor loss from the skin, excluding sweat. TEWL increases with the temperature of the skin. Concrete evidence regarding the difference in TEWL between different races has yet to be established. Aside from TEWL, hydration is also a characteristic of skin. One of the ways to measure hydration, or water content, is conductance. Conductance, the opposite of resistance, is increased in hydrated skin because hydrated skin is more sensitive to the electrical field [33]. Skin conductance is higher in black persons and Hispanics than white persons [33]. Lipid content in black skin is higher than that of white skin [34]. However, black skin is more prone to dryness, suggesting that a difference in lipid content has a role. This includes the ratio of ceramide : cholesterol : fatty acids, the type of ceramides, and the type of sphingosine backbone. One study suggests that the degree of pigmentation influences lipid differences [35]. Pigmentation affects skin dryness. Skin dryness is greater on sun-exposed (dorsal arm) sites for lighter skin, such as Caucasian and Chinese skin, than sites that are primarily out of the sun (ventral arm) [36]. There is no difference in skin dryness between sites for darker skin, such as AfricanAmericans and Mexicans. For adults less than 51 years of age, skin dryness does not change as a function of ethnicity (African-American, Caucasian, Chinese, and Mexican) for sun-exposed sites and sites that are not primarily sunexposed. For those 51 years of age and older, skin dryness is higher for African-Americans and Caucasians than for Chinese and Mexicans. As a function of age, skin dryness in African-American skin increases 4% on the dorsal site and 3% on the ventral site; in Caucasian skin, it increases 11% on the dorsal site and 10% on the ventral site. All of the above findings suggest that sun exposure can dry the skin and that melanin provides protection.

Skin reactivity Mast cells Sueki et al. [37] studied the mast cells of four AfricanAmerican men and four white men (mean age 29 years) by evaluating punch biopsies of the buttocks with electron microscopy, with the following results. The mast cells of black skin contained larger granules (the authors attributed this to the fusion of granules). Black skin also had 15% more parallel-linear striations and 30% less curved lamellae in mast cells. Tryptase reactivity was localized preferentially over the parallel-linear striations and partially over the dark amorphous subregions within granules of mast cells from black skin, whereas it was confined to the peripheral area of granules, including curved lamellae, in white skin. Cathepsin G reactivity was more intense over the electrondense amorphous areas in both groups, while parallel-linear striations in black skin and curved lamellae in white skin were negative.

Patch test antigens Contact dermatit* Irritant contact dermatitis (ICD) is the most common form of dermatitis and loosely defined as non-specific damage to the skin after exposure to an irritant. The various clinical manifestations are influenced by the concentration of chemicals, duration of exposure, temperature, humidity, and anatomic location, and other factors. Acute contact dermatitis presents with the classic findings of localized superficial erythema, edema, and chemosis. Cumulative contact dermatitis presents with similar findings, but with repeated exposure of a less potent irritant [38]. The susceptibility to ICD differs between black and white skin [39]. The structural differences in stratum corneum of black skin (e.g. compact stratum corneum, low ceramide levels) are credited with decreasing the susceptibility to irritants. Reflectance confocal microscopy (RCM) is an imaging tool that permits real-time qualitative and quantitative study of human skin; when used with a near-infrared laser beam, one can create “virtual sections” of live tissue with high resolution, almost comparable with routine histology. Measuring skin reactivity to chemical irritants with RCM and TEWL reveal that white skin had more severe clinical reactions than black skin. The pigmentation in darker skin can make the assessment of erythema difficult and interfere with identification of subclinical degrees of irritancy. Even without clinical evidence of irritation, RCM and histology reveal parakeratosis, spongiosis, perivascular inflammatory infiltrate, and microvesicle formation. Mean TEWL after exposure to irritants is greater for white skin than for black skin. This supports the concept that the stratum corneum of black skin enhances barrier function and resistance to irritants. There are no differences between white persons and African-Americans in objective and subjective parameters of skin such as dryness, inflammation, overall irritation, burning, stinging, and itching [40]. Acute contact dermatitis with exudation, vesiculation, or frank bullae formation is a more common reaction in white skin whereas dyspigmentation and lichenification is more common in black skin [41]. The response to irritation in Caucasian and AfricanAmerican skin differs in the degree of severity. Caucasian skin has a lower threshold for cutaneous irritation than African-American skin [42]. Caucasian skin also has more severe stratum corneum disruption, parakeratosis, and detached corneocytes. Both groups have the same degree of intra-epidermal spongiosis epidermal (granular and spinous layer) vesicle formation. The variability in human skin irritation responses sometimes creates difficulty in assessing the differences in skin reactivity between human subpopulations. There are conflicting results in studies comparing the sensitivity to irritants in Asian skin with that in Caucasian skin [32,43–46].

4. Pigmentation and skin of color

Dermis The dermis lies deep to the epidermis and is divided into two layers: the papillary and reticular dermis. The papillary dermis is tightly connected to the epidermis via the basem*nt membrane at the dermoepidermal junction. The papillary dermis extends into the epidermis with finger-like projections, hence the name “papillary.” The reticular dermis is a relatively avascular, dense, collagenous structure that also contains elastic tissue and glycosaminoglycans. The dermis is made up of collagen fibers, elastic fibers, and an interfibrillar gel of glycosaminoglycans, salt, and water. Collagen makes up 77% of the fat-free dry weight of skin and provides tensile strength. Collagen types I, II, V, and VI are found in the dermis. The elastic fiber network is interwoven between the collagen bundles. There are differences between the dermis of white and black skin. The dermis of white skin is thinner and less compact than that of black skin [47]. In white skin, the papillary and reticular layers of the dermis are more distinct, contain larger collagen fiber bundles, and the fiber fragments are sparse. The dermis of black skin contains closely stacked, smaller collagen fiber bundles with a surrounding ground substance. The fiber fragments are more prominent in black skin than in white skin. While the quantity is similar in both black and white skin, the size of melanophages is larger in black skin. Also, the number of fibroblasts and lymphatic vessels are greater in black skin. The fibroblasts are larger, have more biosynthetic organelles, and are more multinucleated in black skin [6]. The lymphatic vessels are dilated and empty with surrounding elastic fibers [47]. No racial differences in the epidermal nerve fiber network have been observed using laser-scanning confocal microscopy, suggesting that there is no difference in sensory perception between races, as suggested by capsaicin response to C-fiber activation [48]. Skin extensibility is how stretchable the skin is. Elastic recovery is the time required for the skin to return to its

original state after releasing the stretched skin. Skin elasticity is elastic recovery divided by extensibility. Studies that investigated skin extensibility, elastic recovery, and skin elasticity between races yield conflicting results [31,49]. It is likely that elastic recovery and extensibility vary by anatomic site, race, and age.

Intrinsic skin aging in ethnic skin The majority of literature regarding facial aging features Caucasian patients. Facial aging is result of the combination of photodamage, fat atrophy, gravitational soft tissue redistribution, and bone remodeling. Figure 4.1 demonstrates the morphologic changes of the face caused by aging. The onset of morphologic aging appears in the upper face during the thirties and gradually progresses to the lower face and neck over the next several decades [50]. Early signs of facial aging occur in the periorbital region. In the late thirties, brow ptosis, upper eyelid skin laxity, and descent of the lateral portion of the eyebrow (“hooding”) lead to excess skin of the upper eyelids. During the midforties, “bags” under the eyes result from weakening of the inferior orbital septum and prolapse of the underlying intraorbital fat. Lower eyelid fat prolapse may occur as early as the second decade in those with a familial predisposition. Photodamage produces periocular and brow rhytides [50]. Brow ptosis in African-Americans appears to occur to a lesser degree and in the forties opposed to the thirties compared to that in whites [51]. Prolapse of the lacrimal gland may masquerade as lateral upper eyelid fullness in AfricanAmericans [52]. For Hispanics, the brow facial soft tissues sag at an earlier age [53]. In Asians, the descent of thick juxtabrow tissues in the lateral orbit coupled with the absences of a supratarsal fold may create a prematurely tired eye [50]. The midface show signs of aging during the forties. The malar soft tissue adjacent to the inferior orbital rim descends, accumulating as fullness along the nasolabial fold. The malar

Facial expression lines

Figure 4.1 Morphologic signs of aging. (Adapted from figure by Cindy Luu. From Harris MO. (2006) Intrinsic skin aging in pigmented races. In: Halder RM, ed. Dermatology and Dermatological Therapy of Pigmented Skins. Taylor & Francis Group, pp. 197–209.)

High brow

Low brow

Prominent upper eyelid crease

Excess upper eyelid skin

Full lips

Prominent fat pockets Lower lid hollowing ‘dark circles’ Low cheek Prominent nasolabial fold

Smooth jawline

Jowl

High protuberant cheek Soft nasolabial fold

Fat accumulation

BASIC CONCEPTS

Skin Physiology

soft tissue atrophy and ptosis result in periorbital hollowing and tear trough deformity. Early aging is evident in individuals of African, Asian, and Hispanic origin in the midface region more so than the upper or lower regions. Signs include tear trough deformity, infraorbital hollowing, malar fat ptosis, nasojugal groove prominence, and deepening of the nasolabial fold. This predisposition to midface aging is likely the result of the relationship of the eyes to the infraorbital rim, basic midface skeletal morphology, and skin thickness [50]. The soft tissue of the lower face is supported in a youthful anatomic position by a series of retaining ligaments within the superficial musculo-aponeurotic system (SMAS) [54]. The SMAS is a discrete fascial layer that envolps the face and forms the basis for resuspending sagging facial tissues [14]. The SMAS fascia envelope maintains tension on facial muscles and offsets soft tissue sagging. In the late thirties, gradual ptosis of the SMAS and skin elastosis sets the stage for jowl formation. Accumulation of submandibular fat and a sagging submandibular gland may have a role in interrupting the smooth contour of a youthful jaw line. Changes in the lower face lead to changes in the neck because the SMAS is anatomically continuous with the platysma muscle. Sagging of the SMAS–platysma unit and submandibular fat redistribution gradually blunts the junction between the jaw and neck. A “double chin” appears at any age as a result of cervicomental laxity with excess submental fat deposits. During the fifties, diastasis and hypertrophy of the anterior edge of the platysma muscle may produce vertical banding in the cervicomental area. During the sixth, seventh, and eighth decades, progressive soft tissue atrophy and bony remodeling of the maxilla and mandible create a relative excess of sagging skin, further exaggerating facial aging. Jowling is a sign of lower facial aging in black persons [50]. In some cases, a bony chin underprojection make create excess localized submental fatty deposits despite a smoothly contoured jaw line. However, in Asians, jowl formation may result from fat accumulation in the buccal space [50]. The “double chin” is more common in Caucasians under 40 years of age than Asians of the same age group, but more common in Asians over 40 years of age because of redundant cervical skin [55].

Extrinsic aging (photoaging) of ethnic skin Sunlight is a major factor for the appearance of premature aging, independent of facial wrinkling, skin color, and skin elasticity. By the late forties, individuals with greater sun exposure appear older than those with less sun exposure. However, the perceived age of individuals in their late twenties is unaffected by sun exposure. Solar exposure greatly increases the total wrinkle length by the late forties. The extent of dermal degenerative change seen by the late forties correlates with premature aging. There is a high correlation between perceived age and facial wrinkles; perceived age

and elastosis; and perceived age and the quantity of collagen. The grenz zone is a subepidermal band of normal dermis consisting of normal collagen fibers and thought to be a site of continual dermal repair. The grenz zone becomes visually apparent only after there is sufficient elastotic damage. With progressive elastosis, the grenz zone beomces thinner [56].

Histopathology Epidermis The absolute number of Langerhans cells vary from person to person but chronic sun exposure decreases their number or depletes them [57]. The severely sun-damaged skin has many vacuolated cells in the spinous layer, excessively vacuolated basal keratinocytes and melnanocytes, cellular atypia, and loss of cellular polarity. Apoptosis in the basal layer is increased. A faulty stratum lucidum and horny layer result from intracellur vesicles in the cells of the basal and spinous layers (sunburn cells), apoptosis, and dyskeratosis. There is focal necrobiosis in the epidermis and dermis in sun-exposed skin. While histologic findings of photoaging in white sunexposed skin include a distorted, swollen, and distinctly cellular stratum lucidum, the stratum lucidum of AfricanAmerican sun-exposed skin remains compact and unaltered [6]. The stratum lucidum in black skin is not altered by sunlight exposure [6]. With age, the dermoepidermal junction becomes flattened with multiple zones of basal lamina and anchoring fibril reduplication. Microfibrils in the papillary dermis become more irregularly oriented. Compact elastic fibers show cystic changes and separation of skeleton fibers with age. The area occupied by the superficial vascular plexus in specimens of equal epidermal surface length decreases from the infant to young adult (21–29 years) to adult (39–52 years) age groups, then increased in the elderly adult (73–75 years) age group [58]. With the exception of the vascularity in the elderly adult group, the above features are similar to those seen in aging white skin, and suggest that chronologic aging in white and black skin is similar. Oxytalan fibers are found in the papillary dermis of sun-exposed skin of white individuals in their twenties and early thirties but disappear in the forties. In black skin, the oxytalan fibers are still found in the dermis of individuals in their fifties. No solar elastosis is seen in specimens of black sun-exposed skin. Older black subjects have an increased number and thickness of elastic fibers that separate the collagenous fiber layer in the reticular dermis. The single-stranded elastic fibers in individuals <50 years of age resemble braids in those >50 years of age. Finally, the sun-exposed skin of a 45-year-old lightcomplexioned black female shared the same amount and distribution of elastic fibers as those in white sun-exposed skin [6]. The grenz zone consists of small fibers oriented horizontally and replaces the papillary dermis. When elastotic mate-

4. Pigmentation and skin of color rial accumulates in the dermis, it crowds out all the collagenous fibers, which are resorbed. As the elastic material is resorbed, wisps of collagenous fibers form in its place. Widely spaced, larger collagenous fiber bundles lie between the waning elastotic masses. The total volume of the dermis gradually diminishes as the spaces between the remaining collagenous and elastic fibers are reduced. When the epidermis rests directly on top of the horizontally oriented, medium-sized collagenous fiber bundles of the intermediate dermis, the dermis lacks a papillary and grenz zone and the dermis cannot sufficiently support the epidermis. As a result, the shrinking dermis crinkles and small wrinkles form. This may be the reason for the absence of a structural basis in secondary wrinkles and may explain why wrinkles flatten out when fluids are injected into the skin or when edema occurs [57]. Photoaging in skin of color has variable presentations. Wrinkling is not as common a manifestation of photoaging in black persons, South Asians, or darker complexioned Hispanics as in white persons because of the photoprotective effects of melanin. All racial groups are eventually subjected to photoaging. Within most racial groups, the lighter complexioned individuals show evidence of photodamaged skin. Caucasian skin has an earlier onset and greater skin wrinkling and sagging signs than darker skin types. Visual photoaging assessments reveal that white skin has more severe fine lines, rhytides, laxity, and overall photodamage than African-American skin [41]. Photoaging is uncommon in black persons but is more often seen in African-Americans than in Africans or AfroCaribbeans. The reason may be the heterogeneous mixture of African, Caucasian, and Native American ancestry often seen in African-Americans. In African-Americans, photoaging appears primarily in lighter complexioned individuals and may not be apparent until the late fifth or sixth decades of life [59]. Photoaging in this group appears as fine wrinkling and mottled pigmentation. In spite of the photoprotective effects of melanin, persons of skin of color are still prone to photoaging, but the reason is not completely known. Infrared radiation may also contribute to photodamage. There is evidence that chronic exposure to natural or artificial heat sources can lead to histologic changes resembling that of UV-induced changes, such as elastosis and carcinoma [60]. The pigmentary manifestations of photoaging common in skin of color include seborrheic keratoses, actinic lentigi-

nes, mottled hyperpigmentation, and solar-induced facial melasma [61]. However, African-American skin has greater dyspigmentation, with increased hyperpigmentation and uneveness of skin tone [40].

Hair There are two types of hair fibers: terminal and vellus. Terminal hair is found on the scalp and trunk. Vellus hair is fine and shorter and softer than terminal hair. The hair fiber grows from the epithelial follicle, which is an invagin*tion of the epidermis from which the hair shaft develops via mitotic activity and into which sebaceous glands open. The hair follicle is one of the most proliferative cell types in the body and undergoes growth cycles. The cycles include anagen (active growth), catagen (regression), and telogen (rest). Each follicle follows a growth pattern independent of the rest. The hair follicle is lined by a cellular inner and outer root sheath of epidermal origin and is invested with a fibrous sheath derived from the dermis. Each hair fiber is made up of an outer cortex and a central medulla. Enclosing the hair shaft is a layer of overlapping keratinized scales, the hair cuticle that serves as protective layers. Racial differences in hair include the hair type, shape, and bulb. There are four types of hair: helical, spiral, straight, and wavy. The spectrum of curliness is displayed in Figure 4.2. The vast majority of black persons have spiral hair [62]. The hair of black persons are naturally more brittle and more susceptible to breakage and spontaneous knotting than that of white persons. The kinky form of black hair, the weak intercellular cohesion between cortical cells, and the specific hair grooming practices among black persons account for the accentuation of these findings [62]. The shape of the hair is different between races: black hair has an elliptical shape, Asian hair is round-shaped straight hair, and Caucasian hair is intermediate [63,64]. The bulb determines the shape of the hair shaft, indicating a genetic difference in hair follicle structure [30]. The cross-section of black hair has a longer major axis, a flattened elliptical shape, and curved follicles. Asian hair has the largest cross-sectional area and Western European hair has the smallest [64,65]. Black persons have fewer elastic fibers anchoring the hair follicles to the dermis than white subjects. Melanosomes were in the outer root sheath and in the bulb of vellus hairs in black, but not in

Figure 4.2 The spectrum of curliness in human hair. (This figure was published in: Loussouarn G, Garcel A, Lozano I, Collaudin C, Porter Crystal, Panhard S, et al. (2007) Worldwide diversity of hair curliness: a new method of assessment. Int J Dermatol 46 (Suppl 1), 2–6.)

BASIC CONCEPTS

Skin Physiology is completely straight and the Caucasian hair form is intermediate [65]. Mesocortical, orthocortical, and paracortical cells are the three cell types in the hair cortex. In straight hair, mesocortical cells predominate [66]. In wavy hair, the orthocortical and mesocortical cells are interlaced around paracortical cells. In tightly curled hair, the mesocortex disappears, making orthocortical cells the majority. Distinct cortical cells express the acidic hair keratin hHa8. Figure 4.3 displays the distribution of hHa8 cells in straight, wavy, and tightly curled hair. Straight hair has a patchy but hom*oge-

white persons. Black hair also has more pigment and on microscopy has larger melanin granules than hair from light-skinned and Asian individuals. Similarities between white and black hair include: cuticle thickness, scale size and shape, and cortical cells [65]. While the curly nature of black hair is believed to result from the shape of the hair follicle [65], new research shows that the curliness of hair correlates with the distribution of cortical cells independent of ethnoracial origin [66]. Black hair follicles have a helical form, whereas the Asian follicle

(a)

(b)

(c)

Convex

(d)

Concave

(e)

Figure 4.3 hHa8 hair keratin distribution in hair follicles. hHa8 pattern in (a) straight, (b) wavy, and (c) curly hair longitudinal sections. hHa8 pattern in (d) straight and (e) curly hair cross-sections. (From Thibaut et al. (2007) Human hair keratin network and curvature. Int J Dermatol 46 (Suppl 1), 7–10.)

4. Pigmentation and skin of color nous pattern of positively charged hHa8 cells surrounding a core of negatively charged cells. As the degree of curl decreases, the hHa8 pattern becomes asymmetric, independent of ethnic origin. In tightly curled hair, hHa8 accumulates on the concave side of the hair fiber and the medulla compartment disappears. There are no differences in keratin types between hair from different races and no differences in amino acid composition of hair from different races [67]. Among Caucasian, Asian, and Africans, there are no differences in the intimate structures of fibers, whereas geometry, mechanical properties, and water swelling differed according to ethnic origin [68]. One study [69] in 1941 did find variation in the levels of some amino acids between black and white hair. Black subjects had significantly greater levels of tyrosine, phenylalanine, and ammonia in the hair, but were deficient in serine and threonine. The morphologic features of African hair were examined using the transmission and scanning electron microscopic (SEM) techniques in an unpublished study. The cuticle cells of African hair were compared with those of Caucasian hair. Two different electronic density layers were shown. The denser exocuticle is derived from the aggregation of protein granules that first appear when the scale cells leave the bulb region. The endocuticle is derived from the zone that contains the nucleus and cellular organites. The cuticle of Caucasian hair is usually 6–8 layers thick and constant in the hair perimeter, covering the entire length of each fiber. However, black hair has variable thickness; the ends of the minor axis of fibers are 6–8 layers thick, and the thickness diminishes to 1–2 layers at the ends of the major axis. The weakened endocuticle is subject to numerous fractures (Handjur C, Fiat, Huart M, Tang D, Leory F, unpublished data).

References 1 US Census Bureau. (2008) Older and More Diverse Nation by Midcentury. US Census Bureau News. August 14, 2008 online at: http://www.census.gov/Press-Release/www/releases/ archives/population/010048.html. Accessed November 12, 2008. 2 Halder RM, Nandedkar MA, Neal KW. (2003) Pigmentary disorders in ethnic skin. Dermatol Clin 21, 617–28. 3 Fitzpatrick TB, Szabo G. (1959) The melanocytes: cytology and cytochemistry. J Invest Dermatol 32, 197–209. 4 Jimbow K, Oikawa O, Sugiyama S, Takeuchi T. (1979) Comparison of eumelanogenesis and pheomelanogenesis in retinal and follicular melanocytes: role of vesiculo-globular bodies in melanosome differentiation. J Invest Dermatol 73, 278–84. 5 Wakamatsu K, Kavanagh R, Kadekaro AL, Terzieva S, Sturm RA, Leachman S, et al. (2006) Diversity of pigmentation in cultured human melanocytes is due to differences in the type as well as quantity of melanin. Pigment Cell Res 19, 154–62.

6 Montagna W, Carlisle K. (1991) The architecture of black and white facial skin. J Am Acad Dermatol 24, 929–37. 7 Taylor SC. (2002) Skin of color; biology, structure, function, implications for dermatologic disease. J Am Acad Dermatol 46, S41–62. 8 Toda K, Fatnak MK, Parrish A, Fitzpatrick TB. (1972) Alteration of racial differences in melanosome distribution in human epidermis after exporsure to ultraviolet light. Nat New Biol 236, 143–4. 9 Olson RL, Gaylor J, Evertt MA. (1973) Skin color, melanin, and erythema. Arch Dermatol 108, 541–4. 10 Jimbow M, Jimbow K. (1989) Pigmentary disorders in Oriental skin. Clin Dermatol 7, 11–27. 11 Abdel-Malek Z, Swope VB, Suzuki I, Akcali C, Harriger MD, Boyce ST, et al. (1995) Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci U S A 92, 1789–93. 12 Sturm RA, Teasdale RD, Box NF. (2001) Human pigmentation genes: identification, structure and consequences of pylymorphic variation. Gene 277, 49–62. 13 Rees JL. (2003) Genetics of hair and skin color. Annu Rev Genet 37, 67–90. 14 Suzuki I, Cone RD, Im S, Nordlund J, Abdel-Malek ZA. (1996) Binding of melanotropic hormones to the melanocortin receptor MC1R on human melanocytes stimulates proliferation and melanogenesis. Endocrinology 137, 1627–33. 15 Hou L, Kapas S, Cruchley AT, Macey MG, Harriott P, Chinni C, et al. (1998) Immunolocalization of protease-activated receptor-2 in skin: receptor activation stimulates interleukin-8 secretion by keratinocytes in vitro. Immunology 94, 356–62. 16 Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer Gisela, Skov PS, et al. (2003) Proteinase-activated receptor-1 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 23, 6176–80. 17 Shpacovitch VM, Brzoska T, Buddenkotte J, Stroh C, Sommerhoff CP, Ansel JC, et al. (2002) Agonists of proteinase-activated receptor 2 induce cytokine release and activation of nuclear transcription factor κB in human dermal microvascular endothelial cells. J Invest Dermtol 118, 380–5. 18 Seiberg M, Paine C, Sharlow E, Andrade-Gordon P, Constanzo M, Eisinger M, et al. (2000) Inhibition of melanosome transfer results in skin lightening. J Invest Dermatol 115, 162–7. 19 Nystedt S, Ramakrishnan V, Sundelin J. (1996) The proteinaseactivated receptor 2 is induced by inflammatory mediators in human endothelial cells: comparison with the thrombin receptor. J Biol Chem 271, 14910–5. 20 Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A, et al. (1996) Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 314, 1009–16. 21 Scott G, Deng A, Rodriguez-Burford C, Seiberg M, Han R, Babiarz L, et al. (2001) Protease-activated receptor 2, a receptor involved in melanosome transfer, is upregulated in human skin by ultraviolet irradiation. J Invest Dermatol 117, 1412–20. 22 Gilchrest BA. (1977) Localization of melanin pigmentation in skin with Wood’s lamp. Br J Dermatol 96, 245–7. 23 Morelli JG, Norris DA. (1993) Influence of inflammatory mediators and cytokines on human melanocyte function (Review). J Invest Dermatol 100 (2 Suppl), 191S–5S.

BASIC CONCEPTS

Skin Physiology

24 Grover R, Morgan BDG. (1996) Management of hypopigmentation following burn injury. Burns 22, 727–30. 25 Johnston GA, Svukabd KS, McLelland J. (1998) Melasma of the arms associated with hormone replacement therapy (letter). Br J Dermatol 139, 932. 26 Pathak MA, Fitzpatrick TB. (1974) The role of natural photoprotective agents in human skin. In: Fitzpatrick TB, Pathak MA, Harber LC, Seiji M, Kukita A, eds. Sunlight and Man. Tokyo: University of Tokyo Press, pp. 725–50. 27 Kligman AM. (1974) Solar elastosis in relation to pigmentation. In: Fitzpatrick TB, Pathak MA, Harber LC, Seiji M, Kukita A, eds. Sunlight and Man. Tokyo: University of Tokyo Press, pp. 157–63. 28 Kaidbey KH, Agin PP, Sayre RM, Kligman AM. (1979) Photoprotection by melanin: a comparison of black and Caucasian skin. J Am Acad Dermatol 1, 249–60. 29 Manuskiatti W, Schwindt DA, Maibach HI. (1998) Influence of age, anatomic site and race on skin roughness and scaliness. Dermatology 196, 401–7. 30 Courcuff P, Lotte C, Rougier A, Maibach HI. (1991) Racial differences in corneocytes: a comparison between black, white, and Oriental skin. Acta Dermatol Venereol 71, 146–8. 31 Warrier AG, Kligman AM, Harper RA, Bowman J, Wickett RR. (1996) A comparison of black and white skin using noninvasive methods. J Soc Cosmet Chem 47, 229–40. 32 Aramaki J, Kawana S, Effendy I, Happle R, Löffler H. (2002) Differences of skin irritation between Japanse and European women. Br J Dermatol 146, 1052–6. 33 Triebskorn A, Gloor M. (1993) Noninvasive methods for the determination of skin hydration. In: Forsch PJ, Kligman AM, eds. Noninvasive Methods for the Quantification of Skin Functions. Berlin; New York (NY): Springer-Verlag, pp. 42–55. 34 La Ruche G, Cesarini JP. (1992) Histology and physiology of black skin. Ann Dermatovenereologica 119, 567–74. 35 Reed JT, Ghadially R, Elias MM. (1995) Skin type but neither race nor gender, influence epidermal permeability barrier function. Arch Dermatol 131, 1134–8. 36 Diridollou S, de Rigal J, Querleux B, Leroy F, Holloway Barbosa V. (2007) Comparative study of the hydration of the stratum corneum between four ethnic groups: influence of age. Int J Dermatol 46 (Suppl 1), 11–4. 37 Sueki H, Whitaker-Menezes D, Kligman AM. (2001) Structural diversity of mast cell granules in black and white skin. Br J Dermatol 144, 85–93. 38 Modjtahedi SP, Maibach HI. (2002) Ethnicity as a possible endogenous factor in irritant contact dermatitis: comparing the irritant response amoung Caucasians, blacks, and Asians. Contact Dermatitis 47, 272–8. 39 Hicks SP, Swindells KJ, Middelkamp-Hup MA, Sifakis MA, González E, González S. (2003) Confocal histopathology of irritant contact dermatitis in vivo and the impact of skin color (black vs white). J Am Acad Dermatol 48, 727–34. 40 Grimes P, Edison BL, Green BA, Wildnauer RH. (2004) Evaluation of inherent differences between african american and white skin surface properties using subjective and objective measures. Cutis 73, 392–6. 41 Berardesca F, Maibach H. (1996) Racial differences in skin pathophysiology. J Am Acad Dermatol 34, 667–72.

42 Galindo, GR, Mayer JA, Slymen D, Almaguer DD, Clapp E, et al. (2007) Sun sensitivity in 5 US ethnoracial groups. Cutis 80, 25–30. 43 Robinson MK. (2002) Population differences in acute skin irritation responses. Race, sex, age, sensitive skin and repeart subject comparisons. Contact Dermatitis 46, 86–93. 44 Foy V, Weinkauf R, Whittle E, Basketter DA. (2001) Ethnic variation in the skin irritation response. Contact Dermatitis 45, 346–9. 45 Robinson MK. (2000) Racial differences in acute and cumulative skin irritation responses between Caucasian and Asian populations. Contact Dermatitis 42, 134–43. 46 Tadaki T, Watanabe M, Kumasaka K, Tanita Y, Kato T, Tagami H, et al. (1993) The effect of tretinoin on the photodamaged skin of the Japanese. Tohoku J Exp Med 169, 131–9. 47 Montagna W, Giusseppe P, Kenney JA. (1993) The structure of black skin. In: Montagna W, Giusseppe P, Kenney JA, eds. Black Skin Structure and Function. Academic Press, pp. 37–49. 48 Reilly DM, Ferdinando D, Johnston C, Shaw C, Buchanan KD, Green MR. (1997) The epidermal nerve fiber network: characterization of nerve fibers in human skin by confocal microscopy and assessment of racial variations. Br J Dermatol 137, 163–70. 49 Berardesca E, Rigal J, Leveque JL, et al. (1991) In vivo biophysical characterization of skin physiological differences in races. Dermatologica 182, 89–93. 50 Harris MO. (2006) Intrinsic skin aging in pigmented races. In: Halder RM, ed. Dermatology and Dermatological Therapy of Pigmented Skins. Taylor & Francis Group, pp. 197–209. 51 Matory WE. (1998) Aging in people of color. In: Matory WE, ed. Ethnic Considerations in Facial Aesthetic Surgery. Philadelphia: Lippincott-Raven, 151–70. 52 Bosniak SL, Zillkha MC. (1999) Cosmetic Blepharoplasty and Facial Rejuvenation. New York: Lippincott-Raven. 53 Ramirez OM. (1998) Facial surgery in the Hispano-American patient. In: Matory WE, ed. Ethnic Considerations in Facial Aesthetic Surgery. Philadelphia: Lippincott-Raven, pp. 307–20. 54 Stuzin JM, Baker TJ, Gordon HL. (1992) The relationship of the superficial and deep facial fascias: relevance to rhytidectomy and aging. Plast Reconstr Surg 89, 441–9. 55 Shirakable Y. (1988) The Oriental aging face: an evaluation of adecade of experience with the triangular SMAS flap technique. Aesthetic Plast Surg 12, 25–32. 56 Warren R, Garstein V, Kligman AM, Montagna W, Allendorf RA, Ridder GM. (1991) Age, sunlight, and facial skin: a histologic and quantitative study. J Am Acad Dermatol 25, 751–60. 57 Montagna W, Kirchner S, Carlisle K. (1989) Histology of sundamaged human skin. J Am Acad Dermatol 12, 907–18. 58 Herzberg AJ, Dinehart SM. (1989) Chronologic aging in black skin. Am J Dermatopathol 11, 319–28. 59 Halder RM. (1998) The role of retinoids in the management of cutaneous conditions in blacks. J Am Acad Dermatol 39 (Part 3), S98–103. 60 Kligman LH. (1982) Intensification of ultraviolet-induced dermal damage by infrared radiation. Arch Dermatol 272, 229–38. 61 Halder RM, Richards GM. (2006) Photoaging in pigmented skins. In: Halder RM, ed. Dermatology and Dermatological Therapy of Pigmented Skins. Taylor & Francis Group, pp. 211–20.

4. Pigmentation and skin of color 62 Halder RM. (1983) Hair and scalp disorders in blacks. Cutis 32, 378–80. 63 Bernard BA. (2003) Hair shape of curly hair. J Am Acad Dermatol 48 (6 Suppl), S120–6. 64 Vernall DO. (1961) Study of the size and shape of hair from four races of men. Am J Phys Anthropol 19, 345. 65 Brooks O, Lewis A. (1983) Treatment regimens for “styled” black hair. Cosmet Toiletries 98, 59–68. 66 Thibaut S, Barbarat P, Leroy F, Bernard BA. (2007) Human hair keratin network and curvature. Int J Dermatol 46 (Suppl 1), 7–10.

67 Gold RJ, Scriver CG. (1971) The amino acid composition of hair from different racial origins. Clin Chim Acta 33, 465–6. 68 Franbourg A, Hallegot P, Baltenneck F, Toutain C, Leroy F. (2003) Current research on ethnic hair. J Am Acad Dermatol 48 (6 Suppl), S115–9. 69 Menkart J, Wolfram L, Mao I. (1966) Causacian hair, Negro hair and wool: similarities and differences. J Soc Cosmet Chem 17, 769–87.

Chapter 5: Sensitive skin and the somatosensory system Francis McGlone1 and David Reilly2 1 2

Perception and Behaviour Group, Unilever Research & Development, Wirral, UK One Discover, Colworth Park, Sharnbrook, Bedford, UK

BAS I C CONCE P T S • The primary sensory modality subserving the body senses is collectively described as the somatosensory system, and comprises all those peripheral afferent nerve fibers, and specialized receptors, subserving cutaneous, and proprioceptive sensitivity. • Individuals with sensitive skin demonstrate heightened reactivity of the somatosensory system. • A separate set of neurons mediates itch and pain. The afferent neurons responsible for histamine-induced itch in humans are unmyelinated C-fibers. • Low threshold mechanoreceptors are responsible for the sensation of touch, a wide range of receptor systems code for temperature, and as the skin’s integrity is critical for survival, there are an even larger number of sensory receptors and nerves that warn us of damage to the skin – the pain and itch systems.

Introduction The primary sensory modality subserving the body senses is collectively described as the somatosensory system, and comprises all those peripheral afferent nerve fibers, and specialized receptors, subserving cutaneous and proprioceptive sensitivity. The latter processes information about limb position and muscle forces which the central nervous system uses to monitor and control limb movements and, via elegant feedback and feedforward mechanisms, ensure that a planned action or movement is executed fluently. This chapter focuses on sensory inputs arising from the skin surface – cutaneous sensibility – and describes the neurobiologic processes that enable the skin to “sense.” Skin sensations are multimodal and are classically described as sensing the three submodalities of touch, temperature, and pain. We also consider the growing evidence for a fourth submodality, present only in hairy skin, which is preferentially activated by slowly moving, low force, mechanical stimuli. This brief introduction to somatosensation starts with the discriminative touch system. Sensation enters the periphery via sensory axons that have their cell bodies sitting just outside the spinal cord in the dorsal root ganglia, with one ganglion for each spinal nerve root. Neurons are the building blocks of the nervous system and somatosensory neurons are unique in that, unlike most neurons, the electrical signal does not pass through the cell body but the cell body sits off to one side, without dendrites. The signal passes directly

from the distal axon process to the proximal process which enters the dorsal half of the spinal cord, and immediately turns up the spinal cord forming a white matter column, the dorsal columns, which relay information to the first brain relay nucleus in the medulla. These axons are called the primary afferents, because they are the same axons that carry the signal into the spinal cord. Sensory input from the face does not enter the spinal cord, but instead enters the brainstem via the trigeminal nerve (one of the cranial nerves). Just as with inputs from the body, there are three modalities of touch, temperature, and pain, with each modality having different receptors traveling along different tracts projecting to different targets in the brainstem. Once the pathways synapse in the brainstem, they join the pathways from the body on their way up to the thalamus and higher cortical structures. Sensory information arising from the skin is represented in the brain in the primary and secondary somatosensory cortex, where the contralateral body surfaces are mapped in each hemisphere.

Peripheral nervous system The skin is the most extensive and versatile organ of the body and in a fully grown adult covers a surface area approaching 2 m2. This surface is far more than a just a passive barrier. It contains in excess of 2 million sweat glands and 5 million hairs that may be either fine vellous types covering all surfaces, apart from the soles of the feet and the palms of the hands (glabrous skin), or over 100 000 of the coarser type found on the scalp. Evidence is also emerging that non-glabrous skin contains a system of nerves that code specifically for the pleasant properties of touch. Skin consists

5. Sensitive skin of an outer, waterproof, stratified squamous epithelium of ectodermal origin – the epidermis – plus an inner, thicker, supporting layer of connective tissue of mesodermal origin – the dermis. The thickness of this layer varies from 0.5 mm over the eyelid to >5.0 mm over the palm and sole of the foot.

Touch Of the three “classic” submodalities of the somatosensory system, discriminative touch subserves the perception of pressure, vibration, and texture and relies upon four different receptors in the digit skin: 1 Meissner corpuscles; 2 Pacinian corpuscles; 3 Merkel disks; and 4 Ruffini endings. These are collectively known as low threshold mechanoreceptors (LTMs), a class of cutaneous receptors that are specialized to transduce mechanical forces impinging the skin into nerve impulses. The first two are classified as fast adapting (FA) as they only respond to the initial and final contact of a mechanical stimulus on the skin, and the second two are classified as slowly adapting (SA) as they continue firing during a constant mechanical stimulus. A further classification relates to the LTM’s receptive field (RF; i.e. the surface area of skin to which they are sensitive). The RF is determined by the LTM’s anatomic location within the skin, with those near the surface at the dermal– epidermal boundary, Meissner corpuscles and Merkel disks, having small RFs, and those lying deeper within the dermis, Pacinian corpuscles and Ruffini endings, having large RFs (Figure 5.1).

Psychophysical procedures have been traditionally employed to study the sense of touch where differing frequencies of vibrotactile stimulation are used to quantify the response properties of this sensory system. Von Bekesy [1] was the first to use vibratory stimuli as an extension of his research interests in audition. In a typical experiment participants were asked to respond with a simple button-press when they could just detect the presence of a vibration presented to a digit, within one of two time periods. This two alternative force choice paradigm (2-AFC) provides a threshold-tuning curve, the slopes of which provide information about a particular class of LTM’s response properties. Bolanowski et al. [2] proposed that there are four distinct psychophysical channels mediating tactile perception in the glabrous skin of the hand. Each psychophysically determined channel is represented by one of the four anatomic end organs and nerve fiber subtypes, with frequencies in the 40–500 Hz range providing a sense of “vibration,” transmitted by Pacinian corpuscles (PC channel or FAI); Meissner corpuscles being responsible for the sense of “flutter” in the 2–40 Hz range (NPI channel or FAII); the sense of “pressure” being mediated by Merkel disks in the 0.4–2.0 Hz range (NPIII or SAI); and Ruffini end organs producing a “buzzing” sensation in the 100–500 Hz range (NPII or SAII). Neurophysiologic studies have, by and large, supported this model, but there is still some way to go to link the anatomy with perception (Table 5.1). There have been relatively few studies of tactile sensitivity on hairy skin, the cat being the animal of choice for most of these studies. Mechanoreceptive afferents (Aβ fibers) have been described that are analogous to those found in human

Table 5.1 Main characteristics of primary sensory afferents innervating human skin. Class

Modality

Axonal diameter (μm)

Conduction velocity (m s−1)

Aα

Proprioceptors from muscles and tendons

120

Aβ

Low threshold mechanoreceptors

Aδ

Cold, noxious, thermal

2.5

C-pain

Noxious, heat, thermal

C-tactile

Light stroking, gentle touch

C-tutonomic

Autonomic, sweat glands, vasculature

Myelinated

Unmyelinated

Stratum corneum Stratum lucldum Stratum granulosum Melanocyte Stratum splnosum Stratum granulosum Lamina basilaris Melssner’s corpuscle Merkel’s disks

Epidermis Cuticle Scarf skin Stratum mucosum

Pars papillris or Papillary dermis (loose connective tissue) Dermal nerve networks Ruffint endings

Dermis Cuticle True skin

Pars reticularis or Reticular dermis dense connective tissue) Pacinian corpuscles Stratum subsutaneum Tela subcutanea Muscle, ligament, or bone Eccrine gland

(a)

Halr shaft

Melanocyte Erector pilorum muscle

Sebaceous gland

Tactile pad Stratum corneum Stratum lucldum Stratum granulosum Stratum splnosum

Epidermis Cuticle Scarf skin

Stratum granulosum Lamina basilaris Blood vessels Pars papillris or Papillary dermis (loose connective tissue) Ruffint endings Dermal nerve networks

Hair follicle network

Apocrine gland

Blood vessels

Eccrine gland

Dermis Cuticle True skin

Pars reticularis or Reticular dermis dense connective tissue)

Pacinian corpuscles Stratum subsutaneum Tela subcutanea Muscle, ligament, or bone

(b) Figure 5.1 A cross-sectional perspective of (a) glabrous and (b) hairy skin. (This figure was published with permission of the artist, R.T. Verrillo.)

5. Sensitive skin glabrous skin (FAI, FAII, SAI, SAII), and Essick and Edin [3] have described sensory fibers with these properties in human facial skin. The relationship between these sensory fibers and tactile perception is still uncertain. Sensory axons are classified according to their degree of myelination, the fatty sheath that surrounds the nerve fiber. The degree of myelination determines the speed with which the axon can conduct nerve impulses and hence the nerves conduction velocity. The largest and fastest axons are called Aα and include some of the proprioceptive neurons, such as the muscle stretch receptors. The second largest group, called Aβ, includes all of the discriminative touch receptors being described here. Pain and temperature include the third and fourth groups, Aδ and C-fibers. Electrophysiologic studies on single peripheral nerve fibers innervating the human hand have provided a generally accepted model of touch that relates the four anatomically defined types of cutaneous or subcutaneous sense organs to their neural response patterns [4]. The technique they employed is called microneurograpahy and involves inserting a fine tungsten microelectrode, tip diameter <5 μm, through the skin of the wrist and into the underlying median nerve which innervates the thumb and first two digits (Figure 5.2).

Temperature The cutaneous somatosensory system detects changes in ambient temperature over an impressive range, initiated

when thermal stimuli that differ from a homeostatic setpoint excite temperature specific sensory nerves in the skin, and relay this information to the spinal cord and brain. It is important to recognize that these nerves code for temperature change, not absolute temperature, as a thermometer does. The system does not have specialized receptor end organs such as those found with LTMs but uses free nerve endings throughout skin to sense changes in temperature. Within the innocuous thermal sensing range there are two populations of thermosensory fibers, one that respond to warmth (warm receptors) and one that responds to cold (cold receptors), and include fibers from the Aδ and C range. Specific cutaneous cold and warm receptors have been defined as slowly conducting units that exhibit a steady-state discharge at constant skin temperature and a dynamic response to temperature changes [5,6]. Cold-specific and warm-specific receptors can be distinguished from nociceptors that respond to noxious low and high temperatures (<20 °C and >45 °C) [7,8], and also from thermosensitive mechanoreceptors [5,9]. Standard medical textbooks describe the cutaneous cold sense in humans as being mediated by myelinated A-fibers with CVs in the range 12–30 m s−1 [10], but recent work concludes that either human cold-specific afferent fibers are incompletely myelinated “BC” fibers, or else there are C as well as A cold fibers, with the C-fiber group contributing little to sensation (Figure 5.3) [11]. The free nerve endings for cold-sensitive or warmsensitive nerve fibers are located just beneath the skin

Adaptation Fast, no static responses

Slow, static response present

Edge sensitive

Small, sharp borders

FAI

(43%) Meissner

SAI

(25%) Merkel

Large, obscure borders

Regular

Innervation density

Receptive fields

Irregular

Sensitive to lateral skin stretch FAII

(13%) Pacini Golgi–Mazzoni

Figure 5.2 The four types of low threshold mechanoreceptors in human glabrous skin are depicted. The four panels in the center show the nerve firing responses to a ramp and hold indentation and the frequency of occurrence (%) and putative morphologic correlate. The black dots in the left panel show the receptive fields of type I (top) and type II (bottom)

SAII

(19%) Ruffini

afferents. The right panel shows the average density of type I (top) and type II (bottom) afferents with darker area depicting higher densities. (From Westling GK. (1986) Sensori-motor mechanisms during precision grip in man. Umea University medical dissertation. New Series 171, Umea, Sweden.)

BASIC CONCEPTS

Skin Physiology

35˚C 31˚C (a)

35˚C 31˚C (b) Figure 5.3 Resting discharge of a C cold fiber at room temperature [11]. (a) The resting discharge is suppressed by warming of the receptive field (RF) from 31 °C to 35 °C. (b) From a holding temperature of 35 °C, at which the unit is silent, activity is initiated by cooling the RF to 31 °C. (Time bar: 5 s.)

surface. The terminals of an individual temperature-sensitive fiber do not branch profusely or widely. Rather, the endings of each fiber form a small, discretely sensitive point, which is separate from the sensitive points of neighboring fibers. The total area of skin occupied by the receptor endings of a single temperature-sensitive nerve fiber is relatively small (approximately 1 mm in diameter), with the density of these thermosensitive points varying in different body regions. In most areas of the body there are 3–10 times as many cold-sensitive points as warm-sensitive points. It is well established from physiologic and psychologic testing that warm-sensitive and cold-sensitive fibers are distinctively different from one another in both structure and function.

Pain Here we consider a system of peripheral sensory nerves that innervate all cutaneous structures and whose sole purpose is to protect the skin against potential or actual damage. These primary afferents include Aδ and C-fibers which respond selectively and linearly to levels of thermal, mechanical, and chemical intensity/strength that are tissue-threatening. This encoding mechanism is termed nociception and describes the sensory process detecting any overt, or impending, tissue damage. The term pain describes the perception of irritation, stinging, burning, soreness, or painful sensations arising from the skin. It is important to recognize that the perception of pain not only depends on nociceptor input, but also on other processes and pathways giving information about emotional or contextual components. Pain is therefore described in terms of an “experience” rather than just a simple sensation. There are again submodalties within the

nociceptive system (Aδ and C) subserving nociception. Aδ fibers are thin (1–5 μm), poorly myelinated axons of mechanical nociceptors, thermal receptors, and mechanoreceptors with axon potential conduction velocities of approximately 12 m s−1. C-fibers are very thin (<1 μm) unmyelinated slowly conducting axons of <1 m s−1. Mechanical nociceptors are in the Aδ range and possess receptive fields distributed as 5–20 small sensitive spots over an area approximately 2–3 mm in diameter. In many cases activation of these spots depends upon stimuli intense enough to produce tissue damage, such as a pinprick. Aδ units with a short latency response to intense thermal stimulation in the range 40– 50 °C have been described as well as other units excited by heat after a long latency – usually with thresholds in excess of 50 °C. Over 50% of the unmyelinated axons (C-fibers) of a peripheral nerve respond, not only to intense mechanical stimulation, but also to heat and noxious chemicals, and are therefore classified as polymodal nociceptors [12] or C-mechano-heat (CMH) nociceptors [13]. Receptive fields consist of single zones with distinct borders and in this respect they differ from Aδ nociceptors that have multipoint fields. Innervation densities are high and responses have been reported to a number of irritant chemicals such as dilute acids, histamine, bradykinin, and capsaicin. Following inflammation some units can acquire responsiveness to stimuli to which they were previously unresponsive. Recruitment of these “silent nociceptors” implies spatial summation to the nociceptive afferent barrage at central levels, and may therefore contribute to primary hyperalgesia after chemical irritation and to secondary hyperalgesia as a consequence of central sensitization. Nociceptors do not show the kinds of adaptation response found with rapidly adapting LTMs (i.e. they fire continuously to tissue damage), but pain sensation may come and go and pain may be felt in the absence of any nociceptor discharge. They rely on chemical mediators around the nerve ending which are released from nerve terminals and skin cells in response to tissue damage. The axon terminals of nociceptive axons possess no specialized end organ structure and for that reason are referred to as free nerve endings. This absence of any encapsulation renders them sensitive to chemical agents, both intrinsic and extrinsic, and inflammatory mediators released at a site of injury can initiate or modulate activity in surrounding nociceptors over an area of several millimeters leading to two kinds of sensory responses termed hyperalgesia – the phenomenon of increased sensitivity of damaged areas to painful stimuli. Primary hyperalgesia occurs within the damaged area; secondary hyperalgesia occurs in undamaged tissues surrounding this area. One further sensation mediated by afferent C-fibers is that of itch. The sensation of itch has, in the past, been thought to be generated by the weak activation of pain nerves, but

5. Sensitive skin with the recent finding of primary afferent neurons in humans [14] and spinal projection neurons in cats [15], which have response properties that match those subjectively experienced after histamine application to the skin, it is now recognized that separate sets of neurons mediate itch and pain, and that the afferent neurons responsible for histamine-induced itch in humans are unmyelinated C-fibers. Until relatively recently it was thought that histamine was the final common mediator of itch, but clinical observations where itch can be induced mechanically, or is not found with an accompanying flare reaction, cannot be explained by histamine-sensitive pruriceptors leading to evidence for the existence of histamine-independent types of itch nerves [16] in which itch is generated without a flare reaction by cowhage spicules. As with the existence of multiple types of pain afferents, different classes of itch nerves are also likely to account for the various experiences of itch reported by patients [17].

bonding behaviors – pleasant touch [22]. If pain is elicited via sensory C- and Aδ-fibers then it is reasonable to speculate that the same system may be alternatively modulated to deliver a sensation of pleasure. A study employing the pan-neuronal marker PGP9.5 and confocal laser microscopy has identified a population of free nerve endings in the epidermis that may be the putative anatomic substrate for this submodality [23].

Sympathetic nerves Although this chapter deals with sensory aspects of skin innervation it is important to acknowledge the role of a class of efferent (motor) nerves that innervate various skin structures: (a) blood vessels; (b) cutaneous glands; and (c) unstriated muscle in the skin (e.g. the erectors of the hairs). In sensitive skin conditions, and some painful neuropathic states, sympathetic nerves have a role in exacerbating inflammation and irritation (for review see Roosterman et al. [24]).

Pleasure In recent years a growing body of evidence has been accumulating, from anatomic, psychophysical, electrophysiologic, and neuroimaging studies, that a further submodality of afferent, slowly conducting, unmyelinated C-fibers exists in human hairy skin that are neither nociceptive nor pruritic, but that respond preferentially to low force, slowly moving mechanical stimuli. These nerve fibers have been classified as C-tactile afferents (CT-afferents) and were first described by Nordin [18] and Johansson et al. [19]. Evidence of a more general distribution of CT-afferents have subsequently been found in the arm and the leg, but never in glabrous skin sites such as the palms of the hands or the soles of the feet [20]. It is well known that mechanoreceptive innervation of the skin of many mammals is subserved by A and C afferents but until the observations of Nordin and Vallbo C-mechanoreceptive afferents in human skin appeared to be lacking entirely. The functional role of CT-afferents is not fully known, but their neurophysiologic response properties, fiber class, and slow conduction velocities preclude their role in any rapid mechanical discriminative or cognitive tasks, and point to a more limbic function, particularly the emotional aspects of tactile perception [21]. However, the central neural identification of low-threshold C mechanoreceptors, responding specifically to light touch, and the assignment of a functional role in human skin has only recently been achieved. In a study on a unique patient lacking large myelinated Abfibers, it was discovered that activation of CT-afferents produced a faint sensation of pleasant touch, and functional neuroimaging showed activation in the insular cortex but no activation the primary sensory cortex, identifying CTafferents as a system for limbic touch that might underlie emotional, hormonal, and affiliative responses to skin–skin contacts between individuals engaged in grooming and

The central projections The submodalties of skin sensory receptors and nerves that convey information to the brain about mechanical, thermal, and painful stimulation of the skin are grouped into three different pathways in the spinal cord and project to different target areas in the brain. They differ in their receptors, pathways, and targets, and also in the level of decussation (crossing over) within the CNS. Most sensory systems en route to the cerebral cortex decussate at some point, as projections are mapped contralaterally. The discriminative touch system crosses in the medulla, where the spinal cord joins the brain, the pain system crosses at the point of entry into the spinal cord.

Spinal cord All the primary sensory neurons have their cell bodies situated outside the spinal cord in the dorsal root ganglion, there being one ganglion for every spinal nerve root. Tactile primary afferents, or first order neurons, immediately turn up the spinal cord towards the brain, ascending in the dorsal white matter and forming the dorsal columns. In a cross-section of the spinal cord at cervical levels, two separate tracts can be seen: the midline tracts comprise the gracile fasciculus conveying information from the lower half of the body (legs and trunk), and the outer tracts comprise the cuneate fasciculus conveying information from the upper half of the body (arms and trunk). At the medulla, situated at the top of spinal cord, the primary tactile afferents make their first synapse with second order neurons where fibers from each tract synapses in a nucleus of the same name – the gracile fasciculus axons synapse in the gracile nucleus, and the cuneate axons synapse in the cuneate

BASIC CONCEPTS

Skin Physiology

nucleus. The neurons receiving the synapse provide the secondary afferents and cross immediately to form a new tract on the contralateral side of the brainstem – the medial lemniscus – which ascends through the brainstem to the next relay station in the midbrain, the thalamus. As with the tactile system, pain and thermal primary afferents synapse ipsilaterally and then the secondary afferents cross, but the crossings occur at different levels. Pain and temperature afferents enter the dorsal horn of the spinal and synapse within one or two segments, forming the Lissauer tract as they do so. The dorsal horn is a radially laminar structure. The two types of pain fibers, C and Aδ, enter different layers of the dorsal horn. Aδ fibers enter the posterior marginalis and the nucleus proprius, and synapse on a second set of neurons. These are the secondary afferents which will relay the signal to the thalamus. The secondary afferents from both layers cross to the opposite side of the spinal cord and ascend in the spinothalamic tract. The C-fibers enter the substantia gelatinosa and synapse, but they do not synapse on secondary afferents. Instead they synapse on interneurons – neurons that do not project out of the immediate area but relay the signal to the secondary afferents in either the posterior marginalis or the nucleus proprius. The spinothalamic tract ascends the entire length of the cord and the entire brainstem and by the time it reaches the midbrain appears to be continuous with the medial lemniscus. These tracts enter the thalamus together. It is important to note that although the bulk of afferent input adheres to the plan outlined above there is a degree of mixing that goes on between the tracts. We have concentrated on somatosensory inputs from the body thus far, but as facial skin is often the source of sensitive reactions to topical applications, its peripheral and central anatomy and neurophysiology is briefly summarized here. The trigeminal nerve innervates all facial skin structures (including the oral mucosa) and, just as with the spinal afferents, these neurons have their cell bodies outside of the CNS in the trigeminal ganglion with their proximal processes entering the brainstem. Just as in the spinal cord, the three modalities of touch, temperature, and pain have different receptors in the facial skin, travel along different tracts, and have different targets in the brainstem – the trigeminal nucleus – a relatively large structure that extends from the midbrain to the medulla. The large diameter (Aβ) fibers enter directly into the main sensory nucleus of the trigeminal and, as with the somatosensory neurons of the body, synapse and then decussate, the secondary afferents joining the medial lemniscus as it projects to the thalamus. The small diameter fibers conveying pain and temperature enter midbrain with the main Vth cranial nerve, but then descend down the brainstem to the caudal medulla where they synapse and cross. These descending axons form a tract, the spinal tract of V, and

synapse in the spinal nucleus of V, so called because it reaches as far down as the upper cervical spinal cord. The spinal nucleus of V comprises three regions along its length: the subnucleus oralis, the subnucleus interpolaris, and the subnucleus caudalis. The secondary afferents from the subnucleus caudalis cross to the opposite side and join the spinothalamic tract where the somatosensory information from the face joins that from the body, entering the thalamus in a separate nucleus, the ventroposterior medial (VPM) nucleus.

Brain The third order thalamocortical afferents (from thalamus to cortex) travel up through the internal capsule to reach the primary somatosensory cortex, located in the post-central gyrus, a fold of cortex just posterior to the central sulcus (Figure 5.4a). The thalamocortical afferents convey all of the signals, whether from the ventroposterior lateral (VPL) or VPM nucleus, to primary somatosensory cortex where the sensory information from all body surfaces is mapped in a somatotopic (body-mapped) manner [25], with the legs represented medially, at the top of the head, and the face represented laterally (Figure 5.4b). Within the cortex there are thought to be eight separate areas primarily subserving somatosensation: primary somatosensory cortex, SI, comprised of four subregions (2, 1, 3a and 3b); secondary somatosensory cortex, SII, located along the superior bank of the lateral sulcus [26]; the insular cortex; and the posterior parietal cortex, areas 5 and 7b (Figure 5.5). As with studies of the peripheral nervous system, outlined above, the technique of microneurography has again been employed, in this case to study the relationship between skin sensory nerves and their central projections, as evidenced by the use of concurrent functional magnetic resonance imaging (fMRI). Microstimulation of individual LTM afferents, projecting to RFs on the digit, produces robust, focal, and orderly (somatotopic) hemodynamic (BOLD) responses in both primary and secondary somatosensory cortices [27]. It is expected that this technique will permit the study of many different topics in somatosensory neurophysiology, such as sampling from FA and SA mechanoreceptors and C-fibers with neighboring or overlapping RFs on the skin, quantifying their spatial and temporal profiles in response to electrical chemical and/or mechanical stimulation of the skin areas they innervate, as well as perceptual responses to microstimulation. Finally, the forward projections from these primary somatosensory areas to limbic and prefrontal structures has been studied with fMRI in order to understand the affective representations of skin stimulation for both pain and pleasure [28] and it is hoped that studies of this nature will help us to understand better the emotional aspects of both negative and positive skin sensations.

Leg Arm

Face

Thalamus

Cortex Medulla

Spinal cord

(a)

W H rist Li and Rin ttle Mi g Ind ddle ex Thu mb Eye No Fa se ce Up per lip Lips

Somatosensory cortex of left hemisphere of brain

Dorsal column nucleus

Lower lip Teeth, gums and

Cell body of sensory nerve

Tongue ynx al Phar min bdo a a Intr

Finger of right hand

Primary afferent fiber

Midline

arm Fore Elbow Arm Shoulders Head k Nec k Trun Hip

5. Sensitive skin

Leg Foot Toes Genitals

jaw

(b)

Figure 5.4 (a) Outline of the somatosensory pathways from the digit tip to primary somatosensory cortex, via the dorsal column nuclei and the thalamus. (b) Penfield’s somatosensory homunculus. Note the relative overrepresentation of the hands and lips, and the relative underrepresentation of the trunk and arms.

Conclusions Central sulcus Intraparietal sulcus

7 3,1,2

Lateral sulcus Figure 5.5 Cortical areas subserving somatosensation. Primary somatosensory cortex is located in the posterior bank of the central sulcus and the posterior gyrus and comprises areas 2, 1, 3a and 3b, secondary somatosensory cortex is located in the upper bank of the lateral sulcus with two further somatosensory regions in the posterior parietal cortex, areas 5 and 7b.

In this chapter we describe the neural architecture of the skin senses, where it has been shown that the skin surfaces we groom when applying cosmetic agents are receptive to a wide variety of physicochemical forms of stimulation. Low threshold mechanoreceptors are responsible for the sensation of touch, a wide range of receptor systems code for temperature, and, as the skin’s integrity is critical for survival, there are an even larger number of sensory receptors and nerves that warn us of damage to the skin – the pain and itch systems. In addition to this “classic” description of the skin senses, we also provide recent evidence for the existence of another skin receptor system which shares many of the same characteristics as the pain system with one important distinction – this system of sensory nerves is excited by low force, slowly moving tactile stimulation – such as that employed when grooming the body surfaces. This C-fiber-based system of peripheral cutaneous sensory nerves is therefore serving both a protective and hedonic role in body grooming behaviors.

BASIC CONCEPTS

Skin Physiology

References 1 von Bekesy G. (1939) Uber die Vibrationsempfindung. [On the vibration sense.] Akust Z 4, 315–34. 2 Bolanowski SJ, Gescheider GA, Verrillo RT, Checkosky CM. (1988) Four channels mediate the mechanical aspects of touch. J Acoust Soc Am 84, 1680–94. 3 Essick GK, Edin BB. (1995) Receptor encoding of moving tactile stimuli in humans: the mean response of individual lowthreshold mechanoreceptors to motion across the receptive field. J Neurosci 15, 848–64. 4 Valbo AB, Johansson RS. (1978) The tactile sensory innervation of the glabrous skin of the human hand. In: Gordon G, ed. Active Touch. New York: Pergammon, pp. 29–54. 5 Hensel H, Boman KKA. (1960) Afferent impulses in cutaneous sensory nerves in human subjects. J Neurophysiol 23, 564–78. 6 Hensel H. (1973) Cutaneous thermoreceptors. In: Iggo A, ed. Somatosensory System. Berlin: Springer-Verlag, pp. 79–110. 7 Torebjörk H. (1976) A new method for classification of C-unit activity in intact human skin nerves. In: Bonica JJ, Albe-Fessard D, eds. Advances in Pain Research and Therapy. New York: Raven, pp. 29–34. 8 Campero M, Serra J, Ochoa, JL. (1966) C-polymodal nociceptors activated by noxious low temperature in human skin. J Physiol 497, 565–72. 9 Konietzny F. (1984) Peripheral neural correlates of temperature sensations in man. Hum Neurobiol 3, 21–32. 10 Darian-Smith I. (1984) Thermal sensibility. In: Darian-Smith I, ed. Handbook of Physiology, Vol. 3, Sensory Processes. Bethesda, MD: American Physiological Society, pp. 879–913. 11 Campero M, Serra J, Bostock H, Ochoa JL. (2001) Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol 535, 855–65. 12 Bessou M, Perl ER. (1969) Response of cutaneous sensory units with unmyelinated fibres to noxious stimuli. J Neurophysiol 32, 1025–43. 13 Campbell JN, Raja SN, Cohen RH, Manning DC, Khan AA, Meyer RA. (1989) Peripheral neural mechanisms of nociception. In: Wall PD, Melzack R. eds. Textbook of Pain. Edinburgh: Churchill Livingstone, pp. 22–45. 14 Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE. (1997) Specific C-receptors for itch in human skin. J Neurosci 17, 8003–8. 15 Andrew D, Craig AD. (2001) Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4, 72–7.

16 Ikoma A, Handwerker H, Miyachi Y, Schmelz M. (2005) Electrically evoked itch in humans. Pain 113, 148–54. 17 Yosipovitch G, Goon ATJ, Wee J, Chan YH, Zucker I, Goh CL. (2002) Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int J Dermatol 41, 212–6. 18 Nordin M. (1990) Low threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibres in the human supraorbital nerve. J Physiol 426, 229–40. 19 Johansson RS, Trulsson M, Olsson KA, Westberg KG. (1988) Mechanoreceptor activity from the human face and oral mucosa. Exp Brain Res 72, 204–8. 20 Valbo AB, Hagbarth K-E, Torebjork HE, Wallin BG. (1979) Somatosensory, proprioceptive and sympathetic activity in human peripheral nerves. Physiol Rev 59, 919–57. 21 Essick G, James A, McGlone FP. (1999) Psychophysical assessment of the affective components of non-painful touch. Neuroreport 10, 2083–7. 22 Olausson H, Lamarre Y, Backlund H, Morin C, Wallin BG, Starck S, et al. (2002) Unmyelinated tactile afferents signal touch and project to the insular cortex. Nat Neurosci 5, 900–4. 23 Reilly DM, Ferdinando D, Johnston C, Shaw C, Buchanan KD, Green M. (1997) The epidermal nerve fibre network: characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations. Br J Dermatol 137, 163–70. 24 Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. (2006) Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev 86, 1309–79. 25 Maldjian JA, Gotschalk A, Patel RS, Detre, JA, Alsop DC. (1999) The sensory somatotopic map of the human hand demonstrated at 4T. Neuroimage 10, 55–62. 26 Maeda K, Kakigi R, Hoshiyama M, Koyama S. (1999) Topography of the secondary somatosensory cortex in humans: a magentoencephalographic study. Neuroreport 10, 301–6. 27 Trulsson M, Francis ST, Kelly EF, Westling G, Bowtell R, McGlone FP. (2001) Cortical responses to single mechanoreceptive afferent microstimulation revealed with fMRI. Neuroimage 13, 613–22. 28 Rolls E, O’Doherty J, Kringelbach M, Francis S, Bowtell R, McGlone F. (2003) Representation of pleasant and painful touch in the human orbitofrontal cortex. Cereb Cortex 10, 284–94.

Chapter 6: Novel, compelling, non-invasive techniques for evaluating cosmetic products Thomas J. Stephens,1 Christian Oresajo,2 Robert Goodman,1 Margarita Yatskayer,2 and Paul Kavanaugh1 1 2

Thomas J. Stephens & Associates Inc., Dallas Research Center, Carrollton, TX, USA L’Oréal Research USA, Clark, NJ, USA

BAS I C CONCEPTS • Skin care products must be studied for safety and efficacy. • Non-invasive techniques were developed to assess the skin without a biopsy. • Non-invasive techniques are used to evaluate visual appearance, moisturization, barrier integrity, oiliness, elasticity, firmness, erythema, and skin color. • New photography techniques have been developed to detect changes in wrinkling of the face.

Introduction Clinical trials for substantiation of cosmetic claims should be designed with good scientific rigor. In 1999, Rizer et al. [1] described an integrated, multidimensional approach for achieving this goal. The multistep process consisted of the following: careful subject selection, subject self-assessment of product performance, clinical grading, documentation photography, non-invasive bioengineering methods, and statistical analysis. Recently, the use of digital photography combined with image analysis has provided clinical investigators with a powerful new tool for quantifying improvements in wrinkles, hyperpigmentation, pore size, skin tone, and other dermatologic conditions. Unlike past years, in which photographs of subjects were used solely to document clinical changes, use of photographs of subjects has moved beyond simple study documentation. This chapter introduces dermatologists, cosmetic surgeons, and clinical researchers to the cost-effective, non-invasive methods for substantiating cosmetic claims. It includes an overview of commonly used, non-invasive methods in cosmetic studies and a description of various types of highresolution digital photography and their application for evaluating changes in skin.

Supporting cosmetic claims with bio-instrumentation Most scientists would agree that the use of non-invasive methods is an objective way for generating quantitative data about a product’s performance on skin. Does this mean that data from non-invasive instruments provide conclusive evidence to support a cosmetic claim? Consider a topical lotion formulated to improve the appearance of facial wrinkles and moisturize skin. Now imagine that it is your responsibility to substantiate these claims in a clinical study using available non-invasive methods. Undoubtedly, you would choose proven methods such as replica profilometry to assess wrinkle changes and the Skicon™ (IBS Ltd., Tokyo, Japan) or Corneometer® (Courage & Khazaka Electronic GmbH, Köln, Germany) to assess changes in skin hydration. Would favorable data from both of these techniques provide conclusive evidence to support the claims? The answer may surprise you. In many cases, non-invasive methods are more useful in providing indirect lines of evidence to support a cosmetic claim. In clinical research this is called a secondary endpoint. A primary endpoint refers to the most meaningful result in a clinical trial. In the example above, the primary endpoints would be a visible improvement in the appearance of wrinkles and reduction in the signs and symptoms of dry skin while the secondary endpoints would be improvements in wrinkle depth and high skin hydration values. The fact that many non-invasive methods are secondary endpoints does not diminish their importance in clinical research. Non-invasive methods often provide valuable information about the mechanism of action of a cosmetic

BASIC CONCEPTS

Skin Physiology

ingredient or cosmetic product on skin and a more reliable method to quantify improvements in skin. The use of colorimetry, a combination of digital photography and image analysis, is a much better method to quantify changes in skin erythema than by clinical examination, even though the human eye is very sensitive to color shifts. This technique is more fully described at the end of this chapter.

Commonly used non-invasive methods in cosmetic studies Approximately 90% or more of the cosmetic studies performed today are designed to support claims relating to improvements of fine lines or wrinkles, uneven skin pigmentation associated with sun exposure and/or hormonal changes, enlarged pores, skin radiance, skin roughness, skin tone, and skin dryness. Table 6.1 provides a listing of commonly used, non-invasive techniques that are used to help support these specific claims. For the reader who would like to learn more about these techniques or other non-invasive methods, there are a number of excellent books and articles available in the chapter’s reference list [2–8]. Ideally, an investigator would like to see agreement between the clinical grading, non-invasive bio-instrumentation measurements and subject self-perception questionnaires. Occasionally, investigators obtain good concordance between clinical grading and self-perception questionnaires, but discordance with the non-invasive technique.

Table 6.1 Commonly used bio-instruments and non-invasive procedures. Name

Use

NOVA Meter

Moisturization

SKICON

Moisturization

Corneometer

Moisturization

TEWA Meter

Skin barrier function assessment

Derma Lab

Skin barrier function assessment

Cutometer

Firmness and elasticity

ChromaMeter

Skin tone, erythema, skin lightening, brightness

Mexameter

Skin tone, erythema, skin lightening

Sebumeter

Oiliness (sebum)

Sebutapes

Oiliness

D-Squames

Scaling, exfoliation, and cell renewal

Silicone Replica Impressions

Skin texture, wrinkling

Let us return to the example of the topical product designed to improve the appearance of wrinkles. It is not uncommon to see visible improvements in wrinkles during clinical grading while failing to detect the improvements using silicone replica profilometry. The discordance is not a result of grader error, but of limitation of the replica impressions to fully detect changes over the entire periocular area. Replica impressions are usually taken by spreading the unpolymerized replica material a few millimeters from the corner of the eye with the subject’s eyes closed. This is necessary in order to prevent the replica material from running into the eye itself. If the grader makes his or her judgment based on the appearance of wrinkling in the areas adjacent to the corner of the eye as well as the area under the eye with the subject’s eyes open, there is chance the grader might see improvements in wrinkling that might not be detected by the replica impression. Additionally, having the eyes closed while the impression is being taken can occasionally result in situations in which the subject squints, resulting in deeper, more pronounced wrinkles. The end result is a replica impression that detects more or deeper wrinkles. An alternative method, Raking Light Optical Profilometry (RLOP), which provides a newer, more novel approach for analyzing changes in wrinkling, is discussed below. The advantage of this technique is that the subject’s eyes are open and the wrinkling appears in the same way as viewed by the clinical grader.

Application of digital photography as a non-invasive technique for assessing skin The challenge for clinical documentation photography is twofold: to choose the best photographic technique relative to the aims of the study and to maximize consistency of the imaging at each clinic visit throughout the trial. The key to successful photography in clinical trials is the application of standardization, which includes the control subject’s positioning, dress, lighting conditions, depth of field, background, and facial expression from visit to visit. The goal is to have images that accurately show treatment effects for use in medical and scientific journals. There is no place for misrepresenting clinical outcomes by changing viewing angles, altering lighting conditions, or having the subject apply facial makeup after using a product [9,10]. The first step to successful photography is to create the appropriate lighting and other photographic techniques specific to the skin conditions of interest in the clinical study. A study involving a product designed to reduce the appearance of fine lines and wrinkles demands significantly different lighting than would trials involving acne, photodamaged skin, skin dryness or flakiness, scars, wound healing, postinflammatory hyperpigmentation (PIH), or pseudofolliculitis

6. Evaluating cosmetic products barbae. In order to ensure a high degree of color consistency in photographic technique, the photographer should include color standard chips in each documentation image. Typically, these standards include small reference chips of white, 18% reflectance gray, black, red, green, and blue, as well as a millimeter scale for size confirmation. In addition, a more comprehensive color chart such as a ColorChecker® (X-Rite America Inc., Grand Rapids, MI, USA) should be photographed under the exact standard lighting immediately before starting each photo visit. Equally crucial is the careful and detailed recording of all aspects of lighting, camera, and lens settings in order to achieve maximum consistency of documentation photographs. Photographing each different photographic set-up provides more certainty that photographs at subsequent sessions are identical to the images made at baseline visit. Prior to photography, all makeup and jewelry must be removed, and hair kept clear of the subject’s face by use of a neutral-color headband. Clothing should be covered by a gray or black cloth drape to prevent errors caused by color reflected from colored clothing. At each subsequent visit in the study, it is necessary to display the baseline image on the computer monitor for side-by-side comparison with that visit’s photograph. Subject position, size, color, and lighting can thus be checked to make sure that changes in the skin are brought about by product effect, and are not artifacts caused by careless photographic technique. When the study is over, the sequence of images should look similar to a time-lapse video, with the only difference from one image to another being changes in the condition of the subject’s skin. At Stephens & Associates, Inc. we have

designed fully equipped photographic studios within our clinics so that subjects can be photographed under standardized conditions from visit to visit (Figure 6.1). These studios are manned by experienced medical photographers who have been trained in the basic science of conducting a clinical trial. While it is not possible for many clinics to have fully equipped studios with medical photographers in their office, there are other off-the-shelf alternatives which will allow them to control the quality of the images in clinical research. The VISIA, VISIA CR and VISIA CR2 are standardized camera systems that have been designed for use in clinical research. VISIA systems can be operated by individuals with little to no experience in photography. VISIA systems are composed of an oval-shaped plastic shell containing a digital camera and lighting system. Subject positioning is controlled by forehead and chin rests. VISIA contains proprietary software called VISIA Complexion Analysis Software System. The VISIA software system, developed by Procter and Gamble, counts the number of spots, pores, wrinkles, porphyrins, UV spots, red areas, and brown areas on the face of subjects. The VISIA CR® (Canfield Scientific Inc., Fairfield, NJ, USA) system has an advantage over the VISIA system in that quality of the images are usually better, because the VISIA CR system is equipped with higher resolution cameras than the standard or first generation VISIA system. At the time of writing, the Complexion Analysis Software (Figure 6.2) is not available on the VISIA CR or VISIA CR 2. A simpler software, using the Canfield RBx system, is currently compatible with the VISIA CR machines. Images taken with either system must be exported from the

Figure 6.1 An example of a Stephens & Associates, Inc. photographic studio. The studio is equipped for taking photographs using standard lighting, parallel and polarized lighting, cross polarized lighting and raking light.

Figure 6.2 An example of the data reporting for the VISIA Complexion Analysis Software.

BASIC CONCEPTS

Skin Physiology

camera for more detailed image analysis of spots, lines, wrinkles, pores, and color changes. VISIA systems, while easy to use, have limitations in certain situations. The chin and head rests are sometimes too small for individuals with large faces, resulting in “jammed in” appearance. Additionally, it is difficult to see skin details such as acne lesions or PIH marks on images taken of subjects with Fitzpatrick skin types V and VI because of the close proximity of the subject’s face to the camera and lighting system. Unlike viewing software provided by Nikon and Canon, VISIA does not allow images to be displayed from previous treatment visits and the baseline visit for a side-by-side image comparison. Therefore, it is difficult to make sure the head position and facial expressions are the same in all photographs.

Review of terminology in clinical photography Individuals incorporating digital photography into a clinical trial are often faced with the difficult task of understating the vocabulary used by staff at clinical research organizations (CROs). This section provides a concise description of commonly used terms and techniques in clinical photography.

Visible light photography This refers to images made with unfiltered full-spectrum (white) light. It is the most common type of photography used in clinical trials. Proper positioning of the strobe flashes is a critical step for capturing various skin conditions in cosmetic clinical trials. Clinical studies involving evenness of color and skin tone require a more generalized, evenly distributed, visible lighting method while the imaging of fine lines, wrinkles, under eye bags, skin texture, and scaling is best achieved by placing the flashes in an off-axis direction. Off-axis lighting refers to lighting that is placed somewhat above and to the side to create small shadows and highlights on the skin thereby giving a three-dimensional quality to the image. Once the lighting conditions have been optimized, it is imperative that the photographer use documentation notes, setup photographs, light metering and color charts to prevent lighting changes from visit to visit.

Polarized photography This involves the placement of linear polarizing filters on both the lighting flash head(s) and in front of the lens of the digital camera. This allows the documentation of skin in two different ways [11]. The parallel-polarized lighting technique accentuates the reflection of light from the skin and tends to obscure fine

topical detail because of strong reflections from the lighting source(s). Parallel-polarized light minimizes subsurface details, such as erythema and pigmentation, while allowing for enhanced viewing of the surface features of the skin, such as sweat, oily skin, and pores. The cross-polarized lighting technique involves fixing the transmission axis of the lens polarizer 90 ° to the axis of the lighting polarizer. This virtually eliminates the reflection of light (glare) from the surface of the skin and accentuates the appearance of inflammation from acne lesions, erythema, rosacea, and telangiectasia. Photodamaged skin becomes somewhat more apparent and some subsurface vascular features are made visible. Cross-polarized photography is useful for evaluating products designed to mitigate the appearance of dyschromic lesions, erythema, acne, and PIH resulting from acne. This technique is highly recommended for acne studies [12]. Examples of a parallel-polarized lighting technique and cross-polarized lighting technique can be found in Figure 6.3.

UV reflectance photography This is a technique designed to highlight or enhance hyperpigmentation on the face. This is accomplished through filtering a flash source to only allow UV light to pass on to the subject’s skin allowing visualization of subsurface melanin distribution. Figure 6.4 shows before and after UV reflectance photographs of a subject treated with a skin lightening product. A UV-blocking filter is placed in front of the lens of the digital camera. Note the improvement in the appearance and distribution of mottled and diffuse hyperpigmentation in the photograph on the right.

UV fluorescence photography This is primarily used to visualize the locations of Propionibacterium acnes in the pores of subjects with acne. Porphyrins produced by P. acnes exhibit an orange–red fluorescence under UVA light. Excitation of P. acnes on skin is achieved using a xenon flash lamp equipped with an UVA bandpass filter. The resulting fluorescence can be recorded using a high-resolution digital camera equipped with an UV barrier filter. An example of this technique can be found in Figure 6.5. Researchers have reported that UV fluorescence photography is a reliable, fast, and easy screening technique to demonstrate the suppressive effect of topical antibacterial agents on P. acnes [13]. Investigators need to be aware of a problem that can occur with using this technique to monitor P. acnes on the face. Many soaps, cosmetics, or sunscreen products contain quenching agents that can interfere with the accuracy of this imaging process. This can lead to an erroneous conclusion about the elimination of P. acnes from the face.

6. Evaluating cosmetic products

Figure 6.3 Examples of a parallelpolarized lighting technique (a) and cross-polarized lighting technique (b).

(a)

(b)

Figure 6.4 Before and after UV reflectance photographs of a subject treated with a skin lightening product. (a) Ultraviolet reflectance at baseline. (b) Ultraviolet reflectance at 12 weeks.

(a)

(b)

Digital fluorescence photography has other applications in dermatologic research. The technique can be used to detect salicylic acid in the skin and follicles of subjects participating in claim studies, as well as follow the migration of sunscreen products over the surface of face. Following the migration of sunscreen products over the surface can help explain why some sunscreen products find their way into the eyes producing stinging, burning, and ocular discomfort. Guide photographs refer to photographs taken of mock subjects before the clinical trial begins to provide the sponsor and investigator with choices of techniques to best capture the dermatologic condition being studied. The chosen image becomes the guide, or standard, for photographing all subjects in the trial.

Use of RLOP to detect improvements in periocular fine lines and wrinkles Optical profilometry refers to a technique in which photographic images of silicone rubber impressions taken of facial skin can be analyzed for changes in lines and wrinkles. Grove et al. [14] reported that optical profilometry provides an element of objectivity that can complement clinical assessment in the study of agents that are useful for treating photodamaged skin. While no one would argue that optical profilometry is a time proven method for assessing textural changes, preparing quality silicone replicas can be quite challenging even

BASIC CONCEPTS

Skin Physiology

Figure 6.5 Ultraviolet fluorescence technique.

for veteran clinicians. Common problems include replica ring positioning errors, air bubbles in the replica impression, and controlling the polymerization process. Slight variations in temperature, humidity, and body temperature can produce unsuitable replica impressions. In an effort to reduce the frustration level associated with preparing silicone replicas, we began investigations into using high-resolution digital photographs for quantifying changes in fine line and wrinkles on the face. Off-axial lighting, a common lighting technique used for clinical photography, could be used to create small shadows and highlights that could help define the surface texture of skin. Flash lighting can be placed above and at a 45 ° angle to the side of the face to create a three-dimensional effect of texture in a two-dimensional plane. The raw image files can be analyzed for fine lines and wrinkles on the face. The term to describe this technique is RLOP. RLOP is designed to detect the number, length, width, and depth of horizontal wrinkles in the crow’s feet area (coarse wrinkles) and the under eye area (fine lines). Wrinkles appear as dark lines on grayscale images. Deeper wrinkles appear darker because less light is present at the base of the wrinkle. An irregularly shaped area of interest is selected in the crow’s feet area to avoid capturing the eyebrows or hairline, and a rectangular area of interest is used under the eye. Image Pro® v6 software (Media Cybernetics, Bethesda, MD, USA) is used for the analysis. A horizontal edge filter is used to locate the wrinkles and exclude any dark objects caused by hyperpigmentation or scars. Once the wrinkles are identified with the edge filter they are measured for size (length, width, and area) and grayscale density (where

0 = black) on the original grayscale image. Once the data are collected a paired t-test is used to check for significant changes from baseline or between groups. As part of the validation process, RLOP has been included in several photoaging trials of cosmetic products involving several hundred subjects. The effectiveness of the products was evaluated using visual grading, digital photography with RLOP, bio-instrumentation, and subject self-assessment. The duration of these trials were typically 8 weeks, with clinic visits at 2, 4, and 8 weeks (Figure 6.6). RLOP technology complements and supports the results of clinical grading of fine line and wrinkles. RLOP appears to have several advantages over traditional optical profilometry. These advantages include: • RLOP can be performed on multiple sites on the face using a single digital photograph. • RLOP technology allows for precise location of the area of interest in each digital photograph through imaging software. • Digital images can be archived electronically for an indefinite period of time. • Results are expressed in meaningful units and endpoints. • The area of interest is significantly larger than can be captured in a replica impression. • RLOP can measure the full length of a wrinkle unlike traditional optical profilometry which limits the measured area to the size of the replica impression.

A non-invasive method for assessing the antioxidant protection of topical formulations in humans It is well documented that the addition of antioxidants such as vitamins C, E, and A to skin care formulation can be beneficial in preventing and minimizing skin damage associated with UV light [15–17]. Manufacturers often face a difficult task when formulating with antioxidants, because they are easily destroyed or altered by oxidation which can occur during product manufacturing, filling, or storage. To address these concerns, Pinnell and colleagues developed a human antioxidant assay which assesses the potential of topical antioxidants to enter into the skin and provide adequate protection against UV damage generated by a solar simulator. Antioxidants provide protection from UVRinduced damage by diminishing or blocking the formation of reactive oxygen species which is clinically manifested by erythema [17]. The technique involves the open applications of antioxidant products and a vehicle control to the demarcated areas on the lower back of subjects for four consecutive days. On day 3 the minimal erythema dose (MED) is determined for

6. Evaluating cosmetic products

(a)

(b)

(c)

(d) Figure 6.6 Before and after photographs using Raking Light Optical Profilometry. Top row: Digital photographs from a trial of a subject before (a) and 8 weeks after (b) treatment. Note the improvement in the appearance of wrinkling under the eye. Bottom row: Photographs shows the area of interest (AOI) in red. (c) Baseline. (d) Eight weeks after. The AOIs were precisely located in each digital image by using anatomic landmarks as anchors.

each subject. This is the dose of UV light that produces slight redness on fair-skinned individuals. On day 4, the demarcated sites treated with the antioxidant product, vehicle control, and an untreated site receive solar-simulated UV irritation of 1–5X MED at 1X MED intervals. On day 5, digital images are taken and the investigator has the option of collecting punch biopsies at the treatment sites and analyzing the tissues for multiple bio-markers such as thymine dimers, interleukins, metaloproteins, Langerhans cells (CD1a), p53, and sunburn cells [13,14]. Figure 6.7 shows a pattern of UV responses for a site treated with an antioxidant and a site treated with a vehicle control. Using macro-programs written in Image Pro software, it is possible to determine accurately the a* (degree of redness according to the CIE color standard) of each spot

and to calculate a protection factor for the antioxidant product relative to vehicle control treated site (Table 6.2). Using this technique, Pinnell and associates have been able to formulate a third generation antioxidant product that provides protection against the damaging effects of UV light. The formulation containing 15% ascorbic acid, 1% alfatocopherol, and 0.5% ferulic acid was found to be effective in reducing thymine dimers known to be associated with skin cancer [18,19].

Conclusions Photography and other non-invasive techniques are important to assess the efficacy and safety of cosmetic products.

Skin Physiology

BASIC CONCEPTS

Erythema

Control

Test material

xMED

Table 6.2 Results of theorectical antioxidant protection factor calculations. Increase from unexposed (adjusted for MED) No treatment (control)

Protection factor (%)

10.50

0.0

Antioxidant

6.30

60.0

Vehicle control

0.53

2.6

MED, minimal erythema dose.

Often, the non-invasive assessments provide confirmation of the expert grader assessments. It is reassuring to see consistency within the data set to confirm a positive effect of cosmetics and skin care products. This validation technique is necessary to truly evaluate products. This chapter presents several cutaneous research tools.

References 1 Rizer RL, Sigler ML, Miller DL. (1999) Evaluating performance benefits of conditioning formulations on human skin. In: Schueller R, Romanowski P, eds. Conditioning Agents for Hair and Skin. pp. 345–51. 2 Berardesca E. (1997) EEMCO guidance for the assessment of stratum corneum hydration: electrical methods. Skin Res Technol 3, 126–32. 3 Elsner P, Barel AO, Berardesca B, Gabard B, Serup J. (1998) Skin Bioengineering. Basel; New York: Karger. 4 Flosh PJ, Kligman AM. (1993) Non-Invasive Methods for the Quantification of Skin Functions. Springler-Verlag. 5 Serup J, Jemec GBE. (1995) Handbook of Non-Invasive Method and the Skin. Boca Raton, FL: CRC Press. 6 Elsner P, Berardecsa E, Wilhelm KP, Maibach HI. (2006) Bioengineering of the Skin: Skin Biomechanics. Boca Raton, FL: CRC Press.

Figure 6.7 Pattern of UV responses for a site treated with an antioxidant and a site treated with a vehicle control.

7 Elsner P, Berardesca E, Wilhelm KP. (2006) Bioengineering of the Skin: Skin Imaging and Analysis, 2nd edn. Informaword. 8 Elsner P, Berardecsa E, Wilhelm KP, Maibach HI. (1995) Bioengineering of the Skin: Methods and Instrumentation. Taylor & Francis. 9 Stack LB, Storrow AB, Morris MA, Patton DR. (1999) Handbook of Medical7 Photography Philadelphia, PA: Hanley & Belfus, pp. 15–20. 10 Ratner D, Thomas CO, Bickers D. (1999) The use of digital photography in dermatology. J Am Acad Dermatol 41, 749–56. 11 Phillips SB, Kollias N, Gillies R, Muccini A, Drake LA. (1997) Polarized light photography enhances visualization of inflammatory lesions of acne vulgaris. J Am Acad Dermatol 37, 948–52. 12 Rizova E, Kligman A. (2001) New photograqphic technique for clinical evalution of acne. J Eur Acad Dermatol Venereol 15 (Suppl 3), 13–8. 13 Pagnoni A, Kilgman AM, Kollias N, Goldberg S, Stoudemeyer T. (1999) Digital fluorescence photography can assess the suppressive effect of benzoyl peroxide on Propionibacterium acnes. J Am Acad Dermatol 41, 710–6. 14 Grove GL, Grove MJ, Leyden JJ. (1989) Optical profilometry: an objective method for quantification of facial wrinkles. J Am Acad Dermatol 21, 631–7. 15 Rabe JH, Mamelak AJ, EcElgunn JS, Morrison WL, Sauder DN. (2006) Photoaging: mechanisms and repair. J Am Acad Dermatol 55, 1–19. 16 Dreher F, Denig N, Gabard B, Schwindt Da, Maibach MI. (1999) Effect of topical antioxidants on UV-induced erythema formation when administered after exposure. Dermatology 198, 52–5. 17 Pinnell, SR (2003). Cutaneous photodamage, oxidative stress and topical antioxidant protection. J Am Acad Dermatol 48(1), 1–19. 18 Murray JC, Burch JA, Streilein RD, Iannacchione MA, Hall RP, Pinnell SR. (2008) atopical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol 59, 418–25. 19 Oresajo C, Stephens T, Hino PD, Law RM, Yatskayer M, Foltis P, et al. (2008) Protective effects of a topiocal antioxidant mixture containing vitamin C, and phloretin against ultraviolet-induced photodamage in human skin. J Cosmet Dermatol 7, 290–7.

Chapter 7: Contact dermatitis and topical agents David E. Cohen and Aieska de Souza New York University School of Medicine Department of Dermatology, New York, NY, USA

BAS I C CONCEPTS • Hypersensitivity reactions can occur in response to topical agents. • Adverse reactions can be characterized by irritant contact dermatitis and allergtic contact dermatitis. • Patch testing is a reliable method for determining the etiology of adverse reactions to topical products. • Treatment of hypersensitivity reactions involves prompt recognition with identification and withdrawal of the offending agent.

Introduction Topical cosmetic medications, cosmeceuticals, and minimally invasive procedures have always had an important role in dermatologic practice, but recent advances have led to a tremendous expansion in the repertory of treatment modalities available. In addition, the use of over-the-counter cosmetics is rising worldwide, along with potential exposure to irritants and allergenic substances [1]. Adverse skin reactions to cosmetics include irritant contact dermatitis, allergic contact dermatitis, contact urticaria, and foreign body reactions [2]. The clinician should be able to diagnose these cases, prescribe the correct treatment, and – most importantly – identify the causative agent. Most of these reactions are treatable without sequelae once the offending agent is identified and avoided [2]. Approximately 15 million Americans have been diagnosed with contact dermatitis [2]. The US Food and Drug Administration (FDA) regulations on cosmetics are based in two important laws: the Federal Food, Drug, and Cosmetic Act (FD&C) which prohibits the marketing of adulterated or misbranded cosmetics, and the Fair Packaging and Labeling Act (FPLA) which states that improperly labeled or deceptively packaged products are subject to regulatory action [3]. Ingredient labeling is mandatory in the USA and Europe, and compounds are listed in descending order of amount using the nomenclature format of the International Cosmetic Ingredient Dictionary [4,5]. However, with the exception of color additives, cosmetic products and ingredients are not subjected to FDA premarket approval and manufacturers’ reporting of adverse reactions is a voluntary process [3]. In order to review the safety of the cosmetic ingredients, the

Cosmetic, Toiletries and Fragrance Association (CTFA) sponsors the Cosmetic Ingredient Review (CIR). Reactions to cosmetics can manifest in a wide range of clinical signs, therefore it is important for the clinician to be familiar with the diversity of those presentations to enable prompt diagnosis and treatment.

Hypersensitivity reactions: pathophysiology and clinical presentations Irritant contact dermatitis Most skin reactions to cosmetics are classified as irritant contact dermatitis [4]. Irritant contact dermatitis is caused by endogenous and environmental elements and it is defined as local inflammation that is not initially mediated by the immune system. Predisposing factors for the development of irritant dermatitis included the presence of a less effective stratum corneum, either from anatomic conditions (face, eyelids) or secondary to endogenous disorders, such as atopic dermatitis. The severity of the dermatitis depends on the amount and strength of the agent, and length and frequency of exposure. Repetitive exposures even to mild agents, such as soaps and detergents, will often result in irritant dermatitis. In addition, harsh scrubbing with mechanical assistance (brushes, synthetic sponges, or cosmetics containing microabrasive spheres) increases the risk for irritation. Psychiatric disorders, leading to compulsive repetitive behaviors of self-cleaning and handwashing, can sometimes be overlooked and a complete patient history must include cleaning habits, occupation, and a detailed list of all products used on both a daily and occasional basis.

Allergic dermatitis constitutes at least 10–20% of all cases of contact dermatitis and represents a true delayed-type (type IV) immune reaction. Previous exposure and sensitization

BASIC CONCEPTS

Skin Physiology

to the agent is necessary [2]. Chemical agents act as haptens, which are small electrophilic molecules that bind to carrier proteins and penetrate into the skin. HLA-DR or class II antigens act as the binding site in the surface of the antigenpresenting cells (APCs). These epidermal dentritic cells digest the allergen complex and display the antigenic site on their cell surfaces for presentation to T lymphocytes. If the individual has the genetic susceptibility to that allergen, clonal proliferation of T cells starts with the production of cytokines, further stimulating migration of inflammatory cells and keratinocyte proliferation. Clinical distinction between irritant and allergic dermatitis can be challenging because both conditions manifest as eczematous reactions, ranging from mild erythema and scale with minimal itch to vesicular, bullous, and indurated plaques that are highly pruritic. Furthermore, the two conditions can be superimposed, because an irritated and broken epidermal barrier can facilitate the absorption of haptens and elicit an immune response in susceptible individuals.

healing and foreign body reaction. Acute inflammation is characterized by the presence of neutrophils, mast cell degranulation, and fibrinogen adsorption. The degree of the inflammation is highly dependent upon the injury produced, the site of injection, the material used, and the extent of the provisional matrix formed. The acute phase generally resolves within 1 week, and can be followed by chronic phase inflammatory response, which is characterized by the presence of monocytes, lymphocytes, and plasma cells. After resolution of acute and chronic phases of inflammation, a granulation tissue can be identified, rich in macrophages and fibroblasts which act to produce neovascularization and new healing tissue [6]. Prolonged duration of the inflammatory phase (i.e. longer than 3 weeks) should prompt an investigation to rule out complications, such as infection, allergic reaction, gel migration, abscesses formation, or granulomatous reaction. Foreign body granulomatous reactions with deleterious consequences have been previously described with the use of silicon, bovine collagen, hyaluronic acid, and other fillers [2,7–10].

Contact urticaria Contact urticaria syndrome is divided into immunologic and non-immunologic subtypes. Non-immunologic contact urticaria is the most common form and occurs in the absence of previous exposure. Localized wheals appear within 30–60 minutes after exposure and are not followed by systemic symptoms. Allergic contact urticaria is an immediate-type (type I) hypersensitivity reaction and occurs in sensitized individuals within minutes to hours following the exposure to the allergen. The binding between allergens and immunoglobulin E (IgE) triggers mast cell degranulation and consequent release of inflammatory products, such as histamine, prostaglandins, leukotrienes, and cytokines. As a consequence, individuals experience erythema, swelling, and pruritus which may be localized (wheals and fares) or generalized (angioedema, conjunctivitis, bronchoconstriction, hypotension). Severe reactions may be fatal.

Foreign body reactions Gel fillers are a group of exogenous substances used for soft tissue augmentation. Their mechanism of action is the addition of volume per se once injected and also the production of a collagen matrix. Fillers are supposed to be inert materials but the degree of the response elicited varies according to the material and the technique used, as well as the host immunologic pattern of reaction. The normal initial host response to foreign body implantation is the formation of a blood-based matrix on and around the biomaterial, called the provisional matrix. The tissue injury may also lead to activation of the innate immune response and thrombus formation. The provisional matrix is rich in mitogens, chemoattractants, growth factors, and cytokines, proving an excellent medium both for wound

Common allergens Irritants In the clinical setting, irritant substances are used for the purpose of selectively destroying the damaged superficial layers of the skin, and the depth of penetration is correlated with the agent used, concentration, and time of exposure. Examples of “peeling” agents include retinoic, glycolic, and salicylic acids, resorcinol, trichloroacetic acid, and phenol. Undesirable irritant reactions are commonly seen with daily use of topical retinoids, leading to erythema and fine scaling, which tend to improve with time. A wide variety of substances may act as irritants when sufficient exposure in time and/or concentration is ensured (Table 7.1). Mechanical, chemical, and environmental factors can act alone or in combination to produce irritation in the skin. Mechanical factors include cosmetic procedures (shaving, waxing, laser therapy, dermoabrasion), habits (excessive rubbing of the skin with soaps, scrubs, usage of tight clothes or shoes, intense exercise), occupational exposure (latex gloves, microtrauma of the skin). Wet work (i.e. exposure of the skin to liquid), use of occlusive gloves for longer than 2 hours per day or frequent hand cleaning is one of the most common and important skin irritants [11]. Professions at risk include hairdressers, healthcare workers, and food handlers. Almost all chemicals have the potential to cause skin irritation. The list of the chemical compounds capable of producing irritation of the skin is extensive and largely dependent on the concentration, volume, and time of exposure. Some substances are considered universal irritants, for example, strong acids (hydrofluoric, hydrochloric, sulfuric,

7. Contact dermatitis and topical agents

Table 7.1 List of common skin irritants: mechanic, chemical, and environmental factors known to cause skin irritation. The agents can act alone or in combination to produce contact dermatitis, therefore recognition of all factors involved is crucial for proper management of patients. Mechanic

Chemical

Environmental

Shaving, waxing, laser treatment

Soaps

Excessive heat or sun exposure, sunburn

Dermoabrasion

Detergents

Food allergies

Rubbing of the skin (e.g. when using a soap or scrubbing)

Surfactants (cocamidopropyl betaine*)

Saunas and jacuzzis (chlorine*)

Friction and/or occlusion (tight clothes, certain fabrics: wool, synthetic fibers)

Chemical peelings

Extreme cold and windburn

Latex gloves

Alcohol

Stress

Intense exercise

Fragrances and color additives (musk*)

Dry air

Microtrauma

Preservatives (formaldehydes releasing substances: Quaternium 15*, imidazolidinyl urea, DMDM Hydantoin)

Hot and/or prolonged showers

Pressure

Sunscreens (para-aminobenzoic acid*)

Spicy foods, peppers, condiments

Wet work

Bleaches and whitening agents

Water

* Most common chemical compounds involved.

nitric acids) and strong caustics (sodium hydroxide, potassium hydroxide) produce severe burns even in brief and small exposures. Solvents, including alcohol, turpentine, ketones, and xylene, remove lipids from the skin, producing direct irritation and allowing other irritants, such as soap and water, to produce more damage on the exposed skin. Inappropriate skin cleansing with solvents to remove grease, paints, or oils is a common cause of skin irritation. Soaps are alkali substances and may produce irritation by disrupting the skin barrier; in contrast, cleansing agents with a pH of approximately 5.5 and alcohol-based hand-cleansing gels are less aggressive and should be preferred for sensitive skin. Environmental elements may render the skin more susceptible to cutaneous irritants, and include dry air, extremes of temperature (cold, heat), or important weather variations. Food allergies may cause urticarial reactions; spicy foods and condiments may cause lip and perioral irritant dermatitis. Prolonged exposure to water can cause maceration and desiccation of the skin. Acneiform eruptions refer to the presence of comedones, papules, pustules, and nodular cysts. Follicular plugging has been noticed secondary to the use of isopropyl myristate, an emollient and lubricant used in shaving lotions, shampoos, oils, and deodorants. Sodium lauryl sulfate (SLS) is a surfactant found in many topical medications, particularly for acne, and is a classic experimental cutaneous irritant. Pustular eruptions secondary to SLS have also been described. Bergamot oil (5-methoxypsoralen) induced phototoxic reactions in the past and it has subsequently been removed from the formulations of cosmetics. Photosensitivity reactions caused by topical retinoid preparations are common

and patients should be advised to use sunscreens and avoid sun exposure during treatment. Subjective irritation, described as a tingling, burning, stinging, or itching sensation without visible skin alteration is commonly observed with topical medications. Propylene glycol, hydroxy acids, and ethanol are capable of eliciting sensory irritation in susceptible individuals. Commonly used medications such as benzoic acid, azelaic acid, lactic acid, benzoil peroxide, mequinol, and tretinoin may have sensory irritation as a side effect. Sorbic acid is an organic compound used as a preservative in concentrations up to 0.2% in foods, cosmetics, and drugs. Subjective irritation has been demonstrated with 0.5% sorbic acid and to 1% benzoic acid in susceptible individuals [12]. “Sensitive skin” or cosmetic intolerance syndrome is a condition of cutaneous hyperreactivity secondary to substances that are not defined as irritants [13]. The condition encompasses a complex combination of objective and subjective irritative symptoms and may coexist with hidden allergic processes, urticarial reactions, and/or photodermatitis. Endogenous causes include seborrheic dermatitis, psoriasis, rosacea/perioral dermatitis, atopic dermatitis, and body dysmorphobia. Elimination of all cosmetic products for a prolonged period of time (6–12 months) followed by slow reintroduction (a new products every 2–3 weeks) is helpful when managing these cases.

Contact urticaria Cinnamic acid is a white crystalline substance, slightly soluble in water, which is obtained from oil of cinnamon, or from balsams such as storax. Its primary use is in the

BASIC CONCEPTS

Skin Physiology

manufacturing of the methyl, ethyl, and benzyl esters for the perfume industry, producing the “honey, fruit” odor. Type I non-immunologic reactions can be triggered by fragrances that contain cinnamic acid and cinnamal. Immunologic type I reactions can be triggered in susceptible individuals by parabens (preservatives), henna, and ammonium persulfate (oxidizing agent), leading to systemic symptoms and potentially fatal reactions [4]. Contact urticaria to latex is triggered by exposure to the proteins derived from Hevea brasiliensis tree. Risk factors include the presence of spina bifida, genitourinary tract abnormalities, previous contact to latex (from multiple surgical procedures, or occupational exposure) hand dermatitis, atopy, and specific food allergies (avocado, banana, chestnut, potato, tomato, kiwi, pineapple, papaya, eggplant, melon, passion fruit, mango, wheat, and cherimoya).

Allergic reactions Fragrances Allergic reactions to fragrances affect at least 1% of the population. The distribution of the eruption can be restricted to the areas of application (face, neck, hands, axillae) or it can present as generalized dermatitis. Products containing scents are ubiquitous and include cosmetics and toiletries, cleansers, and household goods. Common sensitizers are balsam of Peru, cinnamal, fragrance mix (eugenol, isoeugenol, oak moss absolute, geraniol, cinnamal, alfa-amyl cinnamic aldehyde, hydroxycitronellal and cinnamic alcohol), and colophony. Patch testing to 26 fragrances was performed as a multicenter project in the European Union to further identify possible additional allergens and prevent adverse reactions by proper labeling of cosmetic products [14]. The compounds considered important allergens were defined as group I substances: tree moss, HMPCC (hydroxymethylpentylcyclohexene carboxaldehyde), oak moss, hydroxycitronellal, isoeugenol, cinnamic aldehyde, and farnesol. Group II included substances clearly allergenic, but less relevant regarding sensitization frequency: cinnamic alcohol, citral, citronellol, geraniol, eugenol, coumarin, lilial, amyl-cinnamic alcohol, and benzyl cinnamate. Rarely, substances in group III were sensitizers: benzyl alcohol, linalool, methylheptin carbonate, alfa-amyl-cinnamic aldehyde, alfa-hexylcinnamic aldehyde, limonene, benzyl salicylate, gammamethylionon, benzyl benzoate, and anisyl alcohol [14]. Allergic reactions to Myroxylon pereira (balsam of Peru) have been correlated to scattered generalized dermatitis. Widespread involvement might also suggest a systemic exposure, and oral ingestion of balsam of Peru has been correlated with hand eczema [15].

Preservatives Preservatives are low molecular weight, biologically active compounds that prevent product contamination by micro-

organisms, or degradation. The recent growing replacement of organic solvents and mineral oils to water-based products in the cosmetic industry has increased the need of preservatives. Distribution of the allergic rash includes face, neck, hands, axillae, or generalized. Common sensitizers include formaldehyde and formaldehyde releasers, thiomerosal, Kathon CG, parabens, glutaraldehyde, DMD-hydantoin, quaternium-15 and are widely present in water-containing products (e.g. shampoos, cosmetics, metalworking fluids, and soaps). Formaldehyde allergy is common and is mostly caused by formaldehyde-releasing biocides in cosmetics, toiletries, and other products. In a recent review of 81 formaldehydeallergic patients, allergic reaction to at least one of the 12 formaldehyde-releasing substances were detected in 79% of the cases and isolated reactions to releasers were rare [16]. Formaldehyde allergy is also reported as a common cause of occupational contact dermatitis and the professions at risk include hairdressers, healthcare workers, painters, photographers, housekeeping personnel, metalworkers, masseurs, and workers dealing with creams, liquid soaps, and detergents [16].

Cleansing agents These are applied to remove sebum, desquamated cells, sweat, and microorganisms. Washout products are briefly in contact with the skin, therefore few cases of allergy have been reported. Allergens include surfactants (cocamidopropyl betaine), preservatives (methylchloroisothiozolinone), antimiocrobials (PCMX), and fragrances.

Moisturizers Moisturizers inhibit transepidermal water loss by occlusion, and are composed of a mixture of substances such as petrolatum, lanolin, lanolin derivates, and fatty alcohols. Stasis dermatitis can be a predisposing factor for allergic contact dermatitis to lanolin. Self-tanning agents have become increasingly popular and are sold separately or in conjunction with moisturizers. Such agents may cause allergic contact reactions when dihydroxyacetone degrades to form formaldehyde, formic acid, and acetic acid.

Hydroquinone Hydroquinone is a whitening agent present in up to 2% in over-the-counter creams and 4% in prescription bleaching creams. Irritant and allergic reactions, hypopigmentation and hyperpigmentation, and exogenous ochronosis are known side effects [17].

Shampoos and conditioners Shampoos contain a combination of cleansing agents and surfactants that act to remove sebum, scales, and microorganisms from the hair and scalp. Conditioner agents neutralize static charge and soften the hair. Common ingredients

7. Contact dermatitis and topical agents are moisturizers, oils, surfactants, lubricants, preservatives, and fragrances. Allergic reactions are uncommon because of the limited amount of time the substance is in contact with the skin, however, cocamidopropyl betaine (surfactant), formaldehyde, methylchloroisothiazolone and methylisothiazolone (preservatives) have been reported as causative agents of allergic contact dermatitis.

Hair dyes and bleaches Hair dyes are classified in semi-permanent and permanent. Semi-permanent dyes are derivates from nitroanilines, nitrophenylenediamines, and nitroaminophenols which use low molecular weight elements that penetrate the hair cuticle. Permanent dyes act by the means of primary intermediates (p-phenylenediamine [PPD] or p-aminophenol) which are oxidized by hydrogen peroxide and react with different couplers to produce a wide range of colours. Once oxidized to para-benzo-quinone diamine, PPD is no longer allergenic [18]. A few exceptions include circ*mstances in which unreacted PPD remains in the skin, for instance with inadequate mixture of ingredients with the use of homemade coloring kits or poor rinsing. Distribution is on the hairline, scalp, face, and photo distributed. Consort dermatitis is defined as the presence of the allergic eruption in the partner of the subject using the allergenic substance. It has been described for cosmetics, including PPD [18]. Temporary henna tattooing and hair dying are common practices. Henna is a natural product derived from the leaves of Lawsonia inermis and rarely causes hypersensitivity reaction. The addition of PPD to henna causes contact sensitization to black henna and reported reactions include mild eczema to bullous reactions with scarring and pigmentation alterations [19]. Hair bleaches include hydrogen peroxide solutions that oxidize melanin and ammonium persulfate, a very strong oxidizing agent and a radical initiator, which can be used as a booster supplement in hair dyes. Type I and IV hypersensitivity reactions may arise from the use of ammonium persulfate.

Permanents Permanents use mercaptans to cleave disufide bonds in hair; neutralizers are then added to reshape the configuration. Neutralizers contain hydrogen peroxide, bromates, perbromates, percarbromates, or sodium borate perhydrate. Ammonium thioglycolate, also known as perm salt, is a cleaving agent and if applied improperly can cause extensive hair damage and acute contact irritant dermatitis. Glycerol monothioglycolate (GMTG, “acid” permanents) can cause allergic contact dermatitis. Storrs [20] demonstrated positive allergic reactions to GMTG in concentrations as low as 0.25%, even when it was tested through glove fabric; however, household-weight neoprene gloves were proven to be protective.

Nail products Nail polish and hardener contains nitrocellulose, resins, plasticizers, solvents and diluents, colors, and suspending agents. Most adverse reactions are secondary to tolysamide formaldehyde resin (toluene sulfonamide/formaldehyde resin). The dermatitis tends to affect places commonly reached by the fingers (e.g. face, eyelids, sides of the neck, mouth), sparing the hands and fingers. Nail elongation materials contain acrylics (ethy acrylate, 2-hydroxy ethyl acrylate, ethylene glycol dimethacrylate, ethyl cyanoacrylate, and triethylene glycol diacrylate) all previously reported as allergens.

Local anesthetics Anesthetic agents can be divided in two groups: esters (benzocaine, tetracaine, and procaine) and amide derivates (lidocaine, mepivacaine, bupivacaine, etidocaine, and prilocaine). Cases of eczematous dermatitis have been reported secondary to the use of topical ester agents and rarely secondary to amide derivates. Contact sensitization to 2.5% lidocaine and 2.5% prilocaine emulsion (EMLA, Astra Zeneca Pharmaceuticals LP, Wilmington, DE, USA) is rare, and additional uncommon side effects reported include purpuric eruption, rash, redness, itching, and edema [2]. True IgE-mediated reactions to injectable anesthetics correspond to less than 1% of all adverse events. Although rare, such reactions may present as life-threatening events and prompt recognition of the symptoms and adequate management is imperative. In contrast, delayed-type reactions manifest within 12–48 hours and present as acute dermatitis (erythema, papules, vesicles and itching) [2,21]. The most common systemic adverse reactions to injectable anesthetics are psychosomatic responses, or exaggerated responses to epinephrine present in many products, caused by anxiety and vasovagal reflex. Patients may present with dyspnea, hyperventilation, and sympathetic responses, such as tachypnea, tachycardia, hypertension, and diaphoresis. Vasovagal syncope and peripheral paresthesias may also occur. Systemic toxicity occurs when excessive dosage is administered and manifest as light-headedness, tremors, restlessness, seizures, and depressed myocardial contractility. Methemoglobulinemia is an idiosyncratic reaction reported with local injectable anesthetics [21].

Topical corticosteroids Non-halogenated topical steroids (hydrocortisone, budesonide) are the most common corticosteroids correlated with allergic reactions. Patients at risk are those with stasis dermatitis and chronic leg ulcers, followed by those with hand eczema, atopic dermatitis, anogenital, foot, and facial dermatitis. Patch testing with tixocortol pivalate and budesonide is useful to identify allergy to hydrocortisone and other steroids molecules that may cross-react [22].

BASIC CONCEPTS

Skin Physiology

Injectables

Occupational hand eczema

Botulinum toxin is a highly potent neurotoxin that inhibits acetylcholine release at the neuromuscular junction, blocking neuromuscular transmission and reversibly paralyzing striated muscle. Allergic reactions are rare and include generalized pruritus, psoriasiform eruption, urticaria, and erythema multiforme-type reactions [2,23]. Fillers can be classified as hom*ogenous (polymer gels) and combination gels, which differ not only in composition, but also in duration of effect, tissue interaction properties, and type of adverse reactions evoked. hom*ogenous gels are the most commonly used and are subdivided into degradable (hyaluronic acid and collagen) and non-degradable gels (polyacrylamide and silicone). Degradable polymer gels resemble the elements commonly found in the tissues, therefore are degraded by naturally occurring enzymes, located in the extracellular matrix and/or within macrophages [8]. Hence, fibrous response generated by these hydrophilic gels is minimal. Although generally considered safe, affordable, and ease to use, degradable gels are not permanent, and rare complications include allergic reactions, transient swelling, and cystic swelling [2,7]. Collagen fillers are substances derived from bovine collagen, which become non-allergenic after enzymatic digestion with pepsin. Formulations available on the market are collagen I (Zyderm I and II, INAMED Corporation, Santa Barbara, CA, USA) or cross-linked collagen (Zyplast, INAMED Corporation, Santa Barbara, CA, USA). Transient swelling and erythema are the most common reactions and tend to resolve a few days after the procedure. Hypersensitivity allergic reactions involve localized humoral and cellular inflammatory processes. Such reactions can persist up to 1 year after the procedure and are strongly correlated with the presence of antibovine collagen antibodies, hence prophylactic testing of individuals is recommended. Silicone is the term applied to describe the medical group of compounds derived from silicone-containing synthetics. Polydimethylsiloxanes are the most commonly substances used and contain silicon, oxygen, and methane [9]. The silicon gel is hydrophobic and once introduced in the tissues it is dispersed in vacuoles or droplets, which may be absorbed by macrophages and foreign body giant cells. The cells may then migrate to the reticuloendothelial system and/or evoke a local foreign body reaction in the surrounding tissue. Phagocytes enter and transverse the gel, followed by gradual replacement with connective tissue [8]. Adverse reactions to soft tissue augmentation include bacterial infections, abscesses, local inflammation, discoloration, ulceration, migration, and formation of silicon-type granulomas [2,8]. Deep-seated panniculitis can present early as a tingling sensation followed by local edema [8]. Late signs include the presence of a solid, painless tumefaction, with or without facial disfigurement and facial nerve paralysis [10].

Occupational hand eczema among hairdressers is a significant health problem and common sensitizers include hair dyes, ammonium persulfate, preservatives, amphoteric surfactants, fragrances, and glycerol thioglycolate. The use of gloves, mild soaps, and moisturizing creams alleviate the condition but severe refractory cases may require definitive interruption of the occupational activity. Gloves worn as protection may also constitute a source of allergens for hand dermatitis in hairdressers and healthcare professionals.

Diagnosis Diagnostic evaluation of patients with hypersensitivity reactions should be directed towards identifying the causative agent. Prick tests and radio allergo-sorbent tests (RASTs) are available for detection of IgE antibodies against specific allergens, therefore indicated for patients with some type I hypersensitivity reactions. Allergy to bovine collagen can be detected by intradermal challenge. The screening test is recommended for all cases prior to the procedure and consists of an intradermal injection of 0.1 mL of the filler substance in the volar forearm, with evaluation of the reaction within 48–72 hours. A positive test is defined as induration, erythema, tenderness, or swelling that persists or occurs longer than 6 hours after the injection. Positive subjects must be excluded from the procedure. A second test is recommended for non-reactive subjects to lower the chances of treatment-associated adverse reactions. The test should be performed within 2 weeks after the initial exam, in the contralateral forearm or periphery of the face [2]. Patch-testing is required to diagnose delayed type IV allergic reactions. Epicutaneous application of standardized concentrations of allergen chemicals on flat metal chambers are followed by occlusion and removal in 48 hours. The skin reaction is then graded and a second reading is performed in 1–5 days. The presence of induration, erythema, and/or vesicles denotes a positive reaction.

Treatment Treatment is based on identifying the offending agent and lifetime avoidance. Type I reactions required blockage of histamine receptors. Severe anaphylactic reactions require immediate hospitalization for assessment of cardiorespiratory status and intravenous fluids, subcutaneous epinephrine, systemic steroids, and antihistaminic medication. Mild forms of contact allergic dermatitis are readily treatable with avoidance of the offending agent. Topical steroids can be prescribed for a short period of time to hasten the process, whereas serious reactions may require addition of systemic immunosuppressant medication.

7. Contact dermatitis and topical agents

Conclusions Cosmetic products are widely used and reactions to those products are commonly seen in daily dermatologic practice. Prompt recognition with identification and withdraw of the offending agent are key elements for successful management of such reactions.

References 1 Berne B, Tammela M, Färm G, Inerot A, Lindberg M. (2008) Can the reporting of adverse skin reactions to cosmetics be improved? A prospective clinical study using a structured protocol. Contact Dermatitis 58, 223–7. 2 Cohen DE, Kaufmann JM. (2003) Hypersensitivity reactions to products and devices in plastic surgery. Facial Plast Surg Clin North Am 11, 253–65. 3 US Food and Drug Administration. (2005) FDA authority over cosmetics. CFSAN/Office of Cosmetics and Colors; 2005 [updated March 3, 2005; cited September 6, 2008]. Available from: http:// www.cfsan.fda.gov/∼dms/cos-206.html 4 Engasser PG, Maibach HI. (2003) Cosmetics and skin care in dermatologic practice. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI. Fitzpatrick’s Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, pp. 2369–79. 5 Cosmetic, Toiletry and Fragrance Association (CTFA). (2008) International Cosmetic Ingredient Dictionary and Handbook, 12th edn. Washington, DC: CTFA. 6 Anderson JM, Rodriguez A, Chang DT. (2008) Foreign body reaction to biomaterials. Semin Immunol 20, 86–100. 7 Cohen JL. (2008) Understanding, avoiding, and managing dermal filler complications. Dermatol Surg 34, S92–9. 8 Christensen L. (2007) Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg 33, S168–75. 9 Chasan PE. (2007) The history of injectable silicon fluids for soft-tissue augmentation. Plast Reconstr Surg 120, 2034–40. 10 Poveda R, Bagán JV, Murillo J, Jiménez Y. (2006) Granulomatous facial reaction to injected cosmetic fillers: a presentation of five cases. Med Oral Patol Oral Cir Bucal 11, E1–5.

11 Jungbauer FH, Lensen GJ, Groothoff JW, Coenraads PJ. (2004). Exposure of the hands to wet work in nurses. Contact Dermatitis 50, 225–9. 12 Lammintausta K, Maibach HI, Wilson D. (1988) Mechanisms of subjective (sensory) irritation: propensity to non-immunologic contact urticaria and objective irritation in stingers. Derm Beruf Umwelt 36, 45–9. 13 Primavera G, Berardesca E. (2005) Sensitive skin: mechanisms and diagnosis. Int J Cosmet Sci 27, 1–10. 14 Schnuch A, Uter W, Geier J, Lessmann H, Frosch PJ. (2007) Sensitization to 26 fragrances to be labelled according to current European regulation: results of the IVDK and review of the literature. Contact Dermatitis 57, 1–10. 15 Zug KA, Rietschel RL, Warshaw EM, Belsito DV, Taylor JS, Maibach HI, et al. (2008) The value of patch testing patients with a scattered generalized distribution of dermatitis: retrospective cross-sectional analyses of North American Contact Dermatitis Group data, 2001 to 2004. J Am Acad Dermatol 59, 426–31. 16 Aalto-Korte K, Kuuliala O, Suuronen K, Alanko K. (2008) Occupational contact allergy to formaldehyde and formaldehyde releasers. Contact Dermatitis 59, 280–9. 17 Draelos ZD. (2007) Skin lightening preparations and the hydroquinone controversy. Dermatol Ther 20, 308–13. 18 Veysey EC, Burge S, Cooper S. (2007) Consort contact dermatitis to paraphenylenediamine, with an unusual clinical presentation of tumid plaques. Contact Dermatitis 56, 366–7. 19 Evans CC, Fleming JD. (2008) Images in clinical medicine: allergic contact dermatitis from a henna tattoo. N Engl J Med 7, 627. 20 Storrs FJ. (1984) Permanent wave contact dermatitis: contact allergy to glyceryl monothioglycolate. J Am Acad Dermatol 11, 74–85. 21 Phillips JF, Yates AB, Deshazo RD. (2007) Approach to patients with suspected hypersensitivity to local anesthetics. Am J Med Sci 334, 190–6. 22 English JS. (2000) Corticosteroid-induced contact dermatitis: a pragmatic approach. Clin Exp Dermatol 25, 261–4. 23 Brueggemann N, Doegnitz L, Harms L, Moser A, Hagenah JM. (1008) Skin reactions after intramuscular injection of Botulinum toxin A: a rare side effect. J Neurol Neurosurg Psychiatry 79, 231–2.

Part 2: Delivery of Cosmetic Skin Actives Chapter 8: Percutaneous delivery of cosmetic actives to the skin Marc Cornell, Sreekumar Pillai, and Christian Oresajo L’Oréal Research, Clark, NJ, USA

BAS I C CONCE P T S • Percutaneous delivery is the penetration of substances into the skin. • The goal of effective percutaneous delivery is to provide an effective amount of an active to the skin target site and thereby optimize efficacy while minimizing side effects. • The main barrier of the active permeation through the skin is the stratum corneum. The active must cross this skin barrier and permeate transepidermally to be delivered to the target site. • Molecules with a molecular weight of less than 500 Daltons penetrate the skin better than molecules with a larger molecular weight. The net charge of a molecule is important in enhancing penetration.

Introduction Recent developments in new technologies combined with new knowledge in skin biology have advanced innovations in skin availability of actives and novel methods of substance delivery. The goal of this chapter is to review new advances in delivery of actives to the skin and the effects of penetration enhancers. An understanding of the structure of the skin is very important in managing active delivery.

The basics The goal of percutaneous delivery is to provide an effective amount of an active to the skin target site and thereby optimize efficacy while minimizing side effects. This can be achieved by an understanding of the skin’s complex structure and by relying on physical and chemical parameters of vehicles applied to the skin.

Skin physiology There are defined compartments and biologic structures within the skin that provide opportunities to deliver actives (Figure 8.1). Within these compartments there are many

chemical and biologic processes at work that may alter a given active or the physiology of skin target. The main barrier of active permeation through the skin is the stratum corneum. The active must cross this skin barrier and permeate transepidermally to be delivered to the target site, and the penetration can be moderated by the secretion activity of the appendages. This structure is located at the outermost layer of the epidermis [1]. This transepidermal route can be further subdivided into transcellular and intercellular routes [2]. Delivery of hydrophilic substances can be achieved through sweat gland route; however, this is also minimal in total volume. Therefore, the principal pathway for skin penetration of actives is the transepidermal route (route 1 in Figure 8.1).

Active composition One of the first steps in understanding the phenomenon of active delivery is to completely characterize the active that is intended for delivery to the skin. There are well-known physical and chemical parameters that are specific to all chemical compounds. The essentials for characterization of actives are typically described in the literature or can be measured in the laboratory. This includes the active’s molecular weight, dissociation constant (pK), solubility, and octanol/water [O/W] partition coefficient (log P). These parameters, along with a thorough understanding of the net ionic charge (cationic, anionic, and amphoteric) of the active will help in understanding its penetration profile. As general rule, molecules with a molecular weight of less than 500 Da penetrate the skin better than molecules with

8. Percutaneous delivery

1 Increasing drug diffusion in the skin; 2 Increasing drug solubility in the skin; and/or 3 Increasing the degree of saturation of the drug in the formulation [4]. Equation (1) aids in identifying the ideal parameters for the diffusion of the active across the skin. The influence of solubility and partition coefficient on diffusion across the stratum corneum has been extensively studied in the literature [5].

Vehicle effect Delivery of actives from emulsions Figure 8.1 Possible pathways for a penetrant to cross the skin barrier. (1) across the intact horny layer; (2) through the hair follicles with the associated sebaceous glands; or (3) via the sweat glands. (This figure was published in: Daniels R. Strategies for skin penetration enhancement. Skin Care Forum 37, www.scf-online.com.)

a larger molecular weight. It is also known that the net charge of a molecule is important in enhancing penetration. An un-ionized molecule penetrates the skin better than an ionized molecule. A thorough understanding of the relationship between the dissociation constant and formulation pH is critical. In many cases it is advantageous to keep the pH of a formulation near the pK of the active molecule in an attempt to enhance penetration. When looking at the partition coefficient, molecules showing intermediate partition coefficients (log P O/W of 1–3) have adequate solubility within the lipid domains of the stratum corneum to permit diffusion through this domain while still having sufficient hydrophilic nature to allow partitioning into the viable tissues of the epidermis [3].

Fick’s law The permeation of active across the stratum corneum is a passive process, which can be approximated by Fick’s first law: J=

DK (C) L

(equation 8.1)

This defines steady-state flux (J) is related to the diffusion coefficient (D) of the active in the stratum corneum over a diffusional path length or membrane thickness (L), the partition coefficient (K) between the stratum corneum and the vehicle, and the applied drug concentration (C) which is assumed to be constant. Novel formulation strategies allow for manipulation of the partition coefficient (K) and concentration (C). Skin penetration can be enhanced by the following strategies:

The key for evaluation of the vehicle effect is to understand the dynamics between the vehicle and the active. Based on the physical and chemical nature of the active there are specific formulation strategies that can be designed to enhance delivery of actives. The primary vector for topical delivery of actives is a semisolid ointment or emulsion base. The main reason for selection of this dosage form is convenience and cosmetic elegance. Emulsions are convenient because they typically have two phases (hydrophilic and hydrophobic). The biphasic nature allows for placement of actives based on solubility and stability. This allows the formulator to bring lipophilic and hydrophilic actives into the dosage form while maintaining the optimized stability profile. The effect of the type of vehicle has been well described in the literature [6]. Numerous references are available for altering the delivery of actives from various emulsion forms (O/W, W/O, multiple emulsions, and nano-emulsions).

Formulation strategies A basic formulation has many components. Table 8.1 provides an overview of these formula components and also provides a brief summary of the anticipated effect on active delivery. Some of these chemical functions are more clearly defined below in discussion on chemical penetration enhancers. The ability of vehicles to deliver actives is tied to an understanding of diffusion of actives through various skin compartments (epidermal and dermal). Diffusion of actives across the skin is a passive process. Compounds with low solubility and affinity for the hydrophilic and lipophilic components of the stratum corneum would theoretically partition at a slow rate. These difficulties may be overcome by adding a chemical adjunct to the delivery system that would promote partitioning into the stratum corneum. Partitioning of actives from the dosage form is highly dependent on the relative solubility of the active in the components of the delivery system and in the stratum corneum. Thus, the formulation of the vehicle may markedly influence the degree

BASIC CONCEPTS

Delivery of Cosmetic Skin Actives

Table 8.1 Formulation components. Ingredient

Chemical function

Effect on delivery

Water

Carrier/solvent

Hydration

Alcohol

Carrier/solvent

Fluidizes stratum corneum, alters permeability of stratum cornuem

Propylene glycol

Co-solvent/humectant

Alter permeability of stratum corneum Alter vehicle stratum corneum partition coefficient

Surfactant

Emulsifier/stabilizer

Emulsion particle size reduction, active solubilizer

Emollient

Skin conditioner, active carrier

Alter stratum corneum permeability Alter vehicle stratum corneum partition coefficient

Delivery system

Protect/target actives

Targeted/enhanced active penetration

of penetration of the active. Percutaneous absorption involves the following sequences: • Partitioning of the molecule into the stratum corneum from the applied vehicle phase; • Molecular diffusion through the stratum corneum; • Partitioning from the stratum corneum into the viable epidermis; and • Diffusion through the epidermis and upper dermis and capillary uptake [7]. One of the most effective formulation techniques to boost active penetration is supersaturation. This chemical process happens when an active’s maximum concentration in solution is exceeded by the use of solvents or co-solvents. This type of solution state can happen during the evaporation of an emulsion on the skin. As water evaporates from a cream rubbed on the skin a superconcentrate depot of active forms on the skin. This creates a diffusional concentration gradient across the stratum corneum. One can attempt to boost this effect even further in the formulation by slightly exceeding the maximum solubility of the active in the formula using co-solvents. Supersaturation is an effective technique but the disadvantage is that active recrystallization can take place in this highly concentrated solution state. There are crystallization inhibitors that can be added to supersaturated solution but many experimental data need to be collected on this type of formulation strategy. Eutectic blends are formulation techniques that can enhance penetration of actives. The melting point of an active influences solubility and hence skin penetration. According to solution theory, the lower the melting point, the greater the solubility of a material in a given solvent, including skin lipids. The melting point can be lowered by

formation of a eutectic mixture. This mixture of two components which, at a certain ratio, inhibits the crystalline process of each other such that the melting point of the two components in the mixture is less than that of each component alone. In all cases, the melting point of the active is depressed to around or below skin temperature thereby enhancing solubility. This technique has been used to enhance the penetration of ibuprofen through the skin [8]. Manipulation of the vehicle skin partition coefficient of a formulation can be used as an overall formulation strategy to boost penetration of actives. This can be done by altering the solubility of the active in the vehicle via selection of different excipients. This change in the solubility parameter (δ) of the excipients can be tuned so that the active is more soluble in the stratum corneum than in the vehicle. Hence the diffusional gradient is altered towards the skin and thereby enhancing penetration. It has been shown that a solvent capable of shifting the solubility parameter (δ) of the skin closer to that of the activate will active flux rate [9]. Another strategy is to add a penetration enhancer that alters the membrane permeability of the skin. This strategy is discussed in more detail below. Skin occlusion can increase stratum corneum hydration, and hence influence percutaneous absorption by altering partitioning between the surface chemical and the skin because of the increasing presence of water, swelling corneocytes, and possibly altering the intercellular lipid phase organization, also by increasing the skin surface temperature, and increasing blood flow [10]. The ultimate goal of penetration enhancement is to target the active in the stratum corneum and/or epidermis without allowing for systemic absorption. This remains the biggest

8. Percutaneous delivery challenge for active penetration enhancement and it is one of the keys for targeted active delivery.

available that propel an abrasive against the skin thereby stripping away the stratum corneum.

Penetration enhancers

Penetration enhancement vectors

In this section, the influence of penetration enhancers on the diffusion coefficient and solubility of the active in the stratum corneum is evaluated. The use of topically applied chemical agents (surfactants, solvents, emollients) is a wellknown technique to modify the stratum corneum and also modify the chemical potential of selected actives. Collectively, these materials can be referred to as penetration enhancers (PEs). Based on the chemical structure, PEs can be categorized into several groups such as fatty acids, fatty alcohols, terpene fatty acid esters, and pyrrolidone derivatives [11]. PEs commonly used in skin care products have well-known safety profiles but their ability to enhance penetration of an active is challenging because of the manifold ingredients used in many formulations.

There are customized carriers (vectors) for delivery of actives to the skin. These vectors are a type of vehicle that allow for enhanced penetration via their small size and unique physical chemical composition. These vectors are known as submicron delivery systems (SDS). Discussion focuses on liposomes, niosomes, lipid particles, and nanocapsules.

Solvents A number of solvents (e.g. ethanol, propylene glycol, Transcutol® [Gattefossé, Saint-Priest, France] and N-methyl pyrrolidone) increase permeant partitioning into and solubility within the stratum corneum, hence increasing KP in Fick’s equation (equation 1). Ethanol was the first penetration enhancer co-solvent incorporated into transdermal systems [12]. Synergistic effects between enhancers (e.g. Azone® [PI Chemicals, Shanghai, China], fatty acids) and more polar co-solvents (e.g. ethanol, propylene glycol) have also been reported suggesting that the latter facilitates the solubilization of the former within the stratum corneum, thus amplifying the lipid-modulating effect. Similarly, solvents such as Transcutol are proposed to act by improving solubility within the membrane rather than by increasing diffusion. Another solvent, dimethylsulfoxide (DMSO), by contrast, is relatively aggressive and induces significant structural perturbations such as keratin denaturation and the solubilization of membrane components [13].

Physical enhancers In addition to the chemical penetration enhancers discussed above, there is another class of penetration enhancers known as physical penetration enhancers. These materials stand between chemical enhancers and penetration enhancer devices. This unique classification is because in most cases the materials are particles of chemical origin (polyethylene, salt, sugar, aluminum oxide) but require physical energy to exert an action on the skin. These materials are used to physically débride or excoriate the stratum corneum by abrasive action. This is typically done by rubbing the particles by hand on the skin. New high-tech devices are now

Liposomes Liposomes are colloidal particles formed as concentric biomolecular layers that are capable of encapsulating actives. The lipid bilayer structure of liposomes mimics the barrier properties of biomembranes, and therefore they offer the potential of examining the behavior of membranes of a known composition. Thus, by altering the lipid composition of the bilayer or the material incorporated, it is possible to establish differences in membrane properties. Liposomes store water-soluble substances inside like biologic cells. The phospholipids forming these liposomes enhance the penetration of the encapsulated active agents into the stratum corneum [14]. There is debate on liposome formulations and their mode of action regarding penetration enhancement. Variation in performance may be caused by the variation in formulation and method of manufacture used to prepare this delivery form. Several factors such as size, lamellarity (unilamellar vs. multilamellar), lipid composition, charge on the liposomal surface, mode of application, and total lipid concentration have been proven to influence deposition into the deeper skin layers. It is reported by several authors that the high elasticity of liposome vesicles could result in enhanced transport across the skin as compared to vesicles with rigid membranes. Liposomes have a heterogeneous lipid composition with several coexisting domains exhibiting different fluidity characteristics in the bi-layers. This property can be used to enhance the penetration of entrapped actives into the skin. It is supposed that once in contact with skin, some budding of liposomal membrane might occur. This could cause a mixing of the liposome bi-layer with intracellular lipids in the stratum corneum which may change the hydration conditions and thereby the structure of lipid lamellae. This may enhance the permeation of the lipophilic active into the stratum corneum and ease the diffusion of hydrophilic actives into the interlamellar spaces [15].

Niosomes Niosomes are formed by blending non-ionic surfactants of the alkyl or dialkyl polyglycerol ether class and cholesterol

BASIC CONCEPTS

Delivery of Cosmetic Skin Actives

with subsequent hydration in aqueous media. These vesicles can be prepared using a number of manufacturing processes: ether injection, membrane extrusion, microfluidization, and sonication. Niosomes have an infrastructure consisting of hydrophilic, amphiphilic, and lipophilic moieties together and as a result can accommodate active molecules with a wide range of solubilities. They can be expected to target the active to its desired site of action and/or to control its release [16]. Niosomes are similar to liposomes in that they both have a bi-layer structure and their final form depends on the method of manufacture. There are structural similarities between niosomes and liposomes but niosomes do not contain phospholipids. This provides niosomes with a better stability profile because of improved oxidative stability.

Nanocapsules can be formed by preparing a lipophilic core surrounded by a thin wall of a polymeric material prepared by anionic polymerization of an alkylcyanoacrylate monomer. These very safe types of system have been proposed as vesicular colloidal polymeric drug carriers. Nanocapsules have the ability to enhance penetration but they can also control delivery of actives to the skin. In a recent study, indomethacin was nano-encapsulated for topical use. This study compared cumulative release of indomethacin dispersed in gel base with indomethacin nano-encapsulated and indomethacin nano-encapsulated in a gel. The highest delivery was achieved with the nanoencapsulated indomethacin (Figure 8.2).

Solid lipid nanoparticles

Devices for penetration enhancement

Solid lipid nanoparticles (SLNP) were developed at the beginning of the 1990s as an alternative carrier system to emulsions, liposomes, and polymeric nanoparticles. SLNP have the advantage of requiring no solvents for production processing and of relatively low cost for the excipients. SLNP represents a particle system that can be produced with an established technique of high-pressure hom*ogenization allowing production on an industrial scale. This method also protects the incorporated drug against chemical degradation as there is little or no access for water to enter the inner area core of the lipid particle [17]. Lipid particles can be used as penetration enhancers of encapsulated actives through the skin because of their excellent occlusive and hydrating properties. SLNP have recently been investigated as carriers for enhanced skin delivery of sunscreens, vitamins A and E, triptolide, and glucocorticoids [18].

Nanocapsules

Cumulative amount of indomethacin permeated (μg/cm2)

Nanocapsules are a type of submicron delivery system (SDS). This technology can segregate and protect sensitive materials and also control the release of actives. The more obvious opportunity for penetration enhancement of actives is because of their small size (20–1000 nm in diameter).

Ultrasound waves Ultrasound waves are sound waves that are above the audible limit (>20 kH). During ultrasound treatment the skin is exposed to mechanical and thermal energy which can alter the skin barrier property. Thermal and non-thermal characteristics of high-frequency sound waves can enhance the diffusion of topically applied actives. Heating from ultrasound increases the kinetic energy of the molecules in the

PNBCA nanocapsules in pH 7.4 phosphate buffer (I)

PNBCA nanocapsules in PLF-127 gel (II)

25% w/w PLF-127 gel (III)

0 0

Devices for enhancing skin penetration of actives are at the leading edge of skincare technology. When utilizing devices for enhanced penetration of actives it is imperative to look into the regulatory classification of these instruments. The FDA has several guidelines and requirements for medical devices (510K). The 510K regulatory classification is important for safety and efficacy of any consumer device product and an understanding of the regulatory landscape in this area is essential. Four device technologies are reviewed. They range from moderately invasive to mildly invasive in terms of effect on the skin. In all cases, the goal is to reversibly alter the skin barrier function by physical or electroenergetic means.

4 Time (hours)

Figure 8.2 Cumulative amount of indomethicin (initial loading 0.5% w/v) per unit area, permeating through excised rat skin when released from PNBCA nanocapsule dispersion in pH 7.4 phosphate buffer, PNBCA nanocapsule dispersion in Pluronic F-127 gel and 25% w/w Pluronic F-127 gel. Each value is the mean ± SE of four determinations. (This figure was published in: Miyazaki S, Takahashi A, Kubo W, Bachynsky J, Löbenberg R. (2003) Poly n-butylcyanoacrylate (PNBCA) nanocapsules as a carrier for NSAIDs: in vitro release and in vivo skin penetration. J Pharm Pharmaceut Sci 6, 238–45.)

8. Percutaneous delivery active and in the cell membrane. These physiologic changes enhance the opportunity for active molecules to diffuse through the stratum corneum to the capillary network in the papillary dermis. The mechanical characteristics of the sound wave also enhance active diffusion by oscillating the cells at high speed, changing the resting potential of the cell membrane and potentially disrupting the cell membrane of some of the cells in the area [19]. A recent study on the use of ultrasound and topical skin lightening agents showed the effect of high-frequency ultrasound together with a gel containing skin-lightening agents (ascorbyl glucoside and niacinamide) on facial hyperpigmentation in vivo in Japanese women [20].

Patches Delivery patches have been available for some time. One of the first applications of patch technology was in a transdermal motion sickness (scopolamine) patch. There are commercial products that provide actives in a patch formula. They utilize adhesive technology or a rate-limiting porous

Figure 8.3 Solid microneedles fabricated out of silicon, polymer, and metal, imaged by scanning electron microscopy. (a) Silicon microneedle (150 μm tall) from a 400-needle array etched out of a silicon substrate. (b) Section of an array containing 160 000 silicon microneedles (25 μm tall). (c) Metal microneedle (120 μm tall) from a 400-needle array made by electrodepositing onto a polymeric mold. (d–f) Biodegradable polymer microneedles with beveled tips from 100-needle arrays made by filling polymeric molds. (d) Flat-bevel tip made of polylactic acid (400 μm tall). (e) Curved-bevel tip made of polyglycolic acid (600 μm tall). (f) Curved-bevel tip with a groove etched along the full length of the needle made of polyglycolic acid (400 μm tall). (This figure was published in: McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG, et al. (2003) Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc Natl Acad Sci U S A 100, 13755–13760.)

membrane to target and localize the actives. Some common patch applications are directed towards reduction of age spots or dark circles under the eye. The key delivery enhancement for patches is a combination of localized delivery and occlusion.

Microneedles Another type of delivery device is the microneedle. Microneedles are similar to traditional needles, but are fabricated at the micro size. They are generally 1 μm in diameter and range 1–100 μm in length (Figure 8.3). The very first microneedle systems consisted of a reservoir and a range of projections (microneedles 50–100 mm long) extending from the reservoir, which penetrated the stratum corneum and epidermis to deliver the active. The microneedle delivery system is not based on diffusion as in other transdermal drug delivery products but based on the temporary mechanical disruption of the skin and the placement of the active within the epidermis, where it can more readily reach its site of action. Microneedles have been fabricated

(a)

(c)

(b)

(d)

(e)

(f)

BASIC CONCEPTS

Delivery of Cosmetic Skin Actives

with various materials such as metals, silicon, silicon dioxide, polymers, glass, and other materials. There are already patents granted for these types of moderately invasive delivery system [21].

Iontophoresis Iontophoresis is a technology that has been brought to the cosmetic industry via the pharmaceutical development field. Iontophoresis passes a small direct current through an active-containing electrode placed in contact with the skin, with a grounding electrode to complete the circuit. Three important mechanisms enhance transport: 1 The driving electrode repels oppositely charged species; 2 The electric current increases skin permeability; and 3 Electro-osmosis moves uncharged molecules and large polar peptides [22]. There are limitations related to this technique. The active ingredient must be water-soluble, ionic, and with a molecular weight below 5000 Da. Even with all of these limitations, reported data show that the drug delivery effectiveness can be increased by one-third through iontophoresis [23].

In vitro and in vivo delivery assessment A key in any evaluation assessment of skin bioavailability of actives is a quantitative measurement of activity by in vitro and in vivo methods. In early development phases in vitro methods provide a quick, reproducible way to identify promising formulations for next phase development studies. There are different techniques for evaluating percutaneous absorption of actives.

Franz cell A well-known technique for measuring in vitro skin permeation is the Franz cell apparatus (Figure 8.4). The test apparatus and technique have been well documented for use within the pharmaceutical and cosmetic industries [24]. The technique utilizes a sampling cell which contains a

Cell cap

solution reservoir and a sampling port, the top portion of the Franz cell is covered with a biologic membrane or skin substitute. The formulation is added to the top of the cell and periodic samples are taken from the cell reservoir and assays are plotted versus time to develop a time–penetration profile.

Tape stripping Tape stripping is a technique used for in vivo active penetration evaluation. In this procedure, penetration of the active is estimated from the amount recovered in the stratum corneum by adhesive tape stripping at a fixed time point following application [25]. This technique is also recognized by FDA as a viable screening option for dermatologic evaluation [26].

Microdialysis During the last decade, microdialysis has been shown to be a promising technique for the assessment of in vivo and ex vivo cutaneous delivery of actives. The technique is based on the passive diffusion of compounds down a concentration gradient across a semi-permeable membrane forming a thin hollow “tube” (typically, a few tenths of a millimeters in diameter), which – at least, in theory – functionally represents a permeable blood vessel (Figure 8.5.). Two kinds of probe are in common use: linear and concentric.

Confocal Raman microspectroscopy Confocal Raman microspectroscopy (CRS) is a new, noninvasive technique which can be used for in vivo skin penetration evaluation. This technique combines Raman spectroscopy with confocal microscopy. CRS is a nondestructive and rapid technique that allows information to be obtained from deep layers under the skin surface, giving the possibility of a real-time tracking of the drug in the skin layers. The specific Raman signature of the active agent enables its identification within the skin [27]. There is a range of techniques of in vitro and in vivo evaluation for following penetration of actives through the skin.

Sampling port

Cell clamp

Water jacket Cell body

Figure 8.4 The Franz diffusion chamber.

8. Percutaneous delivery Microdialysis pump Perfusate

Membrane

Application site Figure 8.5 The microdialysis apparatus for the evaluation of penetration through the human skin barrier. (This figure was published in: Schnetz E, Fartasch M. (2001) Microdialysis for the evaluation of penetration through the human skin barrier: a promising tool for future research? Eur J Pharm Sci 12, 165–74.)

Stratum corneum Viable epidermis Dermis

Solute

Dialysate

Diffuson of solutes into the perfusate

Table 8.2 Methods to assess drug penetration into and/or across the skin. (From Herkenne C, et al. (2008) In vivo methods for the assessment of topical drug bioavailability. Pharm Res 25, 87–103.) Method

Measure

Measurement site

Temporal resolution

Technical simplicity

In vitro

Diffusion cell

Transport into and across skin

In vivo: non- or minimally invasive

Tape stripping

Stratum corneum

ATR-FTIR

Stratum corneum

Raman

Q/L

Upper skin

Microdialysis

Q (free)

Dermis (or subdermis)

−

Vasoconstriction

Microcirculation

Blister

Extracellular fluid

Biopsy

Skin

Biopsy

Q+L

Skin (depth)

In vivo: invasive

Q, quantity of drug; A, pharmacological activity of drug; L, drug localization.

Some are more invasive than others and some are more predictive across various dosage forms utilized on the skin. In Table 8.2 a summary chart shows a good comparison of the techniques based on strengths and weaknesses.

Conclusions and future trends There are many formulation options available for delivering actives to targets within the skin. Understanding the skin and its interaction with various actives allows the chemist to select delivery options that provide safe and effective properties. A good understanding of the physicochemical parameters of the active and the desired skin target are needed before deciding on a particular delivery option. Human studies are the “gold standard” against which all methods for measuring percutaneous absorption should be judged. The conduct of human volunteer experiments is well regulated. Study protocols and accompanying toxicologic data must be submitted to an ethics committee for approval [28].

Next generation delivery technologies are being developed and in some cases are already on the way to the market. Researchers from device and skincare companies are already in collaboration to bring combinations of devices and actives to the field of cosmetic dermatology. The approach can vary from non-invasive LEDs all the way to more invasive, laser-based enhanced penetration of actives. There are many home-use devices coming to the market today. These advances in delivery technology will likely culminate in a commercially available topical product that has its efficacy boosted by some type of chemical or physical delivery device as demonstrated in the delivery of estradiol using either a delivery vesicle (ultra-deformable liposomes) or a device (iontophoresis) [29].

References 1 Chien YW. (1992) Novel Drug Delivery Systems, 2nd edn. New York: Marcel Dekker Inc., p. 303. 2 Barry BW. (1987) Penetration enhancers in pharmacology and the skin. In: Shroot B, Schaefer H, eds. Skin Pharmaco*kinetics. Basel: Karger; Vol. 1, pp. 121–37.

BASIC CONCEPTS

Delivery of Cosmetic Skin Actives

3 Heather A, Benson E. (2005) Current drug delivery, penetration enhancement techniques. Curr Drug Deliv 2, 23–33. 4 Moser K, Kriwet K, Naik A, Kalia YN, Guy RH. (2001) Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm 52, 103–12. 5 Katz M, Poulsen BJ. (1971) Absorption of drugs through the skin. In: Brodie BB, Gilette J, eds. Handbook of Experimental Pharmacology. Berlin: Springer Verlag, pp. 103–74. 6 Forster T, Jackwerth B, Pittermann W, Rybinski WM, Schmitt M. (1997) Properties of emulsions: structure and skin penetration. Cosmet Toiletries 112, 73–82. 7 Albery WJ, Hadgraft J. (1979) Percutaneous absorption: theoretical description. Pharm Pharmacol 31, 129–39. 8 Stott PW, Williams AC, Barry BW. (1998) Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen. J Control Release 50, 297–308. 9 Sloan KB, ed. (1992) Prodrugs, Topical and Ocular Drug Delivery Sloan. New York: Marcel Dekker, pp. 179–220. 10 Bucks D, Guy R, Maibach HI. (1991) Effects of occlusion. In: Bronaugh RL, Maibach HI, eds. In Vitro Percutaneous Absorption: Principles, Fundamentals, and Applications. Boca Raton: CRC Press, pp. 85–114. 11 Osborne DW, Henke JJ. (1997) Skin penetration enhancers. Pharm Technol November, 58–66. 12 Walters KA. (1988) Penetration enhancer techniques. In: Hadgraft J, Guy RH, eds. Transdermal Drug Delivery. New York: Marcel Dekker, pp. 197–246. 13 Harrison E, Watkinson AC, Green DM, Hadgraft J, Brain K. (1996) The relative effect of Azone and Transcutol on permeant diffusivity and solubility in human stratum corneum. Pharm Res 13, 542–6. 14 Abeer A, Elzainy W, Gu X, Estelle F, Simons R, Simons KJ. (2003) Hydroxyzine from topical phospholipid liposomal formulations: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model. AAPS PharmSci 5, 1–8. 15 Cevc G, Blume G. (1992) Lipid vesicles penetrate into intact skin owing to the transdermal osmotic gradients and hydration force. Biochim Biophys Acta 1104, 226–32. 16 Baillie AJ, Florence AT, Hume LR, Rogerson A, Muirhead GT. (1985) The preparation and properties of niosomes-non-ionic surfactant vesicles. J Pharm Pharmacol 37, 863–8.

17 Kreuter J. (1994) Nanoparticles. In: Kreuter J, ed. Colloidal Drug Delivery Systems. New York: Marcel Dekker, pp. 219–342. 18 Müller RH, Mäder K, Gohla S. (2000) Solid lipid nanoparticles (SLN) for controlled drug delivery: a review of the state of the art. Eur J Pharm Biopharm 50, 161–77. 19 Dinno MA, Crum LA, Wu J. (1989) The effect of therapeutic ultrasound on the electrophysiologic parameters of frog skin. Med Biol 25, 461–70. 20 Hakozaki T, Takiwaki H, Miyamot K, Sato Y, Arase S. (2006) Ultrasound enhanced skin-lightening effect of vitamin C and niacinamide. Skin Res Technol 12, 105–13. 21 Yuzhakov VV, Gartstein V, Owens GD. (2003) US Patent 6565532. Micro needle apparatus semi-permanent subcutaneous makeup. 22 Barry BW. (2001) Is transdermal drug delivery research still important today? Drug Discov Today 6, 967–71. 23 Yao N, Gnaegy M, Haas C. (2004) Iontophoresis transdermal drug delivery and its design. Pharmaceut Form Quality 6, 42–4. 24 COLIPA Guidelines for Percutaneous Absorption/Penetration. (1997) European Cosmetic, Toiletry and Perfumery Association. 25 Rougier A, Dupuis D, Lotte C. (1989) Stripping method for measuring percutaneous absorption in vivo. In: Bronaugh RL, Maibach HI, eds. Percutaneous Absorption: Mechanisms, Methodology, Drug Delivery, 2nd edn. New York: Marcel Dekker, pp. 415–34. 26 Shah VP, Flynn GL, Yacobi A, Maibach HI, Bon C, Fleischer NM, et al. (1998) Bioequivalence of topical dermatological dosage forms: methods of evaluation of bioequivalence. Pharm Res 15, 167–71. 27 Tfayli A, Piot O, Pitre F, Manfait M. (2007) Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy. Eur Biophys J 36, 1049–58. 28 World Health Organization (WHO). (1982) World Medical Association: Proposed International Guidelines for Research Involving Human Subjects. Geneva: WHO, p. 88. 29 Essa A, Bonner MC, Barry BW. (2002) Iontophoretic estradiol skin delivery and tritium exchange: ultradeformable liposomes. Int J Pharm 240, 55–66.

Chapter 9: Creams, lotions, and ointments Irwin Palefsky Cosmetech Laboratories Inc., Fairfield, NJ, USA

BAS I C CONCEPTS • Creams, lotions, and ointments are both vehicles and delivery systems for dermatologic products. • Creams and lotions are emulsions, which are colloidal dispersions comprising two immiscible liquids (e.g. oil and water), one of which is dispersed as droplets representing the internal or discontinuous phase within the other external phase. • Ointments are semi-solid preparations used topically for protective emollient effects or as vehicles for the local administration of medicaments. • Ointments are mixtures of fats, waxes, animal and plant oils, and solid and liquid hydrocarbons.

Introduction This chapter examines creams, lotions, and ointments as both vehicles and delivery systems for dermatologic products. Creams, lotions, and ointments have a unique composition that can alter the ability of ingredients to reach the skin surface while also influencing product esthetics. The construction of the cream or ointment is an important determining factor in patient compliance, because if patients do not like the feel, smell, or color of a dermatologic they will not properly follow directions for its use.

Definition of creams, lotions, and ointments Creams and lotions Creams and lotions are classified as emulsions. There are several different types of emulsions that function as a vehicle and delivery system for cosmetic and drug materials. The classic definition of an emulsion is a colloidal dispersion comprising two immiscible liquids (e.g. oil and water), one of which is dispersed as droplets representing the internal or discontinuous phase within the other external phase [1]. All emulsions require the inclusion of an emulsifier or dispersing agent responsible for keeping the two immiscible phases together for an extended period of time. All emulsions are unstable and will eventually separate into two or more phases.

Emulsions can be classified as a cream or lotion. There are no legal definition differences between a cream and a lotion. The determination of what constitutes a cream or lotion emulsion is determined by viscosity. If an emulsion can be poured from a bottle or pumped from a jar, it is labeled a lotion. If the emulsion requires a jar or a tube for dispensing and does not readily flow, it is labeled a cream. The term emulsion will be used for the remainder of this chapter to indicate a cream or lotion. The other important part of the definition of an emulsion is based on the materials that comprise the internal phase and the materials that comprise the external or continuous phase. The two categories of emulsions are oil-in-water (O/W) and water-in-oil (W/O). The names describe the composition of the emulsion (Figure 9.1). Emulsions can also be described by their emulsifier type as anionic, cationic, and non-ionic. This terminology refers to the ionic charge, or lack of charge, on the emulsifier system. Emulsions have also been developed that are based on polymeric emulsifiers and liquid crystal emulsifiers. These emulsions are different from traditional emulsions, because the two phases are held together by different mechanisms. Sophisticated emulsion technology is beyond the scope of this chapter; however, additional information can be found in Bloch [1].

Ointments Ointments can be defined as semi-solid preparations used topically for protective emollient effects or as vehicles for the local administration of medicaments. They are mixtures of fats, waxes, animal and plant oils, and solid and liquid hydrocarbons [2]. Ointments are traditionally anhydrous bases, meaning they do not contain water, and therefore pose fewer microbial contamination issues than emulsions, which is a distinct advantage. In addition, because ointments

BASIC CONCEPTS

Delivery of Cosmetic Skin Actives

Table 9.2 A typical “non-ionic” oil-in-water emulsion base. Ingredients

Function

% weight/weight

Deionized water

External phase vehicle

82.95

Carbomer

Thickener

0.20

Disodium EDTA

Chelating agent

0.10

Butylene glycol

Humectant

2.00

Water phase

Water in oil

Oil in water

Figure 9.1 Different emulsion types. (This figure is from “Emulsions” presentation from Cognis Corp. August 2004.)

Table 9.1 Generic composition of a typical oil-in-water emulsion.

Oil phase Cetearyl alcohol (and) ceteaeth-20

Emulsifier

2.00

Ingredients

Cyclopentasiloxane

Silicone emollient

4.00

% (weight/weight)

Water phase Deionized water

60.0–90.0

Dimethicone

Silicone emollient

1.00

Humectant

2.00–7.0

Caprylic/capric triglyceride

Organic emollient

5.00

Preservative*

0.05–0.5 1.25

0.25–2.5

Glyceryl stearate (and) PEG100 stearate

Emulsifier

Water-soluble emulsifier†

Triethanolamine (99%)

Neutralizing agent and pH adjuster

0.50

Preservative

Antimicrobial

1.00

Thickener(s)

0.1–1.0

Water-soluble emollient

0.5–2.0

Chelating agent

0.05–0.20 The pH of this cream would be 5.5–6.5. The viscosity would be approximately 15 000–25 000 centipoise.

Oil phase Emollient system – oils, esters, silicones, etc.

3.0–15.0

Oil-soluble emulsifiers

2.0–5.0

Composition of creams and ointment

“Active ingredients”

As required by regulations

Oil-in-water creams

Oil-soluble antioxidants

0.05–0.5

Fragrance/essential oil, etc.

0.1–2.0

The most popular type of emulsion used in skin care products and cosmeceuticals is oil-in-water (O/W). A generic composition for an O/W emulsion is presented in Table 9.1 [3]. Each of the ingredient classes are discussed in detail to aid in the understanding of O/W formulations. A typical “non-ionic” oil-in-water emulsion composition is shown in Table 9.2.

Color

As required

Preservative*

0.05–1.0

pH adjustments

As required

* Preservatives are frequently added in two places in the formulation. † May also be added into the oil phase.

are anhydrous in nature, they tend to be more waterresistant than emulsions. However, ointments have less esthetic appeal for skin care and dermatology products as they are frequently described as oily, waxy, greasy, sticky, tacky, and heavy. Ointments are used more commonly for the delivery of medications than for skin care products because of their undesirable esthetics.

Emulsifiers Emulsifiers are important to keep the oil and water ingredients miscible. The choice of emulsifier will also determine the emulsion pH and effect the application and stability of the emulsion, as well as the delivery of materials into the skin. Emulsifiers can damage the skin barrier by emulsifying the sebum and intercellular lipids. This has led to the need to develop “skin friendly emulsifiers.” These emulsifiers do not adversely affect the barrier properties of the skin and in some cases even help maintain barrier properties. Because the route of delivery into the skin is primarily through the lipid layer, which constitutes the mortar in the “brick and

9. Creams, lotions, and ointments mortar” model of the skin, the selection of an emulsifier can determine whether the disruption of the lipid layer. Liquid crystal forming emulsifiers are being used more frequently because they maintain the skin barrier. These emulsifiers function like the phospholipids and ceramides found in the skin and therefore do not disrupt barrier function because of their skin lipid compatibility. A popular liquid crystal forming emulsifier is lecithin or hydrogenated lecithin [4]. Another recent trend is the use of emulsifiers as part of the emollient system in the product. Emollients are substances that make the skin feel smooth and soft, which is important to consumer acceptability. The most popular of this emulsifier type are “cationic” emulsifiers, which possess a net positive charge. The skin has a net negative charge because of its amino acid composition. A positively charged emulsifier will be attached to the skin and remain on the skin because of electrostatic attraction. Examples of these emulsifiers are behentrimonium methosulfate and dicetyldimonium chloride. Cationic emulsifiers are also very effective when there is a need to formulate low pH emulsions (less than pH 4.5) as cationic emulsifiers are very stable in low pH environments.

Emollients The choice of emollient or combination of emollients will have a dramatic effect on the feel, application, and delivery of the active to the skin. Matching solubility of active with the oil phase has a big effect in determining the material to be used. Matching the solubility parameter of an organic sunscreen to the solubility parameter of the oil phase has a significant effect on the sunscreen performance. The emollient category has been greatly expanded because of the increased use of silicones and the increasing number of “natural” emollients. The selection of emollient combinations is where art and science are combined. Selecting the right combination which provides the proper initial, middle, and end feel is one of the biggest challenges affecting the successful development of a cream. Concepts such as “cascading effect” describe this type of change which occurs as you apply an emollient system.

Active ingredients Examples of active ingredients are sunscreen materials (e.g. octinoxate, titanium dioxide, avobenzone), antiacne actives (i.e. salicylic acid, benzoyl peroxide), skin lighteners (hydroquinone), etc.

Humectants The humectant, usually a glycol or polyol, will have an effect on “skin cushion” and can also be part of the solvent system for an active ingredient. Glycols, such as propylene glycol and butylene glycol, are very good solvents for salicylic acid (an FDA approved over-the-counter active ingredient used

to treat acne) and are frequently used for this purpose in an emulsion system. In addition, they also function to help with freeze–thaw stability.

Thickeners The thickener(s) are used to control the viscosity and the rheology of the emulsion and can also help in maintaining the stability or product integrity of the emulsion, especially at elevated temperatures. Even in W/O creams thickeners are used for viscosity control. The viscosity of a cream is primarily determined by the thickener used and the viscosity of the external phase. The choice of thickeners, to a large extent, depends upon the compatibility of the thickener with the rest of the ingredients in the formulation, the pH of the formulation, and the desired feel that is trying to be achieved. The predominant thickeners used in O/W emulsions are acrylic-based polymers. The most popular materials are carbomers and its derivatives. Carbomers are a cross-linked polyacrylate polymer and their derivatives which are high molecular weight hom*opolymer and co-polymers of acrylic acid cross-linked with a polyalkenyl polyether [4]. These polymeric thickeners are very effective in stabilizing emulsions at elevated temperatures. (In W/O emulsions the predominant thickeners for the external phase are waxes – natural or synthetic.)

Water-in-oil creams The composition of a W/O emulsion may not look much different on paper than an O/W emulsion except that the emulsifier system would be different and would be designed to make a W/O emulsion. The ratio of the two phases is not an indication of the type of emulsion. There are many O/W emulsions in which the oil phase may be at a higher persentage than the water phase and in a W/O emulsion the water phase is frequently at a higher percentage than the oil phase.

Ointments There are different types of ointments. The traditional type of ointment contains very high levels of petrolatum as this material is a very good water-resistant film former and serves as very effective delivery system for drug actives on the skin. An example of a traditional petrolatum-based ointment is shown in Table 9.3. In reviewing this formulation you will notice that there is no antimicrobial preservative present. Some ointment formulations put in low levels of antimicrobial preservatives for added protection during consumer use, but anhydrous ointments are hostile environments for bacteria and are generally “self-preserving.” The use of an oil-soluble emulsifier helps with the application properties of the ointment as well as the ability to wash it off the skin. Recently, there has been an increased interest in “natural ointments” – ointments that do not use petrochemicals (i.e.

BASIC CONCEPTS

Delivery of Cosmetic Skin Actives

Table 9.3 An example of a traditional petrolatum-based ointment. Ingredients

% (weight/weight)

White petrolatum USP

50.0–80.0

Lanolin

1.0–5.0

Natural and/or synthetic waxes

2.0–10.0

Oil-soluble emulsifier

1.0–3.0

“Drug actives”

As required

Antioxidants

0.1–0.5

Fragrance/essential oils

0.1–1.0

Skin feel modifiers

1.0–5.0

Table 9.4 A typical “natural ointment” composition. Ingredients

% (weight/weight)

Soy bean oil (and) hydrogenated cottonseed oil

50.0–80.0

Lanolin

1.0–5.0

Natural waxes

2.0–10.0

Oil vegetable-soluble emulsifier

1.0–3.0

“Drug actives”

As required

Natural antioxidants

0.1–0.5

Natural fragrance/essential oils

0.1–1.0

Natural skin feel modifiers

1.0–5.0

petrolatum) and are primarily based on plant-derived materials. The primary difference is in the use of the material that replaces petrolatum in the formulation. There are a number of hydrogenated oil/wax mixtures that are offered and used as “natural petrolatums.” A typical “natural ointment” composition is shown in Table 9.4). “Natural ointments” generally do not have the same unctuous, heavy feel that petrolatum-based ointments have and they usually do not leave as much residual feel on the skin. As with petrolatum-based ointments, little or no antimicrobial preservative is needed because of the anhydrous nature of the ointment. However, antioxidants are a very important components, as these “natural oil-based” ointments have a tendency to turn color and go rancid (similar to what you would see in a vegetable oil) without adequate protection.

While the number of different ingredients that can be used in an emulsion or an ointment can sometimes seem overwhelming, once you break down the product into the attributes and benefits and esthetics that are desired, the choices become less daunting.

Cream and ointment stability Once the formulations have been put together and evaluated, the next step is stability testing. This testing is carried out to determine what happens to the product once it is on the market. The ideal test would be to store the product at ambient temperature for 2–3 years and observe any changes that may occur in product integrity and determine the stability of the active ingredient(s) that are present. Because this timeframe is not practical, accelerated stability testing is conducted to predict the long-term stability of the product. For most emulsions, this testing involves storage of the finished product at 5 °C, 25 °C (RT), and 40 °C and sometimes at 50 °C. Stability at 40 °C is traditionally carried out for 3 months [1]. This testing is accepted by the US FDA for expiration dating until a full 2–3 year study is complete. Its purpose is not to ascertain product integrity but to establish the stability of the drug actives in the product. Elevated temperature testing (40 °C for 3 months) is conducted so that a determination can be made in a reasonable amount of time as to the integrity and stability of the product and to allow the product to be marketed in a reasonable amount of time from the completion of formulation development.

Conclusions The development of the final formulation is a combination of art and science, and both have an important role in the use of the product by the patient or consumer. Once the type of formulation is determined, the ingredients have been selected, the formulation developed, and the appropriate safety, efficacy, preservative and stability testing completed, the product is ready to introduce to the market.

References 1 Block LH. (1996) Pharmaceutical emulsions and microemulsions; emulsions and microemulsion characteristics and attributes. In: Lieberman HA, Rieger MM, Banker GS, eds. Pharmaceutical Dosage Forms: Disperse Systems, Vol. 2. New York: Marcel Dekker, pp. 47, 94–5. 2 www.biology-online.org/dictionary/Ointments: Biology on Line; Dictionary-O-Ointments 2008. 3 “Emulsions” presentation from Cognis Corporation, August 2004. 4 www.personalcare.noveon.com/products/carbopol, Carbopol Rheology Modifiers.

Section II Hygiene Products

Part 1: Cleansers Chapter 10: Bar cleansers Anthony W. Johnson and K.P. Ananthapadmanabhan Unilever HPC R&D, Trumbull, CT, USA

BAS I C CONCEPTS • There are two basic types of cleansing bar – soap bars and synthetic detergent bars. • Like all surfactant-based products, cleansing bars can be harsh or mild to skin. • Mild cleansing bars have a key role in fundamental skin care. • Mild cleansing bars have positive benefits for patients with skin diseases.

Introduction Cleansing bars – historical perspective Anecdotally, soap was discovered by prehistoric man, noticing a waxy reside in the ashes of an evening camp fire around a burnt piece of animal carcass. The waxy material was soap. Potash from the ashes (KOH) had hydrolyzed triglyceride from animal fat to produce potassium soap and glycerol. Actual historical records show soap-like materials in use by Sumerians in 2500 BC and there are references to soap in Greek and Roman records and by the Celts in northern Europe. As European civilizations emerged from the Dark Ages in the 9th and 10th centuries soap making was well established and centered in Marseilles (France), Savona (Italy), and Castilla (Spain). In those days soap was a luxury affordable only by the very rich. Mass manufacture of soap started in the 19th century and was well established by the turn of the century with individually wrapped and branded bars. Synthetic detergents emerged in the 20th century, primarily for fabric washing products. While there are many types of synthetic detergent, very few are suitable for making cleansing bars. It is difficult to make a solid product that is able to retain a solid form during multiple encounters with water and at the same time able to resist cracking, crumbling, and hardening when drying between uses. Soap is ideal for making bars but that is not to say that some of the early soap bars did not dry out and develop cracks

or become soft and mushy in humid environments. Modern manufacturers are able to formulate soap bars to control the physical behavior in use and when drying between uses. Soap-based bars continue to dominate the cleansing bar market around the world, but synthetic detergent bars are gaining an increasing share of market (30% of bars sold in the USA). The wide range of soap bars available in the skin marketplace today might suggest a wide range of functionality but this is not the case. To develop new claims and gain shelf space in big supermarkets, manufacturers create variants by minor modifications of their basic bar types – the functional properties of soap bar variants are usually very similar – they all lather and they all clean.

Formulation technology of cleansing bars Cleansing bars are made of surfactants that are solid at room temperature and readily soluble in water. While there are scores of commercially available surfactants only two, alkyl carboxylate (soap) and acyl isethionate (syndet), are used on a large scale for manufacture of cleansing bars (Figure 10.1). These two surfactant types are quite different, leading to different sensory experiences for the consumer and also differences in their interactions with skin. Soap and syndet have in common that they have the physical properties required to be processed into bars that can withstand the challenges of use in the home. As bars they must have a consistent performance – they must lather easily when new but just as readily as the bar is used up over a period of weeks or months. They should produce lather quickly and easily and should not feel gritty in use. The rate of wear should be optimum, neither too fast nor too slow. They must

HYGIENE PRODUCTS

Cleansers O-

Sodium acyl isethionate (syndet) S

Na+

O O O Sodium alkyl carboxylate (soap) O- Na+ O Figure 10.1 Schematic representation of the molecular structures of soap (sodium alkyl carboxylate) and syndet (sodium acyl isethionate) showing the difference in head group structure and size.

fatted soap. Basic soaps are blends of medium chain length fatty acid sodium salts (Figure 10.1). Superfatted soaps are similar but with additional fatty acid. There are other categories of soap bars based on the use of specialist ingredients: transparent bars, antibacterial bars, and deodorant bars. There are large numbers of specialist bars that are simply soap containing a wide range of colors, fragrances, and emotive ingredients such as vitamins, aloe, chamomile, and other natural extracts. The emotive ingredients in specialist bars are there to appeal to the senses and emotions with no real expectation that they have any detectable benefit for the skin.

Basic soap dry quickly after use but must not crack; they should not break apart if dropped, and should not absorb water and become mushy in a humid environment, like a bathroom. There are not many surfactants that can satisfy this list of seemingly simple practical requirements. Broadly speaking, there are two types of manufacturing process for making cleansing bars: (a) a continuous process of milling, extrusion, and stamping; and (b) a batch process of melt casting.

Continuous processing The continuous process starts with synthesis of the basic surfactant, alkyl carboxylate, and then processing this as a solid through various steps during which other ingredients are added until the final composition is attained. After milling and mixing steps to ensure hom*ogeneity, the compounded soap it is extruded as a continuous bar which is chopped and stamped into the individual bar shape of the final product. The technical demands of the continuous process impose constraints on composition and ingredient addition – but it is the fastest and cheapest way to make a cleansing bar.

Soap is the sodium salt of a fatty acid. As the salts of weak acids, soaps form alkaline solutions as they dissociate in water. The pH of soap is typically in the pH range 9–11. This is not sufficient to be overtly irritating to skin but is sufficiently high to negatively impact the pH-dependent processes of the stratum corneum which has a natural pH of around 5.5. The fatty acids used in soap making are natural, derived from animal or plant sources, with the most common chain lengths in the range C12 (e.g. coconut fatty acid) to C18 (e.g. tallow/rendered animal fat). C12–14 soaps are soluble and lather easily. C16–18 soaps are less soluble but good for forming solid bars. The plant oils used in soap making are mostly triglycerides and when treated with lye and/or caustic soda they hydrolyze to the fatty acid sodium salts (soap) and glycerol.

Superfatted soap bars Simple soaps are good cleansers but also drying to skin. Less drying soaps are made by adjusting the soap making process to leave an excess of free fatty acid in the final soap composition (superfatted soaps). This excess fatty acid reduces the lipid stripping and drying effects of a soap bar to a small extent. Beauty soaps are typically superfatted soaps.

Batch processing

Transparent soaps

The essence of the melt cast approach is to make the surfactant and add any desired ingredients to form a hot liquid melt which is poured into individual bar size casts and allowed to set as it cools. This is a much more expensive process but allows for a wider range of additional ingredients in the product formulation. The continuous process is used for most of the mass market bars and the melt cast process for specialist bars often sold in boutiques, custom outlets, and department stores.

There are several types of transparent or semi-transparent soap bars. The earliest was a rosin glycerin soap bar developed by Andrew Pears in 1789. The ingredients of Pears patented transparent soap were sodium palmitate, natural rosin, glycerine, water, C12 soap, rosemary extract, thyme extract, and fragrance. The Pears soap of today is made by essentially the same process, which involves dissolving the raw soap and other ingredients in alcohol, pouring into moulds followed by up to 3 months of evaporation and drying. A different type of transparent bar was introduced in 1955 by Neutrogena based on a patented formulation invented by a Belgian cosmetic chemist, Edmond Fromont. His novel formulation was based on triethanolamine soap (in other words, soap where the neutralizing cation is triethanolamine

Soap bars There are several major compositional types of soap bar with distinct bar properties and in use behaviors – speed and type of lather, rate of use up, aroma, skin compatibility, tendency for mush, etc. Most bars are either basic or super-

10. Bar cleansers instead of the usual sodium). The ingredients of the Neutrogena bar are triethanolamine stearate, C12–18 soaps, glycerine, water, and a range of minor ingredients including a little lanolin derivative and fragrance. Triethanolamine forms acid soaps so the pH of the Neutrogena bar at pH 8–9 is lower than a regular soap with sodium as the cation.

US cleansing bars % total market (volume) Syndet 1 Soap 1 Soap 2 Soap 3 Soap/Syndet Soap 4 Syndet 2 Syndet 3 Soap 5 Private label Syndet 4 Soap 6

Antibacterial and deodorant soap bars Medicated or antibacterial soaps are a large subcategory of the bar soap market. These products are basic soaps containing one of a limited number of approved antibacterial agents. Some of these products are positioned as deodorant soap to inhibit the odor-producing bacteria of the axilla. Washing with any soap is effective for removing and killing the bacteria on skin and the value and contribution of added antibacterial agents is controversial. However, there are a variety of tests developed to assess the effectiveness of antibacterial soaps and there is no doubt that there is some deposition of the antibacterial agents on skin during washing and this is expected to reduce the effectiveness of any residual bacteria and to reduce colonization by other microbes.

US syndet cleansing bars (% of syndet segment)

Bar 1 Bar 2 Bar 3 Bar 4* Bar 5* * Less than 0.1% market share – too low to register

Non-soap detergent bars – syndet bars Because soap is cheap and easy to manufacture the cleansing bar market has remained predominantly soap bars. However, there has been one non-soap bar technology that has achieved a significant place in the US market over the last 50 years and is now extending its reach to other regions of the world. This product, introduced to the US market in 1957 as the Dove bar, is based on patented acyl isethionate as the surfactant component in combination with stearic acid which has a dual function of providing the physical characteristics for forming a stable bar and also acting as a significant skin protecting and moisturizing ingredient. The high level of stearic acid in the Dove bar is the basis of the one-quarter moisturizing cream in the product. When the patents for this novel technology ran out, several other acyl isethionate bars were introduced in the USA market including Caress, Olay, Cetaphil, and Aveeno.

Market overview There are hundreds of cleansing bars on the market but relatively few that are widely sold. Most of the cleansing bar market is supplied by a small number of manufacturers and a limited number of brands. Figure 10.2 shows the segmentation of the US market for soap and syndet cleansing bars.

Preservatives It is of interest that soap bars and syndet bars are self-preserved in the sense that they provide a hostile environment for microorganisms and do not need to contain a preservative to maintain product quality.

US cleansing bar segmentation % total market (volume)

Syndet Soap

Figure 10.2 Segmentation of cleansing bar market (based on average data for 2006, 2007, and 2008). The charts show shares (volume) for leading soaps and syndet bars. Brands not identified. Brands and their market shares vary somewhat year to year and may vary considerably over time.

Impact of cleansing bars on skin structure and function Washing with soap removes dirt and grime from skin and is very effective for removing germs and preventing the spread of infection. There is an appreciation that some soaps are harsh and others mild, but washing with soap is so routine and commonplace that most people give no thought to the cleansing process or its impact on skin. This is a mistake.

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Cleansers

Research over the last few years has revealed several mechanisms by which soap interacts with skin structures to adversely affect normal functioning. It is now clear that mild cleansing has significant benefits for both diseased and healthy skin. Mild cleansing can reduce the symptoms of common skin conditions such as eczema, acne, and rosacea and can enhance the attractiveness of normal skin.

Surfactant interaction with the skin–stratum corneum As described in other chapters of this book, the outer layer of skin, the stratum corneum, is a very effective barrier to the penetration of microorganisms and chemicals unless compromised by damage, disease, or a intrinsic weakness caused by one of the genetic variations now known to impact the functioning of the stratum corneum. Whatever the normal state of the stratum corneum for an individual, the most challenging (i.e. potentially damaging) environmental factor, apart from industrial exposure to solvents and other harsh chemicals, is cleansing. And yet cleansing is a key element of good everyday skincare and there is much variation in the damaging potential of different cleansing products including cleansing bars. Understanding how cleansing products impact skin and knowing the mildest cleansing product technologies is a basic requirement for achieving fundamental skin care.

further cleansing or even simply by contact with water. This process explains the paradox that water is often a major factor for causing dry skin. Effects on the key lipid structures of the stratum corneum add to the damage caused by soap– protein interactions and exacerbate the development of skin dryness – remembering that dry skin is not simply a lack of moisture but a disturbance of normal stratum corneum function with retention and accumulation of superficial corneocytes. The build up of corneocytes at the skin surface is responsible for many symptoms associated with “dry” skin – scaling, flaking, roughness, dull appearance (due to light scattering), tightness, loss of resilience/flexibility/elasticity, and ultimately cracking and irritation. All soaps have the ability to induce dry and irritated skin and these effects are most evident in challenging environmental condition – cold or hot temperatures with low humidity, excessive exposure to solar UV radiation, and prolonged exposure to wind. The drying potential of soap varies according to composition such as the balance between soluble (C12–14) and less soluble chain lengths (C16–18) of the fatty acids most commonly used to make soap – the higher the soluble component the more drying the soap. Superfatted soaps are a little milder than simple soaps, and triethanolamine soap and glycerol bars the mildest of the commonly available soap bars.

Soap bar interactions with the stratum corneum

Synthetic detergent bar interactions with the stratum corneum

The properties of soap that make it an effective cleanser also determine that it can be drying and irritating to skin. The high charge density of the carboxyl head group of the soap molecule promotes strong protein binding which is good for cleansing but bad for skin. Soap binds strongly to stratum corneum proteins and disturbs the water-holding mechanisms of the corneocytes. Soaps also denature stratum corneum enzymes essential for corneocytes maturation and desquamation. The result is an accumulation of corneocytes at the skin surface and the characteristic scaly, flaky, roughness associated with dry skin. In addition to damaging proteins, soap and other cleansers can disrupt and strip out the lipid bi-layers of the stratum corneum. The bipolar structure of the soap molecule is similar to the bipolar structure of the three major lipid types that make up the lipid bi-layers of the stratum corneum (fatty acids, cholesterol, and ceramides). Soap disrupts the bi-layer structure of these lipids in the stratum corneum and thereby reduces the effectiveness of the stratum corneum water barrier. Transepidermal water loss (TEWL) is increased through the leaky barrier. Also, disruption of the structured lipid matrix around stratum corneum cells (corneocytes) allows the highly soluble components of the skin’s natural moisturizing factor (NMF), contained in the protein matrix of the corneocytes, to leach out. Leaching is increased by

Synthetic detergent bars (syndet bars) have been available on the US market for 50 years and represent a clear technologic difference from soap-based cleansing bars. Nearly all common synthetic detergent bars are based on an anionic surfactant, acyl isethionate. At the time of writing (2008) these bars account for 40% of the cleansing bars sold in the USA. Alkyl glycerol ether sulfonate (AGES) and monoalkyl phosphate (MAPS) are two of a small number of other synthetic detergents that have been tried for manufacture of cleansing bars but none of these have been successful in the US market. Ironically, because syndet bars are shaped like soap bars and used for cleansing just like a soap bar, most people believe that synthetic detergent bars are just another variety of soap. Most consumers are unaware that there is a fundamental compositional difference between soap and syndet bars that impacts their interactions with skin such that syndet bars are milder than soap bars during cleansing. There is a greater difference between soap and syndet cleansing in terms of healthy and attractive skin than most people realize. It is important for healthcare professionals and dermatologists to appreciate the difference between soap and syndet bars because studies show the difference in mildness is very relevant for their patient groups (see studies described below).

10. Bar cleansers Soap (alkyl carboxylate) and syndet (acyl isethionate) are both anionic surfactants and like all anionic surfactants they interact with skin proteins and skin lipids. But because of the difference in head group physical chemistry soap interactions are more intense leading to a higher potential for inducing dryness and irritation. The carboxylate head group is compact, leading to a high charge density that facilitates binding and denaturation of proteins. By contrast, the isethionate head group is large and diffuse, producing a low charge density and less ability to interact with proteins (Figure 10.1) A second and most important factor contributing to the mildness of the isethionate syndet bar is the ability to formulate acyl isethionate with high levels of stearic acid without losing the ability to lather. In fact, the lather is more dense and creamy than the lather of a typical soap bar. The stearic acid component of the isethionate syndet bar acts as a moisturizing cream and deposits on skin during cleansing, adding to the relative mildness of these types of bar.

Superfatting is, in principle, a similar way to reduce the harshness of plain soap but the results are much more modest because the initial harshness of soap is higher than syndet and the upper limit of practical superfatting is closer to 10% compared to the 20–25% fatty acid that can be formulated in an isethionate bar. Another difference between soap and syndet bars is pH. Soap has an alkaline pH typically around pH 10–11 whereas isethionate/stearic acid bars are close to pH neutral with a pH of a little over 7. The pH of glycerol bars is in the range pH 8–9. These differences in pH have an effect on the interaction of cleansing bars with the stratum corneum. Skin proteins swell markedly if the cleanser pH is highly alkaline (pH >8). Optical coherence tomography (OCT) pictures of stratum corneum after exposure to acidic, neutral, and alkaline pH conditions and the corresponding swelling show that there is significantly higher swelling in alkaline pH solutions (Figure 10.3). Strongly binding detergent molecules can increase the swelling further.

pH 4

pH 6.5

pH 10 Figure 10.3 Swelling of the stratum corneum in different pH buffer solutions. (a) Optical coherence tomography (OCT) images of ex vivo skin treated with different buffer solutions. The arrows show the position and thickness of the stratum corneum. (b) The bar chart provides a graphic representation of the same difference.

Average stratum corneum swelling (μm)

100 80 60

* *

40 20 0

pH 4

pH 6.5 Buffer

pH 10

* Different from pH 10 P<0.05 (a)

(b)

HYGIENE PRODUCTS

Cleansers

High pH also has an impact on stratum corneum lipids. An alkaline pH can ionize fatty acids in the lipid bi-layers making them more like “soap” molecules and destabilizing the highly organized structure of the bi-layers. These factors contribute to the differences in mildness of soap and syndet bars. Environmental scanning electron microscopy pictures of the skin surface and the corresponding transmission electron microscopy images of the proteinlipid ultrastructure of human skin washed under exaggerated conditions (nine repeat washes) with a syndet and a soap bar are seen in Figure 10.4. It is evident from the micrographs that the syndet bar washed sample exhibits wellpreserved cells with intact proteins and lipids compared with the soap washed sample.

Studies comparing mildness properties of soap and syndet cleansing bars Many consumers are not aware of the differences in drying and irritation potential between soap bars and synthetic detergent bars. In practice, most cleansing products are not drying to an extent that is readily perceivable and under normal conditions of use cleansing bars seldom produce

(ESEM)

irritation and inflammation. However, in other circ*mstances, particularly drying environmental conditions or with compromised diseased skin, some cleansing bars can cause severe dryness and irritation. Why is this? Under normal conditions it is likely that the skin is superficially and temporarily dried by most cleansers but is rapidly able to restore its ability to hold moisture and maintain healthy functioning. However, under challenging environmental conditions, particularly the harsh cold winters of Canada and the northern USA and the hot dry summers of the central plains and western desert areas of the USA, recovery after washing is likely less rapid. Without supplemental moisturization from the cleansing product or a skin cream or lotion applied after washing, a vicious cycle of damage and inadequate recovery is quickly established, leading initially to dry skin but quickly progressing to deeper damage with fissuring of the stratum corneum (cracking), deeper penetration of the surfactant, frank irritation, and ultimately full-thickness cracking of the stratum corneum leading to chapping and bleeding. This may sound extreme but anyone with a tendency to develop dry skin will recognize this scenario of raid deterioration to more severe irritation when the weather is drying – particularly for handwashing.

(ESEM)

Water

(ESEM)

Soap bar

Syndet bar (TEM)

Water

Soap bar

Syndet bar

Figure 10.4 Environmental scanning electron micrographs (ESEM) and transmission electron micrographs (TEM) images of human skin washed with water, soap, and a syndet bar (9 repeat washes). Water washed and mild syndet bar washed skin shows well-preserved lipids and plumped (hydrated) corneocytes. By contrast, images of harsh soap-washed skin show significant removal of lipids and damage to proteins.

10. Bar cleansers The first practical demonstration that syndet bars are fundamentally less damaging to skin than soap bars was a study published by Frosh and Kligman [1]. Using a new and simple method, the soap chamber test, they examined the skin irritation potential of all the cleansing bars they could purchase locally in Philadelphia at that time. One bar stood out as exceptionally mild compared with the rest of the marketplace (17 other bars tested) and this was a patented alkyl isethionate bar called Dove. Now that the Dove patent has expired a number of manufacturers sell similar isethionate syndet bars. The difference in relative mildness of soap and isethionate/stearic acid syndet bars is easily demonstrated in the standard wash and rinse tests used by manufacturers of cleansing products. The forearm controlled application test (FCAT) and leg controlled application test (LCAT) are 5-day repeat washing tests. Skin condition is evaluated daily by a variety of techniques including visual dryness, superficial and deeper hydration measured instrumentally, TEWL to

assess barrier performance, and erythema to assess irritation. Typical results obtained by comparing soap and syndet cleansers in a FCAT test are shown in Figure 10.5. An increase in stratum corneum dryness has a negative effect on the mechanical properties of the corneum. Changes in stratum corneum elasticity/stiffness measured in a standard clinical test after washing with soap and syndet bars are shown Figure 10.6. While soap washing increases skin stiffness markedly, the milder syndet bar maintains the original skin condition. Such effects are magnified further under low humidity and winter conditions and can lead to microcracks in the stratum corneum and increased water loss, plus increased vulnerability to penetration of external chemicals into skin. Concern is sometimes expressed that industry standard tests are exaggerated and do not reflect real consumer experience. The evidence accumulated by manufacturers and published in peer-reviewed journals demonstrates that effects in standard tests are indeed predictive of what can be

Visual dryness

Corneometer 5

Mean change from baseline

* 0 –5 –10 –15 –20

* Syndet less dryness than all soaps (P<0.05)

(a)

(syndet soap differences P<0.05)

(b) TEWL

Skicon 0

8 6 4

2 0

* Syndet sig. less barrier impairment

Mean change from baseline

Syndet Soap 1 Soap 2 Soap 3 Soap 4 TeaSoap

–20

–40

–60

than soaps 1, 2, 3, 4 (P<0.05)

(c)

* Syndet hydrating, soaps drying

* Syndet sig. less drying than soaps 1, 2, 3, 4 (P<0.05)

(d)

Figure 10.5 Skin changes after 5 days of twice daily washing with soaps and syndet using the forearm controlled application test (FCAT) method. (a) Visual dryness; (b) transepidermal water loss (TEWL) – skin moisture barrier; (c) Corneometer – stratum corneum hydration; (d) Skicon – superficial stratum corneum hydration.

Change in stiffness (rheometer)

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Cleansers

2.5

Practical implications of mild cleansing for patients with common skin disease

Soap

2.0 1.5 1.0 0.5 Syndet

0 –0.5 0

2.5

3.5 Days

4.5

5.5

Figure 10.6 Changes in skin mechanical properties (stiffness) after 5 days of twice daily washing with soap and syndet using the FCAT method. Soap washing induced a progressive increase in stratum corneum stiffness as measured using a linear skin rheometer whereas the syndet bar did not induce stiffness.

5-day controlled arm wash test

Less dry

Day 7 score minus baseline

5 day change from baseline

Less dry

–0.5

–1.0

–1.5

–2.0

2–7 day normal use for daily face wash

–0.5

–1.0

–1.5

–2.0

More dry

More dry Soap

Syndet

Figure 10.7 Skin dryness induced by soap and syndet bars in a 5-day controlled arm wash test compared to dryness induced by 2–7 days of normal use once daily for facial cleansing. Arm wash test carried out on the same subjects as the 7-day facial wash test. Most soap users were unable to continue soap use for a full week. Most syndet users were able to complete a full week of daily face washing – dryness scores are based on assessments made on day 7 for the whole panel.

experienced in normal use under realistic but challenging environmental conditions. Figure 10.7 shows results of a study where women used soap or syndet for face washing for a week during the Canadian winter. They were not allowed to use a facial moisturizer during the study. Under the cold drying conditions of this study the soap users rapidly experienced intense drying and soreness whereas the syndet users were mostly able to tolerate the withdrawal of their normal after-wash moisturizer for a week.

The studies described in this section [2,3] were based on a simple hypothesis that switching patients with common skin diseases from their current soap bar cleanser to a milder syndet bar cleanser would minimize symptoms and generally help in managing their skin condition. The patient groups studied were atopic dermatitis, acne, and rosacea. The results show that patient symptoms were reduced and general skin quality improved.

Benefits of mild cleansing for adults and children with mild atopic dermatitis A total of 50 patients with mild atopic dermatitis were enrolled for a 4-week double-blind study carried out under the supervision of a certified dermatologist. One group of 25 patients (19 adults and 6 children <15 years) used a marketed syndet cleansing bar instead of their normal cleansing bar for showering during the 4 weeks of the study. A second group of 25 patients (17 adults and 8 children) used a different syndet bar based on the same acyl isethionate cleansing system. Eczema severity was measured at baseline and 4 weeks using the eczema area severity index (EASI) clinical assessment system. Other evaluations at these times were dermatologist assessment of non-lesional skin, hydration by conductance meter, and patient self-assessment by questionnaire. Results indicated good compatibility with the syndet bar as a substitute for patient’s usual bar cleanser for both adults and children. In addition, it was observed that the severity of eczematous lesions reduced with both bars, general skin condition was improved, and hydration was maintained. The main results are shown in Figure 10.8.

Benefits of mild cleansing for acne and rosacea patients In one study, a group of 50 patients with moderate acne and using topical acne medications (benzamycin or benzamycin/ differin) were split into two treatment cells (25 patients per cell) and instructed to use either a syndet bar or a soap bar for 4 weeks in place of their normal cleansing bar. Patient skin condition was assessed at baseline and after 4 weeks of use. Although the clinical differences between soap and syndet in this test were not statistically significant, there was a clear trend that patients using soap experienced worsening of measures relating to skin compatibility and irritation during the 4-week period of the study and little or no change in patients using the syndet bar (Figure 10.9). A similar protocol was used in a study of rosacea patients. Seventy patients were enrolled and divided into two subgroups for a 4-week study period. Evaluations were per-

10. Bar cleansers Dermatologist clinical evaluation EASI (Eczema Area/Severity Index)

Group mean EASI

2.5 2.0

1.5

Day 0 Day 28

1.0 0.5 0

Syndet bar A

Syndet bar B

* Day 28 eczema area/severity score sig. less than day 0 score (P<0.02) Patient self assessment of change in skin condition from day 0 to day 28 Decreases from baseline Symptom

Change from day 0

Increases from baseline Attribute

Bar A Bar B Dryness Itching Irritation Tightness Tingling

-1.5 -1.3 -1.1 -0.9 -0.7

-2.1 -2.8 -2.7 -1.3 -1.4

Change from day 0 Bar A Bar B

Complexion Smoothness Softness Appearance

0.2 0.7 0.4 1.3

1.3 2.7 2.8 2.3

Red numbers - sig. diff from baseline at day 28 (P<0.05)

Figure 10.8 Changes in dermatologist and patient assessment of skin condition after 4 weeks’ daily use of syndet cleansing bars by adult and child (7–15 years) patients with atopic dermatitis (AD). A total of 25 patients used bar A and 25 used bar B. The patients were patients with chronic AD stabilized using a variety of treatment regimens which they continued during the trial. The bars were similar in composition with the same acyl isethionate synthetic surfactant system and different ratios of emollients.

formed at baseline and at 4 weeks. The results show a similar trend in favor of using the syndet bar (Figure 10.9). The studies described above indicate a benefit of syndet bars for patients with disease compromised skin. Other studies have shown that use of syndet bars is helpful for skin that is compromised by treatments used to reduce the signs of photodamage such as retinoid therapy or chemical peels.

liquid cleansing products. This is most pronounced in the developed markets of North America and Europe. Like many market trends this change is brought about by changes in consumer needs, habits, and attitudes. Cleansing liquids have become the product of choice for the shower, liquid soaps are increasingly used for hand cleansing, and quick foaming liquids, creams, and wipes have largely replaced soap bars for facial cleansing. Nevertheless, there is little doubt that cleansing bars will remain a universal household product for many years to come. This chapter describes the negative effects for skin associated with cleansing and provides evidence that there are real benefits for patients and consumers generally to use the mildest bar cleansers available. It has long been recognized that environmental factors facilitate the drying, irritating actions of surfactants and that people differ in their susceptibility to these effects. Only recently has it become evident that genetic variations are direct drivers of individual variations in susceptibility to develop dry and sensitive skin. It appears that loss-of-function mutations in the filaggrin gene are relatively common in humans and are the cause of mild and severe forms of ichthyosis vulgaris and atopic dermatitis. The insight that filaggrin gene mutations and variations lead to a compromised barrier that predisposes to dry skin is changing how scientists and professionals think about dry skin and healthy skin functioning. Some people have a good barrier but others are much more susceptible to environmental challenges – including cleansing. Gene profiling is not yet a routine diagnostic procedure but susceptibility to develop dry skin is a strong indication of a compromised barrier and the need for mild cleansing to prevent surfactant-induced exacerbation of a poor barrier. The future will see new and more precise diagnostic tests enabling dermatologists and healthcare professionals to more readily identify consumers and patients who have less than optimal stratum corneum functioning. In parallel, the need to identify mild products and good cleansing practice will come into sharper focus. It will be interesting to see if the future consumer product trend is a rebalancing from soap bars to milder syndet bars or if the trend will be a more direct move from bars to liquid cleansers. Most likely the market will develop in both directions – milder bars and more use of liquid cleansers.

Conclusions The future of cleansing bars Bar soaps have been the most common product for skin cleansing for so long that most people never give them a second thought. However, since the late 1990s there has been a slow but steady decline in soap bar sales in favor of

Cleansing is a basic human need and cleansing bars are the universal way to satisfy this need. Liquid products may be gaining in popularity but it will be decades before bars become redundant, if ever. Cleansing is a challenge to skin for everyone, but for patients with skin problems the choice of cleansing product

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Cleansers

Change in acne symptoms – dermatologist assessed

0.3 Soap bar Syndet bar

s Ti gh tn es

Itc hi ng

in gi ng St

Bu rn in g

ne s ry D

el in g

–0.3

he m

Chane day 0 to day 28

0.6

Trend differences (day 28 not statistically significantly different from day 0)

Change in rosacea symptoms – dermatologist assessed

ne ht Ti g

ng hi Itc

ng gi in St

Soap bar Syndet bar

–0.3

in g

he yt

–0.6

Chane day 0 to day 28

0.3

Trend differences (day 28 not statistically significantly different from day 0)

is the difference between exacerbation and minimization of symptoms. There is ample evidence in the literature that syndet bars are milder than soap-based bars and better for patients with common dermatologic conditions such as atopic dermatitis, eczema, acne, and rosacea. Not everyone needs to use a syndet bar but many consumers and patients currently using soap bars could experience a practical benefit by switching to syndet bar.

References 1 Frosch PJ, Kligman AM. (1979) The soap chamber test: a new method for assessing the irritancy of soaps. J Am Acad Dermatol 1, 35–41. 2 Current Stratum Corneum Research. (2004) Optimizing barrier function through fundamental skin care. Dermatol Ther 17(1), 1–68. [A full issue of the journal (9 papers) dedicated to the biology of the stratum corneum barrier and the impact of cleansing and moisturizing products.] 3 Subramanyan K. (2004) Role of mild cleansing in the management of patient skin. Dermatol Ther 17(1), 26–34. [Specific paper dealing with the clinical studies.]

Figure 10.9 Dermatologist assessed changes in skin condition of patients with mild to moderate acne or mild to moderate rosacea after 4 weeks’ use of soap or syndet bar for daily cleansing. In the acne study were 50 patients using topical benzamycin or benzamycin plus differin. In the rosacea study were 70 patients using topical metronidazole. The syndet bar was acyl isethionate synthetic surfactant and the soap bar was a standard 80/20 soap.

Further reading Ananthapadmanabhan KP, Lips A, Vincent C, Meyer F, Caso S, Johnson A, et al. (2003) pH-induced alterations in stratum corneum properties. Int J Cosmet Sci 25, 103–112. Ananthapadmanabhan KP, Subramanyan K, Rattinger GB. (2002) Moisturizing cleansers. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York: Marcel Decker, pp. 405–32. Ertel K, Keswick B, Bryant P. (1995) A forearm controlled application technique for estimating the relative mildness of personal cleansing products. J Soc Cosmet Chem 46, 67–76. Imokawa G. (1997) Surfactant mildness. In: Rieger MM, Rhein LD, eds. Surfactants in Cosmetics. New York: Marcel Dekker, pp. 427–71. Johnson AW. (2004) Overview. Fundamental skin care: protecting the barrier. Dermatol Ther 17, 213–22. Matts PJ. (2002) Understanding and measuring the optics that drive visual perception of skin appeareance. In: Marks R, Leveque JL, Voegeli R, eds. The Essential Stratum Corneum. London: Martin Dunitz, p. 333. Matts PJ, Goodyer E. (1998) A new instrument to measure the mechanical properties of human stratum corneum in vivo. J Cosmet Sci 49, 321–33.

10. Bar cleansers Meyers CL, Thorn-Lesson D, Subramanyan K. (2004) In vivo confocal fluorescence of skin surface: a novel approach to study effect of products on stratum corneum. J Am Acad Dermatol 50, 130. Misra M, Ananthapadmanabhan KP, Hoyberg K, et al. (1997) Correlation between surfactant-induced ultrastructural changes in epidermis and transepidermal water loss. J Soc Cosmet Chem 48, 219–34. Murahata RI, Aronson MP, Sharko PT, et al. (1997) Cleansing bars for face and body: in search of mildness. In: Rieger MM, Rhein LD, eds. Surfactants in Cosmetics. New York: Marcel Dekker, pp. 427–71. Nicholl G, Murahata R, Grove G, Barrows J, Sharko P. (1995) The relative sensitivity of two arm-wash methods for evaluating the mildness of personal washing products. J Soc Cosmet Chem 46, 129–40.

Prottey C, Ferguson T. (1975) Factors which determine the skin irritation potential of soaps and detergents. J Soc Cosmet 26, 29–46. Rawlings AV, Harding CR. (2002) Moisturization and the skin barrier. Dermatol Ther 17, 43–8. Rawlings AW, Watkinson A, Rogers J, et al. (1994) Abnormalities in stratum corneum structure, lipid composition, and desmosome degradation in soap-induced winter zerosis. J Soc Cosmet Chem 45, 203–20. Strube D, Koontz S, Murahata R, et al. (1989) The flex wash test: a method for evaluating the mildness of personal washing products. J Soc Cosmet Chem 40, 297–306. Wihelm KP, Wolff HH, Maibach HI. (1994) Effects of surfactants on skin hydration. In: Elsner P, Berardesca E, Maibach HI, eds. Bioengineering of the Skin: Water and the Stratum Corneum. Boca Raton, FL: CRC Press, pp. 257–74.

Chapter 11: Personal cleansers: Body washes Keith Ertel and Heather Focht Procter & Gamble Co, Cincinnati, OH, USA

BAS I C CONCE P T S • Dry skin on the body is a particular issue for most consumers. Leave-on lotion application is not always viewed as a convenient intervention, so relief is sought from alternative sources such as moisturizing personal cleansing products. • Body washes are a relatively new introduction into the armamentarium of personal cleansing products and their use is growing rapidly, particularly in developed countries. • Body washes present unique formulation challenges and benefit opportunities compared to traditional cleansing bar forms. • There are several distinct types of body washes. Of these, moisturizing body washes represent the greatest departure from traditional personal cleaners, having the potential to improve dry skin condition. • Moisturizing body washes vary widely in terms of their skin effects (i.e. their ability to mitigate dryness). A product must deposit an effective amount of benefit agent on the skin during the wash–rinse process. Understanding the basis for a product’s designation as “moisturizing” is key.

Background Cleansing to remove soils from the skin’s surface is a basic human need that serves both a cosmetic and a health function. While cleansing needs for the face receives considerable attention and few question the logic of specialized facial cleansers, cleansing needs for the body are often given little thought, the assumption being that any personal cleanser will suffice. This view is somewhat surprising given that body skin accounts for more than 90% of the body’s total surface area and, as we will show, consumers have diverse needs and expectations from a body cleanser. Water alone cannot effectively remove all soils from the skin and surfactant-based materials have been the cleansing aids of choice throughout recorded history. Soap was among the first cleansing aids and some of the earliest references to soap preparation are found in Sumerian and Egyptian writings, although legend holds that the article we know as soap originated by chance at Mount Sapo in Ancient Rome when fat and wood ash from sacrifices were mixed with rainwater. Regardless of its origin, soap was the cleansing aid of choice and remained largely unchanged for centuries. The next real step-change in personal cleanser technology occurred around the time of World War I, when the first non-soap surfactant was introduced. However, bars continued as the predominant form for body cleansing and it was

not until the latter part of the 20th century that liquid personal cleansing products for the body (i.e. body washes) were introduced and began to gain a foothold in some regions. Body washes are generally less messy in use than bars (e.g. no soap mush), are more hygienic, and offer greater potential to deliver skin benefits, including dry skin improvement. However, body washes can be less convenient to transport and are generally more expensive on a per use basis than commodity cleansing bars. As a result, body wash adoption tends to reflect countries’ economic development status.

Types of body washes Body washes currently available in the market generally fall into three distinct categories. Regular body washes are products whose primary function is to provide skin cleansing. As such, they are typically based on a relatively simple chassis, although fragrance is sometimes used to define product character or to provide a higher order benefit (e.g. lavender scent may be used to produce a calming effect during use). Moisturizing body washes are intended to provide a dry skin improvement in addition to performing the base skin cleansing function. However, there are different ways to define dry skin improvement for moisturizing body washes. In some cases a product’s benefit is judged relative to another (drying) personal cleanser and “improvement” amounts to producing less dryness than the benchmark. In other cases a product’s benefit is judged relative to an untreated control and “improvement” reflects the effect of the product relative to the condition of untreated skin. Thus, moisturizing body

11. Body washes washes can provide markedly different levels of dry skin improvement depending on the criterion used to judge their performance. Finally, there are products that fall into a broad category best described as specialty body washes. These are extensions of regular and moisturizing body washes that contain ingredients intended to provide additional function or benefit. Examples include products that contain beads or other grit material (e.g. pulverized fruit seeds) to provide exfoliation and an enhanced dry skin benefit, and products that contain menthol or other sensates to provide a “cooling” or “tingling” sensation to the skin.

Major formula components of body washes Water Unlike their cleansing bar counterparts, body wash formulas contain a high percentage of water. This situation is a double-edged sword. On the one hand, eliminating the need to form materials into a bar that will hold its shape while maintaining good performance and wear characteristics removes a number of formulation constraints, and this introduces the possibility of incorporating relatively high levels of non-cleanser materials (e.g. benefit agents) into the formulation. On the other hand, the aqueous milieu present in liquid cleansers and body washes introduces issues not present in bars. For example, many benefit agents are lipophilic in nature and an improperly formulated liquid cleaner may exhibit phase separation or creaming, not unlike the separation of oil and water phases that occurs in some salad dressings. Chemical stability is also a consideration; the greater mobility afforded by a liquid environment increases the likelihood of molecular interactions, and water itself can participate in decomposition reactions (e.g. hydrolysis). An aqueous environment also increases the potential for microbial contamination. Thus, formulating a liquid cleanser or body wash presents a number of unique challenges, particularly if the product is intended to perform a function beyond simple cleansing such as delivering a benefit agent to the skin.

Surfactants Surfactants are the workhorse ingredient in any personal cleansing product. Water is capable of removing some soils from the skin; however, sebum and many of the soils acquired on the skin through incidental contact or purposeful application (e.g. topical medicaments) are lipophilic in nature and are not effectively removed from the skin’s surface by water alone. Surfactants, or surface-active agents, have a dual nature; part of a surfactant molecule’s structure is lipophilic and part of it is hydrophilic. This structural duality allows surfactant molecules to localize at the interface between water and lipophilic soils and lower the inter-

facial tension to help remove the soil. Further, surfactants allow water to more effectively wet the skin’s surface and to solubilize lipopilic soils after removal, which prevents the soils from redepositing on the skin during rinsing. Surfactants are also responsible for the formation of bubbles and lather, which most consumers view as necessary for effective cleansing. As with cleansing bars, the surfactants used in liquid personal cleansers and body washes fall into two primary groups: soaps and non-soaps, also known as synthetic detergents or syndets. Soap is chemically the alkali salt of a fatty acid formed by reacting fatty acid with a strong base, a process known as saponification. The fatty acids used in soap manufacture are derived from animal (e.g. tallow) or plant sources (e.g. coconut or palm kernel oil). These sources differ in their distribution of fatty acid chain lengths, which determines properties such as skin compatibility and lather. Soap’s properties are also affected by external factors such as water hardness; soaps are generally more irritating and lather and rinse more poorly in hard water. Some specialty body washes contain soaps derived from “natural” fatty acid sources such as coconut or soybean oil; these products will behave similarly to products containing soaps derived from traditional fatty acid sources. Syndets, which are derived from petroleum, were developed to overcome shortcomings associated with soaps (e.g. the influence of water hardness on performance) and to expand the pool of available raw materials used in manufacture. Syndets vary widely in terms of their chemical structure, physicochemical properties, and performance characteristics, including skin compatibility. Syndets are not necessarily less irritating than soaps. Sodium lauryl sulfate is an example; many dermatologists view alkyl sulfates as model skin irritants. Most body washes are based on syndet surfactant systems, and because syndets have a wide range of performance characteristics, most body washes combine several surfactant types to achieve specific performance to the finished product. For example, alkyl sulfates, while having relatively poor skin compatibility, lather well. Combining an alkyl sulfate with an amphoteric surfactant such as cocamidopropyl betaine can improve both lather and skin compatibility. Thus, formulating a body wash with syndets involves choosing surfactants to optimize performance and aesthetics, balanced with cost considerations.

Skin benefit agents Some body washes contain ingredients that are intended to provide skin benefits beyond simple cleansing. Dry skin, which is a pervasive dermatologic issue, is one of the most common benefit targets for body washes. Not surprisingly, moisturizing ingredients such as petrolatum, various oils, shea butter, or glycerin, which are found in leave-on moisturizers, are often used in moisturizing body washes. However, simply including a moisturizing ingredient in a

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rinse-off product is not sufficient; the product must deposit an effective amount of the material on skin during the cleansing and rinsing process. As noted earlier, standards for judging moisturizing efficacy differ. Clinical testing shows that moisturizing body washes vary widely in their ability to provide a dry skin benefit, and that some may actually worsen dryness and irritation. In addition to moisturizing ingredients to improve dry skin, body washes may also contain particulates such as beads or pulverized fruit seeds to aid exfoliation. A particulate’s size, surface morphology (i.e. smooth or rough), and in-use concentration will determine its ability to provide this benefit. Finally, body washes may contain ingredients that are intended to protect from or to reduce the effects of environmental insults. As with moisturizing ingredients, an efficacious amount of these materials must remain on skin after washing and rinsing.

Other ingredients Body wash formulas contain additional ingredients that act as formulation and stability aids. The addition of polymers and salt alter a product’s viscosity, which can modify performance characteristics or improve physical stability. Feel modifiers such as silicones are sometimes used to improve the in-use tactile properties of body washes that deposit lipophilic benefit agents on skin. Chelating agents such as ethylenediamenetetraacetic acid (EDTA) and antioxidants such as butylated hydroxytoluene (BHT) and are added to improve chemical stability, and buffering a body wash formula to a specific pH value can help inhibit microbial growth and improve the product’s chemical and physical stability. Color and fragrance are an important part of the in-use experience for many body washes. Colors are US Food, Drug, and Cosmetic Act (FD&C) approved dyes and are usually present in relatively low amounts, so the likelihood of experiencing an issue with a body wash product because of dye is low. Fragrances are also usually present in relatively low amounts, although the apparent concentration may seem higher as a result of “bloom” that results from lathering a body wash on a mesh cleansing puff, the recommended application procedure for many of these products. The incidence of issues with modern fragrances is low. Some body washes incorporate natural oils to impart fragrance but these products are not necessarily without potential issues because some of these natural materials can cause sensitization.

In-use performance considerations for body washes Cleansing ability The mechanical action associated with applying a personal cleanser to the body helps to loosen and remove some soils,

but surfactants are the primary agents responsible for aiding soil removal, particularly lipophilic soils. However, surfactants and the cleansing products based on them differ in their abilities to remove sebum and lipophilic soils [1]. These cleansing performance differences are a greater consideration in body washes than in bars because of the relatively lower surfactant concentrations present in the former compared with the latter. Because lipophilic soils present the greatest cleansing challenge, oil-based makeup materials are often used as model soils in tests intended to measure cleansing efficiency. These materials are poorly removed from the skin by water alone and their inherent color makes them easy to detect visually or instrumentally and measure on the skin’s surface. To test the cleaning efficiency of various methods of skin cleansing, we conducted a study comparing a moisturizing petrolatum-depositing body wash, a syndet detergent bar, and water for cleansing ability. A commercial oil-based makeup product served as a model soil and was applied to discrete treatment sites on the volar forearms of light-skinned females. The makeup was allowed to dry for 15 minutes and baseline colorimeter (L*) values were recorded at each site. Lather was generated from each cleansing product in a controlled manner and applied to a randomly assigned site for 10 seconds with gloved fingers. Sites were rinsed with warm water for 15 seconds, allowed to air dry for 30 minutes then chromameter measurements were repeated. Data were analyzed by a mixed-model procedure. The results show that water has little effect on removing the model soil from the skin and while the makeup used in this study is perhaps an extreme challenge, it nonetheless exemplifies why personal cleansing products are needed for soil removal. Not surprisingly, both personal cleansing products removed a significantly greater amount of the model soil than did water (P < 0.01), but the petrolatum-depositing body wash showed significantly greater makeup removal (i.e. cleansing efficiency) than the syndet bar (mean ΔL* values of 5.2 and 3.2, respectively; P < 0.02). Thus, this study shows that a petrolatum-depositing body wash can clean efficiently and demonstrates that consumers are not restricted to the traditional bar form for their skin cleansing needs.

Consumer understanding and need for moisturizing body washes Patients with dry skin that accompanies a dermatologic condition often require a high level of skin moisturization and may be willing to tolerate poor moisturizer product aesthetics (e.g. skin feel) to obtain relief. A recent habits and practices study among a group of 558 adult females demonstrates that a consideration of consumers’ varied moisturization needs and their desired product aesthetics must be made in

11. Body washes order to create products that improve patient compliance. These participants answered questions that provided a range of information about their needs for body moisturization and their expectations for a moisturizing personal cleansing product (i.e. body wash). Dry skin was a source of discomfort for a majority of participants; 62% said they were “very bothered” or “bothered” by discomfort due to dry skin, while 20% said they were “not bothered” by discomfort due to dry skin. Dry skin also drove these consumers to apply leave-on moisturizers; 68% said they “strongly agreed” or “agreed” that they needed to use a moisturizer every day because of their dry skin, while only 16% “disagreed” that their dry skin necessitated daily moisturizer application. With regard to moisturizing cleanser needs, 97% of the participants stated that they want more moisturization from their personal cleansing product. The needs fell into three groups that aligned with self-perceived body skin type. Women in one group (very dry skin, 32% of the population) want a body wash product that delivers a high level of moisturization and a substantial skin feel; women in a second group (dry skin, 35% of the population) want a body wash product that delivers a moderate level of moisturization and a somewhat perceivable skin feel; and women in a third group (combination skin, 22% of the population) want a body wash that provides a low level of moisturization, rapid absorption of the moisturizing agent, and no residual skin feel. This study is just one example of work conducted to understand female consumers’ needs and expectations with regard to dry skin and moisturization. Traditionally, the needs and expectations of their male counterparts were at best little studied and poorly understood, or at worst assumed to be the same as those of females. To gain insights into male consumers’ needs we conducted a habits and practices study among an adult panel representative of the US adult population comprising 303 males and 313 females. As in the study above, participants responded to a series of questions related to attitudes towards body skin condition, body skin care habits and practices, and attitudes towards various cosmetic interventions. This consumer research showed a strong contrast between the sexes in terms of their usage of products to care for their body skin. Males were on the whole less likely to use a treatment on their body than were females. However, dry skin ranked high on the list of body skin care needs for both sexes. Moisturizer application was identified as the best treatment for dry skin, but males were less likely to apply moisturizer to their bodies than were females because of a perceived time constraint. Skin-feel parameters were also more important to males than females; males wanted to feel clean, not sticky or greasy. Surprisingly, the study results indicate that males are more likely to seek help from a dermatologist for their dry skin than females.

Moisturization from body washes Dry skin on the body is a finding in many dermatologic conditions and the results presented in the previous section show that even in the absence of frank skin disease dry skin ranks as one of the most common body skin complaints for both sexes. Skin that is dry can itch, and flaking on “problem” areas such as legs, knees, and elbows is aesthetically unpleasing and can negatively impact self-confidence. Dry skin worsens with age, and low relative humidity, certain medications, and excessive hot water exposure are among the factors that can exacerbate dry skin. Personal cleansing products are also frequently cited as agents that cause or worsen dry skin via removal of essential skin lipids following excessive cleansing or cleansing with “harsh” surfactants. Dry skin signals that there is an insufficient level of moisture in the stratum corneum. Dermatologists often recommend application of leave-on moisturizers to relieve symptoms and to provide an environment in which the skin can repair stratum corneum damage associated with dry skin. However, surveys show that a high percentage of dermatologists believe that their (female) patients do not moisturize as recommended, a lack of convenience being cited as the primary reason for the perceived non-compliance. This pattern is consistent with the results found in our consumer habits and practices research. Coupling moisturization with an existing habit such as showering can improve compliance but, as noted earlier, there are different ways to define a moisturization or dry skin improvement benefit, and simply including a moisturizing ingredient in a body wash formula does not guarantee that it will deposit on skin or remain in a sufficient amount after rinsing to provide a benefit. We conducted a leg wash clinical study using the industry standard method (leg controlled application test) comparing the dry skin improvement efficacy of a water control and three marketed moisturizing body wash products [2]. Treatment sites on the legs were washed in a controlled manner once daily for 7 days with the randomly assigned treatments. Expert visual scores and instrumental measurements collected at baseline and study end were used to assess the change in dry skin condition produced by the treatments. Expert scoring shows a range of skin effects from these moisturizing products (Figure 11.1). Two of the body washes delivered significant (P < 0.05) improvement in dry skin relative to the water control, while one of the products had little effect on visible dry skin. Skin capacitance measurements showed the former body washes improved stratum corneum hydration (P < 0.05), while the latter reduced stratum corneum hydration relative to the control (P < 0.05), i.e. it dried the skin. Expert erythema scoring and transepidemal water loss (TEWL) showed a similar pattern; two of the body wash products improved skin condition relative to control, while the third significantly (P < 0.05) increased erythema and TEWL. This highlights the importance of

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understanding how products that are labeled as “moisturizing” perform clinically whenever possible. Simply recommending that a patient should use a moisturizing body wash may not produce an optimal benefit, and the wrong product recommendation could actually worsen skin condition. The consumer research presented in the previous section also highlights the need for personal cleansing products that deliver different levels of moisturization and different use aesthetics. Many personal cleansers are available in versions that ostensibly are designed for different skin needs, but such products often involve relatively minor changes in formulation and performance. Body washes, because of the greater formulation flexibility they offer, provide an opportunity to develop product versions that offer different levels of performance to meet specific needs. For example, the habits and practices study conducted among females identified three primary consumer groups in terms of body skin moisturization and body wash performance needs. Various body wash products have been created that offer differences in moisturizer level and dry skin improvement benefit across versions in order to meet these needs.

Who will benefit from using body washes? The body wash is a relatively new-to-market personal cleanser form that will initially appeal to users with practical concerns or to users seeking experiential benefits such as better lather and in-use scent intensity, which are often greater than a bar can deliver. Where body washes really distinguish themselves from traditional bar forms, however, is in their ability to provide higher order skin benefits. As we have shown, some body washes can provide a marked skin moisturization benefit that can affect not only the quantity but also the morphology of dry skin flakes (Figure 11.2). A large segment of the population can benefit from using this type of personal cleansing product. However, the following are two examples of conditions that may derive a particular benefit from a moisturizing body wash.

Figure 11.1 Expert dryness scores after 7 days of once-daily washing with marketed body wash products. The results show marked differences in the products’ abilities to provide a dry skin improvement (i.e. a skin moisturization benefit).

Ashy skin African-Americans and other dark-skinned individuals frequently suffer from ashy skin, a condition in which the skin’s surface appears grayish or chalky as a result of excessive dryness. The condition is often exacerbated by soap bar use which is common among this population. Moisturizers or other oils can provide temporary relief but, as discussed earlier, convenience often limits willingness to use leave-on products. Petrolatum is an effective moisturizer but neat application to the skin is limited by both convenience and esthetics. However, a petrolatum-depositing body wash may circumvent these issues while still delivering a skin benefit. To test this hypothesis, we conducted a study among a group of 83 African-American females who normally applied a leave-on moisturizer to relieve their ashy skin [3]. Subjects used a randomly assigned syndet bar or a moisturizing petrolatum-depositing body wash product for daily home showering for a 4-week period. Endpoint evaluations showed that the body wash produced significantly greater dermatologist-scored dry skin improvement and subject satisfaction for items such as ashy skin improvement and reducing itchy/tight feeling. Perhaps most importantly, subjects assigned to the petrolatum-depositing body wash noted marked improvement in their level of satisfaction with the appearance of their leg skin, their level of confidence in letting others see their legs, and in feeling good about themselves because of the appearance of their leg skin (Figure 11.3). These results indicate that proper personal cleanser choice can not only improve the physical symptoms of dry skin but also impact how users feel about themselves.

Atopic dermatitis Atopic dermatitis is a chronically relapsing skin disorder that currently affects an estimated 10% of children and adults in the Western Hemisphere and whose incidence is growing worldwide. Symptoms include xerosis, skin hyperirritability, inflammation, and pruritus. Personal cleansing products are viewed as a triggering factor for atopic dermatitis and dermatologists frequently recommend that their patients avoid

11. Body washes Subject 17: Baseline

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(b) Figure 11.2 Scanning electron microscope (SEM) photomicrographs of skin flakes adhering to tape strips taken from subjects’ legs before (a) and after (b) using a petrolatum-depositing body wash for 3 weeks. Baseline samples show numerous large, thick, dry skin flakes; endpoint samples show fewer and thinner flakes.

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Figure 11.3 Responses to psychosocial questions answered by African-American subjects before and after using a syndet bar or petrolatum-depositing body wash for 4 weeks. Items were rated on a +3 (strongly agree) to −3 (strongly disagree) scale. Ratings were not significantly different at baseline (P ≥ 0.48); endpoint ratings given subjects assigned to use the body wash were significantly better than those given by subjects assigned to use the syndet bar (P < 0.01).

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harsh cleansers. Therapy typically involves application of a prescription topical corticosteroid, using a mild cleanser for bathing or showering, and applying a moisturizer within 3 minutes of the bath or shower to seal in moisture [4]. The latter suggests that a moisturizing body wash may be ideally suited as a therapeutic adjunct in atopic dermatitis. We conducted two studies among subjects undergoing treatment for mild to moderate active atopic dermatitis to examine the effect of using a moisturizing petrolatumdepositing body wash for cleansing. In both studies a moisturizing syndet bar, which is often recommended to patients undergoing therapy, was used as a control. In one study both cleansers were paired with 0.1% triamcinolone acetonide cream. Subjects applied the topical corticosteroid as directed and used their assigned personal cleanser for daily showering. After 4 weeks SCORAD for subjects who used the moisturizing body wash was significantly (P < 0.01) lower than for subject who used the bar. Subjects using the body wash also noted significantly (P < 0.01) greater improvement in skin dryness and itching. The second study again involved subjects with mild to moderate active atopic dermatitis, but in this case subjects assigned to use the petrolatum-containing moisturizing body wash were prescribed a medium potency topical corticosteroid, while subjects assigned to use the moisturizing syndet bar were prescribed a standard high potency topical corticosteroid [5]. At study end the dermatologist investigator judged that subjects assigned to cleanse with the petrolatum-containing moisturizing body wash showed a significantly (P < 0.01) greater incidence of disease clearing than did subjects who used the syndet bar. The greater therapeutic response observed in the body wash group is important, but so is the fact that it was achieved using a lower potency topical corticosteroid, which can potentially reduce cost and the risk of steroid-related side effects. Subjects in the moisturizing body wash group also rated their skin condition better for a number of parameters related to their atopic condition. The results from both these

studies indicate that therapeutic response in atopic dermatitis is influenced by personal cleanser choice and again highlight the importance of personal cleansing product choice when treating skin disease.

Conclusions Body washes represent a new possibility in personal cleansing products, not only because of their ability to provide effective cleansing and deliver an improved in-use experience (e.g. lather amount, rinse feel, scent display) compared with bar cleanser forms, but also because they have a potential to improve skin condition by mitigating dry skin. Moisturizing body washes are in a position to meet a key consumer need for both men and women – dry skin improvement on the body. However, delivering a skin benefit from a rinse-off product is challenging and the product must leave an effective amount of benefit agent on the skin after washing and rinsing. Not surprisingly, moisturizing body washes vary widely in their ability to deliver a benefit and recommenders must understand these differences when evaluating moisturizing body wash products.

References 1 Bechor R, Zlotogorski A, Dikstein S. (1988) Effect of soaps and detergents on the pH and casual lipid levels of the skin surface. J Appl Cosmetol 6, 123–8. 2 Ertel KD, Neumann PB, Hartwig PM, Rains GY, Keswick BH. (1999) Leg wash protocol to assess the skin mositurization potential of personal cleansing products. Int J Cosmet Sci 21, 383–97. 3 Grimes PE. (2001) Double-blind study of a body wash containing petrolatum for relief of ashy, dry skin in African American women. Cosmet Dermatol 14, 25–7. 4 Hanifin J, Chan SC. (1996) Diagnosis and treatment of atopic dermatitis. Dermatol Ther 1, 9–18. 5 Draelos ZD, Ertel K, Hartwig P, Rains G. (2004) The effect of two skin cleansing systems on moderate xerotic eczema. J Am Acad Dermatol 50, 883–8.

Chapter 12: Facial cleansers and cleansing cloths Erik Hasenoehrl Procter & Gamble Co., Ivorydale Technical Center, Cincinnati, OH, USA

BAS I C CONCEPTS • The four goals of facial cleansing are: (1) to clean skin, removing surface dirt and all make-up; (2) to provide a basic level of exfoliation; (3) to remove potentially harmful microorganisms (bacteria); and (4) to cause minimal damage to the epidermis and stratum corneum. • Cleansing can occur by three means: (1) cleansing by chemistry; (2) cleansing by physical action; and (3) in many cases, cleansing by a combination of both chemistry and physical action. • Chemical cleansing occurs via surfactants categorized into four primary groups: cationic, anionic, amphoteric, and non-ionic. • Facial cleansers can be categorized as follows: lathering cleansers, emollient cleansers, milks, scrubs, toners, dry lathering cleansing cloths, and wet cleansing cloths.

Introduction Facial cleansing is not only a means to remove dead skin, dirt, sebaceous oil, and cosmetics, but also a first step in an overall skincare routine, preparing skin for moisturizers and other treatments. Facial cleansing also has an important role, well beyond skincare, in psychological well-being, helping to provide a ritualistic sense of renewal and rejuvenation [1]. Many cleansing technologies – ranging from water to a traditional bar of soap – are available to meet the facial cleansing needs of different skin types and soil loads. This chapter provides an overview of the many specialty facial cleanser technologies available, discusses technologies best suited to each skin type and cleansing need, and provides an in-depth understanding of substrate-based facial cleansers, which represent the newest technology available for facial cleansing.

History Facial cleansing is observed in the animal kingdom and existed well before hom*o sapiens inhabited Earth. Early facial cleansing consisted primarily of a quick splash or rinse of the face with cold water. In fact, this habit can still be observed in the animal kingdom today among many primates [2].

The first recorded use of facial cleansing utilizing more than water was among the Ancient Egyptians in 10 000 BC [3]. Egyptians were heavy users of makeups made from a base of metallic ores which contained natural dyes for color; this mixture was then painted onto the face. In this period, Early Egyptians typically bathed and removed makeup in a river. Their cleansers consisted of animal fat mixed with lime and perfume, and were similar to some of the homemade natural soaps in use today. Facial cleansing and body cleansing were done with the same soap. More recently, over the past 20 years, specialty facial cleansers have become quite mainstream, a result of an explosion in cleansing technology which has led to a multitude of high-quality, relatively low-cost cleansers. Most of the technical development have focused on three primary areas: 1 Better removal of exfoliated skin, dirt, soil, excess sebaceous oil, and makeup; 2 Synthetic surfactants that induce less skin barrier damage and are thus less likely to dry skin; and 3 Incorporation of cleansing chemistry onto cleansing cloths. Patients tend to take more care with cleaning and maintaining their face than the rest of their bodies. As such, consumer product companies have developed many different technologies and cleansing forms that benefit different facial skin types, cleansing rituals, and soil loads. Because there is such a broad array of cleansing forms, specialty facial cleansers has become a very fragmented category of products, which utilize more different technologies than most other cleaning applications. Although a wide range of products is available, these products share four common traits:

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Cleansers

1 To clean skin (removing surface dirt and all make-up); 2 To provide a basic level of exfoliation; 3 To remove potentially harmful microorganisms (bacteria); and 4 To cause minimal damage to the epidermis and stratum corneum. Additionally, facial cleansers are required to remove a myriad of chemicals and biologic materials, ranging from the latest waterproof makeup to excess skin oils and upper layers of stratum corneum.

Function It is well understood that the use of harsh surfactants and/ or overwashing skin can result in overremoval or distortion of stratum corneum and intercellular lipids, which can lead to reduced skin barrier function [4]. While the wide array of facial cleanser technologies all provide basic levels of skin cleansing, they all clean skin slightly differently. The mechanisms by which cleansing is accomplished can be grouped into three main categories: 1 Cleansing by chemistry; 2 Cleansing by physical action; and 3 In many cases, cleansing by a combination of both chemistry and physical action.

Chemistry of cleansing Two classes of chemicals are used in facial cleansers and are responsible for the cleaning effect: surfactants and solvents. Both of these types of chemicals interact with dirt, soil, and skin to remove unwanted material. Surfactants and solvents work via two different chemical mechanisms to effect removal of these materials. Understanding these mechanistic differences provides dermatologists with the insight needed to prescribe a cleansing regimen based on individual patient needs.

Surfactants Surfactants or “surface acting agents” are usually organic compounds that are amphiphilic, meaning they contain both hydrophilic groups and hydrophobic groups. The combination of both hydrophilic and hydrophobic groups uniquely makes surfactants soluble in both oil and water. Surfactants work by reducing the interfacial tension (the energy that keeps water and oil separated) between oil and water by being adsorbed at the oil–water interface. Once adsorbed at the interface, cleaning surfactants assemble into a low-energy aggregate called a micelle. Surfactant needs to be present at high enough concentration to form a micelle, a level called the critical micelle concentration (CMC), which is also the minimum surfactant concentration required to clean sebaceous oil, cosmetics, etc. When micelles form

in water, their tails form a core that encapsulates an oil droplet, and their (ionic/polar) heads form an outer shell that maintains contact with water. This process is called emulsification. Surfactants clean skin by emulsifying oily components on the surface of skin with water. Once emulsified, the oil can be easily rinsed from skin during the post wash or rinse process. The stronger the surfactant, the more hydrophobic material removed, the greater the potential skin damage from excessive removal of naturally occurring skin lipids, and the greater the ensuing compromise of optimal skin barrier function, therefore correct and careful formulation of these surfactants is required to ensure proper mildness. Recently marketed products show that with careful formulation very strong surfactants such as sodium laurel sulfate (SLS) can be well tolerated by skin. All surfactant-based cleansers require water and generally include a rinsing step. They are best suited to removal of oily residue. Unfortunately, two problems have been associated with cleansing with surfactants (one real and one largely folklore). First, because of their powerful cleansing action, overuse may completely eliminate the protective lipid barrier on the surface of skin, resulting in irritation and dryness. Second, for years consumers have heard negative stories regarding the alkaline (pH around 9) nature of these products. Wrongly assuming that because skin pH is about 5, washing with these high pH surfactants can lead to an increase in skin pH. Recent data suggest that the skin’s natural buffering capacity is more than adequate to eliminate any unwarranted impact of the pH of these products. Classic surfactants used in facial cleansers are categorized into four primary groups: cationic, anionic, amphoteric, and non-ionic. 1 Cationic surfactants used alone are generally poorly tolerated, and are now rarely used in skincare products without carful formulation into coaceravate systems. 2 Anionic surfactants, such as linear alkyl sulfates, consist of molecules with a negatively charged “head” and a long hydrophobic “tail.” Anionic surfactants are widely used because of their good lathering and detergent properties. 3 Amphoteric surfactants, such as the betaines and alkylamino acids, are well tolerated, lather well, and are used in facial cleansers. 4 Non-ionic surfactants, such as polyglucosides, consist of overall uncharged molecules. They are very mild (tolerated better than anionic, cationic surfactants on skin), but do not lather particularly well. Some surfactants are harsh to the skin while others are very mild. Because of the wide variety of available surfactants, not all surfactant-based cleansers are the same. It is important for patients to use products that best fit their skin type. Today, most cleansers use synthetic surfactants.

12. Facial cleansers and cleansing cloths

Solvents A solvent is a liquid that dissolves a solid or another liquid into a hom*ogeneous solution. Solvent-based systems clean skin by dissolving natural sebaceous oil and external oils applied to skin via cosmetics and similar materials. Solvents work under the chemical premise that “like dissolves like.” Solvents can be classified broadly into two categories: polar and non-polar. Typical non-polar solvents used in facial cleansing, such as mineral oil or petrolatum, are from the oil family, whereas typical polar solvents used in cleansing, such as isopropyl alcohol and ethanol, are from the alcohol family. Solvent-based cleansers are usually not used in conjunction with water; rather, they are applied and then “wiped” off with a tissue or cotton ball. Solvent-based cleansers should be chosen carefully on the basis of cleansing need. Non-polar solvents work well for removing oil-based makeups and cosmetics but have little effect on water-based formulations. Similarly, alcohol-based systems work well on water-based makeups. It is also important to note that alcohol-based systems can dry skin, a benefit for younger consumers with acne-prone skin but a potential disadvantage for older consumers and those with dry skin. However, oil-based products can leave a greasy or oily residue, which is beneficial for consumers with dry skin, but undesirable for those with normal to oily skin types. Choosing a solvent-based cleanser based on skin type is critical.

Physical cleaning An alternative to chemical cleansing is physical cleaning of skin. Essentially, physics, primarily in the form of friction, has an important role in cleansing. In facial cleansing, friction is generated primarily by the direct interaction of a washcloth, tissue, cotton ball, or cleansing cloth and the surface of skin. Friction works to help dislodge soils, as well as increase the interaction of chemical cleaning agents (surfactants and solvents) with soils. The role of friction is covered in more detail in the section on substrate cleansers.

Types of facial cleansers Seven primary and popular forms of facial cleansers exist (other rarely used forms exist but are not covered in this chapter). These cleansers can be categorized as follows: lathering cleansers; emollient cleansers; milks; scrubs; toners; dry lathering cleansing cloths and wet cleansing cloths. Each form is described in detail below. A summary of cleansers, technologies, and uses can be seen in Table 12.1.

Lathering cleansers While lathering cleansers constitute one broad classification, they all have one unique characteristic that separates them

from all other cleansing forms – they all generate lather when used in the cleansing process. Typically, these cleansers are formulated with a surfactant level greater than the CMC such that excess surfactant can incorporate air and form lather. Additionally, these cleaners contain surfactants that have short hydrophobic chains; shorter chains enable faster and higher levels of lather. Most lathering cleansers sold today utilize synthetic surfactants that have been especially designed to be mild to skin. These synthetic surfactants have little interaction with skin lipids and therefore produce substantially less skin damage than naturally derived surfactants. However, this quality also compromises to a small extent their capability to remove oil-soluble makeups. Many classes of surfactants are used in facial cleansers; two common ones include sarcosinates and betaines [5]. Even formulations with newer surfactants tend to exhibit some skin barrier damage in clinical studies. Thus, lathering cleansers are generally warranted for patients with normal to oily skin or those who are removing a high cosmetic load (makeup, lipstick, or other cosmetic load). Interestingly, there is a strong consumer bias towards lathering cleansers because high levels of lather provide a very strong signal to consumers that the cleanser is working. Lathering cleansers clean through the chemical process of emulsification, this simply means that the cleanser emulsifies dirt and oils, by suspending or emulsifying materials, thus permitting them to be removed from skin during the rinse process. Many formulators of lathering cleanser products have tried to incorporate skin conditioning technologies that enable deposition of skin conditioners onto skin. Unfortunately, these technologies have generally been less successful at providing skin benefit ingredients than other cleansing forms.

Emollient cleansers Emollient cleansers are a milder alternative to lather cleansers. Although they clean via emulsification, they do not form lather in the presence of water. Surprisingly, however, they do form a structure that suspends dirt and makeup within formulation. Typically, these cleansers provide a very high level of soil removal without drying the skin to the same degree as lathering cleansers. Emollient cleansers generally consist of a special formulation of lathering surfactants in which either lathering is suppressed by an oil (e.g. mineral oil) or the surfactant forms a complex with another charged molecule to inhibit the formation of the air–water interface necessary to provide lather. Clinically, emollient cleansers are generally less harsh on skin than lathering cleansers. However, consumers sometimes complain that emollient cleansers leave a residual film on skin that does not satisfy some cleansing expectations. Typically, these cleansers are best suited to those patients with high cleansing needs who also have dry skin.

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Scrubs Facial scrubs are a subset of emollient cleansers. They generally contain small particles of natural or polymeric ingredients. Scrubs are intended to provide a deep cleansing experience including a higher level of skin exfoliation from abrasion with the particles. A non-exhaustive list of natural scrub particles includes seeds of many fruits (e.g. peach, apple, apricot), nut shells (e.g. almond, walnut), grains (e.g. oats, wheat), and sandlewood. Synthetic scrub particles include polyethylene or polypropylene beads. Because of their abrasive nature, patients with sensitive skin may not want to use these as their daily use cleanser; for those with sensitive skin they should be used once or twice a week in addition to normal cleansing routines.

Cleansing milks Milks are a form of cleaner that is generally not used in conjunction with water. Because they are not used in conjunction with a water rinse, cleansing milks are ideal for depositing beneficial agents, such as humectants, petrolatum, vitamins, and desquamatory ingredients, onto the skin. These cleansers are a good choice for cleaning dry or other diseased skin. One drawback is that the residual ingredients left on skin can make skin feel as though cleansing is incomplete. Milks work by dissolving, as opposed to emulsifying, oils and dirt. Typically, they are applied like a lotion and then wiped off with a tissue, cotton ball, or towel.

Toners Toners are a class of facial cleansers formulated to clean skin and shrink pores. This class of cleanser utilizes solvency as the primary mode of cleaning. Toners are usually applied with a physical substrate, such as cotton balls, tissues, or wash cloths; however, some newer toners can be sprayed on and wiped off. In most cases, toners are used in the absence of water. Toner formulations generally utilize alcohol as the solvent of choice and some level of humectants. Toners usually exist in three strengths: 1 Mild: 0–10% alcohol, refresher; 2 Medium: 10–20% alcohol, tonic; and 3 Strong: 20–60% alcohol, astringent. More recently, some companies have developed two-phase toners, which consist of a solvent and an immiscible oil formulated to provide astringent benefits while minimizing the dry skin feeling. Typical uses of toners are makeup removal and pore cleaning associated with acne care. Toners are popular with teenagers and young adults because of the perceived acne benefits and pore tightening associated with this technology.

Substrate cleansers Over the years, facial cleansers have evolved from traditional bar soaps, to milder synthetic detergents, and, most recently, to cleansing cloths (disposable substrates such as a

non-woven material) pretreated with active cleansing and conditioning ingredients. Introduced in the early 2000s, substrate-based cleansers are a relatively new addition to the cleansing technologies available to dermatologists and consumers. These cleansers combine low levels of mild detergents with conditioning ingredients to provide state-of-the-art cleansing and exfoliation with unprecedented mildness [6]. Further, cleansing cloths can be designed to meet the specific needs of different skin types. The substrates used in cleansing cloths generally consist of natural fibers (e.g. cotton); synthetic fibers (e.g. rayon, polyester terphalate [PET] or polypropylene); or a blend of one or more of these fibers. Depending upon the fibers used and the non-woven manufacturing process, the substrate texture can be tailored to meet differing expectations from very soft to rough, meaning that different exfoliation levels can be delivered to the consumer. Technology introduced in 2007 further improves exfoliation and cleansing capabilities by printing a polymer on the surface of a non-woven cloth. The mechanism by which cleansing is accomplished with a cloth is different from that with the liquid cleansers described above. In the case of substrate cleansers, cleaning is driven by a combination of physics (friction from interaction with cloth and skin) and chemistry (either emulsification or dissolution). This combined action offers several key advantages for product formulation and use. Because of the form itself, the cloth can contain a low level of surfactants. Further, utilizing multiple cleansing mechanisms allows formulators the flexibility to customize formulations that contain smaller amounts of chemical ingredients. As a result, substrate-based cleansers can be formulated with as little as 25% of the surfactant used in traditional liquid cleansers (P&G Beauty, Cincinnati, OH, USA, Comparison of surfactant level in Olay Foaming Face Wash, and Olay Daily Facials; unpublished data). For the patient, use of products with combined cleaning mechanisms results in much cleaner skin. Also, lower surfactant levels translate to less skin damage. (True when directly comparing skin damage versus surfactant level of identical surfactants. Surfactant type alone has a large impact on skin damage and must be considered as well as surfactant level when recommending a cleanser.) Another key trait of substrate cleansing cloths is that dirt, makeup, and oil are picked up by and contained within the cloth. The visible dirt and oils on the cloth provide a subtle clue to patients that the cleansing step is complete, reducing overcleansing, another contributor to skin damage. Despite the low level of surfactants in substrate cleansers, these products can still generate a generous lather via the cloth structure, which incorporates air as the lather is generated. The low levels of mild detergent combined with the ability to deposit conditioning agents directly onto the skin result in improvement in the skin’s overall condition beyond

12. Facial cleansers and cleansing cloths basic cleansing. Finally, the different cloth textures allow individualized, but gentle, exfoliation which removes skin flakes for a more even skin surface. This combination of benefits can eliminate the need for other specialty cleansing products such as toners and exfoliators. Two popular forms of substrate-based cleansers exist today: 1 Dry cleansing cloths; and 2 Wet cleansing cloths. The mechanism by which cleansing is accomplished with a cloth is different from that with the liquid cleansers described above. In the case of substrate cleansers, cleaning is driven by a combination of chemistry (either emulsification or dissolution) and physics (friction from interaction with cloth and skin). This combined action offers several key advantages for product formulation and use. Utilizing multiple cleansing mechanisms allows formulators the flexibility to customize formulations that contain lower levels of chemical ingredients. As a result, substrate-based cleansers can be formulated with as little as 25% of the surfactant used in traditional liquid cleansers [7]. For the patient, use of products with combined cleaning mechanisms results in much cleaner skin. Also, lower surfactant levels translate to less skin damage. Another key trait of substrate cleansing cloths is that dirt, makeup, and oil are picked up by and contained within the cloth. The visible dirt and oils on the cloth provide a subtle clue to patients that the cleansing step is complete, reducing overcleansing, another contributor to skin damage.

Daily Facials is one example in which the cleansing surfactant, skin conditioner, and fragrance are applied separately and to different zones of a cloth. This permits the product to deposit conditioning ingredients directly onto skin during the washing procedure, thus delivering unprecedented conditioning benefits from a lathering cleanser. In fact, cleansing cloths are the only specialty cleansing technology that is proven to provide the cleanest skin and improve skin barrier function. Studies have shown that separate addition of petrolatum onto a cleansing cloth provided unparalleled hydration and transepidermal water loss (TEWL) benefits and resulted in a smoother skin surface, a more compact stratum corneum, and well-defined lipid bilayers at the surface of the stratum corneum [8].

Wet cleansing cloths Wet cleansing cloths are traditionally manufactured and shipped to the consumer in their wet state. They originated from disposable wipes technology that was initially developed for removal of excrement and other soils from babies during diaper changes. Wet cloths are used without additional water in both the cleaning and rinsing (wiping off) rituals. Wet cloths are generally of the non-lathering variety and as such can be used as a “wipe-off” product, as opposed to being rinsed with water. The advantage of wet cloths is that small amounts of beneficial ingredients, such as humectants and lipids, are left behind on the skin. This property makes wet wipes one of the most effective cleansing products for patients with dry skin.

Dry lathering cleansing cloths In early 2000, the advent of daily cleansing cloths ushered in the next generation of facial cleansers. Dry cleansing cloths consist of lathering surfactants that have been incorporated in the manufacturing process onto a disposable wash cloth. The patient is instructed to wet the cloth at the sink with warm water and rub to generate lather. Therefore, these products provide a rich, creamy lather like one would find in the lathering cleansers described earlier. Additionally, many of these products contain and deposit on to stratum corneum moisturizing ingredients such as petrolatum and glycerin. These products became an instant success because they combine multiple skin care benefits into one product: 1 High level of cleansing; 2 High level of exfoliation; 3 Minimal reduction in skin barrier function; 4 Rich lather; and 5 In the case of at least one product, significant moisturization [6]. A unique advantage of dry cleansing cloth technology is that the product can be manufactured so that different ingredients can be placed in different “zones” on a cloth. This simple approach enables skilled formulators to use ingredients that are not compatible in a liquid cleanser. Olay

Guide to selecting facial cleansers Recommending a facial cleansing regimen can be a daunting task given the multitude of cleansing forms available. To choose the most appropriate cleanser, physicians should consider skin type, skin problems, and any skin allergies. The following section provides a short reference guide and tools to help in selection of cleansers based on patient skin type, cleansing need, and preference. The selection guide is broken into three parts or strategies: 1 Selection based on skin type; 2 Selection based on cleansing form; and 3 Selection based on skin problems.

Selection based on skin type The first step in selecting a facial cleanser is to assess the patient’s skin type and to categorize it as dry, oily, or normal. Once skin type has been determined, assess the skin for any problems, such as acne, excessive flakiness, and dryness. Table 12.1 systematically lists the main facial cleansers covered in this chapter, and highlights the key characteristics of each cleanser and the best cleanser for each skin type.

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Table 12.1 Cleanser technology and skin types. Type of facial cleanser

Primary cleaning mechanism

Key characteristics

Primary recommended skin type

Liquid lathering cleansers

Emulsification

Forms lather when wet

Oily

Emollient cleansers

Emulsification

Non-lathering

Dry

Scrubs

Emulsification

Non-lathering, particulates provide exfoliation benefit

Dry, flakey

Milks

Dissolution

High conditioning, generally not used with water

Dry skin

Toners

Dissolution

Low viscosity liquid, pore tightening

Oily/young Acne prone

Dry cleansing cloths

Emulsification and physical removal

Provides multiple benefits: cleansing, conditioning, exfoliating, toning

All skin types

Wet cleansing cloths

Dissolution and physical removal

Provides multiple benefits: cleansing, conditioning, exfoliating, toning. Generally not used with water

Dry skin

Cleansing (sebaceous oil)

Substrate

Cleanser form

Dry cleansing cloth

Emollient

Toner Wet cleansing cloth Milk Milk

Toner Lathering (alcohol-based) cleanser Dry wipe Wet wipe

Scrub

Poor

Excellent

Figure 12.2 Products for the removal of excess sebaceous oil.

No substrate

Emollient Scrub Lathering Lathering

Non lathering

Figure 12.1 One of the main cleansing ritual preferences: no substrate/ substrate and lathering/non-lathering.

Selection based on cleanser form or cleansing ritual The second strategy for selecting facial cleansers is to first assess a patient’s cleansing ritual preference. Figure 12.1 depicts one of the main cleansing ritual preferences: no substrate/substrate and lathering/non-lathering. To use this approach most effectively, first, identify the quadrant of Figure 12.1 that best describes the patient’s ritual preference, and then use Table 12.1 to select a facial cleanser that best matches the patient’s skin type. This may be the best

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approach to selecting a cleanser is when compliance with skincare is critical.

Selection based on skin problems In many cases, cleanser selection may be somewhat subjective. The following figures provide a hierarchy of the primary benefits associated with facial cleansers ranked by cleanser type. The benefits described in this section are cleaning excess sebaceous oil, cleaning dirt and makeup loads, exfoliation, and mildness to skin. Considering these benefits when prescribing a cleansing routine may prove useful in providing a cleanser that fully meets patient expectation and needs.

Cleaning excess sebaceous oil Removal of excess sebaceous oil is a significant concern of teens and young adults. Cleansing of sebaceous oil is best accomplished with either lathering products that emulsify the oils or toners that are specifically formulated to solubilize sebaceous oil. These products and can also give users a sense of control over oily skin by providing pore tightening benefits (Figure 12.2).

12. Facial cleansers and cleansing cloths

Cleaning dirt and makeup One of the primary benefits of a facial cleanser is removal of high makeup loads and dirt. By a wide margin, dirt and makeup removal is best performed by substrate cleansers. The high cleansing capability of these cleansers is brought about by their capability to provide both physical and chemical cleaning, in addition to the substrates’ ability to trap and hold dirt and oil within their fibers (Figure 12.3).

Exfoliation: removing dry, dead skin cells When high exfoliation is required, because of aging or for other reasons, products that provide physical cleansing are an appropriate choice because they also provide the highest level of exfoliation. Exfoliation is brought about by physical abrasion, which removes the top layers of skin. As a side note, most cleansers provide low to insignificant levels of exfoliation; thus, if exfoliation is the main skin need, a substrate-based cleanser is highly recommended (Figure 12.4).

Cleanser mildness For much of facial cleansing history, cleanser mildness was a significant concern. Now, with new surfactant and cleansing technologies, most specialty facial cleansers (with the exception of toners) provide close to neutral or better mildness. Figure 12.5 ranks cleansing forms for skin for patients for whom dry skin is a key complaint.

Cleansing (makeup) Toner (for nonwaterproof makeup)

Scrub

Milk

Emollient

Lathering cleanser

Dry wipe Wet wipe

Poor

Excellent

Figure 12.3 Products for the removal of dirt and makeup.

Exfoliation Milk

Lathering cleanser

Wet wipe Scrub

Dry wipe

Emollient Toner Low

High

Figure 12.4 Products for the removal of dry, dead skin cells.

Mildness/conditioning Dry wipe

Toner Scrub

Emollient

Wet wipe

Lathering cleanser Milk Low

High

Figure 12.5 Products for patients for whom dry skin is a key complaint.

References

Conclusions Many different facial cleansing forms exist today. All can be categorized on the basis of three factors: 1 The type of chemistry used, either surfactant or solvent based; 2 Whether or not the cleansing form creates lather; and 3 Whether or not the cleansing form incorporates physical cleansing as well as chemical cleansing. All of these facial cleansing forms provide the basic level of cleansing required to maintain healthy skin; however, different skin types benefit from different cleansing forms, and patient preference drives usage and compliance. The future of the facial cleansing category is bright. Significant innovation is expected to continue for the foreseeable future, particularly in substrate cleanser applications and formulations for removing the new and more durable makeups and mascaras that are entering the market. Technical development will continue to focus on low damage to skin and improved delivery of specially directed skin ingredients during the cleansing process.

1 Zhong C-B, Liljenquist K. (2006) Washing away your sins: threatened morality and physical cleansing. Science 313(5792), 1451–2. 2 Bolles RC. (1960) Grooming behavior in the rat. J Comp Physiol Psychol 53, 306–10. 3 Nicholson PT, Shaw I. (2000) Ancient Egyptian Materials and Technology. Cambridge UK: Cambridge University Press. 4 Ananthapadmanabhan KP, Moore DJ, Subramanyan K, Misra M, Meyer F. (2004) Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing. Dermatol Ther 17, 16–25. 5 Paye M, Barel AO, Howard I. (2006) Handbook of Cosmetic Science and Technology, 2nd edn. Informa Health Care. 6 Kinderdine S, et al. (2004) The evolution of facial cleansing: substrate cleansers provide mildness benefits of leading soap and syndet. P&G Beauty Science poster presentation, 62nd Annual Meeting of the American Academy of Dermatology, February 6–11, 2004. 7 McAtee D, et al. (2001) US patent 6280757 8-28-2001 8 Coffindaffer T, et al. (2004) Assessment of leading facial skin cleansers by microscopic evaluation of the stratum corneum. P&G Beauty Science poster presentation, 62nd Annual Meeting of the American Academy of Dermatology, February 6–11, 2004.

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Chapter 13: Non-foaming and low-foaming cleansers Duncan Aust DFB Branded Pharmaceuticals, Fort Worth, TX, USA

BAS I C CONCE P T S • Effective cleansing can be achieved without foam production. • Non-foaming and low-foaming cleansers are appropriate for all skin types. • Mild surfactants are key to minimizing barrier damage. • Non-foaming and low-foaming cleansers are typically water-based.

Introduction The effective and appropriate use of a suitable skincare regimen is critical to maintaining healthy skin. This cleansing regimen becomes more important in dermatologic disease, where an inappropriate skin care regimen can impede positive treatment outcomes [1]. Cleansing is the first step in managing any dermatologic disease and the right choice of cleanser can have a considerable impact on treatment success. The earliest cleansers were used by the Babylonians around 2200 BC. The Egyptians subsequently combined animal and vegetable oils with alkaline salts to create soaplike substances. Cleansers then evolved to contain salts of fatty acids derived by reacting fat with lye in a process known as saponification, which marked the beginning of currently available foaming soap-based cleansing systems. Non-foaming cleansers were developed in the 2nd century in the form of cold creams and milks. The Greek physician Galen is considered the father of cold cream, because he combined olive oil, beeswax, water, and rose petals. More modern formulations also add borax. There are now many different classes of cleansers; however, this chapter focuses on non-foaming and low-foaming cleansers. It outlines the different types of non-foaming cleansers and how they vary from their regular foaming, liquid, or bar counterparts. It also outlines the most logical choice of non-foaming or low-foaming cleansers for certain skin types and discusses the merits of various cleanser formats.

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Types of non-foaming and low-foaming cleansers Many consumers mistakenly believe foaming or lathering is a requirement for effective cleansing. However, what is not broadly understood is the fact that, even in the absence of foaming, cleansing can still occur. This is the fundamental premise upon which non-foaming and low-foaming cleansers are based. There are two primary classes of non-foaming and lowfoaming cleansers: aqueous or water-based formulations, which may or may not require water for cleansing, and a second class of waterless cleansers. The majority of nonfoaming and low-foaming cleansers are water-based formulations containing several ingredients: water, surfactants, moisturizers, stabilizing agents, preservatives, fragrances, and dyes (Table 13.1). Key to the efficacy of these aqueousbased cleanser formulations are three primary ingredients; water, surfactants, and humectants.

Surfactants The most important ingredient in the majority of cleansing systems is the surfactant. A surfactant is a chemical that stabilizes mixtures of oil and water by reducing the surface tension at the interface between the oil and water molecules and enhances the formation of foam and its colloidal stability. Surfactants perform two functions in a cleanser. First, they stabilize the cleanser formulation by allowing the oil phase and water phase to coexist in a stable system. Without surfactants, it would be impossible create single-phase formulations. Second, and most importantly, surfactants are required to meet the performance requirements of the cleanser. Surfactants can generally be divided into five classes: anionic, amphoteric (zwitteronic), cationic, non-ionic, and

13. Non-foaming and low-foaming cleansers

Table 13.1 Types of non-foaming and low-foaming cleansers. Cleanser types

Physical forms

Key ingredients

Foaming

Lotions

Surfactants, water, foam boosters, humectants, preservatives Surfactants, waxes, binders, filers

Bars

Low foaming

Non-foaming

Body washes

Surfactants, water, foam boosters, humectants, preservatives, dyes

Lotions Gels

Surfactants, water, humectants, preservatives Surfactants, water, humectants, preservatives

Creams

Surfactants, water, humectants, preservatives

Cold creams Waterless cleansers

Water, oil, wax, surfactants Solvent/alcohol, water, surfactant

Thin lotion/milks

Water, moisturizers, oils, surfactants, solvents, preservatives Oil, water, solvent/alcohol, dyes

Two phase

polymeric surfactants. The anionics are characterized by their good foaming and cleansing abilities, but can be too irritating for the skin. As a result, anionics are combined with milder surfactants or conditioning agents. Non-ionics and polymerics tend to be the mildest surfactants and are used in “gentle” cleansing systems. Traditional cationics can be irritating, but new classes have been introduced, rivaling the performance of the non-ionics. The final class, amphoterics, are also mild but this property can differ with pH. Over the last 40+ years, there has been an effort to develop “gentler acting” surfactants, hence the large number of nonionic surfactants currently available. The non-ionic surfactants are the basis for a new group of low-foaming, reduced irritation cleansers and may be combined with the polymeric or amphoteric classes. Examples of mild surfactants and surfactants with low irritation include sulfoacetates, acyl sarcosinates, amphoproprionates, alkanolamides, alkylglucosides, and the original mild surfactant cocamidopropyl betaine.

Low foam production A major drawback of most mild synthetic surfactant systems is poor lather performance. Generally, the longer the carbon backbone of the surfactant, the less irritating the molecule. However, this mildness is often obtained at the expense of effective cleansing and lathering. In fact, many modern cleansers supplement their formulations with “foam boosters” simply to enhance the appearance of foam. These additional ingredients are not required for cleansing, have no cleansing properties, and are there solely to meet consumer expectations. A careful balance is required between mildness and lather.

Mildness The potential for irritation can be reduced by appropriately matching surfactants. For example, sodium lauryl sulfate (SLS), an anionic surfactant with a high index of irritation, has been shown to elicit less irritation when combined with sodium laureth sulfate (SLES) [2]. Balancing the level of surfactants in the formulation to ensure effective cleansing while not having a detrimental effect on skin barrier lipids and proteins is important. Other ingredients can be added to the cleanser formulations to mitigate any detrimental effects. Some of the milder cleansers contain humectants, such as glycerin, to attract water to the skin. Other humectants, such as butylene glycol or propylene glycol, have been used but are less favored than glycerin. Hyaluronic acid, which has the capacity to bind many times its own weight in water, is very expensive and seldom used. The use of humectants in low-foaming and non-foaming cleansers is now commonplace in high end products. In addition to humectants, other skin barrier building ingredients can be used. For example, ceramides and plant extracts with reported antioxidant, anti-irritant properties can be used. However, it is challenging to ensure that these ingredients are delivered to the skin in a cleanser that is rinsed away. Utilizing controlled or sustained release systems can increase ingredient delivery. One example of a controlled release delivery system employed in a cleanser system is the use of a multivesicular emulsion. This emulsion is composed of multilamellar particles, which allow for the sustained release of substances such as ceramides, glycerin, and hyaluronic acid [3]. The mildness of a cleanser is dependent upon many important factors, most notably the choice of other

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Table 13.2 Principal cleanser types. Cleanser types

Advantages

Disadvantages

Skin type best suited

Non-foaming

Gentle Non-drying Low levels of surfactants

Limited cleansing ability for oily types Limited rinsibility with cold creams Can leave behind residue

Dry to normal

Low foaming

Gentle Non-drying

Limited cleansing ability for oily types

Dry to normal

Easy to remove Low levels of surfactants Bar

Excellent cleansing ability

Can strip barrier of essential oils and lipids Drying Can raise pH of skin Primarily composed of anionic surfactants

Oily

Foaming liquid

Good cleansing ability Easy to remove

Can strip barrier of essential oils and lipids

Normal to oily

ingredients in the formulation and the product’s pH [4,5]. Two of the most irritating classes of ingredients used in formulations are fragrances and preservatives. Often the combination of fragrances and high levels of surfactants gives way to a high irritation index. Several studies have correlated a product’s poor performance in patch testing experiments to the combined effects of surfactants and allergens [6,7]. Because of these effects, mild cleanser products are fragrance free; however, preservatives remain a necessary part of the formulator’s arsenal to ensure the products remain free from microbial contamination.

waxes, sterols, monoglycerides, diglycerides, and phospholipids. Lipid-free cleansers have the advantage of not depositing any lipid-like materials on the skin surface. They balance their cleansing and moisturizing ability. In lipid-free cleansers, moisturization is performed by replacing sebum with synthetic oils along with the addition of humectants, such as glycerin. While good for normal to oily skin, lipid-free cleansers may not be the ideal choice for dry skin. Table 13.2 highlights the principal cleanser types: bar, foaming liquid, non-foaming, and low-foaming (regular and lipid free).

Waterless cleansers

Mechanisms of cleansing

Other means of skin cleansing not involving traditional surfactants is with the use of solvents to dissolve oils and sebum. These waterless facial cleansers are aqueous-based alcoholic preparations, typically containing diluted isopropyl alcohol and a small amount of surfactant. Sebum is soluble in alcohol and glycol-based solvents. These cleansers are convenient to use without access to water, and can be effective in patients with very oily skin; however, long-term usage may be harmful to the skin barrier. Other alternative cleansing systems include two-phase systems, where the oil and water–solvent phase do not mix in the formulation and remain as two distinct layers. These systems are mixed by shaking prior to use. They have the advantage of low surfactant concentrations but do not have broad consumer acceptability.

Lipid-free cleansers A new class of cleansers for normal to oily skin is referred to as a lipid-free cleanser. Lipids are defined broadly as fatsoluble, naturally occurring molecules, such as fats, oils,

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In the case of the non-foaming cleansers, especially cold creams, the primary mode of action is dependent on the formulation’s ability to bind sebum, dirt, bacteria, and dead skin cells. Cold cream formulations are water-in-oil emulsions (W/O) where the external phase of the emulsion is the hydrophobic or oily component and the water is partitioned as small droplets in the internal phase. It is because of the external oil phase that cold creams bind well to sebum, dirt, and cosmetics with easy removal by wiping. Certain lighter lotions or milks also work along a similar principle, although they differ from cold creams because they are primarily oil-in-water (O/W) emulsions. Upon application to the skin surface, the oil phase droplets “seek out” sebum on the surface of the skin, entrapping it, and facilitating its removal with gentle wiping or water rinsing. These lighter lotions also differ from cold cream by containing some classic surfactants. The surfactants are used to maintain a stable emulsion with an internal oil phase and external aqueous phase, but do not provide any foaming

13. Non-foaming and low-foaming cleansers capability. These cleansers have limited cleansing ability and are not the most effective class of cleansers for oily skin, but work well on dry to normal skin.

Cleansing skin barrier damage The cutaneous effects of surfactants are dependent upon the type, duration of exposure, and concentration [8,9]. Many different surfactants affect the stratum corneum, or outer layer of the epidermis, causing dryness, damage to the barrier function of the skin, irritation, itching, and redness [10]. Surfactants interact with various components of the stratum corneum, including proteins and lipids. Interaction occurs with corneocytes or protein complexes made of threads of keratin, as well as with lipids. In the case of the corneocytes, the surfactants bind to these proteins allowing them to swell and making it possible for other ingredients in the formulation to penetrate into the lower layers of the skin where they can cause itching and irritation. The irritation properties of surfactants have been demonstrated to be related to the mechanisms by which surfactants interact with the stratum corneum [11]. As for lipids, the interaction of surfactants with lipids in the stratum corneum is still not fully understood. Surfactants may get between the lipid bilayers causing increased permeability and even disruption of the bilayer [12]. Surfactants can also cause damage to the lipid structures themselves. Surfactants reduce the amount of lipids in the skin and disrupt skin barrier function by removing these lipids as the cleanser is used. It is not always the surfactants themselves that result in irritation, but other ingredients contained in the formulations (e.g. fragrances and preservatives). The surfactant effect on barrier function opens a pathway for the damaging effects of other ingredients. Obviously, compromising the skin barrier is best avoided as a compromised barrier has been correlated with skin disease including, psoriasis, atopic dermatitis, and other ichthyoses [13].

Conclusions In conclusion, the advantages of non-foaming and lowfoaming cleansers are mildness. The disadvantages are

related to little foaming capability, but this should not be perceived by the consumer as representing ineffective cleansing. Cleansers that leave a “squeaky clean” feel to the skin surface and produce abundant foam may not be the best choice in patients with sensitive skin needs. Nonfoaming and low-foaming cleansers achieve a delicate balance between skin cleansing and tolerability.

References 1 Draelos ZD. (2005) Concepts in skin care maintenance. Cutis 76 (6 Suppl), 19–25. 2 Effendy I, Maibach HI. (1994) Surfactants and experienmental irritant contact dermatitis. Contact Dermatitis 33, 217. 3 Coria Laboratories, LTD. Products. Available from: URL:http:// www.cerave.com/mve.htm. Accessed September 2, 2008. 4 Ananthapadmanabhan KP, Moore DJ, Subramanyan K, Misra M, Meyer F. (2004) Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing. Dermatol Ther 17 (Suppl 1), 16–25. 5 Kuehl BL, Fyfe KS, Shear NH. (2003) Cutaneous cleansers. Skin Therapy Lett 8, 1–4. 6 Agner T, Johansen JD, Overgaard L, Volund A, Basketter D, Menne T. (2002) Combined effects of irritants and allergens: synergistic effects of nickel and sodium lauryl sulphate in nickelsensitized individuals. Contact Dermatitis 47, 21–6. 7 Pedersen LK, Haslund P, Johansen JD, Held E, Volund A, Agner T. (2004) Influence of a detergent on skin response to methyldibromoglutaronitrile in sensitized individuals. Contact Dermatitis 50, 1–5. 8 Loffler H, Happle R. (2003) Profile of irritant patch testing with detergents: sodium lauryl sulfate, sodium laureth sulfate, and alkyl polyglucoside. Contact Dermatitis 48, 26–32. 9 Slotosch CM, Kampf G, Loffler H. (2007) Effects of disinfectants and detergents on skin irritation. Contact Dermatitis 57, 235–41. 10 Dykes P. (1998) Surfactants and the skin. Int J Cosmet Sci 20, 53–61. 11 Wilhelm KP, Cua BC, Wolff HW, Maibach HI. (1993) Surfactantinduced stratum corneum hydration in vivo: prediction of the irritation potential of anionic surfactants. J Invest Dermatol 101, 310–5. 12 Walters KA, Bialik W, Brain KR. (1993) The effects of surfactants on penetration across the skin. Int J Cosmet Sci 15, 260–70. 13 Marstein S, Jellum E, Eldjarn L. (1973) The concentration of pyroglutamic acid (2-pyrrolidone-5-carboxylic acid) in normal and psoriatic epidermis, determined on a microgram scale by gas chromatography. Clin Chim Acta 49, 389–95.

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Chapter 14: Liquid hand cleansers and sanitizers Duane Charbonneau Procter & Gamble Co., Health Sciences Institute, Mason, OH, USA

BAS I C CONCE P T S • The hands are a common site for microbial contamination. • Hand cleansers and sanitizers are designed to reduce transient microbes on the skin surface with the intent of reducing the spread of infectious disease. • Hand cleansing products include liquid soaps with antimicrobial agents, alcohol-based hand sanitizers as well as non-alcoholbased hand sanitizers. • Hand hygiene technologies have decreased nosocomial infections. • Hands with damaged skin harbor more transient organisms than hands with healthy skin.

Introduction Hand washes and hand sanitizers are designed to reduce transient microbes on the skin with the intent of reducing the spread of infectious disease. This class of products includes liquid soaps; liquid soaps with antimicrobial agents, alcohol-based hand sanitizers as well as non-alcohol-based hand sanitizers. Over the past 20 years there has been an increasing concern regarding infectious disease within the community and hospital. In the USA, deaths from infectious disease are ranked sixth among all deaths according to statistics published by the Centers for Disease Control and Prevention. Nosocomial infections are one of the most frequent and severe complications of hospitalization. Nosocomial infections are the fourth leading cause of death in Canada and account for approximately 100 000 deaths annually in the USA [1,2]. These statistics are extremely sobering in light of all the advances made in modern medicine today. Several mitigating factors are responsible for the rising numbers of infection rates within the community as well as the hospital setting. First, is the changing nature and ranges of pathogens to which individuals within the community and hospital are exposed. Pathogens such as rotavirus, Campylobacter, Legionella, SARS, Escherichia coli O157 (E. coli), and norovirus were not commonplace prior to 1980. Additionally, methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile were largely considered hospital problems. Today, community-acquired MRSA

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(CA-MRSA), norovirus, and new more virulent strains of C. difficile (02) are circulating within the general populous. Second, there are cultural changes that have a role in this increased infection burden, such as reduced hospital stays, in home care for elderly, ease of travel, and a large population of immunocompromised individuals. Third is the diminished research aimed at the identification of new antibiotics. It is no longer economically feasible for pharmaceutical companies to develop and register novel antibiotic technologies. This situation is further exacerbated by the increasing development of antibiotic resistance among common pathogenic microorganisms. With all of these issues, the mechanisms of dealing with infectious disease for the future must fall on prevention strategies in place of treatment regimes. Because hand contact has a crucial role in the transmission of infectious agents, it is imperative that consumers and hospitals have effective hand hygiene technologies.

Hand microbiota Microbes that inhabit the hand are generally divided into two categories: transient and resident flora (Figure 14.1). The transient flora is microbes that inadvertently become attached to the hands following touching of contaminated surfaces; for example, a raw food item, or, as in the case of healthcare workers, an infected wound or body fluid. Several studies have documented the potential of this transfer of transient flora from hands to other parts of the body within an individual or alternatively between individuals. The classic example is the work by Hendley and Gwaltney [3] which demonstrated the importance of hand-to-hand transmission of the common cold virus.

14. Liquid hand cleansers and sanitizers

Figure 14.1 The common flora of the hand. Transient flora are those microorganisms that are picked up from the environment. Resident flora are the microorganisms that routinely inhabit the skin.

Table 14.1 Constituents of the hand resident flora. Organism Acinetobacter baumannii Acinetobacter johnsonii Acinetobacter lwoffi Corynebacterium spp. Enterobacter agglomerans Enterobacter cloacae Klebsiella pneumoniae

microbes are as essential to the health of the skin as the gut microorganisms are to overall health of the individual [4]. The resident flora provides positive health benefits by inhibition of pathogens, immune modulation, and improving the integrity of the skin barrier. Although the resident skin flora usually has an essential role in protecting the host, under certain circ*mstances the resident flora can be pathogenic itself. For example, Staphylococcus epidermidis, an important member of the resident skin flora, is also a common pathogen associated with wound infections. Further, it is estimated that approximately 32% of the population carries the common pathogen Staphylococcus aureus as a member of the skin resident flora [4]. It would appear that frequent exposure to certain transient microbes may lead to them becoming established as a constituent of the resident flora. For example, studies have shown that nurses performing similar tasks within a hospital will have some similarities among their resident flora; while those assigned to different tasks will have different constituents within their resident flora [5,6]. Furthermore, it has recently been shown that homemakers often carrier bacteria within their resident hand flora that are identical to those environmental isolates identified within the home [7]. In terms of hand hygiene, the majority of hand soaps as well as hand sanitizers are primarily targeted toward reducing the level of transient bacteria and viruses on hands. Some products provide only immediate activity (e.g. alcohol hand sanitizers), whereas others provide immediate and residual protection benefits (e.g. triclosan-containing hand sanitizers). Residual protection provides benefits in between product usage preventing re-establishment of transient flora.

Propionibacterium acnes Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus epidermidis Staphylococcus warneri Streptococcus mitis Streptococcus pyogenes

The resident flora of the hand is defined as the complex community of microbes that consistently inhabit the hand and routinely are not washed off with non-medicated soaps. A summary of the bacteria that have been reported to be isolated as resident flora is presented in Table 14.1. Unfortunately, few studies have been undertaken to clearly define the role that these microbes have in health and disease. However, it is speculated that the resident skin

Hand hygiene Since the mid 1800s with the ground breaking work by Professor Ignaz Semmelweis demonstrating a reduction in puerperal sepsis following the institution of hand hygiene protocols, the concept of hand hygiene as means of infection control has been well accepted. In the late 1970s–1980s our understanding that the part hands play in the transmission of bacterial and viral pathogens including the common cold have become well documented [8,9]. Today, hand washing using soap and water or hand antisepsis using hand sanitizer products is the cornerstone of many infection control programs. Hand washing and hand antisepsis guidelines were published by the Association for Professionals in Infection Control (APIC) in 1988 and updated in 1995 [10]. The most recent updates were published in 2002 by the Hygiene Task Force composed of members of APIC, Center(s) for Disease Control (CDC), Healthcare Infection Control practices

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Advisory Committee (HICPAC), Society for Healthcare Epidemiology of America (SHEA), and Infectious Diseases Society of America (IDSA) [11]. Since 1995 these various guidelines recognize the utility of hand washing with antimicrobial containing soap as well as the use of waterless hand sanitizers. The Food and Drug Administration’s (FDA) Food Code contains specific hand hygiene guidance for retail and food service workers describing when, where, and how to wash and sanitize hands. Hand sanitizers, meeting specific criteria described in section 2-301.16 of the Food Code, may be used after proper hand washing in retail and food service [12].

Hand hygiene compliance The importance of hand washing is well understood by professional and non-professionals; unfortunately, observational studies that measure compliance based on these standards are, at best, disappointing. Hand hygiene compliance studies estimate that healthcare workers are 40% compliant and food service workers are 30% compliant with standard guidelines [13,14]. A recent observational study demonstrated that fewer than 50% of hospital healthcare workers were observed to wash their hands after toileting [15]. Within the general population, observational studies have clearly demonstrated a gender difference among hand washing compliance. A large American Society for Microbiology study demonstrated that 88% of women and only 66% of men wash their hands after visiting the toilet. Other studies have shown that hand washing compliance is inversely proportional to education levels, indicating that the understanding of guidelines is not the issue [16]. Because hand washing compliance is low there is a need for hand sanitizers, especially those with persistent benefit, to be included in hand hygiene strategies.

The most effective mean wash time is considered to be 15–20 seconds, but observational studies on subjects within healthcare and community settings indicate that the average hand wash time lasts less than 8 seconds. This would imply that as currently practiced the removal of transient microorganisms from the hands is suspect at best. Quantitative studies within a community setting have substantiated this hypothesis. A study conducted by Larson et al. [17] in homemakers measured mean colony-forming units count of 5.72 before washing and 5.69 after. These results indicated that the hand washing technique as practiced was ineffective. A final factor for consideration is that of pH. The low pH of the hands has a crucial role in the innate antimicrobial hostility of the hand surface. The pH of the hands is approximately 4–5 routinely; however, the alkalinity of soaps can result in an increase in the skin pH [18]. This poses a concern because some of the antibacterial characteristics of skin are minimized. In one report, pH increased 0.6 to 1.8 units after hand washing with plain soap and then gradually declined to baseline levels over a period of 45 minutes to 2 hours [18]. Recently, a hand sanitizer has been introduced that provides antibacterial efficacy using triclosan formulated into a low pH matrix. This product maintains the low pH of the hand surface for hours. This imparts not only an immediate antimicrobial benefit but a persistent one as well [19]. Several studies have demonstrated that damaged hands harbor more transient microorganisms than healthy hands [20]. Repeated hand washing with soap and water removes the protective lipid layer which is followed by transepidermal water loss and cutaneous signs of redness, scaling, and possibly dermatitis. The use of alcohol-based hand sanitizers can also lead to dehydration of the skin as well as lipid removal and skin damage which may lead to increased colonization by transient flora. Recent investigations have shown that only subjects with healthy skin achieved appropriate levels of decontamination with plain soap and water [20]. Thus, individuals with damaged hands will require more robust antimicrobial formulations.

Hand washing techniques Hand washing when done properly is considered to be the gold standard for removing transient pathogenic bacteria from the hands. The best accepted hand washing protocol established by the CDC is described below.

Proper hand washing with soap and water • Wet your hands with warm, running water and apply liquid soap or use clean bar soap. Lather well. Rub your hands vigorously together for at least 15–20 seconds. • Scrub all surfaces, including the backs of your hands, wrists, between your fingers and under your fingernails. • Rinse well. • Dry your hands with a clean or disposable towel. • Use a towel to turn off the faucet.

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Measurements of efficacy Studies demonstrating the efficacy of antimicrobial hand soaps and sanitizers toward removal of transient microbes can be divided into three categories: 1 In vitro potency and spectrum of activity; 2 In vivo models with artificial inoculate; and 3 Clinical studies demonstrating efficacy.

In vitro measurements In terms of the in vitro measures of efficacy, classic microbiologic protocols of minimum inhibitory concentration (MIC) and time kill studies are usually conducted with bacteria and viruses of interest. The relevance of these in vitro

14. Liquid hand cleansers and sanitizers measurements for products of this nature has been a debate within the research community for decades. The primary information garnered from these studies only provides insights into the potency and spectrum of activity of a formulation within the test laboratory setting. Investigators have also relied on artificial substrates to model removal of transient flora from hands. In these model systems either pig skin or an alternative skin substrate mimic is utilized to model the hand. Bacteria or viruses are inoculated onto the substrate prior to treatment. Measurements of microbial reductions are made following the treatment and efficacy is calculated by comparison with either an untreated control or placebo. Recently, some researchers are using similar models to assess the residual benefits of these formulations. The waterless alcohol-based hand sanitizer technologies have little to no residual benefit versus the triclosan-containing low pH hand sanitizers which provide immediate as well as residual benefit (2008 Nonprescription Medicines Academy).

In vivo models with artificial inoculate mimic transient flora Both in Europe and the USA, there are efficacy standards for antimicrobial soaps and hand sanitizers. In both geographic regions, the tests necessary to fulfill these regulatory requirements involve artificially inoculating subject’s hands with large inoculums of indicator bacteria. This is followed by treatment, neutralization of the active ingredient, and enumeration of remaining viable bacteria. The methods most widely accepted in Europe are EN 1499 for antimicrobial hand soaps and EN 1500 for leave-on hand sanitizers. In both of these test protocols, 12–15 subjects wash their hands with a plain soap and water. The hands are then contaminated by having the subject immerse their hands half-way to metacarpals in a 24-hour broth culture of a non-pathogenic strain of E. coli. Following drying, bacterial recovery is achieved by kneading the fingertips and palms separately into 10 mL Trypticase soy broth plus neutralizers. The hands are removed, disinfected, and again contaminated. The treatments are then applied for 30–60 seconds either with or without a rinsing step depending on product type (rinse-off or leave-on). Post-treatment bacteria are recovered as described above. Extracted bacteria are enumerated using traditional microbiologic plating techniques. In these European tests, efficacy is determined versus internal standards. For EN 1499, antimicrobial hand soaps must provide a superior log reduction to that achieved using a plain soap (sapo kalinus) following a 60-second treatment. When evaluating leave-on products such as hand sanitizers with EN 1500 procedures, the product must deliver a benefit not less than that observed with a 60second application of 60% 2-propanol. In the USA, antimicrobial soaps and sanitizers are regulated by the FDA’s Tentative Final Monograph for Healthcare

Antiseptic Drug Products (FR 1994). The standard method used to evaluate formulations is the American Society of Testing and Materials E 1174. In this test, subjects refrain from utilizing any antimicrobial products for 1 week prior to the start of the study (“washout period”). At the initiation of the study, the subjects perform a cleansing wash to eliminate any residual transient bacteria. The subjects’ hands are then contaminated with 4.5–5.0 mL of a 24-hour broth culture of either a non-pathogenic E. coli or Serratia marcescens. Bacteria are then recovered by separately placing each hand into a glove containing 75 mL sampling solution plus neutralizers. The hand is massaged for 1 minute and bacteria are enumerated using traditional microbiologic plating techniques. This enumeration serves as the baseline measurement. The subjects then perform another cleansing wash and are reinoculated. Following this reinoculation the treatment is applied as described by the manufacture for either an antimicrobial soap or leave-on hand sanitizer. After the treatment is completed the bacteria are again recovered from the hands using the glove method and this is called Test Wash 1. This is followed by another cleansing wash. Once this cleansing wash is complete a cycle of inoculation followed by treatment is performed 10 consecutive times and bacteria are recovered at the 10th cycle. In this protocol, there is no internal standard. The success criteria are determined by log reduction versus the baseline measurement. In Wash 1, a product must achieve a minimum of a 2-log reduction, and at Wash 10, the product must deliver a 3-log reduction versus baseline.

Methodology concerns There is a great deal of critique of these standard methods. First and foremost, these European and US protocols utilize treatment times and typically volumes of product that are far outside of the norm. In the case of the ASTM E1174, there is concern that bacteria are sampled from areas of the hands not involved in transmission such as the back of the hands. An additional concern is the appropriateness of these inocula to the real world situation. In the natural setting, transient bacteria would rarely be present without being incorporated into a soil matrix. To address this issue, investigators have developed methodologies that incorporate the use of a soil matrix such as chicken or hamburger in place of marker bacterial organisms and focused attention is paid to the palms of the hands [21,22]. In the presence of a greasy soil matrix such as chicken, the alcohol-based hand sanitizers lack appreciable efficacy, whereas those containing more potent antimicrobial actives such as triclosan and benzalkonium chloride demonstrate a higher level of effectiveness (Figure 14.2). In addition to these standardized methodologies, other protocols designed to mimic transient flora have been presented within the literature. The most utilized method is commonly referred to as the fingerpad method [23]. In this

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(a)

Cleansers

(b)

(c)

Figure 14.2 Effects of different hand sanitizers on greasy soil. Bacterial growth has been colorized. (a) Untreated. (b) Triclosan-based. (c) Alcohol-based.

method, subjects who have previously refrained from using antimicrobial products have their fingerpads contaminated with either bacteria or viruses. The fingerpads are then treated with test product and the bacteria or viruses are enumerated. Recently, authors have utilized this test to evaluate the residual activity of a hand sanitizer. In this test the fingerpad was treated with the sanitizer and subsequently challenged with bacteria 3 hours later [19]. This study demonstrated that the hand sanitizer provided protection from microbial challenge for up to 3 hours post application. Other models have also been described in the literature with the aim of assessing residual antimicrobial activity as well as transfer of microbial agents. One such method involves the ability of antiseptic hand products to interrupt the transfer of microorganisms from fingerpads to hard surfaces under controlled pressures [24].

Resident flora For consumer or common healthcare, antimicrobial hand soaps and hand sanitizers various methods have been developed to look at the impact of these products on the resident flora. One commonly used method is the Cade test which measures the impact of several washes over a period of 5 days [25]. This test, like the Health Care Personnel Handwash test, begins with a washout period. This is followed by a 5-day baseline period and samples are collected over 2 days to control for day-to-day variations. Following this baseline, subjects are instructed to use the product multiple times daily. Subjects are sampled for 2 days during the treatment phase. Efficacy is determined by comparisons between the baseline and treatment phases. The antimicrobial efficacy of surgical hand antiseptics is determined according to a European standard (prEN 12791) and a US standard (TFM). The two methods differ in several ways as shown in Table 14.2. Because of these differences, Kampf et al. [26] have stressed the need to evaluate potential products using both

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Table 14.2 US and European standard methods. Difference

US method

prEN 12791

Product application

Hands and lower forearm

Hands only

Number of applications

11 over 5 days

Single application

Sampling times

0, 3, 6 hours post-application

0, 3 hours post-application

Sample method

Glove juice

Fingertip sampling

Success criteria

Absolute bacterial reduction

Non-inferiority to reference standard

methodologies to assure efficacy. Overall, the model systems described above have been very helpful for the determination of efficacy for various antimicrobial hand soaps and hand sanitizers. However, it must be pointed out that these models are not always indicative of efficacy under real use conditions.

Effectiveness of hand hygiene in the community setting Unfortunately, clinical trials of hand hygiene regimes are complex and expensive to execute. Community intervention studies have been limited in scope and have delivered mixed and sometimes inconclusive results. Comprehensive reviews of these studies have resulted in less than favorable outcomes in terms of the quality and the conclusions derived [27]. Reduction in gastrointestinal illnesses associated with handwashing have ranged from −10% to 57%. Unfortunately, only three out of the five studies that evaluated gastrointestinal illness produced statistical significance. In these three

14. Liquid hand cleansers and sanitizers studies, the magnitude of the impact was approximately 50% reduction in the incidence of illness. The impact of hand hygiene on respiratory illness is more limited. The magnitude of the overall impact of current available studies has been estimated to be an approximate 23% reduction in the incidence rate of respiratory infections. Thus, current data implies that hand hygiene has its largest impact on gastrointestinal versus respiratory illness. A recent metaanalysis by Aiello et al. [28], using hand hygiene intervention studies, indicated that overall hand hygiene reduces the incidences of gastrointestinal illness by 31% (95% CI = 19– 42%) and, to a lesser extent, respiratory illness by 21% (95% CI = 5–34%). There are many more studies that examined the impact of alcohol-based hand sanitizers on subsequent infection rates. The conclusion by Meadows and LeSaux [29] was that the data were of poor quality and that more rigorous intervention studies were needed. The current studies have demonstrated a reduction in the incidence of gastrointestinal illness from 0 to 59%. The magnitude for respiratory illness and infection and/or symptom reduction ranged from −6% to 26%. Thus, like the hand washing studies, the use of alcohol-based hand sanitizers appears to have a more robust effect on gastrointestinal infections.

Hospital epidemiology noscomial studies To date, several reviews have examined the database of studies evaluating the evidence of a causal link between hand hygiene and the reduced risk of hospital acquired infections. A recent comprehensive review by Backman et al. [30] evaluated 1120 articles on the subject and concluded that “there is a lack of rigorous evidence linking specific hand hygiene interventions with the prevention of health care acquired infections.” The conclusion from the Backman review was somewhat different from that of Larson’s review [31] but was similar to Silvestri et al.’s review [32] concerning the link between hand hygiene interventions and the risk of healthcare acquired infections. However, it is important to note that all three reviews focused on the lack of quality in studies published to date. It is speculated that the nature of the interventions utilized and the diverse factors affecting the acquisition of healthcare-associated infections that complicate the ability to demonstrate an effect of hand hygiene alone.

Safety of handwashes and hand sanitizers

healthcare workers [33]. It is most often attributed to irritation which occurs from repeated contact with detergents and is believed to be exacerbated by the wearing of gloves. A further concern has to do with contact allergies to antibacterial actives and perfumes that are incorporated within the products themselves. Although there are some reports of allergies to these chemistries the accounts of these are limited within the literature [34].

Safety concerns specific to alcohol-based hand sanitizers In terms of the alcohol-based hand sanitizers, there are occupational safety concerns with the chronic use of alcohol. First is the removal of the lipid barrier of the hands, leading to irritation and an increase in bacterial colonization. Second, the flammability of these alcohol-based formulations has caused some to question whether it is good practice to have them in various locations where the potential for ignition exists. Third are the reports in the literature of intentional ingestion of the alcohol-based products by those individuals with alcoholism and the accidental ingestion by children [35]. Lastly, a safety issue that has called alcoholbased systems into question is the misuse of these products for the prevention of infections. For example, use of alcohol-based hand sanitizers for prevention of infections by norovirus or C. difficile is not prudent because it is well established that alcohol has limited efficacy against these pathogens [36,37].

Microbial resistance to antimicrobial agents The major question concerning antimicrobial-containing hand washes and their use in consumer products has to do with the potential for the development of pathogen resistance [38]. The resistance issue has been divided into two questions: 1 Will the use of these agents in broad scale consumer use result in the loss of their effectiveness? 2 Will the use of these agents lead to cross-resistance to antibiotics? The majority of the work has been done with triclosan, which has been utilized as an antibacterial agent in several consumer products for 30 years. Triclosan is broad-spectrum antibacterial and antifungal agent. It is more potent against Gram-positive (e.g. S. aureus) than Gram-negative bacteria. Triclosan is utilized for therapeutic baths of MRSA-infected patients [39] and in the control of MRSA carriage and skin infections [40]. Unlike orally ingested antibiotics, triclosan elicits bactericidal actions against a variety of bacterial targets reducing the potential for resistance development.

Irritation associated with handwashes and hand sanitizers

Laboratory observations

A safety concern for both hand washes and hand sanitizers is the occurrence of dermatitis observed in up to 25% of

Chronic sublethal exposure of laboratory strains of E. coli to triclosan selected clones with reduced susceptibility [41].

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Although these clones were less susceptible, they were still inhibited by in-use triclosan concentrations. Further studies demonstrated that these observations were limited only to laboratory strains of E. coli and in some cases the effects observed with triclosan could be reproduced with a variety of non-antimicrobial materials such as mustard, chili, and garlic [42,43]. Lambert [44] evaluated 256 clinical isolates of P. aeruginosa and S. aureus over a 10-year period. There was no difference in triclosan sensitivity between antibiotic sensitive and resistant strains. The authors concluded that there was a negative correlation between antibiotics and biocides. Suller and Russell [45] used clinical isolates of S. aureus (MSSA and MRSA) to demonstrate no correlation between MRSA and decreased triclosan susceptibility. Furthermore, continuous exposure of a triclosan-sensitive S. aureus strain to subinhibitory triclosan concentrations for 1 month did not decrease susceptibility either to triclosan or to other antibiotics.

Antibacterial exposure results from long-term studies Studies examining exposure to triclosan for 6 months of mixed microbial communities derived from natural environments [46] resulted in no change in triclosan or antibiotic sensitivities. Cole et al. [47] studied 60 homes, 30 of which used antibacterial products and 30 did not. A total of 1238 bacteria were evaluated, with more target bacteria being recovered from biocide users versus non-users. No methicillin, oxacillin, or vancomycin resistant S. aureus were isolated associated with the use of biocides. In fact, the incidence of resistance to antibacterials was higher in non-user households. Aiello et al. [48] conducted a large (224 households), 12-month study addressing the impact of antibacterial products in homes. Logistic regression analysis demonstrated that the use of biocide products did not result in significant increases in antimicrobial drug resistance nor did it impact susceptibility to triclosan. Thus, following a comprehensive review of the scientific literature, it is concluded that there is no evidence to support that use of triclosan in consumer products will reduce effectiveness nor contribute to the societal burden of antibiotic resistance. In fact, several accounts in the literature document the utility of triclosan in the reduction of antibioticresistant microorganisms including MRSA.

Formulations of hand sanitizers and hand washes Hand sanitizers can be categorized into three main classes: 1 Alcohol-based = ≥62% alcohol; 2 Alcohol-based supplemented = ≥62% alcohol plus antimicrobial agent;

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3 Non-alcohol-based = the majority of the product is water plus surfactant and antimicrobial agent. In terms of product forms, they span from liquids to gels and foams. Most base efficacy on the fact that they are leaveon products. With the exception of the alcohol-based products that only deliver an immediate benefit and provide no residual activity, hand sanitizers provide both immediate plus a residual antimicrobial benefit. The antimicrobial hand washes are primarily water-based formulations that are composed of mixtures of surfactants, antimicrobial actives perfumes, and, in some cases, emollients. In many cases, these emollients and skin feel agents are added to improve the consumer experience with the hope of improving the overall compliance. In the USA, antimicrobial actives that can be incorporated within these products are regulated under the TFM. The ingredients are classified into three categories: 1 Category 1. Ingredients determined to be safe and effective; 2 Category 2. Ingredients determined to be neither safe nor effective; 3 Category 3. Ingredients for which there is insufficient evidence; however, the FDA is not objecting to marketing or sale of these products. Only active ingredients in categories 1 and 3 are allowed to be lawfully marketed in products within the USA. The formulating of non-alcohol-based hand sanitizers as well as antimicrobial hand washes must take into consideration the bioavailability of the antimicrobial active. For example, some of the surfactants within the formulation may complex or otherwise inactivate the formulation. Recent data with triclosan-containing formulations have demonstrated a difference in efficacy among various triclosan-containing hand washes [49] with varying formulations.

Future directions It is imperative for our future understanding of this area that improved epidemiologic studies be conducted with a variety of hand hygiene products to better demonstrate the role of hand hygiene for the prevention of infections both in the hospital as well as in the community setting. Additionally, complete hand hygiene strategies must be developed including product efficacy, skin feel, compliance, as well as education. Furthermore, hand hygiene must be examined to assure consumers that both residual as well as immediate germ removal is accomplished. Technologies need to be developed that address consumer as well as healthcare workers’ behavior and occupational needs. These technologies must be easy to use and provide the skin conditioning needs for consumers and be effective against a variety of pathogenic bacteria and viruses.

14. Liquid hand cleansers and sanitizers

References 1 Baker GR, Norton PG, Flintoft V, Blais R, Brown A, Cox J, et al. (2004) The Canadian Adverse Events Study: the incidence of adverse events among hospital patients in Canada. CMAJ 170, 1678–86. 2 Klevens RM, Edwards JR, Richards CL Jr, Horan TC, Gaynes RP, Pollock DA, et al. (2007) Estimating health care-associated infections and deaths in US hospitals, 2002. Public Health Rep 122, 160–6. 3 Hendley JO, Gwaltney JM Jr. (1988) Mechanisms of transmission of rhinovirus infections. Epidemiol Rev 10, 242–58. 4 Cogen AL, Nizet V, Gallo RL. (2008) Skin microbiota: a source of disease or defence? Br J Dermatol 158, 442–55. 5 McBride ME, Montes LF, Fahlberg WJ, Knox JM. (1975) Microbial flora of nurses’ hands. III. The relationship between staphylococcal skin populations and persistence of carriage. Int J Dermatol 14, 129–35. 6 Aiello AE, Cimiotti J, Della-Latta P, Larson EL. (2003) A comparison of the bacteria found on the hands of ‘homemakers’ and neonatal intensive care unit nurses. J Hosp Infect 54, 310–5. 7 Pancholi P, Healy M, Bittner T, Webb R, Wu F, Aiello A, et al. (2005) Molecular characterization of hand flora and environmental isolates in a community setting. J Clin Microbiol 43, 5202–7. 8 Gwaltney JM Jr, Moskalski PG, Hendley JO. (1978) Hand-tohand transmission of rhinovirus colds. Ann Intern Med 88, 463–7. 9 Hendley JO, Wenzel RP, Gwaltney JM Jr. (1973) Transmission of rhinovirus colds by self inoculation. N Engl J Med 288, 1361–4. 10 Larson EL. (1995) APIC guidelines for handwashing and hand antisepsis in health care settings, 1992, 1993, and 1994. APIC Guidelines Committee. Am J Infect Control 23, 251–69. 11 Centers for Disease Control and Prevention. (2002) Guideline for hand hygiene in health-care settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR 51, 1–44. 12 US Department Of Health And Human Services. (2005) Public Health Service. Food Code. http://www.cfsan.fda.gov/∼dms/ fc05-toc.html 13 Green LR, Selman CA, Radke V, Ripley D, Mack JC, Reimann DW, et al. (2006) Food worker hand washing practices: an observation study. J Food Prot 69, 2417–23. 14 Guideline for Hand Hygiene in Health-Care Settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. (2002) Society for Healthcare Epidemiology of America/Association for Professionals in Infection Control/ Infectious Diseases Society of America. MMWR Recomm Rep 51, 1–45. 15 van der Vegt D, Voss A. (2008) Hand hygiene after toilet visits. 18th European Congress of Clinical Microbiology and Infectious Disease April. [Abstract P1103]. 16 Duggan JM, Hensley S, Khuder S, Papadimos TJ, Jacobs L. (2008) Inverse correlation between level of professional education and rate of handwashing compliance in a teaching hospital. Infect Control Hosp Epidemiol 29, 534–8.

17 Larson EL, Gomez-Duarte C, Lee LV, Della-Latta P, Kain DJ, Keswick BH. (2003) Microbial flora of hands of homemakers. Am J Infect Control 31, 72–9. 18 Gunathilake HM, Sirimanna GM, Schürer NY. (2007) The pH of commercially available rinse-off products in Sri Lanka and their effect on skin pH. Ceylon Med J 52, 125–9. 19 Zukowski C, Boyer A, Andrews S, Trowbridge M, Grender J, Widmeyer V, et al. (2007) Immediate and persistent antibacterial and antiviral efficacy of a novel hand sanitizer. Presented at 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; Chicago, IL, September 17–20, 2007. 20 de Almeida e Borges LF, Silva BL, Gontijo Filho PP. (2007) Hand washing: changes in the skin flora. Am J Infect Control 35, 417–20. 21 Charbonneau DL, Ponte JM, Kochanowski BA. (2000) A method of assessing the efficacy of hand sanitizers: use of real soil encountered in the food service industry. J Food Prot 63, 495–501. 22 Hansen TB, Knøchel S. (2003) Image analysis method for evaluation of specific and non-specific hand contamination. J Appl Microbiol 94, 483–94. 23 Sattar SA, Ansari SA. (2002) The fingerpad protocol to assess hygienic hand antiseptics against viruses. J Virol Methods 103, 171–81. 24 Mbithi JN, Springthorpe VS, Boulet JR, Sattar SA. (1992) Survival of hepatitis A virus on human hands and its transfer on contact with animate and inanimate surfaces. J Clin Microbiol 30, 757–63. 25 Gibbs BM, Stuttard LW. (1967) Evaluation of skin germicides. J Appl Bacteriol 30, 66–77. 26 Kampf G, Ostermeyer C, Heeg P, Paulson D. (2006) Evaluation of two methods of determining the efficacies of two alcoholbased hand rubs for surgical hand antisepsis. Appl Environ Microbiol 72, 3856–61. 27 Bloomfield SF, Aiello AE, Cookson B, O’Boyle C, Larson EL. (2007) The effectiveness of hand hygiene procedures in reducing the risks of infections in home and community settings including handwashing and alcohol-based hand sanitizers. Am J Infect Control 35 (Suppl 1), S27–64. 28 Aiello AE, Coulborn RM, Perez V, Larson EL. (2008) Effect of hand hygiene on infectious disease risk in the community setting: a meta-analysis. Am J Public Health 98, 1372–81. 29 Meadows E, Le Saux N. (2004) A systematic review of the effectiveness of antimicrobial rinse-free hand sanitizers for prevention of illness-related absenteeism in elementary school children. BMC Public Health 4, 50. 30 Backman C, Zoutman DE, Marck PB. (2008) An integrative review of the current evidence on the relationship between hand hygiene interventions and the incidence of health careassociated infections. Am J Infect Control 36, 333–48. 31 Larson E. (2005) State-of-the science-2004: time for a “No Excuses/No Tolerance” (NET) strategy. Am J Infect Control 33, 548–57. 32 Silvestri L, Petros AJ, Sarginson RE, de la Cal MA, Murray AE, van Saene HK. (2005) Handwashing in the intensive care unit: a big measure with modest effects. J Hosp Infect 59, 172–9. 33 Larson E, Friedman C, Cohran J, Treston-Aurand J, Green S. (1997) Prevalence and correlates of skin damage on the hands of nurses. Heart Lung 26, 404–12.

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34 Heydorn S, Menné T, Johansen JD. (2003) Fragrance allergy and hand eczema: a review. Contact Dermatitis 48, 59–66. 35 Emadi A, Coberly L. (2007) Intoxication of a hospitalized patient with an isopropanol-based hand sanitizer. N Engl J Med 356, 530–1. 36 Macinga DR, Sattar SA, Jaykus LA, Arbogast JW. (2008) Improved inactivation of nonenveloped enteric viruses and their surrogates by a novel alcohol-based hand sanitizer. Appl Environ Microbiol 74, 5047–52. 37 King S. (2004) Provision of alcohol hand rub at the hospital bedside: a case study. J Hosp Infect 56 (Suppl. 2), S10–2. 38 Aiello AE, Larson E. (2003) Antibacterial cleaning and hygiene products as an emerging risk factor for antibiotic resistance in the community. Lancet Infect Dis 3, 501–6. 39 Zafar AB, Butler RC, Reese DJ, Gaydos LA, Mennonna PA. (1995) Use of 0.3% triclosan (Bacti-Stat) to eradicate an outbreak of methicillin-resistant Staphylococcus aureus in a neonatal nursery. Am J Infect Control 23, 200–8. 40 Rashid A, Solomon LK, Lewis HG, Khan K. (2006) Outbreak of epidemic methicillin-resistant Staphylococcus aureus in a regional burns unit: management and implications. Burns 32, 452–7. 41 Levy CW, Roujeinikova A, Sedelnikova S, Baker PJ, Stuitje AR, Slabas AR, et al. (1999) Molecular basis of triclosan activity. Nature 398, 383–4. 42 Rickard AH, Lindsay S, Lockwood GB, Gilbert P. (2004) Induction of the mar operon by miscellaneous groceries. J Appl Microbiol 97, 1063–8.

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43 McBain AJ, Ledder RG, Sreenivasan P, Gilbert P. (2004) Selection for high-level resistance by chronic triclosan exposure is not universal. J Antimicrob Chemother 53, 772–7. 44 Lambert RJ. (2004) Comparative analysis of antibiotic and antimicrobial biocide susceptibility data in clinical isolates of methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa between 1989 and 2000. J Appl Microbiol 97, 699–711. 45 Suller MT, Russell AD. (2000) Triclosan and antibiotic resistance in Staphylococcus aureus. J Antimicrob Chemother 46, 11–8. 46 McBain AJ, Bartolo RG, Catrenich CE, Charbonneau D, Ledder RG, Price BB, et al. (2003) Exposure of sink drain microcosms to triclosan: population dynamics and antimicrobial susceptibility. Appl Environ Microbiol 69, 5433–42. 47 Cole EC, Addison RM, Rubino JR, Leese KE, Dulaney PD, Newell MS, et al. (2003) Investigation of antibiotic and antibacterial agent cross-resistance in target bacteria from homes of antibacterial product users and nonusers. J Appl Microbiol 95, 664–76. 48 Aiello AE, Marshall B, Levy SB, Della-Latta P, Lin SX, Larson E. (2005) Antibacterial cleaning products and drug resistance. Emerg Infect Dis 11, 1565–70. 49 Fuls J, Fischler G. (2004) Antimicrobial efficacy of activated triclosan in surfactant-based formulation versus Pseudomonas putida. Am J Infect Control 32, E22.

Chapter 15: Shampoos for normal scalp hygiene and dandruff James R. Schwartz, Marcela Valenzuela, and Sanjeev Midha Procter & Gamble Beauty Science, Cincinnati, OH, USA

BAS I C CONCEPTS • Frequent scalp cleansing is important to prevent formation of unhealthy scalp. • Three classes of shampoos can be delineated: (1) cosmetic shampoos and two types of therapeutic products, (2) standard, and (3) cosmetically optimized therapeutics. • Both therapeutic scalp care shampoos are effective for normal scalp to prevent unhealthy conditions and for dandruff/seborrheic dermatitis scalp to treat the condition and subsequently prevent its reoccurrence. • All therapeutic shampoos are not equally efficacious, even though they may contain the same active. • Cosmetically optimized therapeutic shampoos are desirable as they increase compliance long term because of having no esthetic trade-offs and their affordability. • All shampoos, including cosmetics, must be mild to the skin while being effective cleansers to minimize irritation that could initiate scalp problems.

Introduction The scalp is a unique environment of the skin combining a high level of sebaceous lipid production with a physical covering of hair. The hair physically protects the scalp from UV light but also can inhibit the cleansing efficiency of the scalp surface by shampoos. These conditions allow for the colonization of commensal Malassezia yeasts which can, under the right conditions, cause inflammation and hyperproliferation [1] leading to symptoms [2] of flakes and itch (Figure 15.1). Lipases are secreted by the yeast into the surrounding medium to cause liberation of fatty acids from the triglycerides of the sebaceous lipids. Malassezia selectively consume long chain saturated fatty acids to live, the unsaturated fatty acids left behind can then be the initiators of inflammation. Cutaneous inflammation results in hyperproliferation in the epidermis leading to immature stratum corneum cells with incompletely degraded adhesive function resulting in removal as visible clumps. The resultant condition is called dandruff or seborrheic dermatitis (D/SD), depending on the severity of flaking and the presence of outward manifestations of inflammation. The presence of the condition places special requirements on effective scalp cleansing and it has been observed that

scalp issues such as D/SD occur more frequently when cleansing frequency decreases [3]. Because the sebaceous lipids are one of the key factors required for formation of D/SD, infrequent removal leads to the build up of the proinflammatory by-products of Malassezia metabolism.

Product and formulation technology overview Three categories of shampoos can be delineated (Figure 15.2). Cosmetic shampoos are primarily designed to cleanse the hair, but of course the scalp skin is cleansed simultaneously. Modern versions of these shampoos also condition the hair by depositing certain ingredients on the hair to improve cosmetic benefits such as ease of combing, shine maintenance, and other attributes important to all consumers. Therapeutic scalp care shampoos (often termed “antidandruff”) contain active ingredients to control the D/SD conditions, most often by reducing the Malassezia population on the scalp. Standard therapeutic products tend to focus on the drug active without full consideration of product esthetics. Cosmetically optimized therapeutic products also contain a drug active to achieve therapeutic benefits, but without the common esthetic trade-offs of therapeutic products. Recommendations involving therapeutic products must take into consideration that patients also have basic hair care needs and that if the product has significant negative esthetic trade-offs, compliance will be very poor thereby limiting therapeutic efficacy.

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(a)

Cleansers

(b)

(c)

Figure 15.1 (a) Image of normal scalp skin. (b) Dandruff scalp image showing adherent white flakes. (c) Seborrheic dermatitis with more evidence of sebum yellowing on flakes and underlying erythema.

Cosmetic shampoos

Cosmetically-optimized therapeutics

Therapeutic shampoos

Mild for everyday usage Hair conditioning Pleasant product esthetics Cost effective Anti-dandruff efficacy

Figure 15.2 Representation of the shampoo segments, differentiating cosmetic from therapeutic shampoos and their key attributes. The category of cosmetically optimized therapeutics achieves therapeutic benefits without diminishing esthetic attributes.

The primary component of all shampoos is surfactants which help to remove sebaceous lipids, keratin debris, particulates from the air, and residues from styling products (Table 15.1). These materials are responsible for the lathering action of a product; the volume of lather is important in the user’s perception of cleaning activity. Most of the surfactants tend to be negatively charged (anionic), although some contain both positive and negative charges in the same molecule (amphoteric), and some are uncharged (nonionic); these latter types are considered co-surfactants and function to optimize the lather quality and amount and cleaning ability of the primary anionic surfactant. The surfactant system is optimized to achieve two opposing objectives – cleaning while minimizing irritation of the skin. All surfactants have the potential to irritate the skin to various degrees. The goal of the formulator is to achieve

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effective cleaning and lathering while minimizing the irritation potential of the product by using the right surfactants. The addition of co-surfactants can synergistically decrease irritation potential without harming cleaning. Some antidandruff actives also can minimize the irritation potential of surfactants (see below); this is especially important for treatment of the D/SD condition which can be exacerbated by an irritating surfactant system. In addition to surfactants for cleaning, shampoos contain a wide range of other materials to care for the hair and scalp, deliver cosmetic benefits, enhance the usage experience, and to maintain the physical integrity of the product itself (e.g. preservatives, viscosity adjusters, pH control). Hair conditioning agents result in shiny, manageable hair and include such materials as silicones, cationic (positively charged) polymers that show enhanced deposition on the hair fiber to reduce static electricity, humectants to maintain hydration, and materials that penetrate the hair shaft to maintain a healthy-looking appearance. The cationic polymers mentioned as conditioning aids are also a critical component of the delivery system of many shampoos. While shampoos are first and foremost designed to clean, the achievement of additional hair and scalp benefits requires selected materials to be left behind after rinsing to deliver these benefits. The combination of oppositely charged surfactants and polymers results in an electrostatic association complex called coacervate which forms upon product use and rinsing. The coacervate is an aqueous gel that aids in the delivery of hair and scalp benefit agents to their respective surfaces. The manipulation of surfactant and polymer types affects deposition efficiency, and together with the type and level of hair benefit agent(s), affects how much conditioning is delivered to the hair. This is the basis for a wide offering of shampoo versions, to meet the diverse hair and scalp needs of users to deliver cosmetic benefits and a pleasant in-use experience, especially in terms of how much hair conditioning is needed and desired. Standard therapeutic shampoos

15. Shampoos

Table 15.1 Summary of common formulation components of various shampoo types. Function(s)

Material class(es)

Lather/cleaning

Hair conditioning agents

Primary surfactants

Optimization

Co-surfactants

Shine, manageability Detangling, Antistatic Hydration

Silicones

Benefit delivery

Preservatives

Sodium lauryl sulfate, ammonium lauryl sulfate, sodium laureth sulfate, ammonium laureth sulfate Cocamidopropyl betaine, Cocamide MEA

Presence in Cosmetic shampoo

Cosmetically optimized therapeutic

Standard therapeutic shampoo

Yes

Dimethicone, dimethiconol, amodimethicone Polyquaternium-10, cationic guar derivatives Glycerin, urea

Yes

Some

Panthenol and derivatives

Some

Cationic Polymers

Polyquaternium-10, cationic guar derivatives

Yes

Biocides

Isothiazalinone derivatives, parabens

Yes

Yes Some

Yes

Cationic polymers Humectants

Hair health Deposition aids

Common examples

Fragrance Thickeners

Viscosity

Salts Particles

Sodium chloride Glycol distearate

Antidandruff components

Scalp care

Antifungals

Pyrithione zinc (PTZ), selenium sulfide, ketoconazole (Table 15.2) Zinc carbonate

Potentiators

tend to be deficient in hair conditioning benefits. They also do not tend to have a range of versions to meet the esthetic needs of the user. Together these two factors limit compliance with standard therapeutic products. Therapeutic scalp care shampoos additionally contain active materials for resolving D/SD and preventing its reoccurrence. Because the commensal scalp fungus Malassezia clearly has a role in the etiology of the condition [1], the primary function of most scalp care active materials is antifungal; the most common are referred to in Table 15.2, grouped by their intrinsic anti-Malassezia potency. Many of the materials are accepted by global regulatory agencies, while some are used in more limited geographic applications. The most commonly used scalp active is pyrithione zinc (PTZ), a material developed as part of a program to identify biocides based on the naturally occurring antibiotic aspergillic acid [4]. Screening of over 1000 prospective antidandruff

Some

materials in the late 1950s led to the selection of PTZ; novel formulation work then led to commercialization of shampoos with PTZ in the early 1960s [5]. Since that time, the efficacy, ease of formulation, cost, and compatibility with esthetic shampoos has resulted in very broad use and acceptance of PTZ and technical developments which continue to improve its therapeutic benefit (see below). Other effective actives such as ketoconazole and selenium sulfide are used fairly broadly, but tend to be more limited to the standard therapeutic class of shampoos either because of cost, regulatory, or esthetic limitations. Such products are generally used when especially difficult cases of D/SD occur. If such products are needed, subsequently switching to cosmetically optimized therapeutic shampoos should be advised for prophylactic usage. Materials such as climbazole and octopirox have been used regionally, but have been limited by the lack of acceptance by the US Food and Drug

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Table 15.2 Overview of scalp care active materials. Common actives

Primary mechanism

Typical amount used

Appearance

Odor

Physical characteristics

Usage

Most potent antifungal activity Pyrithione zinc (PTZ)

Antifungal

0.5–2%

White powder

Neutral

Wide. Positive impact on esthetics and hair care benefits

Ketoconazole

Antifungal

1–2%

White powder

Neutral

Limited. Is expensive and requires regulatory approval

Selenium sulfide

Antifungal

1–2%

Red powder

Sulfur-like

Limited. Color and odor affect esthetics

Moderately potent antifungal activity Climbazole

Antifungal

0.5–2%

White powder

Neutral

Limited. Not accepted globally by regulatory bodies

Octopirox

Antifungal

0.5–2%

White powder

Neutral

Limited. Not accepted globally by regulatory bodies

Yellow powder

Sulfur

Limited. Color and odor affect esthetics

Sulfur Least potent antifungal activity Salicylic acid

Keratolytic agent

1.8–3.0%

White powder

Neutral

Limited. Low antifungal potency

Coal tar

Regulator of keratinization

0.5–1.0%

Black viscous liquid

Off-odor

Limited. Color and odor affect esthetics

Administration (FDA). Although the FDA does accept the safety and efficacy of salicylic acid, coal tar, and sulfur, either low potency or poor esthetics have limited their broad utilization.

Table 15.3 Formulation factors affecting the realization of full efficacy. 1 Retention of active material on scalp after rinsing 2 Physical bioavailability: spatial coverage of active on scalp surface 3 Chemical bioavailability: prevalence of active species of active

Unique attributes of scalp care products The complexity of the shampoo delivery vehicle described above in combination with the unique attributes of the active material accounts for varying levels of efficacy obtained when using similar actives at identical levels. The case is well-illustrated for shampoos based on PTZ, in which the physical form of the material as well as the shampoo composition affect resultant activity [1] by three parameters (Table 15.3). Regardless of the type of active material used in shampoos, activity is derived from how much material is retained on the scalp surface after rinsing. This is a complex formulation technology task because cleaning is occurring simultaneously. The efficiency of the coacervate technology delivery system directly impacts how much of a material such as PTZ is retained on the scalp after rinsing. This efficiency of this deposition can vary dramatically between commercial prod-

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ucts and will directly affect efficacy [6]. The achievement of effective active delivery is a complex balancing of parameters to maximize delivery while not compromising the esthetic properties of the product. While the amount of material remaining on the scalp surface is critically important, the physical distribution and bioavailability of the material is just as important. For a particulate material such as PTZ, there is substantial technology in the optimization of the particle morphology (shape and size) to improve physical distribution on the scalp surface. There are two types of PTZ in use today. Standard PTZ has a submicron size and a nondescript morphologic shape. Optimized PTZ is used by one manufacturer where the morphology is platelet (Figure 15.3) and the particle size has been optimized to 2.5 μm. Both of these parameters are designed to maximize the efficiency of scalp surface cover-

15. Shampoos age to achieve uniform benefits throughout the microenvironment of the scalp. This is important as the effective zone around a PTZ particle (Figure 15.4a) is limited by the molecular solubility of PTZ in the surrounding medium of sebaceous oils. By use of platelet morphology particles, the

tive zo fec n

PTZ particle

Figure 15.3 Electron micrograph of a unique form of pyrithione zinc (PTZ), optimized for size and morphology to maximize the efficiency of surface coverage.

spatial coverage is more efficient than use of a three-dimensionally symmetric particle. Particle size of the platelet is also important to achieve uniformity of coverage. Ideally, smaller particles are better, but they suffer from a trade-off that they are more difficult to retain through the rinsing step. Thus, practically, it has been observed [1] that an optimum particle size is 2.5 μm, which represents the average size of the optimized PTZ material. Together, these attributes constitute physical bioavailability. The third factor affecting delivered efficacy is optimization of chemical bioavailability [7]. Chemically, PTZ is considered a coordination complex between inorganic zinc ion (Zn) and the pyrithione (PT) organic moiety. In such a material, the bonds are weak and an equilibrium exists between the intact species and the separate components (Figure 15.4b). Neither of the separated components (Zn and PT) are effective antifungals; thus, to the extent this dissociation occurs, PTZ chemical bioavailability and resultant efficacy is reduced. By adding a common ion to the system (in the form of zinc carbonate), the equilibrium is shifted (exploiting LeChatelier’s principle) to the intact and more effective PTZ; this unique potentiated PTZ formula thus maximizes bioavailability of the deposited material. Another important aspect in product selection is that the cleaning activity of the shampoo not result in irritation of

(a) Standard PTZ formula O

Active species

Potentiated PTZ formula

Zn O

N N

Zn O

Plus zinc carbonate O S

O +

(b) Figure 15.4 (a) Conceptual representation of the zone of inhibition of fungal growth surrounding PTZ particles and the importance of spatial distribution of particles to achieve uniformity of coverage. (b) PTZ can dissociate into component pyrithione (PT) and zinc (Zn) which reduces the presence of the intact bioactive species. The addition of zinc carbonate alters this equilibrium to maintain PTZ in its bioactive intact form.

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Table 15.4 Summary of advantages and disadvantages of using scalp care shampoos.

Table 15.5 Summary of usage habits to maximize the therapeutic benefit.

Advantages Convenient form for treatment and prevention of dandruff/seborrheic dermatitis For cosmetically optimized therapeutics, compliance is increased • Affordability • No esthetic trade-offs For PTZ-based products, over 50 years of safe utilization For PTZ-based products, no tachyphylactic responses

1 Use the therapeutic shampoo for every shampooing to prevent a relapse 2 Use a therapeutic product that is cosmetically optimized and affordable 3 Shampoo as frequently as possible 4 Lather exposure time is not important but repeating the entire process can be beneficial 5 Product should be utilized all year 6 If a rinse-off conditioner is needed, use one that contains antidandruff active

Disadvantages For straight therapeutic products, compliance is reduced • Can be very expensive • Can have substantial esthetic trade-offs

the scalp. For those with D/DS this would interfere with the natural cutaneous repair processes that occur upon Malassezia population reduction. In addition to appropriate selection of the surfactant system as described above, some antifungal actives such as PTZ have been shown to reduce the irritation potential of the surfactants [8].

Advantages and disadvantages The use of therapeutic shampoos for effective treatment of D/SD as well maintenance of normal scalp hygiene is very convenient because the patient will be utilizing this product in the shower already (Table 15.4). By choice of a cosmetically optimized therapeutic product, the user suffers no esthetic trade-offs (compared to cosmetic shampoos) that would limit compliance. This class also tends to be more affordable than standard therapeutic products, which also increases long-term (prophylactic) usage. No diminution of benefit (e.g. tachyphylaxis) occurs upon long-term use of PTZ-based products; this is based on both designed clinical studies [9] as well as anecdotal evidence associated with over 50 years of usage history. The only disadvantage of using such scalp care products occurs when a strict therapeutic product is chosen. The expense and esthetic negatives that normally accompany such products limit patient compliance leading to frequent frustrating condition reoccurrence; these products should be limited to the most recalcitrant of cases.

Effective use of products D/SD is a chronic condition characterized by frequent reoccurrence, resulting in frustration on the part of the patient (Table 15.5) [10]. Initial treatment of the condition appears

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to be managed fairly effectively by either independent use of therapeutic antifungal shampoos or by combination with topical corticosteroid usage. However, preventative treatment is required for long-term management of the condition. Because Malassezia easily recolonize, using a cosmetically optimized therapeutic product for each shampoo experience is the optimum method for preventing reoccurrence. If cosmetic shampoo usage is interspersed with therapeutic products, efficacy is decreased [11]; not only does the cosmetic shampoo not deliver active to the scalp, it washes off any deposited material from the prior exposure to the active-containing shampoo. The desire to switch between a cosmetic shampoo and therapeutic product is either the real or perceived esthetic trade-offs in use of a therapeutic product. It has been shown [12] that therapeutic products do not provide all of the desired esthetic benefits and that this will drive patients to choose cosmetically optimized therapeutic shampoos for treating scalp conditions. Even with cosmetically optimized therapeutic products, there is often a perception that these products are not equivalent to cosmetic shampoos. While this may have been true in the past, modern technologies can deliver efficacious therapeutic and cosmetic benefits without the traditional trade-offs of standard therapeutic treatments. A wide range of D/SD shampoo treatments are available [13], with widely ranging costs. By recommending a therapeutic product that has been cosmetically optimized and one that is affordable for ongoing usage, the patient is best advised to use this product as their normal product to prevent reoccurrence. Even by selection of an effective therapeutic product, how it is used can make a difference to the magnitude of benefit achieved. The length of time the lather is exposed to the scalp is generally not important as it is the material that is retained on the scalp after rinsing that provides the benefit. Using coacervate-based deposition technologies, it is the rinsing that triggers the deposition. Repeating the lathering and rinsing process twice will more thoroughly remove the sebaceous lipid and allow more active to be deposited.

15. Shampoos D/SD symptoms occur year-round and should be treated all year. There is a misperception that it is a seasonal condition, primarily occurring in cold, dry seasons. This has been shown not to be true [11]. Winter months with less humid air combined with the tendency to wear darker clothing make the patient more able to detect the flaking symptoms under these conditions, but they occur all of the time. Higher frequency of shampooing may occur in summer months resulting in a slight decrease in severity of symptoms. Another critical usage factor involves whether a rinse-off conditioner is used after the shampoo [11]. Rinse-off conditioners that do not contain antidandruff actives remove a portion of the deposited active from the prior therapeutic shampoo exposure thereby reducing efficacy. If the patient desires use of a rinse-off conditioner, one containing antidandruff active should be recommended so that loss of retained active does not occur once the entire hair care regimen is practiced.

Benefits of use of scalp care shampoos Resolution of D/SD is the primary motivation for initiation of use of therapeutic shampoos. The choice of shampoo should be motivated by, in order: efficacy, cosmetic hair benefits, and cost. Assessing the relative efficacy of a product usually involves double-blind placebo-controlled drug studies using medical experts to grade the severity of flaking and erythema. A review of the comparative efficacy of products [3] supports that the most effective products are those that contain an effective antifungal, the most potent of which are PTZ, selenium sulfide, and ketoconazole. Further rank-ordering within this group is somewhat difficult because of conflicting studies and the part that the specific formulation then plays. However, it is clear that cosmetically optimized therapeutics can be as effective as standard therapeutics; the marketing strategy used to position these products is not necessarily a good predictor of the true technical efficacy. The use of certain scalp care shampoos also demonstrate the ability to deliver anti-irritancy effects [14]. There appears to be a wide range in activities depending on the specific active used. PTZ, and especially the potentiated PTZ formula, appears to be most effective at reducing irritation. Irritation and inflammation are early steps in the etiology of D/SD as well as many other scalp conditions. Thus, use of the zincbased therapeutic products may well have general scalp health benefits beyond D/SD mitigation [15]. The scalp health benefits associated with use of antidandruff shampoos may extend to hair benefits as well. A number of studies have demonstrated (e.g. Berger et al. [16]) that use of these products can reduce the rate at which hair is lost. The mechanism for this benefit is not known, but may be speculated to originate in the reduction of inflam-

mation referred to above as follicular inflammation may impede regrowth of lost hairs. A further benefit of the scalp inflammation being reduced by these products is less itch and subsequent scratching which reduces hair damage and improves the quality and appearance of hair.

Conclusions Normal scalp hygiene requires frequent and effective cleaning of the scalp. Cosmetic shampoos do this effectively while providing conditioning benefits for the hair. For many individuals, this frequent cleaning is sufficient to prevent adverse scalp effects. However, many still experience the symptoms of D/SD. For this group, therapeutic products are required that contain antidandruff actives that control the scalp Malassezia population. A subset of this class is cosmetically optimized therapeutics in which the product delivers the therapeutic benfits without loss of the typical cosmetic shampoo esthetics. This leads to much higher compliance, leading to effective long-term care of the chronic condition. Other factors relevant for selecting the most useful product are that the active and shampoo composition be optimized to maximize the physical and chemical bioavailability of the active; this is especially true for PTZ-based treatments. Once the best shampoo is chosen, effective habits are required to realize the full benefit: frequent use without switching to cosmetic shampoos, use all year around, and the use of a rinse-off conditioner that also contains antidandruff active.

References 1 Schwartz J. (2007) Treatment of seborrheic dermatitis of the scalp. J Cosmet Dermatol 6, 18–22. 2 Elewski B. (2005) Clinical diagnosis of common scalp disorders. J Investig Dermatol Symp Proc 10, 190–3. 3 Schwartz J, Cardin C, Dawson T Jr. (2005) Dandruff and seborrheic dermatitis. In: Barran R, Maibach H, eds. Textbook of Cosmetic Dermatology, 3rd edn: New York: Taylor & Francis, pp. 259–72. 4 Shaw E, Bernstein J, Losee K, Lott W. (1950) Analogs of aspergillic acid. IV. Substituted 2-bromopyridine-N-oxides and their conversion to cyclic thiohydroxamic acids. J Am Chem Soc 72, 4362–4. 5 Snyder F. (1969) Development of a therapeutic shampoo. Cutis 5, 835–8. 6 Bailey P, Arrowsmith C, Darling K, Dexter J, Eklund J, Lane A, et al. (2003) A double-blind randomized vehicle-controlled clinical trial investigating the effect of ZnPTO dose on the scalp vs. antidandruff efficacy and antimicotic activity. Int J Cosmet Sci 25, 183–8. 7 Schwartz J. (2005) Product pharmacology and medical actives in achieving therapeutic benefits. J Investig Dermatol Symp Proc 10, 198–200. 8 Warren R, Schwartz J, Sanders L, Juneja P. (2003) Attenuation of surfactant-induced interleukin 1α expression by zinc pyrithione. Exog Dermatol 2, 23–7.

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9 Schwartz J, Rocchetta H, Asawanonda P, Luo F, Thomas J. (2009) Does tachyphylaxis occur in long-term management of scalp seborrheic dermatitis with pyrithione zinc-based treatments? Int J Dermatol 48, 79–85. 10 Chen S, Yeung J, Chren M. (2002) Scalpdex: a quality-of-life instrument for scalp dermatitis. Arch Dermatol 138, 803–7. 11 Schwartz J. (2004) A practical guide for the treatment of dandruff and seborrheic dermatitis. J Am Acad Dermatol 50, P71. 12 Draelos Z, Kenneally D, Hodges L, Billhimer W, Copas M, Margraf C. (2005) A comparison of hair quality and cosmetic acceptance following the use of two anti-dandruff shampoos. J Investig Dermatol Symp Proc 10, 201–4.

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13 Schwartz R, Janusz C, Janniger C. (2006) Seborrheic dermatitis: an overview. Am Fam Physician 74, 125–30. 14 Margraf C, Schwartz J, Kerr K. (2005) Potentiated antidandruff/ seborrheic dermatitis formula based on pyrithione zinc delivers irritation mitigation benefits. J Am Acad Dermatol 52, P56. 15 Schwartz J, Marsh R, Draelos Z. (2005) Zinc and skin health: overview of physiology and pharmacology. Dermatol Surg 31, 837–47. 16 Berger R, Fu J, Smiles K, Turner C, Schnell B, Werchowski K, et al. (2003) The effects of minoxidil, 1% pyrithione zinc and a combination of both on hair density: a randomized controlled trial. Br J Dermatol 149, 354–62.

Part 2: Moisturizers Chapter 16: Facial moisturizers Yohini Appa Johnson & Johnson, New Brunswick, NJ, USA

BAS I C CONCEPTS • Facial moisturizers can be used to improve skin texture, treat dry skin, and provide sun protection. • Occlusives, humectants, emollients, and sunscreens are important ingredient categories in facial moisturizers. • The efficacy of a facial moisturizer can be measured via transepidermal water loss and corneometry. • Facial moisturizers can be an important adjunct in the treatment of facial dermatoses, such as atopic dermatitis and eczema.

Introduction The face is the most conspicuous representation of age and health. While the eyes are considered the windows to the soul, the face is its billboard. No other body part demonstrates personal past history as convincingly as the face. Wrinkles form on the face well before the rest of the body and serve as an indicator of age and lifestyle. The relative color and luminosity of the facial skin represents overall health and emotional state. Facial skin can be dull to vibrant representing poor to excellent physical health. The face mirrors acute changes in well-being. For example, persons experiencing cardiac distress appear “ashen” while anger or embarrassment may be expressed as a reddened face. Thus, the face represents the current physical state of the individual. Moisturizers can enhance the appearance of the face and are thus important cosmeceuticals. The face is rarely covered and constantly subjected to the elements. It is one of the most light-exposed areas of skin on the body, the other areas being the shoulders, upper chest, and forearms; as a result it receives high amounts of UV radiation. The incidence of cutaneous melanoma as measured by relative tumor density is highest on the face in subjects over the age of 50 years, a statistic that is interpreted as directly correlating to the amount of long-term UV exposure [1]. This means that facial photoprotection is of great importance, thus the incorporation of efficacious UVA and UVB protection in daily facial moisturizers is worthwhile.

Facial skin is physiologically unique. It possesses numerous sweat glands and a relatively thin dermis. It is densely populated with sebaceous glands, possessing 400–900 glands per square centimeter [2]. The face is a major point of contact for sensory input, the facial skin possesses high innervation and is therefore more sensitive than skin elsewhere on the body [3]. The skin covering the face also has to allow for the subtleties of facial expressions and phonoation. Of all the areas on the body, the skin on the face has the highest level of hydration. When the ratio of transepidermal water loss (TEWL) to skin surface hydration was calculated in order to determine the most consistently hydrated area of the body, the forehead and cheek showed the lowest ratios (Figure 16.1).

Dry facial skin Dry skin is a term used to describe the condition that arises when the normal functioning of the skin is compromised. More specifically, it is a manifestation of the consequences that arise from a loss of water from the outermost layer of the dermis: the stratus corneum (SC). The SC is formed when keratinocytes, cuboidal cells in the lower half of the epidermis, migrate from the basal layer to the most superficial layer, producing large amounts of the water-insoluble protein keratin along the way. The keratinization and migration process results in flattened, keratin-filled keratinocytes, referred to as corneocytes, which create an overlapping barrier with a “brick and mortar” appearance that is nearly waterproof. The gaps between the corneocytes, or “bricks,” are filled with intercellular lipids, or “mortar” that is produced by keratohyaline granules. The SC layer is also

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Moisturizers Forehead 257 0.055 Cheek 345 0.04

H2O TEWL/H2O ratio

Back of hand 97 0.12 Upper leg 106 0.1

Top of foot 72 0.14 Figure 16.1 Skin surface hydration and transepidermal water loss (TEWL) and SciCon ratio.

referred to as the “dead layer” because by this point the cells have stopped synthesizing proteins and are unresponsive to cellular signaling. Cells in the SC are eventually sloughed off and replaced by more cells coming up through the epidermis, thereby maintaining a continuous barrier. It normally takes 26–42 days for the epidermis to cycle completely [4]. The process of skin cell differentiation and maturation is a delicate balance that is easily disrupted. If the water content of the SC drops below 20% for an extended period of time, the enzymes involved in desquamation will be unable to function and the process of orderly epidermis cycling will be compromised. This especially apparent in dry facial skin. There are many functions that the epidermal barrier performs: 1 Maintains a 20–35% water content; 2 Limits TEWL; 3 Preserve water homeostasis in the epidermis; 4 Sustains optimal lipid synthesis; and 5 Allows for orderly desquamation of SC cells.

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A shift away from equilibrium in one of these five functions can result in a compromise of the barrier and the basic consequence is what we refer to as “dry skin.” More specifically, when TEWL is increased to the point that the water content in the SC is reduced to below 10%, the clinical signs of xerosis will appear [5]. The orderly desquamation of the SC is a complex process which if disturbed can lead to a self-renewing cycle of dry skin. The corneocytes that make up the SC are highly interconnected and able to withstand a large amount of mechanical stress. When new cells are formed, enzymatic digestion of the proteins anchoring the old cells is required for removal. The level of humidity in the SC is a critical factor modulating the activity of these desquamatory enzymes, specifically stratum corneum chymotryptic enzyme (SCCE). When this process breaks down, desquamation becomes irregular and dead SC cells slough off in large clumps; representing the “flaking” seen in so many dry facial skin conditions [6]. The sebum-rich skin of the face can appear moisturized but possess a low water content. Sensory symptoms can include but are not limited to: dryness, discomfort, pain, itching, stinging, or tingling sensations. Tactile signs are rough, uneven, and sand-like feeling skin. Visible signs, which can be macroscopic or microscopic, are redness, dull surface, dry white patches, flaky appearance, and cracks and fissures. There are many causes for these signs and symptoms. In all, the presence of dry skin represents disorder in the complex system that continually renews the facial skin.

Facial moisturization The physiologic goal of facial moisturization is to restore the elasticity and flexibility of the SC, thereby restoring its barrier function. Additionally, the reintroduction of humidity to the SC allows for proper functioning of desquamation enzymes and restores the natural skin renewal cycle. Kligman and Leyden [7] defined a moisturizer as “a topically applied substance or product that overcomes the signs and symptoms of dry skin.” The esthetic goal of moisturization is achieving soft, supple, glowing, healthy looking skin, as subjectively evaluated by the end-user. Regular use of facial moisturizers mitigate and prevent signs of aging, especially when formulated with broad-spectrum sun protection for daytime use. Because the face is one of the most sensitive areas of the body, a facial moisturizer must meet esthetic goals in addition to fulfilling a broad set of performance attributes. Consumers expect a facial moisturizer to reduce dryness, improve dull appearance, smooth and soften the skin, and increase suppleness [8]. Furthermore, these expectations

16. Facial moisturizers

Table 16.1 Function of common moisturizer ingredients. This listing represents the common ingredients found in a moisturizer formulation identifying the role of each of the substances in the ingredient disclosure. Humectant

Emollient

Occlusive

Dimethicone

Trisiloxane

Glycerin

Emulsifier

Preservative

Glyceryl stearate

PEG 100 stearate

Potassium cetyl phosphate

Behenyl alcohol

Caprylyl methicone

Hydrogenated palm glycerides

Hexanediol

Caprylyl glycol

Cetearyl glucoside

Cetearyl alcohol

Methylparaben

Propylparaben

Methylisothiazolinone

must be achieved by a moisturizer with a minimal presence and pleasant sensory qualities. A properly formulated moisturizer can supplement the function of the endogenous epidermal lipids and restore the epidermal barrier function. This allows the skin to continue its natural process of renewal and desquamation at a normal rate. The substances utilized by all moisturizers to achieve this desired effect fall into a handful of basic categories (Table 16.1). Humectants, such as glycerin, attract and hold moisture, facilitating hydration. Emollients, typically lipids or oils, enhance the flexibility and smoothness of the skin and provide a secondary soothing effect to the skin and mucous membranes. Occlusives create a hydrophobic barrier to reduce water loss from the skin. Emulsifiers work to bring together immiscible substances; they are a critical element in the oil and water mixtures employed in moisturizer formulas. Preservatives prevent the premature breakdown of components and inhibit microbiologic growth. Fragrances not only add to the esthetic value but can also mask the odor of formulation ingredients. These components make up the basic formulation of any moisturizer, and the choices available to achieve the preferred outcome are vast. The formulation of an acceptable and effective moisturizer for the face, one that will enable

the natural processes of skin desquamation to occur and maintain healthy barrier function while meeting high esthetic standards, is as much an art as it is a science.

Facial moisturizer formulation Facial moisturizers are typically oil-in-water emulsions. The water improves skin feel and offers an acceptable, universally tolerated base for the active ingredients. The water or oil solubility of components is inconsequential because both are present. Emulsions allow for a wide range of properties, such as slow to fast absorption rates depending on the final viscosity of the formulation. The fine-tuning of these properties is important for achieving the high esthetic expectations of a facial moisturizer. For example, a daily-use formula with high emollient content may feel heavy in a cream but be acceptable in liquid form. Conversely, overnight creams with antiaging additives may be thick in order to remain on the face during sleep and to slow the absorption of active components. Therefore, by utilizing a range of water to oil ratios, and varying humectant and emollient mixtures, the desired effects can be formulated within the acceptable esthetic parameters for a facial moisturizer.

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Moisturizer ingredients and function Humectants The overall hydration level of the SC affects its mechanical properties. If the water level in the SC drops below 10%, its flexibility can be compromised and it becomes susceptible to damage from mechanical stress [9]. Humectants are key substances to maintain skin hydration. Natural humectants, such as hyaluronic acid, are found in the dermis, but external humectants can be externally applied in moisturizers. Humectants draw water from the viable epidermis and dermis, but can draw water from the environment if the ambient humidity is over 80%. Humectants are water-soluble organic compounds that can sequester large numbers of water molecules. Glycerin, sorbitol, urea, and sodium lactate are all examples of externally applied humectants. Glycerin, also referred to as glycerol, is one of the most widely utilized compounds in cosmetic formulations because of its effects on multiple targets and its universal applications. Its chemical structure brings together the stability of three carbon atoms with three water-seeking oxygen atoms in an anisotropic molecule that is perfectly designed for use in skin and hair moisturizers. Glycerin also allows for the construction of different product physical forms that cover the spectrum from sticks to microemulsions to free-flowing creams that maintain stability over time. The degree of purity to which glycerin can be manufactured not only ensures consistency and facilitates microbiologic stability, but also guarantees the minimization of allergic reactions by contaminants. The pure form of glycerin has been tested on thousands of patients and millions more have used it with extremely few reports of ill effects. Glycerin is generally classified as a humectant; however, this characteristic is not the sole reason for its ability to achieve skin moisturization, in fact, it performs a number of different functions that are not directly related to its water-holding properties. Glycerin can restore the suppleness of skin without increasing its water content, a trait that is exploited by its use in the cryopreservation of skin, tissue, and red blood cells, where water would freeze and damage them. Glycerin enhances the cohesiveness of the intercellular lipids when delivered from high glycerin therapeutic formulations, thereby retaining their presence and function. Furthermore, glycerin has been identified as a contributor to the process of desquamation, a critical component of the dermal renewal cycle, through its ability to enhance desmosome digestion. In addition to its direct, humectant effects on skin moisturization, endogenously produced glycerin has exhibited effects at the molecular level in knockout mouse model studies, confirming its role in maintaining SC hydration and barrier maintenance. A recent study showed that glycerin content was three times lower, SC hydration was reduced,

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and barrier function was impaired in mice deficient in the water/glycerin transporter protein, aquaporin-3 (AQP3) despite normal SC structure, protein–lipid composition and ion–osmolyte content. Glycerin, but not other small poly glycols, restored normal SC moisturization and TEWL values when applied to the AQP3-deficient mice, confirming that glycerin was physiologically necessary in the modulation of SC hydration and barrier maintenance [10]. Glycerin remains the gold standard for moisturization. The fact that it acts on so many different parameters with a nearly non-existent side-effect profile makes it a prime candidate for facial moisturizer formulations. It is also an excellent example of how moisturizer components, especially those used on the face, should be considered for their ability to enhance and protect the skin. Glycerin raises the bar for moisturizers in that it is capable of enhancing, or even rescuing, the intrinsic processes that are in place to maintain the orderly maturation of keratinocytes and the barrier function of the skin.

Occlusives Humectants are only partially effective in moisturizing the skin. In order to maintain epidermal water content and preserve the barrier function of the SC, occlusive agents are employed in a role meant to complement the water-attracting nature of humectants. Occlusive agents inhibit evaporative water loss by forming a hydrophobic barrier over the SC and its interstitial areas. Occlusion is successful in the treatment of dry skin because the movement of water from the lower dermis to the outer dermis is a guaranteed source of physiologically available water. Moreover, these occlusive agents have an emollient effect, as is the case with behenyl alcohol. Petrolatum and lanolin are two historically popular occlusives that are slowly being replaced by more sophisticated alternatives. Petrolatum is a highly effective occlusive, but it suffers from an unfavorable esthetic. Lanolin is not recommended for use in facial formulations because of its odor and potential allergenicity [11]. Newly constructed silicone derivatives have been employed in moisturizers for their occlusive properties, and they further enhance the esthetic quality of the formulation by imparting a “dry” touch. This technologic advancement is also an example of how the esthetic parameter of a facial moisturizer can have a major effect on compliance and willingness to apply.

Emollients Emollients are agents, usually lipids and oils, designed to soften and smooth the skin. Lipids are non-polar molecules and as such they repel polarized water molecules, thereby limiting the passage of water to the environment. The most prevalent lipids in the SC, especially within the extracellular membranes, are ceramides. They comprise about 40% of the lipid content of the SC, the remainder of which is 25%

16. Facial moisturizers cholesterol, 10–15% free fatty acids, and smaller quantities of triglycerides, stearyl esters, and cholesterol sulfate. These lipids are synthesized throughout the epidermis, packaged in lamellar granules, and eventually differentiate into multilamellar sheets that form the ceramide-rich SC water barrier [12]. The purpose of an emollient is to replace the absent natural skin lipids in the space between the corneocytes in the SC. Additional benefits include the smoothing of roughened skin thereby changing the skin’s appearance, and providing occlusion to attenuate TEWL and enhance moisturization. Of the three components of skin moisturizers listed in the CTFA Cosmetic Ingredients Directory, emollients outnumber occlusives 2 to 1 and the humectants 10 to 1. This is an indication not only of the number of available compounds that can perform this function, but also the variety of lipids that can be utilized [13].

A key immediate event that leads to chronic photoaging is the production of proteases in response to UV irradiation at doses well below those that cause skin reddening. Matrix metalloproteinases (MMPs), for example, are zinc-dependent endopeptidases expressed in many different cell types and are critical for normal biologic processes. They may also be involved in desquamation processes, and overexpression would lead to early sloughing and increase in TEWL. With a proper sunscreen regimen, production of MMPs is minimized and their participation in chronic photoaging can be avoided. The addition of sunscreens to facial moisturizers also contributes to the prevention of reactive oxygen species (ROS) production, Langerhans cell depletion, and sensitivity to UV radiation, as is observed in polymorphous light eruption.

Facial moisturizer testing Fragrance Fragrance is a component of facial moisturizers that is often dismissed as an unnecessary potential irritant, but this idea is becoming increasingly antiquated as the science supporting its proper use and evaluation is improved. Vigorous protocols have been developed that comprehensively and conclusively assess the tolerance of formulations on human subjects. Fragrances are screened separately first and then together in both normal and sensitive populations, and utilized at the minimum concentration required to mask the smell of certain components, if necessary. Fragrance improves the overall esthetic qualities of the moisturizer, which is an important component of any moisturizer formulation, especially one that is applied to the face.

Preservatives Preservatives are also subject to the same rigorous testing protocols as fragrances. The preservative must be strong enough to completely inhibit bacterial growth, but must not be sensitizing or irritating. Preservatives are an important component in facial moisturizers to prevent the lipids in the formulation from becoming rancid. All facial moisturizers have some type of preservative, because there is really no such thing as a preservative-free formulation.

Photoprotection and facial moisturizers Sunscreens could be considered to be the most globally effective ingredient added to a facial moisturizer. Because the incidence and mortality rates of skin cancer have been steadily rising in the USA, the use of sunscreen as a daily protectant has become more important to consumers. There are both immediate and long-term benefits from photoprotection. The immediate benefit is the prevention of a painful sunburn while long photoprotection results in reduced photodamage manifesting as wrinkling, inflammation, and dryness.

The formulation of a moisturizer centers on the primary goal of delivering the perception of moisture to the skin. This includes not only adding moisture to the skin, but also the improvement of the barrier function and reinstating natural skin reparative processes. The testing of the efficacy of a moisturizer is based on barrier function assessment. There are many ways to assess the barrier function of the skin based on SC integrity. Measurement of the TEWL is one method. A damaged SC allows water to evaporate resulting in high TEWL readings. These measurements are taken with an evaporimeter, which measures the amount of water vapor leaving the skin. The amount of water in the skin can also be measured via skin conductance. This technique, known as corneometry, measures the amount of low level electricity conducted by the skin. Because water is the conductor of electricity in the skin, the amount of current conducted is directly related to the water content. Thus, the efficacy of a moisturizer can be measured by its effect on water vapor loss and skin conductance. Another method for evaluating skin dryness is D-squames. D-squames are circular, adhesive discs placed on the skin surface with firm pressure and then pulled away. The removed skin is observed and parameters such as the amount of skin removed, size of flakes, and coloration can be recorded. Differences between dry skin and normal moisturized skin are clearly evident upon examination of the disc, and further characterization can be carried out to differentiate levels of dryness and qualitative differences in desquamation. The barrier function of the skin can be assessed following application of an irritant to the skin surface. The introduction of an irritant can cause erythema and scaling in the compromised SC. A frequent irritant used for the assessment of barrier function is sodium lauryl sulfate (SLS). The amount of erythema and TEWL is measured following

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scrubbing of the skin with SLS. Skin with a better barrier following use of an efficacious moisturizer will experience less damage than skin that possesses a compromised barrier. Finally, after testing the efficacy of the formulation in a controlled, laboratory setting, its efficacy must be evaluated on a group of consumers. Consumer testing is usually carried out in a blind study involving 200–300 subjects, from geographically disparate locales in order to normalize any differences in skin types or backgrounds. This testing will introduce parameters that are evaluated subjectively by the population of subjects such as skin feel, perception of texture, ease of application, and scent, among other things, that define its esthetic qualities. The functional qualities of the moisturizer, such as “immediate comfort” and “longlasting effect” will also be evaluated by the consumer group and incorporated into the overall assessment.

Use of facial moisturizers in common inflammatory dermatoses The face presents a set of unique challenges regarding the treatment of skin disorders. What may be acceptable for treatment regimens elsewhere on the body, such as a strong occlusive such as petrolatum or a humectant such as urea, will be esthetically challenging to the user and stand in the way of compliance. While it is easy to think of esthetics as secondary to efficacy of treatment, it should be considered of primary importance where the face is concerned. This concept cannot be overstressed because the sensitivity of the facial skin to the sensory and olfactory qualities of moisturizers is much higher than the rest of the body. It is generally believed that facial atopic dermatitis and various other facial skin diseases are associated with disturbances of skin barrier function as evidenced by an increase in TEWL, a decrease in water-binding properties, and a reduction in skin surface lipids. When chronic, inflammatory skin diseases manifest on the face, there is the challenge of reducing the lesion as quickly as possible to prevent it from worsening and further compromising the integrity of the skin involved. Because of the high sensitivity of the facial skin, what may start as a small lesion can quickly be exacerbated through physical intervention and quickly worsened. These problems can be addressed through the continual use of appropriate moisturizers, which have been shown to improve skin hydration, reduce susceptibility to irritation, and restore the integrity of the SC. Some moisturizers also supply the compromised SC with lipids that further accelerate barrier recovery. Moisturizers can serve as an important first-line therapeutic option for patients with atopic dermatitis and other chronic skin diseases [14]. Historically, moisturizers have been shown to have a steroid-sparing effect in patients with atopic dermatitis and eczema. Many of the elements in moisturizers, from lipids

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to emollients, have been shown to significantly improve the condition of the skin when used by patients with various dermatoses [15]. Glycerin has been implicated in the molecular mechanism controlling keratinocyte maturation, an important aspect of normal desquamation and barrier maintenance. Furthermore, its role in maintenance of hydration for the proper functioning of proteases, especially filaggrin, is critical to the successful treatment of eczemas [16,17]. Recently, a comprehensive clinical study provided evidence that moisturizers not only enhance the efficacy of topical corticosteroids in patients with atopic dermatitis, but may also prevent the recurrence of disease [15]. In general, the maintenance of the SC along with rapid repair of disruptions to the barrier that would otherwise become larger and increase inflammation and discomfort as well seem to be central tenets in the approach to treating potential dermatoses on the face with moisturization. Therefore, facial moisturizers may represent a valuable first-line treatment option for many dermatologic diseases and confer a number of important therapeutic benefits that go beyond the surface of the facial skin and have a critical role in the molecular mechanisms that maintain healthy skin.

Conclusions Facial moisturizers fulfill an important need by providing skin comfort and alleviating dryness. Efficacious formulations contain ingredients that work directly to bring moisture to the skin, but also indirectly, as is the case with glycerin, induce the transport and retention of water molecules at the subcellular level. The goal of facial moisturizers is to enhance, or restart, the processes intrinsic to the skin’s natural ability to maintain its barrier function through the multiple pathways utilizing proteases, lipids, cell differentiation and, eventually, desquamation, all while maintaining an esthetically pleasant presence.

References 1 Elwood JM, Gallagher RP. (1998) Body site distribution of cutaneous malignant melanoma in relationship to patterns of sun exposure. Int J Cancer 78, 276–80. 2 Montagna W. (1959) Advances in Biology of Skin. Oxford, New York: Symposium Publications Division, Pergamon Press. 3 Montagna W, Kligman AM, Carlisle KS. (1992) Atlas of Normal Human Skin. New York: Springer-Verlag. 4 Baumann L. (2002) Cosmetic Dermatology: Principles and Practice. New York: McGraw-Hill. 5 Draelos ZK. (2000) Atlas of Cosmetic Dermatology. New York: Churchill Livingstone. 6 Watkinson A, Harding C, Moore A, Coan P. (2001) Water modulation of stratum corneum chymotryptic enzyme activity and desquamation. Arch Dermatol Res 293, 470–6. 7 Kligman AM, Leyden JJ. (1982) Safety and Efficacy of Topical Drugs and Cosmetics. New York: Grune & Stratton.

16. Facial moisturizers 8 Barton S. (2002) Formualtion of skin moisturization. In: Leyden JJ, Rawlings AV, eds. Skin Moisturization. New York: Marcel Dekker, pp. 547–84. 9 Rawlings AV, Canestrari DA, Dobkowski B. (2004) Moisturizer technology versus clinical performance. Dermatol Ther 17 (Suppl 1), 49–56. 10 Hara M, Verkman AS. (2003) Glycerin replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice. Proc Natl Acad Sci U S A 100, 7360–5. 11 Draelos ZK. (1995) Cosmetics in Dermatology, 2nd edn. New York: Churchill Livingstone. 12 Downing S, Stewart ME. (2000) Epidermal composition. In: Loden M, Maibach HI, eds. Dry Skin and Moisturizers: Chemistry and Function. Boca Raton: CRC Press, 2000: pp. 13–26. 13 Draelos ZK, Thaman LA. (2006) Cosmetic Formulation of Skin Care Products. New York: Taylor & Francis. 14 Lebwohl M. (1995) Atlas of the Skin and Systemic Disease. New York: Churchill Livingstone. 15 Ghali FE. (2005) Improved clinical outcomes with moisturization in dermatologic disease. Cutis 76 (Suppl), 13–8. 16 Hanifin JM. (2008) Filaggrin mutations and allergic contact sensitization. J Invest Dermatol 128, 1362–4. 17 Presland RB, Coulombe PA, Eckert RL, et al. (2004) Barrier function in transgenic mice overexpressing K16, involucrin, and filaggrin in the suprabasal epidermis. J Invest Dermatol 123, 603–6.

Further reading Bikowski J. (2001) The use of therapeutic moisturizers in various dermatologic disorders. Cutis 68 (Suppl), 3–11. Burgess CM. (2005) Cosmetic Dermatology. Berlin: Springer. Crowther JM, Sieg A, Blenkiron P, et al. (2008) Measuring the effects of topical moisturizers on changes in stratum corneum thickness, water gradients and hydration in vivo. Br J Dermatol 159, 567–77. Del Rosso JQ. (2005) The role of the vehicle in combination acne therapy. Cutis 76 (Suppl), 15–8.

Fisher GJ, Datta SC, Talwar HS, et al. (1996) Molecular basis of suninduced premature skin ageing and retinoid antagonism. Nature 379, 335–9. Fisher GJ, Varani J, Voorhees JJ. (2008) Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol 144, 666–72. Fisher GJ, Voorhees JJ. (1996) Molecular mechanisms of retinoid actions in skin. FASEB J 10, 1002–13. Fisher GJ, Wang ZQ, Datta SC, et al. (1997) Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 337, 1419–28. Fluhr J. (2005) Bioengineering of the Skin: Water and Stratum Corneum, 2nd edn. Boca Raton: CRC Press. Friedmann PS. (1986) The skin as a permeability barrier. In: Thody AJ, Friedmann PS, eds. Scientific Basis of Dermatology. Edinburgh, London: Churchill Livingstone, pp. 26–35. Held E, Jorgensen LL. (1999) The combined use of moisturizers and occlusive gloves: an experimental study. Am J Contact Dermatol 10, 146–52. Jungermann E, Norman O, Sonntag V. (1991) Glycerin: A Key Cosmetic Ingredient. Vol. 11, Cosmetic Science and Technology Series. New York: Marcel Dekker. Kafi R, Kwak HS, Schumacher WE, et al. (2007) Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol 143, 606–12. Loden M, Maibach HI. (1999) Dry Skin and Moisturizers: Chemistry and Function. Boca Raton: CRC Press. Orth DS. (1993) Handbook of Cosmetic Microbiology. New York: Marcel Dekker. Page-McCaw A, Ewald AJ, Werb Z. (2007) Matrix metalloproteinases and the regulation of tissue remodeling. Nat Rev Mol Cell Biol 8, 221–33. Rattan SI. (2006) Theories of biological aging: genes, proteins, and free radicals. Free Radic Res 40, 1230–8. Streicher JJ, Culverhouse WC Jr, Dulberg MS, et al. (2004) Modeling the anatomical distribution of sunlights. Photochem Photobiol 79, 40–7. Verdier-Sevrain S, Bonte F. (2007) Skin hydration: a review on its molecular mechanisms. J Cosmet Dermatol 6, 75–82.

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Chapter 17: Hand and foot moisturizers Teresa M. Weber1, Andrea M. Schoelermann2, Ute Breitenbach2, Ulrich Scherdin2, and Alexandra Kowcz1 1 2

Beiersdorf Inc, Wilton, CT, USA Beiersdorf AG, Hamburg, Germany

BAS I C CONCE P T S • Xerosis of the hands and feet is common, caused by a paucity of sebaceous glands. • Moisturization of the hands and feet can prevent eczematous disease and aid in disease eradication. • Effective moisturizers provide occlusive lipophilic substances that act as protectants and barrier replenishers, as well as hydrophilic agents that function as humectants to bind and hold water. • Recent recognition of the role of aquaporins, special moisture regulating channels, in skin cells has provided the opportunity for a new moisturization technology, focusing on substances that stimulate and operate through aquaporins.

Introduction The hands and feet are prone to dryness and impaired barrier function because of their unique functional roles, predisposing the skin to heightened irritant sensitivity and the development of dermatoses. Protective and regenerative moisturizing skin care is the foundation for averting and treating dry skin associated skin diseases and disorders. Effective moisturizers provide occlusive lipophilic substances that act as protectants and barrier replenishers, as well as hydrophilic agents that function as humectants to bind and hold water. The importance of urea as a physiologic humectant and natural moisturizing factor is discussed. Application of moisturizers containing urea is shown to increase its concentration and exert ultrastuctural changes in the stratum corneum, hydrate severely compromised skin, and support and enhance barrier function. In addition, the role of aquaporins and the underlying mechanisms of moisture homeostasis of the skin are discussed vis-à-vis new opportunities to create better actives and product formulations which can help regulate moisturization from within the skin.

Moisturization needs of the hand and foot Skin of the hands and feet is different from other body sites. In particular, skin on the palms and soles is thicker, and has

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a high density of eccrine sweat glands; however, it lacks apocrine glands. These sites are highly innervated and involved in most of the daily activities of life. Repetitive use of the hands and feet accompanied by pressure and friction can promote the formation of areas of thickened keratinized skin or calluses, which can crack and fissure. Site-specific requirements for hygienic care and diseases common to these sites have been described [1]. In addition, the hands and feet have special skincare needs for efficacious moisturization as well as unique requirements for formulations that are compatible with their special sensory and functional roles and needs. Hand skin is particularly susceptible to xerosis and dermatitis. Constant use of the hands, frequent washing, and environmental, chemical, and irritant exposure can provoke these problems. Further, because the hands are especially prone to injury and exposed to irritants and pathogens, specific protectant skincare formulations can be highly beneficial to prevent irritation or occupational dermatoses such as hand eczema [2]. While the feet may be less likely to suffer from deleterious occupational exposures, environmental factors can have an impact on the moisture status of the foot skin. Cold, dry weather in winter, bare feet in summer, and the confinement of shoes can compromise the hydration state. Occlusive shoes and socks can also trap moisture and render the foot susceptible to microbial infections, especially from fungus, damaging the barrier function and dehydrating the skin. In addition, certain metabolic diseases can impact circulation and innervation of the extremities, which in turn affects skin hydration. In particular, reduced circulation and eccrine sweat gland activity in diabetics cause severe xerosis which can spiral into other severe foot problems.

17. Hand and foot moisturizers Protective and regenerative moisturizing skin care is the foundation for treating all dry skin associated skin diseases and disorders. While the underlying cause of dry skin in any specific skin disorder needs to be addressed, frequently the symptomatic control of severe xerosis by appropriate moisturizers may reduce the need for more potent treatments, such as prolonged use of topical steroids and immune modulators, which can have detrimental side effects. Moisturizing creams containing urea have been reported to improve the physical and chemical nature of the skin surface, with the manifest benefits of smoothing, softening, and making dry skin more pliable [2]. Traditional moisturizing emulsions have utilized non-physiologic emollients, humectants, and skin protectants to rehydrate the skin and reduce moisture loss. The identification and understanding of the structure and function of the stratum corneum barrier lipids and the role of water binding physiologic substances collectively referred to as natural moisturizing factors (NMF) led to the development of formulations enriched in these actives. Recent recognition of the role of aquaporins, special moisture regulating channels, in skin cells has provided the opportunity for a new moisturization technology, focusing on substances that stimulate and operate through aquaporins.

Moisturizing formulations and technologies For thousands of years oils, animal and vegetable fats, waxes and butters have been used to moisturize the skin. Recognized for their emollient or skin smoothing and softening properties, these substances were used to help restore dry skin to a more normal moisture balance. The first significant advancement from these simple moisturizers occurred over a hundred years ago when emulsifiers were developed to create the first stable water-in-oil emulsion [3]. A simple emulsion can be defined as a heterogeneous system that contains very small droplets of an immiscible (or slightly miscible) liquid dispersed in another type of liquid. These emulsions consist of a hydrophilic (water loving) and a lipophilic (oil loving) portion, either of which can make up the external or internal phases of the emulsion system. The external phase generally comprises the majority of the emulsion while the smaller internal phase consists of the dispersed droplets. Most commonly used moisturizer formulations are either oil-in-water (O/W) emulsion systems, where aqueous components predominate, or water-in-oil (W/O), where the majority of ingredients are nonaqueous. Emulsifiers are necessary components of emulsion systems as water-soluble and oil-soluble ingredients are not miscible. Emulsifiers are surface active agents that reduce the inter-

facial tension between the two incompatible phases to create stable emulsion systems. The properties of the chosen emulsifiers determine the final emulsion type. Major progress in recent decades has enabled the formulation of increasingly complex emulsions (e.g. water-in-oil-inwater emulsions, multilamellar emulsions), which combine and stabilize many incompatible ingredients for moisturizing products with unique delivery characteristics that are both highly effective and esthetically pleasing [4,5]. However, it is beyond the scope of this chapter to discuss the multitude of emulsion technologies which have been developed since the advent of the simple W/O system [6]. Occlusive materials and humectants are two major classes of moisturizing ingredients in many current moisturizers (Table 17.1). Occlusive materials coat the stratum corneum to inhibit transepidermal water loss (TEWL). Additionally, cholesterol, ceramides, and some essential and non-essential free fatty acids present in oils can help to replenish the natural lamellar barrier lipids that surround the squames in the stratum corneum, fortifying the barrier function of the skin. Some common examples of occlusive materials are petrolatum, olive oil, mineral oil, soybean oil, lanolin, beeswax, and jojoba oil. Petrolatum, lanolin, and mineral oil are considered occlusive materials, yet they also serve as emollients on the skin [7,8]. Humectants are materials that are capable of absorbing high amounts of water from the atmosphere and from the epidermis, drawing water into the stratum corneum for a smoother skin feel and look. Examples of well-known humectants include glycerin (or glycerol), sorbitol, urea, sodium hyaluronate, and propylene glycol. Glycerin is a widely used humectant with strong water binding capacity and holding ability, making it ideal for dry skin moisturizing formulations. Because of its importance in moisturizing products, it has been extensively reviewed elsewhere [9,10]. A number of commercially available hand and foot moisturizers incorporate combinations of both humectants and occlusive materials to deliver the optimal skin benefits (Table 17.2).

Natural moisturizing factors The NMF are a collection of hygroscopic substances in the skin that act synergistically to confer effective water binding properties. The NMF has been reported to be composed of approximately 40% amino acids, 12% pyrrolidone carboxylic acid, 12% lactates, 7% urea, 18% minerals, and other sugars, organic acids, citrates, and peptides [11]. These substances, derived from eccrine sweat, extracellular components, largely from breakdown products of the insoluble protein filaggrin, have an important role in maintaining

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Table 17.1 Key classes of commonly used moisturizing ingredients. Key classes

Moisturizing ingredients

Function in skin

Occlusives

Petrolatum Waxes Lanolin Mineral oil Cholesterol Ceramides Triglycerides and free fatty acids Sunflower oil Soybean oil Jojoba oil Olive oil Evening primrose oil Borage oil

Moisturization by occlusion of the stratum corneum and/or replenishment of lamellar barrier lipids

Humectants

Glycerin/glycerol Sorbitol Sodium hyaluronate Propylene glycol Amino acids* Lactate* Pyrrolidone carboxylic acid* Urea* Salts*

Draws water from the formulation base, atmosphere, and from the underlying epidermis to increase skin hydration *Natural moisturizing factors – absorb large amount of water even in relatively low humidities. Provide aqueous environment for key enzymatic functions in the skin

Table 17.2 Examples of commercially available hand and foot creams. Key ingredients

Functions and claims Hand cream

Foot cream

Glycolic acid, mineral oil, petrolatum

Exfoliation and moisturization by “occlusives” to both smooth and soften skin

Glycerin, shea butter, almond oil, olive oil

Moisturization of hands and softening of cuticles

Moisturizes, soothes, and protects dry, cracked, and callused heels

III

Caprylic/capric triglycerides, glycerin, sunflower oil, olive oil, almond oil

Moisturization of hands, nails, and cuticles

Soothes and heals severely dry, cracked heels

Beeswax, sweet almond oil

Moisturizes and softens dry skin

Prevents and heals cracked heels, calluses, corns, blisters

Lanolin, allantoin, glycerin, sunscreens: avobenzone, octinoxate

Moisturizes skin and helps treat the signs of aging

Glycerin, petrolatum, dimethicone, mineral oil

Helps form a protective moisture barrier; heals and protects dry hands with 24-hour moisturization

VII

Urea, sodium lactate, glycerin

Gently exfoliates and moisturizes; relieves dry skin associated with hand eczema

Intensively moisturizes, smoothes and heals dry, cracked feet

VIII

Prescription urea (25%, 30%, 40%, or 50%), mineral oil, petrolatum

Healing and debriding of hyperkeratotic skin and nails

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17. Hand and foot moisturizers moisture in the non-viable layers of the epidermis. Because of the moisture gradient that exists from the well-hydrated dermis to the relatively moisture-deprived stratum corneum, the cutaneous moisturization state is a function of the occlusive barrier lipids in the stratum corneum and the humectant properties of the NMF [12]. Both are critical to retain moisture and resist TEWL and the dehydrating effects of the environment. Therefore, qualitative or quantitative changes in either the barrier lipids or the NMF components can alter skin hydration. Urea is a major constituent of the water-soluble fraction of the stratum corneum [13]. Because of the high water binding capacity of urea, the water content in the skin depends on its concentration. In dry skin and in keratinization disorders, a deficit of urea is often found in the stratum corneum, confirming its importance in skin moisture balance. The concentration of urea has been reported to be reduced by approximately 50% in clinically dry skin compared to healthy skin [14,15]. The stratum corneum of unaffected psoriatic skin reveals no deficit in urea content, but levels in psoriatic lesions are reduced by 40% [16]. However, in patients with atopic dermatitis there is a deficit of about 70% in unaffected skin and about 85% in involved skin [17]. Urea has been demonstrated to be an effective moisturizer for a range of dry skin conditions [18] and especially xerosis of the elderly [19,20]. Lodén has recently compiled a summary of clinical data on the treatment of diseased skin with urea-containing formulations [21]. Besides improvements in skin hydration, urea may be enhancing the levels of linoleic acid and ceramides [22], providing an additional skin benefit. Urea is very soluble in water, but practically insoluble in lipids and lipid solvents. By its hydrogen-bond breaking effect, urea may expose water binding sites on keratin allowing the transport of water molecules into the stratum

corneum, thereby leading to a plasticizing effect [23]. In addition, urea has proteolytic and keratolytic effects in concentrations above 10% [21]. These activities are exploited in prescription formulations of 12–50%, which are often employed for debriding purposes in keratinization disorders. Lactic acid and salts of lactic acid, other efficacious components of the NMF, have also been used to treat dry skin conditions [11]. Like urea, the principal moisturizing effect is brought about by their humectancy. However, additional benefits of barrier support and restoration may be attributed to these NMF as an increase in ceramide synthesis in keratinocytes treated with lactic acid has been reported [24].

Ultrastructural effects Differential changes in skin hydration state and ultrastructure after the application of various moisturizing products can be observed using scanning electron microscopy (SEM) of frozen sections from skin biopsies [25]. Figure 17.1 depicts the epidermis of skin treated with a commercial lotion with 10% urea, sodium lactate, and glycerin (right), or treated with a vehicle lotion without urea, sodium lactate, and glycerin (left). From the SEM images it could be concluded that the product penetrated the entire stratum corneum, resulting in a more compact stratum corneum layer, with a 20–40% reduction in corneocyte thickness. When compared with an untreated control (not shown), the vehicle treatment did not have an influence on the stratum corneum thickness. The compaction of the stratum corneum by the urea product suggests an improved barrier function which has been confirmed in other clinical studies demonstrating a reduction in TEWL [22].

(a)

(b) Figure 17.1 Freeze–fracture scanning electron micrographs of the stratum corneum of skin treated with a vehicle lotion (a) or the vehicle lotion containing 10% urea and sodium lactate (b).

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Clinical demonstrations of product efficacy of sodium lactate and urea formulations Hand care Several clinical studies were conducted to evaluate the ability of a fragrance-free, O/W emulsion containing 5% urea and 2.5% sodium lactate to fortify the skin of healthy subjects, and to moisturize, protect, and treat others with compromised hand skin.

Improvements in urea content Thirty-one volunteers with healthy skin were enrolled in this study. Subjects refrained from the use of topical treatments for a period of 1 week and then applied the test product twice daily for 2 weeks. Urea content of the skin, moisturization state, and skin roughness were assessed at baseline, after 2 weeks of treatment, and 3 days after the last application. A significant increase (p < 0.05) in the urea content of the skin compared with untreated skin was observed (Figure 17.2) as well as significant improvements in skin hydration levels and roughness (data not shown). Franz cell porcine skin penetration studies confirmed the

Stratum corneum urea levels (% of baseline)

1600 Untreated Urea cream

1200

800

400

3 days regression Length of treatment

Baseline

2 weeks

*Significant difference relative to untreated, p < 0.05 Figure 17.2 Stratum corneum urea content before application, after 2 weeks of daily use, and 3 days after discontinuing application of an oil-in-water emulsion containing 5% urea and 2.5% sodium lactate.

Table 17.3 Mean clinical grading scores at baseline and after 4 weeks of daily use of a 5% urea and sodium lactate oil-in-water emulsion. Cracking/fissuring

Dryness/scaling Eczema severity

Baseline

4.78

6.61

3.04

Week 4

2.91*

3.59*

1.66*

* Significant difference relative to baseline, p ≤ 0.05.

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penetration and distribution of urea throughout the skin compartments 24 hours after application of a 5% urea body cream formulation: 54% stratum corneum, 7% in the viable epidermis, 22% in the dermis, and 17% in the receptor phase.

Improvement in eczema and xerosis In a second 4-week controlled usage study, 23 subjects with hand eczema and 14 subjects with hand dermatitis/xerosis were enrolled. The subjects applied the test cream at least twice per day (morning and evening), and as often as needed. Clinical evaluations were made at baseline, and after 2 and 4 weeks of hand cream use for cracking/fissuring and dryness/scaling (0–8 scale), and erythema, edema, burning, stinging, and itching (0–3 scale). Subjects with eczema were also evaluated using an Investigator’s Global Assessment for Eczema (0–5 scale). Digital photographs were taken at each of the clinical visits. Significant improvements (p < 0.05) in clinical grading scores at week 4 relative to baseline were observed for dryness/scaling and cracking/fissuring, and the Investigators Global Assessment for Eczema (Table 17.3). Average irritation scores were also significantly reduced and negligible by week 4 for itching, stinging, and burning (data not shown). Digital photographs captured the dry, compromised hand skin condition at the baseline visit, and demonstrated improvements that reflected the clinical assessments. Figure 17.3 shows the typical improvements observed in subjects at week 4 (right), compared with baseline (left). In conclusion, appropriate hand care can both treat and prevent common dermatoses such as hand eczema.

Foot care Patients with diabetes mellitus can exhibit a number of cutaneous manifestations as a result of changes in metabolic status and/or circulatory and neural degeneration [26]. Management of dry skin in these individuals is important to preserve barrier integrity which can help prevent bacterial and fungal infections. In particular, the heel skin can be very dry and scaly, prone to forming cracks and fissures which can lead to wounds that have difficulty healing. A 6-week controlled usage study of a cream containing 10% urea, 5% sodium lactate, and glycerin as a daily treatment for the feet was conducted in 31 type I and II diabetic patients. This patient population was chosen because of their highly compromised foot skin condition. The subjects’ heels were evaluated for roughness, scaling and cracking, and subjective irritation was also documented. Color photographs of the heels, taken before and after 6 weeks of treatment, documented the marked improvement in heel skin condition (Figure 17.4). In addition, significant reduction of roughness, scaling, and cracking was observed. In spite of the severely compromised skin condition at baseline, only one patient reported a mild irritation on the application site

17. Hand and foot moisturizers

Figure 17.3 Improvement in hand eczema (top) and xerosis (bottom) after 4 weeks of daily usage (right) of a hand cream containing 5% urea and sodium lactate.

which did not interfere with his completing the study according to the protocol. A second multicenter study of 604 patients with dry or severely dry, chapped feet and generalized xerosis (258, 42.7%), diabetes (179, 29.6%) or atopic dermatitis (113, 18.7%) was conducted in Germany and Austria. The patients applied a foot cream containing 10% urea, 5% sodium lactate, and glycerin at least twice daily for 2 weeks. While 319 patients used specific foot treatment products to care for their feet at the baseline visit, only 20 used other topical products in addition to the foot cream during the study period. The foot skin was clinically graded for xerosis, scaling, and cracking at baseline and after 2 weeks of treatment on a 5-point scale (none, slight, moderate, severe, or very severe). Table 17.4 documents the improvement in skin condition after 2 weeks of foot cream usage, showing significant and marked decreases in the percentage of patients with severe or very severe symptoms, and overall noticeable improvements in 95% of the patients. In this large patient population, the investigating dermatologists judged the tolerability to be very good or good in 96.7% of the patients, recommending continued product use.

These data and many other published studies [18–22] support the therapeutic value and excellent safety profile of urea when administered topically to treat various dry skin conditions.

The future: Next-generation moisturizers Water homeostasis of the epidermis is important for the appearance and physical properties of skin, as well as for the water balance of the body. Skin moisture balance depends on multiple factors including external humidity, uptake of water into the epidermis, skin barrier quality, and endogenous water binding substances. Biosynthesis and degradation of skin components is also influenced by water balance, impacting the moisturization state of the epidermal layers. In recent times, aquaporins (AQP), important hydrationregulating elements in the lower epidermis, have been described [27]. The first indications of the critical importance of AQP in regulating tissue hydration came from investigations of

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Figure 17.4 Improvement in diabetic foot skin after 6 weeks of daily usage of a foot cream containing 10% urea and 5% sodium lactate. Pretreatment photos (left) of two different subjects (top and bottom) and their corresponding week 6 photos (right).

Table 17.4 Clinical grading scores before and after 2 weeks of treatment. Percentage of patients with none or slight and severe or very severe symptoms (100% = 604 patients). None or slight (%)

Severe or very severe (%)

Xerosis

Baseline Week 2

5 69

67 6

Scaling

Baseline Week 2

22 79

44 6

Cracking

Baseline Week 2

26 66

32 8

resulted in dry, compromised skin, showed a significant decrease in the number of AQP3 pores (p = 0.04). The pores were quantified by analysis of Western blots, and a 43% reduction in the dry skin samples was observed. Further, in other skin conditions associated with skin dryness, a reduction in AQP3 has also been observed. Specifically, an age-related decline in AQP3 levels, as well as decreases associated with chronic sun exposure were reported [31]. Water and the moisturizing substances glycerol and urea have been found to be transported through the AQP in skin, providing moisture from within to the epidermis [32]. Expanding knowledge on the activity and regulation of AQP3 has led to the pursuit of a new class of actives that can modulate the expression of these water channels.

Enhanced glycerol derivatives other organ systems, in particular the kidney [28]. Since their initial discovery, AQP genes have been cloned and, to date, 13 different genes (AQP1–13) have been identified [29]. The first proof for their relevance in skin came from Ma et al. [30] who produced knockout mice lacking AQP3, which exhibited a reduced stratum corneum hydration. Studies confirmed the importance of these findings in dry human skin. Subjects whose epidermal barriers were damaged by a week-long tenside-based treatment that

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In vitro studies on human keratinocytes demonstrated a significant increase in AQP3 levels by a specific enhanced glycerol derivative (EGD), designed and synthesized to confer specific structural and osmotic properties. Figure 17.5 depicts the enhanced AQP3 levels of EGD treated human keratinocytes after 48 hours of incubation. Additional in vitro studies measuring AQP3 mRNA levels in human keratinocytes confirmed these findings. In contrast to glycerol treatment, EGD increased mRNA expres-

17. Hand and foot moisturizers

Figure 17.5 Immunohistochemical localization of the AQP3 protein in keratinocyte monolayers stained with a rabbit antihuman AQP3 antibody. Background control (left), untreated control (center), treatment with 3% enhanced glycerol derivative for 48 hours (right).

Change in mean TEWL relative to baseline (%)

110

Conclusions *

100

Vehicle

Vehicle + glycerol

Vehicle + glycerol+ EGD

*Significantly different, p < 0.05. Figure 17.6 In vivo study of 23 volunteers with dry skin. Transepidermal water loss (TEWL) measurement after the following treatments: vehicle; vehicle with 6.5% glycerol; and vehicle with 6.5% glycerol and 5% enhanced glycerol derivative (EGD).

sion relative to the control. Further, to assess the efficacy of this new active, in vivo placebo-controlled studies were conducted. Figure 17.6 demonstrates the results of a study of 23 subjects, whose epidermal barriers were damaged by a tenside-based treatment, resulting in dry, compromised skin. The restoration of the epidermal barrier was assessed weekly by measuring TEWL on treated skin sites. The applied topical test lotions included a vehicle preparation, vehicle plus 6.5% glycerol, and the vehicle with 6.5% glycerol and 5% EGD. After damaging the skin’s barrier for 1 week, vehicle treatment was ineffective at restoring the barrier to baseline levels, exhibiting greater moisture loss levels in the skin. Treatment with the glycerol-containing vehicle showed a reduction of the TEWL compared with the vehicle. However, a superior and significant barrier restoration and fortification is observed with the glycerol–EGD containing formulation compared with both vehicle and vehicle with glycerol.

Moisturizing substances have been used for thousands of years to improve the condition of compromised skin. The advent of stable emulsions and subsequent advancements in emulsion technologies provided improved elegance and efficacy for moisturizing products. More than 100 years of process refinements, discovery of new ingredients, and the growing understanding of the NMF and biologic mechanisms that regulate the skin’s moisture balance have contributed toward products with greatly enhanced stability, esthetics, and efficacy. In contrast to ingredients that exert their effects solely from the surface of the skin, the recent discovery and understanding of the function of AQP and new appreciation of the underlying mechanisms of moisture homeostasis of the skin provides new opportunities to create even better actives and product formulations which can help regulate moisturization from within the skin.

References 1 Draelos ZD. (2006) Cutaneous formulation issues. In: Draelos Z, Thamen L, eds. Cosmetic Formulation of Skin Care Products. New York: Taylor & Francis, pp. 3–34. 2 Zhai H, Maibach HI. (1998) Moisturizers in preventing irritant contact dermatitis: an overview. Contact Dermatitis 38, 241–4. 3 Lifschütz I. (1906) Verfahren zur Herstellung stark wasseraufnahmefähiger Salbengrundlagen. Patent DE 167849. 4 Fluhr JW, Darlenski R, Surber C. (2008) Glycerol and the skin: holistic approach to its origin and functions. Br J Dermatol 159, 23–34. 5 Epstein H. (2006) Skin care products. In: Paye M, Barel A, Maibach H, eds. Handbook of Cosmetic Science and Technology, 2nd edn. Boca Raton: CRC Press, pp. 427–39. 6 Schneider G, Gohla S, Kaden W, et al. (1993) Skin cosmetics. In: Uhlmann’s Encyclopedia of Industrial Chemistry. Weinheim: VCH Verlagsgesellschaft, pp. 219–43. 7 Rajka G. (1995) Atopic dermatitis. In: Baran R, Maibach H, eds. Cosmetic Dermatology. London: Martin Dunitz, pp. 253–8.

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8 Draelos ZD. (2005) Dry skin. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders, pp. 167–8. 9 Zocchi G. (2006) Skin feel agents. In: Paye M, Barrel A, Maibach H, eds. Handbook of Cosmetic Science and Technology, 2nd edn. Boca Raton: CRC Press, pp. 247–64. 10 Sagiv A, Dikstein S, Ingber A. (2001) The efficiency of humectants as skin moisturizers in the presence of oil. Skin Res Technol 7, 32–8. 11 Harding CR, Rawlings AV. (2006) Effects of natural moisturizing factor and lactic acid isomers on skin function. In: Maibach HI, Lodén M, eds. Dry Skin and Moisturizers: Chemistry and Function, 2nd edn. Boca Raton: CRC Press LLC, pp. 187–209. 12 Rawlings AV, Harding CR. (2004) Moisturization and skin barrier function. Dermatol Ther 17, 43–8. 13 Swanbeck G. (1992) Urea in the treatment of dry skin. Acta Derm Venereol 177, 7–8. 14 Mueller KH, Pflugshaupt C. (1979) Urea in dermatology I. Zbl Haut 142, 157–68. 15 Mueller KH, Pflugshaupt C. (1982) Urea in dermatology II. Zbl Haut 167, 85–90. 16 Proksch E. (1994) Harnstoff in der Dermatologie. Dtsch Med Wochenschr 119, 1126–30. 17 Wellner K, Wohlrab W. (1993) Quantitative evaluation of urea in stratum corneum of human skin. Arch Dermatol Res 285, 239–40. 18 Schölermann A, Filbry A, Rippke F. (2002) 10% urea: an effective moisturizer in various dry skin conditions. Ann Dermatol Venereol 129, 1S422, P0259. 19 Schoelermann A, Banke-Bochita J, Bohnsack K, et al. (1998) Efficacy and safety of Eucerin® 10% urea lotion in the treatment of symptoms of aged skin. J Dermatolog Treat 9, 175–9. 20 Norman RA. (2003) Xerosis and pruritus in the elderly: recognition and management. Dermatol Ther 16, 254–9. 21 Lodén M. (2006) Clinical evidence for the use of urea. In: Lodén M, Maibach HI, eds. Dry Skin and Moisturizers. Chemistry

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26 27 28

and Function, 2nd edn. Boca Raton: Taylor & Francis, pp. 211–25. Pigatto PD, Bigardi AS, Cannistraci C, Picardo M. (1996) 10% urea cream (Eucerin) for atopic dermatitis: a clinical and laboratory evaluation. J Dermatolog Treat 7, 171–6. McCallion R, Wan Po AL. (1993) Dry and photo-aged skin: manifestations and management. J Clin Pharm Ther 18, 15–32. Rawlings AV, Davies A, Carlomusto M, et al. (1995) Effect of lactic acid isomers on keratinocyte ceramide systhesis, stratum corneum lipid levels and stratum corneum barrier function. Arch Dermatol Res 288, 383–90. Richter T, Peuckert C, Sattler M, et al. (2004) Dead but highly dynamic: the stratum corneum is divided into three hydration zones. Skin Pharmacol Physiol 17, 246–57. Nikkels-Tassoudji N, Henry F, Letawe C, et al. (1996) Mechanical properties of the diabetic waxy skin. Dermatology 192, 19–22. Hara-Chikuma M, Verkman AS. (2008) Roles of aquaporin-3 in the epidermis. J Invest Dermatol 128, 2145–51. Agre P. (2006) Aquaporin water channels: from atomic structure to clinical medicine. Nanomedicine: Nanotechnology, Biology and Medicine 2, 266–7. Verkman AS. (2008) Mammalian aquaporins: diverse physiological roles and potential clinical significance. J Exp Med 10, 1–18. Ma T, Hara M, Sougrat R, et al. (2002) Impaired stratum corneum hydration in mice lacking epidermal water channel aquaporin-3. J Biol Chem 27, 17147–53. Dumas M, Sadick NS, Noblesse E, et al. (2007) Hydrating skin by stimulating biosynthesis of aquaporins. J Drugs Dermatol 6 (Suppl), 20–4. Hara M, Verkman AS. (2003) Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice. Proc Natl Acad Sci U S A 100, 7360–5.

Chapter 18: Sunless tanning products Angelike Galdi, Peter Foltis, and Christian Oresajo L’Oréal Research, Clark, NJ, USA

BAS I C CONCEPTS • Tanned skin is considered attractive among fair-skinned individuals. • Self-tanning preparations containing dihydroxyacetone (DHA) induce a temporary safe staining of the skin simulating sun-induced tanning. • Self-tanners are formulated into sprays, lotions, creams, gels, mousses, and cosmetic wipes. • The tanning effect of DHA begins in the deeper part of the stratum corneum before expanding over the entire stratum corneum and stratum granulosum resulting in the production of brown melanoidins. • DHA products do not confer photoprotection unless sunscreen filters are added to the formulation.

Introduction Social norms for tanning in the USA have dramatically changed in recent times. The presence of a tanned body at one time conveyed the social status of an outdoor laborer. Now, having a tan, especially during the winter months, indicates affluence. More information has become available regarding the deleterious effects of UV exposure. [1–3]. The public is beginning to understand the dangers, thereby modifying their lifestyle choices towards safer practices. However, the change has been slow because sun exposure behavior is in part influenced by psychologic and societal factors [4–6]. Selftanning preparations are becoming an increasingly important option for those desiring the tanned look but not exposing themselves to undue harm.

Sunless tanning products Definition Self-tanning products, or sunless tanners, are preparations that when applied topically impart a temporary coloration to the skin mimicking skin color of naturally sun-tanned skin. Depending on the formulation and the active ingredients, the onset of color formation can be anything from immediate to several hours and can last up to 1 week. Self-tanning formulations were introduced in the 1960s. Consumers’ acceptability soon waned because of unattrac-

tive results such as orange hands, streaking, and poor coloration. Because of these drawbacks, consumers today still associate sunless tanning with these undesirable results. However, improved formulations have appeared on the market. Refinements in the dihydroxyacetone (DHA) manufacturing process has aided in the creation of formulations that produce a more natural-looking color and better longevity.

Active ingredients The most widely used and most efficacious active ingredient in self-tanners is DHA. It is the only ingredient that is currently recognized as a self-tanning agent by the US Food and Drug Administration (FDA) [7]. DHA-based sunless tanners have been recommended by the Skin Cancer Foundation, the American Academy of Dermatology Association, and the American Medical Association [8–10]. DHA is a triose and is the simplest of all ketoses (Figure 18.1).

Mechanism of action of DHA Ketones and aldehydes react with primary amines to form Schiff bases [11]. This is similar to the Maillard reaction, also known as non-enzymatic browning, and involves, more specifically, the reaction between carbohydrates and primary amines [12]. DHA is able to penetrate into the epidermis because of its size. Pyruvic acid is formed from DHA and either can react with sterically unhindered terminal amino groups in the amino acids of epidermal proteins. The epsilon amino group of lysine and the guanido group of arginine are particularly susceptible to nucleophilic attack by the reactive carbonyl oxygen. Epidermal proteins contain high concentrations of both of these amino acids. Based on photoacoustic depth profilometry, the tanning effect of DHA begins in the deeper

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Figure 18.1 Chemical structure of dihydroxyacetone (DHA).

part of the stratum corneum layer (15–22 μm) before expanding over the entire stratum corneum and stratum granulosum [13,14]. Subsequent steps of the reaction mechanism are not fully understood. The resultant products are brown in color and are collectively referred to as melanoidins.

Alternate actives As previously stated, US federal regulations recognize only DHA as a sunless tanning agent [7]. Alternative technologies exist, however, with the capability to impart an artificial tan to the skin. Reducing sugars other than DHA can act as Maillard reaction intermediates and therefore have the potential for use as sunless tanning agents [15]. Reducing sugars, in basic solution, form some aldehyde or ketone. This allows the sugar to act as a reducing agent in the Maillard reaction of non-enzymatic browning. Reducing sugars include glucose, fructose, glyceraldehyde, lactose, arabinose, and maltose. Unfortunately, a large amount of heat energy is required to trigger the glycation reaction between glucose, the most commonly known reducing sugar, and free amines. Such properties render many reducing sugars useless for sunless tanning products. An exception is the keto-tetrose, erythulose. Although this reducing sugar produces a more gradual tan than DHA, it has been utilized as a self-tanning enhancer for years. As corporations continue to aggressively pursue new sunless tanning technologies, reducing sugars may provide the next generation of self-tanning actives.

Formulation challenges The content of DHA in self-tanning products depends on the desired browning intensity on the skin and is normally used in the range 4–8%. Depending on the type of formulation and skin type, a tan appears on the skin about 2–3 hours after use. During product storage, the pH of a DHAcontaining formulation will drift over time to about 3–4. At this pH, DHA is particularly stable. In order to ensure end product stability, certain key factors must be considered.

However, investigations have since shown that the storage stability of DHA could be increased when formulations are kept at a pH of 3–4 and buffering at a higher pH enhances the degradation of DHA [16]. The pH of a formulation may be adjusted to approximately 3–4 by using a small amount of citric acid or using acetate buffers as they do not affect DHA stability [17].

Processing and storage of DHA Storage and heating of DHA above 40 °C should be avoided as it causes rapid degradation. During manufacturing processes that require heating (as in the case of emulsions), DHA should not be added until the formulation has been cooled down to below 40 °C. Additionally, finished products containing DHA should be sold in opaque, or other UV-protective packaging, as well as resealable packaging, to limit exposure to air.

Nitrogen-containing compounds Amines and other nitrogen-containing compounds should be avoided in DHA-containing formulations. This includes collagen, urea derivatives, amino acids, and proteins. The reactivity of DHA towards these compounds can lead to its degradation, therefore resulting in the loss in efficacy and acceptability of resulting color. However, some commercial formulations combine DHA with nitrogen-containing containing compounds (e.g. amino acids). This combination provides a perceptual advantage to customers as provides within tanning 1 hour as a result of the accelerated reaction between DHA and amino acids. This tan is not substantive, however, and most of it is easily washed off [17].

Sunscreens A tan achieved with DHA alone does not offer sun protection comparable to that of sunscreens. However, it is possible to combine DHA with sunscreens to achieve a product with sun protection. Inorganic sunscreens such as titanium dioxide, zinc oxide, and nitrogen-containing sunscreens should be avoided as they induce rapid degradation of DHA. As a final stability check, periodic determination of DHA dosage is recommended to ensure end product and longterm stability and efficacy. A simple high performance liquid chromatography (HPLC) method exists using an amine column with acetonitrile/water (75 : 25) as a mobile phase. Detection is at 270 nm.

Delivery vehicles Creams and lotions

pH and buffers The pH of DHA-containing formulation drops during storage. The resulting pH lies in the range of 3–4. In the past, buffering was recommended to keep the pH at a level of 4–6.

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Self-tanning creams and lotions tend to be the most widely used of all of the self-tanning vehicles. Our studies have confirmed that although conventional, creams and lotions are preferred by consumers because of their ease of use and

18. Sunless tanning products reduced likelihood of having streaky color results. This is most likely because of the extended play time (e.g. rub-in time) offered by cream and lotion vehicles. In selecting the appropriate ingredients for formulation, the use of non-ionic emulsifiers is recommended over ionic emulsifiers because of improved stability of the DHA [16]. Additionally, xanthan gum and polyquaternium-10 may be used for thickening emulsions. Emollients have an important role in many self-tanning formulations as they impart hydration to the skin, play time during application, and a smooth and silky after feel. Types of emollients include oils, waxes, fatty alcohols, silicone materials, and certain esters. Emulsions with DHA are particularly susceptible to microbial attack. Parabens, phenoxyethanol, and mixtures thereof are recommended [16].

Gels and gelees Thickening formulations containing DHA, particularly to produce a clear gel, is relatively difficult because many of the conventional thickeners are not compatible with DHA. Studies have found that hydroxyethylcellulose, methylcellulose, and silica are good choices, whereas carbomers, PVM/MA decadiene crosspolymer, and magnesium aluminum silicate are not acceptable as they cause rapid degradation of DHA [16]. Silicones such as dimethicone and cyclomethicones have increased in popularity over recent years, particularly for producing water-in-silicone emulsions (typically classified as gelees). Gelees are similar in appearance to gels; however, they tend to offer improved play time and skin feel over gels as they contain high levels of the silicone emollients.

Regulatory considerations The US FDA considers sunless tanning actives as color additives as they impart color to the skin. According to 21CFR70, color additives are defined as: “A dye, pigment, or other substance…that, when added or applied to a food, drug or cosmetic or to the human body or any part thereof, is capable (alone or through reaction with another substance) of imparting a color thereto” [18]. The actives permitted in the sunless tanning products in the USA are limited to those approved for use as such. The following color additives appear in the Code of Federal Regulations in Tables 18.1 and 18.2. Labeling requirements are also specified under current FDA guidelines. All sunless tanning products that do not contain sun protection factor (SPF) protection must be labeled with the following warning statement (US Code of Federal Regulations): “Warning – This product does not contain a sunscreen and does not protect against sunburn. Repeated exposure of unprotected skin while tanning may

Table 18.1 Color additives exempt from certification per 21CFR73 2003 (US Code of Federal Regulations). Aluminum powder

Copper powder

Luminescent zinc

Annatto

Dihydroxyacetone

Manganese violet

β-Carotene

Disodium EDTA copper

Mica

Bismuth citrate

Ferric ammonium ferrocyanide

Potassium sodium copper

Ferric ferrocyanide

Pyrophyllite

Guaiazulene

Silver

Guanine

Sulfide

Henna

Titanium dioxide

Iron oxides

Ultramarines

Lead acetate

Zinc oxide

Bismuth oxychloride Bronze powder Caramel Carmine Chromium oxide greens Chlorophyllin

Table 18.2 Color additives per 21CFR73 2003 (US Code of Federal Regulations). Citrus Red No. 2

D&C Red No. 17

D&C Yellow No. 10

D&C Blue No. 4

D&C Red No. 21

D&C Yellow No. 11

D&C Blue No. 6

D&C Red No. 22

Ext. D&C Violet No. 2

D&C Blue No. 9

D&C Red No. 27

Ext. D&C Yellow No. 7

D&C Brown No. 1

D&C Red No. 28

FD&C Blue No. 1

D&C Green No. 5

D&C Red No. 30

FD&C Blue No. 2

D&C Green No. 6

D&C Red No. 31

FD&C Red No. 3

D&C Green No. 8

D&C Red No. 33

FD&C Red No. 4

D&C Orange No. 4

D&C Red No. 34

FD&C Red No. 40

D&C Orange No. 5

D&C Red No. 36

FD&C Yellow No. 5

D&C Orange No. 10

D&C Red No. 39

FD&C Yellow No. 6

D&C Orange No. 11

D&C Violet No. 2

Orange B

D&C Red No. 6

D&C Yellow No. 7

Phthalocyaninato2-Copper

D&C Red No. 7

D&C Yellow No. 8

increase the risk of skin aging, skin cancer and other harmful effects to the skin even if you do not burn” [18].

Product attributes Coloration The onset of coloration starts at approximately 2–3 hours and will continue to darken for 24–72 hours after a single application, depending on formulation and skin type.

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Because DHA forms covalent bonds with epidermal proteins, the tan will not sweat off or wash away with soap or water. The color gradually fades over 3–10 days, in conjunction with stratum corneum exfoliation. Any product or process that increases the rate of cell turnover or removes portions of the stratum corneum will decrease the longevity of the color. Thus, preparations containing alpha- and betahydroxyacids and retinoids, as well as microdermabrasion creams and the process of shaving, decrease the longevity of coloration from self-tanning products.

Evaluation Various spectrophotometric methods can be used to evaluate the coloration parameters of self-tanners such as onset of color and longevity of color. The most popular is the L*a*b* standard from Commission Internationale d’Eclairage (CIE). The three coordinates of CIELAB represent the lightness of the color (L* = 0 yields black and L* = 100 indicates diffuse white), its position between red/magenta and green (a*, negative values indicate green while positive values indicate magenta), and its position between yellow and blue (b*, negative values indicate blue and positive values indicate yellow). The total color difference between any two colors in L*a*b* can be approximated by treating each color as a point in a three-dimensional space (with three components: L*, a*, b*) and taking the Euclidean distance between them (ΔE). ΔE is calculated as the square root of the sum of the squares of ΔL*, Δa* and Δb* [19]. It is generally recognized that 1.5 ΔE units is the minimal difference detectable to the eye. Comparisons to baseline readings can yield onset of tanning (usually readings at 30 minutes, 60 minutes, etc.) and longevity of tanning (readings at 48 hours, 72 hours, etc.).

Moisturization The recent trend in cosmetic products is to be multifunctional. Moisturizing formulations are increasing in popularity in keeping with this trend. Formulations with 8–24 hour hydration claims are not uncommon. Current self-tanners are formulated into sprays, lotions, creams, gels, mousses, and cosmetic wipes. In general, there are no obstacles to obtaining satisfactory levels of hydration, although there are some compromises that may have to be made. Alcohol is often incorporated to achieve quick-drying formulations. The trade off is sacrificing some level of hydration. This can be offset with humectants such as glycerin or sodium hyaluronate.

Trends in sunless tanning Daily use moisturizers/glow Face and body moisturizers with low levels of DHA have grown in popularity over the past 5 years. Although not new

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to the market, the concept of using a daily moisturizer that imparts gradual color was particularly well-received by the faint in heart who were afraid of making mistakes and/or turning orange with the use of traditional sunless tanners. Typically formulated with 1–3% DHA, glow moisturizers are easy to apply and, depending on the formulation and user’s skin tone, may impart a darker shade to the skin after 1–3 applications.

No-rub mists No-rub sunless tanning mists have been sought out as the less expensive alternatives to the airbrushing trend. These multiangle applicator systems allow for simple, even, and often hands-free application. The formulation base systems are typically hydroalcoholic or aqueous solutions, therefore allowing for quick-drying properties.

Sunless tanning products with UV protection The tan imparted by sunless tanners is not adequate to protect against UVB and UVA damage. Sunless tanners must therefore carry the required FDA warning statement [19]. Sunless tanning products that do contain sunscreen are growing in popularity because of their multifunctional properties.

Conclusions With an increasing awareness of the harmful acute and chronic effects of UV damage, sunless tanning use remains a popular alternative to tan seekers. Modern day formulations are efficacious, well-tolerated, easy-to-use, and provide natural looking results. A probable increase in patient compliance of safe sun practices can therefore be anticipated.

References 1 Jemal A, Siegel R, Ward E, et al. (2006) Cancer statistics, 2006. CA Cancer J Clin 56, 106–30. 2 American Cancer Society. (2006) Cancer Facts and Figures 2006: American Cancer Society. 3 Elwood JM (1993). Recent developments in melanoma epidemiology, 1993. Melanoma Res 3, 149–56. 4 Garvin T, Wilson K. (1999) The use of storytelling for understanding women’s desires to tan: lessons from the field. Professional Geographer Vol. 51, 2, 297–306. 5 co*kkinides V, Weinstock M, Glanz K, Albano J, Ward E, Thun M. (2006) Trends in sunburns, sun protection practices, and attitudes toward sun exposure protection and tanning among US adolescents, 1998–2004. Pediatrics 118, 853–64. 6 co*kkinides V, Weinstock MA, O’Connell MC, Thun MJ. (2002) Use of indoor tanning sunlamps by US youth, ages 11–18 years, and by their parents or guardian caregivers: prevalence and correlates. Pediatrics 109, 1124–30. 7 United States Code of Federal Regulations 21CFR 73.2150, 2002.

18. Sunless tanning products 8 9 10 11

www.skincancer.org www.aad.org www.ama-assn.org Morrison RT, Boyd RN. (1973) Organic Chemistry. Boston, MA: Allyn and Bacon. 12 Lloyd RV, Fong AJ, Sayre RM. (2001) In Vivo formation of Maillard reaction free radicals in mouse skin. J Invest Dermatol 117, 740–2. 13 Puccetti G, Tranchant JF, Leblanc RM. (1999) The stability and penetration of epidermal applications visualized by photoacoustic depth profilometry. Sixth Conference International Society of Skin Imaging, Skin Research and Technology, Berlin, Germany.

14 Puccetti G, Leblanc R. (2000) A sunscreen-tanning compromise: 3D visualization of the actions of titanium dioxide particles and dihydroxyacetone on human epiderm. Photochem Photobiol 71, 426–30. 15 Shaath N. (2005) Sunscreens Regulation and Commercial Development. Boca Raton, FL: Taylor & Francis Group. 16 Chaudhuri R. Dihydroxyacetone: Chemistry and Applications in Self-Tanning Products. White Paper; 7. 17 Kurz T. (1994) Formulating effective self-tanners with DHA. Cosmet Toiletries 109, 55–60. 18 United States Code of Federal Regulations. 21CFR740.19, 2003. 19 Minolta. (1993) Precise Color Communication, Color Control from Feeling to Instrumentation. Minolta Camera Co. Ltd.

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Chapter 19: Sunscreens Dominique Moyal,1 Angelike Galdi2, and Christian Oresajo2 1 2

L’Oréal Recherche, Asnières, France L’Oréal Research, Clark, NJ, USA

BAS I C CONCE P T S • Sunscreens provide photoprotection from UV radiation (UVR). • Photoprotection is required for both UVB and UVA radiation. • Organic and inorganic filters are used in sunscreens. • Sunscreen filters must be carefully combined to achieve esthetically pleasing products with photostability and broad spectrum photoprotection.

Introduction

Regulatory status of sunscreens

Human exposure to UVR from sunlight can cause many adverse effects. They involve both UVB (290–320 nm) and UVA (320–400 nm). UVB radiation is mainly responsible for the most severe damage: acute damage such as sunburn, and long-term damage including cancer. It has a direct impact on cell DNA and proteins [1]. Unlike UVB, UVA radiation is not directly absorbed by biologic targets [2] but can still dramatically impair cell and tissue functions: • UVA penetrates deeper into the skin than UVB. It particularly affects connective tissue where it produces detrimental reactive oxygen species (ROS). ROS cause damage to DNA, cells, vessels, and tissues [3–8]. • UVA is a potent inducer of immunosuppression [9,10] and there is serious concern about its contribution in the development of malignant melanoma and squamous tumors [11,12]. • Photosensitivity reactions and photodermatoses are primarily mediated by UVA [13]. As a result, a major concern has been raised that most available sunscreen products are incapable of preventing the harmful effects of UVA. It is important to note that under any meteorologic condition, the UVA irradiance is at least 17 times higher than the UVB irradiance. For all these reasons, it is evident that sunscreens must contain both UVA and UVB filters to cover the entire range of harmful radiation.

With increased knowledge about UV-induced skin damage and particularly the effects of UVA, public education programs have been developed with an emphasis on the proper use of sunscreen products. Many new UV filters have been made available in the last decade with improved efficacy and safety. The availability of new filters has been slow in some countries for regulatory reasons. An example is the USA where certain UVA and UVB filters, which are marketed elsewhere, are not approved for use. The availability of efficient sunscreen products depends not only on the regulatory status of the UV filters but also on the ability to inform the consumer about product efficacy with appropriate labels based on sun protection factor (SPF) and UVA protection levels. Sunscreen products can be classified in two main categories according to their purpose: 1 Primary sunscreens. Products whose main purpose is the protection of the skin from the effects of the sun, such as beach sunscreens and products used for outdoor activities. 2 Secondary sunscreens. Products that have a primary use other than skin protection, such as daily moisturizing creams, antiwrinkle/antiaging creams, and whitening skin products. In these products, sun protection is necessary to optimize the claimed effect. For this category of products, sun protection is an additional claim but not the main purpose.

Sunscreen classification

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Sunscreen products can also be classified in terms of regulatory status. Sunscreen products are ordinary cosmetic products in Europe, EU and non-EU countries (e.g. Russia), most African and Middle-Eastern countries, India, Latin America,

19. Sunscreens and Japan. They can be classified “special” cosmetic products as in China (special cosmetics), Korea and Ethiopia (functional cosmetics), South Africa (under SABS standard), Australia (under standards) [14], and Taïwan (medicated cosmetics). They are over-the-counter (OTC) drugs in the USA [15] (all sunscreens and products with SPF). In Canada, they can be either OTC drugs or natural health products (NHP), in this case the sunscreen contains only “natural” active ingredients: titanium dioxide, zinc oxide.

Approved UV filters In Europe, the UV filters are listed in Annex VII of the Cosmetics Directive. There are 27 UV filters on this list. In the USA, there are 16 filters included in the sunscreen monograph (Table 19.1). There are two main regulatory methods to market OTC products: monograph or a New Drug Application (NDA). An NDA is necessary to obtain the approval of a formula containing a new UV filter, or a new concentration for an approved active, or a new mixture of approved actives. A Time and Extent Application (TEA) is a new procedure for an active ingredient already approved abroad. It allows the FDA to accept commercial data obtained on external markets in place of use of an authorized drug on the US market; however, toxicologic data requirements for a TEA are very similar to those for an NDA. Seven UV filters are currently eligible for evaluation through a TEA procedure (not yet finalized):

Table 19.1 Sunscreen approved in the USA. Sunscreen approved in USA

Maximum concentration (%)

p-Aminobenzoic acid (PABA) Avobenzone Cinoxate

15 3 3

Dioxybenzone

Ensulizole (phenylbenzimidazole sulfonic acid) hom*osalate

4 15

1 Isoamyl p-methoxycinnamate (amiloxate) 10% max. 2 Methyl benzylidene camphor (enzacamene) 4% max. 3 Octyl triazone 5% max. 4 Methylene bis-benzotriazolyl tetramethylbutylphenol (Tinosorb® M, Ciba, Basel, Switzerland). 5 Bis-ethylhexyloxyphenol methoxyphenol triazine (Tinosorb® S, Ciba, Basel, Switzerland). 6 Diethylhexyl butamido triazone 3% max 7 Terephthalylidene dicamphor sulfonic acid (Ecamsule, Mexoryl® SX). In Australia, 26 UV filters are accepted by Therapeutic Goods Administration (TGA) and in Japan 31 UV filters are allowed. When comparison is made between the common UV filters approved in Europe and USA, only 11 filters are common, but p-aminobenzoic acid (PABA) will most likely be deleted in Europe and terephtalilydene dicamphor sulfonic acid (TDSA) is only available in USA under NDA for four formulas. Because of the importance of being well protected against UVA radiation, there are many new UVA filters or broad UVB/UVA filters, which have been developed and authorized in Europe, Australia, and Japan. It is obvious that the number of these filters is limited in the USA (Table 19.2). In addition, there are some limitations in the use of avobenzone in the USA. Combinations with some other UV filters, such as titanium dioxide and enzulizole, are not permitted and the maximum use level according to the sunscreen monograph is limited to 3%.

Development of sunscreens A proper sunscreen product must fulfill the following critical requirements: • Provide efficient protection against UVB and UVA radiation; • Be stable to heat and to UVR (photostable);

Table 19.2 Regulatory approval status for the main UVB/UVA and UVA filters.

Meradimate (menthyl anthranilate)

Octinoxate (octyl methoxycinnamate) Octisalate (octyl salicylate)

7.5

Benzophenone Oxybenzone BMDM (avobenzone)

EU, Japan, Aus, Can, USA EU, Japan, Aus, Can, USA

TDSA (Mexoryl SX)

EU, Japan, Aus, Can, USA (NDA)

DTS (Mexoryl XL)

EU, Japan, Aus, Can

Octocrylene

Octyl dimethyl PABA

DPDT (Neo-Heliopan AP)

EU, AUS

Oxybenzone

DHHB (Uvinul A+)

EU, Japan

Salisobenzone

MBBT (Tinosorb M)

EU, Japan, Aus

Titanium dioxide

BEMT (Tinosorb S)

EU, Japan, Aus

Trolamine salicylate

Titanium dioxide

EU, Japan, Aus, Can, USA

Zinc oxide

Japan, Aus, Can, USA

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• Be user-friendly to encourage frequent application and provide reliable protection; and • Be cost-effective. In order to protect against both UVB and UVA, the sunscreen product must contain a combination of active ingredients within a complex vehicle matrix. Active ingredients can be either organic or inorganic UV filters. According to their chemical nature and their physical properties, they can act by absorption, reflection, or diffusion of UVR.

Zinc oxide has better absorption in the long UVA than titanium dioxide, but it is not very efficient. Because of possible photocatalytic activity, inorganic particles are frequently coated with dimethicone or silica for maintenance of their efficacy. When nanosized titanium dioxide (<100 nm) is combined with organic UV filters, it allows high SPF products to be formulated with a lower dependence on organic UV filters. In combination with organic UV filters, nanosized titanium dioxide has more a synergistic rather than only an additive effect.

Organic UV filters

Steps toward more efficient sunscreens

How do organic filters work?

As far as UVB protection is concerned, a large choice of filters has been available for a number of years. They are photostable except for the most common, ethylhexyl methoxy cinnamate (EHMC). The choice of UVA filters depends on the countries and is limited in the USA, as already explained. Inorganic pigments offer poor protection against UVA when used alone. Benzophenones are photostable but they are primarily UVB filters with some absorption in the short UVA range (peak at 328 nm). Butyl methoxy dibenzoyl methane (BMDM or avobenzone) has a high potency in the UVA1 range peaking at 358 nm; however, it undergoes significant degradation under UV exposure and this leads to a decrease in its protective UVA efficacy. Research on the photochemistry of filters has led to the identification of some potent photostabilizers (e.g. octocrylene) of avobenzone and the development of new UVA filters that have a photostable structure. Recently, in 2005, diethylamino hydroxybezoyl hexyl benzoate (DHHB) was approved in Europe and Japan. This UVA1 filter has UV-spectral properties similar to BMDM but DHHB is photostable. In order to provide full protection in the entire UVA range, it is necessary to have efficient absorption in the short UVA range. TDSA or Mexoryl SX™ (Chimex, Le Thillay, France), with a peak at 345 nm at the boundary between short and long UVA wavelengths, was first approved in Europe in 1993. This was followed by the approval of the broad UVB/ UVA filter drometrizole trisiloxane (DTS or Mexoryl XL) with two peaks (303 and 344 nm) in 1998. Since 2000, other short UVA (disodium phenyl dibenzimidazole tetrasulfonate [DPDT] or Neo-Heliopan AP®, Symrise, Holzminden, Germany, peak at 334 nm) and broadband UVB/UVA filters (MBBT, Tinosorb M and BEMT, Tinosorb S) have been approved in Europe. All these filters are photostable. UV filters are either hydrophilic or lipophilic. When combined a synergetic effect can be observed. This property is used to obtain higher efficacy against UVB and UVA radiation. Combinations of highly efficient and photostable filters provide an optimally balanced protection against both UVA and UVB [17]. Studies [18–20] have shown that the protection against UV induced skin damage provided by sunscreen

Organic filters are active ingredients that absorb UVR energy to a various extent within a specific range of wavelength depending on their chemical structure [16]. The molecular structure responsible for absorbing UV energy is called a chromophore. The chromophore consists of electrons engaged into multiple bond sequences between atoms, generally conjugated double bonds. An absorbed UV photon contains enough energy to cause electron transfer to a higher energy orbit in the molecule [16]. The filter that was in a low-energy state (ground state) transforms to a higher excited energy state. From an excited state, different processes can occur: • The filter molecule can simply deactivate from its excited state and resume its ground state while releasing the absorbed energy as unnoticeable heat. • Structural transformation or degradation may occur and the filter losses its absorption capacity. The filter is then said to be photo-unstable. • The excited molecule can interact with its surroundings, other ingredients of the formula, ambient oxygen, and thus lead to the production of undesirable reactive species. The filter is said to be photoreactive. The control of filter behavior under UV exposure is a critical point that needs to be investigated when new sunscreen products are developed.

Inorganic UV filters Pigment grade powders of metal oxides such as titanium dioxide or zinc oxide have been used for many years in combination with organic filters to enhance protection level in the longer UVA range. Unlike organic filters, they work by reflecting and diffusing UVR. However, as a result of the large particle sizes, these powders also diffuse light from the visible range of the sun spectrum and they tend to leave a white appearance on the skin. To overcome this drawback, which affects cosmetic acceptance, micronized powders of both titanium dioxide and zinc oxide have been made available. However, micronization leads to changes in the protective properties of titanium dioxide: the smaller particles shift the protection range from the longer UVA toward the UVB.

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19. Sunscreens products with same SPF but different UVA protection factor is markedly different, emphasizing the importance of high UVA protection in preventing cell damage. Only wellbalanced, photostable sunscreens with absorption over the entire UV spectrum of sun radiation have been able to maintain intact essential biologic functions.

Formulation types Emulsions are the most popular of sunscreen vehicles. They offer versatility of texture (cream, lotion, milk) while exhibiting good performance. Emulsions can be placed into two main categories, oil-in-water (O/W) and water-in-oil (W/O). The W/O emulsions are intrinsically very water-resistant and will consistently yield higher SPF for the same concentration of sunscreen actives when compared with O/W emulsions. However, O/W emulsions are, by far, more widely used in sunscreens. This may be explained by the lower inherent cost for an O/W vehicle (where water is the outer phase) versus a W/O (where oil, a more expensive ingredient, is the outer phase). Aerosol spray vehicles have grown in popularity over the past few years. The multiposition spray nozzles allow for quick and easy application. Attention needs to be taken, however, that enough product is applied to ensure adequate protection. Oil, gel, stick, and mousse vehicles have decreased in popularity among formulators and consumers for several reasons. They are typically oil or wax-based, which makes then rather expensive and less efficacious. Additionally, they tend to be oily and greasy which result in lower usage and compliance.

Evaluation of the efficacy of sunscreen products Evaluation methods must take into account the photo-instability of products in order to avoid an overestimation of protection. In vivo SPF and in vivo UVAPF (Persistent Pigment Darkening) test methods take photodegradation into account. Appropriate UV doses are used to induce erythema on human skin for SPF determination or pigmentation for UVAPF determination. When in vitro methods are used they should also take into account this phenomenon to provide relevant evaluation [21].

Evaluation of the sun protection factor The international test method for SPF determination was first introduced in 2003. This method was published jointly by the Japanese Cosmetic Industry Association (JCIA), the European Cosmetic Industry Association (Colipa), and the Cosmetic Industry Association from South Africa (CTFA SA). In 2006, a revised version of this method was published with the support of the Cosmetic Toiletries and Fragrance Association (CTFA) from the USA [22]. In 1999, the US Food

and Drug Agency (FDA) published a final monograph [15]. FDA received comments and in August 2007 published a proposal of amendments [23]. This proposal includes a new SPF cap at 50+ and some amendments on technical points made in the 1999 monograph on sunscreen products. The Australian standards on SPF testing published in 1998 are similar to the other methods [14]. The International Standard Organization (ISO) TC217 WG7 working group is currently dealing with the standardization of a SPF method. The future ISO standard will be based on the international SPF test method including some improvements and it is expected to be published at the end of 2009.

Determination of UVA protection level The EU issued a recommendation on September 22, 2006 [24] to use a persistent pigment darkening (PPD) method similar to the JCIA method [25] or any in vitro method able to provide equivalent results. In addition, the critical wavelength [26] must be at least 370 nm. The EU Commission also recommends that the method used should take into account photodegradation. The first country that published an official in vivo method to assess UVA protection level was Japan. The JCIA adopted the PPD method as the official method for assessment of the UVA efficacy of sunscreen products in January 1996 [25]. Korea and China also adopted this method in 2001 and 2007, respectively. The PPD method was officially recommended by European Commission in September 2006 [24] and was recently proposed by FDA in the 2007 Sunscreen Monograph Amendment [23]. The method has been described with some minor differences by different countries or authorities. Finally, UVA method is currently in progress for standardization through the ISO. Since the PPD response requires doses greater than 10 J/ cm−2 (approximately 40 minutes of midday summer sunlight), the photostability of sunscreens is also challenged during the test procedure. To illustrate this point, avobenzone (BMDM, Parsol®1789) was tested [27] at concentrations of 1.0, 3.0, and 5.0% individually and in combination with 10% of octocrylene, a UVB filter, known to stabilize BMDM. The results of UVA-PF of avobenzone alone ranged from 2.2 with 1% BMDM to 4.6 with 5% BMDM. In combination with 10% octocrylene the results ranged from 4.6 with 1% BMDM to 10.6 with 5% BMDM. It is evident that UVA protection efficacy of avobenzone is significantly increased when it is combined with octocrylene, compared with the same concentration of BMDM alone. This can be explained by the fact that the PPD UVA doses affect the photostability of BMDM. It has been verified under real sun exposure conditions that when a photo-unstable product applied at 1 mg/cm2 is exposed to a UVA dose of about 30 J/ cm2 (about 2.5 hours) there is a dramatic decrease of the UVA absorption properties of avobenzone leading to a decrease of the UVA protection efficacy [28].

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Moisturizers

Critical wavelength method An in vitro approach to measure UVA protection using a thin film technique was proposed by Diffey et al. [26]. The UVB and UVA absorbance of the product is measured on a film of product applied on a substrate which can be quartz or polymethyl methacrylate (PMMA). The method yields a measure of the “breadth” of UVA protection using a test method called “critical wavelength” [26]. In this test proposal, the absorbance of the thin film of the sunscreen is summed (starting at 290 nm) sequentially across the UV wavelengths until the sum reaches 90% of the total absorbance of the sunscreen in the UV region (290–400 nm). The wavelength at which the summed absorbance reaches 90% of total absorbance is defined as the “critical wavelength” and is considered to be a measure of the breadth of sunscreen protection. The critical wavelength λc is defined according to equation (19.1):

∫

λc

290

lg [1 T (λ )] dλ = 0.9 ⋅

∫

400

290

lg [1 T (λ )] dλ

(equation 19.1)

Because this is a relative measurement, the “absolute” absorbance of the sunscreen is not necessary, eliminating the operator dependence of the test method. Critics of the methods based on absorbance criteria point to the fact that it is not a true measurement of UVA protective potency of the test product. The critical wavelength determination (λc) addresses the broadness of the protection rather than the specific protection in the UVA. Products with widely different in vivo protection indices (i.e. UVAPF PPD) can have identical critical wavelengths [29]. Combining both the in vivo PPD method for measuring the level of UVA protection efficacy and the critical wavelength method to measure the broadness of UVA absorbance has been proposed for UVA protection assessment of sunscreen products by the European Commission [24]. Other studies have shown that the higher the UVA protection level as assessed by the PPD method the better the protection against damage induced by UVA radiation [18–20]. On the other hand, critical wavelength higher than 370 nm is not a sufficient, reliable criterion to ensure that a product can provide efficient protection against UVA damage.

Conclusions It is important that a minimal proportionality between UVA and UVB protection be ensured in order to avoid high UVB protection with low UVA protection. A UVAPF : SPF ratio of at least one-third as defined by the European Commission [24] should be universally adopted for harmonization of consumer protection. In order to reach balanced protection, combination of UV filters is necessary. The criteria of choice are the following: UV filters with different maximum absorb-

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ance peaks (UVB, short UVA, and long UVA) to cover the entire UV spectrum, appropriate filters in different phases of sunscreen emulsion (lipophilic and hydrophilic), and ensuring the photostability of the UV filters. A high level of efficacy and protection against UVB and UVA radiation can be achieved by using available new filters.

References 1 Urbach F. (2001) The negative effect of solar radiation: a clinical overview. In: Giacomoni PU, ed. Sun Protection in Man, ESP Comprehensive Series in Photosciences. Vol. 3. Amsterdam: Elsevier Sciences, pp. 41–67. 2 Peak MJ, Peak JG. (1986) Molecular photobiology of UVA. In: Urbach F, Gange RW, eds. The Biological Effects of UVA Radiation. New York: Praeger Publishers, pp. 42–52. 3 Lavker RM, Kaidbey K. (1997) The spectral dependence for UVA-induced cumulative damage in human Skin. J Invest Dermatol 108, 17–21. 4 Lavker R, Gerberick G, Veres D, Irwin C, Kaidbey K. (1995) Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin. J Am Acad Dermatol 32, 53–62. 5 Lowe NJ, Meyers DP, Wieder JM, Luftman D, Bourget T, Lehman MD, et al. (1995) Low doses of repetitive ultraviolet A induce morphologic changes in human skin. J Invest Dermatol 105, 739–43. 6 Séité S, Moyal D, Richard S, de Rigal J, Lévêque JL, Hourseau C, et al. (1997) Effects of repeated suberythemal doses of UVA in human skin. Eur J Dermatol 7, 204–9. 7 Séité S, Moyal D, Richard S, de Rigal J, Lévêque JL, Hourseau C, et al. (1998) Mexoryl SX: a broadspectrum absorption UVA filter protects human skin from the effects of repeated suberythemal doses of UVA. J Photochem Photobiol B Biol 44, 69–76. 8 Moyal D, Fourtanier A. (2004) Acute and chronic effects of UV on skin. In: Rigel DS, Weiss RA, Lim HW, Dover JS, eds. Photoaging. New York: Marcel Dekker, pp. 15–32. 9 Moyal D, Fourtanier A. (2002). Effects of UVA radiation on an established immune response in humans and sunscreen efficacy. Exp Dermatol 11 (Suppl 1), 28–32. 10 Kuchel J, Barnetson R, Halliday G. (2002) Ultraviolet A augments solar-simulated ultraviolet radiation-induced local suppression of recall responses in humans. J Invest Dermatol 118, 1032–7. 11 Garland CF, Garland FC, Gorham EC. (2003) Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates. Ann Epidemiol (AEP) 13395–404. 12 Agar NS, Halliday GM, Barnetson RS, et al. (2004) The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci U S A 101, 4954–9. 13 Moyal D, Binet O. (1997) Polymorphous light eruption (PLE): its reproduction and prevention by sunscreens. In: Lowe NJ, Shaat N, Pathak M, eds. Sunscreens: Development and Evaluation and Regulatory Aspects, 2nd edn. New York: Marcel Dekker, pp. 611–7. 14 Australian/New Zealand standard AS/NZS 2604 (1998) Sunscreen Products: Evaluation and Classification. Standards Australia and New Zealand.

19. Sunscreens 15 Department of Health and Human Services, Food and Drug Administration (USA). (1999) Sunscreen drug products for over-the-counter human use. Fed Register 43, 24666–93. 16 Kimbrough DR. (1997) The photochemistry of sunscreens. J Chem Ed 74, 51–3. 17 Marrot L, Belaidi J, Lejeune F, Meunier J, Asselineau D, Bernerd F. (2004) Photostability of sunscreen products influences the efficiency of protection with regard to UV-induced genotoxic or photoaging-related endpoints. Br J Dermatol 151, 1234–44. 18 Fourtanier A, Bernerd F, Bouillon C, Marrot L, Moyal D, Seité S. (2006) Protection of skin biological targets by different types of sunscreens. Photodermatol Photoimmunol Photomed 22, 22–32. 19 Moyal D, Fourtanier A. (2001) Broad spectrum sunscreens provide better protection from the suppression of the elicitation phase of delayed-type hypersensitivity response in humans. J Invest Dermatol 117, 1186–92. 20 Damian DL, Halliday GM, Barnetson RSC. (1997) Broad spectrum sunscreens provide greater protection against ultravioletradiation-induced suppression of contact hypersensitivity to a recall antigen in humans. J Invest Dermatol 109, 146–51. 21 Colipa. (2007) Method for the in vitro determination of UVA protection provided by sunscreen products. Guidelines. 22 Colipa, JCIA, CTFA SA, CTFA. (2006) International Sun Protection Factor (SPF) Test Method.

23 Department of Health and Human Services. Food and Drug Administration. (2007) CFR Parts 347 to 352. Sunscreen drug products for OTC human use: proposed amendment of final monograph; proposed rule. 24 European Commission Recommendation on the efficacy of sunscreen products and the claims made relating thereto. OJL 265/39, (26.9.2006). 25 Japan Cosmetic Industry Association (JCIA). (1995) Japan Cosmetic Industry Association measurement standard for UVA protection efficacy. November 15. 26 Diffey BL, Tanner PR, Matts PJ, Nash JF. (2000) In vitro assessment of the broadspectrum ultraviolet protection of sunscreen products. J Am Acad Dermatol 43, 1024–35. 27 Moyal D, Chardon A, Kollias N. (2000) UVA protection efficacy of sunscreens can be determined by the persistent pigment darkening (PPD) method. Part 2. Photodermatol Photoimmunol Photomed 16, 250–5. 28 Moyal D, Refrégier JL, Chardon A. (2002) In vivo measurement of the photostability of sunscreen products using diffuse reflectance spectroscopy. Photodermatol Photoimmunol Photomed 18, 14–22. 29 Forestier S. (1999) Pitfalls in the in vitro determination of critical wavelength using absorbance curves. SÖFW J 125, 8–9.

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Part 3: Personal Care Products Chapter 20: Antiperspirants and deodorants Eric S. Abrutyn TPC2 Advisors Ltd. Inc. Boquete, Chiriqui, Republic of Panama

BAS I C CONCE P T S • Antiperspirants are US Food and Drug Administration (FDA) regulated drugs to be used in the underarm axilla vault only. • Antiperspirants are primarily complexes of aluminum (e.g. Aluminum Chlorohydrate) and aluminum zirconium (e.g. Aluminum Tetrachlorohydrex-GLY). • Deodorants, not to be confused with antiperspirants, are cosmetics and do not typically contain any aluminum-type salt complexes. • Antiperspirants are associated with few dermatologic issues; slightly irritating under certain conditions, but not scientifically associated with breast cancer or Alzheimer disease.

Introduction This chapter deals with the technologies for wetness and odor protection of the human axilla, how they are applied, and potential adverse effects of use of these products on a regular basis. Antiperspirants and deodorants have been used for centuries,1 evolving from simple fragrances that masked offensive odors to today’s complex ingredients based on aluminum and zirconium chemistries that act to slow or diminish sweat production. Odors (scents) and sweating have a biologic significance. Body scents are primeval and most likely evolved genetically to attract the opposite sex. Sweating is regulated by the sympathetic nervous system and is an important body temperature regulator, especially in warm weather climates or during heavy exercise, and functions to remove waste and toxic by-products of the body. The axilla area of the body represents a small contribution to sweating to control body temperature and removal of biologic by-products, so the controlling of sweat from this area has less health risks than other portions of the body. There is little scientific evidence that supports the use of antiper-

Over 5500 years ago, every major civilization has left a record of its efforts to mask body odors. The early Egyptians recommend following a scented bath with an underarm application of perfumed oils (special citrus and cinnamon preparations).

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spirants, based on aluminum or aluminum–zirconium chemistry causes appreciable lasting adverse effects other than possible temporary and reversible irritation.

Physiology Sweat glands and how they work Sweat by itself is odorless and only establishes a characteristic odor when exposed to moisture (humidity) in the presence of bacterial flora on the skin surface, breaking down the sweat’s composition and resulting in unpleasant odors. The use of antimicrobial agents is a good defense in preventing odor development from bacteria and yeast present on the skin. Another defense is the reduction of excretion from the eccrine gland to minimize the appearance of uncomfortable or unsightly wetness production. According to Gray’s Anatomy [1], most people have several million sweat glands distributed over their bodies, to include the underarm axilla and thus providing plenty of opportunity for underarm odors to develop. Skin has two types of sweat glands: eccrine glands and apocrine glands (Figures 20.1 and 20.2). Eccrine glands open directly on to the surface of the skin and exude sweat in the underarm, subsequently contributing to odor formation. These glands are located in the middle layer of the skin called the dermis, which is also made up of nerve endings, hair follicles, and blood vessels. Sweat is produced in a long coil embedded within the dermis where the long part is a duct that connects the gland to the opening (pore) on the skin’s surface. When body temperature rises, the autonomic nervous system stimulates these

20. Antiperspirants and deodorants

Eccrine sweat

Apocrine sweat

H2O, Na+, K+, Cl– Urea, lactic acid, ammonia Traces of amino acids and proteins

H2O anorganic substances S-containing organic substances, lipids Steroids, pheromones

No odor

Bacterial growth

Unpleasant odor

Deodorants Less odor or not noticed

Antiperspirants Less sweat

Perfume Antibacterials (preservatives) Smell ‘catchers’

Aluminium derivatives Water-soluble salts AlC13 or Al2Cl6 first on market Al(OH)6Cl3 • H2O AlZr(OH)Cl • H2O

Figure 20.1 Underarm sweat gland mechanism.

Stratum corneum Pigment layer Stratum germinativum: - Stratum spinosum - Stratum basale

Sweat pore Hair shaft

Dermal papilla Epidermis Sensory nerve ending for touch

Sebaceous gland Arrector pili muscle

Hair follicle Dermis Papilla of hair Sweat gland Pacinian corpuscle Subcutis (Hypodermis)

Blood and lymph vessels

Vein

Artery

Nerve fiber

Figure 20.2 Cross-section of skin and sweat glands.

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Personal Care Products Iso-valeric acid

3-methyl 4-hexanoic acid

Androstenone

O COO COOH O

Acidic odor

S.epidermiis (smell of sweat acidic odor)

Sterilizing pathogens

Suppressing microorganism enyzmes

Axillary odor

Brevibacterium (smell of axillary odor)

Volatile steroids odor

Propionibacterium sp. (smell of steroid odor)

Microorganisms

Bacillus spp. Corynebacterium spp. (smell of spoiled socks-like odor) Sweat (sebaceous lipid)

Eccrine gland

Apocrine gland

Figure 20.3 Sweat metabolism cycle.

glands to secrete fluid on to the surface of skin, where it then cools the body as it evaporates. The composition of the eccrine gland secretion is about 55–60% fluid, mostly water with various salts (Primarily: sodium chloride, potassium chloride) and various electrolytic components (ammonia, calcium, copper, lactic acid, potassium, and phosphorus). The warmth and limited air flow is conducive to allowing for rapid decomposition of organic matter made up of primarily low molecular weight volatile fatty acids (Figure 20.3). These fatty acids and the steroidal compounds produce the recognizable body odors. The apocrine glands are triggered by emotions. These glands are dormant until puberty, at which time they start to secrete. Apocrine glands secrete a fatty substance. When under emotional stress, the wall of the tubule glands contract to push the fatty exudates to the surface of skin where bacterial flora begin breaking it down. In a regulatory monograph [2] the FDA, through the Food Drug and Cosmetic Act, defines antiperspirants as an overthe-counter (OTC) drug when applied topically to reduce production of underarm sweat (perspiration). They are considered drugs because they can affect the function of the body by reducing the amount of sweat that reaches the skin surface. In the USA, OTC drugs are subjected to monograph rules, which define standards and requirements, premarket approval process, acceptable actives, and allowable formulation percentages of actives. Other countries’ regulations vary in content and scope. Some countries consider antiperspirants as cosmetics and not affecting the biologic physiology

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of the body; as such they are not held to the same strict standards as in the USA. As an example, Canada has recently (2008) ruled that antiperspirants will longer be considered a drug; use of them now only needing to comply with cosmetic regulations.

Wetness and odor control and testing The consumer typically confuses what antiperspirants and deodorants do, mostly caused by a misunderstanding of marketing claims and product positioning. For the most part, antiperspirants are based on aluminum-based cationic salt chloride complexes (as well as complexes with zirconium acid salts) and are referred to as “actives” on back label of consumer antiperspirant products. There are numerous types of antiperspirant actives listed in the FDA monograph as well as in the US Pharmacopia (USP) [3]. Antiperspirant actives are responsible for blocking sweat expulsion through the formation of temporary plugs within the sweat duct, thus stopping or slowing down the flow of sweat to the surface of the eccrine gland. A theory to wetness control that has been accepted over the years is that the hydrated aluminum or aluminum–zirconium cationic salt chloride is transported to the eccrine gland, interacting with the protein contained within the gland. In this basic protein environment, the antiperspirant active is reduced, producing a gelatinous proteinaceous plug. By plugging the gland, sweat is prohibited from transporting to the surface, causing osmotic pressure. Eventually, this plug is pushed out of the eccrine gland and the gland is

20. Antiperspirants and deodorants allowed to operate again in a normal fashion. This can take 14–21 days for all the eccrine gland, to begin firing; known as a wash-out period. Without going into detail, one can describe how antiperspirants are tested for their Wetness Inhibiting Performance (“WIP”™)2 effectiveness. The FDA prescribes a methodology for testing the effectiveness of an antiperspirant by having participants tested in a controlled environment – 30–40% relative humidity at approximately 100 °C. Sweat is continuously collected during 20-minute intervals and reported as the production or percentage change in production over the average of two 20-minute collection periods. To be accepted as a participant one must exceed production of 100 mg collected sweat per 20-minute period and should not exceed more than 600 mg difference between the highest and lowest sweat production within the test population. The results of testing need to meet a minimum of 20% sweat reduction in 50% of the test population in order to be considered an antiperspirant. Deodorants cover odor through a variety of mechanisms, which include the neutralization or counteracting of odoriferous axilla odor through the retardation of the odor development, or the reduction in perception of odor through masking of the odor. Masking is basically accomplished via use of fragrances and other volatile components. Neutralization is the chemical reaction to modify low molecular weight fatty acids that are excreted from the apocrine gland. One type of neutralization agent is antimicrobials that disrupt cell barrier viability causing the bacterial microbes to perish (triclosan is one popular example). Deodorants are designed to minimize underarm axilla odor, not to reduce or eliminate perspiration. So, deodorants are best for those people who do not have a problem with sweating yet want to feel fresh and odor free. It is important to note that deodorants have no antiperspirant physiologic activity, but antiperspirants can function both as antiperspirants and deodorants; thus, consumers needing odor and wetness control will require the use of antiperspirants to achieve their needs.

Chemistry and formulation of antiperspirants It is important to have some understanding of the chemistry of antiperspirants to gain a better appreciation of their physiologic action in the axilla mantle. Antiperspirants are divided into two categories of functional aluminum-based and zirconium-based actives (typically: aluminum chlorohydrate, aluminum zirconium tetrachlorohydrex-GLY, alumi-

2 Trademarked 2008 and property of Eric Abrutyn, TPC2 Advisors Ltd., Inc., Republic of Panama Corporation.

num zirconium trichlorohydrex-GLY, or aluminum chloride) plus an inactive formula matrix for consumer acceptable aesthetics. The basic building block of antiperspirant actives is based on aluminum chemistry in which elemental aluminum is reduced in an acidic medium to produce what is traditionally known as aluminum chlorohydrate (ACH) with an atomic ratio of 2 : 1 aluminum to chloride. These inorganic cationic polymer salts are classified as octahedral complexes of a basic aluminum hydroxide, stabilized with an anionic chloride to maintain their water solubility. Within the monograph boundaries [2], the atomic ratio of aluminum to chloride can range from 2 : 1 to 1 : 1 within three different segmentations (aluminum chlorohydrate, aluminum sesquichlorohydrate, and aluminum dichlorohydrate). Antiperspirant actives can also be complexed with hydrated acidic zirconium cationic salts of chloride to make what is traditionally known as aluminum zirconium chlorohydrate (ZAG or AZG). Like ACHs, AZGs can have various ratios of atomic aluminum to zirconium of 2 : 1 to 10 : 1 and atomic total metals to chloride of 0.9 : 1 to 2.0 : 1. These AZG complexes can be buffered with glycine (an amino acid) to stabilize the complex and mitigate the acidic harshness which could result when applied to underarm axilla. There is a growing interest in aluminum-free odor and wetness controlling products. One product that has emerged is based on a natural stone “crystal.” “Crystal” products are made from a mineral known as potassium alum, also known as potassium aluminum sulfate and contain aluminum. Unlike aluminum salts used in antiperspirants, alum does not prohibit sweating; it only helps control the growth of bacteria that can cause an underarm odor.

Delivery systems The formulation matrix delivery system is the key to effectiveness of antiperspirant active performance and acceptable consumer application. The most common delivery systems are roll-ons (either aqueous or cyclosiloxane suspensions), aerosol (hydrocarbon propellant suspensions), extrudable clear gels (water-in-cyclosiloxane emulsions), extrudable opaque soft solids (anhydrous cyclosiloxane suspension pastes), or sticks (anhydrous cyclomethicone suspension solids) (Figure 20.4). Within each form there are typical inactive ingredients that support a stable formula with consumer-acceptable esthetics so as not to interfere with the WIP™ delivery of the antiperspirant active. Although this chapter does not focus on details of formulation development, this subject can be researched in more detail in the literature [4,5]. In general, aqueous-based hydrous formulas (mostly based on roll-on and clear gel delivery systems) will have some type of emulsifier or stabilizing agent. In the case of aqueous roll-ons, they tend to

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Personal Care Products

Gel

Stick

Soft solid

Roll-on

Aerosol

16% Cyclics

40-50% Cyclics

60% Cyclics

45-75% Cyclics

8-15% Silicones

1% Dimethicone copolyol

20-25% AP salts (no water)

25% AP salts

20-25% AP salts

8-15% AP salts

50% AP salts in water

15-25% Waxes

11% Organic emulsifier

2-4% Bentone 0-10% Other

0-10% Others 15% Propylene glycol

2% Bentone 75-85% Propellant

4% Organic thickener

17% Water Figure 20.4 Antiperspirant formula matrix delivery systems.

be Polyethylene Glycol (PEG) or Polypropylene Glycol (PPG) ethoxylated alcohols (INCI e.g.: PEG-2, PEG-20) and for clear gel emulsions they are based on PEG and PPG alkoxylated functional siloxanes (INCI e.g.: PEG/PPG-18/18 Dimethicone Copolymer). Anhydrous-based formulas (typically: solid sticks, some types of roll-ons, extrudable creams) include cyclosiloxane (preferably Cyclopentasiloxane) for transient solvent delivery of the active and its eventual evaporation to leave no residue on the skin, solidification agent (INCI e.g.: Stearyl Alcohol, Hydrogenated Castor Oil, and miscellaneous fatty acid ester wax), and dispersing agent (INCI e.g.: PPG-14 Butyl Ether). Most antiperspirant formulas include other ingredients for cosmetic purposes, such as fragrance, antioxidants (BHT – Butylated Hydroxytoluene), chelating agents (Disodium EDTA – Disodium Edetate), soft feel powders (Talc, Corn Starch, and Corn Starch Modified), and emollients and/or moisturizers (petrolatum, mineral oil, fatty acid esters, non-volatile hydrocarbons). These ingredients have been used in the industry for well over 25 years with accepted safety profiles; reviewed by Cosmetic Ingredient Review (http://www.cir-safety.org/) and other governmental or medical agencies.

Dermatologic concerns Each manufacturer of antiperspirants keeps a thorough record of adverse affects as reported by the consumer. For the most part, there is a low incident of adverse affects when the product is use as prescribed. Issues tend to revolve around skin irritation and sensitization. These adverse affects are reversible with cessation of use. Irritation can be brought

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about for a number of reasons, but most often by application on broken skin (e.g. from shaving) or sensitivity to the fragrance or one of the metallic components of the antiperspirant active. Switching brands or fragrances types is one remedy to alleviate adverse affects. In some cases a person is so sensitive to an antiperspirant active that he or she can no longer use a product containing an aluminum-based antiperspirant. Health concerns regarding antiperspirants have been discussed in the literature over the last 40–50 years and mostly relate to breast cancer or Alzheimer disease. According to the Alzheimer’s Association (http://www.alz.org/index.asp), the linkage of aluminum and Alzheimer disease is most likely linked to a single study in the 1960s where an abnormally high concentration of aluminum was observed in the brains of some Alzheimer patients. However, “After several decades of research,” reports the Alzheimer’s Association, “scientists have been unable to replicate the original 1960s study.” In fact, there is still no scientific correlation on the cause and effect relationship for contracting Alzheimer disease. The research community is generally convinced that aluminum is not a key risk factor in developing Alzheimer disease. Public health bodies sharing this conviction include the World Health Organization, the US National Institutes of Health, the US Environmental Protection Agency, and Health Canada. According to the National Cancer Institute (NCI) and the American Cancer Society, rumors connecting antiperspirant use and breast cancer are largely unsubstantiated by scientific research. The rumors suggest that antiperspirants prevent a person from sweating out toxins and that this helps the spread of cancer-causing toxins via the lymph

20. Antiperspirants and deodorants nodes. The NCI discusses two studies that address the breast cancer rumor. A 2002 study of over 800 patients at the Fred Hutchinson Cancer Research Institute found no link between breast cancer and the use of antiperspirant and/or deodorant [6]; and a study of 437 cancer patients, published in 2003 in the European Journal of Cancer Prevention, found no correlation between earlier diagnosis of breast cancer and antiperspirant and/or deodorant use [7]. The NCI’s analysis of the second study was that it “Does not demonstrate a conclusive link between these underarm hygiene habits and breast cancer. Additional research is needed to investigate this relationship and other factors that may be involved.” Through the evaluation of these and other independent studies, it can be concluded that there is no existing scientific or medical evidence linking the use of underarm products to the development of breast cancer. The FDA (Food & Drug Administration), the Mayo Clinic, the American Cancer Society, and the Personal Care Products Council (formerly Cosmetic, Toiletry, and Fragrance Association) have come to a similar conclusion. Sweating is necessary to control body temperature, especially during times of exercise and warm or hot surroundings. In a small portion of the population the sympathetic nervous system can go awry, affecting the complex biologic mechanism of perspiration, resulting in either excessive perspiration (hyperhidrosis) or little or no perspiration (anhidrosis). Currently, there are no known cures for hyperhidrosis but there are a number of treatment options: injectable treatment such as botulinum toxin type A (Botox), topical agents such as prescribed antiperspirants, oral medications, and surgery. Based on information from the International Hyperhidrosis Society, over 87% of people with hyperhidrosis say that OTC antiperspirants do not provide sufficient relief. Thus, it is important for the medical community to understand the other options available to treat excessive sweating. Botox, a drug that has been approved for use as an injectable treatment in the axilla area, works to interrupt the chemical messages (anticholinergic) released by nerve endings to signal the start of sweat production. It is important to understand how to administer Botox in a manner that will not cause medical issues, thus only a trained practitioner should administer treatment. Unfortunately, Botox is not a permanent solution, and patients require repeat injections every 6–8 months to maintain benefits. There are other options for treating excessive sweating, but none have been demonstrated to be either safe or effective for use by consumers. Most systemic medications, in particular anticholinergics, reduce sweating but the dose required to control sweating can cause significant adverse effects (e.g. dizziness), thus limiting the medications’ effectiveness. Iontophoresis is a simple and well-tolerated method for the treatment of hyperhidrosis without long-term adverse effects; however, long-term maintenance treatment is

required to keep patient’s symptom free. Psychotherapy has been beneficial in a small number of cases.

Strengths and weakness of antiperspirants Based on all the information known about antiperspirants one would surmise there are few weaknesses regarding the use of them. Basically, they serve the purpose of reducing the discomfort and potential observation of underarm wetness, and can lead to reduced underarm offensive odors. Except in the case of hyperhidrosis, antiperspirants serve to provide cosmetic esthetics and social acceptance. It is important to note that, even if used twice a day, antiperspirants do not completely stop axilla sweating, but provide a significant reduction in the amount of sweating produced in the axilla. With almost 70 years of use for antiperspirant actives, there is almost no association with adverse affects when properly used in the underarm area. So, the risk–benefit is minimal and is balanced by the ability to maintain a more comfortable and socially appealing state.

Conclusions Because they are regulated in the USA and other countries as drugs, it is foreseen that introduction of new antiperspirant actives will be restricted. To introduce new antiperspirant actives, one would have to go through an extensive New Drug Application process, requiring costly studies on safety and effectiveness. Aside from the introduction of new antiperspirant drugs, dermatologists need to continue monitoring the introduction of unregulated new ingredients that would be included in existing or new formula matrices.

References 1 Gray’s Anatomy: The Anatomical Basis of Clinical Practice, 39th edn. (2004) CV Mosby. 2 USA Department of Health and Human Services: Food and Drug Administration. (2003) Antiperspirant Drug Products for Over-the-Counter Human Use, Final Rule. 68 CFR, Part 110. http://www.fda.gov/cder/otcmonographs/Antiperspirant/ antiperspirant_FR_20030609.pdf 3 USP 27/NF 22 (2004) United States Pharmacopeial Convention, Rockville, MD, pp. 83–91; 93–106. 4 Abrutyn E. (1998) Antiperspirant and Deodorants: Fundamental Understanding. IFSCC Monograph Series No. 6. Weymouth, Dorset, UK: Micelle Press. 5 Abrutyn E. (2000) Antiperspirant and deodorants. In: Reiger MM, ed. Harry’s Cosmetology, 8th edn. New York: Chemical Publishing Company, Inc., 6 http://jncicancerspectrum.oxfordjournals.org/cgi/reprint/jnci; 94/20/1578.pdf (Vol. 94, No. 20, Pg 1578, October 16, 2002). 7 McGrath KG. (2003) An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. Eur J Cancer Prev 12, 479–85.

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Chapter 21: Blade shaving Keith Ertel1 and Gillian McFeat2 1 2

Procter & Gamble Co, Cincinnati, OH, USA Gillette, Reading Innovation Centre, Reading, UK

BAS I C CONCE P T S • Hair removal practices have their roots in antiquity. While modern global attitudes towards hair removal vary, consumers around the world use blade shaving as a method to effect hair removal. • Modern blades and razors are the product of extensive research and technologically advanced manufacturing procedures; these combine to provide the user with an optimum shaving experience. • Effective shaving involves three steps: preparation, including skin cleansing and hair hydrating; hair removal, including the use of an appropriate shaving preparation; and post-shave skin care, including moisturizer application.

Introduction Like many personal care practices, the roots of shaving lie in the prehistoric past. Hair removal for our cave dwelling ancestors was probably more about function than esthetics; hair could provide an additional handle for an adversary to grab during battle, it collected dirt and food, and provided a home to insects and parasites. Flint blades possibly dating as far back as 30 000 BC are some of the earliest examples of shaving implements. Archaeologic evidence shows that materials such as horn, clamshell, or shark teeth were used to remove hair by scraping. Pulling or singeing the hair, while somewhat more painful, were also methods used to effect hair removal. Attitudes towards hair became more varied in ancient times. The Egyptian aristocracy shaved not only their faces, but also their bodies. The Ancient Greeks viewed a beard as a sign of virility but Alexander the Great, who is said to have been obsessed with shaving, popularized the practice among Greek males. Greek women also shaved; a body free from hair was viewed as the ideal of beauty in Greek society. Shaving was viewed as a sign of degeneracy in early Roman society, but an influx of clean-shaven foreigners gradually changed this attitude. For affluent Romans shaving was performed by a skilled servant or at a barbershop, which was popularized in Ancient Rome as a place of grooming and socializing. Shaving implements at this time were generally made from metals such as copper, gold, or iron. The barbershop took on an expanded role in the Middle Ages. In these shops barbers provided grooming services and

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routinely performed other duties such as bloodletting and minor surgical and dental procedures. Shaving injuries were common and the striped pole that is today associated with barbershops has its origin in these times, its red and white stripes symbolizing blood and the bandages that were used to cover the wound, respectively. The Industrial Revolution heralded a number of advancements in shaving technology. The straight razor was first introduced in Sheffield, England and became popular worldwide as a tool for facial shaving. While an improvement over earlier shaving implements, the straight razor dulled easily, required regular sharpening or stropping, and a high skill level, and shaving injuries were still a problem, which earned it the nickname of “cutthroat razor.” Many credit Jean Jacques Perret with inventing the safety razor in 1762. His device, which he apparently did not patent, consisted of a guard that enclosed all but a small portion of the blade. Variations on the design followed from other inventors, many using comb-like structures to limit blade contact with the skin. The Kampfe brothers filed a patent in 1880 for a razor, marketed as the Star Safety Razor that used a “hoe” design in which the handle was mounted perpendicular to the blade housing. The blade, essentially a shortened straight razor, was held in place by metal clips. While generally successful, the blade in the Star Safety Razor still required stropping before each use. In 1904, King C. Gillette introduced the real breakthrough that brought shaving to the masses. Unlike its predecessors, the Gillette Safety Razor used an inexpensive, disposable blade that was replaced by the user when it became dull. The new razor quickly gained popularity because of a variety of promotional efforts, including a “loss leader” marketing model pioneered by Gillette. Shaving was not only promoted to males. The practice of shaving among females was prompted by the May 1915

21. Blade shaving issue of Harper’s Bazaar magazine that featured a picture of a female model wearing a sleeveless evening gown and sporting hairless axillae. The Wilkinson Sword Company built on the idea by running a series of advertisem*nts targeting women in the 1920s to promote the idea that underarm hair was not only unhygienic, but was also unfeminine. Sales of razor blades doubled over the next few years. Razor developments during the next several decades were primarily limited to improvements in single blade technology, including the switch from carbon steel to stainless steel blade material in the 1960s pioneered by Wilkinson Sword. This prevented corrosion, thus increasing blade life. The next major change occurred in the 1971 with the introduction of the Trac II, the first multiblade razor. Innovation has continued along this track and today consumers can choose from a variety of razor models having multiple blades contained in a disposable cartridge, with specialized designs available to meet the shaving needs of both sexes. The relatively simple appearance of these devices belies their sophistication; they are the product of years of development and technically advanced manufacturing processes. Of course, not all shaving is done with a blade. Electric razors remove hair without drawing a blade across the skin. There are two basic types of electric razors, both relying on a scissor action to cut hairs using either an oscillatory or circular motion. When the razor is pressed against skin the hairs are forced up into holes in the foil and held in place while the blade moves against the foil to cut the trapped hairs. Colonel Jacob Schick patented the first electric razor in 1928. Electric razors were for many decades confined to use on dry skin, but some modern battery-powered razors are designed for use in wet environments, including the shower.

Hair biology basics Much of the hair targeted for removal by shaving or other means is terminal hair (i.e. hair that is generally longer, thicker, and more darkly pigmented than vellus hair). In prepubescent males and females this hair is found primarily on the head and eyebrow regions, but with the onset of puberty terminal hair begins to appear on areas of the body with androgen-sensitive skin, including the face, axillae, and pubic region. Further, vellus hairs on some parts of the body, such as the beard area, may convert to terminal hairs under hormonal influence.

The pilosebaceous unit A pilosebaceous unit comprises the hair follicle, the hair shaft, the sebaceous gland, and the arrector pili muscle. The hair follicle is the unit responsible for hair production. Hair growth is cyclical, and depending on the stage of hair growth, the follicle extends to a depth as shallow as the upper dermis

to as deep as the subcutaneous tissue during the active growth phase. The hair shaft is the product of matrix cells in the hair bulb, a structure located at the base of the follicle. The hair shaft is made up primarily of keratins and binding material with a small amount of water. A terminal hair shaft comprises three concentric layers. Outermost is the cuticle, a layer of cells that on the external hair are flattened and overlapping. The cuticle serves a protective function for external hair, regulates the water content of the hair fiber, and is responsible for much of the shine that is associated with healthy hair. The cortex lies inside the cuticle and is composed of longitudinal keratin strands and melanin. This layer represents the majority of the hair shaft and is responsible for many of its structural qualities (e.g. elasticity and curl). The medulla is the inner most layer found in some terminal hair-shafts, made up of large loosely connected cells which contain keratin. Large intracellular and intercellular air spaces in the medulla to some extent determine the sheen and colour tones of the hair. Each hair follicle is associated with a sebaceous gland. This gland lies in the dermis and produces sebum, a lipophilic material composed of wax monoesters, triglycerides, free fatty acids, and squalene. Sebum empties into the follicle lumen and provides a natural conditioner for the forming and already extruded hair. The arrector pili is a microscopic band of smooth muscle tissue that connects the follicle to the dermis. In certain body sites, when stimulated the arrector pili contracts and causes the external hair to stand more erect, resulting in the appearance of goose bumps.

Hair growth cycle Hair growth is not a continuous process but occurs over a cycle that is conveniently divided into three stages; at any given time hairs on a given body site are at various points in this cycle. The dermal papilla orchestrates the hair growth cycle. Anagen is the phase of hair follicle regrowth and hair generation. During this stage the hair follicle grows downward into the dermis and epidermal cells that surround the dermal papilla undergo rapid division. As new cells form they push the older cells upward. The number of hairs in anagen varies according to body site. At any given time approximately 80% of scalp hairs are in anagen. This is lower for beard and moustache hairs (around 70%) and only 20–30% for the legs and axillae. The length of the anagen phase also varies; on the scalp anagen typically lasts from 3 to 6 years, in the beard area this is closer to 1 year and in the moustache area anagen lasts from 4 to 14 weeks. Anagen is typically 16 weeks for the legs and axillae. The time in anagen determines the length of the hair produced [1]. Anagen is followed by catagen, a transitional phase in the hair growth cycle that sets the stage for production of a new follicle. In catagen the existing follicle goes through

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controlled involution, with apoptosis of the majority of follicular keratinocytes and some follicular melanocytes. The bulb and suprabulbar regions are lost and the follicle moves upward, being no deeper than the upper dermis at phase end. The dermal papilla becomes more compact and moves upward to rest beneath the hair follicle bulge. On the scalp catagen lasts 14–21 days. Telogen is a phase of follicular quiescence that follows catagen. The final cells synthesized during the previous cycle are dumped at the end of the hair shaft to form a “club” that holds the now non-living hair in place. These hairs are lost by physical action (e.g. combing) or are pushed out by the new hair that grows during the next anagen phase. The percentage of follicles in telogen also varies by body site (e.g. 5–15% of scalp follicles are normally in telogen whereas 30% of follicles on the beard area are normally in telogen and 70–80% of leg and axillae hairs). Telogen typically lasts for 2–3 months, although this is slightly longer for leg hairs [1].

(a)

Properties of hair – impact on shaving The beard area of an adult male contains between 6000 and 25 000 hair fibers and beard growth rate has been reported in the literature to be 0.27 mm per 24 hours, although this can vary between individuals [2]. There are two types of hair fibers found in the beard area. Fine, non-pigmented vellus hairs are distributed amongst the coarser terminal hairs. While the literature abounds in publications on the properties of scalp hair, studies of beard hair are relatively scarce. Tolgyesi et al. [3] published the findings of a comparative study of beard and scalp terminal hair with respect to morphologic, physical, and chemical characteristics. Scalp fibers were reported to have half the number of cuticle layers compared to beard hairs from the same subject (10–13 in facial hair, 5–7 in scalp hair). Scalp fibers also had smaller cross-sectional areas (approximately half the area) and were less variable in shape than beard hairs, which exhibited asymmetrical, oblong, and trilobal shapes. These differences can be seen in Figure 21.1. Thozur et al. [4] further showed considerable variations in beard hair follicle shape and diameter within and between individuals. A number of factors contribute to this variation including anatomical location, ethnicity, age, and environmental factors. The structural properties of the hair impact shaving. The force required to cut a hair increases with increasing fiber cross-sectional area [5]. Thus, it requires more force to cut a larger fiber. Indeed, it requires almost three times the force to cut a beard hair than a scalp or leg hair. One important property of hair is that the force required to cut it can be greatly reduced by hydrating the hair. Hydration causes the hair to become significantly softer and much easier to cut so that it offers less resistance to the blade and minimizes any discomfort.

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(b) Figure 21.1 Optical micrographs of hair cross-sections taken from the beard (a) and scalp (b) area of the same subject. Beard fibers have a greater cross sectional area and more cuticle layers.

The human hair follicle and the surrounding skin are richly innervated. In particular, the terminal hairs of the human skin are supplied with several types of nerve endings most of which are sensory in nature. It is hypothesized that discomfort associated with shaving (during shaving or postshave) is a result of localized skin displacement and/or the rotation and extension of the beard fiber in its follicle. The current neurologic literature clearly demonstrates that such local cutaneous distortions bring about the release of various chemical communicators (e.g. histamine, prostaglandins, bradykinins) that heighten the sensitivity of the response of pain-mediating nerve endings for a period of time [6]. The contribution to shaving comfort and irritation remains to be elucidated. Shaving can also cause irritation by physical damage. There is evidence to suggest that shaving irritation involves the removal of irregular elevations of the skin by the razor blade, particularly around follicular openings [7,8]. The topography of the skin is highly variable and combined with the presence of hairs this creates a very irregular terrain over which an incredibly sharp blade traverses (Figure 21.2). This can result in irritation, generally characterized in this context by the presence of attributes such as nicks or cuts, redness, razor burn, sting, or dryness. In order to achieve a close and comfortable shave with minimal irritation it is essential to use a good quality, sharp blade and

21. Blade shaving

Shaving angle

Exposure

Blade

Tangent

Cap Guard

Figure 21.3 Cross-section of a double-edge razor showing exposure geometry.

Figure 21.2 A scanning electron micrograph of a replica of an area of cheek on a male face. The topography of the skin is highly variable and combined with the presence of hairs this creates a very irregular terrain over which an incredibly sharp blade traverses.

adopt a shave care regimen designed to remove as much hair as possible while inflicting minimal damage to the underlying skin.

Shaving and the razor explored Since the invention of the safety razor, consumer product industries have invested a considerable amount of time, money, and expertise in improving the design of the razor and blade in order to provide a closer, more comfortable, and safer shave. To date, few reports have been available in the literature detailing the shaving process and the mechanisms involved. The following section aims to provide an overview of the razor and the complex mechanisms by which the blade cuts the beard hair and interacts with the underlying skin.

Evolution of the system razor With a system razor, only the cartridge containing the blades is replaced, unlike a disposable razor which is thrown away in its entirety when blunt. In the first double edge razor systems, the consumer had to position and tension a single blade within the handle. As a result, there was variability and inconsistency in how the blade interacted with the skin. In contrast, the advanced shaving systems of today are precisely assembled during manufacture. Figure 21.3 shows a cross-section of a double edge razor with the key parameters of the cartridge geometry indicated. The shaving angle is the angle between the center plane of the blade and a plane tangent to the guard. The blade exposure is the amount by which the tip of the blade projects beyond the plane tangent to the cap and guard. Altering any

of these parameters has both good and bad effects. For example, an increase in blade exposure brings the blades into closer contact with the underlying skin and hair, increasing the closeness of a shave at the expense of more nicks and cuts and discomfort. A reduction in the shaving angle improves comfort but reduces cutting efficiency. Consequently, all aspects of the double edge blade system were compromises and the user was able to adjust the razor to suit their individual preferences [9]. Modern systems have reduced the need to compromise and achieved the previously unattainable: improving closeness, safety, and comfort simultaneously. The improvement in closeness is attributed to, and exploits the mobility of the hairs within the follicle. Observation of the movement of hairs during shaving has shown that they are not cut through immediately upon contact with the blade; rather, they are carried along by the embedded blade tip, and effectively extended out of the follicle. This extension is primarily brought about by the distortion of the soft tissue between the hair root and the skin surface layers. Because of the viscoelastic nature of the tissue, once severed the hair rapidly retracts back into the follicle. If a second blade follows closely behind the first, it can engage the hair in the elevated state, cutting it further down the hair shaft, before it has time to fully withdraw into the follicle [9]. By having multiple blades, this process can be exploited to give a measurable improvement in closeness. It is therefore possible to use a lower blade exposure to achieve closeness while minimizing skin contact and thus the potential for nicks, cuts, and discomfort. Simply adding more blades to razors is not a new idea (the first US patent for a 5-blade razor was filed in 1929, US1920711) and from the above it is clear that on its own this will not deliver a great shave. In addition to precisely controlling the razor geometry, it is essential that the underlying skin is carefully managed to ensure a safe and comfortable shave. Adding more blades improves closeness by virtue of hair extension and probability of cutting, but can also create drag and discomfort. The pressure exerted on the skin by the additional blades can cause the skin to bulge between

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the inter blade span. By spacing the blades closer together, both the drag and skin bulge are reduced and a more uniform stress is placed on the skin leading to a safer, more comfortable shave (Figure 21.4). Manipulating these parameters can greatly alter the characteristics of a shave; consequently cartridge geometry and blade spacing are carefully controlled and set during manufacturing using specifications determined through extensive research. This ensures that the consumer receives a targeted and consistent shave with the optimum blade– skin contact.

Cutting edge technology A further critical component of the shaving process, and central to a great shave, is the razor blade edge. The narrower the blade edge the more easily it can cut through a hair, leading to a closer and more comfortable shave. However, if the blade is too narrow it can collapse under the

cutting force. Thus, the industry strives to produce the thinnest blade edge possible while retaining blade edge strength. This is typically achieved by treating a stainless steel substrate with thin film coatings such as diamond-like carbon to enhance edge strength or platinum-chromium to enhance corrosion resistance. The blades are further coated in a telomer like material to create a low friction cutting surface. This greatly reduces the force required to cut hair, minimizing hair “pulling,” providing additional comfort. Additional key components of a modern razor are shown in Figure 21.5. First introduced in 1985, lubricating strips are now found on most disposable and permanent system cartridges. The strips distribute water-soluble lubricant following each shaving stroke, resulting in a significant reduction in drag of the cartridge over the skin and allowing additional strokes to be taken comfortably even after most of the shaving preparation has been shaved off. The strips also allow the skin to release freely from the tension created

(a)

(b) Figure 21.4 Multiple blade razors and skin management. Spacing 5 blades closer together (b), creates a shaving surface that helps spread shaving force for a safer, more comfortable shave.

Lubricating strip: Low friction, releases skin tension, lubricates for next stroke

Fin guard: Tensions skin ahead of blades

Pivot: Rotation point of cartridge, ensure cartridge follows contours

Trimmer blade: Precision trimming

Blade springs: Allows blades to react to load

Blades: Extend and cut hair Interact with skin Figure 21.5 The key components of a razor and their functions.

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21. Blade shaving

Cutting force relative to dry hair (%)

Dry hair

Figure 21.6 Effect of hydration time on force required to cut (beard) hair. The most significant reduction occurs over the first 2 minutes.

by the skin guard. The guard is typically comprised of soft, flexible microfins or rigid plastic which precede the blades. These microfins gently stretch the skin, causing beard hairs to spring upward so they can be cut more efficiently. Additional features include pivoting heads that allow the cartridge to follow the contours of the face and trimmer blades allow the shaver to get exact positioning of the blade for a closer, more precise shave. The recent introduction of oscillating wet shaving systems increases razor glide for improved comfort. Such advances in blade edge and razor technology, coupled with an understanding of the needs of the consumer, have significantly enhanced the quality, closeness, safety, and comfort of the shave. This is most evident when combined with a shave care regimen designed to maximize hair removal and minimize skin damage.

The shaving process Drawing a sharpened implement across the skin’s surface has the potential to cause damage and dry shaving can result in the immediate appearance of uplifting skin cells and perturbation of stratum corneum barrier function, with an increase in dryness observed several days subsequent to the initial damage [10]. Body site will likely influence the response to this insult because the number of stratum corneum cell layers varies over the body surface, averaging 10 layers on the cheek or neck and 18 layers on the leg [11]. The potential for damage is compounded by non-uniform skin surface topography and the presence of hair (Figure 21.2), which when dry is relatively tough. A dry hair has about the same tensile strength as a copper wire of equivalent diameter. A few simple steps can help prepare the skin and hair for an optimum shaving experience. First, the skin should be thoroughly cleansed. Cleansing removes surface soils that

100 90

Significant reduction in cutting force after 2 min hydration

80 70 60 50 40 0

6 8 10 Hydration time (min)

can interfere with the shaving process and also helps hydrate the hair. The latter is especially important and shaving during or after showering or bathing is ideal but short of this, the area to be shaved should be washed with a cleanser and warm water. In some situations applying a warm, wet towel or cloth to the skin for a few minutes before shaving may also help. Hair is mostly keratin, and keratin has a high affinity for water. Hydrating softens the hair to make it more pliable and easier to cut; the force required to cut a hair decreases dramatically as hydration increases (Figure 21.6). Short-term hydration will also improve the skin’s elasticity [12], making it better able to deform and recover as the blade is drawn over its surface. However, more is not necessarily better; prolonged soaking can macerate skin and cause the surface to become uneven, making effective hair removal more difficult and increasing the risk of damaging the skin. Excessive soaking can also deplete the stratum corneum of substances such as natural moisturizing factor (NMF) that help it hold on to water [13], which can exacerbate any dryness induced by the shaving process. A preparation such as a shaving gel or cream can also improve the shaving experience. A preparation serves several functions. The physical act of applying preparation to the skin can remove oils and dead skin cells from the surface and aid in the release of trapped hairs, with the potential to improve the efficiency of the cutting process. Shaving preparation formulas typically contain a high percentage of water, which provides an additional hydration source for the hair and skin. Finally, shaving preparations are usually based on surfactants and contain other ingredients such as oils or polymers. For reasons already noted hydrating hair and skin is important for the shaving process, but hydration increases the coefficient of friction for an object sliding across the skin’s surface [14]. The surfactants, oils, and polymers in shave gels can reduce friction to improve razor glide, provide a cushion between the blade and skin, and improve cutting efficiency.

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Table 21.1 Summary of some differences between males and females related to hair characteristics and blade shaving behaviors and attitudes. Male

Female

Onset of shaving behavior

Most males begin shaving between the ages of 14 and 15

Most females begin shaving between the ages of 11 and 13

Body areas shaved

Most male shaving occurs on the face and neck areas. The average male shaves an area of ∼300 cm2

Female shaving is focused on the leg and underarm areas. The average female shaves an area of ∼2700 cm2

Relative hair density

Higher hair density. On average the male face has 500 hair follicles per cm2 [7]

Lower hair density. On average the leg and axillae have 60–65 hair follicles per cm2 [7]

Hair growth pattern

Hair on the face tends to grow in multiple directions

Hair on the legs tends to grow in the same direction, but hair in the underarm area grows in multiple directions

Location where shaving occurs

Males tend to shave at the bathroom sink

Females tend to shave in the shower or bath

Attitudes towards shaving

Males tend to view shaving as a skill

Females tend to view shaving as a chore

Equipment and technique are also important for an optimum shaving experience. The razor should be in good condition with a sharp blade. A dull blade will not cut the hair cleanly and will pull the hair, increasing discomfort and the likelihood of nicks and cuts. Shaving in the direction of hair growth with a light pressure is recommended to reduce pulling, at least for the first few strokes. These preliminary strokes can be followed up with strokes against the grain if additional hair removal is needed. On the face, feeling the beard with the hand can help identify hair growing patterns and guide stroke direction. Skin on some areas of the body, such as the underarms, has a naturally uneven or very pliable surface. Pulling the skin taut on these areas during shaving can improve the efficiency of the hair removal process and reduce nicking or cutting. In all cases the razor should be rinsed often to keep the blade surface clean. Some situations may require extra care during the shaving process. For example, pseudofolliculitis barbae (PFB) is a condition that affects individuals with very tightly curled hair, such as those who are of African descent. In PFB hairs may grow parallel to, rather than out from, the skin’s surface and in some cases the tip of the hair curves back and grows into the surface of the skin, causing inflammation. Individuals prone to developing PFB should thoroughly hydrate the hair before shaving, liberally use a shaving preparation and if blade shaving, shave daily with a sharp razor. Following the shave, skin should be thoroughly rinsed with water to remove all traces of shaving preparation, because these products are generally surfactant-based and leaving surfactant in contact with the skin can induce or exacerbate irritation. Rinsing with cool water can have a soothing effect on the skin. Applying a moisturizer can also have a soothing effect and will hydrate the skin to help

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prevent dryness. Moisturizers can also speed the barrier repair process and thus help to mitigate any stratum corneum damage that might result from shaving. These steps apply generally to blade shaving needs for both sexes. However, there are differences between males and females in terms of hair characteristics and blade shaving behaviors and attitudes. As a result, razors for females are often designed to accommodate body specific needs. Some of these differences are summarized in Table 21.1.

References 1 Richards R, Meharg, G. (1991) Cosmetic and Medical Electrolysis and Temporary Hair Removal: A Practice Manual and Reference Guide. Medric Ltd, Toronto. 2 Saitoh M, Uzuka M, Sakamoto M. (1969) Rates of hair growth. Adv Biol Skin 9, 183–201. 3 Tolgyesi E, Coble DW, Fang FS, Kairinen EO. (1983) A comparative study of beard and scalp hair. J Soc Cosmet Chem 34, 361–82. 4 Thozhur SM, Crocombe AD, Smith AP, Cowley K, Mullier M. (2007) Cutting characteristics of beard hair. J Mater Sci 42, 8725–37. 5 Deem D, Rieger MM. (1976) Observations on the cutting of beard hair. J Soc Cosmet Chem 27, 579–92. 6 Michael-Titus A, Revest P, Shortland P, Britton R. (2007) The Nervous System: Basic Science and Clinical Conditions. Elsevier Health Sciences, UK. 7 Bhaktaviziam C, Mescon H, Matoltsy AG. (1963) Shaving. I. Study of skin and shavings. Arch Dermatol 88, 874–9. 8 Hollander J, Casselman EJ. (1937) Factors involved in satisfactory shaving. JAMA 109, 95. 9 Terry J. (1991) Materials and design in Gillette razors. Mater Des 12, 277–81. 10 Marti VPJ, Lee RS, Moore AE, Paterson SE, Watkinson A, Rawlings AV. (2003) Effect of shaving on axillary stratum corneum. Int J Cosmet Sci 25, 193–8.

21. Blade shaving 11 Ya-Xian Z, Suetake T, Tagami H. (1999) Number of cell layers of the stratum corneum in normal skin: relationship to the anatomical location on the body, age, sex and physical parameters. Arch Dermatol Res 291, 555–9. 12 Auriol F, Vaillant L, Machet L, Diridollou S, Lorette G. (1993) Effects of short-term hydration on skin extensibility. Acta Derm Venereol [Stockh] 73, 344–7.

13 Visscher MO, Tolia GT, Wickett RR, Hoath SB. (2003) Effect of soaking and natural moisturizing factor on stratum corneum water-handling properties. J Cosmet Sci 54, 289–300. 14 Highley DR, Coomey M, DenBeste M, Wolfram LJ. (1977) Frictional properties of skin. J Invest Dermatol 69, 303–5.

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Part 1: Colored Facial Cosmetics Chapter 22: Facial foundation Sylvie Guichard and Véronique Roulier L’Oréal Recherche, Chevilly-Larue, France

BAS I C CONCEPTS • Facial foundation places a pigment over the skin surface to camouflage underlying defects in color and contour. • Facial foundations must be developed to match all ethnicities and facial needs. • New optic technologies have allowed modern facial foundations to create a flawless facial appearance more effectively. • Facial foundations impact skin health because they are worn daily for an extended period.

Introduction

Complexion makeup – an ancient practice

Complexion makeup is anything but a trifling subject. The practice is deeply rooted in human history. It has evolved along with civilizations, fashions, scientific knowledge, and technologies to meet the various expectations depending on mood, nature, culture, and skin color. A prime stage to beautifying the face, complexion makeup creates the “canvas” on which coloring materials are placed. Women consider it as a tool to even skin color, modify skin color, or contribute to smoothing out the skin surface. To fulfill these different objectives, substances extracted from nature took on various forms over time until formulation experts developed a complex category of cosmetics including emulsions, poured compacts, and both compact and loose powders. These developments have improved the field of skin care providing radiance, wear, and sensory effects. It remains a challenge to adequately satisfy the varying makeup requirements of women from different ethnic origins, who do not apply products in the same way and do not share the same diverse canons of beauty. It is therefore necessary to gain a thorough understanding of the world’s skin colors. Finally, as a product intended to be in intimate contact with the skin, facial foundations must meet the most strenuous demands of quality and safety. This has motivated evaluation teams to develop methods for assessing product performance.

Modifying one’s self-appearance by adding color and ornament to the skin of the face and body skin is hardly a recent trend [1–3]. From Paleolithic times, man has decorated himself with body paint and tattoos for various ritual activities. In the Niaux Cavern (Ariège, France), the cave of Cougnac (Lot, France), and the Magdalenian Galleries of le Mas d’Azil (Ariège), the past ages have left evidence of these practices. Along with the flint tools in the Magdalenian Galleries at le Mas d’Azil ochre nodules were found that look like “sticks of makeup” as well as grinding instruments, jars, spatulas, and needle-like “rods” 8–11 cm long, tapered at one end and spatula-shaped on the other end, suitable for applying body paint. From the earliest of ancient civilizations, there are cosmetic recipes containing a variety of ingredients which are often closer to magic than to rational chemistry, aimed particularly at modifying the complexion. Usually used exclusively by high dignitaries, cosmetics were intended to whiten the complexion.

Ancient Mesopotamia (2500

BC)

The queen and the princes of Ur used cosmetics consisting of a mixture of mineral pigments based on Talak (from which the word “talc” is derived). Nowadays such cosmetics are still commonly used in some parts of the Middle East.

BC)

The priests used plaster to cover their faces. It was also desirable for women to exhibit very white skin without blemishes, as these were indications of a privileged life of leisure.

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The complexion was whitened with mixtures of plaster, calcium carbonate, tin oxide, ground pearls, and lead carbonate (ceruse) mixed with animal grease, waxes, and natural resins. Evidence of the complexity of the ancient recipes has been determined by chemical analyses carried out jointly by the Centre National de la Recherche Scientifique, L’Oréal’s Recherche department, the Research Laboratory of the Museums of France, and the European Synchrotron Radiation Facility on the content of cosmetic flasks found in archeologic excavations [4]. The earliest cosmetic formulary is attributed to Cleopatra – “Cleopatrae gyneciarum libri.”

have made them disappear from the market, but it was not until 1915 that the use of ceruse was officially prohibited. In 1873, Ludwig Leichner, a singer at the Berlin Opera, sought a way to preserve his skin tone by creating his own foundation base from natural pigments. In 1883, Alexandre Napoléon Bourjois devised the first dry or pastel foundation. Bourjois was about to launch his first dry blush, Pastel Joue. With the birth of the cosmetics industry, products were widely distributed. Modern manufacturing techniques with production on an industrial scale coupled with the beginning of mass consumer use started at the beginning of the 20th century.

Ancient Greece In Ancient Greece, the white, matte complexion symbolizing purity was obtained through generous application of plaster, chalk, kaolin (gypsos), and ceruse (psimythion), but Plato was already denouncing the harmfulness of these cosmetics.

Ancient Rome Ancient Rome raised the use of makeup to the level of an art form. In addition to cosmetics that enhance the beauty of face and body, cosmetics were applied to improve appearance and hide flaws, notably those caused by the aging process. Women of the upper classes “coated” their face with complex mixtures with recipes reported in Ovid’s Cosmetics or in Pliny the Elder’s Natural History. For instance, hulled barley, powdered stag antlers, narcissus bulbs, spelt, gum, and honey were the components of a mixture to make the face shiny. Dried crocodile excrement, ceruse, vegetal extracts, as well as lanolin or suint (also known as oesype) were used to whiten the complexion. Recently, an analysis was made of an ointment can, christened Londinium, discovered in London when excavating a temple dated at the middle of the 2nd century AD. It contained glucose-based polymers, starch, and tin oxide. The white appearance of the cream reflects a certain level of technological refinement [5].

From the Middle Ages to the 19th century In Europe, from the Middle Ages up to the middle of the 20th century, good breeding and good manners were associated with a white complexion. In the Middle Ages, makeup was based on water, roses, and flour, which did not prevent ceruse from making a strong comeback in the Renaissance. It was then subsequently mixed with arsenic and mercury sublimates to give the complexion a fine silver hue. Toxic effects of these cosmetics, however, was beginning to worry the authorities. In 1779, following the onset of a number of serious cases, the manufacture of “foundation bases” was placed under the control of the Société Royale de Médicine, which had just been set up in 1778. The toxic components were then removed. This measure seems to

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20th century: the industrial era and diversification In the 20th century, fashionable powders for the complexion became more sophisticated [6,7]. Market choice extended with the launch of new brands such as Gemey, Caron, and Elizabeth Arden. The 1930s saw the development of trademarks such as Helena Rubinstein and Max Factor created by professional movie and Hollywood makeup artists. The products were suited to the requirements of the movie studios. Extremely opaque, tinted with gaudy colors, they were compact and difficult to apply. After the success of Max Factor’s Pancake and Panstick cosmetics, use of the word “makeup” became widespread. Initiated by Chanel in 1936, the fashion in Europe and the USA began to switch from white to a tanned complexion. Even though women were more inclined to wear cosmetics, makeup was still not part of everyday life. Pancake makeup, a mixture of stearate, lanolin, and dry powders, was not easy to apply. Technical advances gradually made products more practical. The box of loose powder was equipped with a sieve in 1937 (Caron). In 1940, Lancôme launched Discoteint, a creamy version of its compact. Coty micronized its powder (Air Spun) in 1948. Yet, it was not until the 1950s that a real boom occurred in the number of products on the market. Compact makeup was made available in creamy form; foundation became a fluid cream (Gemey, Teint Clair Fluide, 1954). It was the start of a great diversification of formulations: fluids, dry or creamy compacts, sticks, and powders. Makeup became multifaceted, with more sophisticated effects, including moisturizing, protection from damaging environmental factors, and other skincare properties in addition to providing color. Since then, complexion makeup has followed the continuous changes in regulations and advances in biologic knowledge, especially in the area of skin physiology. Over the last decades, it has benefitted from technologic progress in the field of raw materials, as well as from enhanced understanding and gains in optics and physical chemistry. Finally, makeup was enriched with the diversity of cultures from all over the world prompted by globalization. The

22. Facial foundation beginning of the 21st century opens a new era of visual effects, sensory factors, and multiculturalism.

Formulation diversity Women expect foundations to effect a veritable transformation that hides surface imperfections, blemishs, discolorations, and wrinkles, while enhancing a dull complexion and making shiny skin more satiny. Whereas making up the eyes and the lips is generally done playfully, the complexion receives more attention. It is in this area that women display their greatest expertise and are the most demanding. Women have high expectations for their foundation including: • Guaranteed evenness and concealment of flaws; • Hiding of wrinkles and pores; • Good adherence to the skin; • Matting of lustrous skin; • Excellent wear all day long; • Unaltered color over time; • Pleasant, easy application; and • Appropriate for sensitive skin.

Variety of formulations In order to satisfy diverse demands, a large number of products types and forms have been developed (Figure 22.1): • Fluid foundations; • Compact, easy-to-carry foundations with adjustable effects; and • Powders to be used alone or in combination with a fluid foundation.

Fluid foundations: emulsions Fluid foundations include both oil-in-water (O/W) and water-in-oil (W/O) emulsions. Until the 1990s, most foun-

dations were O/W emulsions. Generally intended for mixed to oily skin, they are characterized by: • Very rapid drying, which can complicate even application; • Poor coverage; • Reduced wear; • Appropriate for mixed to oily skin with their external aqueous continuous phase, which makes them feel fresh on the skin. In the 1990s, the first W/O formulations revolutionized the foundation market. The external oil continuous phase gives textures with longer drying times more suitable for perfect product application. The progressive coating of pigments has improved their dispersion in the oil phase and helped to stabilize the emulsion. Throughout the years, the oil phase has been diversified mainly as a result of introducing silicone oils, first in conventional then in volatile forms. Silicone oils have dramatically changed the cosmetic attributes of facial foundation. Foundation no longer has to be spread evenly over the face. Its slickness makes it slide on the skin evenly with a single stroke without caking. The use of volatile oils, siliconated or carbonated, gave rise to the design of long-lasting foundations. As the volatile phase evaporates, the tinted film concentrates on the skin. Adhering during drying on the skin surface, the tinted film withstands friction and does not stain clothes. Thus, the “non-transfer” facial foundation was born. In the 21st century, combining volatile oils with different volatilities will lead to novel cosmetic attributes; the oily phase gradually evaporates accompanying finger strokes during application. Today, 90% of the foundations on the market are water/silicone/oil emulsions. Over the past few years, the chemistry of the emulsifying agents have also expanded as new functionalized emulsifiers become available. Either endowed with moisturizing effects or able to enhance optical properties, they contribute to the comfort and the performance of facial foundations.

Compact foundations

Figure 22.1 Diversity of textures: from fluid emulsion to paste dispersion.

Compact foundations are made up of waxes and oils in which powders and pigment phases are dispersed under heat, but compact foundations can be greasy, heavy, and streaky. The more recent use of esters and siliconated oils has made it possible to lighten the texture and improve application qualities. Volatile oils also help the facial foundation film remain unaltered for a longer time and provide long-lasting coverage. Compact foundations display the advantage of being adjustable with a sponge, which is ideal for concealing localized defects. Packaging the foundation in compact cases makes it practical for touching up during the day. Waterpacts are a special compact type that contain water. They consist of W/O or O/W emulsions rich in waxes that

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are poured into the compact under heat. The water content makes it necessary to use waterproof packaging. These solid emulsions are difficult to manufacture and preserve, but they have the huge advantage of making the compact fresh as well as practical in use. Compacts can also be packaged as sticks for more precise and localized strokes, such as around the eyes.

Powders Compact powders are distinct from loose powders as they represent the “portable to go” version of loose powders. They are composed of fillers and pigments. A binder containing 10% oils and grease ensures the compact powder particle cohesion, while also providing comfort and ease of application. To make a high-quality powder a suitable milling procedure must be used in order to disperse the pigments finely and evenly throughout the powder phase.

Figure 22.2 The four iron oxides used in foundations.

Loose powders A loose powder is characterized by weak particle cohesion. It does not contain binder or may contain just enough to provide a degree of cohesion that controls the final product volatility. Loose powders are generally applied with a puff, but manufacturers are developing tricks for easy application by using more finely tuned application brushes. Unlike with a puff, the powder does not scatter.

are formulated to provide fuller coverage than powder foundations. They give a very matte appearance that will not wear off in hot, humid conditions such as in the Asiatic climate. The main drawback of all powders is a certain discomfort relative to foundation, mainly because of the absence of any moisturizing effect (Table 22.1).

Compact powders There are different kinds of compact powders: • Finishing powders provide sheer coverage and are used for touch-up during the day. They are usually applied with a sponge over a foundation to mask facial shine. The fillers used in these powders tend to be organic, because they are more transparent. They also have the advantage of absorbing sebum while still leaving a natural look. The formulation challenge is to find a good balance between texture quality and the ease in placing the proper amount of powder on the applicator. • Powder foundations are compact or loose powders whose covering power is equivalent to that of a foundation (i.e. better than a finishing powder). They can be used instead of foundation, for instance by women who dislike fluid textures. The loose powder version known as mineral makeup is currently enjoying considerable success. • Two-way cakes, which are available in compact form, can be used either wet or dry. This kind of powder is popular with Japanese women. Using it dry gives the same kind of makeup as a powder foundation, while using it wet gives more even coverage. This dual usage requires the vast majority of the fillers to be hydrophobic. Treated fillers, coated with silicone oils that cannot be wetted, are mostly used. In this way, the compact remains unaltered after contact with water and does not cake. These two-way cakes

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Color creation At the core of foundation formulations there is a combination of colored powders that must be: • As finely dispersed as possible with optimal stability; and • Able to create a natural-looking tinted film once smeared over the skin. To achieve this end, the formulator has available various colorants that comply with the different cosmetics legislations (positive lists) and are thus certified to be harmless, chemically pure, and microbiologically clean. These are inorganic pigments such as metallic oxides – yellow, red, and black iron oxides – to which colored and uncolored pearls can be added to give a lustrous effect. To brighten foundations (especially the darkest ones) blue pigment can be substituted for black. For improved pigment dispersion and formula stability, the process of pigment coating has gradually become the standard. In water/silicone emulsions, a silicone coating is most frequently used. Coating with an amino acid aims at developing products for sensitive skin.

Pigments and coverage The amount of titanium oxide pigment in the product is an indication of its ability to cover skin flaws (i.e. the level of coverage provided). A foundation is characterized by theoretical coverage on a scale from 7 (natural effect) to 50

22. Facial foundation

Table 22.1 Products categories overview. Skin type target

Formulations characteristics

Name of category

Main objectives

All types of skin but adapted to Asian routine

Uncolored formulations To be applied under foundation

Foundation base

Application: Lasting effect – spreadability Moisturizing effect – matt finish

All types of skin

Weakly colored

Tinted creams

Strong skincare attributes

All types of skin

Weakly colored but pearly

Bronzers Highlighters

Healthy “glow” effect, suntan color

All types of skin

Greens, purples, blues, apricot

Complexion correctors

Correction of discoloration (red spots by green tints) Complexion freshener (apricot – blue)

All types of skin

Low to full coverage

Fluid foundations

Wear – matt finish Antiaging – radiance

Normal to oily skin

Low to full coverage

Compacted powders, such as two-way cakes (adapted to Asian routine)

Matt finish – complexion evenness

Normal to dry skin

Medium to full coverage

Compact foundation

Evenness – adjustability of the result. Comfort – mobility

Normal to oily skin

Weak to medium coverage

Waterpacts (poured emulsions)

Same properties as compacts, plus freshness and hydrosoluble actives

Eye contour

Medium to full coverage

Concealers

Hides dark circles under the eyes

All types of skin

Transparent to opaque (mineral makeup)

Loose powders

Matt finish and adhesion – evenness

(corrective makeup). However, this ignores the optical properties of the product, which may also be able to mask skin defects through a soft focus effect [8]. It also does not take into account the influence of texture, which will determine how transparent or opaque the colored deposit is according to the ability of the product to spread evenly as a thin layer over the skin.

• Different varieties of silica, sometimes porous forms; • Polymers such as nylon and polymethylmethacrylate (PMMA); and • Mica platelets that can also be coated. Not only are these powders essential to the basic properties of a product, but they also contribute to its optical properties. Transparent or opaque, lustrous, matte, or soft focus, they help to achieve the desired finish on the skin.

Importance of fillers Fillers are all the non-pigment powders introduced in the product to provide: • Covering power; • The ability to absorb sebum and sweat so as to make the skin velvety and fix the color to the skin; • Fineness and smoothness, which enhances cosmetic qualities of the textures; and • Spreadability, which makes application easier. Both form and chemical nature govern the final qualities of fillers (Figures 22.3a–c). Talc is an example of a spreadable, lamellar powder that is widely used for its extreme softness and absorbing power. Kaolin, starches, and calcium carbonate used to be widely employed but they have now been superseded by:

Facial foundation application Most women usually apply their facial foundation first when applying cosmetics. They may choose to modify their complexion color or make it more glowing and even without changing the color. Whatever effect is desired, makeup is used to recreate an ideal of color and finish peculiar to each individual according to ethnic and cultural practices. It must also be adapted to suit the woman’s routine: application of a single product, use over a base or under a powder, stroked on by finger or by sponge. There is a great diversity in the use of complexion makeup. The formulator must address several issues. Being familiar

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(a)

(b)

(c)

Figure 22.3 Shape variety of fillers (a–c).

with the various skin color characteristics is a primary requisite for recreating the shades that closely match the ethnic origin of the user. For any given product, this is a necessary prerequisite for creating a range of shades that will likely satisfy the women throughout the world, whether Caucasian, Hispanic, African, or Asian. A large study carried out on a widely representative panel demonstrated significant differences in the colorimetric characteristics of skin color of six ethnic groups living in nine different countries [9,10]. The recorded measurements enabled the definition of a wide color space showing the various color spectra typical of each ethnic group’s skin color mesh and overlap (Figure 22.4). Further studies showed that the variety of makeup routines reflected the ethnic origin and cultural heritage which determines whether a woman feels positive toward her natural skin color. For many women, skin color is a major factor in their cultural identity. Complexion makeup is the easiest way to achieve even skin color by erasing surface color variations or correcting color unevenness. Some women wish to appear more deeply “tanned” than their natural color. This behavior is commonly found in Caucasian and Hispanic women. Japanese women, however, desire their makeup to give them a lighter complexion (Figure 22.5) [10]. The formulator works within this defined scope to develop shades matching natural skin colors. To meet women’s expectations, it is necessary to analyze how women selfperceive their complexion. By identifying skin colors within a definite color range and precisely identifying the makeup habits of women over the world, it is now possible to formulate a variety of shades that match up with the wishes of all women.

undergo a battery of tests to confirm its safety and performance. There are several steps in this process.

Design stage The formulator must ensure high quality ingredients are used by defining specifications and analytical controls and carrying out screening for the non-toxicity of the ingredients with in vitro tests on reconstructed skin models. Each raw material used must be cleared for safety and have a proper toxicologic dossier.

Formulation stage It is necessary to: • Evaluate stability by subjecting products to thermal cycles to accelerate aging. • Confirm the level of microbiologic preservation of the formulas using challenge tests. The selected method of preservation and the nature of the preservatives depend on the technology involved (powder emulsion, anhydrous compact). The risk of microbiologic contamination increases with the water content. It also depends on the packaging; a pump bottle provides better protection than a jar. • Check it is harmless through using alternate methods: in vitro testing and including tests run on reconstructed skin model, e.g. (EpiSkin®, L’Oréal Episkin SNC, Lyon, France); clinical tests (simple patch test [SPT] and repeated patch test [RPT]); and, finally, user tests under dermatologic controls, carried out on the product’s targeted skin types, particularly on sensitive skins and using wide ranging, representative panels. Use testing under ophthalmologic controls is carried out systematically on products intended to mask under-eye rings.

Performance stage

Emphasis on quality, safety and confirmed performance Complexion makeup creates an intimate relationship between the skin and a complex formulation that is left on for hours. Before being marketed, every product has to

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The performance of the product must be studied to ensure that it complies with consumer wishes and to obtain an unbiased opinion on advertising claims and consumer complaints. Sensorial analysis tests provide qualitative and quantitative assessments of a product’s features by a trained panel of experts, as well as by untutored panels performing the tests under the formula’s normal user conditions.

22. Facial foundation

(a)

(b)

Reflectance 0.8 0.7 0.6 Figure 22.4 (a) The color of the forehead was measured using a spectroradiometer inside a Chromasphere™. (b) The volunteer placed her face into the Chromasphere. A standardized camera was used to acquire pictures of the face. (c) A spectroradiometer measured the reflectance of forehead in the visible field 400–700 nm every 4 nm. The recorded spectrum was expressed in the CIE 1976 standard colorimetric space L*C*h D65/10 ° where each color is described through three coordinates that reflect perception by human eye. h, Hue angle (angular coordinate); C*, chroma (radius coordinate); L*, lightness (z axis).

0.5 0.4 0.3 0.2 0.1 Wavelength (nm) 0 350

(c)

400

450

L*=62.7

Additionally, a complexion product can be tested with the conventional methods used for skincare cosmetics: • Measurement of moisturizing effects using SkinChip® (L’Oréal, Chevilly-Larue, France) or Corneometer® (Courage & Khazaka, Köln, Germany); • Effects on skin firmness with using the Dermal Torque Meter® (Dia-Stron Ltd, Andover, UK); • Image analysis on skin imprints or, even better, projection of light fringes involving no contact with skin (i.e. skin in real conditions with makeup as applied) to assess antiwrinkle performance.

500

550

C*=27.0

600

650

700

750

h=58.8

Also specific tests: • Color appraisal using the Chromasphère® (L’Oréal, Chevilly-Larue, France): the difference in the color of the skin before and after applying makeup quantifies the improvement in color evenness and change in color effect. Moreover, it makes it possible to monitor both. As a result, the manufacturer can claim that its makeup effects last a given number of hours. • Evaluation of the matt finish with a suitable device (Samba® [Bossa Nova Technologies, Venice, CA, USA]).

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LIGHTENESS L*

Group 5 Group 6 Group 3

Group 4

Group 2 50 Group 1 40

HUE h

20 20

Figure 22.5 The worldwide skin color space depicted in (h, L*) and split in six groups of skin tones that reflect the color diversity.

Conclusions and prospects Beauty is diverse. Textures, tones, matte or lustrous results, play time, and sensoriality must all come together to give a woman a simple means to recreate her ideal complexion. Complexion makeup products today benefit from knowledge of physical chemistry, resulting in better understanding of the relationships between chemical composition, texture, and application behavior. Facial foundations benefit from technologic advances in optics, which has generated formulations that are sheer, glowing, matte, able to provide soft focus concealment of flaws, while simultaneously giving shades that mirror the natural hues of the skin. Complexion makeup products have been expanded to deliver multisensory effects and address ethnic diversity issues. From simple emulsions applied by finger, facial foundations have evolved into mousses, creamy compacts, and soft powders that can be applied by brush or sponge, and layered. Facial foundations contribute to beauty of the face respecting the women’s own skin, but also addressing their

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culture and ethic diversity [11,12]. New forms, new optical effects, and new application methods will permit users to attain their ideal complexion irrespective of origin or own canons of beauty.

References 1 Claude C. (2006) Histoire du maquillage du teint: une vision croisée des cultures, des modes et des évolutions technologiques. Thèse pour l’obtention du Diplôme d’Etat de Docteur en Pharmacie Faculté Paris V. 2 Gröning K. (1997) La Peinture du Corps. Arthaud Editions. 3 Gründ F. (2003) Le Corps et le Sacré. Editions du Chêne Hachette Livre. 4 Walter P, Martinetto P, Tsoucaris G, Breniaux P, Lefebvre MA, Richard G, et al. (1999) Making make-up in ancient Egypte. Nature 397, 483–4. 5 Evershed RP, Berstan R, Grew F, Copley MS, Charmant AJH, Barham E, et al. (2004) Formulation of a Roman cosmetic. Nature 432, 35–6. 6 Chanine N, Deprund MC, De La Forest F, et al. (1996) 100 Ans de Beauté. Atlas Editions. 7 Pawin H, Verschoore M. (2001) Maquillage du Teint du Visage. Paris: Encyclopédie Médicale Chirurgicale, Cosmétologie

22. Facial foundation Dermatologie Esthétique Editions Scientifiques et Médicales Elsevier. 8 Takayoshi I, Miyoji O. (2002) Appealing the technical function of the optical characteristic foundation from the view point of marketing. Fragrance J 30, 59–63. 9 Caisey L, Grangeat F, Lemasson A , Talabot J, Voirin A. (2004) Skin color and make-up strategies of women from different ethnic groups. Int J Cosmet Sci 28, 427–37. 10 Baras D, Caisey L. Skin, lips and lashes of different skins of color: typology and make-up strategies. In AP Kelly and SC Taylor,

Dermatology for Skin of Color. McGraw-Hill, Berkshire, UK, pp. 541–9. 11 Mulhern R, Fieldman G, Hussey T, Lévêque JL, Pineau P. (2003) Do cosmetics enhance female Caucasian facial attractiveness? Int J Cosmet Sci 25, 199–205. 12 Korichi R, Pelle-de-Queral D, Gazano G, Aubert A. (2008) Why women use make-up: implication of psychological traits in make-up functions. J Cosmet Sci 59, 127–37.

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Chapter 23: Camouflage techniques Anne Bouloc Cosmetique Active International, Asnières, France

BAS I C CONCE P T S • Camouflage makeup is used to cover facial defects of contour and color. • Camouflage makeup must be artistically applied to achieve an optimal result. • Camouflage techniques can improve quality of life. • Camouflage therapists can train patients in the proper application techniques for cosmetics.

Introduction Camouflage techniques can be helpful in patients who do not achieve complete or immediately attractive results from dermatologic therapy. Because appearance is one of the pivotal factors influencing social interactions, facial blemishes and disfigurements are a psychosocial burden in affected patients leading to low self-esteem and poor body image. Camouflage makeup can normalize the appearance of skin and improve quality of life. Training in camouflage techniques is essential because the application is different from regular foundations. This chapter discusses the use of camouflage cosmetics.

Definitions Camouflage cosmetics were introduced more than 50 years ago to improve the appearance of World War II pilots who had sustained burns. The products provided an opaque cover over the damaged skin areas. Modern high quality camouflage products provide a excellent coverage, but with a more natural appearance (Figure 23.1). There are several brands of camouflage makeup on the market. They aim to conceal skin discoloration and scars and to impart a natural, normal appearance. Camouflage products differ from makeup products purchased over the counter. They contain up to 25% more pigment, as well as fillers endowed with optical properties. Camouflage makeups are waterproof and designed to cover and mask a problem, but must be mixed to match the patient’s skin tone. The goals of camouflage cosmetics are to provide [1]:

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1 Color: Camouflage makeup must match all skin tones as it should blend into the color of the area on the face it is intended to cover evenly. 2 Opacity: Camouflage makeup must conceal all types of skin discoloration, yielding as natural and normal an appearance as possible. 3 Waterproof: Camouflage makeup must be rain and sweatresistant, remaining unaltered with athletics (e.g. swimming). 4 Holding power: Camouflage makeup must adhere to skin without sliding off. 5 Longer wear: Camouflage makeup must provide the assurance of long wear with easy reapplication, if necessary. 6 Ease of application: Camouflage makeup must be easy to apply. Too many steps and color applications may create patient confusion. There are several different types of camouflage cosmetics: 1 Full concealment: A method referring to complete coverage of the damaged skin and extending beyond the boundaries of the injured area. High coverage foundation creams or cover creams should be used for full concealment. 2 Pigment blending: A method that involves selection of a cover cream that matches the color of patient’s foundation. 3 Subtle coverage: A light application of foundation cream that conceals only moderately. Contouring is used to minimize areas of hypertrophy or atrophy present in facial scars, using highlighting or shading to create the illusion of smoothness.

Camouflage makeup application procedures It is important to remember that camouflage makeup is most effective when applied over skin with color abnormalities or

23. Camouflage techniques High level of coverage High coverage potential Difficult to apply No natural result Heaviness

IDEAL CORRECTIVE MAKE-UP High coverage potential Easy to apply Natural result

Less coverage potential Good playtime Comfortable texture

10 Low level of coverage Figure 23.1 Ideal corrective makeup: a compromise between coverage and cosmetic qualities. After Sylvie Guichard, L’Oreal Recherche.

Low cosmetic qualities

discoloration. The size of the defect is immaterial, because it is as easy to cover a large blemish as a smaller one. However, the camouflage of texture abnormalities is more challenging. Rough scars are more difficult to conceal than smooth scars because unevenness is exaggerated after camouflaging [2]. This section of the chapter presents the steps necessary to complete a camouflage makeup application procedure for a given patient. First, patients should be asked about prior experience in attempting to camouflage their lesions with or without medical makeup. If they have no experience, the necessary steps should be discussed in detail. Second, the patient’s skin should be cleansed with a product selected according to patient’s skin type. For an optimal camouflage result, the skin should be well exfoliated and moisturized. If using a camouflage product without sun protection factor (SPF) protection, a sunscreen-containing moisturizer should be selected otherwise a bland moisturizer can be used. Third, the camouflage product must be selected to match the patient’s skin. The camouflage therapist should identify the underlying tones that contribute to skin color: haemoglobin produces red, keratin produces yellow, and melanin produces brown [3]. Thinner skin possesses more red tones while thicker skin appears more yellow. For this reason, it is almost impossible to mimic natural skin color with only one shade. Fourth, the camouflage therapist must understand color. There are three color coordinates: hue, value, and intensity. 1 Hue is the coordinate for the pure spectrum colors commonly referred to as “color name” – red, orange, yellow, blue, green, violet – which appear in the hue circle or rainbow. Each different hue is a different reflected wavelength of light. White light splitting up through a prism has seven hues: red, orange, yellow, green, blue, indigo, and violet. 2 Value is defined as the relative lightness or darkness of a color. Adding white to a hue produces a high value color,

Excellent cosmetic qualities

often called a tint. Adding black to a hue produces a low value color, often called a shade. 3 Intensity, also called chroma or saturation, refers to the brightness of a color. A color is at full intensity when not mixed with black or white – a pure hue. The intensity of a color can be altered, making it duller or more neutral by adding gray to the color. Matching a color from one manufacturer to another one is a very difficult procedure because of the variety of shades that can be produced by combining various colors and the tints of the color that can be made by varying the amount of white. Judgment of color should always be made on the skin and never in the container because what seems to be the same shade may appear quite different on the skin. The use of neutralizers in camouflaging is somewhat controversial. Some experts think it is possible to neutralize undesirable skin discoloration [2]. For example, green undertoner neutralizes a red complexion and lavender undertoner negates a yellow complexion. Other authors think that makeup undertoners do nothing but create a third color [4]. They consider that when two colors are mixed, the result is a third color. Mixing opposite colors on the color wheel (e.g. green and red or yellow and purple) will result in an unattractive gray–brownish color that must be concealed with a color that matches the skin, which adds an extra step and thickness to the makeup. For contouring, several products have to be applied. Hypertrophic scars appear lighter than surrounding skin, and have to be camouflaged applying a darker product than to surrounding skin. Atrophic scars, however, appear darker than surrounding skin, and have to be corrected using lighter product. Once the shades have been selected, the camouflage therapist should apply them to the back of the hand as a painter uses a palette to warm and soften the product (Figure 23.2a,b). The warm skin makes the product more malleable so it will apply more easily. Camouflage products are best

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(a)

(b)

(c)

(d)

(e)

(f)

Figure 23.2 Camouflage makeup technique. (a) Remove a small amount of the corrective makeup. (b) Warm the product on the back of the hand. (c) Apply over the imperfection to be covered. (d) Blend in round the edges. (e) Generously apply the powder. (f) Remove any surplus with a brush.

applied with a sponge in a patting motion but can also be applied with the fingertips (Figure 23.2c). The patting motion applies the product to the surface of the skin and does not clog pores, which allows the skin to retain its natural characteristics. Distinct borders are eliminated by blending the edges (Figure 23.2d). A camouflage product often is not used over the entire face like a regular facial foundation, but the surrounding skin must be matched as closely as possible. Patients have to be reminded that skin color on the hands does not really correspond to skin color of the face. The application is generally followed up with an application of powder which sets and waterproofs the camouflage product (Figure 23.2e,f). The setting powder used should be translucent so that the camouflage product does not change color. For patients with very dry skin, it is not necessary to use a powder as the oils are quickly absorbed into the skin. Many patients may prefer using only one shade even when the color match is not perfect. Men may not wish to mix colors. It might be of interest to show the patient the

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coverage with one shade and the coverage using more than one shade while demonstrating that color blending is relatively easy and worthwhile. For men, common skin flaws must be reproduced in order to prevent a “mask-like” appearance [5]. Beard stubble can be recreated by using different sponges and a brown or black pigment that mimics surface irregularities. Other colored powdered blushes can be used on the cheeks to simulate the natural glow of youth and around the eyes and mouth to attract the attention on other parts of the face [6]. Pictures should be taken before and after the application to document the cosmetic results. Finally, the cosmetics must be removed each evening prior to bed. Removing camouflage makeup is more difficult than regular makeup. Alcohol or acetone-based removers are too irritating for sensitive skin, thus it is better to use watersoluble cream-type makeup remover. The remover is applied generously to emulsify the makeup followed by wiping with cotton pads. The face is then rinsed with tepid water and patted dry [7].

23. Camouflage techniques

Other camouflage therapies A few other options than camouflage makeup therapies have been suggested. Dihydroxyacetone, the main ingredient in self-tanning creams, has been proposed for camouflaging in patients with vitiligo [8]. It may be a cheap, safe, and effective alternative especially for the hands and the feet as cover creams are waterproof but not rubproof. Medical tatooing under local anesthesia has also been tried to create the appearance of hair in hairless areas [9]. The pigment used is made of ferrous oxide, glycerol, and alcohol. A test on a small area should be performed to evaluate the outcome. The needle should be introduced into the dermis similarly to the natural hair pattern of the patient.

Medical indications for camouflage makeup There are various medical indications for camouflage makeup. The lesion requiring camouflage can be permanent or temporary. The best results are obtained with macules, but papules, nodules, or scars can also be camouflaged. Macular lesions for camouflaging include pigmentary disorders such as vitiligo (Figure 23.3), chloasma (Figure 23.4), lentigenes, postinflammatory hypopigmentation or hyperpigmentation (Figure 23.5); hypervascular disorders such as telangiectasia (Figure 23.6) and angioma (Figure 23.7); and tattoos. Papulonodular lesions for camouflaging include discoid lupus, acne, dermatosis papulosa nigra, and facial scars. After a graft for oncologic surgery, or for other postsurgical scars, there may be variation in pigmentation and/or relief and corrective cosmetics may be of interest. Depending on

Figure 23.3 Perioribital hyperpigmentation: (a) before and (b) after camouflage.

the skin’s ability to heal, camouflage therapy can be applied 7–10 days after most surgical procedures. However, the premature use of makeup following epidermal damage may cause a secondary infection or tattooing effect. There may be transient injuries or lesions of the skin that can be camouflaged with makeup. An injury may produce hematoma and oedema that should be concealed for occupational reason or social event. Corrective makeup can also be used after medical procedures such as laser resurfacing, peels, and microdermabrasion to camouflage erythema. After filler injections, redness may also appear. Laser hair removal will induce temporary redness, but following some lasers the skin may become purpuric. Camouflage makeup optimizes the patient’s postprocedure appearance. Indeed, if the patient knows he or she will be red, he or she will require an appointment at the end of the day or of the week. With corrective makeup, patients are able to go back straight to work. Similarly, after filler or botulinum toxin injections, hematomas may appear which can be camouflaged with corrective makeup.

Beginning a camouflage clinic It is important to offer patients camouflaging makeup knowledge [6]. In general, the dermatologist will delegate this activity to a staff member. Many physicians find that a camouflage therapist can bring an added value to the practice by enhancing patient recovery. The room for teaching camouflaging techniques should contain a table with a mirror and fluorescent bulbs to provide adequate light. A chair should be placed in the room tall enough to allow the camouflage therapist to stand. Several camouflage products should be available in various shades to match the different skin colors.

(a)

(b)

179

(ai)

(bi)

(aii)

(bii)

Figure 23.4 Vitiligo: (a) (i & ii) before and (b) (i & ii) after camouflage.

(a)

(b)

Figure 23.5 Melasma: (a) before and (b) after camouflage.

23. Camouflage techniques

Figure 23.6 Vascular malformation: (a) (i & ii) before and (b) (i & ii) after camouflage.

(ai)

(bi)

(aii)

(bii)

The camouflage therapist In the USA, camouflage therapists are state-licensed and medically trained skincare professionals, with both clinical knowledge and therapeutic skill [5]. They do not treat patients but educate them by providing information on the best way to go about applying camouflage makeup. In other countries of the world such a degree does not exist. Camouflage therapists should obtain appropriate training

and education. They should be trained to select and apply cosmetics beyond the application of standard cosmetics. Their training should include the study of facial anatomy, highlighting and contouring techniques, and prosthetic makeup techniques similar to those used in the stage and motion picture industry. The camouflage therapist should be a good communicator to teach patients how to apply various products, which the patient can easily reproduce without assistance. Camouflage therapists should be genuinely interested in the patient’s

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(a)

(b) Figure 23.7 Telangiectasia: (a) before and (b) after camouflage.

well-being. Therefore, they should be mature enough to work with people who have a severely damaged appearance. The camouflage therapist must record the patient’s history and identify needs based on the patient’s perception of the problems. Because of the clinical knowledge and personal qualities required, a trained nurse would be an ideal camouflage therapist [7,10]. The camouflage therapist can design a cosmetic treatment plan. During the interview four issues should be addressed [5]: 1 The ability of the patient to follow simple instructions. 2 The patient’s social activities and job environment. 3 The patient’s prior makeup experience. 4 The financial status of the patient.

Camouflage makeup and quality of life Psychosocial aspects of skin disease has important implications for optimal management of patients. The presence of abnormal visible skin lesions may result in significant psychologic impairment. Health-related quality of life (QOL) is a measurement method to describe physical, social, and

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psychologic well-being and to assess the burden of disease on daily living. Several general measures have been developed [11]. Surprisingly, women who used facial foundation reported a poorer QOL than those who did not. This was interpreted to mean that more severely impacted patients are more likely to hide the disorder using camouflage cosmetics, albeit inadequately. Yet, wearing makeup may improve appearance and looking better translates into feeling better. Those who feel better show signs of higher self-esteem. Many studies have been performed in order to demonstrate the effects of corrective makeup on patients’ QOL [12–14] and remove misconceptions that the use of cosmetics can be tedious and difficult for ordinary people. A wide range of facial blemishes and disfigurements such as pigmentary disorders, vascular disorders, scars, acne, rosacea, lupus, lichen sclerosus, and keratosis pilaris have been included in these studies. QOL questionnaires were completed before the first application and after applying corrective makeup. Results show that corrective cosmetics are well-tolerated and patients report high satisfaction rates. There is an immediate improvement in skin appearance and no significant adverse effects. Corrective cosmetics rapidly improve QOL, which persists with continued use. There was

23. Camouflage techniques no difference in QOL according to the type of facial disfigurement or the size of the affected area. Not only were patients improved with pigmentary or vascular disorders, but also with scars. Camouflage therapy can help patients cope with skin disorders that affect appearance. The cosmetics can be used long-term without difficulty. Camouflage therapy is of great help to patients who cannot be medically improved.

Conclusions Camouflage techniques help affected patients cope with the psychologic implications of facial blemishes or disfigurements. Covering visible signs of the disease minimizes stigmatization. Today’s high quality camouflage products provide excellent good coverage with a natural appearance. Many physicians find that a camouflage therapist can bring an added value to the practice by enhancing patient recovery.

References 1 Westmore MG. (2001) Camouflage and make-up preparations. Dermatol Clin 19, 406–12. 2 Draelos ZK. (1993) Cosmetic camouflaging techniques. Cutis 52, 362–4.

3 LeRoy L. (2000) Camouflage therapy. Dermatol Nurs 12, 415–6. 4 Westmore MG. (1991) Make-up as an adjunct and aid to the practice of dermatology. Dermatol Clin 9, 81–8. 5 Rayner VL. (1995) Camouflage therapy. Dermatol Clin 13, 467–72. 6 Deshayes P. (2008) Le maquillage médical pour une meilleure qualité de vie des patients. Ann Dermatol Venereol 135, S208–10. 7 Rayner VL. (2000) Cosmetic rehabilitation. Dermatol Nurs 12, 267–71. 8 Rajatanavin N, Suwanachote S, Kulkllakarn S. (2008) Dihydroxyacetone: a safe camouflaging option in vitiligo. Int J Dermatol 47, 402–6. 9 Tsur H, Kapkan HY. (1993) Camouflaging hairless areas on the male face by artistic tattoo. Dermatol Nurs 5, 118–20. 10 McConochie L, Pearson E. (2006) Development of a nurse-led skin camouflage clinic. Nurs Stand 20, 74–8. 11 Balkrishnan R, McMichael AJ, Hu JY, et al. (2006) Correlates of health-related quality of life in women with severe facial blemishes. Int J Dermatol 45, 111–5. 12 Boehncke WH, Ochsendorf F, Paeslack I, Kaufmann R, Zollner TM. (2002) Decorative cosmetics improve the quality of life in patients with disfiguring diseases. Eur J Dermatol 12, 577–80. 13 Holme SA, Beattie PE, Fleming CJ. (2002) Cosmetic camouflage advice improves quality of life. Br J Dermatol 147, 946–9. 14 Balkrishnan R, McMichael AJ, Hu JY, et al. (2005) Corrective cosmetics are effective for women with facial pigmentary disorders. Cutis 75, 181–7.

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Chapter 24: Lips and lipsticks Catherine Heusèle, Hervé Cantin, and Frédéric Bonté LVMH Recherche, Saint Jean de Braye, France

BAS I C CONCE P T S • The lips possess a complex anatomy consisting of mucosa and skin. • Lipsticks are designed to enhance the appearance of the lips. • Lipstick is an anhydrous paste of oils and waxes in which pigments are dispensed along with other coloring agents.

Introduction Lip makeup is an essential element in seduction and women frequently use lipsticks to make their faces more attractive. The lips are muscular membranous folds surrounding the anterior part of the mouth. This tissue is both mucosa and skin and has a complex anatomy. Labial tissue has a dense population of sensory receptors, is very sensitive to environmental stress, can present pigmentation defects, and is modified during aging. Lipstick formulations are most widely used to enhance the beauty of lips and to add a touch of glamour to women’s makeup. The lipstick that we know today is a makeup product composed of anhydrous pastes such as oils and waxes in which are dispersed pigments and other coloring agents designed to accentuate the complexion of the lips. This chapter draws together our knowledge of the biology of this special tissue, and gives detailed information on the formulation elements of lipsticks.

Lip anatomy The lips are muscular membranous folds surrounding the anterior part of the mouth. The area of contact between the two lips is called the stomium and forms the labial aperture. The external surfaces of the lips are covered by skin, with its hair follicles, sebaceous glands, and sweat glands; the inner surface is covered by the labial mucosa, a non-stratified, non-keratinized epithelium bearing salivary glands. The transitional zone between these two epithelia is the red vermilion border of the lips (Figure 24.1). It has neither hair follicles nor salivary glands, but sebaceous glands are present in about 50% of adults [1]. The red area

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is also keratinized, with rete ridges more marked than in the neighboring cutaneous zone. Several studies have identified an intermediate area between the vermilion zone and the mucosa that does not contain a cutaneous annex; it is covered by a stratified epithelium that lacks a stratum granulosum but does have a thick parakeratin surface layer. This intermediate zone increases with age [2–4]. The deeper region of this soft tissue forming the lips is made up of a layer of striated muscle, the orbicularis orbis muscle, and loose connective tissue. The muscle makes a hooked curve towards the exterior at the edge of the vermilion area which gives the lips their shape. Immediately above the transition between the skin and the vermilion zone is the Cupidon arch, a mucocutaneous ridge, also called a white roll, or the white skin roll. Its physical appearance and lighter color seem to be essentially caused by the configuration of the underlying muscle [5]. This region is rich in fine, unpigmented, “vellous” hairs that may influence the appearance of this zone. The lips have great tactile sensitivity. Labial tissue has a dense population of sensory receptors, including Meissner corpuscles, Merkel cells, and free nerve endings. The sensitivity of the lips is somewhere between that of the tongue and the fingertips [6].

Labial epidermis The epidermis of the vermilion region is twice as thick (180 μm) as the adjacent skin [4,7,8]. It still has the markers of cutaneous epidermis differentiation, even though it has fewer keratinized layers than the skin [9]. Barrett et al. [4] found that the distribution of cytokeratins (CK) differed from that of the intermediate zone, with a loss of the skin cytokeratins CK1 and CK10 and the presence of the mucosal cytokeratins CK4, CK13, and CK19. CK5 and CK14 were still present in the basal layer and occasionally in the suprabasal layer. CK8, CK18, and CK20 were found only in Merkel cells. Involucrin was present in all the zones, but its

24. Lips and lipsticks MUCOSA Lamina propria Salivary glands VERMILION BORDER

Epithelium

Orbicularis orbis muscle Blood vessels Follicles

Dermis

SKIN

Epidermis

Figure 24.1 Lip histology.

restricted distribution in the stratum granulosum of the skin extended to the stratum spinosum and the parabasal keratinocytes of the lip zone and the mucosa. Loricrin, profilaggrin, and filaggrin were found in the stratum granulosum of the orthokeratinized zones but not after the junction between the vermilion zone and the intermediate zone. The corneocytes in the mucosa are flat, smooth cells. In contrast, most of the corneocytes on the surface of the vermilion border are seen to have microvilli on all their internal surfaces when examined under the high power microscope [10]. These projections are rarely seen on the corneocytes of the adjacent skin [11]. The cell turnover of the epidermis of the vermilion border seems to be more rapid than that of the adjacent skin cells. The vermilion border also appears to lose water three times as fast as the cheeks and to have only one-third the conductance. Thus, the lips function as a barrier but their capacity to retain water is much poorer than that of facial skin [1]. Hikima et al. [11] showed that the surface of the lips, like the surface of the skin, has cathepsin D-like activity and chymotrypsin-like activity. These enzymes are involved in the hydrolysis of corneodesmosomes, and hence in the release of corneocytes from the skin surface. Like the skin, the vermilion border epithelium contains melanocytes and there is melanin in the cytoplasm of basal cells [4]. However, as the melanin pigmentation is light and associated with reduced keratinization, the color of the hemoglobin is seen more clearly. There are also Langerhans cells in this zone [8]. Cruchley et al. [12] used immunodetection of CD1a to show that there were more Langerhans cells per unit area of the lips than in abdominal skin.

Sallette et al. [13] recently showed that there is more neuropeptide-type neurotransmitter in the epidermis of the lips than in the eyelids, which seems to indicate that the lips are better innervated.

Lip dermis and lamina propria The epithelium of the vermilion border lies on a layer of connective tissue, which ensures the continuity of the cutaneous dermis and the lamina propria. This tissue is composed of collagen fibers and a network of elastic fibers. There is a thin layer of fatty tissue between the muscle and the dermis in the cutaneous part of the lips with many attachments between the muscle and the skin [14]. The deep part of the lamina propria of the mucosa lies above the hypodermis of the subcutaneous zone. The invagin*tions at the junction between the epithelium and the connective tissue of the vermilion border are higher than those of the skin [15]. These papillae contain blood capillaries. The capillary loops in the vermilion border are higher than those of the skin, which accentuates the red color of the lips because of the hemoglobin in them [16]. The lymph drainage of the red border is not uniform; it flows towards the cutaneous system on the external side of the lips and towards the mucosal system on the inner side [17].

Lip topology The description of lip topology first interested legal medicine because each individual has a different organization, much like fingerprints. The study of lip prints is called cheiloscopy. The development of kiss-proof lipsticks led legal medicine to develop protocols for revealing latent prints at a crime scene [18]. Lip prints can be classified in several ways and their distributions in populations have been quantified [19–22].

Sensitivity of lips to the environment As the lips have little cornified tissue or melanin they are very sensitive to chemical, physical, or microbial damage. Their prolonged exposure to sunlight, particularly for fairskinned people, may lead to the appearance of actinic cheilitis and even spinocellular carcinoma [23]. Pogoda and Preston-Martin [24] suggested that frequent applications of sunscreen can have a positive protective effect. Smoking has also been found to be a major risk factor for lip cancers.

Aging of the lips The esthetic consequences of aging of the superficial lip tissues (sagging, distension, and ptosis) are aggravated by changes in the shape of the bone and dental infrastructure and the aging of the underlying muscles and adipose tissue. The orientation of the labial aperture changes with a drooping of the lateral commissures: from a concave curve in newborns and children to a horizontal line in adults, and then to an inverted curve in the elderly. In profile, the lips,

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particularly the lower lip, recede with age. The upper lip becomes lower and enlarged [3,22]. Tissues become less extensible and elastic because of repeated mechanical stresses and the weakening of the orbicularis orbis muscle with age [3,25]. The vermilion border becomes larger, longer, and thicker at the corners of the mouth [2]. While wrinkles develop in the skin around the lips with age, the outline of the lips themselves becomes sunken [22]. The depth and organization of the lips varies greatly from one person to another and some young people have deep furrows. Both the spatial resolution and the tactile sensitivity of the lips decrease with age [3,6,25,26]. There may also be histologic signs of solar elastosis. The superficial microcirculatory network (both papillary and mucosal) may become smaller and less dense (reticular and mucosal), together with an apparent thinning of the lips in older people who have lost their teeth [15]. Cosmetic surgery can be used to “refresh” and to fill the tissue to rejuvenate the lips. This might involve reducing the upper lip or recovering the shape of a young lip by a series of interventions to reinforce the shape and projection of the lips and restructure the Cupid’s bow, better define the lip outline, and lift the corners of the mouth. This surgery is accompanied by a rejuvenation of the perioral region, including removal of peribuccal wrinkles, peeling, laser resurfacing, and dermabrasion [27–30].

Lip plumpness and cheilitis Cheilitis can be caused by a cold or dry environment, repeated pressure on the lips – as it can develop in players of wind instruments – or by defective dental work. It can also occur in people taking oral retinoids, or from a lack of dietary vitamin B12 (riboflavin), B6 (pyridoxine), nicotinic acid, folic acid, or iron [31]. Hikima et al. [11] reported that the corneocytes at the edges of dried out lips become flattened and their surface area increased. This suggests that the turnover of these cells is slowed in dried out lips. The degree of visible dryness is also correlated with a reduction in cathepsin D, one of the enzymes involved in desquamation, but the chymotrypsinlike activity remains unchanged. The upper lip seems to dry out less than the lower lip as it is less exposed. While the hydration measured by the capacitance does not seem to change with age, the loss of water via the lips decreases [25]. Clinically assessed drying out increases with age [22].

Defects of lip pigmentation Pigmentation defects, particularly ephelides and lentigos, may also occur. The lips of some populations, like those from Thailand, may become dark because of the accumulation of melanin in the basal layer of the epidermis without any increase in the number of melanocytes [32]. This disorder may be congenital, caused by smoking, or an allergic reac-

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tion to a topical compound. Smoking can also increase pigmentation of the buccal mucosa in darker-skinned people (Africans, Asians, Indians) [33].

Lipsticks Lipstick, a symbol of feminine beauty and sensuality and a method of attracting attention, has a very long history. The red color and bloom (lively, plump) of the lips was first accentuated in the ancient world. Today, a woman uses lipstick to highlight her individuality, character, and seductive capacity and to underline her smile [34]. It is everything but an empty gesture; it reflects the image that the woman has of herself and what she wants to project in society. In the 18th century, people distinguished between the red coloring used for the lips and the rouge used for the cheeks. Many rather toxic substances have been used in the past. The red coloring material used can be of animal, vegetable, or mineral origin. It could be obtained from the cochineal beetle imported from Mexico, the purple dye extracted from molluscs, red sandalwood from Brazil, or the orcanette root. The minerals most frequently used were lead oxide (minium), mercuric sulfate (cinnabar), and antimony. The popularity of lipstick exploded in the 20th century with the use of lip makeup based on a colored paste made from grapes and sold in little jars. These were deep colors. The mouth became much fuller with the arrival and spread of talking movies in the 1930s. The first “indelible” or “kissproof” lipstick was the lipstick Rouge Baiser sold by the French chemist Paul Baudecroux in 1927. Red, pouting lips became all the rage in the 1950s, while in the 1990s lip gloss or brilliant was produced as a paste rather than a stick.

Lipstick formulation The lipstick that we know today is a makeup product composed of anhydrous pastes in which are dispersed pigments and other coloring agents designed to accentuate the complexion of the lips. It is formed into a stick by pouring the hot material into a mould. A classic lipstick formula is: • Wax (about 15%) which is solid at room temperature. It provides hardness and creaminess when applied; • Waxy paste (20%) helps lubricate the lipstick after application; • Oil (30%) for dispersing the pigments; • Texturing agents (about 10%) to improve the texture; • Coloring agents, pigments, and/or pearls (20%) to give color; • Preserving agents and antioxidants (1%) to stabilize the formulation; • Perfume (1%); • Active ingredients including UV filters to improve longterm benefit.

24. Lips and lipsticks

Table 24.1 Waxes. Origin

Wax

Properties

Source

Appearance

Animal

Beeswax

Composed of fatty acids and alcohols Thickener

Bees

Relatively solid, give a lustrous appearance

Plant

Carnuba wax

Harder than bees wax Very slightly acid, but brittle Often used mixed with bees wax Very hard wax

From the leaves of the carnuba palm (Brazil)

Relatively hard, and give a lustrous appearance

From the candelilla plant

Matte appearance

Non-stick Non-polar White, fairly transparent and odorless

Paraffin is obtained from oil refining

More malleable

Candelilla wax Mineral

Paraffin Ozokerite

Table 24.2 Waxy pastes. Origin

Name

Properties

Source

Appearance

Synthetic

Polybutene

Adherence Brilliance Extremely hydrophobic

Synthesis from ethylene

Very viscous transparent, viscous liquid

Synthetic

Methyl hydrogenated rosinate

Waxes The wax may be of vegetable, animal, or synthetic origin. They are solid at room temperature and must be melted for use. They create a crystalline network within the formulation that gives the lipstick its shape. The wax is chosen to give the stick a suitable hardness so that it does not break during application. They also give the lipstick a rather matte appearance (Table 24.1). Lipsticks are currently made using specific fractions of wax that provide specific fusion points. These refined fractions are whiter and more odorless than the original waxes, which were a complex mixture of natural lipids.

Table 24.3 Oils. Name

Properties

Source

Appearance

Di isostearylmalate

Emollient Not oxidized Colorless Odorless

Synthetic

Colorless liquid

Trimethylolpropane Triisostearate

Emollient Comfort

Synthetic

Colorless, viscous liquid

Polyglyceryl-2 Triisostearate

Emollient Comfort Dispersant

Synthetic

Transparent pale yellow liquid

Waxy pastes They are called pastes because they are semi-solid forms of wax at room temperature (Table 24.2). They contribute to the cosmetic function of the lipstick by helping to keep the color on the lips. They can do this because they are sticky and because their fusion point is close to the temperature of the lips, thus enabling the stick to melt during application.

Oils These hydrophobic liquids are solvents for the coloring agents that allow them to diffuse so as to develop their color. The oils provide comfort, lubrication during application, and contribute greatly to the cosmetic effect. They may also

provide brilliance and subtlety (Table 24.3). Castor oil has been used for many years but is now less often utilized. It has excellent pigment-dispersing properties because of its polarity; its main inconvenience is its unpleasant taste and odor (caused by oxidation). It is gradually being replaced by stable, odorless, fatty acid esters.

Texturing agents These components can be very different; they provide moisturizing, brightness, and subtlety. For example, polyamide

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Active ingredients

Table 24.4 Pigments and coloring agents. Component

Origin

Titanium (IV) oxide – mica

Mineral

Ferrous oxide (II)

Mineral

Ferric oxide (III)

Mineral

DC Red 33

Organic

DC Red 27

Organic

DC Red 21

Organic

DC Red 7

Organic

DC Red 6

Organic

DC Red 28

Organic

DC Red 30

Organic

powders bring softness, silica beads provide subtlety and a matte finish, titanium dioxide flakes give a soft-focus effect, while bismuth oxychloride gives a satin, shimmering effect.

Pigments Pigments are synthetic substances or of mineral origin. They are fine powders when dry and are used because they are very opaque and have great coloring properties (Table 24.4). The solid powders are suspended and dispersed in oil. The covering property of a lipstick depends on its pigment content; these pigments can hide the underlying lip color. International regulations strictly limit the use of pigments. Only a restricted number can be used on the face because of the risk of ingestion. The pearly and metallic effects are obtained with composite materials, often multilayered. These are interference pigments because they create long wavelength interference patterns in natural light. Holographic effects may be obtained by liquid crystals (cholesterol derivatives) or multilayer plastic slabs (terephthalates).

Antioxidants and preserving agents The most frequently used antioxidants are the β-carotenes (provitamins A), ascorbic acid, and tocopherol, which are all powerful, natural antioxidants. The preserving agents are used to control bacterial proliferation. There are few preserving agents (phenoxyethanol mainly) in anhydrous products such as lipsticks.

Perfume Perfume provides the desired smell to the lipstick. It is generally used as an oil-based concentrate that is miscible with the other oils in the formulation.

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These are used to provide their specific properties to the finished product and often permit claims of antiaging or moisturizing. They must be included at the considered concentration to be effective. Vitamin A, as β-carotene, vitamin E (tocopherol), and vitamin C are classically used in lipstick. Sunscreen can be used to protect the lips against UV rays for an antiaging quality.

Lip glosses and brilliances A lip brilliance is a makeup product that generally has low covering qualities but reflects light and gives the lips a shiny appearance. A brilliant lipstick has a gloss effect. So, by extension, the term lip gloss includes lip brilliants. Lip glosses nourish the lips and give them a light, wonderfully supple appearance and a long-lasting sparkle. Their crystalline effect is brought about by their ultra-brilliant, transparent base. They may be used over a lipstick to give a new sparkle to the lipstick color, or simply provide the lips with a very pure, superfine color. Its formulation differs from that of lipstick only in the quantity and nature of the components classically used in lipsticks. Lip glosses are frequently sold in small flasks and are applied with a special applicator. They are not applied directly to the lips, so they do not need to have a solid structure like a lipstick. The wax content is lower and the content of waxy paste higher.

Conclusions Lipsticks and lip glosses are essential to a women’s makeup, and have a key role in the affirmation of her personality and well-being. These skin surface products – thanks to their simple formula that contains a limited number of constituents – are usually well accepted and adverse reactions are very rare. Pink, purple, even blue, the colors follow the fashion trends, and, most of the time, they are coordinated with clothes and nail polishes. The shapes and textures that women appreciate remain quite classic. Indeed, if raw materials are constantly evolving, cosmetic regulations worldwide lay down some new restrictions to the manufacturers of the beauty sector. Nevertheless, these regulatory evolutions still allow the creation of ever more innovative and qualitative products.

References 1 Kobayashi H, Tagami H. (2005) Functional properties of the surface of the vermilion border of the lips are distinct from those of the facial skin. Br J Dermatol 150, 563–7. 2 Binnie WH, Lehner T. (1970) Histology of the muco-cutaneous junction at the corner of the human mouth. Arch Oral Biol 15, 777–86.

24. Lips and lipsticks 3 Fogel ML, Stranc MF. (1984) Lip function: a study of normal lip parameters. Br J Plast Surg 37, 542–9. 4 Barrett AW, Morgan M, Nwaeze G, et al. (2005) The differentiation profile of the epithelium of the human lip. Arch Oral Biol 50, 431–8. 5 Mulliken JM, Pensler JM, Kozakewich HPW. (1993) The anatomy of vermilion bow in normal and cleft lip. Plast Reconstr Surg 92, 395–404. 6 Stevens JC, Choo KK. (1996) Spatial acuity of the body surface over the life span. Somatosens Mot Res 13, 153–66. 7 Lafranchi HE, de Rey BM. (1978) Comparative morphometric analysis of vermilion border epithelium and lip epidermis. Acta Anat 101, 187–91. 8 Heilman E. (1987) Histology of the mucocutaneous junctions and the oral cavity. Clin Dermatol 5, 10–6. 9 Kuffer R. (1982) Pathologie de la muqueuse buccale et des lèvres. Encyclopédie Médicochirurgicale (Paris), Dermatologie, 12830 A10. 10 Muto H, Yoshioka I. (1980) Relation between superficial fine structure and function of lips. Acta Dermatol Kyoto Engl Ed 75, 11–20. 11 Hikima R, Igarashi S, Ikeda N, et al. (2004) Development of lip treatment on the basis of desquamation mechanism. IFSCC Magazine 7, 3–10. 12 Cruchley AT, Williams DM, Farthing PM, et al. (1994) Langerhans cell density in normal human oral mucosa and skin: relationship to age, smoking and alcohol consumption. J Oral Pathol Med 23, 55–9. 13 Sallette J, Al Sayed N, Laboureau J, Adem C, Soussaline F, Breton L. (2006) Neuropeptide Y may be involved in human lip keratinocytes modulation. J Invest Dermatol 126, suppl 3, s13. 14 Choquet P, Sick H, Constantinesco A. (1999) Ex vivo high resolution MR imaging of the human lip with a dedicated low field system. Eur J Dermatol 9, 452–4. 15 Wolfram-Gabel R, Sick H. (2000) Microvascularisation of lips in ageing edentulous subjects. Surg Radiol Anat 22, 283–7. 16 Iwai I, Yamash*ta T, Ochiai N, et al. (2003) Can daily-use lipstick make lips more fresh and healthy? A new lipstick containg αglucosyl hesperidin can remove the dull-color from lips. 22nd IFSCC Conference, pp. 162–77. 17 Ricbourg B. (2002) Vascularisation des lèvres. Ann Chir Plast Esthet 47, 346–56. 18 Ball J. (2002) The current status of lip prints and their use for identification. J Forensic Odontostomatol 20, 43–6.

19 Sivapathasundharam B, Prakash PA, Sivakumar G. (2001) Lip prints (cheiloscopy). Indian J Dent Res 12, 234–7. 20 Hirth L, Göttsche H, Goedde HW. (1975) Lips print: variability and genetics. Humangenetik 30, 47–62. 21 Hirth L, Goedde HW. (1977). Variability and formal genetics of labial grooves. Anthrop Anz 36, 51–7. 22 Lévêque JL, Goubanova E. (2004) Influence of age on the lips and perioral skin. Dermatology 208, 307–14. 23 Calvalcante ASR, Anbinder AL, Carvalho YR. (2008) Actinic cheilitis: clinical and histological features. J Oral Maxillofac Surg 66, 498–503. 24 Pogoda JM, Preston-Martin S. (1996) Solar radiation, lip protection, and lip cancer risk in Los Angeles County women (California, United States). Cancer Causes Control 7, 458–63. 25 Caisey L, Gubanova E, Camus C, Lapatina N, Smetnik V, Lévêque JL. (2008) Influence of age and hormone replacement therapy on the functional properties of the lips. Skin Res Technol 14, 220–5. 26 Wohlert AB. (1996) Tactile perception of spatial stimuli on the lip surface by young and older adults. J Speech Hearing Res 39, 1191–8. 27 Simon E, Stricker M, Duroure F. (2002) Le vieillissem*nt labial: composantes et principes thérapeutiques. [The lip ageing.] Ann Chir Plasti Esthét 47, 556–60. 28 Aiache AE. (1997) Rejuvenation of the perioral area. Dermatol Clin 15, 665–72. 29 Guerrissi JO. (2000) Surgical treatment of the senile upper lip. Plast Reconstr Surg 92, 938–40. 30 Ali MJ, Ende K, Maas CS. (2007) Perioral rejuvenation and lip augmentation. Facial Plast Surg Clin North Am 15, 491–500. 31 Zugerman C. (1986) The lips: anatomy and differential diagnosis. Cutis 38, 116–20. 32 Kunachak S, Kunachakr S, Kunachark S, Leelaudomlipi P, Wongwaisatawan S. (2001) An effective treatment of dark lip by frequency-doubled Q-switched Nd:YAG laser. Dermatol Surg 27, 37–40. 33 Sarswathi TR, Kumar SN, Kavitha KM. (2003) Oral melanin pigmentation in smoked and smokeless tobacco users in India: clinico-pathological study. Indian J Dent Res 14, 101–6. 34 Dong JK, Jin TH, Cho HW, et al. (1999) The esthetics of the smile: a review of some recent studies. Int J Prosthodont 12, 9–19.

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Chapter 25: Eye cosmetics Sarah A. Vickery, Peter Wyatt, and John Gilley Procter & Gamble Cosmetics, Hunt Valley, MD, USA

BAS I C CONCE P T S • Mascara is intended to darken, thicken, and lengthen the lashes to make them more noticeable. Careful selection of mascara film materials and new applicator technologies are enhancing women’s abilities to accentuate these characteristics quickly and effectively. • Other eyelash products, beyond mascara, such as lash perms and lash tints are becoming more prevalent and are beginning to gain mainstream acceptance. These new products are changing the way women think about eyelash beauty. • Eyeshadow is color applied to the upper eyelids that is used to add depth and dimension to the eyes, thus drawing attention to the eye look or eye color. • Eyeliner is used to outline the eyelids, serving to define the eyes and to make the eye look more bold or to give the illusion of a different eye shape. • New eye cosmetic products are being introduced that feature enhanced long wear, new applicator surfaces, novel color effects, sustainable natural materials, improved application, and even lash growth.

Introduction This chapter gives a broad introduction to eye cosmetics. Mascara, eyeshadows, and eyeliners are presented along with the physiology of eyelashes and future trends.

Eye cosmetic history Cosmetics have been used to decorate the eyes for thousands of years. In Ancient Egypt materials such as charcoal and kohl were mixed with animal fat to create ointment for darkening the lashes and eyelids. They used eye cosmetics for the same reasons that we do now: in youth to attract by accentuating and drawing attention to the eyes, and in age to preserve beauty as it starts to fade [1,2]. Moving forward to more modern times, in the 18th and 19th centuries, men would condition their hair and mustaches with a touch-up product for graying hair called Mascaro. This was also used in stage makeup as both an eyelash and brow cosmetic. In the 19th century women darkened their lashes with lamp black, which they could collect simply by holding up a plate to catch the soot above a lamp or candle flame. They also used cake mascara (soap, wax, and pigment wetted with a moistened brush) to darken their lashes, or they could plump their lashes with petro-

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leum jelly. Since then a wide variety of innovations have changed both the way we decorate eyes and the penetration of these products into daily use by the majority of women [3]. The first half of the 20th century saw a range of new product forms emerge including liner pencils, melted wax dripped onto lashes, eyelash curlers, eyebrow pencils, lash dye, cream mascara (toothpaste style tube with brush), false lashes, liquid drops, and even turpentine-based waterproof mascara. As the century progressed, more and more women were using eye cosmetics, driven in part by the makeup of the popular actresses in the Hollywood movies and also because of new distribution systems, such as Maybelline’s mail order mascara and availability at local stores. By the late 1930s, the majority of women applied cosmetics around their eyes [4]. In 1957, Helena Rubenstein launched the first modern day mascara – a tube of mascara cream with the applicator stored inside the tube. No longer was the mascara applicator separate from the mascara formulation. This efficient and more sanitary design took off quickly and, by the 1960s, became the standard form of mascara. Once this new product form was established, the applicator quickly changed from a simple grooved aluminum rod to the ubiquitous twisted wire brush applicator that is the predominant applicator today [3]. By the 1970s, waterproof mascaras were more appealing than the past turpentine-based versions because of the availability of purified petroleum-based volatile solvents [4]. Fibers were introduced into mascaras for a “lengthening” benefit. Eyeshadows were available in a broad range of

25. Eye cosmetics matte and sparkling colors, partly because of the growth of iridescent pigments in the 1960s. By the 1980s and into the 1990s, the rapidly improving performance of polymers resulted in more durable eye cosmetics that would glide on with ease and maintain their effect for hours [5].

Eyelash physiology Eyelashes are terminal hairs growing from follicles around the eye. Like all hair, the eyelash is a mixture of dead cells that have been keratinized, binding material, melanin granules, and small amounts of water. The outer surface is comprised of a series of overlapping, transparent scales called cuticle cells that protect the inside, called the cortex. The cortex contributes to the eyelash’s shape, mechanical properties, and color. Eyelashes vary by ethnicity and, as a result, can have an elliptical or circular cross-section with an average diameter of 60–120 μm, tapering to a fine, barely pigmented tip [6–8]. Figure 25.1 is a series of scanning electron micrographs that show the shape, cross-section, and surface morphology of an eyelash. While hair over the body is likely there for thermal insulation and proximity sensation, eyelashes protect the eye from debris and signal the eyelid to close reflexively when something is too close to the eye. Chemically, eyelashes are the same as scalp hair, and across ethnicities the chemistry of lashes is the same. Eyelashes have a substantially shorter, slower growth phase than scalp hair, hence their shorter length, and they typically last for 5–6 months before falling out. An active follicle, during the anagen (growth) cycle, will typically produce a lash at approximately 0.15 mm/day, half the growth rate of scalp hair. If a lash if plucked from the hair follicle, a new hair can begin growing in as little as 8–10 weeks [6–7,9].

Figure 25.1 Scanning electron microscope images of the eyelash. The eyelash tapers to a fine tip. The cross-section may be circular or elliptical (A), and the surface is composed of overlapping cuticle cells (B).

The direction that the eyelash protrudes from the eyelid is based on the follicle’s position in the skin. The curvature of the lash is derived from the shape of the follicle. As the lash forms inside the follicle, and the protein strands are bonded together, the lash shape that is formed corresponds to the shape of the follicle they are formed within. Eyelashes are arranged around the eye in a narrow band 1–2 mm wide. Lashes are longer (8–12 mm) and more numerous (90–200) on the upper eyelid, while lower eyelid lashes number 30– 100 and are typically 6–8 mm long [8]. There are a number of ailments to which the eyelashes are prone, the most common of which are listed in Table 25.1.

Mascara Over half of women who wear cosmetics wear mascara. In fact, mascara is a product that women tend to be passionate about. When asked which cosmetic they would choose if they could only choose one, over 50% of women would choose mascara. Mascara is intended to darken, thicken, and lengthen the lashes to make them more noticeable. Through careful selection of materials, mascara films can be produced to accentuate these characteristics. Mascara formulations can be roughly divided into two different types: water-resistant and waterproof.

Table 25.1 Common eyelash ailments. Ailment

Description

Madarosis, or hypotrichosis

Thinning, or loss, of eyelid and eyebrow hairs. Can be caused by aging, physical trauma, burns, X-ray therapy, overuse of glued false lashes, and trichotillomania (impulse to pull out one’s hairs, including eyelashes)

Stye

A stye can be caused, among other things, from a bacterial infection of the eyelash follicle’s sebaceous glands, leading to an inflammation of skin tissue around the eyelash follicle

Poliosis

Lashes losing their pigmentation with age, caused by less melanin granules being present in the lashes. Gray lashes are pigmented, just with less pigment than those of a younger person. Completely unpigmented lashes are white

Trichiasis

This is the abnormal growth of lashes directed towards the eyeball, causing irritation and possibly leading to infection

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Mascara composition Water-resistant mascaras typically deliver a combination of waxes, polymers, and pigments in a water-based emulsion to the lashes. The water helps contribute to the enhanced lash attributes by absorbing into the lash, bloating its diameter by as much as 30% and in many cases forcing the lashes to curl. The waxes are emulsified into the water creating a thick, creamy texture that glides onto the lashes in a thick film that resists fading, abrasion, and flaking throughout the day, but is still easily removed with warm water and soap. Polymers are often included to bind the mascara to itself as well as to the lashes. Advances in polymer technology over the last 20 years have led to very substantive films that last throughout the day, even though they are delivered to the lash in an aqueous medium. Consumers who desire the longest lasting mascara will select the anhydrous waterproof formulations which contain little to no water and deliver very durable, but difficult to remove films. Waterproof mascaras usually use hydrocarbon solvents and anhydrous raw materials. They provide a longwearing film on the lashes, which is very resistant to water, smudging, and smearing. Its anhydrous nature makes it more difficult to both apply and remove, and it may have more eye irritation potential. A list of common water-resistant and waterproof mascara ingredients and their functions can be found in Table 25.2.

Additional ingredients can be added to a formulation to enhance particular eyelash characteristics. A common method for producing lengthening mascara is to include fibers in the formulation so that, when applied, the fibers will extend beyond the natural ends of the eyelashes. Similarly, large, lightweight, hollow particles may be incorporated into the mascara film to create a thicker film for bolder lashes. Synthetic or natural polymers with novel properties can also be incorporated to induce a curling effect on the lashes. Other forms of mascara are available such as clear mascaras, waterproofing topcoats, pearlescent topcoats, and lash primers. This breadth of cosmetic options gives consumers many choices to groom and decorate their lashes.

Mascara applicator technology Consumers will typically judge a better mascara applicator as one that creates more clumps of lashes that are uniformly spaced apart [10]. However, different consumers apply their mascara for different end looks – some aspiring for only a few (spiky) clumps of lashes, others working towards wellseparated lashes. The twisted wire brush has been the mainstay mascara applicator for 50 years. As seen in Figure 25.2, it is simply a metal wire bent back upon itself into two parallel wires. Bristles, typically made of nylon, are inserted between the bent wire and it is twisted around to form a

Table 25.2 Water-resistant and waterproof mascara ingredients and function. Class

Material type

Examples

Function

Water-resistant solvent

Carrier fluid

Water, propylene glycol

Deliver mascara ingredients to lashes in liquid vehicle

Waterproof solvent

Carrier fluid

Isododecane, cyclomethicone, petroleum distillates

Deliver mascara ingredients to lashes in liquid vehicle

Film former

Polymers/binder

Cellulosic polymers, acrylates co-polymer/xanthan or acacia gum

The main constituent of the mascara film and serves to bind the other ingredients together in the wet and dried film

Structurant

Waxes/clays

Beeswax, carnauba wax/bentonite clay

Provides body and structure to the mascara film during application and wear

Surfactant or emulsifier

Anionic/non-ionic, etc.

Sodium laureth sulfate/TEA soap, polysorbates

In a formulation with two immiscible substances, an emulsifier stabilizes the two dissimilar parts of the formulation, preventing separation

Colorant

Pigments

Iron oxides, mica, ultramarines

Provides color to the mascara film

Care or attribute

Hair treatment/ lengthening, etc.

Panthenol, keratin/nylon or silk fiber

An ingredient included for a specific effect in the mascara film

Preservatives

Antimicrobial/pH adjuster/chelator

Parabens, potassium sorbate/citric acid/EDTA

Prevents contamination of harmful microorganisms such as bacteria, mold, and fungus

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25. Eye cosmetics helical arrangement of bristles. The bristles are very effective at depositing mascara onto lashes, but the inconsistent spacing between bristles on the brush can lead to excessively large clumps of lashes, uneven lash separation, and the need for compensatory grooming of the lashes. The skill of the consumer plays a large part in achieving her desired look in a timely manner, and the twisted wire applicator has seen many adjustments over the years to make mascara application easier and quicker for consumers to achieve their desired lash appearance. Innovations include tapering the end of the applicator, curving the brush, hollow

bristles, changing the diameter or length of the applicator, and even cutting shapes out from the applicator’s profile to create channels within the collection of bristles. Despite the wide variety of twisted wire applicator innovations, the bristles all converge around a central shaft and the spacing between adjacent bristles is highly variable. This limits the consistency of both lash clump size and gaps between clumps of lashes. In the last 5 years, technology advancements have enabled a whole new category of molded mascara applicators to emerge. The precisely engineered surfaces of a molded applicator, shown in Figure 25.3, give control over the placement, number, and physical properties of bristles or other grooming surfaces. The result is consistent gaps between bristles, enabling the bristles to penetrate deeper into the lashes for increased mascara transfer and more efficient and regular separation of lashes. In addition, the varieties of colors, shapes, and textures that can be created are almost limitless and offer new opportunities to delight consumers. A few examples of these are shown in Figure 25.4.

Other eyelash treatments

Figure 25.2 Twisted wire brush mascara applicators.

The ability to change the appearance of eyelashes extends beyond mascara. False eyelashes may be applied as entire strips or as individual groups of lashes. They are adhered to the eyelid with a non-permanent adhesive. This allows easy application and removal at the end of the day. Lash tinting involves application of a semi-permanent dye for color that lasts about a month. This is a two part product, just like permanent coloring for scalp hair. An oxidative cream is mixed with an oxidizing agent and then applied

Figure 25.3 Molded mascara applicator with precisely engineered, parallel bristles.

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Figure 25.4 Various molded mascara applicator designs showing the wide range of possibilities that are possible with this emerging applicator type.

onto the lashes and left for 15–20 minutes. The dye forms while it is penetrating into the lashes. Lash perming is achieved by rolling the lashes of the top eyelid around a thin cotton tube. The lashes are then coated with a high pH gel that penetrates into the lashes and breaks disulfide bonds holding together keratin protein strands in the cortex. After about 15 minutes, a second neutralizing coat is applied to the lashes to neutralize the high pH and reform bonds between protein strands to hold the lash in its new shape after the cotton cylinder is removed. Eyelash extensions are synthetic fibers that are bonded to individual lashes, usually with a cyanoacrylate adhesive. Typically, 30–80 lashes per eyelid will have eyelash extensions applied, and they typically last 1–2 months. Eyelash transplants involve relocating scalp follicles to the eyelids. Small incisions are made in the top and bottom eyelids into which are placed the transplanted follicles. Manual curling and trimming is necessary because the scalp follicles will continue to grow hair for years in a relatively straight direction. Blepharopigmentation, or eyelid tattooing, involves application of pigmentation into skin at the edges of the eyelid to simulate either eyeliner or the appearance of lashes. This is permanent but can be reversed with laser surgery. Over the past 3 years, a number of products have launched with claims that suggest physiologic stimulation of lash growth for darker, thicker, longer, and curlier lashes. Most of these make use of prostoglandin analogs that are typically used for treating glaucoma, but are known to have the above (beneficial) side effects [11].

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Eyeshadow Eyeshadow is color applied to the upper eyelids. It is used to add depth and dimension to the eyes, thus drawing attention to the eye look or eye color. The predominant form is powder, both pressed and loose, but eyeshadow is also available in other forms, such as creams, sticks, and liquids. Eyeshadows are very similar to blushes and pressed powder in terms of their key ingredients (Chapter 22). They are usually comprised of pigments and pearls, and fillers bound together with a volatile or non-volatile binder. They may also contain other powder particles such as boron nitride or polytetrafluoroethylene to improve slip and pay-off on application.

Eyeliners Eyeliner is used to outline the upper and lower eyelids. This serves to define the eyes against the backdrop of the face. Eyeliner can also be used to make the eye look more bold or to give the illusion of a different eye shape. They are typically available in liquid form and wood or mechanical pencils. Wood pencils excel at creating a softer, more natural look. Mechanical pencils tend to be a bit bolder, and the gel forms are good for gliding easily across the eyelid. Liquid liners can create a distinctively defined eye and provide longer wear but can be difficult to apply correctly. Most eye pencils are comprised of colorants dispersed in a waxy

25. Eye cosmetics matrix for ease of application and to help the color adhere to the skin. Liquid liners, although not as popular as the pencil form, contain colorants that are dispersed in volatile solvents so they can be applied with a brush or pen-like applicator.

Product application Eyeshadow application techniques vary according to the look you are trying to achieve but, generally, an appealing look can be achieved using three complementary shades in light, medium, and dark. The lightest shade highlights the area below the eyebrow, the medium shade is applied to the creased area, and the darkest shade is reserved for the area immediately above the upper eyelashes. Matte, silky shadows tend to blend nicely and are better for mature eye skin than iridescent or sparkly shades which can highlight fine lines or puffiness. Generally, eyeliner is applied to the outer two-thirds of the lower lid below the lashes and to the entire upper lid above the lashes in a thin line. An angled brush can be used to gently soften the look. Although dark liners draw a lot of attention to the eyes, softer shades of brown, especially in the daytime, can be used to avoid looking too harsh. Curling the lashes with an eyelash curler prior to mascara application will make the eyes seem more wide open and bright. Usually, mascara is applied generously to upper lashes and to a lesser extent to the lower lashes. Color choice of mascaras can change the look obtained. For instance, on light-haired individuals brown mascara can be used for a softer, more natural look. Black or brown–black is best for deeper skin tones or for a more dramatic look. Figure 25.5 shows the effect of applying eye cosmetics.

Safety and regulatory considerations for eye area cosmetics Most countries or regions regulate cosmetics to a varying degree of complexity, largely because of safety considerations. Because cosmetics touch and interact directly with the human body, the various regulations are in place to ensure that consumers are not exposed to materials that may be harmful. This stems from various safety incidents that have occurred with personal care products. For instance, consumers can have allergic reactions to lash dyes, which were becoming a popular product in the 1930s. In one case, an allergic reaction to a lash dye led to one consumer becoming blind [4]. Ultimately this was one of many cases in the USA that led to Food and Drug Administration (FDA) overseeing of cosmetics. In particular, it led to a positive list of colorants that could be used for eye area cosmetics [12]. In later years, other regulatory bodies, such as the European Commission, adopted similar restrictions to the FDA’s on colorants for use in the eye area [13]. Because of their intimate contact with the human body, all cosmetics should be adequately preserved from microbiologic insults. This is especially true for eye cosmetics where contact with a contaminated product could lead to an eye area infection and the possibility of more serious complications.

The future of eye cosmetics For a mature category such as eye cosmetics, it is surprising how much potential still exists for product innovation. New products are being introduced that feature enhanced long wear, new applicator surfaces, novel color effects,

(a)

(b) Figure 25.5 The impact of eye cosmetics on eye beauty. (a) Before. (b) After.

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Figure 25.6 Digital simulations of lashes aid cosmetic scientists in visualizing potential lash looks for product design.

sustainable natural materials, improved application, and even lash growth. The mascara application experience is being improved with automated applicators that use vibrating or rotating brushes to take away some of the skill necessary to achieve beautiful lashes. These applicators can be held up against the lashes while they work for the consumer by exposing more of the applicator surface to the lashes, encouraging more deposition of mascara and more grooming of the lashes. Products are coming onto the market that claim to actually stimulate and enhance lash growth. While there are regulatory considerations that make these products controversial, if approved for consumer use they may negate the need of some women to use mascara to achieve beautiful lashes. Scientists around the world are even starting to tap in to virtual modeling to peel back the individual factors of eye beauty, and to design looks not yet achievable with today’s products. Three-dimensional modeling and simulation are being exploited to mimic consumers’ real eyelashes, and then simulate how those lashes may be made more beautiful. For the first time we can explore both the true limits of eye beauty and the individual impacts of single lash variables (e.g. lash separation, thickness, lift, color, curl) on beauty. An optimized digital representation of a consumer’s lashes can be used to design a formula and applicator to deliver the right personalized lash look for them. Figure 25.6 shows several related simulations where only lash clumping is adjusted [14].

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References 1 Kunzig R. (1999) Style of the Nile. Discover September, p. 80. 2 Ahuja A. (1999) Chemistry and eye make-up – science. Times September 22. 3 Geibel V. (1991) Mascara. Vogue August. 4 Riordan T. (2004) Inventing Beauty: a history of the innovations that have made us beautiful. New York: Broadway Books, pp. 1–31. 5 Balaji Narasimhan R. (2001) Pearl luster pigments. In: Paintindia Vol. 51, pp. 67–72. 6 Elder MJ. (1997) Anatomy and physiology of eyelash follicles: relevance to lash ablation procedures. Ophthal Plast Reconstr Surg 13, 21–5. 7 Na J, Kwon O, Kim B et al. (2006) Ethnic characteristics of eyelashes: a comparative analysis in Asian and Caucasian females. Br J Dermatol 155, 1170–6. 8 Liotet S, Riera M, Nguyen H. (1977) Les cils: Physiologie, structure, pathologie. Arch Opht 37, 697–708. 9 http://www.atsdr.cdc.gov/hac/hair_analysis/2.4.html. 10 Sheffler RJ. (1998) The revolution in mascara evolution. Happi April, pp. 48–52. 11 Wolf R, Matz H, Zalish M, Pollack A, Orion E. (2003) Prostaglandin analogs for hair growth: great expectations. Dermatology 9, 7. 12 21C.F.R. Part 700, Subchapter G. 13 Directive 76/768/EC, OJ L 262, p. 169 of 27.9.1976. 14 Wyatt P, Vickery S, Sacha J. (2006) Poster given at SIGGRAPH 2006.

Part 2: Nail Cosmetics Chapter 26: Nail physiology and grooming Phoebe Rich1 and Heh Shin R. Kwak2 1 2

Oregon Dermatology and Research Center, Portland, OR, USA Knott Street Dermatology, Portland, OR, USA

BAS I C CONCEPTS • Knowledge of nail unit anatomy and physiology and an understanding of nail plate growth and physical properties are important prerequisites for understanding nail cosmetics. • Disruption and excessive manipulation of certain nail structures, such as the hyponychium and eponychium/cuticle, should be discouraged during nail cosmetic procedures and nail salon services. • In addition to beautifying natural nails, nail cosmetics are beneficial in camouflaging unsightly medical and infectious nail problems, especially during the lengthy treatment period. • Some nail cosmetics provide a protective coating for fragile, weak, and brittle nails. • Proper nail grooming is crucial for maintaining nail health. • Although most nail cosmetics are used safely, it is important to be aware of potential complications associated with nail cosmetic materials and application processes.

Introduction: Nail physiology Nail unit anatomy Understanding nail unit anatomy is an essential first step to comprehending the complexity of nail cosmetics use, including pathology induced by cosmetic materials and procedures. The nail unit is composed of the nail matrix, proximal and lateral nail folds, the hyponychium, and the nail bed (Figure 26.1). Table 26.1 lists common nail signs and definitions relevant to nail cosmetics.

Nail matrix The nail matrix is comprised of germinative epithelium from which the nail plate is derived (Figure 26.2). The majority of the matrix underlies the proximal nail fold. The distal portion of the nail matrix is the white lunula visible through the proximal nail plate on some digits. It is hypothesized that the white color of the lunula can be attributed to both incomplete nail plate keratinization and loose connective tissue in the underlying dermis. The proximal nail matrix generates the dorsal (superficial) nail plate, while the distal nail matrix generates the ventral (inferior) nail plate. This

concept is crucial to understanding nail pathology. Preserving and protecting the matrix during nail cosmetic processes is essential for proper nail plate formation. Significant damage to the nail matrix can result in permanent nail plate dystrophy. The nail plate is derived from the nail matrix and composed of closely packed, keratinized epithelial cells called onychocytes. Cells in the matrix become progressively flattened and broadened and lose their nuclei as they mature into the nail plate. The nail plate is curved in both the longitudinal and transverse planes, allowing for adhesion to the nail bed and ensheathment by in the proximal and lateral nail folds. Longitudinal ridging may be present on both the dorsal and ventral surface of the nail plate. Mildly increased longitudinal ridging on the dorsal nail plate is considered a normal part of aging. Ridging on the ventral surface of the nail plate is caused by the structure of the underlying nail bed and vertically oriented blood vessels. The composition and properties of the nail plate are further discussed below.

Nail folds The nail folds surround and protect the nail unit by sealing out environmental irritants and microorganisms through tight attachment of the cuticle to the nail plate. The cuticle is often cut or pushed back during cosmetic nail procedures which can allow moisture, irritants, bacteria, and yeasts under the nail fold, resulting in infection or inflammation of the nail fold, termed paronychia (Figure 26.3). Chronic

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Table 26.1 Common nail signs associated with or helped by nail cosmetics. Nail sign

Definition

Association

Onycholysis

Separation of the nail plate from the nail bed

Vigorous cleaning of hyponychium exacerbates. Polish hides

Onychorrhexis

Increased longitudinal ridging

Associated with aging, distal notching. Polish may help

Onychoschizia

Lamellar splitting of the free end of the nail plate

Paronychia

Inflammation of the nail fold

Dyschromia yellow

Staining of the surface of the nail plate yellow from the dye in nail polish

Green/black discoloration

Pseudomonas is a bacteria that generates a green–black pigment that discolors the nail plate

Nail bed changes as in psoriasis, onychomycosis

Nail matrix (nail root) Cuticle (stratum corneum of the nail fold) Lunula

Free edge of nail plate

Eponychium Cuticle

Lunula

Nail bed

Nail plate Nail bed

Proximal nail fold

Hyponychium Hyponychium Distal groove

Lateral nail fold

Figure 26.1 Nail unit with lines indicating important structures.

Figure 26.2 Diagram of the nail unit.

paronychia may disrupt the underlying nail matrix and subsequently lead to nail plate dystrophy.

Hyponychium

Figure 26.3 Paronychia.

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The hyponychium is the cutaneous margin underlying the free edge of the nail plate. The nail bed ends at the hyponychium. It is contiguous with the volar aspect of the fingertip. The hyponychium has a similar function as the cuticle and acts as an adherent seal to protect the nail unit. The hyponychium should not be overmanipulated during nail grooming to avoid onycholysis, or separation of the nail plate from the nail bed. This space created between the nail plate and

26. Nail physiology and grooming bed retains moisture and establishes an environment for potential pathogens, such as yeast, bacteria, or fungi.

Nail bed The nail bed is thin, 2–5 cell layer thick epithelium that underlies the nail plate. It extends from the lunula to the hyponychium. The nail bed is composed of longitudinal, parallel rete ridges with a rich vascular supply which is responsible for the pink coloration of the bed, as well as longitudinal ridges on the ventral surface of the nail plate. In chronic onycholysis the nail plate is separated from the nail plate for an extended duration, the nail bed epithelium may become keratinized, form a granular layer, and lead to permanent onycholysis (Figure 26.4).

Several factors affect nail growth. Nail growth peaks at 10–14 years and declines after 20 years. Nail growth is proportional to finger length, with fastest growth of the third fingernail and slowest growth of the fifth fingernail. Nails grow slower at night and during the winter. Other factors causing slower nail plate growth include lactation, immobilization, paralysis, poor nutrition, yellow nail syndrome, antimitotic drugs, and acute infection. Faster nail growth has been noted during the summer and in the dominant hand. Pregnancy, psoriasis, and nail biting are other factors linked to faster nail growth. Table 26.2 summarizes factors influencing nail growth.

Physical properties of nails Nail composition

Other structures The distal phalanx lies immediately beneath the nail unit. The extensor tendon runs over the distal interphalangeal joint and attaches to the distal phalanx 12 mm proximal to the eponychium. Given that there is little space between the nail unit and distal phalanx, minor injury to the nail unit may extend to the periosteum and lead to infection.

Nail growth Normal nail growth has been cited to vary from less than 1.8 mm to more than 4.5 mm per month. Average fingernail growth is 0.1 mm per day, or 3 mm per month. This information is useful when determining the duration of nail pathology. For example, if splinter hemorrhages are located 6 mm from the proximal nail fold, it can be estimated that they occurred from injury approximately 2 months prior. Based on this growth rate, fingernails grow out completely in 6 months. Toenails grow at one-third to half of the rate of fingernails and take 12–18 months to grow out completely.

The nail plate is composed mainly of keratin, which is embedded in a matrix of non-keratin proteins. There is wide variation in reported percentage of inorganic elements found in the nail plate. Several elements, including sulfur, calcium, iron, aluminum, copper, silver, gold, titanium, phosphorus, zinc, and sodium, are constituents of the nail plate. Of these elements, sulfur has the greatest contribution to nail structure and comprises approximately 5% of the nail plate. Nail plate keratin is cross-linked by cysteine bonds, which contain sulfur. Some studies attribute brittle nails to decreased cysteine levels. There is a popular misconception that calcium content is responsible for nail hardness. This idea likely stems from knowledge that bone density is related to calcium intake. Calcium comprises less than 1% of the nail plate by weight. No evidence supports that decreased calcium is linked to brittle nails and that calcium supplementation increases nail strength. In fact, kwashiorkor, a nutritional deficiency caused by insufficient protein intake, is manifested by soft, thin nails and demonstrates increased nail plate calcium.

(a)

(b) Figure 26.4 (a & b) Onycholysis.

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Table 26.2 Nail cosmetic products: ingredients and uses. Product

Ingredients

Application procedures

Benefits of use

Potential complications

Nail polish

Film former: nitrocellulose Thermoplastic resin: (toluene sulfonamide formaldehyde resin) Plasticizer: dibutyl pthalate Solvents and pigments

Polish is applied in several coats with a small brush and allowed to dry by evaporation

Provides an attractive glossy smooth decorative surface and camouflages nail defects Protects nail from dehydration and irritants

Yellow staining of nail plate. Potential for allergy to toluene sulfonamide formaldehyde resin and other ingredients

Nail hardener

May contain formaldehyde in a nail polish base, also may have fibers that reinforce the nail

Application similar to nail polish which is applied in several coats

Forms several layers of protection on the nail plate

Potential allergy to formaldehyde and possible brittleness

Acrylic nail extensions

Acrylic monomer, polymer, polymerized to form a hard shell attached to the nail plate or to a plastic tip glued to the nail

Monomer (liquid) and polymer (powder) mixed to form a paste and polymerized with a catalyst to a harden the product

Cover unsightly nail defects, may help manage onychotillomania and habit tic disorder

Possible allergy to acrylates, inflexibility of artificial nail may cause injury to nail unit

Cuticle remover

Contains potassium hydroxide or sodium hydroxide plus humectants

Applied to cuticle for 5–10 minutes to soften cuticle adhered to nail plate

Gently removes dead skin attached to the nail plate without mechanical trauma

Over removal of cuticle and result in the potential for paronychia and secondary bacteria and Candida infections. Can soften the nail plate

Nail polish remover

Acetone, butyl acetate, ethyl acetate, may also contain moisturizer such as lanolin or synthetic oils

Wiped across nail plate with cotton or tissue to remove nail polish

Removes polish smoothly without removing layers of nail plate

May dehydrate the nail plate and periungual tissue

Water content of the normal nail plate is reported to range between 10% and 30%. The most commonly accepted value is 18% water content in normal nails and 16% in brittle nails. However, a study aimed at confirming this demonstrated no statistically significant difference between normal and brittle nails [1]. In addition, this study showed lower water content than previously thought, with a mean water content of 11.90% in normal nails and 12.48% in brittle nails. Some limitations in this study were noted, including analysis of only the distal nail plate. In addition, the time between sample collection and analysis was variable, with an average of 24 hours, and a subanalysis demonstrated loss of water content varied significantly between those samples analyzed at 1 and 24 hours. Lipids, including squalene and cholesterol, are also constituents of the nail plate and comprise 5% of the nail plate by weight. These lipids are thought to diffuse from the nail bed to the nail plate.

Nail flexibility Most references to nail strength and hardness actually refer to nail flexibility. A flexible nail will bend and conform to

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physical force, whereas a hard nail will break and become brittle. Nail flexibility is aided by plasticizers, which are liquids that make solids more flexible. Examples of nail plasticizers are water and lipids. Flexibility is decreased by solvents, such as nail polish removers, which remove both water and lipids, and detergents, which remove lipids. Nail brittleness is caused by loss of flexibility. Brittle nails are a common complaint and are found in 20% of the general population and more commonly in females (Figure 26.5). Brittleness encompasses several nail features including onychoschizia which is lamellar peeling of distal nail plate (Figure 26.6), splitting and notching sometimes associated with ridges, and fragility of the distal nail plate, lamellar splitting of the free end of the nail plate. Several attempts have been made to define brittleness with objective measurements, including Knoop hardness, which evaluates indentation at a fixed weight; modulus of elasticity, which describes the relationship between force/area and deformation produced; tensile strength; and a brittleness grading system. Although there are systemic and cutaneous conditions that may cause brittle nails, exogeneous causes are more

26. Nail physiology and grooming

(a)

(b)

(c)

Figure 26.5 (a–c) Brittle nails.

(a)

(b) Figure 26.6 Onychoschizia, distal lamallar peeling of the nail plate.

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(a)

(b)

(c)

(d) Figure 26.7 (a) Manicure; (b–d) Pedicure.

common. These include mechanical trauma, exposure to solvents and extraction of plasticizers, and repeated hydration and drying of nails.

Nail grooming principles

Manicure and pedicures are the process of grooming the fingernails and toenails respectively at home or in a nail salon (Figure 26.7). The procedure involves soaking the nails to soften prior to trimming and shaping the nail plate. Excess cuticle is removed from the nail plate using a chemical cuticle remover and often a metal implement. The nails are then finished with a shiny, smooth coat of nail enamel, commonly called nail polish, sandwiched between a base coat and top coat, or the nails may be buffed to a soft luster. Other procedures such as acrylic gel or silk wrap enhancements may be added to the basic manicure. These nail extension procedures involve applying product to the natural nail or to a plastic tip glued to the nail. The material are applied and shaped before curing or polymerizing to form a hard surface.

Nail care

Nail trimming

Several principles of nail care should be observed during nail grooming to maintain normal nail structure.

Most nail experts advocate shaping nails with an emery board rather than clipping or cutting nails. Filing should be

Nail thickness Thickness of the nail plate is determined primarily by matrix length and rate of growth. Measurements of distal plate thickness demonstrate greatest thickness in the thumbnail, followed by the second, third, fourth, and fifth fingernails. Thickness also is influenced by sex, with males having an average nail plate thickness of 0.6 mm, compared to 0.5 mm in females.

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26. Nail physiology and grooming carried out with the file exactly perpendicular to the nail surface to avoid inducing onycholysis. Proper filing of the free edge of nail plate reduces sharp edges that may catch and cause nail plate tearing. If nails must be clipped or cut, this should be performed after they have been hydrated which maximizes nail flexibility and prevents breakage during trimming. Nails should also be kept as short as possible. Long nails, especially those that are brittle, may act as a lever and create onycholysis.

Nail buffing and filing The dorsal nail plate surface is often filed to remove shine from the natural nail plate at nail salons prior to application of nail products or artificial nails. Care must be taken to avoid excessive filing, especially with electric drills. The nail plate is approximately 100 cell layers thick. If filing must be done, only 5% of the nail plate thickness, or approximately five cell layers, should be removed which is just enough to remove the shine of the dorsal nail plate in order to facilitate adherence of the product to the nail plate. Limited buffing to reduce nail ridging is acceptable, but excessive buffing thins the nail plate and should be avoided.

Figure 26.8 Psoriasis: salmon patch oil drop discoloration.

Care for brittle nails Brittle nails should be treated by avoiding nail trauma and increasing flexibility. Nails should be kept short. This prevents lifting of the nail plate, disruption of the hyponychium, and onycholysis. In addition, nails should be trimmed after they have been hydrated and are the most flexible. Moisturizing the nail plate increases flexibility and helps avoid brittle nails. Some experts recommend moisturizing up to four times daily. Avoiding solvents and frequent hydration and dessication of nails also helps maintain flexibility. There is controversy regarding avoidance of nail cosmetics in the management of brittle nails. Some believe that nail polish is protective and seals the moisture in the nail plate by preventing rapid evaporation. Nail polish also protects the nail plate from some environmental irritants. There is some concern that overuse of nail polish remover will dehydrate the nail and exacerbate brittleness. Biotin has also been advocated for brittle nails, but results are inconclusive. The recommended dose is 2.5–5 mg/day, which is 100–200 times the recommended daily allowance. Given that biotin has relatively few side effects, most experts recommend its use, in addition to the above grooming recommendations.

Adverse effects from nail grooming Nail cosmetics are safely used by millions of people worldwide. In addition to enhancing the appearance of normal nails, cosmetics are useful for improving the appearance of unsightly nail dystrophy caused by medical disease, such as psoriasis (Figure 26.8), onychomycosis (Figure 26.9), or trauma. Although nail cosmetics rarely cause problems, it is

Figure 26.9 Onychomycosis.

important to be aware of possible adverse effects related to procedures or to materials used in nail cosmetics (Figure 26.10).

Allergic reactions to nail cosmetic ingredients The most common allergen in nail polish is toluene sulfonamide formaldehyde resin with sensitization occurring in up to 3% of the population. Other potential allergens are cyanoacrylate nail glue, formaldehyde in nail hardeners, and ethylmethacrylate in sculptured nails. Allergic contact dermatitis from nail cosmetics is seen on periungual skin, as well as the eyelids, face, and neck, caused by touching these areas with freshly polished fingernails (Figure 26.11).

Irritant reactions Common nail products that cause irritant reactions include acetone or acetate nail polish removers and cuticle removers

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Nail Cosmetics with sodium hydroxide. Reactions are manifested as an irritant dermatitis of the periungual skin and as brittle nails, including onychoschizia. Prolonged use of nail polish induce keratin granulations on the nail plate. This commonly is seen when fresh coats of nail enamel are applied on top of old enamel for several weeks. These granulations cause superficial friability of the nail plate (Figure 26.12).

Nail cosmetic procedures

Figure 26.10 Yellow staining from nail polish.

Several nail problems, including paronychia, onycholysis, and thinning of the nail plate, may be mechanically induced by cosmetic procedures. Paronychia, or inflammation of the proximal nail fold, is often caused by cutting or pushing back the cuticle, leading to separation of the proximal nail fold and the nail plate. Sharp manicure instruments used to clean under the nail plate may induce onycholysis and create an environment for secondary bacterial and

(a)

(b) Figure 26.11 Allergic contact dermatitis from nail cosmetics. (a) On the eyelid. (b) On periungal skin caused by acrylates.

(a)

(b) Figure 26.12 (a & b) Keratin granulations.

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Table 26.3 Information for patients for safe nail cosmetic use. After Rich [2]. • Be sure that the salon sterilizes instruments, preferably with an autoclave. Some salons offer instruments for clients to purchase • Stinging, burning, or itching following a nail salon treatment may be signs of an allergic reaction to a cosmetic ingredient. Remove the product and seek medical evaluation by a dermatologist • If using artificial nail extensions, keep them short. Long nails can cause mechanical damage to the nail bed. Remove extensions at the first sign of onycholysis and avoid enhancements until the nail is reattached • Do not allow nail technician to cut or clip cuticles. Cuticles serve an important function and should not be cut. They may be pushed back gently with a soft towel after soaking the nails or bathing

References

Figure 26.13 Infection caused by Pseudomonas.

1 Stern DK, et al. (2007) Water content and other aspects of brittle versus normal fingernails. J Am Acad Dermatol 57, 31–36. 2 Rich P. (2001) Nail cosmetics and camouflaging techniques. Dermatol Ther 14, 228–36.

Further reading fungal infection. Onycholysis may be exacerbated by long artificial nails because of increased mechanical leverage. Nail drills or excessive filing and buffing may lead to thinning of the nail plate and brittle nails. Breaks in the integrity of the nail unit allow access of microorganisms such as Candida and Pseudomonas (Figure 26.13) and result in exacerbation of paronychia and onycholysis. Some basic principles for safe use of nail cosmetics are outlined in Table 26.3.

Conclusions Nail cosmetics is a multibillion dollar industry which continues to grow. Thorough knowledge of nail anatomy and physiology is essential for the safe use and development of nail cosmetics.

Chang RM, Hare AQ, Rich P. (2007) Treating cosmetically induced nail problems. Dermatol Ther 20, 54–9. Baran R, Dawber RPR, de Berker DAR, Haneke E, Tosti A. (2001) Diseases of the Nails and their Management, 3rd edn. Malden, MA: Blackwell Science. DeGroot, AC, Weyland JW. (1994) Nail cosmetics. In: Unwanted Effects of Cosmetics and Drugs used in Dermatology, 3rd edn. New York, Oxford: Elsevier, 524–9. Draelos Z. (2000) Nail cosmetic issues. Dermatol Clin 18, 675–83. Iorizzo M, Piraccini B, Tosti, A. (2007) Nail cosmetics in nail disorders. J Cosmet Dermatol 6, 53–6. Paus R, Peker S, Sundberg JP. (2008) Biology of hair and nails. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd edn. Elsevier, pp. 965–86. Rich P. (2008) Nail surgery. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd edn. Elsevier, pp. 2259–68. Schoon DD. (2005) Nail Structure and Product Chemistry, 2nd edn. Thompson Corporation. Scher RK, Daniel CR. (2005) Nails: Diagnosis, Therapy, Surgery, 3rd edn. Elsevier.

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Chapter 27: Colored nail cosmetics and hardeners Paul H. Bryson and Sunil J. Sirdesai OPI Products Inc, Los Angeles, CA, USA

BAS I C CONCE P T S • Nail lacquers contain resins that create a thin, resistant film over the nail plate. • Adding color to the nail plate surface is accomplished with a variety of nail lacquers including a basecoat, color coat, and topcoat. • Nail hardeners cross-link nail protein to increase strength, but overuse may contribute to brittle nails. • Nail lacquers are resistant to contamination and cannot spread nail infectious disease.

Introduction

Application techniques

The use of colored nail polish and nail hardeners has increased among consumers with the rise of the manicure industry. With nail salons found in almost every strip mall, painting nails is a very popular service for the customers of the professional manicurist. The use of nail cosmetics is well rooted in history. Ancient Chinese aristocrats colored their nails red or black with polishes made with egg white, bees wax, and gelatin. The Ancient Egyptians used henna to dye the nails a reddish brown color (J. Spear, editor of Beauty Launchpad, Creative Age Publications, Van Nuys, CA, personal communication). In the 19th and early 20th centuries, “nail polish” was a colored oil or powder, which was used to rub and buff the nail, literally polishing and coloring the nail simultaneously. Modern nail polish was created in the 1920s, based on early nitrocellulose-based car paint technology [1]. The term “nail polish” is somewhat of a misnomer for modern products, because no actual polishing is involved in its application. The product is composed of dissolved resins and dries to a hard, glossy coat, so the technically correct name is “nail lacquer.” However, the terms “nail polish,” “nail enamel,” “nail varnish,” “nail paint,” and “nail lacquer” are used interchangeably. Several specialty products have developed from nail lacquer, including basecoats, topcoats, and hardeners. A newer technology involves pigmented UVcurable resins. This chapter discusses the current use of these modern formulations (Table 27.1).

These nail products are applied by painting the nail with a brush. In best manicuring practices, old nail lacquer is removed with a solvent followed by application of a basecoat, two coats of colored nail lacquer, and a topcoat allowing sufficient time for drying between coats. The basecoat increases the adhesion of the colored nail lacquer to the nail while the topcoat increases the chip-resistant characteristics of the colored nail lacquer. These products are applied on both natural and artificial nails. Nail hardener is only applied to natural nails, either as a basecoat or a stand alone product. UV-curing nail “lacquers” are hardened with a UV light after application; no evaporation is necessary. In all cases, best practice dictates that the products be kept off the skin. Failure to do so can result in eventual, irreversible sensitization and allergic contact dermatitis [2]. Proper nail cosmetic application dictates the maintenance of excellent hygiene in the nail salon. Unsanitary procedures may result in medical problems [3]. Nail technicians must use cleaned, disinfected, or disposable nail files and tools. Clipping or cutting the cuticles before applying nail lacquer can also lead to infection. Infections with staphylococcus [4] and herpetic whitlows [5] have been attributed to unsanitary manicures. Nail technicians should not perform services on diseased nails.

Lacquers, topcoats, and basecoats

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Nail lacquers contain six primary ingredients: resins, solvents, plasticizers, colorants, thixotropic agents, and color stabilizers. By law, all ingredients must be disclosed on the

27. Colored nail cosmetics and hardeners

Figure 27.2 Painting a nail. Reproduced by permission of OPI Products, Inc.

Figure 27.1 Lacquered nails. Reproduced by permission of OPI Products, Inc.

Figure 27.3 Be careful with the cuticle. Reproduced by permission of OPI Products, Inc.

Table 27.1 Overview of product types. Product class

Nail lacquer

Basecoat

Topcoat

Nail hardener

UV curable

Coating created by

Solvent evaporation

Mainly solvent evaporation; some polymerization of formalin may occur

Polymerization

Resin type or mix

Balanced

Biased toward adhesion

Biased towards glossiness, hardness

Balanced or biased towards adhesion

Balanced; resin formed by reacting directly on nail

Pigment

Yes

Little or none

Usually none

Yes

Removal

Easily dissolves in solvent

Soften by acetone soak, then peel

Benefits

Attractive color; can be applied over natural nails or enhancements

Helps color coat last longer; protects natural nail from staining

Helps color coat last longer; some contain optical brighteners or UV protectants

Strengthens natural nail by cross-linking proteins; may be used as a basecoat

Attractive color; tough cured-in-place resin protects nail

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Figure 27.5 Dermatitis on the finger. Reproduced by permission of Nails Magazine.

Figure 27.4 Infected nail. Reproduced by permission of Nails Magazine.

product packaging, usually by means of the International Nomenclature for Cosmetic Ingredients (INCI) names. Understanding the chemistry nomenclature is important for isolating the causes of allergic contact dermatitis. Each of these ingredients is discussed in detail.

Resins Resins hold the ingredients of the lacquer together while forming a strong film on the nail. Chemically, the resins are polymers – long-chain molecules – that are solid or gummy in their pure state. Two types of resins are used. Hard, glossy resins give the lacquered nail its desired appearance; these include nitrocellulose and the methacrylate polymers or co-polymers (usually labeled by their generic INCI name, “acrylates co-polymer”). Topcoat formulations have a higher percentage of these harder resins. Softer, more pliable resins, which enhance adhesion and flexibility, include tosylamide/ formaldehyde resin, polyvinyl butyral, and several polyester resins. Basecoats incorporate a higher proportion of pliable resins. Of all the resins, tosylamide/formaldehyde resin is the most commonly implicated in allergic reactions [6] affecting not only the fingers, but other parts of the body by transfer [7].

Solvents Solvents are the carriers of the lacquer. They must dissolve the resin, suspend the pigments, and evaporate leaving a smooth film. The drying speed must be controlled to prevent bubbling and skinning, thus faster drying is not necessarily better. Optimum drying speed requires a careful blend of solvents. Ethyl acetate, n-butyl acetate, and isopropyl alcohol are common solvents, other acetates and alcohols are also

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occasionally employed. All solvents have a dehydrating and defatting action on the skin, but this usually occurs during the removal of the lacquer, not its application. Formerly, toluene was a commonly used solvent, but the industry trend is to move away from it in response to expressed health concerns. Research indicates that toluene exposure for a nail technician and consumer is far below safe exposure limits [8]; however, consumer perceptions are negative for toluene, necessitating its replacement. A related chemical, xylene, has already virtually vanished from the industry. Ketones such as acetone or methyl ethyl ketone are not amenable to suspension of pigments and are therefore used at low levels, if at all, in lacquers, although these substances will dissolve the resins effectively and therefore are useful as lacquer removers. A few water-based nail lacquers are now on the market. Because of their much slower drying time they are unlikely to replace solvent-based products in the foreseeable future. If they are ever perfected, they will completely take over the industry, because water is cheaper, non-flammable (which reduces shipping costs), and odorless.

Plasticizers Plasticizers keep the resins flexible and less likely to chip. Camphor and dibutyl phthalate (DBP) have long been used for this purpose; however, the EU maintains its 2004 ban of DBP, despite authoritative findings regarding its safety in nail lacquer [9]. Because many manufacturers sell globally, DBP has largely been replaced by other plasticizers, including triphenyl phosphate, trimethyl pentanyl diisobutyrate, acetyl tributyl citrate, ethyl tosylamide, and sucrose benzoate.

Colorants Colorants are selected from among various internationally accepted pigments. They are mostly used in the “lake” form,

27. Colored nail cosmetics and hardeners of the spectrum. It can usually be prevented by using a basecoat between the lacquer and the natural nail [10]. Topcoats can also cause apparent yellowing, but this is usually the product rather than the natural nail – as can be easily seen by removing the product [10].

Thixotropic agents Thixotropic agents provide flow control and keep the lacquer colorants dispersed. They are usually clay derivatives such as stearalkonium bentonite or stearalkonium hectorite. Most topcoats and basecoats are uncolored and do not require these additives. Silica is also sometimes used as a thickener.

Color stabilizers

Figure 27.6 Nail lacquer. Reproduced by permission of OPI Products, Inc.

meaning that the organic colorants have been adsorbed or co-precipitated into inorganic, insoluble substrates such as the silicates, oxides, or sulfates of various metals. A shimmer effect is created by minerals such as mica, powdered aluminum, or polymer flakes. Guanine from fish scales is falling out of favor but is still occasionally used. Following INCI convention, most colorant materials are labeled by their international “Color Index” (CI) numbers. This is a convenient way to identify colors, which have different national designations. Labeling colorants by their CI numbers is either legal or de facto accepted by most regulatory agencies around the world; even so, out of deference to local custom, colors are often declared binonially (e.g. CI 77891/Titanium Dioxide). However, because of space limitations, lacquer manufacturers may declare only the CI numbers on the bottle – often on a small peel-off sticker at the bottom of the bottle. This can pose a problem as few nail lacquer users are aware that, for example, “CI 60725” means the same as “D&C Violet #2” (USA) or “Murasaki 201” (Japan). Fortunately, the full designations of the colors are usually listed on the box (which has more space than the bottle) and/or the Material Safety Data Sheet (MSDS). If these are unavailable, a web search or a phone call to the manufacturer is usually sufficient to obtain this information. Another difficulty with international designations is that some closely related colorant chemicals and their lakes are lumped under one CI number. An example is the ubiquitous CI 15850, which covers D&C Red #6, D&C Red #7, and all the various lakes of both. Normally, the manufacturer can provide more specific information if needed. Colorants sometimes cause staining of the nail. Although uncommon, it is more often seen with colors at the red end

Color stabilizers, such as benzophenone-1 and etocrylene, are added to prevent color shifting of the lacquer on exposure to UV light. These substances are better known as sunscreens, but their use in nail lacquer is to protect the color. Some specialty topcoats have a high level of UV protectants, for application over colored nail lacquer to prevent fading during tanning booth use.

Minor ingredients Minor ingredients may include vitamins, minerals, vegetable oils, herbal extracts, or fibers such as nylon or silk. Some companies may include adhesion-enhancing agents in lacquers or basecoats, or other proprietary ingredients whose functions they elect not to disclose (Table 27.2).

Antifungal agents Antifungal agents may be added to nail lacquer for therapeutic purposes. However, as of this writing, there is only one prescription US Food and Drug Administration (FDA) approved antifungal nail lacquer, a topical solution of 8% ciclopirox (Penlac®, Sanofi-Aventis, Bridgewater, NJ, USA). According to FDA Consumer Magazine, “There are no approved nonprescription products to treat fungal nail infections … fungal infections of the nails respond poorly to topical therapy … the agency ruled that any OTC product labeled, represented or promoted as a topical antifungal to treat fungal infections of the nail is a new drug and must be approved by FDA before marketing” [11]. Furthermore, the FDA’s policy is to “prohibit claims that nonprescription topical antifungals effectively treat fungal infections of the scalp and fingernails” [12].

Preservatives Preservatives are not present in nail lacquer. Regulatory authorities inquired if microbial cross-contamination could occur when the same nail lacquer bottle and brush are used on multiple clients. In response, a series of experiments was performed to investigate microbe survival in nail lacquer. The results indicate that nail lacquers do not support micro-

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Table 27.2 Common ingredients of nail lacquer and related products. Ingredient category and examples

Function

Hard resins Nitrocellulose Acrylates co-polymer

Gloss Toughness

Soft resins Tosylamide/formaldehyde resin Polyvinyl butyral

Flexibility Adhesion

Solvents Ethyl acetate Butyl acetate Isopropyl alcohol Acetone (removers only)

Carrier for the resin and pigment Removing lacquer Soaking and removing UV-cured colors

Monomers and oligomers Polyurethane acrylate oligomer Hydroxypropyl methacrylate Various other acrylates and methacrylates

Hardens to hold color on nail Only in UV-curable colors, not standard lacquer

Photoinitiators Benzoyl isopropanol Hydroxycyclohexyl phenyl ketone

Initiates the light cure reaction Only in UV-curable colors, not standard lacquer

Colorants FDA/EU approved colorant Mica

Esthetic

Plasticizers Camphor Dibutyl phthalate (formerly)

Keeps resin flexible to prevent chipping

Thixotropic agents Stearalkonium hectorite Stearalkonium bentonite UV stabilizers Benzophenone-1 Etocrylene

Controls flow Suspends pigment until use

Prevents light-induced color fading

Hardeners Formalin Dimethyl urea

Hardens nail protein by cross-linking Only in hardener products

Hydrolyzed proteins Keratin Wheat, oats, etc.

Thought to bond with formalin and nail protein Usually used in hardeners

bial growth in the laboratory or salon (OPI Products Inc., and Nail Manufacturers Council, unpublished data) [13]. The solvents are sufficiently hostile to microbes that no preservative is required. This does not apply to water-based products, because water is required for microbial growth. Although solvent-based water-free lacquer is hostile to microbes, it would be a mistake to assume that it has any curative value for nail fungus or other infections.

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Nail hardeners Modern nail hardeners are quite a contrast to an antique method of nail hardening which used fire. On the early American frontier, the combat sport called “rough and tumble” or “gouging” allowed fingernails to be used as weapons, and expert “gougers” hardened their nails by

27. Colored nail cosmetics and hardeners heating them over candles [14]. The heat of the candle flame caused cross-linking of the nail proteins. Modern nail hardeners contain a chemical cross-linking agent. Otherwise, their composition is similar to ordinary nail lacquer. As with lacquers, care must be taken to avoid skin contact during application to avoid allergic sensitization, particularly to the most common hardener, formalin (which is mistakenly equated with “formaldehyde” under current labeling rules.) Formalin cross-links proteins primarily by reacting with their nitrogen-containing side groups, forming methylene bridges [15]. Overuse causes too many cross-links, reducing the flexibility of the protein and causing brittleness, yellowing, and cracking of the nails. Manufacturers generally recommend avoiding overuse by cycling the products, alternating between the hardener and a non-hardening topcoat every week or two. Other hardeners include dimethyl urea (DMU), which is does not cross-link as aggressively as formalin. It is also less allergenic [16]. Glyoxal, a relative of formaldehyde, is larger and less able to penetrate the skin, also contributing to reduced allergenicity. Hydrolyzed proteins are common additives in hardeners and may chemically bond to the formalin. Many nail hardeners are simply clear lacquers with no cross-linking agents at all. These products rely on the

Figure 27.7 Brittle nail. Reproduced by permission of Nails Magazine.

strength of the resins to protect the nails. Until DMU or some other alternative proves itself, the most effective nail hardeners will likely continue to rely on formalin.

Formaldehyde issues Formalin, formaldehyde, and tosylamide/formaldehyde resin warrant some additional discussion. True formaldehyde is a highly reactive gas. Obviously, it cannot be a part of nail products in that form. It is therefore combined with water to make a product traditionally called “formalin.” Formalin contains water and a reaction product of water and formaldehyde, properly known as methylene glycol. Published literature [17] on the hydration of formaldehyde reveals a chemical equilibrium constant for this reaction, which confirms the near complete conversion of formaldehyde to methylene glycol. This chemical equilibrium constant yields the presence of 0.0782% free formaldehyde in formalin. A nail hardener that is 1.5% formalin, the typical upper limit, therefore contains less than 0.0012% or 12 parts per million of formaldehyde. This is not to dismiss “formaldehyde allergy”, which causes significant suffering to some patients, but it would be more accurately known as methylene glycol or formalin allergy (Figure 27.8). Unlike formaldehyde, methylene glycol is non-volatile; this explains why a California study showed that formaldehyde gas levels in nail salons were not above the normal background levels found in other settings such as offices [8]. This is significant because the only identified cancer risk associated with formaldehyde exposure results from inhalation in industrial settings [18], not cosmetic skin or nail exposure. Tosylamide/formaldehyde resin is also a cause for controversy solely because of the word “formaldehyde” in its name. It is an inert macromolecule, created by reacting tosylamide and formaldehyde. However, the formaldehyde is consumed in the reaction, and any leftover formaldehyde is hydrated to methylene glycol by the water molecules generated in the reaction. Hence the formaldehyde content of the resin is essentially nil. However, allergies nevertheless occur; it has been speculated that trace formaldehyde is

H Figure 27.8 Formaldehyde versus methylene glycol. Reproduced by permission of OPI Products, Inc.

Formaldehyde (gas)

Methylene glycol (liquid)

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CH3

Nail Cosmetics CH3

SO2

CH3

SO2

N CH2

CH3

SO2

N CH2

SO2

N CH2

Figure 27.9 Tosylamide formaldehyde resin. Reproduced by permission of OPI Products, Inc.

CH3

N CH2

responsible but sensitization to tosylamide/formaldehyde resin can occur in the absence of formaldehyde sensitization [19,20], and tests indicate that side products of the synthesis reaction can be responsible for the resin allergies [21] (Figure 27.9). A final concern occasionally raised regarding formaldehyde is its absence. Because formaldehyde-releasing agents have a long history as preservatives in other forms of cosmetics, it is sometimes mistakenly assumed that formaldehyde was added to nail lacquer for preservative purposes. As a result, publicity regarding “formaldehyde-free” products has inspired fears of microbial cross-contamination via nail lacquer brushes. As noted above, experiments have shown that solvent-based nail lacquer is hostile to microbes and needs neither formaldehyde nor any other preservative.

CH2

Table 27.3 Common health effects of nail color ingredients. Ingredients

Health concerns

Resins

Possible allergies, particularly to tosylamide/formaldehyde resin

Solvents

Dehydration and defatting of skin and nails Irritant dermatitis

UV-curable acrylates/methacrylates

Allergy after repeated exposure to uncured monomer or oligomer

Photoinitiators

Possible allergies Possible photosensitization

Colorants

Occasional staining Occasional allergies

Plasticizers

Possible allergies Camphor exposure is contraindicated for some patients with fibromyalgia

Thixotropic agents

None known

UV stabilizers

Possible allergies

Hardeners (cross-linkers)

Formalin sensitization and allergies are common Overuse may cause brittleness or splitting of nail Not recommended for nails that are already brittle

Hydrolyzed proteins

Possible allergies May trigger gluten sensitivity via transfer to mouth

UV-cured “lacquers” UV-cured nail enhancements are discussed elsewhere (Chapter 28); however, a relatively new class of UV-curing nail “lacquers” merits mention here. The same pigments are used as in standard nail lacquer but instead of a solvent/resin base, curable methacrylate or acrylate oligomers and monomers are used. A photoinitiator causes polymerization of the monomers on exposure to UV light, leaving a polymer/ pigment coat. Unlike the products to create nail enhancements, these curable colored products are not used to sculpt nails, but are designed to apply as a thin coat of color, resembling conventional lacquer. Allergic sensitization may result from repeated skin exposure to uncured or incompletely cured monomers; the fully cured coat is inert. Good manicuring technique can mitigate this risk, but once an allergy is established it is irreversible. Allergies to the photoinitiators and pigments are also possible. The low-power UVA lamps used to activate the photoinitiator are comparable to summer sunshine [10], so the 1–3 minute curing time poses no hazard to healthy skin (Table 27.3).

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Nail lacquer removers In contrast to nail enhancements for nail elongation purposes, no polymerization takes place during the drying of nail lacquer; the resin is simply deposited on the nail as the

27. Colored nail cosmetics and hardeners

Figure 27.10 UV curing lamp. Reproduced by permission of OPI Products, Inc.

solvent evaporates. Therefore, removing nail lacquer is easy: it can be redissolved and wiped off with a solvent-soaked cloth pad, tissue, or cotton ball. Any solvent that dissolves the resin, and is safe for skin exposure, can be successfully used. Although UV-curable nail colors are polymerized, they are far less cross-linked than enhancements, and can be removed with a short acetone soak. Acetone, chemically known as dimethyl ketone or 2propanone, is the preferred solvent, because it is the least physiologically hazardous. Other removers are based on ethyl acetate or methyl ethyl ketone (MEK). Ethyl acetate has the advantage of not damaging acrylic nails, so it is used for removing lacquer from nail elongation enhancements. However, because of air quality regulations in California, ethyl acetate, MEK, and most other acetone alternatives are prohibited for nail lacquer removers, and other states and countries are considering similar actions. Acetone is exempt because its atmospheric breakdown produces less photochemical smog than almost any other solvent. One other “clean air” solvent, methyl acetate, is allowed in California, but has been avoided by most manufacturers because of toxicity concerns; those who use it add an embittering agent to deter accidental ingestion. Other hazardous solvents such as methanol and acetonitrile are seldom used, and are not California-compliant (Figure 27.11). All solvents can have significant drying and defatting effects on the skin, leading to irritation. This can be mitigated by using a lacquer remover with added moisturizers, or by using lotion afterwards. Drying and cracking of the nail can also result; oiling the nail is the most common way to counteract this. Some removers contain fragrances or botanical additives, which may pose allergy risks. Low-odor, non-volatile removers have been created based on methylated vegetable oils and/or various dibasic esters. As with water-based nail lacquer, however, the slow speed of nail polish removal with these products prevents them from finding general marketplace acceptance. These products are less damaging to the skin barrier.

Figure 27.11 Polish remover in action. Reproduced by permission of OPI Products, Inc.

Conclusions and future developments Arguably the largest potential for future improvement lies in cleaner application techniques, not new products. As more cases of manicure-transmitted infection are publicized, customers and governments will demand that nail technicians practice proper sanitation and disinfection. Most manufacturers are looking to develop “greener” products, whether in perception or reality. The trends away from toluene and DBP will surely continue, as will efforts to find a functional substitute for formalin. As for removers, most likely only acetone will survive the regulatory concerns. Water-based and UV-cured products have the potential to reduce solvent emissions, but still have unresolved disadvantages compared to traditional lacquers. Research continues in realm of nail polish as adding nail color is commonly practiced form of adornment.

References 1 Gorton A. (1993) History of nail care. Nails, February. Torrance, CA: Bobit Business Media. 2 Schultes SE. (Ed.) (2007) Miladay’s Standard Nail Technology, 5th edn. New York: Thomson Delmar Learning, pp. 129–32. 3 Baran R, Maibach HI. (2004) Textbook of Cosmetic Dermatology. New York: Taylor & Francis, p. 295. 4 Lee W. (2005) Bill targets nail salon outbreaks. Los Angeles Times, August 25, p. B-1. 5 Anon. (2002) Nightmare manicure: woman who says she got herpes from manicure is awarded $3.1 million ABCNews.com, May 29. 6 Linden C, Berg M, Färm G, Wrangsjö K. (1993) Nail varnish allergy with far reaching consequences. Br J Dermatol 128, 57–62. 7 Frosh PJ, Menne T, Lepoittevin JP. (2006) Contact Dermatitis, 4th edn. Basel: Birkhäuser, p. 499.

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8 McNary JE, Jackson EM. (2007) Inhalation exposure to formaldehyde and toluene in the same occupational and consumer setting. Inhalat Toxicol 19, 573–6. 9 Dibutyl phthalate – Summary risk assessment (2003, with 2004 addendum), European Commission Joint Research Centre, Institute for Health and Consumer Protection, European Chemicals Bureau, Italy. 10 Schoon DD. (2005) Nail Structure and Product Chemistry, 2nd edn. New York: Thomson Delmar Learning. 11 Kurtzweil P. (1995) Fingernails: Looking good while playing safe. FDA Consumer Magazine, December. 12 US Food And Drug Administration (1993) Answers, September 3. Available from: http://www.fda.gov/bbs/topics/ANSWERS/ ANS00529.html; retrieved September 3, 2008. 13 Nail Manufacturers Council (NMC) data, publication forthcoming. 14 Fischer DH. (1989) Albion’s Seed: Four British Folkways in America. Oxford: Oxford University Press, p. 738. 15 Kiernan JA. (2000) Formaldehyde, formalin, paraformaldehyde and glutaraldehyde: What they are and what they do. Microscopy Today 00-1, 8. 16 Schoon DD. (2005) Formaldehyde vs. DMU; What’s the Difference? Vista, CA: Creative Nail Design. Available from: www.

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beautytech.com/articles/out.php?ID=354; retrieved August 25, 2008. Winkelman JGM, Voorwinde OK, Ottens M, Beenackers AACM, Janssen LPBM. (2002) Kinetics and chemical equilibrium of the hydration of formaldehyde. Chem Engineering Sci 57, 4067–76. International Agency for Research on Cancer (IARC) – Summaries & Evaluations (Group 2A) (1995) Formaldehyde. 62, 217. Available at: www.inchem.org/documents/iarc/vol62/ formal.html; retrieved July 4, 2009. Fuchs T, Gutgesell C. (1996) Is contact allergy to toluene sulphonamide-formaldehyde resin common? Br J Dermatol 135, 1013–14. Final Report on Hazard Classification of Common Skin Sensitisers (January 2005), National Industrial Chemicals Notification and Assessment Scheme, Australian Government, Department of Health and Ageing, p. 106. Hausen BM, Milbrodt M, Koenig WA. (1995) The allergens of nail polish. (I). Allergenic constituents of common nail polish and toluenesulfonamide-formaldehyde resin (TS-F-R), Contact Dermatitis 33(3), 157–64.

Chapter 28: Cosmetic prostheses as artificial nail enhancements Douglas Schoon Schoon Scientific and Regulatory Consulting, Dana Point, CA, USA

BAS I C CONCEPTS • Artificial nail enhancements are commonly used to address malformed fingernails. • The major forms of artificial nail enhancements include nail wraps, liquid and powder, or UV gels. • Methacrylate monomer liquid systems remain the most widely used type of artificial nail enhancement. • Proper application of artificial nail enhancements can avoid infection and sensitization.

Introduction The natural nail plate can not only be cosmetically elongated and enhanced to beautify the hands, but also to effectively address discolored, thin, and weak or malformed fingernails. When used properly, these cosmetic products and services provide great value and enhance self-esteem. Artificial nails not only add thickness and strength to the nail plate, they extend its length, typically 0.25–0.75 inches. A skilled nail technician can closely mimic the length and shape of the final product to create natural-looking artificial nails. Certain techniques utilizing custom blending of colored products allow the appearance of the nail bed to be extended beyond its natural boundary, which can dramatically lengthen the appearance of the fingers (Figure 28.1). A typical nail salon client wears artificial nail products to correct problems they are having with their own natural nails such as discoloration, splitting, breaking, unattractive or deformed nails (i.e. median canal dystrophy or splinter hemorrhages). There are several basic types from which to choose: nail wraps, liquid and powder, or UV gels. An overview of each type is given in Table 28.1.

Liquid and powder Liquid and powder systems (“acrylic nails”) were the original artificial nail enhancements. These systems were similar to certain dental products made from methacrylate monomers and polymers. Methacrylates are structurally different

from acrylates, have different safety profiles, and should not be confused with one another. The literature frequently confuses methacrylates with acrylates and/or incorrectly suggests they are a single category (i.e. [meth] acrylate). The first structure shown in Figure 28.2 has a branching methyl group (–CH3) attached to the double bond of ethyl methacrylate. The branching changes both the size (10% larger) and shape of the methacrylate molecule, which reduces the potential for skin penetration. This helps explain why methacrylate monomers are less likely to cause adverse skin reactions than hom*ologous acrylate monomers (i.e. ethyl acrylate and ethyl methacrylate). It is also one important reason why artificial nails containing acrylates are more likely to cause adverse skin reactions than those based solely on methacrylate monomers [1]. Methacrylate monomer liquid systems remain the most widely used type of artificial nail enhancement in the world. The “liquid” is actually a complex mixture of ethyl methacrylate (60–95%) and other di- or tri-functional methacrylate monomers (3–5%) that provide cross-linking and improved durability, inhibitors such as hydroquinone (HQ) or methyl ether hydroquinone (MEHQ) (100–200 p.p.m.), UV stabilizers, catalysts such as dimethyl tolyamine (0.75–1.25%), flexibilizing plasticizers and other additives. The “powder” component is made from poly methyl and/or ethyl methacrylate polymer beads (approximately 50–80 μm), coated with 1–2% benzoyl peroxide as the polymerization initiator, colorants, opacifiers such as titanium dioxide, and other additives. Liquid and powder systems are applied by dipping a brush into the monomer liquid, wiping off the excess on the inside lip of a low volume container (3–5 mL) called a dappen dish. The excess monomer is removed by wiping the brush on the edge of the dappen dish. The tip of the brush is drawn through the polymer powder, also in a dappen dish, and a small bead or slurry forms at the end of the brush. Three to

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Table 28.1 The three main types of artificial nail enhancements. Type

Chemistry

Also known as

Hardener

Nail wraps

Cyanoacrylate monomers

Fiberglass wraps, resin wraps, no-light gels, silk or paper wraps

Spray, drops, powder, or fabric treated with an tertiary aromatic amine

Liquid and powder

Methacrylate monomers and polymers

Acrylic, porcelain nails, solar nails

Polymer powder treated with benzoyl peroxide; monomer liquid contains tertiary aromatic amine

UV gels

Urethane acrylate or urethane methacrylate oligomers/monomer

Gel nails UV gels Soak-off gels

Low-power UVA lamp to activate the photoinitiator and tertiary aromatic amine catalyst

Figure 28.1 The use of custom-blended colored powders with methacrylate monomers to “illusion sculpt” and extend the apparent length of a short nail bed while also correcting a habitually splitting nail plate. (Courtesy Creative Nail Design, Inc., Vista, CA, USA.)

six beads are normally applied and smoothed into shape with the brush. Pink powders are applied over the nail bed and white powders are used to simulate the free edge of the nail plate. The slurry immediately begins to polymerize and hardens on the nail within 2–3 minutes. Over 95% of the polymerization occurs in the first 5–10 minutes, but complete polymerization can take 24–48 hours [2]. After hardening, the nail is then shaped either by hand filing or with

216

an electric file to achieve the desired length and shape. The finished nail can be buffed to a high shine or nail color applied. Length is added to the nail plate in one of two ways: 1 Adhering an ABS plastic nail tip to the nail plate with a cyanoacrylate adhesive, coating the tip with the liquid and powder slurry, and filing as described above. This technique is called “tip and overlay.” 2 A non-stick (Mylar© or Teflon© coated paper) form is adhered underneath the free edge of the natural nail and used as a support and guide to which the liquid and powder slurry is applied, then shaped and filed. This technique is called “nail sculpting.” Proper preparation of the natural nail’s surface is the key to ensuring good adhesion. Before the service begins, natural nails should be thoroughly scrubbed with a clean, disinfected, soft-bristled brush to remove contaminants from the service of the nail plate as well as underneath the free edge (Figure 28.3). This removes surface oil and debris that can block adhesion. The nail is then lightly filed with a low grit abrasive file (180–240 grit) to increase surface area for better adhesion. Nail surface dehydrators containing drying agents such as isopropyl alcohol are applied to remove surface moisture and residual oils. Adhesion promoting “primers” are then applied to increase surface compatibility between the natural nail and artificial nail product. These adhesion promoters contain proprietary mixtures of hydroxylated monomers or oligomers, carboxylic acids, etc. In the past, methacrylic acid was frequently used but has fallen out of favor because of its potential as a skin and eye corrosive [3].

UV gels Products that cure under low intensity UVA lights, typically 435–325 nm, to create artificial nails are called “UV gels.” UVB and UVC are not used to create UV gel nails [4]. Unlike liquid and powder systems, UV gels are not mixed with

28. Artificial nail enhancements O O

O O

Ethyl methacrylate Figure 28.2 Chemical structure differences between methacrylates and acrylates.

Ethyl acrylate

C6H10O2

C5H8O2

Molecular weight 114 Daltons

Molecular weight 100 Daltons

of the uppermost layers of UV gel products. This layer can also be observed with certain types of liquid monomers: “odorless” products that utilize hydroxyethyl or hydroxypropyl methacrylate as the main reactive monomer. This residual sticky surface layer is called the “oxygen inhibition layer” [5]. UV gels can be clear, tinted, or heavily colored. The natural nail is cleaned, filed, dehydrated, and coated with adhesion promoters. The UV gel is then applied to the nail, shaped, and finished in the same fashion as two-part liquid and powder systems and produces very similar looking results. In most cases, the same equipment used to create other types of artificial nails is used (Table 28.2). A notable exception is UV gel curing achieved by placing the artificial nail under a UVA lamp for 2–3 minutes per applied layer. Because UVA does not efficiently penetrate more than a few millimeters into the UV gel, these products are applied and cured in several successive layers. UV gels are also applied over ABS nail tips or non-stick nail forms to lengthen the appearance of the natural nail.

Nail wraps

Figure 28.3 Equipment used to create liquid and powder artificial nails. 1, Nail scrub brush; 2, dappen dishes containing liquid and powder; 3, Mylar nail form; 4, abrasive files; 5, nail enhancement application brush; 6, ABS preformed nail tips; 7, plastic-backed cotton pad; 8, Nitrile gloves; 9, N-95 dust mask. (Courtesy Paul Rollins Photography, Inc. Laguna Niguel, CA, USA.)

another substance to initiate the curing process. Historically, UV gels have been blends of polymerization photoinitiators (1–4%), urethane acrylate oligomers, and durability improving, cross-linking monomers (approximately 75–95%), and catalysts such as dimethyl tolyamine (0.75–1.25%). Newer formulations using urethane methacrylate oligomers and monomers lower the potential for adverse skin reactions. Rate of cure is a hindrance for UV-curable artificial nails. Slow cure rates allow atmospheric oxygen to prevent curing

Methyl and ethyl cyanoacrylate monomer is used not only for adhering ABS nail tips to the natural nail, but also to create artificial nail coatings called “nail wraps.” This technique is not widely used, but accounts for at least 1% of the worldwide market [6]. The natural nail is precleaned, shaped, and filed as described above, but the cyano functional group provides tremendous adhesion to the natural nail plate, eliminating the need for adhesion-promoting primers (Figure 28.4). Nail enhancements relying on cyanoacrylate monomers do not contain other cross-linking monomers and therefore are inherently weaker than cross-linking artificial nail enhancement systems. To improve durability and usefulness, a woven fabric (silk, linen, or fiberglass) is impregnated with cyanoacrylate monomer and adhered to the nail plate. Even so, these types of coatings are not strong enough to be sculpted on a non-stick nail form and cannot be extended beyond the free edge of the natural nail plate, unless the

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Table 28.2 Specialized equipment used to create artificial nail enhancements. Item

Description

Brush

Natural or synthetic hair brush for application, spreading, and shaping of monomer and oligomers products on the nail plate

Dappen dish

Small containers that hold liquid artificial nail monomer, oligomers, or polymer powders during the application process

Manual files

Wooden or plastic core boards coated with abrasive particles (e.g. silicon nitride, aluminium oxide or diamond) used to shape, shortening, smooth, thin, or buff both natural and artificial nails

Electric files

Handheld, variable speed, rotary motors that securely hold barrel-shaped abrasive bits and are use for the same purposes as manual files

Nippers

Small clippers sometimes used to remove old artificial nail product from the nail plate

Wood stick

A thin, pencil-shaped, plastic implement used to remove cuticle tissue from the nail plate

Buffers

Block shape, high grit abrasive buffers use for shape refining (180–240 grit) or buffing to a high shine (>1000 grit)

UV lamp

Electrical device that holds either 4 or 9 W UVA producing bulbs and is used to cure UV gel nail products

Cotton pads

Disposable pads or balls used to remove old nail polish and/or dusts after filing

Scrub brush

Soft bristle, disinfectable brushes used to clean natural and artificial nails

Nail forms

Mylar© or Teflon© coated paper used as a support and guide to extending artificial nails beyond the natural nail’s free edge

Nail tips

Preformed ABS plastic tips adhered to the natural nail to support artificial nail products and create nail extensions beyond the nail’s free edge

Wrap fabric

Loosely woven silk, linen, or fibreglass strips adhered to the natural nail plate with cyanoacrylate monomer to create nail wraps

Droppers

Used to transfer product from larger containers into dappen dishes or to apply nail wrap curing accelerators

Scissors

Slightly curved blades use for trimming or cutting natural nails and wrap fabrics

Disinfectant container

Containers designed to hold EPA registered disinfectants needed to properly disinfectant tools and implements

Remover bowl

Container that holds solvents (e.g. acetone) for artificial nail removal

nail wrap is applied over an ABS nail tip, as previously described. Usually, cyanoacrylate monomers are very low viscosity, mobile liquids, but they are sometimes thickened with polymers (e.g. polymethyl methacrylate) and used without a reinforcing fabric. Such systems are referred to as “no-light gels.” Cyanoacrylate monomers are applied without the use of a brush, directly from the container’s nozzle and will cure

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upon exposure to moisture in the nail plate, but the process can be greatly hastened by solvent mixtures containing a tertiary aromatic amine such as dimethyl tolylamine (0.5– 1%), which is either sprayed on, applied with an dropper, or impregnated into the woven fabric. After curing (5–10 seconds), the nail wrap coating can be shaped and buffed to a high shine or nail color applied. This technique is also used to mend cracks or tears in the nail plate, by using the

28. Artificial nail enhancements

Figure 28.4 Materials needed to apply nail wraps. 1, Abrasive file for nail preparation and final shaping; 2, scissors for cutting fabric; 3, block buffer for high-shining; 4, cyanoacrylates; 5, spray-on catalyst; 6, silk fabric; 7, pusher to gently remove skin from the nail plate. (Courtesy Paul Rollins Photography, Inc. Laguna Niguel, CA, USA.)

cyanoacrylate monomer to adhere a small piece of fabric over the broken or damaged area of the plate.

Artificial nail removal Improper removal of artificial nails can lead to nail damage; however, they can be safely removed if the proper procedures are followed. Acetone (dimethyl ketone) is the preferred remover for artificial nail products, but methyl ethyl ketone (MEK) is also used. The artificial nails are placed in a small bowl and immersed in solvent. Nail wraps are the easiest to remove because they are not cross-linked polymers and have lower solvent resistance. They usually require less than 10 minutes immersion for full removal. Liquid and powder products are cross-linked polymers and can take 30–40 minutes to remove. UV gels are also cross-linked and these urethane acrylate or methacrylate based artificial nails have inherently greater solvent resistance so removal can take 45–60 minutes. The removal process is greatly accelerated by prefiling to remove the bulk of the artificial nail. Improper removal can cause significant damage to the nail plate. Prying or picking off the artificial nails can lead to onycholysis [7]. A common myth is that artificial nail should be regularly removed to allow nails to “breathe”; in reality they should only be removed when there is a need. Frequent removal is not advised.

Rebalancing As the natural nail grows, the artificial nail advances leaving a small space of uncoated nail plate. Every 2–3 weeks the

Figure 28.5 Example of an adverse skin reaction caused by repeated contact to the skin. (Courtesy Paul Rollins Photography, Inc. Laguna Niguel, CA, USA.)

nail technician will file the artificial nail down to one-third its thickness, reapply fresh product, and reshape the artificial nail, thereby covering the area of new growth. This process is called “rebalancing” and is essential to maintaining the durability and appearance of the artificial nail. “Soak-off gels” are highly plasticized, which softens the coating, making it more susceptible to solvent removal. This type of artificial nail often has low durability and therefore must be frequently removed and replaced, which can lead to excessive nail damage.

Adverse reactions Both nail technicians and those wearing artificial nails can develop adverse skin reactions if steps are not taken to avoid prolonged and/or repeated skin contact with artificial nail products. For example, the product should be applied to the nail plate in such a manner that skin contact is avoided (i.e. a tiny free margin left between the eponychium and artificial nail). Typically, reactions are a result of many months of overexposure to eponychium, hyponychium, or lateral side walls (Figure 28.5). Reactions can appear as paronychia, itching of the nail bed and, in extreme cases, paresthesia and/or loss of the nail plate [8,9]. Onycholysis can be a result of allergic reactions, but the nail plate is resistant to penetration from external agents and this condition is more likely to be caused by overly heavy handed, aggressive filing techniques with coarse abrasives or overzealous manicuring of the hyponychium area [10]. Allergic contact dermatitis can affect the chin, cheeks, and eyelids as a result of touching the face with the hands [11]. Filings and dusts may contain small amounts of unreacted monomers and oligomers, because it can take

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24–40 hours for the artificial nails to finish the curing process. Nail technicians should be instructed to wash their hands thoroughly before touching the face or eye area. They should be warned to avoid contact with the dusts and filings, especially the oxygen inhibition layer created on the surface of UV gels and odorless monomer liquid systems (see above), which can contain substantial amounts of unreacted ingredients. Gloves (nitrile) and/or plastic-backed cotton pads should be used to remove the oxygen inhibition layer as skin contact should be avoided. The UV bulbs in the curing lamps should be changed every 2–4 months (depending on usage) to ensure thorough cure and lessen the amount of unreacted ingredients, thereby lowering the potential for adverse skin reactions. For liquid and powder systems, it is common for technicians to use excessive amounts of liquid monomer, creating a wet consistency bead. Nail technicians should avoid applying beads of product with a wet mix ratio because this can lower the degree of curing and increase the risk of overexposure to unreacted ingredients. Nail technicians should be instructed to avoid all skin contact with uncured artificial nail products or dusts and not to touch them to client’s skin prior to curing.

Nail damage and infection Avoiding the use of heavy grit abrasives (<180 grit) or electric files directly on the nail plate will lessen the potential for damage and injury (e.g. onycholysis). Plate damage can occur when nail technicians aggressively file the natural nail, rather than use safer, smoother abrasive files (>180 grit). These gentler methods also increase the surface area for better adhesion, but without overly thinning or damaging the nail plate. Methyl methacrylate (MMA) monomer is sometimes used illegally in artificial nail monomer liquids because of its low cost when compared to better alternatives (e.g. ethyl methacrylate [EMA]). MMA has very poor adhesion to the natural nail plate so technicians who use these liquid monomers frequently abrade away the uppermost layers of the natural nail plate to achieve significantly more adhesion by allowing for deposition into the more porous layers underneath. However, this poor technique can compromise the nail plate’s strength and durability, so liquid monomer MMA containing products should be avoided [12]. The other artificial nail systems described in this chapter have improved adhesion and do not require technicians to heavily abrade the nail plate in order to achieve proper adhesion. Infections can occur underneath the artificial nail to produce green or yellow stains (Figure 28.6). Several types of bacteria and dermatophytes can cause such infections (Pseudomonas aeruginosa, Staphylococcus aureus, Trichophyton rubrum). To avoid this, state regulations require nail techni-

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Figure 28.6 Example of an nail infection growing underneath an artificial nail. (Courtesy Paul Rollins Photography, Inc. Laguna Niguel, CA, USA.)

cians to properly clean and disinfect all implements in an Environmental Protection Agency (EPA) registered disinfectant to avoid transmission of pathogenic organisms, and to dispose of all single-use items. Clients should wash their hands, scrubbing under the nails with a clean and disinfected, soft-bristled brush before receiving any services.

Education Almost every US state requires specialized nail training and education, typically 300–750 hours depending on the state, to obtain a professional license and some states have continuing education requirements. The textbooks teach a surprisingly wide range of topics including anatomy and physiology of the skin and nails, product chemistry, an overview of common nail related diseases and disorders, contamination and infection control and universal precautions, safe working practices, as well as manicuring, pedicuring, and the artificial nail techniques described in this chapter [13–15]. Multilingual information sources for proper use and other safety information can be found from a wide range of sources, including the EPA [16] and Nail Manufacturers Council [17].

References 1 Baran R, Maibach HI. (2005) Cosmetics for abnormal and pathologic nails. Textbook of Cosmetic Dermatology, 3rd edn. Taylor & Francis, London/New York, pp. 304–5. 2 Schoon D. (1994) Differential scanning calorimeter determinations of residual monomer in ethyl methacrylate fingernail formulations and two addendums. Unpublished data submitted by the Nail Manufacturers Council to the Cosmetic Ingredient Review (CIR) Expert Panel. 3 Woolf A, Shaw J. (1998) Childhood injuries from artificial nails primer cosmetic products. Arch Pediatr Adolesc Med 152, 41–6.

28. Artificial nail enhancements 4 Newman M. (2001) Essential chemistry of artificial nails. The Complete Nail Technician. London: Thompson Learning, p. 41. 5 Schoon D. (2005) Liquid and powder product chemistry. Nail Structure and Product Chemistry, 2nd edn. New York: Thomson Delmar Learning, p. 138. 6 Kanerva S, Fellman J, Storrs F. (1966) Occupational allergic contact dermatitis caused by photo bonded sculptured nail and the review on (meth) acrylates in nail cosmetics. Am J Contact Derm 7, 1–9. 7 Schoon D. (2005) Trauma and damage. Nail Structure and Product Chemistry, 2nd edn. New York: Thomson Delmar Learning, p. 52. 8 Fisher A, Baran R. (1991) Adverse reactions to acrylate sculptured nails with particular reference to prolonged paresthesia. Am J Contact Derm 2, 38–42. 9 Fisher A. (1980) Permanent loss of fingernails from sensitization and reaction to acrylics in a preparation designed to make artificial nails. J Dermatol Surg Oncol 6, 70–6. 10 Baran R, Dawber R, deBerker D, Haneke E, Tosti A. (2001) Cosmetics: the care and adornment of the nail. Disease of the

11 12

13 14 15

Nails and their Management, 3rd edn. Oxford: Blackwell Science, p. 367. Fitzgerald D, Enolish J. (1994) Widespread contact dermatitis from sculptured nails. Contact Derm 30, 118. Nail Manufactures Council (NMC). (2001) Update for Nail Technicians: Methyl Methacrylate Monomer. Scottsdale, AZ: Professional Beauty Association, www.probeauty.org/NMC Jefford J, Swain A. (2002) The Encyclopedia of Nails. London: Thompson Learning. Frangie C, Schoon D, et al. (2007) Milady’s Standard Nail Technology, 5th edn. New York: Thomson Delmar Learning. Schoon D. (2005) Trauma and damage. Nail Structure and Product Chemistry, 2nd edn. New York: Thomson Delmar Learning. United States Environmental Protection Agency (2007) Protecting the Health of Nail Salon Workers, Office of Pollution Prevention and Toxics. EPA no. 774-F-07-001. Nail Manufacturers Council (NMC). A series of safety related brochures for nail technicians. Scottsdale, AZ: Professional Beauty Association. www.probeauty.org/NMC.

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Part 3: Hair Cosmetics Chapter 29: Hair physiology and grooming Maria Hordinsky,1 Ana Paula Avancini Caramori,2 and Jeff C. Donovan3 1

Department of Dermatology, University of Minnesota, Minneapolis, MN, USA Department of Dermatology, Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, Brazil 3 Division of Dermatology, University of Toronto, Toronto, Canada 2

BAS I C CONCE P T S • The hair follicle is a complex structure that produces an equally complex structure, the hair fiber. • Human hair keratins consist of at least 19 acidic and basic proteins which are expressed in various compartments of the hair follicle. • The science behind modern shampoos and conditioners has led to the development of rationally designed products for normal, dry, or damaged hair.

Definitions The use of hair cosmetics is ubiquitous among men and women of all ages. Virgin hair is the healthiest and strongest but basic grooming and cosmetic manipulation cause hair to lose its cuticular scale, elasticity, and strength. Brushing, combing, and shampooing inflict damage on the hair shaft, much of which can be reversed with the use of hair conditioners. In this chapter, the physiology of hair, grooming techniques including the science and use of shampoos and conditioners, are reviewed.

Physiology Hair follicle The hair follicle is a complex structure that demonstrates the ability to completely regenerate itself – hair grows, falls out and then regrows. Plucked hairs can regrow. Important cells for the development of hair follicles include stem cells in the bulge region and dermal papilla cells [1]. Hair follicle stem cells are described as being present just below the entrance of the sebaceous duct into the hair follicle. The hair follicle’s complexity is further appreciated when examining the organization of follicles in the scalp and the complexity of

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its vascular complex and nerve innervation. Scalp hair follicles present in groups of one, two, three, or four follicular units (Figure 29.1). The hair follicle is defined histologically as consisting of several layers (Figure 29.2). It is the interaction of these layers that produces the hair fiber. The internal root sheath consists of a cuticle which interdigitates with the cuticle of the hair fiber, followed by Huxley’s layer, then Henle’s layer. Henle’s layer is the first to become keratinized, followed by the cuticle of the inner root sheath. The Huxley layer contains trichohyalin granules and serves as a substrate for citrulline-rich proteins in the hair follicle. The outer root sheath has specific keratin pairs, K5–K16, characteristic of basal keratinocytes and the K6–K16 pair characteristic of hyperproliferative keratinocytes, similar to what is seen in the epidermis. Keratin K19 has been located in the bulge region [2,3]. The complexity of the hair follicle is further demonstrated by the fact the follicle cycles from the actively growing phase (anagen), through a transition phase (catagen), and finally a loss phase (telogen). The signals associated with the transition from anagen, catagen to telogen are the subject of current research activities in this field.

Product of the hair follicle: the hair fiber The hair follicle generates a complex fiber which may be straight, curly, or somewhere in between. The main constituents of hair fibers are sulfur-rich proteins, lipids, water, melanin, and trace elements. The cross-section of a hair shaft has three major components, from the outside to the inside: the cuticle, the cortex and the medulla [4].

29. Hair physiology and grooming

(a)

(b)

Figure 29.1 (a) Horizontal section of a 4 mm scalp biopsy specimen demonstrating follicular units containing 1, 2, 3, or 5 anagen follicles. (b) Vertical section of a 4-mm scalp punch biopsy specimen from a normal, healthy Caucasian female in her early twenties.

Fibers can be characterized by color, shaft shape – straight, arched, or curly – as well as microscopic features. The cuticle can be defined by its shape – smooth, serrated, or damaged, and whether or not it is pigmented. The cortex can be described by its color and the medulla by its distribution in fibers. It can be absent, uniform, or randomly distributed. Lastly, fibers can be abnormal and present with structural hair abnormalities such as trichoschisis or trichorrhexis nodosa. Both of these structural abnormalities can commonly be seen in patients with hair fiber injury related to routine and daily cosmetic techniques including application of high heat, frequent perming as well as from weathering, the progressive degeneration from the root to the tip of the hair initially affecting the cuticle, then later the cortex [3]. The cuticle is also composed of keratin and consists of 6–8 layers of flattened overlapping cells resembling scales. The cuticle consists of two parts: endocuticle and exocuticle. The exocuticle lies closer to the external surface and comprises three parts: b-layer, a-layer, and epicuticle. The epicuticle is a hydrophobic lipid layer of 18-methyleicosanoic acid on the surface of the fiber, or the f-layer. The cuticle protects the underlying cortex and acts as a barrier and is considered to be responsible for the luster and the texture of hair. When damaged by frictional forces or chemicals and subsequent removal of the f-layer, the first hydrophobic defense, the hair fiber becomes much more fragile. The cortex is the major component of the hair shaft. It lies below the cuticle and contributes to the mechanical properties of the hair fiber, including strength and elasticity. The cortex consists of elongated shaped cortical cells rich in

keratin filaments as well as an amorphous matrix of sulfur proteins. Cysteine residues in adjacent keratin filaments form covalent disulfide bonds, which confer shape, stability, and resilience to the hair shaft. Other weaker bonds such as the van der Waals interactions, hydrogen bonds and coulombic interactions, known as salt links, have a minor role. These bonds can be easily broken just by wetting the hair. It is the presence of melanin in the cortex that gives hair color; otherwise, the fiber would not be pigmented [4]. The medulla appears as continuous, discontinuous, or absent under microscopic examination of human hair fibers. It is viewed as a framework of keratin supporting thin shells of amorphous material bonding air spaces of variable size [4]. Fibers with large medullas can be seen in samples obtained from porcupines or other animal species. Other than in gray hairs, human hairs show great variation in their medullas.

Human hair keratins Human hair keratins are complex and, until recently, research suggested that the hair keratin family consisted of 15 members, nine type I acidic and six type II basic keratins, which exhibited a particularly complex expression pattern in the hair-forming compartment of the follicle (Figure 29.2). However, recent genome analyses in two laboratories has led to the complete elucidation of human type I and II keratin gene domains as well as a completion of their complementary DNA sequences revealing an additional small hair keratin subcluster consisting of genes KRT40 and KRT39. The discovery of these novel genes brought the hair keratin family to a total of 17 members [3].

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CO CO

CU mod

mod

CU dp

dp K40

K35

K85

ORS

K31

K82

K38*

Matrix/cortex

Figure 29.2 Schematic presentation of the complex pattern of hair keratin expression in the human hair follicle. (Reprinted by permission from Macmillan Publishers Ltd, J Invest Dermatol 127, 1532–5, 2007.)

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*Zone of keratinization*

Ku Hu Ho

Suprabasal Basal

Cortex

Cuticle

IRS

K36 K33a K86 K33b K83 K37** K81

K32/K35

K38* (Ha8)

K34

Start of mRNA/protein synthesis

K81 (Hb1) K83 (Hb3) K86 (Hb6)

K37** (Ha7)

K33a (Ha3-I) K33b (Hb3-II) K36 (Ha6) K31 (Ha1)

K85 (Hb5)

1:1

K35 (Hb5)

K82 (Hb2) K85 (Hb5)

K35 (Ha5) K32 (Ha2)

1:2

Cuticle

Type II

K39

1:1#

2:1

Type I

Ho Hu Ku

Basal Suprabasal

K39 (Ka35)

K39 (Ka35) K40 (Ka36)

2:1

Zones of mRNA/protein synthesis

K34 (Ha4)

2:1

K32+K40 Hair fiber

h ORS

K40

IRS

K32+K39

Cuticle

K39

Cortex

K39

29. Hair physiology and grooming The human type II hair keratin subfamily consists of six individual members which are divided into two groups. Group A members hHb1, hHb3, and hHb6 are structurally related, while group C members hHb2, hHb4, and hHb5 are considered to be rather distinct. Both in situ hybridization and immunohistochemistry on anagen hair follicles have demonstrated that hHb5 and hHb2 are present in the early stages of hair differentiation in the matrix (hHb5) and cuticle (hHb5, hHb2), respectively. Cortical cells simultaneously express hHb1, hHb3, and hHb6 at an advanced stage of differentiation. In contrast, hHb4, has been undetectable in hair follicle extracts and sections, but has been identified as the most significant member of this subfamily in cytoskeletal extracts of dorsal tongue [3].

Grooming Shampoos: formulations and diversity Cleaning hair is viewed as a complex task because of the area that needs to be treated. The shampoo product has to also do two things – maintain scalp hygiene and beautify hair. A well-designed conditioning shampoo can provide shine to fibers and improve manageability, whereas a shampoo with high detergent properties can remove the outer cuticle and leave hair frizzy and dull.

Formulations Shampoos contain molecules with both lipophilic and hydrophilic sites. The lipophilic sites bind to sebum and oilsoluble dirt and the hydrophilic sites bind to water, permitting removal of the sebum with water rinses. There are four basic categories of shampoo detergents: anionics, cationics, amphoterics, and non-ionics (Table 29.1). A typical shampoo will typically have two detergents. Anionic detergents have a negatively charged hydrophilic polar group and are quite good at removing sebum; however, they tend to leave hair

Table 29.1 Four categories of shampoo detergents. 1. Anionics Lauryl sulfate Laureth sulfates Sarcosines Sulfosuccinates 2. Cationics

rough, dull, and subject to static electricity. In contrast, ampotheric detergents contain both an anionic and a cationic group allowing them to work as cationic detergents at low pH and as anionic detergents at high pH. Ampotheric detergents are commonly found in baby shampoos and in shampoos designed for hair that is fine or chemically treated [5]. The number of shampoo formulations on the market can be overwhelming but when the chemistry behind those marketed for “normal hair” or “dry hair” is understood, recommending the best product becomes easier (Table 29.2). Shampoos for “normal” hair typically have lauryl sulfate as the main detergent and provide good cleaning of the scalp. These are best utilized by those who do not have chemically treated hair. Shampoos designed for “dry hair” primarily provide mild cleansing but also excellent conditioning. An addition to shampoo categories has been the introduction of conditioning shampoos which both clean and condition. The detergents in these types of shampoos tend to be amphoterics and anionics of the sulfosuccinate type. These work well for those with chemically damaged hair and those who prefer to shampoo frequently. For individuals with significant sebum production, oily hair shampoos containing lauryl sulfate or sulfosuccinate detergents can work well but can by drying to the hair fiber. Hydrolyzed animal protein or dimethicone are added to conditioning shampoos, also commonly called 2-in-1 shampoos. These chemicals create a thin film on the hair shaft to increase manageability and even shine. For individuals with tightly kinked hair, conditioning shampoos with both cleaning and conditioning characteristics that are a variant of the 2-in-1 shampoo can be beneficial. These shampoos can be formulated with wheatgerm oil, steartrimonium hydrolyzed animal protein, lanolin derivatives, or dimethicone and are designed for use either weekly or every 2 weeks.

Conditioners Conditioners can be liquids, creams, pastes, or gels that function like sebum, making hair manageable and glossy appearing. Conditioners reduce static electricity between fibers following combing or brushing by depositing charged ions on the hair shaft and neutralizing the electrical charge. Another benefit from conditioners is improved hair shine

Table 29.2 Categories of shampoos are available for the following hair types.

3. Amphoterics Betaines such as cocamidopropyl betaine Sultaines Imidazolinium derivatives

Normal hair

4. Non-ionics

Tightly kinked hair

Dry hair Oily hair

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Table 29.3 Categories of hair conditioners. Category

Primary ingredient

Cationic detergent

Quaternary ammonium compounds

Film-former

Polymers

Protein-containing

Hydrolyzed proteins

Silicones

Dimethicone Cyclomethicone Amodimethicone

reduce static electricity and friction. Dimethicone is the most common form of silicone used.

Conclusions The hair follicle is recognized as being a complex structure consisting of at least 17 different keratins as well as lipids, water, melanin, and trace elements. The follicle produces an equally complicated structure, the hair fiber which may be straight, wavy, or curly. Hair is cited as a factor contributing to attractiveness and is frequently styled to convey cultural affiliations [4].

References which is related to hair shaft light reflection. Conditioners may also improve the quality of hair fibers by reapproximating the medulla and cortex in frayed fibers [5,6]. There are several hair conditioner product types including instant, deep, leave-in, and rinse. The instant conditioner aids with wet combing; the deep conditioner is applied for 20–30 minutes and works well for chemically damaged hair. A leave-in conditioner is typically applied to towel dried hair and facilitates combing. A rinse conditioner is one used following shampooing and also aids in disentangling hair fibers. There are at least four conditioner categories, summarized in Table 29.3. The quaternary conditioners are cationic detergents. The film-forming conditioners function by coating fibers with a thin polymer layer. Protein-containing conditioners contain small proteins with a molecular weight of 1000–10 000 Da. These penetrate the hair shaft and are thought to increase fiber strength temporarily. Silicone conditioners form a thin film on the hair shaft and, by doing so,

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1 Cotsarelis G, Millar SE. (2001) Towards a molecular understanding of hair loss and its treatment. Trends Mol Biol 293–301. 2 Langbein L, Rogers MA, Praetzel-Wunder S, Böckler D, Schirmacher P, Schweizer J. (2007) Novel type I hair keratins K39 and K40 are the last to be expressed in differentiation of the hair: completion of the human hair keratin catalog. J Invest Dermatol 127, 1532–5. 3 Langbein L, Rogers MA, Winter H, Praetzel S, Schweizer J. (2001) The catalog of human hair keratins. II. Expression of the six type II members in the hair follicle and the combined catalong of human type I and type II keratins. J Biol Chem 34, 35123–32. 4 Gray J. (2008) Human hair. In: McMichael A, Hordinsky M, eds. Hair and Scalp Diseases. New York: Informa Healthcare, pp. 1–17. 5 Draelos ZD. (2008) Nonmedicated grooming products and beauty treatments. In: McMichael A, Hordinsky M, eds. Hair and Scalp Diseases. New York: Informa Healthcare, pp. 59–72. 6 McMullen R, Jachowicz J. (2003) Optical properties of hair: effect of treatments on luster as quantified by image analysis. J Cosmet Sci 54, 335–51.

Chapter 30: Hair dyes Frauke Neuser1 and Harald Schlatter2 1 2

Procter & Gamble Technical Centres Ltd, Egham, Surrey, UK Procter & Gamble German Innovation Centre, Darmstadt, Germany

BAS I C CONCEPTS • Hair dyes are a cosmetic product category that can be traced back thousands of years. Modern hair dyes have been developed since the late 19th century and are now available in a broad range of products delivering a variety of color results and usage conditions. • Hair dyes constitute a large product category – over 70% of women in the developed world color their hair at least once, and many do so regularly. Psychologic aspects of color transformation should not be underestimated; especially dyeing gray hair can contribute significantly to the confidence and self-perceived attractiveness of many people. • Within the category, permanent or oxidative hair dyes represent the largest market share with around 80% of all products. A combination of hydrogen peroxide and an alkalizing agent (typically ammonia) form the basis to lighten the natural hair color while at the same time depositing oxidatively coupled dyes inside the hair shaft. • Disadvantages of using particularly permanent hair dyes regularly include a high maintenance routine, and changes to the hair structure which require special care and attention. • Because of the complex chemistry of hair dyes, safety and regulatory criteria are important aspects of modern hair dyes. Special emphasis needs to be put on proper safety and use instructions to further minimize a potential allergy risk.

Introduction Modern hair dyes offer a broad range of products and a variety of color results. They constitute a large category – over 70% of women in the developed world color their hair at least once, and many do so regularly. The number one reason for dyeing hair is to cover gray hair and look younger. Within the category, permanent or oxidative hair dyes represent the largest market share with around 80% of all products. A combination of hydrogen peroxide and an alkalizing agent (typically ammonia) form the basis to lighten the natural hair color while at the same time depositing wash-resistant color complexes inside the hair shaft. Because of the complex chemistry of hair dyes, safety and regulatory criteria are important aspects of modern hair dyes. Special emphasis needs to be put on proper safety and use instructions to further minimize a potential allergy risk.

thousands of years humans have attempted to enhance or change their natural hair color, initially with the help of natural preparations such as kohl and henna [1], nowadays with modern products which offer anything from subtle results to dramatic changes. Hair dyes can be defined as products that alter the color appearance of hair temporarily or permanently, by removing some of the existing color and/or adding new color. They constitute a significant category in the cosmetics market – it is estimated that over 70% of women in the developed world have used hair color, and a large proportion of those do so regularly [2]. Consumers have the choice between home hair dye kits, and having their hair dyed professionally at a salon. While each woman may have a very individual reason for coloring her hair, covering gray can be considered a universal key motivator. Other desired performance aspects include enhancing the existing color, wanting a different color from the one given by nature, or achieving a more striking looking appearance.

Definitions Product subtypes Natural hair color manifests itself in a vast multitude of shades and tones – from the lightest blonde and warmest brunette to the most vibrant red and deepest black. Yet, for

• Temporary hair dyes. • Semi-permanent hair dyes. • Permanent (oxidative) hair dyes. • Hair bleaching. A wide range of products for changing the color of hair is available to consumers. Today’s hair dyes can remove (lift)

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Table 30.1 Overview of hair dye product types. Hair dye product types

Dye technology

Level of lastingness

Temporary

Preformed FD&C and D&C dyes

Wash out (with one wash)

Semi-permanent

Preformed HC and disperse dyes

Wash out (with 6–8 washes)

Demi-permanent

Oxidative dyes, reduced peroxide concentration

Wash out (with up to 24 washes)

Permanent

Oxidative dyes

Permanent (grows out)

Bleaching

Oxidative bleaching, no dye deposition

Permanent (grows out)

D&C, dyes to be used in drugs and cosmetics; FD&C, dyes allowed to be used in food, drugs and cosmetics; HC, dyes to be used in hair colorants.

Figure 30.1 Hair cross-section showing color penetration after semi-permanent dyeing.

natural hair color, add (deposit) new artificial color, or indeed do both at the same time. They offer a variety of results, from a subtle color refresher to a significant change in the natural hair color, based on very different dye technologies. The classification of hair dyes is based on the permanency of the induced color change (Table 30.1). It should be noted that home and salon hair dyes are based on the same technologies, while there are key differences in shade and application variety.

Nitro-dyes are the most important group of dyes used in semi-permanent colorants [5]. These uncharged (non-ionic) dyes are barely influenced by negative charges on the surface of the hair. As a result, and because of their relatively small size, they are able to penetrate into the hair cuticle. Washing hair opens the cuticle, allowing color to escape over time because of the solubility of the dyes in water. The products contain a mixture of preformed dyes and are usually on the hair for approximately 20–30 minutes. Color results are limited (no lightening, blend away first grays).

Temporary dyes

Demi-permanent and permanent dyes

Temporary dyes or color rinses are usually formulated with high molecular weight acid or dispersed dyes, which have little affinity for hair and are quite soluble in the dye base. The dye is complexed with a cationic polymer to decrease solubility and increase affinity for hair, and the complex dispersed in the dye base by surfactants. The complex coats the hair and excess can be rinsed off [3]. The binding forces between hair substrate and dyes are low so color is easily washed out after the first shampoo. Each product contains a mixture of generally two to five color ingredients to achieve the desired shade [4]. Typical product forms include shampoos and sprays. While color results are very limited (no lightening, no grey coverage), temporary dyes may be a good option to test colors or refresh dyed hair.

Demi-permanent and permanent hair dyes involve oxidative chemistry, requiring different product components to be mixed just before they are applied. Oxidative dyes are the most frequently used and commercially most relevant hair dyes. Within this category we differentiate two product groups: permanent and demi-permanent dyes. The primary distinctions between those two are the type and level of alkalizing agent and the concentration of peroxide, which result in different color results with regard to lastingness, gray coverage, and lightening performance. Demi-permanent colors typically use 2% hydrogen peroxide (concentration on head) and low levels of alkalizer (usually monoethanolamine, not ammonia), leading to a less efficient dye penetration (ring dye effect; Figure 30.2). They wash out in up to 24 shampoos. While they can be used to enhance and brighten natural color and blend or cover up grays up to 50%, they have little or no lightening potential. Permanent colorants use up to 6% peroxide (concentration on head) and contain ammonia as alkalizer to bring the pH of the final product to 9.0–10.5. This allows complete penetration across the cortex (Figure 30.3). They are the

Semi-permanent dyes Semi-permanent hair dyes use a combination of preformed (direct) dyes to obtain results that last up to 6–8 shampoos. The dyes are generally characterized by their low molecular weight, allowing them to diffuse into the outer cuticle layers without binding firmly to the hair protein (Figure 30.1).

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30. Hair dyes reapplication is needed to prevent visible regrowth of the naturally darker hair.

Chemistry Natural hair pigmentation

Figure 30.2 Hair cross-section showing color penetration after demi-permanent dyeing.

Figure 30.3 Hair cross-section showing color penetration after permanent dyeing.

most versatile and long-lasting hair dyes and are also available in the widest spectrum of shades. Permanent dyes can lighten hair significantly, change color in subtle or dramatic ways, and provide 100% gray coverage, even on resistant grays. Reapplication is required every 4–6 weeks to avoid a noticeable regrowth at the root line.

Bleaches Hair bleaches are products that lighten hair without adding a new color. In addition to hydrogen peroxide and ammonia they contain persulfates to boost and accelerate the bleaching efficacy. Bleaching is the most efficient method of lightening natural and precolored hair. In the case of a partial bleaching, especially on very dark hair, the results can be an unwanted yellow to orange-colored shade. Bleaches can lift the natural hair color most significantly and are often used with special techniques to apply highlighting effects to hair. Just as with permanent dyes, regular

The natural coloration of hair is caused by the presence of melanin in the cortex of the hair shaft, which occurs in the form of minute pigment granules. All natural hair color shades are created by just two types of melanin: the more common brownish black eumelanin, and the less common reddish yellow pheomelanin. The final color of hair is determined by the amount of melanin it contains, by the size of the pigment granules, and by the ratio between the two melanin types [6]. Black hair contains eumelanin in high concentration, whereas we find less pigment overall – and higher ratios of pheomelanin – in blonde and red hair. Despite clear differences in molecular size and general properties, the two melanin types are biogenetically related and develop from a common metabolic pathway involving dopaquinone as a key intermediate [7]. The pigments are present as oval or spherical granules, generally in the range 0.2–0.8 μm in length, and constitute less than 3% of the total hair mass [4]. Production of the pigment particles is located in specialized cells, the melanocytes, deep within the hair follicle. Melanocytes are hidden in the dermal papilla of the hair bulb where they secrete tiny packages called melanosomes into the surrounding keratinocytes. Natural hair color changes are often observed over the years from birth to old age. Many fair-haired children gradually become darker and by middle age have brown hair. Graying hair affects all to a greater or lesser extent as part of the aging process. It seems to appear earlier in dark- than in light-haired people, and is less common in black people. Graying of the hair is usually a gradual process and irreversible. The reason for going gray is not the production of a new “gray” pigment, but the visual result of a mixture of dark and non-pigmented, colorless hair. Due to the dispersion of light, hair which no longer contains any melanin appears to be white. The precise causes of graying hair are still under discussion. Hereditary factors seem to be predominant, meaning that genes regulate the exhaustion of the pigmentary potential of each individual hair follicle leading to reduced melanogenic activity with age. Recent research specifically traced the loss of hair color to the gradual dying off of melanocyte stem cells. Not only do they become exhausted with age, they also progressively make errors, turning into fully committed pigment cells in the wrong place within the hair follicle, where they are ineffective for providing color to hair [8]. For products designed to change the natural color of hair it is important to consider that the melanin granules are

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distributed throughout the cortex of the hair shaft, showing the greatest concentration towards the outer edge (Figure 30.4). As a general rule, the cuticle layer of hair carries no natural pigments and is therefore transparent. It is therefore imperative for any effective hair dye product to penetrate past the cuticle layer into the cortex of the hair fiber.

Permanent hair dyes There are two chemical processes that take place during the permanent dyeing process, both of which contribute to the final color. The first is the oxidation of the melanin pigments and previously deposited dyes that lightens the underlying color. The second is the oxidation of the dye precursors to form color giving chromophores [9].

Melanin bleaching Permanent hair dyes and hair bleach products have the capability to lighten the natural color of hair by removing some of the existing pigment. The melanin granules are partly dissolved and broken down. During a complete bleaching procedure the melanin granules are dissolved completely, leaving behind a tiny hole in the cortex of the hair. The process can be described as oxidative degradation of the melanins, leading to a variety of smaller degradation products. The reaction is diffusion-controlled and therefore time dependent [4]. It has been reported that pheomelanins is more resistant to photobleaching, and probably also chemical bleaching, than eumelanins [10].

Oxidative dye formation Permanent hair dyes are based on the oxidation by hydrogen peroxide of so-called dye precursors or primary intermediates which typically belong to the chemical groups of p-diamines and p-aminophenols, in the presence of various couplers (for examples see Figure 30.5). To start the process, the highly alkaline pH of the dye formulations swells the hair fiber and allows the small active molecules to penetrate into the cortex where the dye formation takes place in three

Figure 30.4 Longitudinal section of hair fiber showing melanin distribution across the cortex.

NH2

p-Phenylenediamine

NH2

p-Toluenediamine

230

OH m-Aminophenol

p-Aminophenol

Resorcinol

1-Naphthol

Figure 30.5 Some typical oxidative dye precursors (top) and couplers (bottom).

30. Hair dyes NH

NH2

NH2 NH

NH + H2N

H2N

NH2

Figure 30.6 The three main steps in oxidative dye formation (here with p-phenylenediamine and m-phenylenediamine).

H2N

Table 30.2 Variety in color results given by different couplers in the presence of p-diamines and p-aminophenols. Coupler

Color on hair with p-diamines

Color on hair with p-aminophenols

m-Phenylenediamine

Bluish brown–black

Reddish brown

1-Napthol

Blue–violet

Red

Resorcinol

Greenish brown

Light brown

3-Aminophenol

Warm brown/magenta

Red–brown

o-Aminophenol

Warm brown

main steps. The first step of the dye formation process is the oxidation of the primary intermediates to highly active imines, which are capable of reacting with their unoxidized counterparts to form polynuclear brown or black colored complexes. In the presence of couplers or color modifiers the imines then react preferentially with the coupler molecules at the most nucleophilic carbon atom on the structure. In step 3 this coupled reaction product is oxidized to form wash-resistant indo dyes (for an overview of the dye formation process see Figure 30.6). Couplers do not themselves produce color but modify the color produced by the oxidation of the primary intermediates (Table 30.2). The final color is a function of the amounts and nature of the individual primary intermediates and couplers in the composition and consists of a variety of large color molecules. Their size makes them particularly resistant to removal by washing the hair, and means they undergo little fading [5].

NH NH2

NH2

H2N

Formulation All permanent hair dyes are generally marketed as two component kits. One component (tint) contains the dye precursors and an alkalizer (typically ammonia or monoethanolamine) in a surfactant base, and the other is a stabilized solution of hydrogen peroxide (developer). The two components are mixed immediately prior to use and then applied to the hair. With the developer component being a liquid, the tint is usually a cream or a liquid. Which one to use is mainly a matter of individual preference, the liquids might be easier to mix while the creams might be applied with less dripping. Table 30.3 summarizes common hair dye components and their functions, while also naming some specific examples as they would appear in the ingredients list of a marketed product.

Advantages and disadvantages If all goes well, coloring hair can be life-transforming but there are a couple of considerations when it comes to weighing advantages and disadvantages of this category.

Advantages The key strength of the hair dye category lies in its transformational potential. Changing one’s hair color can have a dramatic physical effect but, more importantly, it can also have an impact on a psychologic level. Patients may not only feel more attractive and younger looking, they also report increased confidence both in their private and work environments which should not be discounted or belittled [2].

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Table 30.3 Overview of common hair dye ingredients. Component

Function

Sample ingredients

Peroxide

Oxidant, bleaching

Hydrogen peroxide

Alkalizer

Swell hair, bleaching

Ammonia, monoethanolamine (MEA), aminomethylpropanol (AMP)

Dye precursors

Impart color

p-Aminophenol, 1-naphtol, p-phenylenediamine, 4-amino-2-hydroxytoluene

Solvent

Dye vehicle

Water, propylene glycol, ethanol, glycerin

Surfactant

Foaming, thickening

Sodium lauryl sulfate, ceteareth-25, cocoamide MEA, oleth-5

Buffer

Stabilizing

Disodium phosphate, citric acid

Fatty alcohols

Emollients

Glyceryl stearate, cetearyl alcohol

Quaternary compounds

Conditioning

Polyquaternium, cetrimonium chloride

In our youth-obsessed society coloring gray hair can be seen as a simple yet powerful tool in the arsenal of “antiaging” procedures and products. Another advantage of modern hair dyes is the variety of technologies and benefits that it offers. Virtually everyone can find a product that suits them and their personal requirements, and the range of offered shades is ever-expanding.

as poor shine, poor feel, and reduced strength [11]. It should be noted that these problems mostly occur with frequent use and that they can be reduced with the right application techniques. We return to this in more detail in the section “Physiological changes to hair during coloring”.

Product application Disadvantages Most hair dyes (with the exception of pure bleaching products) have the potential to cause allergic reactions, even if only a small fraction of the population is affected (see section on ‘Safety and regulatory considerations’ for more detail). All oxidative hair dyes, including demi-permanent, permanent, and bleaching products, contain ingredients such as hydrogen peroxide and ammonia, which may cause irritation. It is imperative that usage instructions are followed carefully, and that all products are kept well out of the reach of children. It should also be mentioned that permanent hair dyes require a certain amount of upkeep and maintenance from the user. Visible root regrowth, especially if the natural color has been significantly changed, necessitates the regular reapplication of product. This is one of the main reasons why a large group of consumers who color their hair choose to do so themselves, at home, rather than visiting a professional hairdresser every single time they feel the need to recolor. Lastly, one drawback of hair dyes, again mainly relevant to oxidative products, lies in the fact that hydrogen peroxide at alkaline pH conditions can alter the hair structure, leading to undesirable sensorial attributes described by consumers

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The most important step in hair dyeing is the right choice of product, including both the type of hair dye and the color shade. Individuals with no previous experience in dyeing their hair who want to blend away some first grays, or a subtle enhancement of their natural color, are perhaps best advised to choose a semi-permanent colorant. If the person has a higher percentage of gray (up to 30%) and wants to stay close to their natural hair color, a demi-permanent product could be the best solution. Covering larger percentages of gray and/or achieving significant changes in the natural hair color will require the application of a permanent hair dye product. Once the right type of hair dye has been identified, it is all about finding the right shade. The final color result is a combination of the existing hair color and the shade produced by the colorant – shade guides on the packaging are usually very helpful in exploring which result should be expected based on those two parameters. For home hair dyes a useful guideline is to stay within two shades of one’s natural color, and if in doubt chose a lighter over a darker shade. To be sure about the outcome of the coloring process, which will also be affected by the condition of the hair and

30. Hair dyes previous treatments, a strand test can be helpful. For this test a small strand of hair (0.25 inch) is cut from the darkest or grayest part of the head and covered with the product for the advised time. Checking after different time points allows finding the optimum processing time to accomplish the desired end result. Another check that should always be completed before coloring hair is a skin sensitivity test. The test should be carried out 48 hours prior to product use and involves applying a small amount of the product to the skin (typically recommended is the inside of the elbow). If a rash or redness, burning, or itching occurs the patient may be allergic to certain product ingredients and must not use the tested product. Lastly, it is very important, especially for first time colorers, to read the (admittedly often lengthy) product usage directions carefully. Oxidative colorants require the mixing of several components before application and each product might be slightly different in terms of how it should be mixed and used. It is therefore imperative for a successful coloring experience to follow the recommended procedure step by step.

to oxidative degradation products. The resulting physicochemical changes of the hair surface are irreversible and can lead to hair that feels coarse, is more difficult to comb, lacks shine, and is weakened [11,13]. Importantly, hair that has been treated and thus changed by oxidative treatments is more prone to physical and environmental stress and subsequent damage [14].

Recent formulation strategies to minimize fiber damage While the above described hair fiber changes can be mainly attributed to hydrogen peroxide itself, it is also well known that hydrogen peroxide at high pH is likely to form reactive radical species which have been shown to be an additional source of fiber damage. The reaction is catalyzed by the presence of redox metal ions such as copper and iron which are prevalent in tap water. It has been reported that the addition of metal chelating agents to oxidative colorants can reduce the surface damage caused in the presence of copper in tap water [15]. Key is to find a chelant that selectively binds to transition metal ions such as copper in the presence of high concentration of water hardness ions, especially calcium. N,N′-ethylenediamine disuccinic acid (EDDS) has been found to fulfill this requirement [15].

Impact of hair dyes on hair structure Caring for colored hair Oxidative coloring and bleaching have been shown to cause several changes to the hair structure, especially with frequent use (Figure 30.7). Alkaline peroxide partially removes the outer hydrophobic surface barrier of hair, called the f-layer, made of 18-methyl eicosanoic acid. This layer can be considered a natural protection or conditioning system of hair and its destruction leads to significant changes in how hair feels and behaves [12]. At the protein level, peroxide at alkaline pH conditions attacks certain amino acids which are part of the hair fiber structure, especially cystine, leading

Based on the described changes to the hair surface structure, it is important that consumers take the right steps to care for their hair after coloring. This will help in keeping the color vibrant for as long as possible, and in protecting the already weakened hair from further damage from daily wear and tear. The first step in treating colored hair correctly is to use the most appropriate application technique when recoloring. Covering visible regrowth only requires the hair dye to be used on the hair sections affected – the hair roots. This

(a)

(b) Figure 30.7 Change in surface hydrophobicity before (a) and after (b) bleaching.

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will protect the bulk of the hair from unnecessary exposure and overprocessing. The basis for a suitable hair care routine after dyeing should be the use of a shampoo and conditioner specifically developed for colored hair. They contain ingredients that are tailored to the altered hydrophilic surface conditions of the hair and help to smoothen the cuticle surface, protecting it against mechanical damage. Secondly, sun exposure should be minimized because UV radiation not only contributes to hair damage but also has a direct impact on color fading. Lastly, it should be pointed out that water exposure is the biggest contributor to color fading (also called wash fading). It can therefore be beneficial not to wash freshly colored hair too frequently.

Safety and regulatory considerations As part of cosmetics, hair dyes are thoroughly safety regulated by global regulatory authorities such as the US Food and Drug Administration (FDA) or EU Cosmetic Directive, and their scientific advisory board, the Scientific Committee on Consumer Safety (SCCS, formerly SCCP, SCCNFP) [16,17]. Hair dyes are one of the most thoroughly studied cosmetics and consumer products and there is an overwhelming amount of safety data on hair dyes [18]. Despite the extensive safety testing and close safety regulation regimen, two safety concerns are typically associated with hair dyes: skin allergy and allegations regarding a slightly increased cancer risk.

Allergy Like other products such as certain foods or drugs, hair dyes can cause allergic reactions in a few individuals. Allergic reactions to hair dyes are well known but still relatively rare when compared to the daily global use of millions of hair colorants. The majority of allergic reactions to hair dyes are classified as delayed hypersensitivity or type IV reactions. Type IV reactions are normally localized to the area where the product is applied. Only in very rare exceptional cases more severe and spreading symptoms like facial oedema can occur. Type IV reactions are triggered by a different immuneresponse mechanism than the systemic type I allergies, which are more typically reactions to food or drugs and in severe cases may be life-threatening. Type IV reactions typically are not life-threatening. Key hair dye ingredients such as para-phenylenediamine (pPD), but also para-toluenediamine (pTD), are known skin sensitizers. pPD is part of the standard patch test series in certain countries; pTD is part of the hairdresser patch test series [19]. Used for many decades as key hair dyes, no superior technology emerged to date, despite intensive research efforts.

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Among consumers and clients, allergy incidence against pPD has been more or less stable over the past years [20]. While a few authors have concluded that pPD allergy incidence among patch-tested individuals has slightly increased over the years [21], most authors conclude that pPD allergy incidence is stable or even slightly decreasing [22–24]. Nonetheless, hair dye allergy remains an issue for a small number of consumers and therefore following safety measures can help to minimize the allergy risk [25]: • Consumers should read and follow the usage instructions of hair colorants carefully. All concerned hair dyes carry clear allergy warning labels, making aware of the potential allergy risk. • For permanent and most semi-permanent hair colorants, consumers are advised to conduct a product tolerance test (also called skin sensitivity or consumer self test) with the shade of interest 48 hours before each hair coloring, by following the recommendations of each product. However, the absence of a reaction at the test site is no guarantee that a reaction will not occur during hair coloring. In case of a skin reaction at the test site, consumers should not color their hair and seek dermatologic advice. When consumers experience initial signs of an adverse reaction at the scalp during the hair coloring session, the hair dye should be rinsed off immediately. • Temporary black henna tattoos are an important contributor to pPD allergy in humans [26,27]. Consumers may develop an allergy to hair dyes over time as a result of other products than hair dyes. This emphasizes the importance of conducting a skin sensitivity test. • Professional hairdressers should follow key occupational safety measures, such as wearing protective gloves during preparation, application, and rinsing of hair colorants [28]. • In the case of consumers who are positively patch-tested against a specific hair dye ingredient, special caution should be applied to using a hair dye lacking the respective allergen. Some hair dyes are known to cross-react (e.g. pPD and pTD). Overall, it should be emphasized that vast majority of consumers can safely use hair colorants and that following the use instructions plus the above guidance can help to minimize the allergy risk for the small number of individuals who may be allergic to hair dyes.

Cancer Cancer concerns were raised early in the context of oxidative hair dyes, because of their chemical nature. Numerous epidemiologic studies into hair dye safety have been conducted, the vast majority concluding that there is no association of hair dye use and an increased cancer risk. Occasional, single epidemiologic studies reporting a slightly increased risk for certain cancer types have not been confirmed by multiple epidemiologic studies. Early 2008, leading cancer experts of the International Agency of Cancer Research

30. Hair dyes (IARC, a subsidiary of the WHO) reviewed all relevant studies and scientific papers published to date and concluded that there is no evidence that personal hair dye use is associated with any increased cancer risk [29]. The US Cosmetic Ingredient Review (CIR) panel came to the same conclusion.

Conclusions Modern hair dyes are an effective tool in altering the natural color of hair. Different product types offer a wide range of results, from subtly enhancing color to dramatic color changes and complete gray coverage. While the potentially huge beneficial effect on peoples’ perceived attractiveness is undisputed, a thorough understanding of the different available technologies and their benefits and drawbacks is essential to advise consumers on the most suitable products to use. The main future challenge in hair color lies in preventing or even reversing hair graying via stimulating melanocyte activity at the molecular or even genetic level. The recently reported modulation of hair follicle melanocyte behavior with corticotropin-releasing hormone peptides could be a first step into an exciting new world of changing hair color [30].

References 1 Zviak C. (1986) The Science of Hair Care. New York: Marcel Dekker. 2 Gray J. (2005) The World of Hair Colour. London: Thomson. 3 Brown K. (2000) Hair coloring products. In: Schlossman M, ed. The Chemistry and Manufacture of Cosmetics, Vol. II Formulating. Carol Stream, IL: Allured Publishing, pp. 397–454. 4 Robbins CR. (2002) Chemical and Physical Behavior of Human Hair. New York: Springer. 5 Corbett JF. (1998) Hair Colorants: Chemistry and Toxicology. Cosmetic Science Monographs. Weymouth, UK: Micelle Press. 6 Schwan-Jonczyk A. (1999) Hair Structure. Darmstadt, Germany: Wella AG. 7 Prota G, Ortonne JP (1993) Hair melanins and hair color: Ultrastructural and biochemical aspects. J Invest Dermatol 101, 82S–9S. 8 Nishimura EK, Granter SR, Fisher DE. (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307, 720–4. 9 Brown KC, Pohl S, Kezer AE, Cohen D. (1985) Oxidative dyeing of keratin fibers. J Soc Cosmet Chem 36, 31–7. 10 Wolfram LJ, Albrecht L. (1987) Chemical and photobleaching of brown and red hair. J Soc Cosmet Chem 38, 179–91. 11 Jachowicz J. (1987) Hair damage and attempts to its repair. J Soc Cosmet Chem 38, 236–86. 12 Lodge RA, Bhushan B. (2006) Wetting properties of human hair by means of dynamic contact angle measurement. J Appl Polym Sci 102, 5255–65.

13 Wortmann FJ, Schwan-Jonczyk A. (2006) Investigating hair properties relevant for hair “handle”. Part I: hair diameter, bending and frictional properties. Int J Cosmet Sci 28, 61–8. 14 Takada K, Nakamura A, Matsua N, Inoue A, Someya K, Shimogaki H. (2003) Influence of oxidative and/or reductive treatment on human hair (I): Analysis of hair damage after oxidative and/or reductive treatment. J Oleo Sci 52, 541–8. 15 Marsh JM, Flood J, Damaschko D, Ramji N. (2007) Hair coloring systems delivering color with reduced fiber damage. J Cosmet Sci 58, 495–503. 16 European Union Cosmetic Directive (76/768/EEC): http://ec. europa.eu/enterprise/cosmetics/html/consolidated_dir.htm. 17 SCCP/1005/06 Notes of guidance for testing of cosmetic ingredients for their safety evaluation, 6th revision, adopted by the SCCNFP during the plenary meeting of December 19, 2006. 18 Nohynek GJ, Fautz R, Benech-Kieffer F, Toutain H. (2004) Toxicity and human health risk of hair dyes. Food Chem Toxicol 4, 517–43. 19 Diepgen TL, Coenraads PJ, Wilkinson M, Basketter DA, Lepoittevin JP. (2005) Para-phenylendiamine (PPD) 1% pet. is an important allergen in the standard series. Contact Dermatitis 53, 185. 20 Gerberick GF, Ryan CA. (2005) Hair dyes and skin allergy. In: Tobin DJ, ed. Hair in Toxicology: An Important Biomonitor. London: CRC Press, pp. 212–28. 21 McFadden JP, White IR, Frosch PJ, Sosted H, Johansen JD, Menne T. (2007) Allergy to hair dye. Br Med J 334, 220. 22 Uter W, Lessmann H, Geier J, Schnuch A. (2003) Contact allergy to ingredients of hair cosmetics in female hairdressers and clients: an 8-year analysis of IVDK data. Contact Dermatitis 49, 236–40. 23 DeLeo VA. (2006) p-Phenylenediamine. Dermatitis 17, 53–5. 24 Wetter DA, Davis MDP, Yiannias JA, et al. (2005) Patch test results from the Mayo Clinic Contact Dermatitis Group, 1998– 2000. J Am Acad Dermatol 53, 416–21. 25 Schlatter H, Long T, Gray J. (2007) An overview of hair dye safety. J Cosmet Dermatol 6, 32–6. 26 Onder M. (2003) Temporary holiday “tattoos” may cause lifelong allergic contact dermatitis when henna is mixed with PPD. J Cosmet Dermatol 2, 126–30. 27 Nawaf AM, Joshi A, Nour-Eldin O. (2003) Acute allergic contact dermatitis due to para-phenylenediamine after temporary henna painting. J Dermatol 30, 797–800. 28 Dickel H, Kuss O, Schmidt A, Diepgen TL. (2002) Impact of preventive strategies on trend of occupational skin disease in hairdressers: population based register study. Br Med J 324, 1422–3. 29 Baan R, Straif K, Grosse Y, Secretan B, Ghissassi FE, Bouvard V, et al. (on behalf of International Agency for Research on Cancer, IARC). (2008) Carcinogenicity of some aromatic amines, organic dyes and related exposures. Lancet Oncol 9, 322–3. 30 Kauser S, Slominski A, Wei ET, Tobin DJ. (2006) Modulation of the human hair follicle pigmentary unit by corticotropinreleasing hormone and urocortin peptides. FASEB J 20, 882–95.

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Chapter 31: Permanent hair waving Annette Schwan-Jonczyk and Gerhard Sendelbach Wella/Procter & Gamble Service GmbH, Darmstadt, Germany

BAS I C CONCE P T S • Permanent hair waving is a two-step chemical treatment modifying hair protein to achieve and retain a curly shape. • The chemical treatment involves a thioglycolate reduction reaction that plasticizes hair while being wound on a rod. The following oxidation step with hydrogen peroxide reforms the hair in a new curly shape. • Curl retention depends on hair thickness, rod diameter, and hair quality. • Undesirable hair damage can occur with the wrong choice of perm and neutralizer, too much heat, incorrect processing time, or improper perm solution amount.

Introduction Since ancient cultures curly hair represented femininity and beauty. Women with straight hair purchased expensive wigs or spent hours for hair ondulation with water and heat, which was temporary. A ground breaking invention occurred in 1906 when Carl Nessler offered irreversible hair shaping to clients by means of heat and borax. Improvements followed during the 20th century by creation of “cold waves,” using sulfite or thioglycolate as actives, which still are the most popular waving agents in home and salon perms.

Hair physiology Hairs are composed of cells packed in tight cell bundles that grow out from up to 3 mm skin depth. About 5 million hairs cover the human body and scalp classified as vellus hairs (5–10 μm in diameter) or terminal hairs (5–120 μm in diameter). The human head contains 100 000–150 000 fibers, which grow 1 cm per month through rapid cell division in the living, lowest part of their hair follicle, known as the hair bulb. The hair surface contains flattened cells, known as the cuticle, which forms an imbricated structure resembling shingles on a roof. The cuticle provides protection and support for the inner spindle-shaped “cortical cells,” which makeup 80% of the hair mass. During hair growth, the interdigitated cells are organized into a three-dimensional

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network resembling a jigsaw puzzle. This construction contributes to cell cohesion and hair fiber strength (Figure 31.1). While all hair fibers contain a cuticle, only thicker hair fibers with a diameter greater than 75 μm contain a central line of hollow cells, known as the medulla (Figure 31.2). The medulla functions in animal hair to provide enhanced thermal insulation. The active growth period of scalp hair is known as the anagen phase and is limited to 3–6 years. Then the hair disconnects from the papilla, a period known as the catagen phase, and enters a 2-month resting phase, known as the telogen phase, and subsequently sheds. Hair shedding and renewal results in an average loss of up to 100–125 scalp hairs per day. With constant hair growth and no cutting, bulk hair may reach up to 1 m in length (for more hair growth details, the reader is referred to more detailed references [1,2]).

Permanent wave hair relevant properties Hair geometry Usually, scalp hair is visualized as a circular fiber but crosssections of individual hairs reveal variation in hair shape. The typical appearance of a person’s hair is determined by its special mixture of thick, thin, elliptical, kidney-shaped, and triangular cross-sectional shapes [3]. Unmanageable hair is often because of a high percentage of irregular hair shapes. Irregular hair geometry, small diameter, and large hair diameter all create permanent waving challenges. Hair thickness has a large influence on the shape and hold of permanent wave curls [4]. Naturally curly hair [5] can also be challenging as it is sometimes desirable to use a permanent for straightening purposes.

31. Permanent hair waving

4 3

2 2 1

1 (a)

(b)

Figure 31.1 (a) The fracture plane of a hair fiber clearly shows the composite of a fibrillar core with flattened cuticle cell coating (SEM ×1420). (b) Just emerging hair: 1, scalp surface; 2, cuticle pattern of hair fiber surface; 3, interior of the hair with cortical cells; 4, medullary cells; 5, cell membrane.

step in the curling process. Under certain climatic conditions, hair adsorbs atmospheric water up to 30% of its weight. Although feeling dry at ambient temperature, hair still contains 15% water. Excess water can be bound by capillary forces. The hair water content dictates its chemical reactivity because water widens the hydrogen-bond network of protein side chains and acts as the vehicle for all permanent waving ingredients. Proper water balance is important for a successful permanent waving. Moreover, water functions as the plasticizer for hair; permed hair loses curls more rapidly after washing or exposing it to humid conditions, which can be measured by a curl retention test [7]. In presence of water, hair displays its amphoteric character. A hair “isoionic point” exists where the positive and negative charges of hair proteins are at equilibrium. The natural “intrinsic point of neutrality” of hair is pH 6, slightly more acidic than water at pH 7. This is the point of greatest stability. This intrinsic point of neutrality must be restored after permanent waving to maintain the structural integrity of the hair. Closely related to hair fiber water hydrophilicity is its thermal behavior. Dry hair can withstand a temperature of 240 °C for a short time but wet hair suffers damage at 140 °C. Figure 31.2 The intact cuticle pattern of the hair fiber near the scalp (SEM ×800).

Hair and water interaction Although hair is not soluble in water, its interaction with water is of particular importance [2,6]. Hair surface is hydrophobic and water repellent. Permanent waving lotions contain surfactants for enhanced wetting, which is the first

Hair aging Hair fibers undergo aging when exposed to grooming trauma and the environment [2,6,8]. The hair emerges in a virgin state but suffers heat damage during blow-drying, physical trauma from daily brushing with constant stretching, and photodamage. Oxygen radicals further cause chemical oxidation of the hair surface. The final effect is chemical and mechanical wear of the hair. Hair proteins are cleaved, amino acids are converted,

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cystine is oxidized to cysteic acid, and histidine is decomposed. As a consequence, stability and elasticity of hair ends decrease, flexibility is reduced, and hair fibers get more rigid and brittle, a process termed “weathering” of hair. Unsightly split ends occur and the hair feels dry (Figure 31.3). The structural differences between hair roots and hair ends require special attention in hair permanent waving because hair ends react faster and break more easily.

Hair chemical structure The protein content of a normal hair at ambient conditions is approximately 80 wt% [2,9]. Further components are approximately 5 wt% internal lipids; <1 wt% trace elements and metals; 14 wt% water. Of the 22 amino acid types found in hair, the most important is “L-cystine” (56-89-3), a sulfur-containing amino acid (Figure 31.5), which facilitates covalent cross-linking between two different protein chains. Up to the high amount of 9 mol% (750 μmol/g hair) [10] is typical for cornified tissues, such as hair, nail, hooves, horn, or cornea. Covalently cross-linked by this interproteinacous amino acid, hair demonstrates high mechanical strength and shear resistance, insolubility in water, but is prone to swelling.

Two types of proteins constitute the hair content: low and high sulfurous proteins. It is their typical arrangement that differentiates hair proteins from proteins in the rest of the body: • About 50% of the proteins are present in an unorganized, amorphous form, called matrix proteins, with frequent disulfide bridges. • The rest coil up to form a helical configuration in certain sections, constitute microfibrils, which are embedded in and anchored to the matrix proteins. Figure 31.4 shows the network of hair proteins, with the “disulfide bonds” marked in yellow, which gives hair properties similar to a fiber-reinforced plastic [11] or the elastic rubber of a tire. This special architecture is the source of hair’s elasticity. Perming agents cleave disulfide bonds in these matrix proteins, causing the plastification or softening that is necessary for shaping hair.

Figure 31.4 Coiled (alfa-helical) and amorphous molecules of hair proteins are cross-linked by disulfide bonds inside the cortical cells. Helical proteins are stabilized by hydrogen bonds.

H2N Figure 31.3 The worn cuticle-free split end of hair (SEM ×800).

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NH2

Figure 31.5 Chemical formula of the amino acid “cystine”.

31. Permanent hair waving However, an excess of a reducing agent is necessary, as cross-linked sulfur proteins in the cuticle make the hair mantle hard to dissolve and penetrate. Additional support of the chemical network is provided by the acid and basic amino acids in hair protein. As these make up more than 40%, low energy bridges, salt linkages, and hydrogen bonds are formed, which are also cleaved and reformed in the perming process.

Chemophysical principles of hair waving Because of hair’s great elasticity and strong resilient forces, it quickly resumes its original straight shape. Therefore it has to be softened and subsequently rehardened chemically to maintain a conformation change. Especially with permanent waving, it is important to select a reversible reaction to allow repeated treatments without hair destruction. The sulfur bridges of the amino acid cystine, linking the proteins, are best suited [6,12,13]. The conditions for permanent waving to be well tolerated are: • Low temperature (20–50 °C), convection or contact heat; • Short process time (5–30 minutes); and • Mildness to the skin.

A permanent wave occurs with two solutions: 1 Solution 1: the perming lotion, which contains a reducing agent, a “thiol” compound, designed to split off about 20– 40% of hair cystine bonds. 2 Solution 2: a fixing lotion, which contains an oxidizing agent, usually hydrogen peroxide, designed to rebuild cystine bridges between proteins at new sites in the curled hair shape (Figure 31.6). It must be emphasized that permanent waving is a twostep procedure where the chemical reaction and physical effects run in parallel (Figures 31.7 and 31.8) [14–16]: reduction of disulfide-bonds, softening of hair, lateral swelling and length contraction, stress development and protein flow, then reoxidation of cystin bonds and deswelling, fixation of a new curly shape. Table 31.1 summarizes how hair reacts chemically and physically during each of the permanent waving steps. Usually only 85% of the cleaved disulfide is reformed during neutralization. Some hair cysteine oxidizes to give cysteic acid (Figure 31.6, formula 2), which renders hair more hydrophilic, incompletely cross-linked, and more vulnerable to subsequent treatments. Therefore, permed hair gradually loses its curl and relaxes to a straight hair conformation again (for additional details, the reader is referred to Robbins [2] and Wickett and Savaides [17]).

Step 0: Activation R-SH

OH–

Thioglycolic acid

Alkali

RS–

Thiolate

H2O

Water

Step 1: Reduction Hair–SS–Keratin

2 RS–

2 Hair–S–

Thioglycolate

Reduced hair

R–SS–R

Dithio-diglycolic acid

Step 2: Oxidation 2 Hair–SH Reduced hair

H2O2

Hair–SS–Keratin

Hydrogen

Re-oxidized hair

2 H2O Water

peroxide Hair–SO3H Cysteic acid Figure 31.6 Chemical reaction formulas 0–2.

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(a)

(b)

(c)

Figure 31.7 (a) Sulfur bridges between the proteins are closed. (b) Part of the sulfur bridges are being cleaved, proteins shift, take on the form. (c) Sulfur bridges are being rebuilt at a different site, neutralizer fixes the new shape.

(a)

(b)

(c)

Figure 31.8 (a) Shampooed hair is wound on curlers while still moist. Bending strain is applied to the protein chains. (b) Perm-wave lotion 1 is applied to the hair and cleaves part of the sulfur bridges by the reducing (thioglycolic acid) and the alkalizing agent. Hair is softened, proteins creep and adjust to the shape of the curler. (c) Neutralizing process: an acid neutralizer (peroxide) rebuilds the sulfur bridges at different sites and the new shape is permanent.

Perm products and types Permanent waving products contain an elaborate mixture of ingredients to make the reactions controllable and appropriate for different hair types, such as normal hair (N-type), sensitive hair (S-type), coarse/difficult hair (F-type), and colored/bleached hair (C- or G-type). Typical formulations for a one-component perm lotion and a fixing lotion are shown in Table 31.2. Each ingredient is listed by its International Nomenclature of Chemical Ingredients (INCI) name as is on the package; each ingredi-

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ent has its own distinct role in making the solution active, pleasant to the hair, and odor free (for different formulations see [18,19]).

Role of permanent waving product ingredients This section reviews the individual ingredients important in achieving a successful permanent waving solution [20].

Reducing agents Reducing agents, most commonly ammonia or sodium salts of thioglycolic acid (TGA), have been used since the late 1950s to avoid skin and hair irritation while producing a

31. Permanent hair waving

Table 31.1 The usual steps of perming. Steps in practical perming

Hair reacts chemically/physically

1. Ask and consult the client concerning the desired hairstyle (curly head or gentle waves)

–

2. Assess the hair quality regarding the hair thickness, hair and scalp health, split ends

–

3. Shampoo the hair with a mild shampoo to remove fat and residual cosmetics

Water swells hair by 15% in diameter, about 2% in length and softens it at the same time

4. Apply a conditioning pre-product, aqueous or oily

Hair surface, root to tip differences in hair structure are equalized, lowers chemical reactivity of hair tips

5. Divide hair into sections with comb to get flat and small hair tresses

–

6. Take/use endpapers, wrap them around the weathered hair tips, wind the hair tightly on curlers, up to 60 on one head of hair

Paper helps to align tip end hair fiber, protects and delays instant reaction. Moistened hair is usually wound on a rigid rod. Bending hair around the curler produces a slight tension on hair

7. Take on gloves, protect clients face by cotton plugs

Protection for hands and face/neck skin against dripping solution

8. Apply the perming lotion (about 75 mL), avoid dripping

Fluid penetrates into the hair, starts chemically reducing it from outside in, softens hair

9. Apply heat by means of a hairdryer, heat processor or use ambient temperature

Heat accelerates: (a) penetration; (b) the reduction step; (c) moveability of hair proteins

10. Develop process time of perming lotion with heat for 5–20 minutes

Reductive cleavage of the hair cystine-network proceeds, hair swells up to 50%, contracts approx. 2% generates internal stress, which relaxes by creeping and flowing of the protein mass The hair substance is transferred from an elastic into a “plastic” state adopting the shape of the curler

11. Monitor curl development unwinding a test curler

Although wet, unwound test lock shows degree of wave/hair deformation (measurable by an electronic test curler), proteins cysteine side chains changed their position relative to each other

12. Rinse thoroughly off the perming lotion with water (up to 3 minutes)

Chemicals are diluted, removed from hair, reaction stops, but physical swelling and shrinking onto the curler peaks by osmotic forces

13. Apply a neutralizing liquid or foam. Process the neutralizer for up to 10 minutes followed by rinsing and unwinding the hair

Reoxidation of cysteine to cystine by hydrogen peroxide restores hair’s protein network again, fixing new cystine cross-links at different positions. Residual cysteine oxidizes to cysteic acid Deswelling and hardening occurs Unwinding the hair results in curl relaxation

14. Apply an acid conditioning product as an after treatment

Restores hairs neutrality, also neutralizes residual perm molecules. The deformation process is now complete

15. Dry and style the hair by means of a brush or setting curlers and a hairdryer

Curl relaxation starts in wet hair, brushing, combing diminishes curl retention. Best: air drying

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Table 31.2 Ingredients in a typical perm solution 1 and neutralizer solution 2. Ingredient

Content % w/w

Action

Ammonium thioglycolate 70%

Waving agent

Ammonium hydrogen carbonate

Buffer

Ammonia 25%

Alkalizing agent

1,2 Propylene glycol

Carrier

Styrene/PVP copolymer

0.1

Opacifier

Polyquaternium-6 [poly(dimethyl diallyl ammonium chloride)]

0.2

Conditioning agent

Perfume

0.4

Fragrance

Coceth-10 (alkyl polyglycol ether)

0.4

Solubilizing agent

Water pH

76.9

Basis

8.2–8.5

Neutralizer Hydrogen peroxide 50%

Oxidizing/fixing agent

Ammonium hydrogen phosphate

0.3

Stabilizing agent

Phosphoric acid

0.1

Stabilizing agent

EDTA

0.2

Complexing agent

Perfume, conditioning agent, surfactant, water pH

As in perm solution 2.5–3.5

lasting hair curl. Other alternatives are glycerol monothioglycolate (GMT), active at neutral pH. Cysteine [21] and cysteamine (2-mercaptoethylamine) are used for perming Asian hair. Thiolactic acid, with less reducing power, can be used as co-reducing agent. Many home permanent waves contain sulfite.

Alkalizing additives Alkalizing additives, such as ammonia or monoethanol amine, are included in the formulation to achieve the appropriate pH at which the reducing agent as well as the hair disulfide is activated, which is normally at pH 7–9.5 (Figure 31.6, step 0). Glycerol monothioglycolate, the active component of an “acid wave”, works at pH 7; however, TGA requires a pH of 8.5–9. Hair damage is often related to a higher product pH.

Buffer salts Buffer salts, such as ammonium (hydrogen) carbonate, affect the alkalinity. These ingredients buffer the working pH as hair, a natural ion exchanger, lowers the pH when it comes into contact with the perm solution.

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Carriers Carriers (e.g. urea, ethanol, or 2-propanol) enhance penetration of actives into hair and thus the effectiveness of the perm product.

Surfactants Surfactants are included to ensure wettability of the originally hydrophobic hair surface. They also facilitate foaming of perm solutions or neutralizers to be applied without dripping. In permanent wave foams, the type and concentration of surfactants are especially critical for skin compatibility [13].

Conditioning polymers Conditioning polymers are included to allow an easy manageability of the new shape and mask the somewhat harsh handle of hair after perming.

Complexing agents Complexing agents in thioglycolate-based perm lotions prevent intensive red–violet coloring with iron contamina-

31. Permanent hair waving tion. In the neutralizer lotion, complexing agents avoid decomposition and boosting of hydrogen peroxide.

Opacifiers Opacifiers, such as styrene-vinyl-pyrrolidone-copolymers, and coloring agents (e.g. azulene) give a pleasant appearance to the product, but also serve as an identifying feature.

Thickeners Thickeners (e.g. cellulose derivatives or polyacrylate salts) are used to convert fluid preparations to gels, which prevent dripping off from the hair or enable a more intensive perm treatment of the hair root portion.

Solubilizing agents Oily fragrances afford a solubilizing agent for better miscibility.

Acidic and neutral permanent wave Acidic and neutral permanent wave preparations mostly contain glycerol monothioglycolate (GMTG) as reducing agent. It allows easy control of the processing behavior, leaves hair with a pleasant feel, and the danger of overwaving is slight. Often it is highly retained in hair, imparts an unpleasant smell, and causes sensitization of hairdressers’ hands even by touching hair that was processed weeks ago. Therefore, although it is not legally forbidden, esters must not be used according to the technical directives for dangerous substances in hair salons [22].

Thermal waves Thermal waves produce heat during the perming procedure. Hydrogen peroxide reacts with excess thioglycolic acid to release heat. Such warming is meant to generate a pleasant feeling on the client’s head and to render the addition of external heat unnecessary.

Neutralizers Neutralizer ingredients are in principle oxidizing agents, mostly hydrogen peroxide at concentrations of roughly 0.5– 3% and acid at pH 2–4.5. Advantages are: • Low solution concentrations; • Excellent environmental compatibility; and • Physiologic safety. Moreover, at acid pH hydrogen peroxide has no bleaching power for the natural hair color, but specifically reoxidizes hair cystein to cystin and truly neutralizes the alkaline hair. However, metal salts catalyze the explosion of hydrogen peroxide, which contains as stabilizer inorganic phosphates, phenacetin, or 4-acetaminophenol. As alternatives, bromate salts are used. The concentration is roughly 6–12 wt% at pH 6–8.5. Bromate-based neutralizers are preferentially used in Asia, because they do not lighten dark hair. Less widely used are sodium perborate and percarbamid.

Different product types The majority of commercial waving and neutralizing lotions are aqeuous solutions, but a few are designed as gels, creams, or aerosol permanent waves [17,18]. Preparations chiefly differ in: • Mixture of reducing agent; • Concentration of reducing agent; • pH value; • Form of application.

Alkaline perms Alkaline perms are alkalinized by ammonia to a pH 9–9.5. Because of their frequent association with skin inflammation, these products were largely replaced by mildly alkaline preparations at pH 7.5–9.

Sulfite perms Perming lotions containing ammonium sulfite are used in home waving. At neutral pH 7 and without thiols, they act best on healthy, undamaged hair. However, stable “Bunte” salts are formed during their chemical reaction with hair. This leads to poor fixation, rough feel, and hair damage on tinted or fine hair. An overview of product types is summarized in Lee et al. [23].

Regulatory aspects Formulation is limited by some legal regulations [20]. First, the cosmetic chemist selects the ingredients from a pool of chemicals, which are compatible with the cosmetic legislation in the countries where the product is introduced. The EC Cosmetics Directive, Annex III, Part 1 [24], restricts the pH of permanent wave preparations with thioglycolic acid, its salts, and esters to pH 7–9.5 for the acid and salts, pH 6–9.5 for esters. The maximum concentration calculated as thioglycolic acid is 8 wt% ready for use for retail and 11 wt% for professional use. A special warning label is required. In the USA, the Cosmetic Ingredient Review (CIR) expert panel considers 15.4 wt% maximum of thioglycolic acid as safe in permanent wave products. The CIR recommendations are respected by the manufacturers. In Japan, permanent wave products are classified as quasidrugs. Thioglycolic acid and its salts are permitted, as is cysteine, but restrictions on concentration and pH are given. Thioglycolic esters are not allowed. Hydrogen peroxide concentrations are limited to 12% in the EU [24].

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(a)

(b)

Figure 31.9 Hair, properly wound, fixed on rollers, and wetted by the perming lotion (a) delivers perfect locks (b).

Perming practise – how to achieve a perfect curl The question of perming safety is not only a function of product composition, but also depends on the use conditions [6,25]. Therefore, each package of perms on the market contains a list of instructions for the hairdresser or consumer. Table 31.2 summarizes the recommended steps and how hair answers (i.e. reacts), chemically and physically. Any deviations from this course of action will be specified in the instructions for use. The correct execution of each step should produce the desired result, a curl lasting up to 3 months, a well-preserved hair structure, and an easy styling of the hair assembly (Figure 31.9). In salons, where hairdressers use long-lasting perms, an appropriate permanent wave must be selected to achieve the best result. The hair thickness and quality must be assessed to determine if the hair is healthy or damaged. If the hair feels rough, is of a lighter color, or possesses split ends, it may have a porous structure produced by previous weathering, bleaching, coloring, or perming. This increased porosity allows the perming lotion to react faster. Damaged hair requires bigger curlers, a reduced perm strength, and shortened processing time. Heat from a drying hood (45 °C) accelerates the chemical reaction, but should not be used in persons with sensitive scalp skin.

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To ensure that the proper amount of curling has been achieved, a test curl should be performed. A test curl is loosely unwound from a curler after several minutes to determine the degree of curl achieved and whether to extend the processing time. After thoroughly rinsing off the perming lotion, complete hair neutralization is strongly advised as the second fundamental step in perming. Three to ten minutes are recommended to obtain a lasting perm, to reoxidize the hair, and to neutralize the alkalinity of the reducing step. Physically, hair only gains its strength and integrity with thorough neutralization. Application of an acidic conditioning lotion as an aftertreatment, removes residual peroxide, restores the hair internal pH to neutrality, helps to stabilize the hold of the curl, and makes it less prone to future damage.

Safety and adverse reactions to perm products Safety requirements from consumer expectations are adequately summarized by the corresponding text within the EU Cosmetics Directive: “A cosmetic product put on the market within the Community must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use” [24].

31. Permanent hair waving Therefore, as permanent wave preparations contain reactive chemicals, these have to pass a complete toxicologic characterization. Essentially, the potential for: • Acute systemic toxicity; • Local compatibility and irritation; • Sensitizing potential, allergenicity; • Mutagenicity; • Tumorigenicity; • Teratogenicity; and • Percutaneous absorption. From past experience with the safety of waving products, and regularly updated statistics published by intoxication advisory centeres, manufacturers obey the rules. Statistics of adverse reactions from cosmetic products sold between 1976 and 2004 revealed only 1.1 undesired effects per 1 million packages sold [26]. This confirms cosmetic products are very safe (for more detailed information about toxicologic test methods and safety assessment processes see references [20,27,28]). Even though a perm product has been approved as safe by legal authorities, occasional hair or skin damage can occur from incorrect usage: • Consumers apply a home wave without reading/understanding instructions; or • New hairdressers in salons are untrained and less skilful. The first signs of a failure in perming are lack or excess of curliness. This is not only because of the wrong choice of product, excessive development time, and temperature, but may also result from incomplete rinsing of the active substances and shampoo components. Surfactant residues, residual reducing, and oxidizing agents in the hair encourage irreversible side reactions, such as incomplete reoxidation and cysteic acid formation. Moreover, the stylist or the client may try to “repair” the unexpected result by repetition of the permanent waving process. Multiple treatments, as well as the combination of perming and bleaching or coloring in the same session, lead to heavily damaged hair. Electron microscopy reveals residual softening, even complete peeling of hair surfaces (Figures 31.10 and 31.11). Instrumental methods can further detect the degree of damage. These include hair tensile testing, elasticity, curl hold, swelling behavior, and static charging [2,20]. Chemical damage of hair may also be assessed by analyzing dissolved hair proteins [29,30] and hair lipids [30]. Residual cysteine and cysteic acid are signs of weak hair structure [30]. Table 31.3 lists examples for hair and skin symptoms indicating mistakes during a perm treatment [25,31–34]). Although ammonium thioglycolate has been reported to have a low sensitization potential, occasionally sensitization, skin irritation, contact dermatitis [33,34], or seborrhea occur [32]. Itching, burning, and redness are normally con-

Figure 31.10 The curtain-like structure of a hair surface indicates heavy perming damage.

Figure 31.11 A bleach applied immediately after a perming treatment chips off the cuticle as a whole (SEM ×700).

fined to the neck and scalp margins after prolonged contact with perm solution [31]; however, high levels of alkalinity and heat [33,34] may also precipitate irritation. Scalp skin damage seldom occurs. Scalp skin, which contains keratin proteins like hair, is less reactive to reduction by thioglycolate. This contributes to a lower swelling response of the skin than hair (22% vs. 38%) and the lower cystine content and hydrophobic nature of skin vs. more cystine and hydrophilicity in hair [35]. The skin is more susceptible to surfactants, however, causing hairdresser’s hands to be affected by an allergy to perms. When the hands are softened by routinely shampooing of clients’ hair, monothioglycolate esters found in acid waves may be problematic [31].

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Table 31.3 Symptoms of hair/skin damage by perm products. Symptom

How it happened

Hair loss (rarely)

Telogen hair effluvium Temporary contact allergic reaction

Hair breakage Near root

False hair quality diagnosis Perm choice too strong for fine or predamaged/ bleached hair Stress on root hair by tight winding or rubber band Winding against hair growth direction Hair growth with thinning diameters Winding on curlers with “ fish hooks” Incomplete neutralization Forgot pretreatment with equalizer Processing without wrap end paper protection Excess perm solution stored by hair tips

In hair length

Near tip ends

Hair modification (consumer complaints) Unwanted kinky curls

Limp hair/curls without springiness

Wet hair feels plastified, spongy, extensible

Dry hair feels rough, brittle, uncombable, “matting”, is dull, ready to break Highlighted natural color or tint

Perming power of product too high Curler thickness too thin Processing time with heat too long Loose winding, impaired protein creep False time and fluid saving as well as excess time, heat, fluid Overprocessed by extended application Loss of keratin elasticity Increased hydrophilicity Neutralization too short Intermediate rinsing too short Increased hair surface friction by shrunken cuticle cells Loss of hair lipids and proteins Dissolution of natural pigment/tint Excess perm conditions

Skin damage Redness

Too much heat (heat rollers, hood defect)

Pustules

Skin swelling during extensive prewash

Irritant skin

Soaked cotton pads for face protection not removed

References 1 Jollès P, Zahn H, Höcker H, eds. (1997) Formation and Structure of Human Hair. Basel: Birkhäuser Verlag. 2 Robbins CR. (2002) Chemical and Physical Behaviour of Human Hair, 4th edn. Berlin, Heidelberg: Springer Verlag. 3 Schwan-Jonczyk A, Schmidt CU. (2007) Hair geometry changes during lifespan. Proceedings of the 15th International Hair Science Symposium, HAIRS 07, Banz. 4 Robbins CR. (1983) Load elongation of single hair fiber coils. J Soc Cosmet Chem 34, 227–39. 5 Wolfram L, Dika E, Maibach HI Hair anthropology, or Swift JA. The transverse dimensions of human head hair. (2007) In: Berardesca E, Leveque JL, Maibach HI, eds. Ethnic Skin and Hair. New York: Informa Healthcare. 6 Schwan-Jonczyk A, Arlt T, Maresch G, Schonert D. (2003) Curls, Curls, Curls. Darmstadt: Wella AG (inhouse publication).

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7 Franbourg A, et al. (2005) Evaluation of product efficacy. In: Bouillon C, Wilkinson J, eds. The Science of Hair Care. Boca Raton, FL: CRC Press, pp. 351–76. 8 Swift JA. (1997) Fundamentals of Human Hair Science. Weymouth UK: Micelle Press. 9 Franbourg A, Leroy F. (2005) Hair structure and physicochemical properties. In: Bouillon C, Wilkinson J, eds. The Science of Hair Care. Boca Raton, FL: CRC Press, pp. 351–76. 10 Marshall RC. (1986) Nail, claw, hoof and horn keratin. In: Bereiter-Hahn J, Matoltsy AG, Richards KS, eds. Biology of the Integument II. Berlin: Springer Verlag, pp. 722–38. 11 Zahn H. (1977) Wool as a biological composite structure. Lenzinger Ber 42, 19–34. 12 Umprecht JG, Patel K, Bono KP. (1977) Effectiveness of reduction and oxidation in acid and alcaline permanent waving. J Soc Cosmet Chem 28, 717–32.

31. Permanent hair waving 13 Lang G, Schwan-Jonczyk A. (2004) Haarverformungsmittel (Hair waving preparations). In: Umbach W, ed. Kosmetik und Hygiene, 3rd edn. Weinheim: Wiley-VCH Verlag, pp. 264–78. 14 Schwan A, Zang R. (1993) Method and apparatus for the shaping treatment of hair wound on to rollers, including human hair. Wella AG EP 0321939B1. 15 Borish ET. (1997) Hair waving. In: Johnson D, ed. Hair and Hair Care, Cosmetic Science and Technology, Vol. 17. Marcel Dekker, pp. 167–90. 16 Garcia ML, Nadgorny EM, Wolfram LJ. (1990) Letter to the Editor: Physicochemical changes in hair during permanent waving. J Soc Cosmet Chem 41, 149–53. 17 Wickett R, Savaides A. (1993) Permanent waving of hair. In: Knowlton J, Pearce S, eds. Handbook of Cosmetic Science and Technology, 1st edn. Oxford: Elsevier Science, pp. 511–34. 18 Shipp JJ. (1996) Hair care products. In: Williams DF, Schmitt WH, eds. Chemistry and Technology of the Cosmetics and Toiletries Industry, 2nd edn. Chapman & Hall. 19 Dallal JA. (2000) Permanent waving, hair straightening and depilatories. In: Rieger MM, ed. Harry′s Cosmeticology, 8th edn. New York: Chemical Publishing, Chapter 32. 20 Clausen T, Schwan-Jonczyk A, Lang G, Clausen T, Liebscher KD, et al. (2006) Hair preparations. In: Ullmann′s Encyclopedia of Industrial Chemistry, 7th edn, Vol. A 12, Weinheim: Wiley, pp. 571. 21 Shansky A. (2008) Antichaotropic salts for stabilizing cysteine in perm solutions. In: Koslowsky AC, Allured J, eds. Hair Care: From Physiology to Formulation. Carol Stream, IL: Allured, pp. 341–6. 22 Technische Regeln für Gefahrstoffe, Friseurhandwerk TRGS530 (2007) GMBL, Bundesministerium für Arbeit und Soziales. 23 Lee AE, Bozza JB, Huff S, Mettric R. (1988) Permanent waves: an overview. Cosmet Toiletr 103, 37–56.

24 EU Council Directive of 27 July 1976 on the approximation of the laws of the Member States relating to cosmetic products (76/768/EEC). 25 Meisterburg M, Riehl U, et al. (2007) Friseurwissen (Hairdresser’s knowledge). Schmidt W, ed. Troisdorf, Germany: Bildungsverlag EINS. Available at www.bildungsverlag1.de 26 IKW information. (2008) Undesireable effects of cosmetics. Available at www.ikw.org. 27 Draelos ZD. (2000) Safety and performance. In: Rieger MM, ed. Harry’s Cosmeticology, 8th edn. New York: Chemical Publishing, Chapter 34. 28 Hourseau C, Cottin M, Baverel M, Meurice P, Riboulet-Delmas G. (2005) Hair product safety. In: Bouillon C, Wilkinson J, eds. The Science of Hair Care. Boca Raton, FL: CRC Press, pp. 351–76. 29 Han M, Chun J, Lee J, Chung C. (2008) Effects of perms on changes of protein and physicomorphological properties in human hair. J Soc Cosmet Chem 59, 203–15. 30 Hilterhaus-Bong S, Zahn H. (1989) Protein and lipid chemical aspects of permanent waving treatments. Int J Cosmet Sci 11, 164–74, 221–34. 31 Wilkinson JD, Shaw S. (2005) Adverse reactions to hair products. In: Boullion C, Wilkinson J, eds. The Science of Hair Care. Boca Raton, FL: CRC Press, p. 521. 32 Bergfeld WF. (1981) Side effects of hair products on the scalp and hair. In: Orfanos CE, Montagna W, Stüttgen G, eds. Hair Research. Berlin: Springer Verlag, pp. 507–12. 33 Ishihara M. (1981) Some skin problems due to hair preparations. In: Orfanos CE, Montagna W, Stüttgen G, eds. Hair Research. Berlin: Springer Verlag, pp. 536–42. 34 Orfanos CE, Sterry W, Leventer T. (1979) Hair and hair cosmetic treatments. In: Orfanos CE, ed. Hair and Hair Diseases. Stuttgart: G. Fischer Verlag, pp. 853–85. 35 Robbins CR, Fernee KM. (1983) Some observations on the swelling of human epidermal membrane. J Soc Cosmet Chem 34, 21–34.

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Chapter 32: Hair straightening Harold Bryant, Felicia Dixon, Angela Ellington, and Crystal Porter L’Oréal Institute for Ethnic Hair and Skin Research, Chicago, IL, USA

BAS I C CONCE P T S • Hair is straightened to improve manageability and provide style versatility. • To straighten hair, an alteration of the cortex must occur. • To achieve temporary straightening – a lower energy process – hydrogen bonds and salt linkages are altered while permanent straightening is achieved through the modification of covalent bonds, which requires more energy. • Permanent hair straightening can be accomplished with ammonium thioglycolate, sulfites, and hydroxide.

Introduction The desire for straight hair was once attributed to a “universal” vision of beauty and social status associated with straight hair; however, recent information links this style preference to improved manageability and style versatility. In order to achieve the straight look, it is necessary to transform the natural hair configuration, which has been linked to the shape of the follicle. Bernard et al. [1,2] found that the asymmetric protein expression in curved follicles was associated with the formation of curly hair. At this time, it is not possible to straighten hair by changing the shape of the follicle. However, it is possible to straighten hair based on its chemical composition. For mature hair, the composition is generally the same and consists of roughly 90% protein with smaller quantities of water, lipids, and minerals but does not vary by degree of curl, despite differences that exist in the early stages of hair production. To understand how hair can be transformed, it is important to know the different components of hair. Hair is made-up of three macro structures including the cuticle, cortex, and medulla, the latter being of little significance. The major morphologic part of the hair is the cortex, which is made up of highly organized α-helical proteins packed in a cystine-rich matrix. To straighten hair, an alteration of the cortex must occur. There are three types of bonds in hair: hydrogen, electrostatic salt linkages, and covalent, each consecutively requiring more energy to break. Based on the bonds that can be affected, there are two categories of straightening: temporary and permanent. To achieve temporary straightening, a lower energy process is required involving alteration of

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hydrogen bonds and salt linkages while permanent straightening is achieved through the modification of covalent bonds, which requires more energy. Thermal appliances can be used to disrupt and rearrange the weaker hydrogen bonds and salt linkages required for temporary straightening. Depending on the approach, the results can last from a few days to several months. However, permanent straightening is obtained through a chemical process that alters the protein structure by cleaving and reforming covalent bonds, preventing the hair from returning to its natural curly state until it grows out from the scalp. The following are usually considered when choosing the type of hair straightening process or treatment: degree of curl, degree of desired straightness, point of service, convenience, environmental conditions, and the desired frequency of straightening. All of these are important; however, the degree of curl in hair may be the most influential because it impacts other desired attributes. It is often subjectively described and ranges from various degrees of wavy to tightly curled. These descriptors are relative and can be confusing because they often overlap. Thus, the L’Oréal Curl Classification was recently developed to quantitatively describe the degree of curl in hair (Figure 32.1) [3]. This classification used hair from around the world and identified eight distinct curl types, where the degree of curl increases directly with number. People with curl types I–IV often have concerns about hair frizz and volume while higher curl types are more concerned about manageability. Thermal techniques can be used to achieve straight hair for all curl types but, typically, curl types V and above are difficult to straighten permanently without the use of hydroxide-based systems. Hair straightening appliances and chemicals are centuries old; however, instrument designs and formulations have evolved to improve effectiveness while limiting the negative attributes. New materials are used for the heated surface of flat irons and product formulas have been modified and

32. Hair straightening

III

VII

VIII

Figure 32.1 Hair classification types to differentiate the degree of curl in hair.

developed to protect hair and scalp and aid in the ease of application. In some markets, the combination of heat and chemicals is often used. This chapter briefly reviews the most common straightening practices, including a description of the procedures and perceived advantages and disadvantages.

Thermal processing The use of thermal appliances dates back to the Egyptian period and is still considered to be a necessity to most women in today’s world. In the Egyptian period, hot metal was used to straighten hair. A less aggressive method was popularized in the late 1800s with the invention of the blow-dryer; the handheld version for home use became available in the 1920s. This increased the ability for women with curl types I–IV to have a variety of temporary and permanent styles (hot waving). Because curl types V–VIII were inherently more resistant to reconfiguration, there was a specific need to straighten these hair types. This was achieved with the popularization of the hot comb combined with pressing oil, attributed to Madame C.J. Walker in the early 1900s. The hot comb, still in use today, is a metal comb heated to temperatures

reaching 450 °F. Whether utilizing a hot comb, professional tongs heated in a Marcel oven, or one of the electronic devices such as a blow-dryer, curling iron, or flat iron, the process involves using heat and mechanical stress. These common thermal appliances represent an alternative way for people with naturally curly hair to achieve manageability and straight hair styles. The combination of heat and mechanical stress, in the form of combing or brushing while blow-drying and smoothing with the other devices, straightens hair by rearranging hydrogen bonds. Once straightened, the new configuration of the hair is only temporary and will revert back to its natural state after exposure to moisture from any source such as environmental conditions and perspiration. Temperatures of thermal appliances typically range from 150–232 °C (302–450 °F). While thermal processing is considered temporary in terms of styling, it can have a permanent effect on hair. For example, the proteins in hair can start to denature at high temperatures. Protein denaturation is a process by which proteins are irreversibly altered by an external stimulus, and for hair can result in decreased fiber integrity. The denaturation temperature is 235–250 °C (455– 482 °F) and 155–160 °C (311–320 °F) for dry and wet hair, respectively [4–6]. The upper temperature limits for some of the appliances exceeds the denaturation temperature for

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wet and dry hair so care must be taken to avoid repeated applications and overheating. Of all heat appliances currently available to straighten hair, the flat iron is rapidly becoming the most popular; therefore, it is the focus of technologic advancements. Important attributes of a good flat iron are the ability to provide even heat and maintain a consistent temperature. Recent improvements in temperature control promote thermal stability and coatings, including ceramic and titanium, provide durability and reduced friction. Reduced friction is critical to maintaining a smooth cuticle surface and reducing breakage during thermal processing. Other advances in materials include the incorporation of pure ceramic heating elements and minerals (tourmaline) that allow manufacturers to make claims about the positive effects of ions and far infrared radiation on the final state of the hair. The product offerings associated with the use of thermal appliances typically contain hydrocarbon-based ingredients (e.g. petrolatum and mineral oil) and polymers (e.g. silicone-derived, cationic, and non-ionic) to condition, protect, and accommodate styling preferences. Because blow-drying typically starts in the wet state when hair is vulnerable to damage, conditioning polymers (e.g. polyquaternium 10) that improve wet combing by reducing frictional forces are typically used. Prior to heat application, products that contain ingredients such as sugars and silicones can be applied. Sugars help to increase thermal integrity while silicones protect the hair by acting as a thermal barrier. Silicones also can function as lightweight films whereas hydrocarbons are often used when a heavier coating is desired for style preferences.

Reducing agents Reducing treatments are traditionally known to curl hair (hot and cold permanent waving); however, they can also be used to straighten hair. The chemistry involves a two-step process where the disulfide bonds in hair keratin are cleaved in the first (reducing) step followed by oxidization in the second step to form new disulfide bonds (Scheme 32.1). The difference between straightening and waving using reducing agents is the configuration of hair prior to oxidation and the form of the product during the reducing step. The reducing product for waving the hair is usually a liquid and the hair is curled using rollers before oxidizing. For straightening, the product is usually in the form of a thick cream so that the viscosity of the product can assist in holding hair fibers in a straightened configuration during manipulation. The most commonly used reducing agents in this process are ammonium thioglycolate (thiols) and sulfite.

Ammonium thioglycolate Thioglycolate straighteners come in several product strengths. Treatment procedures and strength should be based on the hair attributes according to product recommendations. For curl types V–VIII, these products usually leave the hair with residual curl so the result can be disappointing if a straight style is desired. In addition, the hair can feel dry as a result of the treatment; thus, products that contain glycerin are used to provide moisture. Thioglycolate straighteners can be used on hair that has been previously colored or permed; however, it is not recommended for bleached or relaxed hair.

Reduction step

CO CH

CH2

CO + 2R

2 HS

CH2

R +

Oxidation step

CO 2 HS

CH2

CH NH

CO +

1/2O2

CH NH

CH2

H2O

NH Scheme 32.1

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32. Hair straightening In addition to traditional thiol straighteners, a new technique is becoming popular that includes the incorporation of heat with thiol-based cream products. These treatments are used to permanently straighten and/or reduce volume in curl types I–V. They are commonly used on Asian and Brazilian hair and go by several names that are listed in Table 32.1. Even though there are several names, they all use similar processes to achieve hair characteristics that consumers describe as straight, soft, and shiny. The main point of differentiation between this new treatment and the traditional straightening method is the application of heat prior to the oxidation step for the Asian and Brazilian treatments. Details about the specific procedure can be found in the appendix. This straightening technique is not recommended for natural hair that is higher than curl type V, particularly hair from people of African descent because it is inherently more fragile than other hair [7]. After a period of time, the processes described above will need to be repeated to the new hair growth because of its natural configuration. The treatment should only be per-

Table 32.1 Common names for thiol-based straighteners that use heat. Culture that introduced the technique

Popular thiol-based treatments

Japanese/Filipino

Hair rebonding Thermal reconditioning and restructuring Ion retexturizing Bio ionic system Japanese hair restructuring Straightening and reconditioning Japanese straightening perm

Brazilian

Sulfites are an additional class of reducing agents that can be used for hot waving or straightening depending on the procedure. Even though sulfite straighteners have been around for decades, they are less common than hydroxide relaxers because they tend to result in less effective straightening of highly curled hair (types VI–VIII). However, they are believed to be less irritating to the scalp. The decrease in straightening efficacy may be related back to the reactivity of the disulfide bonds, which depends on the pH of the active solution. The maximum reactivity is reached at pH 4–6, but sulfites are not stable at such low pH conditions [8,9]. Because of this, commercial products generally range in pH from 6.5 to 7.5. At pH 7, only about 15% of the cystine residues can be reduced [10]. The first step of the reaction mechanism involves a reduction of the cystine via a nucleophilic reaction similar to thioglycolate, with the exception of the formation of Bunte salt (Scheme 32.2). To lock the hair into the desired conformation, a neutralizing solution is used which typically contains sodium carbonate or bicarbonate. The application procedure is similar to that of a thioglycolate straightener except no oxidant is used, resulting in poor or modest straightening.

According to legend, Garrett A. Morgan was the first person to stumble upon a chemical to permanently straighten hair in the early 1900s [11]. While experimenting with substances to reduce the heat of friction during sewing, he wiped his hands on a cloth that was made of curly pony fur. Later, he found that the fur had been straightened. Following trials on different types of hair, including his own, he started selling the G.A. Morgan Hair Refining Cream. To this day, the identity of this substance is a mystery, but the first known composition for chemically straightening hair was formulated in household kitchens in the 1930s. This contained a chemical mixture of potato starch, lard, egg, and sodium or potassium hydroxide. Because of its corrosive

Note: To be comprehensive, it is cautiously noted that products containing or that are altered with formaldehyde (formol) at higher than approved levels (0.2% as an antimicrobial) are sometimes used to straighten hair. However, formaldehyde is classified as a probable human carcinogen by the Environmental Protection Agency and should not be used to straighten hair.

Scheme 32.2

Sulfite

Hydroxide straighteners

Chocolate, strawberry, kelp, milk, sugar, passion, mint, gold, orchid, French, gumbo, etc. treatment (or brushing) Brazilian keratin treatments (may contain up to 2% formaldehyde)

formed on the new growth, referred to as a “touch-up,” to minimize overlapping of treatments which may result in overprocessed hair. It is recommended that the time between treatments is maximized, with a minimum of 6 weeks, depending on the rate of hair growth.

CO CH2

CH2

CO 2–

CH + SO3

CO CH2

–

SO3

Bunte salt

–S

CH2

CH NH

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nature, it was advised to protect or base the scalp with petrolatum before treatment. The use of this concoction led to the development of relaxers. The first commercially available relaxer, based on sodium hydroxide (lye), was introduced in the 1950s by Johnson Products. Even though the relaxer formula included petrolatum, basing the scalp was still a requirement to minimize scalp irritation. The relaxer technology continued to improve in the early to mid 1960s with the invention of the no-base relaxer. This version incorporated higher percentages of petrolatum and mineral oil in the formula and decreased the amount of sodium hydroxide to make it less irritating, thus it claimed to eliminate the need to base the scalp. In the late 1970s, the first no-lye relaxer was marketed that significantly reduced the amount of irritation during treatment [12]. The technology uses a two-part system where a calcium hydroxide cream is mixed with a guanidine carbonate liquid activator to produce guanidine hydroxide. Several other relaxer versions were introduced over time that improved the product attributes, the cosmetic properties, and integrity of the hair. This was achieved through the addition of conditioning agents such as cationic polymers and by incorporating various alkali metal hydroxides in both product forms, mix or no-mix [13,14]. The most commonly used hydroxides are sodium, guanidine, lithium, and potassium (see Table 32.2 for definitions of key terms).

abstraction of the hydrogen beta to the disulfide (Scheme 32.3) [15]. This results in the formation of dehydroalanine, cysteinate ion, and sulfur. Dehydroalanine is a highly reactive intermediate that continues to react with cysteine and lysine moieties in hair to form lanthionine and lysinoalanine, respectively. It can also react with ammonia to form betaaminoalanine. The new thioether bonds (lanthionine) are stable in the presence of reducing agents, such as thioglyco-

Table 32.2 Vocabulary list of select terms related to straightening curly hair.

Chemistry of relaxing Amino acid analysis of relaxed hair hydrolysates indicates lanthionine is the primary product of the reaction. The formation of lanthionine can occur via two pathways. The first is through a binuclear nucleophilic substitution reaction [10]. The second is beta-elimination that is initiated by

CO β

Lye relaxer

Technology that commonly utilizes sodium hydroxide as the active ingredient

No-lye relaxer

Non-sodium hydroxide-based system that includes but is not limited to guanidine and lithium hydroxides. Some of these products require mixing prior to use; those that do not are sometimes referred to as no-lye no-mix

No-base relaxer

A relaxer that may not require basing the scalp with a petrolatum product prior to relaxer application

Texturizer

A lower concentration version of relaxer used to permanently reduce or loosen curl in hair

Perm

Thiol-based products used to permanently curl hair according to a sequential reduction– oxidation process

OH– S

CH2

Dehydroalanine

Cysteinate Ion

CO CH

–S

CH2 +

(CH2)4

NH Lysinoalanine

CH2

Cysteine

Lysine

252

Hydroxide technology used to permanently straighten curly hair. It is sometimes mistakenly referred to as a “perm”

CO α CH2

Relaxer

CO CH2

CH2

CH NH

Lanthionine

Scheme 32.3

32. Hair straightening late or sulfite, compared to cystine. This is evidenced by the decrease in solubility of hair protein and the inability to permanently curl relaxed hair. While lanthionization is popularly believed to be the cause of permanent straightening of curly hair, Wong et al. [16] believe that it is not the critical step in hair straightening. They propose that the permanent straightening depends on supercontraction of the fiber. They report that fiber supercontraction is what “locks” the fiber into the straight configuration and the formation of lanthionine is a by-product rather than a requirement.

Effect of relaxers on hair

quality, and relaxer efficiency. Users of lye technology reported a higher incidence of scalp irritation while no-lye users experienced more hair quality issues. The same study showed that consumers were more likely to take action for hair quality issues and more often seek advice from a stylist as opposed to consulting a dermatologist or physician. In a separate study, it was noted that those who frequently obtain services at a salon, more than 50% of them were unaware of the specific relaxer type being used [20]. All hydroxide-based relaxers follow the same chemistry and are designed to straighten hair but to varying degrees. Due to the high pH, relaxers cause swelling of the fiber, cuticle abrasion, loss of the hydrophobic lipid layer, an increase in porosity, a loss in tensile strength, and an increase in plasticity.1 All of these affects weaken the hair compared with its natural state. The swelling and deswelling of the hair during the process may in part, be responsible for loss in fiber strength as it can result in cracks proposed to be related to the change in osmotic pressure also associated with permanent waving [18]. In addition to cracks, cuticle swelling may cause cuticle erosion. Figure 32.2 shows the progression of the cuticle surface during the relaxer process. After the relaxer has been rinsed from the hair before neutralizing, the image shows the presence of cuticle scales that have been abstracted from the hair fiber but still remain on the hair. After neutralizing, the loose cuticle scales are removed. The images representing neutralized and conditioned fiber surfaces show that while relaxers erode cuticle layers from the hair, some amount of the protective layer is still present. In addition to the cuticle, the cortex, which is mainly responsible for the hair’s strength, is also affected during relaxing. The original protein linkages in hair are altered, and when this occurs the hair becomes more fragile. The decrease in break stress and increase in break extension indicates that the hair becomes weaker and is more prone to deformation after relaxing. Even though hair quality is compromised, the straightened configuration of hair increases combability as shown in Figure 32.3. This in turn helps to decrease breakage that is known to be associated with combing curly hair and mitigates further decreases in mechanical properties [21]. It is important to follow relaxer services with post-relaxer treatments such as conditioners to further enhance manageability and improve the quality of hair. A good conditioner should exhibit the following qualities: improved wet and dry combing, flyaway reduction, and surface protection of the hair. These qualities can be achieved by adding conditioning agents that will reduce the frictional force during combing. Key ingredients commonly used are conditioning agents

In 2006, Yang and Barbosa [19] performed a national study to obtain consumer perceptions of relaxers. From this study, consumer responses on the effects from relaxer use were grouped into three categories including scalp irritation, hair

1 Plasticity: a material property whereby it undergoes irreversible deformation when a high enough force is applied.

Application The relaxer process involves a chemical reaction in addition to mechanical manipulation, which involves the action of smoothing the hair into the desired configuration during application. This can be accomplished with the back of a comb, an application brush, or the fingers. However, the most recommended tool is a comb. Applicator brushes can increase the chance of scalp irritation and the use of fingers is not suggested because of the caustic nature of the relaxer ingredients. The initial relaxer is applied to the full length of the fiber. Subsequent treatments are only applied to new growth, which typically occurs within 6–8 weeks. The exact period of time should be determined based on the amount of new hair growth, which varies with the individual. For example, hair growth rates can range from approximately 4 mm/month to 18 mm/month [17]. Several key factors are used to determine the relaxer type, such as hair diameter, degree of curl, porosity, and type of prior chemical treatments. To help maintain the integrity of hair, it is important to follow the directions on the package carefully. Overprocessing and improper neutralization are problems that are commonly associated with relaxer misuse. Similar to thermal processing, repeat application on the same section of hair and treating the hair longer than the recommended time can result in overprocessing and may result in hair breakage. Determination of proper application time can be achieved by performing the recommended strand test. To insure proper removal of the relaxer, hair should be rinsed thoroughly followed by the application of a neutralizing shampoo, sometimes referred to as chelating or decalcifying. These shampoos are acidic with a pH typically ranging from 4.5 to 5.5. The neutralizing step is an important part of the relaxer process because it helps return the hair to a neutral pH. This is necessary because, at high pH, hair swells up to 70–80% during relaxing making the hair susceptible to damage [18].

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(a)

(b)

(c)

(d)

Figure 32.2 Scanning electron micrograph images of hair fibers under different treatment conditions, (a) virgin; (b) after relaxer rinse only; (c) after neutralization; (d) after conditioning.

Combing force vs. distance

160

Combing force (g)

Curly Straightened

120

0 0

80 40 60 Combing distance (mm)

such as polyquaternium-6, behentrimonium chloride, and hexadimethrine chloride. In addition, ceramides and panthenol are linked to increasing the cuticle integrity and relative strength of hair [22]. Although sodium hydroxide (lye) and guanidine (no-lye) relaxers straighten the hair via the same chemical pathway, some important differences exist between the two technologies. It is well established through published and unpublished studies that the guanidine systems are milder to the

254

100

120

Figure 32.3 Combing profiles of curly and straightened hair.

scalp causing less incidence of irritation [23]. In addition, unpublished laboratory studies indicate that guanidine systems create more lanthionine (7.4% vs 5.2% lanthionine) in the same time than the sodium hydroxide systems. The majority of sodium hydroxide relaxer users visit the salon while home users tend to use the guanidine system. These differences should be considered by professionals, home users, and dermatologists involved in deciding which relaxer system is most appropriate for individual use.

32. Hair straightening

Conclusions Hair straightening treatments are popular and can be used to achieve individually desired styles. However, care must be taken to decrease the chances of overprocessing that may occur when processes and chemical treatments are performed improperly. The future of straightening processes and treatments is only limited by science and technology. History shows that even though there have been major scientific advancements, the technology to straighten hair either temporarily or permanently still involves the use of heat with mechanical stress or chemical products. Over time, incremental improvements in thermal appliances and formulations for chemical treatments will continue to occur. Despite the advances, it will remain important to understand the advantages and disadvantages and proper techniques of each method based on personal style preference, hair type, and quality to reduce adverse effects.

Appendix Thiol procedure with heat After the hair is washed and towel-dried, the reducing cream is applied to a small section of hair for the recommended time for a strand test. The minimum time that it takes to achieve the level of curl reduction in that section is noted and the section of hair is rinsed after that time. The hair is then saturated with the cream and gently smoothed into a straight configuration. The cream should be left on the hair for the minimum time that was noted during the strand test; however, the time should not exceed the recommended time. The hair is rinsed thoroughly with water then the hair is 80% dried. A protecting smoothener is applied to the hair and then a brush in conjunction with a blow-dryer or a flat iron is used to straighten the hair in small sections. The hair should be neutralized using an oxidizing solution which should be left on the hair for the recommended time during that step. To keep from drying out, the neutralizing solution is usually reapplied (for 5 minutes) and then the hair is rinsed abundantly with warm water followed by towel drying. The hair should be conditioned with a rinseout conditioner and styled as desired. The time for the procedure can be up to 6 hours.

References 1 Lindelöf B, Forslind B, Hedblad MA, Kaveus U. (1988) Human hair form: Morphology revealed by light and scanning electron microscopy and computer aided three-dimensional reconstruction. Arch Dermatol 124, 1359. 2 Thibaut S, Gaillard O, Bouhanna P, Cannell DW, Bernard BA. (2005) Human hair shape is programmed from the bulb. Br J Dermatol 152, 632.

3 De la Mettrie R, Saint-Léger D, Loussouarn G, Garcel AL, Porter C, Langaney A. (2007) Shape variability and classification of human hair: a worldwide approach. Hum Biol 79, 265. 4 Wortmann FJ, Sendelbach G, Popescu C. (2007) Fundamental DSC investigations of alpha-keratinous materials as basis for the interpretation of specific effects of chemical, cosmetic treatments on human hair. J Cosmet Sci 58, 311–7. 5 Marsh JM, Clarke CJ, Meinert K, Dahlgren RM. (2007) High pressure differential scanning calorimetry of colorant products. J Cosmet Sci 58, 621–7. 6 Wortmann FJ, Deutz H. (1993) Characterizing keratins using high-pressure differential scanning calorimetry. J Appl Polym Sci 48, 137. 7 Porter C, Diridollou S, Dixon F, Bryant H, de la Mettrie R, Barbosa VH. Comparisons of curly hair from people of different ethnicities. (in press) Int J Dermatol. 8 Stoves JL. (1942) The reactivity of the cystine linkage in keratin fiber. I. The action of alkalies. Trans Faraday Soc 38, 254. 9 Wolfram LJ. (1981) The reactivity of human hair: a review. In: Orfanos CE, Montagna W, Stuttgen G, eds. Hair Research. Berlin/ Heidelberg, Germany: Springer Verlag, pp. 479–500. 10 Zviak C, Sabbagh A. (2008) Permanent waving and hair straightening. In: Bouillon C, Wilkinson J, eds. The Science of Hair Care, 2nd edn. New York: Informa Healthcare, pp. 201. 11 Haber L, Morgan GA. (1991) Black Pioneers of Science and Invention. Harcourt Trade. 12 de la Guardia MJ. (1981) Hair straightening process and hair curling process and compositions therefore. USA: Carson Products Company. 13 Darkwa AG, Newell F. (1994) Conditioning hair relaxing system. USA: Johnson Products Co. Inc. 14 Nguyen NV, Cannell DW. (2003) Hair relaxer composition utilizing complexing agent activators. USA: L’Oreal SA. 15 Tolgyesi E, Fang F. (1981) Action of nucleophilic reagents on hair keratin. In: Orfanos CE, Montagna W, Stuttgen G, eds. Hair Research. Berlin/Heidelberg, Germany: Springer Verlag, p. 116. 16 Wong M, Wis-Surel G, Epps J. (1994) Mechanism of hair straightening. J Soc Cosmet Chem 43, 347. 17 Loussouarn G, Rawadi C, Genain G. (2005) Diversity of hair growth profiles. Int J Dermatol 44, 6. 18 Shansky A. (1963) The osmotic behavior of hair during the permanent waving process as explained by swelling measurements. J Soc Cosmet Chem 14, 427. 19 Yang G, Barbosa VH. Relaxer Use and Side Effects. (in press) Int J Dermatol. 20 Bryant H, Yang G, Barbosa VH. (2005) Lye vs. no-lye relaxers: comparison of laboratory results and end-user perceptions. Presented at Ethnic Hair and Skin: Advancing the Scientific Frontier. Chicago, IL. 21 Khumalo NP, Doe PT, Dawer RPR, Ferguson DJP. (2000) What is normal black African hair? A light and scanning electronmicroscopic study. J Am Acad Dermatol 43, 814–20. 22 Bernard BA, Franbourg A, Francois AM, Hallegot P. (2002) Ceramide binding to African-American hair fibre correlates with resistance to hair breaking. Int J Cosmet Sci 24, 1–12. 23 Syed AN, Ayoub H, Kuhajda A. (1998) Recent advances in Treating Excessively Curly Hair. Cosmetics & Toiletries 113, 47–56.

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Chapter 33: Hair styling – technology and formulations Thomas Krause1, Rene Rust1, and Dianna C. Kenneally2 1 2

Wella/Procter & Gamble Service GmbH, Darmstadt, Germany Procter & Gamble Co., Mason, OH, USA

BAS I C CONCE P T S • Hair styling aids arrange and maintain hair in a groomed position and impart conditioning, shine, body, and increased manageability. • There are a wide variety of styling aids including hairsprays, gels, mousses, creams, waxes, lotions, and brilliantines. Heated styling implements such as blow-dryers and curling or straightening irons are also used to achieve style. • Polymers, emollients and waxes are the main functional ingredients in styling aids. Polymers bond hair strands together to provide hold. Emollients and waxes – amongst other ingredients – increase single hair fiber intercation and smooth cuticles, imparting shine and reduced hair frizz. • Styling aids are in general safe for skin and hair; however, misuse can result in hair damage. • Styling aids may be useful in improving the appearance of hair dermatologic conditions that result in thinning hair, hair dullness, or unruliness.

Introduction

Definitions

The appearance of person’s hair, its length, shine, and smoothness, is a strong indicator of general age, health, and attractiveness [1]. Additionally, hair style or conformation may be used to express personality traits or may make a social statement. Marie Antoinette was said to have changed her iconic hairstyle to promote her French identity [2], and who can forget the long flowing hair of the rebellious 1960s flower child? However, today as in the days of Marie Antoinette, hair does not grow naturally into the wide variety of hair styles desired by men and women – manipulation through brushing, setting, and the use of styling aids is necessary to smooth and arrange the hair into a pleasing style. The use of hair styling agents to help achieve hair styles is also not new – Ancient Egyptians were know to use castor and other oils as hair dressings and bees wax to help style and plait wigs [3]. Styling aids not only correct the hair, but can also help transform hair for those with hair loss or hair damage resulting from medical concerns – hairsprays give lift to thinning hair, smoothing creams help tame unruly frizz, and gloss serums can help restore a more youthful shine. This chapter describes the wide variety of hair styling aids – their basic chemistry, utility, and potential issues that clinicians need to be aware of in their everyday practice.

Hair styling is the act of reshaping the hair mass to an arrangement or style that can be maintained over time. Hair, by its nature, is easily reshaped when wet and dried or through the application of heat; however, because of hair’s susceptibility to atmospheric humidity these changes require the assistance of chemical styling aids to maintain the shape over time. Styling aids with polymers can help improve hair volume and height by increasing hair strand stiffness and hair fiber interactions. Styling aids with emollients and waxes can help smooth out frizz and increase hair shine by aligning fibers and reducing friction and can also have a conditioning effect on the hair fibre (Figure 33.1). Styling products, such as sprays, gels, and waxes, modify only the surface of hair – not the structure itself. These products are not meant to be permanent, unlike permanent waves and chemical straighteners, and the majority of these products are designed for easy removal by shampooing.

256

Physiology Hair strands are made up of lengths of bundles of keratin polymer chains [4]. These chains are linked by two main types of bonds: strong and weak (Figure 33.2). Strong bonds are made of cystein amino acids and can only be broken chemically (e.g. by permanent wave solutions). Weak bonds include van der Waals, salt bonds, and hydrogen bonds which can be affected by changes in water concentration alone [5,6].

33. Hair styling

Figure 33.1 Styling aids can provide improved appearance of hair volume and smoothness. (a) Frizzy unruly hair dried without styling aids. (b) Frizzy unruly hair smoothed with application of styling aids. (c) Fine/thin hair dried without styling aids. (d) Fine/thin hair volumized through the application of styling aids.

(a)

(b)

(c)

(d)

Interaction

Strong

CH2 – S – S – CH2

Cystein bonds

CH2NH3+ –O2C – CH2

Salt bridging

C = O . . . HN CH2 – OH. . . .O = C

Figure 33.2 Mechanisms to stabilize hair structure and shape via keratin chain interactions [7].

Weak

Only affected by chemical treatment (perm)

CH2 – CH2 – CH3 CH3 – CH2 – CH2

Affected by water Hydrogen bonds

van der Waals interaction

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Wet setting is the mechanism of shaping hair strands through controlled wetting and drying conditions. Hydrogen bonds can be easily opened by humidity or water accessing the hair from the environment. Rearrangement of the hydrogen bonds will occur by removing water while drying and reformation of new bridges into a different shape by holding the hair strand in the desired shape while drying. Unfortunately, these new bonds are also susceptible to humidity from the environment and may revert back to their natural state of frizzy, curly or weak, straight hair over time. Styling aids help make the styling process and finished style to be more independent of the molecular interactions inside the hair and more robust against environmental influences because the polymers are less affected by humidity. With the correct polymers, adequate deposition, and sufficient distribution of styling product significant style holding

power can be achieved. Figure 33.3 shows hair treated with styling aids in a high humidity environment will keep the shape much longer than wet set hair alone.

Formulation Because of very different hair structures, needs, and fashion trends a very broad range of styling products covers today’s consumer needs and demands (Figure 33.4). In general, there are two technologies to differentiate: • Polymer-based formulations that cover hair with a film and form dry welds between hair strands: • Advantage: high mechanical strength, dry touch, gloss • Disadvantage: will break with mechanical stress, cannot be reformed once broken except by rewetting • Wax and emollient-based formulations that deposit hydrophobic material on hair. These hydrophobic materials do not dry over time and create fluid bonds that can be broken and reformed. • Advantage: no spot welds will break, interaction of single hair fibers can be opened and closed again, styling is remoldable • Disadvantage: limited mechanical strength, in high concentrations can feel waxy/oily, potentially look negative on thin hair

Polymer formulations

Excellent product Poor product Wet setting

Figure 33.3 Curl retention with and without addition of spray in high humidity (85% relative humidity [8].)

Speciality stylers

Smoothers

Hairsprays, gels, mousses, and liquid settings work on the principle of film-forming polymers. The active ingredients can be divided into three groups: 1 Film-forming polymers: main ingredient in application such as hairsprays and gels but also as minors in waxes. 2 Conditioning and film-forming polymers: usually in wet applications such as mousses to improve wet combability. 3 Rheology modifier: usually does not contribute to fixation but controls consistency of the product.

Core stylers

Waxes classic Soft waxes

Emulsions Pomades Microemulsions

Shine fluids

Aerosol-waxes and emulsions

Aerosolpomade

Wax sticks Liquid settings

Hairsprays

Polymer based speciality stylers

Mousses

Pastes and putty

Gels

Aerosols Figure 33.4 The broad range of modern styling aid forms and chemistries.

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33. Hair styling

Table 33.1 Typical ingredients for polymer-based styling aids. Ingredient (INCI)

Function

PVP (Polyvinylpyrrolidone)

Film former

Octylacrylamide/Acrylates/Butylaminoethylmethacrylate Copolymer

Film former

PVP/VA Copolymer (PVP/Vinylacetate)

Film former

PQ-11

Film former

PQ-16

Film former

PQ-4

Film former

Chitosan (derived from Chitin)

Film former

Carbomer (cross-linked Acrylic Acid)

Rheology modifier

Acrylates/Ceteth-20-itaconate Copolymer

Rheology modifier

Hydroxyethylcellulose

Rheology modifier

Alcohol

Solvent

(x)

Water

Solvent

(x)

Dimethicone

Plasticizer

Panthenol

Moisturizer

Propane/butane

Propellant

DME (Dimethylether)

Propellant

Ethylhexymethoxycinnamate

UV-absorber

PEG-40-hydrogenated Castor oil

Emulsifier

Laureth-4

Emulsifier

Aminomethylpropanol

Neutralizer

Phenoxyethanol

Preservative

Methylparaben

Preservative

Fragrance

Scent

These film-forming active ingredients are modified to optimized performance by additional ingredients such as emollients (including silicone), solvents, plasticizers, fragrance, and preservatives. Table 33.1 provides a list of typical ingredients found in polymer-based styling aids.

Hairspray

Gel

Mousse

x x

• Cream emulsions: contain three main types of ingredients: water, emulsifiers, and oil/wax components. Consistency from soft lotion to rich cream. Table 33.2 provides a list of typical ingredients found in wax and emollient-based styling aids.

Wax and emollient formulations The area of waxes and emollients covers a broad range of products: • Pure waxes: water-free formulations often without preservatives. Mostly compact appearance and provide high control. Matte (i.e. low shine) derivatives are also called clay, paste, or putty.

Product forms, application, and uses Hairsprays and liquid settings Aerosol hairspray is one of the most widely used styling products. The ease of use and broad application areas make it a versatile tool for stylists and consumers. These products

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Table 33.2 Typical ingredients in wax and emollient-based styling aids. Ingredient (INCI)

Function

Wax

Cream

Carnauba wax

Hard wax

Paraffin liquid

Oil

PEG-60 (Polyethylene glycol)

Wax

Cetyl alcohol

Wax

PEG-90M (Polyethylene glycol high molecular)

Creates thread-like consistency

PVP (Polyvinylpyrrolidone)

Film former

PVP/VA Copolymer (PVP/Vinylacetate)

Film former

Carbomer

Stabilizer

Hydroxyethylcellulose

Stabilizer

Triceteareth-4-phosphate

Emulsifier

PEG-24 hydrogenated Castor oil

Emulsifier

PEG-40-hydrogenated Castor oil

Emulsifier

Dimethicone

Care/combability

Panthenol

Moisturizer

Ethylhexylmethoxycinnamate

UV-absorber

Aminomethylpropanol

Neutralizer

Phenoxyethanol

Preservative

Benzyl alcohol

Preservative

Fragrance

Scent

Figure 33.5 Hairspray bond – spot weld.

are usually finishing products and are applied in the very last step of styling on dry hair. Aerosol hairsprays contain a solution of polymer ingredients, alcohol, water, and liquefied propellants under pressure. The release of propellant pressure during dispensing results in a fine mist of polymer-

260

x (x)

x x

containing liquid that deposit on the hair fibers, spreads, covers hair, and forms spot welds between the fibers (Figure 33.5). Besides the aerosol version, hairsprays are also sold in non-aerosol sprays where distribution of the liquid to droplets is done mechanically by a pump. These sprays are perceived by consumers to be wetter than aerosol hairsprays on application because of the bigger droplet size resulting from the pump spray mechanism. The main ingredients of hairsprays in general are: • Polymer: film-forming polymer; • Solvents: ethanol, water; • Propellant: e.g. Dimethylether (DME), Propane/butane, Fuorinated Hydrocarbons (HF-152 A) for VOC-formulations in USA; • Additives: e.g. silicones, UV-absorber, vitamins; • Fragrance; • Non-aerosols have similar ingredients only without any propellant. Hairsprays have been the target of regulatory restrictions ever since the banning of CFHC-based propellant com-

33. Hair styling pounds in the 1970s because of concerns about the ozone layer. A more recent development has been the restriction of volatile organic compounds (VOCs) to 80/55% of hairspray formulas in the USA. Formulas have now been developed that substitute propellants judged to have a lower risk of impacting the ozone layer water (such as Hydrofluorocarbon 152A or HFC 152A) and an increased proportion of water in the formulas. While initially this negatively impacted hairspray performance, more recently new polymer systems have been developed to work at these lower alcohol and higher water contents [9]. Hairsprays are safe when used as directed; however, there are some potential issues surrounding misuse. First, aerosols can create a fine mist of droplets which may be inhaled. Hairspray manufacturers carefully check the droplet size and proportion of the formulas and dispensers in order to avoid significant inhalable quantities of droplets to insure consumer safety during typical use at home or in a hair salon [10]. Additionally, hairsprays need to be removed periodically by shampooing. Hairspray polymers have been formulated to breakdown in the presence of shampoo surfactants. However, if hair is not shampooed frequently, hairspray and other styling aids can build up on the hair causing dullness, potential hair breakage, and polymer flaking reminiscent of dandruff. Setting lotions are a special application form of hairspray and pump-spray. The formulation is similar but the usage is different. Typically, the damp hair is prepared with rollers and the product is applied from a small bottle with a nozzle. After blow-drying the rollers are removed and the hair is brushed. The deposition of polymer increases surface friction and creates volume, the main benefit of this product type. One significant consumer segment has gray hair and uses lotions containing blue dyes to make their hair color brighter and less yellowish. Overdosing and build up resulting from low shampoo frequency may cause a bluish appearance of the hair that can be removed by washing.

In the last 25 years gels became more popular for a more visible styling effect. Today, gels are designed to create every style from smooth hold to extreme looks with spikes to express personality or fashion. The use depends strongly on habits; different looks result if applied to wet hair or dry hair or when the hair is blow-dried or air-dried. Spray gels start at the lower end of the hold scale and provide a well-groomed look. Spray gels are easy to apply evenly throughout the hair. The consistency is usually from water-thin to low viscous. Tube gels have a medium to high viscosity and represent the upper end of a hold scale. The amount of film-forming polymer usually determines the hold level. Typical ingredients for gels include: • Thickener: e.g. polyacrylates (carbomer), polysaccharides; • Polymer: “film former”; • Moisturizer: e.g. glycerin for wet look; • Solvents: water, ethanol; • Additives: e.g. silicones, UV-absorber, vitamins; • Preservatives: e.g. paraben types, phenoxyethanol; • Fragrance. Removal of a gel requires shampooing – in some cases a second lathering is recommended. Dry, brittle gels with high hold levels may tend to generate flakes when touched, similar to hairsprays. Build up is not usually observed with regular shampooing. Some gels may also be sold as creams as their appearance is not clear but turbid to white and texture is more rich and soft than a typical gel.

Mousse

Creams, pomades, and emulsions

Mousses belong also to the widely used products such as hairsprays. Typically, they are wet application products for volume in combination with a blow-dryer. As combing and/ or brushing are important parts of the styling procedure, good wet combability is a base requirement. Mousses in general consist of: • Polymer: mostly quaternized, single or in combination with other cationic on non-ionic polymers (“film former”); • Surfactants • Solvents: water, ethanol • Additives: e.g. silicones, UV-absorber, vitamins; • Propellant: e.g. propane/butane, DME; • Fragrance; • Non-aerosol mousses have similar composition without propellants but a mechanical actuator to create the mousse.

Creams, pomades, and emulsions are a growing segment which contains very specialized niches for texture and styling results. The common base of cream-like products is always: • Hydrophobic base such as wax, oil, or related chemistry; • Water, mainly as the continuous phase (oil-in-water emulsions); • Emulsifier combination. The composition and structure of the emulsion control the application properties. By adding polymers the level of hold can be modified, the texture might be changed by adding polymeric thickeners or particles such as bentonite or diathomaceous earth to provide a rough, clay-like feel with a matte effect to take away shine. The following list shows typical components:

As mousses contain cationic charged polymers they may interact in special conditions (hair structure) with anionic polymers from hairsprays. The resulting complex could be hard to remove because of its poor solubility. Repeated shampooing in combination with a conditioner will remove depositions. Overdosing may create a weighted down effect, residues, reduction of shine, or appearance of white flakes similar in appearance to dandruff.

Gels and spray gels

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• Wax compound: • Synthetic: e.g. paraffin type, polyethylene glycol • Natural: e.g. carnauba wax, bees wax • Surfactants/emulsifiers: Trideceteareth-4-phosphate • Solvent: water; • Polymers: if required for hold or texture; • Additives: e.g. silicones, UV-filter, vitamins; • Particles (optional): e.g. bentonite, silica for special texture; • Preservatives: e.g. paraben types; • Fragrance. Application is related to desired effect or style in dry or damp hair for finger styling. Usually, this procedure is part of the finishing touches to a hairstyle. The advantage over polymer-based formulations is the softer nature of hair and the remoldability of the style without reapplication of new product. A special type of emulsion is the clear jelly-like microemulsion. One attribute is the so-called ringing effect that will be recognized when the jar is held with two fingers and another finger hits the container. These formulations contain a high amount of surfactants so formulators must keep in mind irritation, especially eye irritation, in their selection of ingredients. In combination with sweat there is a risk of running into the eye. Good formulations contain a combination of emulsifiers and surfactant that are not irritating in in vitro and patch testing.

Waxes and clays Water-free waxes are a special group that provides strong control and bigger effects than cream-like products. Their consistency is harder and application needs more education or skills by the consumer – especially to prevent overusage and build up. • Wax compound: • Synthetic: e.g. Polyethylene glycol • Natural: e.g. Carnauba wax, Bees wax

• • • • •

Surfactants/emulsifiers: only for washability; Additives: e.g. silicones, UV-filter, vitamins; Particles: e.g. bentonite, silica for special texture; Preservatives: usually not required; Fragrance: if desired. Application is on damp or dry hair similar to creams. The stiff consistency requires warming in the hands before application. Shampooing and use of conditioning agents remove waxes, but in some cases may require repeated application to ensure no build up is formed after repeated usage.

Silicone serums and sprays Silicones – mostly used as oils – are a part of many of the formulations described above to add care properties, improve combability, shine, or modify polymer-based formulations as plasticizer. Apart from this use of silicones, some formulations are mainly based on silicones. The main benefit of these products is to provide pure shine or highlight strands to finish the styling process (Table 33.3). Formulations differ from application form and heaviness of the effect: 1 Serums: • Oily liquids that provide long-lasting, high gloss effects; • Contain low volatile silicones and low amounts of solvents such as alcohol; • Designed to highlight strands, no fill head application; • Have to be carefully applied by hands – need expertise in use. 2 Pump sprays: • Are lighter in effect than serums; • Effect is less durable as the silicones are more volatile; • Contain solvents such as alcohol; • Easier to apply for consumers; • Also for full head application.

Table 33.3 Typical ingredients in silicone products. Ingredient (INCI)

Function

Serum

Spray/Aerosol

Dimethicone

Shine enhancer

Dimethiconol

Shine enhancer

Cyclopentasiloxane

Shine enhancer

Alcohol

Solvent

Propane/butane

Propellant

Panthenol

Moisturizer

Ethylhexymethoxycinnamate

UV-absorber

Fragrance

Scent

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33. Hair styling 3 Aerosol sprays: • Are comparable to pump sprays in performance; • Designed to intensify gloss of styling for finish; • Also suitable to refresh shine. Table 33.4 shows hair products according to categories, physical description, typical applications, and desired result.

Products designed for African hair types Hair of people of African descent has always been treated very differently from Caucasian or Asian hair. The structure of African hair is different from other hair types, as its extreme curvature is thought to be caused by the different profile of the hair shaft, which may be caused by differences in the morphology of the upper hair follicle. African hair has a distinctively more oval profile than Caucasian or Asian hair (Figure 33.6). These structural characteristics go hand in hand with further challenges when styling African hair, especially as the time and effort spent on styling African hair tend to be higher than Caucasian hair for example: heightened brittleness of the hair shaft, regular use of relaxing chemistry, knotting, braiding, use of extensions. Excessive braiding and the use of extensions can often cause strain on the hair shaft in the follicle and therefore can lead to temporary hair loss,

which is often seen especially along the hairline of the forehead and the partings. The majority of the African specialty styling products are targeted at helping to relax and smooth the curly African hair. Therefore, most products (such as brilliantines and pomades) contain high levels of waxes and oils and/or polymers. These ingredients deliver the hold African hair needs and are typically applied with the fingers and whole hand to achieve good coverage and maximum hold benefits. Another advantage of the high levels of oils and waxes in these products, but also in other products like oil sheens, is that they enhance the light reflected from the hair surface, which gives especially dark hair a more healthy appearance. Lotions are often used to protect the hair shaft and are useful for African hair as it tends to be more brittle and more prone to breakage. Lotions are mainly emulsions that offer combinations of conditioning ingredients and styling ingredients. The conditioning ingredients (such as silicones and fatty alcohols) protect the hair and enhance its appearance. Lotions are highly beneficial for African hair as they have a good efficacy as leave-in products and as they can help to counteract the negative effects of the variety of damaging styling techniques used.

Table 33.4 Hair products (categories, physical description, typical applications, desired result). Category

Physical description

Typical applications

Desired result

Typical packaging

Hairspray (aerosol)

Liquid, clear, low viscous

Spray with propellant on dry hair after styling

Hold of finished styling, invisible net

Aerosol can, aluminum or tinplate with actuator

Hairspray (non-aerosol pump spray)

Liquid, clear, low viscous

Spray without propellant on dry hair or on damp hair for blow-drying

Hold of finished styling

Bottle with mechanical actuator

Gel/Gel spray

Medium to viscous, clear jelly-like consistency

Dry hair for air drying or wet hair for blow-drying

Visible styling effects, shaping of hair bundles, creating spikes, etc.

Tube or dispenser

Mousses

Soft, creamy mousse, semi-stable that breaks under mechanical stress

Wet hair with blow-drying, rollers might be used, typically brushed

Volume and hold

Aerosol can

Emulsions

Creamy consistency, typically white appearance, soft feel, and slightly fatty touch

Mostly wet hair, but also dry hair as finish product

Weight down effect, antifrizz properties, alignment, and control of shape, moldability

Jar, tube, or dispenser

Waxes

Tough to hard consistency that melts under mechanical stress

Dry hair

Visible styling effects, bundling of hair, textured looks, also matte effects desired

Jar

Silicones

Clear, oily liquids

On dry hair for styling purpose with fingers or as spray

Pure shine in addition to hold provided by styling products applied before

Small bottles

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(a)

(b)

Figure 33.6 Comparison of African (a), Caucasian (b), and Asian (c) hair structure.

(c)

As the vast majority of African specialty products tend to have higher levels of styling polymers and/or waxes/oils, it is crucial to wash the hair regularly to prevent excessive build up and associated hair negatives.

Considerations for consultations with patients about hair styling Despite the many advantages and fundamental benefits for appearance – and consequently confidence – misuse of styling products can have an adverse effect on the hair quality and appearance [11,12]. Often, patients overuse or misuse styling products, and especially styling appliances, in their quest for a better appearance. For example, the misuse of heat styling appliances has wide consequences for the hair

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quality, as studies have shown [13]. Some modern heat styling appliances operate with temperatures of well over 200 °C, which is beyond the temperature that the hair’s molecules, especially keratin and its amino acids, can withstand without major structural damage. Patients with high heat styling needs and habits should be advised to use tailored products that have a reduced heat output and/or tailored technology to minimize hair damage and overheating. Furthermore, modern ion technology in heat styling appliances can help to reduce some adverse effects from excessive heat styling. Mechanical stress whilst heat styling is one factor that can cause damage to the hair fiber. Therefore, the use of appliances especially designed to reduce hair damage during the heat styling process is recommended. Design features of these include low friction styling surfaces such as ceramics, flexible plates, etc.

33. Hair styling Other potential issues with styling products include overuse or mix of the wrong styling product technologies. Overuse of styling products without removal through proper hair hygiene can lead to negative effects on the appearance and tactile properties of hair. The polymers used as main actives can – when overused and not removed – accumulate on the hair surface and can lead to dullness, adhesion of dust and dirt, and to hair being less easy to manage and prone to tangling – the opposite effect to what users are trying to achieve. Because of the character of the ingredients used, styling products are generally safe to use. However, as with other cosmetic products, in rare cases the use of some styling products may be associated with allergies or irritations if there is a history of contact allergic reactions to selected ingredients. These may stem from single ingredients in the product formulations such as fragrance ingredients. Even though the risk of this is low because of limited prolonged contact of the products with skin, in case of irritations or adverse reactions that could be associated with styling products, it is advisable to investigate the type of product used, and the ingredients contained, and to identify known allergies of the patient. In case of an identified allergic reaction, dermatologists are advised to patch test the patient and/or to contact the manufacturer of the product to find out about the nature of the ingredients used in the product. In consultations with patients concerning styling-related issues, it is imperative to assess the specific hair-related issues of the patients first and then to understand what styling and haircare products were used. This should enable a good understanding of what caused the issues and the psychologic impact on the patient. The advice to patients with hair styling-related issues should be focused on the right selection, and the right amount of styling products targeted at their hair needs and used in combination with a good quality haircare regime. Often manufacturers of high quality haircare and styling products tailor their different product technologies to match and provide maximum styling benefits with minimum negative effects. A recommendation to patients who overuse or misuse styling products should include a recommendation to reduce the amount and to select the right products.

Future of hair styling aids – trends and technologic development As there are continuous research efforts dedicated to hair, the knowledge of hair (hair biology, hair structure, and hair biochemistry) is growing and will continue to grow in the future. Styling aides are a prime example that trends and science and technology advancements are closely interwoven. Over the course of the last 50 years or so, emerging trends demanded new technologies to be developed to

enable the creation of new hair styles. Vice versa, the development of new styling technologies enabled the creation of new trends in fashion and beauty. One example is the trend of “big hair” in the 1980s which drove the development of maximum volume and hold products, which in turn allowed for the creation of even bigger hair styles. A key development over the years, which will continue into the future, is the focus on ease of use of the new styling products to enable everybody to create impressive styles. Consequently, the current science and technology advancements will – no doubt – have a profound effect on future trends and will enable new hair styles that everybody can create and recreate, from the most advanced fashion stylists to consumers in their homes.

Conclusions Styling aids come in a wide variety of types and are used by many to augment hair appearance. Familiarity with the range and use of hair styling aids will help a clinician not only diagnose potential problems arising from misuse or allergy, but can also help when counseling those with thinning, aging, or damaged hair. Styling products can impart the appearance of healthier hair by improving hair shine and smoothness, increasing the appearance of hair amount by building in body and volume.

References 1 Gray J. (2007) Assessment of Hair Quality Using Eye Tracking Technology. London: Royal Society of Medicine Press, p. 2. 2 Rosenthal A. (2004) Raising hair. Eighteenth Century Studies 38 (1), 1–16. 3 Lucas A, Harris JR. (1999) Ancient Egyptian Materials and Industries. Courier Dover Publications, p. 332. 4 Wella AG. (2001) The Fascination of Hair. Available from Procter & Gamble Service GmbH, Berliner Allee 65, 64274 Darmstadt, Germany, pp. 6–7. 5 Robbins CR. (2002) Chemical and Physical Behavior of Human Hair, 4th edn. Springer, pp. 133–4. 6 Wella AG, Schwan-Jonczyk A. (2003) Haar umformung, 1st edn. Pocter & Gamble Service, Darmstadt, Germany, pp. 10–11. 7 Umbach W. (2004) Kosmetik und Hygiene, 3rd edn. Wiley-VCH, Weinheim, Germany, pp. 264–7. 8 Wella AG. (2001) The Fascination of Hair. Pocter & Gamble Service, Darmstadt, Germany, p. 43. 9 Pfaffernoschke M. (2005) Formulating low VOC aerosol hairsprays. Int J Aerosol Spray Pack Technol April. 10 Zviak C. (1986) The Science of Hair Care. New York: Marcel Dekker, pp. 167–8. 11 Gray J. (1997) World of Hair: A Scientific Companion. MacMillan Press. 12 Gray J. (2000) Human Hair Diversity. Oxford: Blackwell Science. 13 German Wool Research Institute (2007) Study on the Effects of Heat on Human Hair Structure. Aachen, Germany: DWI.

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Section IV Antiaging

Part 1: Cosmeceuticals Chapter 34: Botanicals Carl Thornfeldt CTDerm, PC, Fruitland, ID, and Episciences, Inc., Boise, ID, USA

BAS I C CONCEPTS • Botanicals represent a class of frequently used active agents in cosmeceuticals. • The constituents of a botanical can be influenced by growing conditions, harvesting procedures, the part of the plant utilized, and extraction methods. • Botanical extracts must be evaluated for cleanliness, purity, and contaminants. • Botanicals contain terpenoids, alkaloids, and phenolics, which have been chemically characterized for their biologic effects. • Products containing botanical extracts should be rigidly evaluated using the scientific method for efficacy.

Introduction The number of skincare products with “active” ingredients extracted from plants has increased to annual sales of $12.5 billion [1]. Herbs are species of higher plants whose extracts have medicinal, fragrance or flavoring use [2]. One-quarter of US adults used an herbal remedy to treat a medical illness in 2003 [3]. Herb-based products usually also provide multiple functionalities and stable formulations of highly reactive ingredients such as antioxidants. While it is difficult to create efficacious and stable cosmeceutical formulations, herbs contain unique active ingredients normally existing in nature [4]. While 73% of women polled said it is important to have younger looking skin, the vast majority of topical botanical products promise youth but lack clinical evidence [5]. It remains unclear whether antioxidants actually improve photodamaged skin [6]. The vast majority of the more than 320 herbs used in skincare products are at concentrations far below therapeutic ranges.

International regulations A surprising 78.7% of women polled did not know that claims made for skincare products are not regulated, evaluated, or verified by any governmental agency [4]. Only in the USA are herbal products sold as dietary supplements Cosmetic Dermatology: Products and Procedures. Edited by Z.D. Draelos. ©2010 Blackwell Publishing.

which is governed by the Dietary Supplement, Health and Education Act, 1994. Such products are intended to affect the structure and function of the human body, not just as an energy source. Certain US cosmeceutical ingredients may be claimed to be therapeutic for very common skin diseases. They are regulated as over-the-counter (OTC) drug monographs for acne, dermatitis/psoriasis, skin protectant, topical analgesia, and sunscreens, by the Food and Drug Administration (FDA). Non-prescription products that list the active ingredients used in a certain concentration range in certain formulations may claim the finished product to be effective and safe therapy for the specific skin conditions listed in the FDA OTC drug monographs [4]. Regulation of herbal products is under federal law in Germany, Japan, Australia, India, China, and the European Union. The German Commission E approves traditional phytomedicine products based on the quality of scientific clinical evidence of the herbal effects upon diseases and conditions as well as its safety. Certain herbs may be registered as prescription medicines if the evidence of therapeutic effect compares to synthetic ingredients. In Japan, herbal products may be prescription drugs but also may be OTC “quasi-drugs,” or in functional foods. Both of the latter are allowed to make very restricted therapeutic claims [2,7,8]. There is no consistent definition of “natural” in US skincare products [9]. It was recently recommended that a definition of natural might read: “Five percent or more of the ingredients are found in nature.” In contrast, organic products are certified free of synthetic chemicals during agriculture and product manufacture [8]. The FDA has certification criteria for this designation.

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Factors affecting concentration and quality of active ingredients The skincare practitioner should select an herb for a specific desired beneficial effect based on scientific research and/or traditional medical knowledge founded on ethnobotany. The interest in phytomedicines for improving health, as well as treating disease, is rapidly growing resulting in many exotic species creating cosmeceutical fads. Most of these exotic ingredients are added at subtherapeutic doses for marketing cache, as little is known about their efficacy and safety. Some herbs are obtained by wildcrafting, which is harvesting wild plants for commercial use. Unfortunately, this activity has brought certain plant species, such as American ginseng (Panax quinquefolium), to the brink of being an endangered species as a result of unregulated overharvesting. It is important that all botanical species are harvested in a sustainable fashion, noting those substances that are listed on the International Trade in Endangered Species of Fauna and Flora (www.cites.org) [10]. Herbal extracts exhibit more variation than synthetic products because of solubility, stability, pharmaco*kinetics, pharmacology, and toxicity of the active ingredients. Sources of variability include: 1 Growing conditions of the plant contribute to variation in botanical extracts. These variables include climate, habitat, weather including catastrophes such as hurricanes, time of year, elevation, number of sunny days, hours of daylight, amount of rain or lack thereof, soil conditions such as leaching of nitrogen in a year of heavy rain fall, wind conditions, type and amount of fertilizer, ambient temperatures, pests, and plant disease exposure, and if cultivated or in its natural habitat, plant growth periods and diurnal variation. 2 The conditions following harvesting may also affect the constituents of the botanical. These variables include harvesting time, care of botanical products during transport, storage time for the botanical, processing methods, and manufacturing of the finished product. 3 The biologic activity of the herbal extract is affected by the condition of the plant, which must be healthy and disease free [11]. 4 Botanicals are affected by the portion of the plant selected for harvesting. There are differences in the mix and concentrations of the active ingredients between flowers, berries, stems, bark, roots, and rhizomes. Familiarity with phytomedicine is important to ensure the recommended product contains the correct plant parts for the desired effect. 5 Proper processing is necessary to insure herbal potency. The timing, degree, and type of processing determine the functionality of the herbal product. The first step in processing is air or oven drying to achieve a moisture content ≤10% and prevent mildew. This material is then milled into pieces less than 1 cm in diameter. If the desired actives are highly 270

sensitive to light, heat, dessication, oxygen, or enzymes, they need to be extracted without drying as soon as the plant is harvested. For example, volatile essential oils evaporate during drying so the plant source should undergo steam distillation as soon as harvested. Other processing methods include crushing, pressing, grinding, comminuting (fracturing) followed by extraction [2,8,10,11]. The methods for extraction are discussed below.

Extraction methods The active ingredients of plants are generally small molecules not involved in regular metabolic processes, known as secondary metabolites (SM). The goal of extraction processes is to improve consistency of SM concentration, increase SM potency, and increase product purity. The most common extraction method is placing the dried plant material in the solvent of choice. The extraction duration and temperature must be optimized. Milled dried plant material is exposed to one or more solvents selected from water, alcohol, butylene glycol, glycerin, methanol, and an oil or ester. Herbal enzymes, such as cellulases, may be used to break cell walls releasing SM. A secondary purification is usually performed with a different solvent after alcohol extraction. Column chromatography is then used to separate the resulting two or more solutes. Ultrafiltration or nanofiltration are used to purify aqueous extracts. A “green” extraction process uses CO2 supercritical fluids, which includes pressure and low heat to convert CO2 into a fluid is the most efficient methods to extract non-polar constituents such as carotenoids and essential oils. Nitrogen blankets used during filling of the final packages significantly prolong stability of SM with highly reactive SM such as catechins and salicylates. The standardization of the SM in the extract for consistency is performed by analytical chemistry methods, including chromatography and/or a DNA fingerprint [2,10,11].

Quality control The major quality issues of herbal products revolve around the extract itself. Other significant issues involve quality of the finished product regarding its safety and product effectiveness. Quality control evaluation must include: 1 Identify the active SM and the plant part with the optimum concentration for desired activity. 2 Evaluate cleanliness of extract. Foreign organic matter is limited to 2% dry weight and ash value of 3–5% by weight by the US Department of Agriculture. 3 Purity must be determined to ensure no destructive adulterants or microbes are present. Dangerous adulterants

34. Botanicals include: heavy metals, radioactive ingredients, and most pesticides. Salmonella and Escherichia coli are microbial contaminants that must not be present in herbal formulations. 4 Contaminants may reduce activity since they may dilute the SM out of the therapeutic concentration. Because most synthetic pharmaceutical and cosmeceutical active ingredients produce their cutaneous modulation at 1% or less, even the above allowed concentrations of foreign organic material may dilute SM enough to blunt expected product activity. Maximum concentration limits for more than 30 pesticides have been set by the US Pharmacopia in the chemical tests section for dietary supplements but not for cosmetics. Pesticides not listed in this reference are known as toxins and must not be present in any product [2,10,11].

Safety The US woman uses an average of nine products daily on her skin, so the skincare professional has an obligation to be concerned about product safety. Thus, safety studies should be performed on all herbal products. Fortunately, the incidence of dangerous adverse reactions to herbal medicines is extremely rare. The clinical relevance of topical safety tests is that 40% of US women claim to have sensitive skin [2,4–6]. A “natural” product does not equal a safe product. Chinese practitioners are concerned about the well-known side effects of hepatotoxicity, contact dermatitis, and teratogenicity which occur in up to one-third of people using topical Chinese herbal preparations. Moreover, a significant number of congenital anomalies occur when these herbs are used topically during pregnancy [12]. Another risk of herbal products is the relatively high incidence of cross-reactivity with other herbs. For example, in 106 dermatitis afflicted people, 12 were allergic to tea tree oil and all 12 had one or more patch test reactions to 10 other herbs [13]. A preferred safety test for a cosmeceutical product would be the Repeat Insult Patch Test (RIPT) on 50 panelists to evaluate risk of contact irritant and allergic dermatitis with topical use. It will not predict systemic reactions, however, such as gynecomastia with topical lavender [2,11].

Effectiveness Double-blinded, placebo-controlled studies do not exist for all ancient and herbal medicines. Yet, there have been many such studies conducted on herbal products throughout Asia, India, and Europe [12]. Rarely, herbal products have shown statistically significant superiority to placebo or an approved prescription drug in double-blind clinical trials, which is the most convincing scientific evidence of therapeutic efficacy. The vast majority

have never undergone this type of clinical evaluation because cosmetics cannot claim cutaneous structure change, but only temporary change in appearance claims. Cosmeceutical claims for a product should be supported by at least one double-blind clinical trial with enough panelists to determine statistical significance [2,5,6]. A major challenge to the clinical efficacy of any herbal extract is the delivery of therapeutic concentration(s) of the desired active ingredients across the stratum corneum intact to affect organelles, cells, receptors, and metabolic and cell signaling pathways. The different solubilities, polarities, size, and architecture of the several to hundreds of SM in herbal extracts creates difficulty. Moreover, the degree of biodegradability, biocompatibility, toxicity, release profile, and antigenicity also vary among the multitude of SM in one extract. Contributing to the challenge is different SM bind to cells and receptors in different cutaneous strata. To meet this challenge of negotiating the tortuous proteohydrolipid stratum corneum several novel methodologies have been developed. The first group is biochemical delivery via manipulating the barrier itself by: 1 Modulating the synthesis of the three key physiologic lipids of stratum corneum lipid lamellae: cholesterol, ceramide, and free fatty acids; as well as the metabolism and catabolism of them. 2 Inducing phase separation within and between the lipid lamellae with application of anomalous or excess three key lipids and their precursors [14]. The second group consists of manipulation of the formulation itself using microemulsion, liposome, phytosome, nanoemulsion, nanocrystal, nanosome, or pearlescent beads. These methods enhance bioavailability, depth, and speed of penetration and increase concentration of SM delivered [15]. Microemulsions use lecithin and alkyl glucoride to encapsulate non-polar molecules including arbutin, kojic acid, and cinnamates. Liposomes often composed of soy phospholipids, deliver hydrophilic, lipophilic, and amphiphilic compounds such as 2% citrus into the outermost epidermal strata. Phytosomes consist of herbal extracts complexed within phospholipids. Silymarin’s soothing activity was increased by sixfold, while grape seed, gingko biloba, hawthorn, green tea, and ginseng respond better in phytosomes than liposomes. Other herbal SM are delivered by nanotechnology. Ginseng’s delivery is also improved with nanosomes. Flavonoids have increased delivery with nanocrystals where large crystals are milled in a water-based stabilizer solution producing nanometer-sized drug crystals. Nanoemulsions have a droplet size of 20–300 nm with those ≤70 are transparent and >100 are opaque. Both hydrophilic and lipophilic herbal extracts have increased bioavilability with these nanoemulsions. Aloe vera has improved delivery when formulated in pearlescent beads [15]. Finally, mechanical modulation of the barrier can be affected by sound waves (sonophoresis), electrical current, 271

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ionic gradients (iontophoresis), vibration, ultrasound, water stream devices, and microdermabrasion infusion.

Mechanism of action of herbal actives via secondary metabolites Phytomedicines usually consist of mixtures of molecules which often act on two or more human cellular processes to treat and/or prevent diseases. These multifunctional extracts usually consist of multiple SM. Plants are also equipped with protective defensive mechanisms, which include low molecular weight compound SM. SM are not used in primary metabolic processes such as photosynthesis, respiration, assimilation of nutrients, transport, growth, or differentiation. They are rarely used as storage compounds, but usually provide protection against UV light and herbivores, such as parasites and pathogenic microbes as well as animals. SM are also useful for producing color and smell to attract pollinators and for seed dispersal. Certain fatty acids and carbohydrates function within both metabolic processes and as SM. The purified SM are equal in activity to synthetic molecules if equal concentration and weight. About 20% of the higher plants have been studied with spectrometry, nuclear magnetic resonance, and/or X-ray diffraction which have identified about 40 000 SM. Several have been useful to humans for millennia such as indigo for dye, strychnine and curare for poisons, caffeine and nicotine as stimulants, essential oils such as rosehip and lavender for fragrances, as well as mustard, vanilla, and turmeric as food spices [2]. To produce a measurable or clinical effect the SM must modulate at least one molecular target in human skin but often multiple are affected because SM usually reside within complex mixtures with other SM. The molecular targets occur at any of the cell sites such as: • Cell membrane receptors, ion channels, phospholipid bilayer, transporters, signal transduction; • Cytoplasm: enzymes, cytoskeleton actin, microtubules; • Ribosomes: protein biosynthesis, post-translational protein modification; • Gogli apparatus: post-translational protein modification, protein biosynthesis, enzymes; • Lysosome: enzymes; • Mitochondria: enzymes, electron transport, nucleic acid replication, transcription and repair; • Nucleus: nucleic acid replication, transcription and repair; • Endoplasmic reticulum: biosynthetic enzymes. SM are divided into more than 15 500 terpenoids, 12 000 alkaloids, and 6000 phenolics that have been chemically characterized from herbal extracts, as have 10 other chemical classes representing the other 6500 SM [2,11]. Terpenes are generally highly lipophilic compounds that readily penetrating organism and cellular membranes

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including the blood–brain barrier. Monoterpenes consist of 10 carbon atoms, sesquiterpenes have 15, diterpenes have 20, triterpenes have 30, tetraterpenes have 40, and polyterpenes up to 1000 carbon atoms. Most essential oils are monoterpenes and sesquiterpenes. Phytosteroids contain 27 carbon atoms, are derived from triterpenes, and mimic the functionality of endogenous glucocorticoids. Saponins are water-soluble triterpenes with attached saccharides that are synthesized by 70% of all plants. They are also antiinflammatory, inhibit phospholipases, oxygenases, complex with membrane cholesterol and modulate nuclear receptors to impact gene function, increase cell membrane fluidity, modulate the architecture of the membrane itself, damage ionic channels and membrane transporters to induce cell content leakage and disturb signal transduction, while providing broad-spectrum antimicrobial effects and cytotoxicity effects. Sesquiterpene lactones have a high risk of inducing allergic contact dermatitis. Carotenoids such as beta-carotene, lutein, lycopene, and zeaxanthine are tetraterpenes. About 15% of plants synthesize alkaloids. The targeted cell functions include: neuroreceptor agonist, ionic channels, neurotransmitter deactivating enzymes, uptake and release of synaptic vesicles, ionic channel restoring enzymes, and modulate signal pathway enzymes such as adenyl cyclase, phosphodiesterase, phospholipase C, protein kinase C, and tyrosine kinase. They also intercalate or alkylate DNA, inhibit microtubular assembly, inhibit carbohydrate processing enzymes, and induce aptosis. Caffeine is an alkaloid. The third major group of SM are compounds that have a phenolic (6 carbon) ring. Polyphenols have several rings of different numbers of carbon atoms. Phenolics are antiinflammatory, antioxidant, antimicrobial, and modulate cell replication. Well-known phenolics include salicylic acid, salicin from willow bark, cinnamic and caffeic acids, furocoumarins, psoralens, and lignans. This phenylpropanoid subgroup is the foundation for flavonoids, which includes naringenin; isoflavones such as genistein, flavones, and flavonols; stilbenes such as resveratrol; chalcones such as liquiritin; catechins such as epigallocatechin gallate (ECGC); and anthocyanins. Tannins are catechins with 20 or more hydroxyl groups. Catechins polymerize to form oligomeric procyanidins (OPCs). The greater number of hydroxyl groups in catechins is correlated with greater therapeutic potency of the extract. Other biologic effects of certain phenolic SM inhibition of tyrosine kinases, astringent, denatures protein, agonist for signal transduction and inhibits enzymes and prostaglandin and leukotriene formation as well as alkylate DNA and bind peptides and proteins. Mucilages contain hexose and pentose polysaccharides to soothe skin. A polyketide used in cosmeceuticals for depigmenting and antibacterial activities is arbutin [2,10,11].

34. Botanicals

Cosmeceutical product development Producing an effective and safe non-prescription topical product requires complying with a known development path to overcome previously mentioned challenges. Laboratory data of function of an herbal extract cannot lead to the assumption of its effectiveness in treating human skin conditions with topical application because only 1 in 350 new chemical entities by in vitro data reach human prescription drug approval by the FDA. Moreover, of the 8000+ known antioxidants, only about 30 have been tested in human clinical studies to treat photoaging, with only 20 producing statistically significant positive results. This product development path should also be followed to ensure the finished product is safe. One must be aware that US fatalities have been reported to topical use of 10 different herbal extracts including arnica and comfrey. Herbs rich in certain SM, particularly sesquiterpene lactones extracted from feverfew and arnica, induce a high rate of allergic reactions including life-threatening anaphylaxis. Certain companies have developed manufacturing processes to remove toxic parthenolide and helanaline in feverfew and arnica, respectively, from the marketed products. Remember cosmeceutical products with these extracts are not regulated, so buyer beware of the risk to the user. Allantoin, the oldest SM in time of market use, is now synthesized rather than extracted from comfrey to improve consistent potency [7,8,11,12]. To help separate true scientifically based herbal cosmeceuticals from “snake oil” products, and before making a decision on retailing or recommending any particular brand of skincare product, the practitioner should ask the following questions: 1 Is the herb being used in other living breathing organisms (i.e. used as a veterinary or dental medicine), or a part of traditional Asian or homeopathic medicines, or used in food technology for mammalian exposure? 2 Is the biologically active or therapeutic concentration range known and used in the cosmeceutical? 3 The development of the formulation should include chemical, physical, and photostability to ensure efficacy and that toxic metabolites are not formed. Stability with other interacting actives must be achieved as with other ingredients necessary to product a cosmetically acceptable product. Every human tissue contains 6–8 antioxidants to regenerate each other or they become pro-oxidants. How can a practitioner expect significant, much less optimal, clinical results with a single antioxidant SM? 4 Does the herbal SM penetrate the stratum corneum permeability barrier in its active state at a high enough concentration to manipulate its target cell, organelle, enzyme, receptor, or compound? Soothing mucilage or occlusive SM function by placement upon the mucocutaneous surface, thus need not penetrate SC.

5 When was the finished product manufactured? Freshness matters with herbal products. All cosmeceutical active ingredients including antioxidants, vitamins, and herbal SM undergo chemical reactions when combined in any formulation. This auto-oxidation reaction is affected by formulation manufacturing method. For example, heating speeds up the auto-oxidation process. Thus, the longer the time between product use from the manufacturing date is important in regards to optimum clinical benefit or lack thereof and increased risk of adverse reactions. Caution must be raised for any cosmeceutical that is sold by companies where products are contract manufactured in small quantities because minimum production volumes may be 12–18 months of finished product. If the product has been tested for stability for an 18-month period, then the preservative system is robust and the product can claim stability for the tested period. 6 Does the product really work in the skin? The only way a skincare practitioner can confidently recommend and sell herbal cosmeceuticals that are not based on “ingredient of the month” or “voodoo science” is by a prospective, doubleblind, controlled clinical trial for treatment of any or all parameters of photoaging. These trials must include enough panelists to establish statistical significance with a p value <0.05 against placebo or an approved prescription product. The tested product should be the final marketed formulation, not just one marquee ingredient in a stripped down preservative formulation. The clinical trial should be conducted by an established independent researcher. The FDA has established these studies are sufficiently unbiased to draw valid conclusions of product efficacy, even when paid for (sponsored) by a company. The tested parameters should include panelists’ subjective analysis of visible changes, not just statistical measurements to assure clinical relevance of the statistics. Observations of employee responses are not considered unbiased. If the herb is approved the German Commission E or other international regulatory group, its efficacy and safety have been thoroughly reviewed. 7 Has the skincare practitioner thoroughly evaluated the product? Patients/clients when consulting with a skincare practitioner assume that any product has undergone the practitioner’s evaluation for efficacy and safety. They expect the practitioner to be a clearing house for accurate information for all skin products, prescriptions, and treatments. Moreover, the patient/client assumes the practitioner uses the same criteria to establish which prescription drugs and treatments are offered as is used to determine which cosmeceuticals are recommended and sold. Patients/ clients do not consider themselves “profit centers” so practitioners should fulfill their Hippocratic obligations and commitments. The cosmeceutical product development steps include the following:

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1 Select and optimize the ingredient concentrations of the excipients of the type of a formulation (i.e. gel or lotion) to maximize the physicochemical activity and stability of the active ingredients. 2 Select and optimize the suitable stratum corneum penetration enhancers based on the physicochemical properties of the active. 3 Document the active ingredient will leave the formulation to cross through the membrane permeability barrier. 4 Document the permeation of the active ingredient through human stratum corneum. Also document the concentration to make sure it is high enough to produce the desired clinical effect. 5 Conduct human in vivo localized patch studies for formulation cosmetic acceptability, and to see if the formulation effectively changes a visible skin parameter such as roughness, wrinkling, or erythema. These human tests are much more accurate than animal tests because human skin is about six times more resistant to penetration than mouse skin. 6 The basic safety test is the aforementioned RIPT. 7 Determine the excretion and catabolism of the SM if it is not known to establish clearance from the body. This information is available if the extract is used in other biologically active systems such as health care, or food or veterinary fields. 8 Perform human double-blind clinical studies as previously mentioned [4,7,8,16,17]. To ensure effective delivery through the stratum corneum permeability barrier of an herbal SM requires employing the following principles of drug delivery (dermatopharmaco*kinetics): 1 The SM must be completely dissolved in the vehicle molecules. 2 Completely cover the skin surface with the formulation. 3 The SM must be released from the topical formulation and move (partition) into the lipophilic stratum corneum. 4 The SM must permeate through the entire stratum corneum. 5 The SM must partition into the aqueous epidermis. 6 The SM must permeate through the entire epidermis, transit through the basem*nt membrane into the dermis if the SM targets reside there. 7 The SM is excreted via dermal vasculature or catabolized in the epidermis or dermis. Failure of the formulation to comply with any of these principles will likely result in performance failure or inadequate clinical response to the product [14]. When evaluating the scientific validity of clinical trial data several factors must be considered: 1 Was the herbal product compared head to head with an approved prescription or heavily studied non-prescription product, or placebo controlled? 2 Were the same parameters including anatomic site, duration, time of year, frequency of use, climate, age of patient, and race compared?

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3 Determine if the trial was conducted in-house or sponsored like an FDA trial and conducted by an independent research organization. 4 Was the finished marketed product studied? 5 Has the data been presented in peer reviewed journals or as poster exhibits at refereed meetings such as the American Academy of Dermatology? 6 Do the panelists observe any visible or palpable skin changes on subjective analysis?

Specific safety issues Certain regulatory and safety issues have been published. These include: 1 The National Cancer Institute has officially recognized the chemopreventive effect of glycyrrhizia, a primary constituent of licorice (Glycyrrhiza glabra) [18]. 2 Allantoin is listed in the US FDA OTC drug monograph as a skin protectant at 0.5–2.0% concentration [19]. 3 Oat is approved as an US FDA OTC drug monograph as skin protectant at 0.007% concentration if the only active in a bath or by weight in a bath with oil [20]. 4 Lavender has demonstrated toxicity to fibroblasts. Topical lavender products induced gynecomastia in one boy and two teenagers using lavender products with high concentrations over widespread areas of their body for many months [3,8]. 5 Tea tree oil (Melaleuca alternifolia) is a potent UV photosensitizer and phototoxic agent, so be careful using products containing it for use on sun-exposed body parts [3,7,8].

Specific herbs with esthetic utility There have been multiple reviews of herbal-based products in dermatology and cosmetic journals in the past 2 years. Licorice, green tea, soy and its isoflavones have been discussed in at least 18 recent publications, and so will not be included. This review is focused on herbs that were cited in 5–15 publications. More than 50 other herbs were cited 1–4 times each. The major clinical parameters evaluated in clinical studies for products treating photoaging include tactile roughness, mottled hyperpigmentation, fine lines, wrinkles, laxity, sallowness, and neoplasia. Many of the 320 herbs mentioned in publications in cosmeceutical products for treatment of skin aging and conditions are antioxidants. Of the approximately 900 herbs used in industry and traditional medicine reviewed by this author, 190 have anti-inflammatory functionality. About 130 of these contain antioxidant SM while the other 60 consist of anti-inflammatory natural steroids, salicylates, and other non-antioxidants. Table 34.1 consists of the 27 herbal extracts used in topical cosmeceuticals and/or oral products tested in human clinical

34. Botanicals

Table 34.1 Antiaging with clinical studies in humans.

Table 34.2 Emollients.

Aloe (Aloe barbadensis, A. capensis, A. vera) Apple (Malus domestica)

Almond (Prunus dulcis) Aloe (Aloe barbadensis, A. capensis, A. vera)

Avocado (Persea americana)

Black cohosh (Cimicifuga racemosa)

Borage (Borago officinalis)

Blueberry (Vaccinium myrtillus): oral only

Coconut (Cocos nucifera)

Cat’s claw (Uncaria guianensis, U. tomentosa)

Cucumber (Ecballium elaterium)

Coffeeberry (Coffea arabica)*

Fenugreek (Trigonella foenum-graecum)

Date palm kernel (Phoenix dactylifera)*

Grape (Vitis vinifera)

Flax (Linum usitatissimum)

Jojoba (Simmondsia chinensis)

German chamomile (Matricaria recutita)†

Licorice (Glycyrrhiza glabra, G. inflate, G. uralensis)

Grapefruit (Citrus paradisi): oral only

Macadamia (Macadamia integrifolia, M. tetraphylla)

Grape seed (Vitis vinifera): oral only

Peanut (Arachis hypogaea)

Green tea (Camellia sinensis)*†

Pomegranate (Punica granatum)

Lavender (Lavandula angustifolia)

Safflower (Carthamus tinctorius)

Licorice (Glycyrrhiza glabra, G. inflate, G. uralensis): oral only

Sesame (Sesamum orientale)

Mangosteen (Garcinia mangostana)

Slippery elm (Ulmus rubra)

Meadowfoam (Limnanthes alba) Mushroom–wheat complex Pomegranate (Punica granatum)† Rose hips (Rosa canina) Safflower (Carthamus tinctorius) Soy milk, total soy (Glycine soja, G. max), Soy protease inhibitors*† Sweet orange (Citrus sinensis): oral only Tomato (Lycopersicon esculentum): oral only White sandalwood (Santalum album) White tea (Camellia sinensis)† White willow (Salix alba) * Single active in product;

†

Is oral + topical administration.

trials, either double-blinded or open label, that effectively treated signs of photoaging. Only four extracts contained one herb as the sole active ingredient: coffeeberry, date palm kernel, soy milk, total soy and soy protease inhibitors [21–25]. Green tea was used as a solitary active but was administered orally and topically in the studies [17,24]. The other 22 herbs were used in products with mixtures of only herbs or with synthetic active ingredients. Seven mixtures were tested with double-blind, controlled clinical trials against placebo or approved prescription topicals including: 1 Purified date palm, meadowfoam, flax, avocado, safflower, apple, rose hips, and lavender [26]. 2 White willow, date, and meadowfoam [27]. 3 Green tea, white tea, mangosteen and pomegranate, aloe, grapefruit, lavender, soybean, sweet orange, and synthetic antioxidants [28]. 4 Bisabolol from chamomile, caffeine, glycyrrhetinic acid from licorice along with two synthetic active ingredients [29]. 5 Cat’s claw and ursolic acid with two synthetic antioxidants [30]. 6 Black cohosh with two synthetic antiaging actives [31].

7 Multiple mushrooms and a wheat protein proprietary mix [32]. Three oral preparations containing mixtures of synthetic and herbal antioxidants selected from those listed on Table 34.1 has positive clinical trials for reversing photoaging [16,33]. A number of herbal extracts are claimed to modulate one or more abnormalities which occur in extrinsically aged skin. Thus, these should be beneficial in reducing visible skin aging. Table 34.2 consists of 16 herbs that yield effective emollient SM to reverse photoaging roughness and replace petroleum emollients [3,7,8,25–32,34–37]. The lighteners/ brighteners in Table 34.3 consist of 25 herbs documented to lessen or reverse mottled hyperpigmentation, melasma, and/ or lentigines [3,7,8,25–32,34–37]. The eight tighteners in Table 34.4 reverse skin laxity and help reverse fine lines and cellulite [7,8,25–32,34–37]. Table 34.5 consists of SM found to modulate nucleic acids which include cat’s claw and six types of mushrooms [7,8,38]. Table 34.6 lists photoprotective herbs. These 11 herbs are used as solitary actives or in mixtures but are all administered orally [3,7,8,25–32,34–38]. Orally administered photoprotective products should be an important lifestyle adjunct as only 40% of the population routinely wear sunscreen [39]. Incorporating active herbal extracts into mineral makeup also assists in photoprotection [40].

Aloe (Aloe barbadensis, A. capensis, A. vera) Aloe may cross-react in people allergic to garlic, onions, and tulip. The leaves are the best source for SM. The gel is rich in aloe resins, dithranol, chrysorobin, allantoin, salicylates, flavonoids, and polysaccharides. Aloe is antibacterial to Heliobacter pylori, Bacillus subtilis, and methacillin-resistant Staphylococcus aureus. It is anti-antihistaminic (AH), antiinflammatory (AI), and antioxidant (AO). This herb increases

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Table 34.3 Lighteners/brighteners.

Table 34.6 Photoprotective.

Aloesin (Aloe barbadensis, A. carpensis, A. vera) Bearberry (Arctostaphylos uva-ursi)

Black tea (Camellia sinensis) Cocoa (Theobroma cacao): oral only

Black mulberry (Morus nigra)

Feverfew (Tanacetum parthenium)

Blueberry (Vaccinium angustifolium)

Golden fern (Polypodium leukotomas): oral only

Blue skull cap (Scutellaria lateriflora)

Grapeseed (Vitis vinifera)*

Carrot (Daucus carota)

Green tea (Camillia sinensis)*

Citrus fruit flavonoid [Hesperidin]

Oat (Avena sativa)

Cranberry (Vaccinium macrocarpon, V. oxycoccos, V. erythrocarpus)

Olive (Olea europea)

Cucumber (Ecballium elaterium)

Pomegranate (Punica granatum)*

Echinacea (Echinacea angustifolia, E. pallida, E. purpurea)

Tamarind (Tamarindus indica)

Ginseng, American (Panax quinquefolius)

White sandalwood (Santalum album)

Ginseng, Asian (Panax ginseng) Ginseng, Siberian (Eleutherococcus senticosus)

* Is oral + topical administration.

Gingko (Gingko biloba) Grape seed (Vitis vinifera) Hibiscus (Hibiscus sabdariffa) Indian gooseberry (Emblica officinalis) Licorice (Glycyrrhiza glabra, G. inflata, G. uralensis) [ammonium glycyrrhizinate], [glabridin], [liquriritin] Pear (Pyrus communis) Saxifrage (Pimpinella saxifraga) Soy (Glycine soja, G. max) White mulberry (Morus alba) White willow (Salix alba) Wormwood (Artemisia absinthium)

collagen synthesis and is a vasoconstrictor. Aloe gel is antiviral against herpes simplex, varicella zoster, and influenza. This gel had positive clinical trials for both psoriasis and herpes simplex therapy. Wound healing and acne have had mixed results in clinical trials. Aloe did not decrease UVBinduced erythema in a human in vivo study. Aloesin extract is a potent tyrosinase inhibitor and inhibits UV-induced melanogenesis but less so than kojic acid. As one of five herbal ingredients plus synthetic antioxidants, aloe effectively reversed the signs of photodamaging in a placebo controlled trial [7,8,19,37,41].

Yellow dock (Rumex crispus, R. obtusifolius)

Bromelain and papain – enzymes from pineapple (Ananas comosus) Table 34.4 Tighteners. Birch (Betula alba) Gingko (Gingko biloba) Hops (Humulus lupulus) Horse chestnut (Aesculus hippocastanum) Peppermint (Mentha piperita) Red sandalwood (Pterocarpus santalinus) Rose hips (Rosa canina) Spearmint (Mentha spicata) Witchhazel (Hamamelis virginiana)

Table 34.5 Modulates nucleic acids. Cat’s claw (Uncaria guianensis, U. tomentosa) Mushrooms: Agaricus blazei Cordyceps sinesis Coriolus (Tremetes versicolor) Maitake (Grifolia frondosa) Reishi (Ganoderma lucidum) Shiitake (Lentinula edodes)

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These cysteine proteinase enzymes of pineapple stem and root have skin débridement, AI, and anticarcinogenic (AC) properties. Allergic reactions to these may cross-react with wheat, grass, celery, carrot, echinacea, chamomile, ragweed, marigold, and daisy. The clinical effects on therapy of traumatic and surgical cutaneous injury had both positive and negative clinical studies [7,8,36].

Coffee (Coffea arabica, C. canephora) Coffea arabica yields three commercial products: coffee beans which are the seeds, the fruit which is coffeeberry, and coffee charcoal which is roasted (until black) green fruit. The major actives of coffee include purine alkaloids such as caffeine, theobromine, and theophylline from the beans and caffeine from the charcoal. The beans also include the phenolics caffeic, chlorogenic, and ferulic acids, diterpenes, phytoestrogens, and magnesium. Coffee charcoal is approved by German Commission E for mucositis therapy. Coffee beverage is AO. Adverse reactions include three deaths from rectal enemas; coma, stroke, and anaphylactic immunoglobulin E (IgE) reactions are rare. Caffeine extracted from the C. arabica leaf is the major ingredient in many cellulite products which are supported by human clinical trials. Murine studies suggest caffeine has

34. Botanicals AC effects similar to green tea catechins while improving skin roughness and fine lines [42]. Coffeeberry extract is obtained from subripe coffee fruit which is rich in such polyphenols as chlorogenic and ferulic acids, proanthocyanidins, and saccharides. The Oxygen Radical Absorbance Capacity (ORAC) score is allegedly 10fold higher than green tea, 20-fold higher than vitamin C, yet is only one-sixteenth that of feverfew. A 6-week, double-blind study of a formulation with only coffeeberry as the active used on 20 females applying it to the full face compared with baseline concluded there was a significant 30% improvement in hyperpigmentation, 20% improvement in fine lines and wrinkles. In a 10 female, split face companion trial versus placebo there was a significant 25% vs. 3% improvement in fine lines and wrinkles and a 15% vs. 5% improvement in hyperpigmentation [7,8,22,32,43].

Feverfew (Tanacetum parthenium) About 40 SM are extracted from this total herb or only a leaf. Parthenolide is a sesquiterpene lactone that is the most active SM but also the most toxic. Other SM include the flavonoids, tanetin and apigenin, polyynes, volatile oils such as camphor, chrysanthyl acetate, linalool, and melatonin. The commercially available powdered leaves lack sesquiterpene lactones, yet are AC, AI, AH, AO, photoprotective, vasoconstrictor, inhibit serotonin release and gene transcription. Feverfew’s ORAC for AO activity score is 144 000 which is 16-fold stronger than coffeeberry’s score. Its inhibition of tumor necrosis factor (TNF) release was 35–1000 times higher than black, green, and white tea, echinacea, chamomile, aloe vera, and licorice. This tremendous AI potency resulted in developing methods to extract the dangerous parthenolide. A double-blind study of 31 women with sensitive skin using a parthenolide-free feverfew moisturizer twice daily for 3 weeks produced statistically significant decrease (p < 0.05) in erythema, tactile roughness, and overall irritation. It was also effective therapy for shaving irritation. Feverfew is a Compositae so it cross-reacts with marigold, daisy, ragweed, bromelain, arnica, and chamomile. Feverfew should not be used during pregnancy and lactation, or in children under 2 years of age [3,7,8,32,35–37,43].

German chamomile (Matricaria recutita) The major SM of this herb are mucilages extracted from the entire plant. Volatile oils such as bisabolol and flavonoids such as apigenin, quercetin, chalmazulene, rutin, and coumarins are extracted from the flower. Chamomile has AC, AH, AI (superior to 0.5% hydrocortisone), and AO effects as well as antibacterial against staphylococcus, antiviral, and anticandida. It is an effective wound healing and inflammatory skin condition therapy as approved by German Commission E. It is reported to relieve rough, xerotic, inelastic skin and signs of photodamage.

This herb is a member of the Compositae family thus cross-reacts with marigold, daisy, ragweed, arnica, feverfew, and bromelain. There has been at least one death to anaphylactic reactions and uncommonly allergic contact dermatitis occurs [1,3,7,8,32,36].

Golden fern (Polypodium leucotomos) This herb has documented therapeutic efficacy in clinical trials for vitiligo, psoriasis, sunburn, phototoxic and UVAinduced photodamage when administered orally. A topical 10–50% concentration lotion also reduced photodamage in vivo. The primary SM are obtained from the rhizome and aerial parts. These include the phenolics, chlorogenic, ferulic, and caffeic acids. This extract is AI, inhibits mast cells, AO yet stimulates humoral immunity. Orally administered golden fern significantly decreases erythema, sunburn cells, mast cells, pyrimidine dimers (p < 0.05), and epidermal proliferation while reducing loss of Langerhans cells in nine panelists with Fitzpatrick type II or III skin. In another trial treating 25 panelists with polymorphous light eruption and solar urticaria with 480 mg/day orally, 41% improved more than 50% compared with baseline [3,24,32,35–37,44–46].

Grape (Vitis vinifera) Grape products are obtained from the seed, fruit, fruit skin, and leaf. They are rich in flavonoids including quercetin, tannins, monomeric catechins, oligomeric proanthocyanidins (OPC) polymers, resveratrol, and fruit acids. These SM provide potent AC, AH, AI, AO, and vasodilating matrix metalloproteinases (MMP) inhibition, stabilize collagen, and are cytotoxic to neoplastic cells. The OPCs in grape are 50fold more potent than AO vitamins C or E. They also stimulate terminal hairs from telogen to anagen phase increasing hair growth. There is a significant correlation between total phenolic content, pro-anthocyanidin content, and AO activity of the grape product. Taken orally, grape seed significantly reduced melasma in Japanese women by 6 months. When combined in an oral antiaging product with soy, white tea, chamomile, tomato, fish protein, and polysaccharides it improved skin firmness and structures by 6 months. There is one report of non-fatal anaphylactic reaction to grape skin [3,7,8,33,47,48].

Milk thistle (Silybum marianum) Silybin, a flavonoid, accounts for 75% of the volume of this extract taken from the seeds or total plant. It provides AC against human skin cancer cells, AI, inhibits UVB sunburn, AO, and stabilizes membranes. Other SM from the seeds include fatty oils and other flavonoids such as apigenin and quercetin. The total herb also contains sterols, glucosides, fumaric acid, and polyynes.

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This herb is a member of the Compositae family thus cross-reacts with ragweed, marigold, daisy, arnica, chamomile, feverfew, and bromelain allergy [7,8,16,17,36].

Mushrooms The major medicinal mushrooms come from Asian traditional medicine. These include Cordyceps sinensis, Coriolus (Trametei versicolor), reishi in Japan, lingzhi in China (Ganoderma lucidum), maitake (Grifola frondosa), and shiitake (Lentinus edodes). Less known are Agaricus blazei, Hypsizygus ulmarius, and yambush*take (Hericium erinaceum). The entire herb body is a rich source of immune stimulating polysaccharides such as beta glucan. Mushroom extracts also contain potent AO peptides, triterpenes, polyphenols, and AI sphingolipids. These SM have AC, AI, AO, and broadspectrum antibacterial and anti-HIV effects. Maitake inhibits in vitro photoaging markers on UVA-exposed human fibroblasts. Several mushrooms inhibit MMPs and activating protein-1. In a 45 patient 4-week in vivo study, a mushroom– wheat protein complex was used twice daily to induce epidermal cell renewal and turnover. An open clinical study of topically applied mushroom complex treated 31 women with moderate photoaging. Statistically significant improvements in texture, clarity, and fine lines within 4 weeks, and irregular pigmentation, overall photoaging, with improved pinch recoil by 8 weeks versus baseline occurred [3,7,8,24,35–37].

Oat (Avena sativa) This herb has been approved by German Commission E for treatment of inflamed skin, which have been supported by positive clinical trials for relief of pruritic skin, xerosis, and seborrheic dermatitis. The SM are extracted from bran, whole grain, or dehulled kernels. They include polysaccharides, such as beta glucan, steroid saponins, flavonoids such as apigenin, and polyphenols such as avenathramide, phenolics including caffeic and ferulic acids, hydroxycinnamate, coumaric acids, and tocotrienols. Oat is AI, AO, and UVA blocking. Avenanthramides at 3% were nearly comparable to 1% hydrocortisone in anti-inflammatory effect. In an open trial treating epidermal growth factor receptor agonists, 60% achieved complete remission and 30% partial response of the acneiform eruption that afflicts two-thirds of these patients. Oat can be safely used in people with celiac disease. Contact dermatitis to oat occurs infrequently [3,7,8,20,32,35–37].

Pomegranate (Punica granatum) Pomegranate juice and fruit contains more polyphenols than green tea, red wine, cranberry, blueberry or orange juice, with AO activity three times higher than green tea or red wine. Other SM include tannins such as ellagic acid, citric and tartaric acids. Pomegranate juice is antiviral

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HIV, antibacterial to Staphylococcus aureus, antifungal, and antiparasitic. Pomegranate seed oil is also rich in linoleic acid and estrogenic substances. It stimulates keratinocyte proliferation, AC, and AO. The major SM of pomegranate fruit peel is a group of tannins that improve wound healing as well as inhibiting MMP-1, increase procollagen synthesis by fibroblasts, raises the minimal erythema dose (MED) to UVB with oral ingestion. Its ellagic acid inhibits melanin synthesis. In one open human trial, oral (300 mg) twice daily plus topical sunscreen and topical pomegranate raised the MED to UVB to a significant degree (p < 0.05) [1,3,7,8,36].

Pycnogenol (Pinus pinaster, P. maritima) This herbal extract is from the bark of the French maritime pine tree. Its SM include flavonoid monomers, dimers, oligomers and polymers of catechins, epicatechin, and taxifolin. These larger molecules are known as OPC. Pycnogenol also contains phenolics such as ferulic, caffeic and coumaric acids, and polysaccharides. Pycnogenol has AH, AI, and AO functions, by recycling ascorbic acid and tocopherol. This ingested herb effectively treats chronic venous insufficiency, reduces UVB-induced photosensitivity and sunburn, stimulates wound healing, inhibits MMPs, stimulates cellular and humoral immunity. Clinical trials document it is effective therapy for psoriasis, atopic dermatitis, and lupus. In a 30-day, open human clinical trial for melasma therapy, there was highly statistical significant (p < 0.001) decrease in melasma area and pigment intensity with oral dose at 30 mg, three times daily [1,7,8,17,24,49].

Turmeric (Curcuma longa, C. domestica) This herb is best known as the food spice, curry. Curcumin is the therapeutic component extracted from the rhizosome that is AC, AI, AO, and stimulates wound healing. SM include volatile oils such as tumerone, the source of the aroma; curcuminoids including curcumin, the yellow pigment; and polysaccharides. Tumerone inhibits mast cells. Curcumin has weak estrogenic effects binding to estrogen and progesterone receptors, prevents genetic transcription, suppresses MMPs, has greater AI than ibuprofen, and inhibits angiogenesis while stimulating immunity. Curcumin is antibacterial, antiviral against HIV, and antiprotozoal. When combined with neem, it effectively treated scabies with topical application. Topical curcumin is considered one of the few safe therapies for radiation dermatitis wound repair. Turmeric extracts should not be used in pregnancy [1,3,7,8,32,33,50]. Scientific evaluation of herbal extracts have found clinically valuable SM common to several of the herbs to have known effectiveness in treating skin conditions. These include allantoin, apigenin, bisabolol, beta-carotene, caffeic

34. Botanicals acid, caffeine, ellagic acid, ferulic acid, genistein, lutein, lycopene, quercetin, resveratrol, soy proteinases, sesquiterpene lactones, and triterpenes.

Conclusions The use of botanicals remains a very active area of research in cosmetic formulations. Their popularity is in part a result of the perceived safety of botanicals, which are derived from nature. Consumer perceptions of botanicals as positive ingredients also make them a welcome addition to otherwise mundane formulations. This chapter has evaluated some of the key considerations when evaluating and testing cosmetic products.

References 1 Choi C. (2006) Seminars in cutaneous medicine and surgery. Cosmeceuticals 25, 163–8. 2 VanWyk BE, Wink M. (2004) In: Medicinal Plants of the World. Portland, OR: Timber Press, pp. 16–26, 371–94. 3 Baumann L. (2007) Less-known botanical cosmeceuticals. Dermatol Ther 20, 330–42. 4 Winnington P. (2007) Skin care and medical dermatology. Pract Dermatol Nov, 35–44. 5 Baumann L. (2007) Products promise youth, but lack evidence. Dermatol Times Dec, 56–63. 6 Matsui M, Spencer J, Draelos Z. (2008) Anti-oxidants: truth or hype? Dermatol Times 19, 26. 7 Greenwald J, Brendler T, Jaenicke C, eds. (2007) PDR for Herbal Medicines, 4th edn. Montvale, NJ: Thomson Healthcare. 8 Jellin JM, ed. (2007) In: Natural Medicines Comprehensive Data Base, 9th edn. Stockton, CA: Therapeutic Research Faculty. 9 Draelos Z. (2008) Optimizing redness reduction, part 2. Cosmet Dermatol 21, 433–6. 10 Cornuelle T, Lenhart J. (2006) Topical botanicals. In: Cosmetic Formulations of Skin Care Products. New York: Taylor and Francis, pp. 299–308. 11 Skidmore-Roth L. (2006) Herbs and Natural Supplements, 3rd edn. Philadelphia, PA: Elsevier Mosby, pp. xiii, xvii. 12 Koo J, Arain S. (1999) Traditional Chinese medicine in dermatology. Clin Dermatol 17, 21–7. 13 Jancin B. (2002) Cross-sensitivity in tea tree oil allergy. Skin Allergy News Mar, 38. 14 Thornfeldt C, Mak V, Elias PM, Feingold FR. (1999) Interference of stratum corneum lipid biogenetics: an approach to enhance transdermal drug delivery. In: Bronaugh RC, Maibach HI, eds. Percutanous Absorption. New York: Marcel Dekker, pp. 418–25. 15 Chanchal D, Swarnlata S. (2008) Novel approaches in herbal cosmetics. J Cosmet Dermatol 7, 89–95. 16 Rabe JH, Marmelak AJ, McElgunn PJ, Morison WL, Sauder DL. (2006) Photoaging: Mechanisms and repair. J Am Acad Dermatol 55, 1–22. 17 Bruce S. (2008) Cosmeceuticals for attenuation of extrinsic and intrinsic dermal aging. J Drugs Dermatol 7, (Suppl 2), S17–S22. 18 Craig WJ. (1999) Health promoting properties of common herbs. Am J Clin Nutr 70, 4915–95.

19 Draelos Z. (2008) Cosmetic consultation. Cosmet Dermatol 21, 433–6. 20 Kurtz E, Wallo W. (2007) Colloidal oatmeal: history, chemistry and clinical properties. J Drugs Dermatol 6, 167–70. 21 Bauza E, Dal Farra C, Berghi A, Oberto G, Peyronel D, Domloge N. (2002) Date palm kernel extract exhibits antiaging properties and significantly reduces skin wrinkles. Int J Tissue React 24, 131–6. 22 Cohen J. (2007) Coffeeberry. Skin Allergy News 1, 34. 23 Wallo W, Nebus J, Leyden J. (2007) Efficacy of a soy moisturizer in photoaging: a double-blind, vehicle controlled, 12-week study. J Drugs Dermatol 6, 917–22. 24 Berson D. (2008) Natural antioxidants. J Drugs Dermatol 7 (Suppl), 7–11. 25 Baumann LS, Wu J. (2008) Cosmeceutical Critique Compendium. Skin Allergy News Suppl, pp. 1–19. 26 Thornfeldt C, Sigler M. (2006) A cosmeceutical with novel mechanisms of action effectively reduces signs of extrinsic aging. Poster presented at: Am Acad Dermatol 64th Annual Conference, San Francisco, CA. Poster 1128. 27 Thornfeldt C, Sigler M. (2006) Comedolytic anti-inflammatory cosmeceutical reduces signs of maturity. Poster presented at Am Acad Dermatol 64th Annual Conference, San Francisco, CA. Poster 229 28 Hsu J, Skover G, Goldman M. (2007) Evaluating the efficacy in improving facial photodamage with a mixture of topical antioxidants. J Drugs Dermatol 6, 1141–8. 29 Lupo M, Cohen J, Rendon M. (2007) Novel eye cream containing a mixture of human growth factors and cytokines for periorbital skin rejuvenation. J Drugs Dermatol 6, 725–9. 30 Smiles K, Walfield M, Yarosh D. (2006) Remergent barrier repair formula restores many aspects of skin health. Proprietary Report, AGI Dermatics. Freeport, NY. 31 Rao J, Erhlich M, Goldman M, et al. (2004) Facial skin rejuvenation with a novel topical compound containing transforming growth beta and vitamin C. Cosmet Dermatol 17, 705–10. 32 Wu J. (2008) Anti-inflammatory ingredients. J Drugs Dermatol 7 (Suppl), 13–6. 33 Skougaard G, Jensen A, Sigler M. (2006) Effect of novel dietary supplement on skin aging in post menopausal women. Eur J Clin Nutr 60, 1201–6. 34 Yarosh D. (2008) The New Science of Perfect Skin. New York: Broadway Books, pp. 62–73, 100. 35 Baumann LS. (2007) Botanical ingredients in cosmeceuticals. J Drugs Dermatol 6, 1084–7. 36 Baumann LS. (2005) Advancing the science of naturals. Cosmet Dermatol Suppl 18, 51–8. 37 Baumann LS. (2006) Cosmeceutical Critique Compendium. Skin Allergy News Suppl pp. 3–23. 38 Bruno G. (2008) An herbal powerhouse. Healthy Aging Jan/Feb, 39–41. 39 Lewis W. (2007) Cosmeceuticals roundup. Plastic Surg Products Sept, 38–42. 40 Saluja R, Yosowitz G, Goldman M. (2007) Evaluation of mineral cosmetics. Cosmet Dermatol 20, 382–7. 41 Jin Y, Lee S, Chung, M. (1999) Aloesin and arbutin via a different action mechanism. Arch Pharm Res 22, 232–6. 42 Viera M, Sadegh M, et al. (2008) What’s new in natural compounds for photoprotection. Cosmet Dermatol 21, 279–89.

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43 Charurin P, Ames J, Del Castillo M. (2007) Antioxidant activity of coffee model systems. J Agric Food Chem 50, 3751–6. 44 Middlekamp-Hup M, Puthak M, Parrado C, et al. (2004) Oral Polypodium leukotomos extract decreases ultraviolet induced damage of human skin. J Am Acad Dermatol 51, 910–8. 45 Caccialanza M, Percivalle S, Piccino R, et al. (2007) Photoprotective activity of oral Polypodium leukotomos extract in 25 patients with idiopathic photodermatoses. Photodermatol Photoimmunol Photomed 23, 46–7. 46 Baumann LS. (2007) Melasma and its newest therapies. Cosmet Dermatol 20, 349–53.

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47 Yamakoshi J, Sano A, Tokutake S, et al. (2004) Oral intake of proanthocyanidin-rich extract of grape seeds improves chloasma. Phytother Res 18, 895–9. 48 Zhu W, Gao J. (2008) The use of botanical extracts as topical skin lightening agents for the improvement of skin pigmentation disorders. J Invest Dermatol 13, 20–4. 49 Ni A, Mu Y, Gulati O. (2007) Treatment of melasma with Pycnogenol. Phytother Res 16, 567–71. 50 Wu J. (2006) Treatment of rosacea with herbal ingredients. J Drugs Dermatol 5, 29–32.

Chapter 35: Antioxidants and anti-inflammatories Bryan B. Fuller University of Oklahoma Health Sciences Center, and Therametics, Oklahoma City, OK, USA

BAS I C CONCEPTS • An antioxidant is a molecule that prevents the oxidation of other molecules thereby protecting cells from damage caused by free radicals. ) and the hydroxyl radical ( iOH ). • The most common oxygen radicals in the body are the superoxide anion ( O•− 2 • Free radicals cause extensive and irreversible damage to proteins, DNA, and lipids, with serious consequences affecting cell survival, malignant transformation, and the development of disease. • Antioxidants include vitamin C, vitamin E, curcumin, green tea, carotenoids, and ubiquinone. • Anti-inflammatories include botanical extracts, corticosteroids, non-steroidal anti-inflammatories, and immunomodulators. • Endogenous antioxidants and anti-inflammatories are necessary to prevent damage that contributes to both extrinsic and intrinsic aging.

Antioxidants The use of oral and topical antioxidants to provide protection from and treatments for various diseases, including cancer, and to prevent aging, has gained considerable popularity over the past 25 years. While it is clear that antioxidants such as vitamins C, E, A, and carotenoids can protect cells from free radical damage, it is not clear whether taking large quantities of antioxidants can prevent the occurrence of disease or slow the aging process. Some clinical studies have suggested such a role for antioxidants, while other studies have not provided clear evidence that antioxidant supplements can reduce the risk of cancer, heart disease, or aging [1]. Regardless of clinical study results, the fact that antioxidants can block free radical damage to cells has led to rapidly growing markets for antioxidant nutritional supplements, antioxidant beverages, and has fueled an entire industry focused on finding foods with ever-higher antioxidant potential. Most, if not all, topical skincare products manufactured today contain antioxidants such as vitamin E, vitamin C, and carotenoids. The question of whether the antioxidants in topical skincare products provide any skin benefits will be explored.

Antioxidants and free radicals An antioxidant is simply a molecule that can prevent the oxidation of other molecules. Their importance in protecting

cells from damage results from their ability to block the progression of oxidative damage caused by free radicals. Free radicals are molecules or atoms with unpaired electrons. Having an unpaired electron leaves an incomplete electron shell and makes the atom or molecule more chemically reactive than those with complete electron shells. Because atoms seek to reach a state of maximum stability, they will try to fill the outer shell by “stealing” an electron from another molecule. When the target molecule loses an electron to the free radical it then, in turn, becomes a free radical and must find a “donor” it can steal an electron from. Thus, a chain reaction begins that causes considerable damage to cellular proteins, lipids, membranes, and DNA. Most free radicals in biological systems are derivatives of oxygen. The most common oxygen radicals in the body are the superoxide anion (O•− 2 ) and the hydroxyl radical ( iOH). While free radicals have extremely short half-lives, in the order of nanoseconds or microseconds, this is sufficient time to attack molecules and generate new free radicals. In addition to the above oxygen radicals, there are other reactive oxygen species (ROS) which are not actually radicals, but which are reactive and of biological importance. These include hydrogen peroxide and hypochlorite ion [2]. Free radicals can cause extensive and irreversible damage to proteins, DNA, and lipids, and these can have serious consequences on cell survival, malignant transformation, and the development of disease. One of the most damaging free radical events is lipid peroxidation to membrane lipids that have a key role in cell signaling. In this case a hydroxyl radical may remove a hydrogen atom from the side chain of a fatty acid, thereby converting the fatty acid into a radical. The fatty acid then reacts with oxygen to form a very

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reactive peroxyl radical. A chain reaction begins in which one lipid radical becomes two lipid radicals. Ultimately, the lipid radicals may form covalent cross-links with each other thereby ending the chain reaction. Unfortunately, the result is cross-linked and functionally damaged lipids. A good example of this is the free radical damage to low density lipoprotein (LDL). This damage has been shown to lead to atherosclerosis. Antioxidants protect cells from free radical damage by either donating an electron to a free radical thereby stabilizing it and halting the chain reaction, or by accepting the one unpaired electron, again stabilizing the free radical and preventing it from interacting with and damaging proteins, DNA, and lipids. By donating an electron to the free radical to stop the chain reaction, the antioxidant itself becomes a free radical. However, because of its structure, the antioxidant is far less reactive than other radicals. If it is relatively large, the effect of the unpaired electron is “diluted” along its structure. The antioxidant “radical” may also be neutralized by another antioxidant or it may be enzymatically restored to its non-free radical form. Glutathione is one antioxidant that can donate a hydrogen atom to a hydroxyl radical thereby neutralizing it. The oxidized glutathione is converted back to its reduced form by glutathione reductase and is then ready to reduce additional free radicals. An antioxidant’s “potency” may be quantified by use of Oxygen Radical Absorbance Capacity (ORAC) assays. ORAC is a method of measuring antioxidant capacities of different foods, vitamins, and compounds [3]. The assay measures the oxidative destruction of a fluorescent molecule (e.g. fluorescein) after it is mixed with a free radical producer that generates peroxyl and hydroxyl radicals. By comparing the change in fluorescence in a reaction tube that contains only the fluorescent molecule and free radical with the change in fluorescence measured in the assay tube containing the antioxidant along with the free radical, a measure of antioxidant potential (ORAC score) can be obtained. Table 35.1 shows the ORAC scores of some representative antioxidants. Of the many antioxidants that are now being formulated into topical products, two of the most common and most important are vitamins C and E. Vitamin C is the most prominent antioxidant in the aqueous compartment of cells. It can neutralize hydroxyl, alkoxyl, and peroxyl radicals by hydrogen donation and is thus an extremely important antioxidant for biological systems. Further, vitamin C can regenerate oxidized vitamin E and is, in turn, regenerated by glutathione. It is a useful antioxidant to incorporate into topical products, including suncare products because, in the skin, vitamin C neutralizes free radicals generated by either UVA or UVB radiation. Unfortunately, vitamin C needs to be continually replaced because even a low dose of UV radiation (UVR) from the sun can deplete 30–40% of the vitamin C present in the skin [4].

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Table 35.1 Oxygen Radical Absorbance Capacity (ORAC) values of some antioxidants. Antioxidant

ORAC (μmol TE/100 g)

Olive extract

2 700 000

Clove

1 078 700

Quercetin

1 090 000

Resveratrol

620 000

Cinnamon

267 536

Vitamin C

189 000

Vitamin E

135 000

Cocoa

80 000

Acai

38 700

Pomegranate

10 500

Blueberry (raw)

7 700

Lycopene

5 800

Vitamin E is one of nature’s most important lipid antioxidants because it associates with membranes and protects the lipid environment by scavenging lipid peroxyl radicals. Vitamin E is found in the stratum corneum where it can act as a “front line” defense against UVR-induced free radicals. The vitamin E radical can be regenerated by vitamin C, and also by glutathione and ubiquinol (coenzyme Q10). There are many other antioxidants that have been formulated into skincare products, including ferulic acid, CoQ10 (ubiquinone), retinol, idebenone, α-lipoic acid, and epigallocatechin gallate. Some of the skin benefits these antioxidants provide may be the result of actions on cells that go beyond their ability to simply scavenge free radicals.

Effects of antioxidants on cell signaling pathways Many antioxidants that have been incorporated into topical skincare products have significant anti-inflammatory activities while others up- or downregulate various genes. Vitamin C, for example, not only serves as a co-factor for enzymes involved in collagen and neurotransmitter production, but also stimulates the collagen I and III genes, inhibits the UVRinduced levels of inflammatory hormones including prostaglandin E2 (PGE-2), and stimulates cell proliferation in dermal fibroblasts [5]. The major lipid-soluble antioxidant, vitamin E, has been shown to alter the expression of cell cycle genes in human T cells and suppress PGE-2 production [6]. This PGE-2 inhibition may explain, in part, vitamin E’s ability to protect skin from UVR-induced erythema. One of the best anti-inflammatory antioxidants produced by nature may be curcumin. While this compound can neu-

35. Antioxidants and anti-inflammatories inhibits hyaluronidases and thus preserves hyaluronic acid levels in the skin [13]. A related polyphenol, genistein, blocks intracellular signaling pathways by inhibiting tyrosine kinases, and the phosphorylation of the epidermal growth factor receptor (EGF-R) [14]. A bar graph showing the effect of several antioxidants on inhibition of IL-1 induced PGE-2 levels in human dermal fibroblasts is shown in Figure 35.1(a), while the effect of luteolin and ascorbyl acetate in inhibiting a variety of inflammatory cytokines in human keratinocytes induced with tissue plasminogen activator (TPA) is shown in Figure 35.1(b). Clearly, the polyphenolic antioxidants as well as simpler antioxidants such as vitamins C and E can reduce inflammation in the skin. However, for these compounds to be effective when topically they must penetrate into the skin at a sufficient concentration to exert their protective effects on both keratinocytes in the epidermis, fibroblasts in the dermis, and immune cells migrating in from the vasculature.

Topical formulation of antioxidants The development of effective topical formulations that can deliver antioxidants into the skin to protect cells in the epidermis and dermis from free radical attack by UVR, pollutants, and from aging is not a trivial undertaking. Although a number of factors influence the ability of a given molecule to penetrate through the stratum corneum and down to the dermal layer, two important considerations are molecular size and charge. As a rule of thumb, molecules with a molecular weight over 500 Da have a more difficult time penetrating through the stratum corneum along the intercellular lipid route than do smaller molecules. In regard to charge, a molecule that is somewhat hydrophobic has a better chance of penetrating the lipids in the stratum corneum than a water-soluble antioxidant, such as vitamin

Luteolin

(a)

-6

-8 l Fα TN

α F-

-8

-6

0 IL

PG E-

Ascorbyl palmitate

100

Inhibition of IL-1 induced PGE-2 (%)

Eu Fe gen ru o lic l a Cu cid rc u Q mi ue n rc et in T r A o sc lo or L x by ute l p ol in al m ita t Co e Q 10 Re Ret tin ino l oi c ac id

Inhibition of IL-1 induced PGE-2 (%)

100

PG E-

tralize free radicals, it can also interfere with cell signaling pathways involved in inflammation. A considerable amount of research has investigated the cellular mechanism of action of curcumin. These studies have shown that one action of curcumin is to block NF-κB transcription, activation, and translocation to the nucleus. This transcription factor is involved in the upregulation of several inflammatory genes including tumor necrosis factor α (TNF-α), interleukin 8 (IL-8), and cyclo-oxygenase 2 (COX-2) [7]. Curcumin also inhibits the activation of the inflammation related genes, intercellular adhesion molecule 1 (ICAM) and IL-12, which are controlled, at least in part, by Jak-STAT signaling pathways. This inhibition is brought about by curcumin’s ability to block the phosphorylation and activation of the STAT transcription factor [8]. While curcumin inhibits transcription of pro-inflammatory genes, such as COX-2, it can upregulate the gene for the anti-inflammatory signaling receptor peroxisome proliferator-activated receptor γ (PPAR-γ) [9]. In addition to curcumin, a large number of other phenolic and polyphenolic compounds derived from plants have now been shown to have direct anti-inflammatory effects on cells as well as antioxidant activity: quercetin, luteolin, resveratrol, ferulic acid, eugenol, apigenin, genistein, and epigallocatechin gallate [10–12]. While some reduce inflammatory gene expression through interfering with NF-κB driven genes, others interfere with the JNK cell signaling pathway that leads to the activation of the transcription factor, activator protein 1 (AP-1). By interfering with the ability of AP-1 to activate target genes, these compounds, such as luteolin, prevent the activation of such inflammatory genes as IL-6, COX-2, IL-18, and monocyte chemotactic protein 1 (MCP1). In regard to skin antiaging benefits, not only can luteolin reduce the expression of inflammatory hormones, but it

(b)

Figure 35.1 Anti-inflammatory properties of antioxidants. (a) Inhibition of the inflammatory mediator prostaglandin E2 (PGE-2) in human keratinocytes by antioxidants. (b) Inhibition of four important skin inflammatory mediators by luteolin and vitamin C.

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C. However, if the compound is too hydrophobic, although it may move into the stratum corneum, it cannot easily enter the aqueous environment of the epidermis and dermis. The likelihood that a given antioxidant will penetrate the skin and thus be useful in a topical formulation can be predicted, somewhat, on its partition coefficient value (logP). This is simply a measure of the antioxidant’s solubility in octanol to that in water. Thus, an antioxidant with a logP of 2 is somewhat hydrophobic (it is more soluble in octanol than water). For topical application, antioxidants with logP values of 1–3 have the best chance of moving into the skin and down to the dermal layers, with a logP of about 2.5 being optimal. Curcumin has a molecular weight of 368 Da and a logP of 3.77. Thus, it is somewhat more hydrophobic than desired for a molecule that can penetrate down into the dermal layers but should still be effective when applied topically. In contrast, ubiquinone (CoQ10) has a molecular weight of 863 Da and a logP of 11. Although the molecular weight is not too large for topical application, the logP indicates that this compound is so hydrophobic that it will have little tendency to move from the lipid environment of the stratum corneum to the aqueous environment of the epidermal or dermal layers. Thus, CoQ10 may be useful as a topical antioxidant that neutralizes free radicals at the skin’s surface but may not protect cells in the lower layers of the skin. Interestingly, although vitamin E (molecular weight 430 Da) is also extremely hydrophobic with a logP of 10, it has been shown to reach the dermis 24 hours after topical application. Whether it is actually traversing the stratum corneum or penetrating the skin via the appendageal route (hair follicles or sebaceous glands) is not known. Vitamin C is water-soluble and because of this polarity it will not readily enter the stratum corneum. Various efforts have been taken to increase skin delivery of vitamin C, including lowering the pH to remove the charge on the compound. At a pH of 3.5, vitamin C loses its ionic charge and will penetrate the skin [15]. Vitamin C, like vitamin E, presents formulation challenges relative to the stability of the molecule. Neither are stable in most aqueous emulsions, so non-aqueous “serums” have been developed that are better at maintaining the stability of the vitamins. Alternatively, aqueous-based emulsions can be used if the more stable ester forms of the vitamins are incorporated into the formulation. Vitamin E acetate is fairly stable and penetrates into the skin although its antioxidant activity is less than vitamin E [16]. In regard to vitamin C, ascorbyl palmitate, or more recently tetrahexydecyl ascorbate, both of which are fairly stable, have been used in topical formulations. At least for tetrahexyldecyl ascorbate, this vitamin C derivative has been shown to have not only excellent antioxidant activity, but also to produce the same biologic effects on the skin (e.g. collagen production, increased lipid synthesis) as the un-derivatized vitamin C [17].

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To determine how much antioxidant penetrates into the skin from a given topical formulation, a Franz cell is typically used. The device consists of an upper chamber and a lower reservoir. Human skin, either full-thickness or dermatomed skin, is sandwiched between the two chambers. The formulation to be tested is applied to the surface of the skin in the upper chamber and the amount of antioxidant (or other “active”) that penetrates the skin and falls into the buffer solution in the lower chamber determined by either high performance liquid chromatography (HPLC) or, if the compound is radiolabeled, by scintillation counting. From this analysis it is possible to determine: 1 How much antioxidant penetrates the skin; 2 How fast it penetrates; 3 How long a finite dose placed on the skin’s surface will continue to supply antioxidant to the skin; and 4 The steady state concentration of the antioxidant in the skin. In conclusion, the incorporation of antioxidants into skincare and topical dermatologic products provides substantial skin benefits. Not only do these compounds protect the skin from free radical damage caused by skin aging and exposure to UVR, but many of them reduce skin inflammation by repressing the activity of inflammatory cytokine and chemokine genes. Further, some, such as vitamin C, have marked antiaging properties by upregulating matrix promoting genes such as collagen I and III genes, while inhibiting matrix-eroding genes such as the those for matrix metalloproteinases (MMP).

Anti-inflammatories Inflammatory skin disorders are common and range from occasional rashes accompanied by skin itching and redness to more chronic conditions such as atopic dermatitis, rosacea, seborrheic dermatitis, and psoriasis. This discussion provides a brief overview of the inflammation process, reviews current drug topical treatments for several inflammatory diseases, and presents data on new, botanically derived, anti-inflammatory technologies.

Biology of the skin inflammatory process Skin inflammation, which is characterized by redness, swelling, heat, itching, and pain, can exist in either an acute or chronic form, with acute disease frequently progressing to a more chronic condition. Acute inflammation can result from exposure to UVR, ionizing radiation, allergens, or to contact with chemical irritants (e.g. soaps, hair dyes). Assuming that the triggering stimulus is eliminated, this type of inflammation is typically resolved within 1–2 weeks with little accompanying tissue destruction. A chronic inflammatory condition, however, can last a lifetime, and cause considerable damage to the skin.

35. Antioxidants and anti-inflammatories Some of the cellular and biochemical events that occur in the skin in response to a triggering stimuli (e.g. UVR, chemical or antigen) and which lead to an inflammatory response are shown in Figure 35.2. Within minutes of exposure of skin to an insult there is a rapid release of inflammatory mediators from keratinocytes and fibroblasts and from afferent neurons. Keratinocytes produce a number of cytokines and chemkines including PGE-2, TNF-α, IL-1, IL-6, and IL-8. Dermal fibroblasts also respond to the insult and to IL-1 produced by keratinocytes by increasing production and secretion of cytokines including IL-1, IL-6, IL-8, as well as PGE-2. PGE-2 increases vasodilatation and vascular permeability, facilitates the degranulation of mast cells, and increases the sensitivity of afferent neuronal endings. Increased vasodilatation and vascular permeability by PGE-2 and histamine leads to increased blood flow and extravasation of fluid from blood vessels, resulting in visible redness and swelling. Increased production of TNF-α and IL-1 leads to the expression of intracellular adhesion molecules, such as VCAM and ICAM, on endothelial cells of the blood vessels

Resident Ag

Chemical irritant

[18]. These proteins, as well as P and E selectin, serve as anchoring elements for bloodborne monocytes and neutrophils. The attachment of leukocytes to the adhesion molecules slows their movement through the bloodstream and finally causes their adhesion to the endothelial wall [19]. In the presence of chemokines, particularly, IL-8 produced and released by both keratinocytes and fibroblasts, the adherent leukocytes undergo chemotaxis and migrate from the blood vessel out into the skin where they act to scavenge the area of debris and also produce additional inflammatory mediators. The initial acute response occurs within minutes of the insult to the skin [20]. The subsequent movement of neutrophils and monocytes into the “wounded” area typically takes up to 48 hours to occur. If the triggering stimulus is eliminated, inflammatory mediator production by keratinocytes, fibroblasts, and mast cells ceases, the influx of leukocytes to the “wounded” area decreases and inflammation subsides. In contrast to acute inflammation, which typically resolves in 1–2 weeks, chronic inflammation results from a sustained

Bacteria/fungal infection Epidermis Keratinocytes

Insult

Dermis Fibroblasts MMPs

Nerve cell TNFα

IL-1α Mast cell PGE2

(TNFα, IL-all, MCP-1, prostaglandins) Upregulation of endothelial cell adhesion molecules (E-selectin, ICAM-1, VCAM-1)

Increased excitability

Sub P

IL-6 Lymphocyte, monocyte activation

Histamine

Monocytes/ macrophages/ T cells

Vasodilation, increased permeability Diapedesis

Rolling

Skin venules

IL-8

Firm adhesion

E-selection ICAM-1 VCAM-1

Figure 35.2 Skin inflammation pathway.

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immune cell-mediated inflammatory response within the skin itself and is long-lasting. This response involves antigen presenting cells (APC) in the skin, called Langerhans cells in the epidermis and dendritic cells (DC) in the dermis, that, when activated, transport antigens through the lymphatics and to T lymphocytes where the antigen is “presented.” The T lymphocytes are activated and travel back to the skin where they proliferate and express a wide range of inflammatory mediators as well as matrix-eroding enzymes (MMP1; collagenase) [21]. Cytokines produced by T lymphocytes can stimulate fibroblasts and keratinocytes to produce additional cytokines and chemokines, and can also induce the expression of a variety of tissue-destructive enzymes by fibroblasts, including MMP-1 (collagen), MMP-3 (stomelysin-1), and MMP-9 (gelatinase B). As long as the antigen or insult stimulus persists in the skin, the inflammatory response will continue, resulting in significant and serious tissue destruction [22]. Inflammatory processes in the skin, particularly those triggered by long-term exposure to solar radiation, trigger molecular pathways that escalate the aging process. Actinic aging, or photoaging, which occurs following prolonged exposure of the skin to UV light from the sun, results in increased cytokine production with attendant activation of genes in both keratinocytes and fibroblasts that cause erosion of the normal skin structure. MMPs, which break down the skin extracellular matrix causing sagging and wrinkling, are stimulated in sun-exposed skin. Furthermore, dermal fibroblast synthesis and assembly of collagen, which is required to maintain and restore the extracellular matrix, is inhibited while elastin production is overstimulated, leading to elastosis. It is now widely accepted that sun-exposed skin in most individuals remains in a constant state of low level UV-induced inflammation, and that this “smoldering” inflammation is responsible for the signs of skin aging that appear in middle age [23–25].

Prescription medicines for inflammation and mechanism of action Corticosteroids Some of the most effective and commonly used prescription drugs for treating inflammation are the corticosteroids, particularly the glucocorticoid-related steroids. They are effective for many forms of eczema, including atopic dermatitis and allergic contact dermatitis, and are fairly effective in ameliorating the symptoms of psoriasis. Corticosteroids can be used topically or orally. Given the efficacy of corticosteroids in treating many different types of skin inflammation and autoimmune-based inflammatory diseases such as rheumatoid arthritis, asthma, lupus erythematosus, and allergic rhinitis, considerable research has been directed toward understanding their mechanism of action.

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Corticosteroids act on target cells by binding to the glucocorticoid receptor present primarily in the cytosol. This binding “activates” the receptor resulting in its translocation to the nucleus. The steroid hormone receptor complex then binds, as a hom*odimer, to DNA regulatory elements along the promoter regions of specific genes. This binding usually results in the upregulation of gene activity but can also cause transcriptional repression of the target gene [26]. The effectiveness of corticosteroids as inhibitors of inflammation stems from the ability of the steroid activated glucocorticoid receptor complex to interfere with the activation of genes regulated primarily by two transcription factors: NF-κB and AP-1 [27,28]. These two transcription factors are largely responsible for the transcriptional activation of a wide variety of pro-inflammatory genes including cytokines IL-1, IL-2, IL-3, IL-4, IL-6, IL-11, IL-12, and IL-13, TNF-α, and granulocyte macrophage colony-stimulating factor (GMCSF), chemokine genes IL-8, RANTES, MCP-1, adhesion molecules ICAM-1, VCAM-1, and E-selectin, the COX-2 gene, and the MMP gene, MMP-1 [29]. The transcription factors, NF-κB or AP-1, are activated by kinases which, in turn, are activated as a result of a hormone or cytokine binding to, and activation of, a surface receptor. In the case of the NF-κB activation pathway, a kinase, IκK, when activated, phosphorylates an inhibitor protein, IκB. Unphosphorylated, IκB binds to and represses the activity of NF-κB, but when phosphorylated, it dissociates from NF-κB and is degraded. Once freed from the IκB, NF-κB can translocate to the nucleus where it binds to the promoter region of specific genes and activates them [30]. In regard to the AP-1 transcription factor, it is phosphorylated and activated as a result of a kinase “signaling cascade” that begins with the binding of a hormone/cytokine, such as IL-1 or TNF-α, to a surface receptor on target cells [27]. While some genes are regulated only by either NF-κB or AP-1, other inflammatory genes have both an NF-κB and AP-1 binding site in their promoter regions and thus can be regulated by either or both transcription factors. The anti-inflammatory activity of corticosteroids comes from their ability to repress either the activation or activity of the NF-κB and AP-1 transcription factors, thereby suppressing transcription of genes coding for inflammatory mediators. A model showing one mechanism glucocorticoids use to block the transcriptional activity of NF-κB is shown in Figure 35.3(a). When activated by hormone binding, the glucocorticoid receptor translocates to the nucleus where it can bind to NF-κB and suppress its transcriptional activity, either by preventing its binding to the promoter region of target genes or by preventing NF-κB’s ability to activate the transcriptional machinery when bound to the promoter. Thus, inflammatory genes that require NF-κB for activation remained turned off [30–33]. Similarly, the activated glucocorticoid receptor interacts with the AP-1 transcription factor and prevents it from binding to and activating target

35. Antioxidants and anti-inflammatories

IL-1/TNF-α receptor G

Plasma membrane Ca2+ IKK

G Glucocorticoid receptor

P IKB

IKB NF-κB

Plasma membrane

Degradation

PLCγ

NF-κB

CAMK IL-8

G NF-κB No binding of NF-κB

Immunoreceptor

CRAC

No transcription

Nucleus

(a)

Tacrolimus, Pimecrolimus

COX-2 IL-12 MCP-1 MMP-1 TNF-α IL-6

Ca2+ Calcineurin P P P NFAT P P P P P

? Ca2+

IP3 IP3R ER

(b)

NFAT

Target genes

Figure 35.3 Glucocorticoid and immunomodulator inhibition of inflammatory pathways. (a) Mechanism of glucocorticoid inhibition of the NF-κB driven inflammation pathway. (b) Calcineurin and nuclear factor of activated T cells (NFAT) activation and inhibition by tacrolimus/pimecrolimus.

inflammatory genes. Recent evidence also suggests that glucocorticoids may block AP-1 phosphorylation and activation [27]. While the glucocorticoids are very effective in suppressing the activation of pro-inflammatory genes they unfortunately produce a variety of undesirable side effects. First, because of their potent inhibition of genes involved in an immune cell driven inflammatory response, they have an overall immunosuppressive effect. Prolonged use of glucocorticoids leads to a reduction in B and T lymphocyte populations, and a reduced ability to fight skin infections. Further, steroids adversely affect the ability of dermal fibroblasts to synthesize collagen and at high doses they reduce the proliferation rate of these cells. Consequently, long-term use of topical steroids leads to skin thinning and a decrease in the dermal matrix. Other potential negative side effects caused by prolonged use of steroids include altered carbohydrate metabolism, suppression of the hypothalamic-pituitary-adrenal axis, increased osteoporosis, and increased risk of developing cataracts. Because of undesirable side effects which limit the length of time steroids can be used to treat inflammatory diseases, non-steroidal topical therapeutics have been developed to treat inflammation. One group of drugs, the non-steroidal anti-inflammatory drugs (NSAIDs) have been used for many years as oral drugs to control inflammatory responses.

Non-steroidal anti-inflammatory drugs The most well-known of all the NSAIDs, aspirin, has been used for over 100 years to control various forms of inflammation . NSAIDs are available in over-the-counter (OTC) and prescription forms. Common OTC forms are ibuprofen, naproxen, aspirin, and acetaminophen. Those available with a prescription include celecoxib (Celebrex®, Pfizer, New

York), diclofenac (Voltaren®, Novartis, Parsippany, NJ, USA), etodolac (Lodine®, Almirall, Uxbridge, UK), indometacin (Indocid®, Aspen Pharma, Durban, South Africa), ketoprofen (Orudis®, Sanofi-aventis, Paris, France), and rofecoxib. One topical prescription NSAID that has received Food and Drug Administration (FDA) approval in the USA is diclofenac (SOLARAZE, PharmaDerma, Florham Park, New Jersey) which is indicated for the treatment of actinic keratoses [34]. When one examines the published data on the efficacy of topical NSAIDs in treating various inflammatory symptoms, the results show considerable disparity. A statistical analysis of clinical data from a wide number of trials with various topical NSAID preparations concluded that with long-term use the effectiveness of the NSAID-treated group was not significantly different from the placebo group [35]. Other studies, however, do suggest that topical NSAID treatment for joint pain provides relief beyond that observed with the placebo group [36–38]. Few studies have evaluated topical formulations that contain newer NSAIDs, including the specific COX-2 inhibitors, but it seems likely that a topical preparation of a potent NSAID that delivers adequate levels of an effective COX inhibitor through the skin would likely be effective in treating a variety of inflammatory conditions in which PGE-2 is indicated as a causative factor. The target for NSAIDS is the enzyme cyclo-oxygenase (COX), which exists in two forms: COX-1 and COX-2. While most older versions of NSAIDs including aspirin, ibuprofen, and acetaminophen are not selective inhibitors of any particular form of COX, newer drugs have been designed to target primarily COX-2 [39]. Because of their ability to lower PGE-2 levels, topical NSAIDs have been evaluated for their ability to reduce the severity of a sunburn, which is largely mediated by PGE-2.

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Topical indometacin (1%) if administered immediately after sun exposure is more effective than steroids, being able to block the onset of sunburn, produced by a 6 minimal erythema dose (MED) dose of UVB radiation [40]. Topical application of the COX-2 inhibitor, celecoxib, after UVB irradiation of skin, reduced erythema, edema, PGE-2 levels, the number of sunburn cells, and dermal infiltration of neutrophils [41]. The topical NSAID, diflofenac (Solareze), which is approved for use in the USA to treat actinic keratoses, has been shown to reduce sunburn symptoms when applied within 4 hours of the initial onset of sunburn [42]. Interestingly, several studies implicate PGE-2 as a causative factor in skin cancer, and results from mouse experiments show that topical application of a PGE-2 inhibitor lowers the UVB-induced number of papillomas detectable 12 weeks after UVB dosing [43,44].

Immunomodulators A newer type of NSAID is represented by the immunomodulators. Two anti-inflammatory drugs that have received FDA approval for topical use are the immunomodulators, tacrolimus and the related drug, pimecrolimus. These drugs, along with ciclosporin, which exerts its effects through the same mechanism of action, had their origin as immunosuppressive agents used to prevent organ rejection after transplant surgery [45]. Both pimecrolimus and tacrolimus have been approved for topical use in treating atopic dermatitis, but not for psoriasis. As is the case with the glucocorticoids, the immunomodulators inhibit the production of inflammatory mediators but, unlike the corticosteroids, both tacrolimus and pimecrolimus are more cell specific in that they target primarily mast cells and T lymphocytes. The drugs have fewer inhibitory effects on Langerhans cells/dendritic cells, fibroblasts and keratinocytes [46]. Thus, the skin thinning complications seen with topical corticosteroids are eliminated [47,48]. Tacrolimus, pimecrolimus, and ciclosporin repress inflammatory genes in target cells through a common mechanism that involves the repression of activity of a ubiquitous calcium-activated phosphatase, calcineurin, which is involved in the activation of specific inflammatory genes [49]. A cartoon showing the calcineurin pathway is shown in Figure 35.3(b). When surface membrane receptors are activated by binding to a hormone or cytokine, there is an increase in intracellular calcium. The increased calcium causes the activation of calmodulin which then binds to the calciumdependent enzyme, calcineurin, and activates it. The activated calcineurin enzyme is a phosphatase, which can dephosphorylate the cytosolic subunit of a transcription factor, nuclear factor of activated T cells, cytosol (NFATc). The dephosphorylation of the cytosolic NFAT subunit allows it to translocate to the nucleus where it forms a complex with the nuclear subunit of NFAT (NFATn) whose synthesis

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was induced by signaling cascade initiated by the antigen binding to the T-cell surface receptor. Once the NFAT dimer has formed in the nucleus, it can bind to the promoter region of several inflammatory genes including those for IL-2, IL-3, IL-4, and TNF-α [49]. When the drugs tacrolimus, pimecrolimus, or ciclosporin enter the cell they bind to a cytosol protein, either FKBP for tacrolimus or pimecrolimus or cyclophilin for ciclosporin. Once formed, this complex is able to bind to and inactivate calcineurin. The now inactive calcineurin can no longer dephosphorylate NFATc, which results in the transcription factor remaining unactivated and in the cytosol. Thus, the NFATn protein in the nucleus has no binding partner and cannot bind to and activate inflammatory genes [49]. One of the genes in T cells that is inhibited by tacrolimus is the IL-2 gene, which is necessary for full T-cell activation. Thus, in the presence of these immunomodulators, T lymphocyes do not differentiate in response to antigen stmulation. While tacrolimus and other calcineurin inhibitors are much more specific than corticosteroids in terms of the types of cells they act on, they still inhibit a wide variety of inflammatory genes and are therefore immunosuppressive. In 2006, the FDA issued a “black box” warning that the use of either Elidel® (Novartis Pharmaceutics, East Hanover, New Jersey) (pimecrolimus) or Protopic (Astellas Pharma, Tokyo, Japan) (tacrolimus) may be linked to an increase risk for skin cancer and lymphoma. Another class of immunomodulators, called “biologic response modifiers” (BRM) or simply “biologics” because they are made from living organisms, have been developed over the past 5 years [50]. These are essentially “designer” drugs because they target a specific event or mediator involved in inflammation. Most of these are “humanized” monoclonal antibodies that bind to and inactivate various inflammatory cytokines. Anti-inflammatory drugs in this category include the TNF-α inhibitors, Enbrel (Wyeth, Collegeville, PA, USA) (etanercept), Remicade® (Centocor Ortho Biotech, Centocor, Horsham, Pennsylvania), (infliximab), and Humira (Abbott Laboratories, Abbott Park, IL, USA) (adalimumab) [51], a fusion protein that can bind to the CD2 binding site on T lymphocytes and prevent the antigen-mediated activation of the cell (Amevive®, Astellas Pharma, Tokyo, Japan) and finally, an antibody, Raptiva (Genentech, South San Francisco, CA, USA), that prevents leukocytes cells from binding to adhesion molecules on endothelial cells, thereby preventing migration of these cells into the skin. However, these new protein-based biologic immunomodulators, although effective and useful for treating various dermatologic conditions are not without side effects. Because of their potent immunosuppressive effects, particularly on T lymphocytes, the risk of infection among patients taking these medications is elevated. Additionally, these drugs are

35. Antioxidants and anti-inflammatories expensive and can only be used by injection and not applied topically.

Anti-inflammatory cosmeceutical “actives” The demand for effective non-prescription topical products to treat inflammatory diseases such as eczema, atopic dermatitis, seborrheic dermatitis, and even psoriasis has led to the introduction of products based on either novel synthetic chemicals or on botanical “actives” which claim to be effective anti-inflammatory compounds. Some of the many purported botanical anti-inflammatory “active” ingredients in cosmeceutical products include bee pollen, curry extract, jewelweed, green tea extract, aloe, bilberry, tea tree oil, lavender essential oil, Boswellia, and willow bark. Given the abundance of botanicals which claim anti-inflammatory activity, is there any scientific evidence to suggest that any actually have inhibitory effects on the production or action of inflammatory mediators in the skin? The answer is yes for a few botanically derived ingredients. One of the most widely studied botanicals for its antiinflammatory activity is curcumin, the active ingredient in turmeric. A large number of scientific studies published in peer-reviewed scientific journals over the past 5–10 years have shown remarkable and potent anti-inflammatory activities of curcumin. Another plant-derived “active” that has been shown through rigorous scientific studies to have anti-inflammatory activity is quercetin, a flavonoid derived from several plants and fruits, including apples. Its efficacy as an antioxidant and anti-inflammatory seems to provide some substantiation for the old expression, “an apple a day keeps the doctor away.” Recent studies have shown that quercetin, like curcumin, can block NF-κB driven genes and thus prevent the production of a variety of inflammatory mediators [52,53]. Other plant-derived compounds that have been scientifically shown to have anti-inflammatory activities, at least in cell culture model systems include resveratrol, derived from grapes and knotweed; boswellic acid, derived from Boswellia; the polyphenol, epigallocatechin gallate, derived from green tea; and bisabolol, derived from chamomile. All of these compounds have been shown to exert some anti-inflammatory effect on cells in culture, either inhibiting the production of PGE-2, cytokines, chemokines, adhesion molecules, or other molecules involved in the inflammatory process.

Conclusions Although there are a wide number of topical anti-inflammatories available as prescriptions which are effective in treating skin inflammation, all have some side effects that negatively impact their usefulness. Topical steroids are effec-

tive for treating many dermatologic diseases but can lower collagen production in dermal fibroblasts, reduce their proliferation, and cause skin thinning. Topical immunomodulators are immunosuppressive and can lead to increased risk for infection and even cancer. Clearly, there is a continued need for identifying newer anti-inflammatory technologies that effectively treat skin disorders without having such strong immunosuppressive effects. Botanically derived antiinflammatory compounds as well as newer synthetic drugs, should help meet this need.

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13 Kuppusamy UR, Khoo HE, Das NP. (1990) Structure-activity studies of flavonoids as inhibitors of hyaluronidase. Biochem Pharmacol 40, 397–401. 14 Zhang LL, Li L, Wu DP, Fan JH, Li X, Wu KJ, et al. (2008) A novel anti-cancer effect of genistein: reversal of epithelial mesenchymal transition in prostate cancer cells. Acta Pharmacol Sin 29, 1060–8. 15 Pinnell SR, Yang HS, Omar M, et al. (2001) Topical L-ascorbic acid: percutaneous absorption studies. Dermatol Surg 27, 137–42. 16 Azzi A. (2007) Molecular mechanism of α-topopherol action. Free Radic Biol Med 43, 16–21. 17 Fitzpatrick RE, Rostan EF. (2002) Double-blind, half-face study comparing topical vitamin C and vehicle for rejuvenation of photodamage. Dermatol Surg 28, 231–6. 18 Shindo Y, Wit E, Han D. (1994) Dose–response effects of acute ultraviolet radiation on antioxidants and molecular markers of oxidation in murine epidermis and dermis. J Invest Dermatol 23, 470–5. 19 Ley K. (2003) The role of selectins in inflammation and disease. Trends Mol Med 9, 263–8. 20 Esche C, de Benedetto A, Beck LA. (2004) Keratinocytes in atopic dermatitis: inflammatory signals. Curr Allergy Asthma Rep 4, 276–84. 21 Kupper TS, Fuhlbrigge RC. (2004) Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol 4, 211–22. 22 Nathan C. (2002) Points of control in inflammation. Nature 420, 846–52. 23 Fisher GJ, Choi HC, Bata-Csorgo Z, Shao Y, Datta S, Wang ZQ, et al. (2001) Ultraviolet irradiation increases matrix metalloproteinase-8 protein in human skin in vivo. J Invest Dermatol 117, 219–26. 24 Jenkins G. (2002) Molecular mechanisms of skin ageing. Mech Ageing Dev 123, 801–10. 25 Ma W, Wlaschek M, Tantcheva-Poor I, Schneider LA, Naderi L, Razi-Wolf Z, et al. (2001) Chronological ageing and photoageing of the fibroblasts and the dermal connective tissue. Clin Exp Dermatol 26, 592–9. 26 Dostert A, Heinzel T. (2004) Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des 10, 2807–16. 27 De BK, Vanden BW, Haegeman G. (2003) The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev 24, 488–522. 28 Hermoso MA, Cidlowski JA. (2003) Putting the brake on inflammatory responses: the role of glucocorticoids. IUBMB Life 55, 497–504. 29 Tak PP, Firestein GS. (2001) NF-κB: a key role in inflammatory diseases. J Clin Invest 107, 7–11. 30 Almawi WY, Melemedjian OK. (2002) Negative regulation of nuclear factor-κB activation and function by glucocorticoids. J Mol Endocrinol 28, 69–78. 31 Necela BM, Cidlowski JA. (2004) Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc 1, 239–46. 32 De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, Haegeman G. (1997) Glucocorticoid-mediated repres-

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Chapter 36: Peptides and proteins Karl Lintner Enterprise Technology/Sederma SAS, Le Perray en Yvelines, France

BAS I C CONCE P T S • Amino acids are the building blocks of peptides that link together to from proteins. • Peptides are biologically active communication tools that direct skin functioning. • Engineered peptides are a new category of active skin ingredients usually applied in a moisturizing vehicle. • Gene chip array analysis can be used to evaluate the effect of engineered peptides in fibroblast cultures.

Introduction Peptides, proteins, and amino acids are often mislabeled and the terms applied as if they were interchangeable, yet they are different in their characteristics, uses, biological activities, and cosmetic potential [1]. After defining peptides and proteins, the first part of the chapter discusses the specificities of these molecules and their physiologic, biological function, particularly in the skin; what can they do, what are the obstacles to their use in cosmetic products and how these obstacles can be overcome. In the second part, concrete examples of peptides and proteins in dermocosmetics, in particular for the “antiaging” sector, are discussed before concluding with an outlook for the future of this ingredient category in skincare.

Definitions It is important to understand the differences between amino acids, peptides, and proteins.

Of the essentially unlimited theoretical number of amino acids that can be imagined on paper, only 20 (e.g. alanine, proline, tyrosine, histidine, phenylalanine, lysine, glutamine) are incorporated into peptides and proteins via the genetic code. Individually, these amino acids in isolation have no specific intrinsic biological activity. Within cells, they exist in a pool from which they can be called upon to make peptides and proteins or, sometimes, biogenic amines, such as serotonin or dopamine. In the upper layers of the skin, they are part of the natural moisturizing factor (NMF) where they participate in the skin water holding capacity contributing to both osmolytic and hygroscopic properties. The specific interest in amino acids lies in their ability to function as an acid (pH < 7) and amine (pH > 7) simultaneously and the chemical fact that reacting an acid with an amine leads to the formation of an amide, which is a peptide bond, whereas this linkage is achieved in living cells by enzymatic means. The result of linking two or more amino acids in a linear chain is called a peptide, when the length of the chain is less than approximately 100 amino acids, or a protein when the chain is longer.

Peptides Amino acids Amino acids are the building blocks of which peptides and proteins are made. They are small molecules, with a molecular weight of 100–200 Da, characterized by the fact that both an amino group (NH2) and a carboxylic acid group (COOH) are attached to the central carbon atom which also carries further quite variable structures, known as side chains, by which the different amino acids are distinguished (Figure 36.1).

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The general terminology uses prefixes to describe the type of a peptide. For example, when the peptide is made of two amino acids, such as tyrosine and arginine written as TyrArg, it is called a dipeptide. Three amino acid combinations yield a tripeptide, four amino acid combinations yield a tetrapeptide, etc. “Oligo” stands for a “few” so that oligopeptides can have 2–20 amino acids linked in a chain. The term polypeptides is used to mean many amino acids, although these latter distinctions are not strict and not governed by official rules. The most important characteristic of a peptide, besides its length determined by the number of amino acids in the chain, is its sequence. The sequence is the precise order in which the various amino acids are linked together. Both

36. Peptides and proteins glycyl-histidyl-lysine and glycyl-lysyl-histidine are tripeptides, composed of the three amino acids glycine, histidine, and lysine. However, the fact that these amino acids are linked in the Gly-His-Lys sequence in the former and in Gly-Lys-His sequence in the latter is crucial. The former peptide, usually abbreviated GHK, stimulates collagen synthesis in fibroblasts [2], the latter GKH stimulates lipolysis in adipocytes [3]. The primary function of most peptides is to bring a biochemical message from place A in the body to place B allowing effective communication.

Proteins A peptide chain of more than approximately 100 amino acids is termed a protein. However, interleukins, cytokines, and interferon are also sometimes referred to as peptides, even though they possess a much higher molecular weight (Figure 36.2). Sometimes the distinction between the two categories relies more on the function of the molecule rather than the size. Proteins can be categorized by their function, roughly into the following: • Structural proteins: building tissue, such as collagen, elastin, fibronectin and many others;

O OH NH2 Figure 36.1 Phenylalanine, one of the 20 proteinogenic amino acids. The “side chain” which is characteristic of each amino acid (here a phenyl group) is shown in the box.

• Enzymes: very specific proteins that catalyze biochemical reactions, such as superoxide dismutase (SOD), chymotrypsin, tyrosinase; • Transport proteins that bind to a specific substrate and carry it along in the body (e.g. hemoglobin as oxygen carrier, ferritin for iron transport, lipoprotein for lipids, including cholesterol); • Difficult to categorize proteins with highly specific functions: receptors such as protein G, genetic regulators such as peroxisome proliferator-activated receptor (PPAR), antibodies, coagulants, histones. Proteins with individual molecular mass of hundreds of thousands of Daltons often autoassemble into large complexes of even larger size with very complex mechanisms of activity.

Biological functions of peptides and proteins in the skin Peptides Single amino acids very seldom have specific biological functions other than being present in the cytoplasmic pool for enzymes to be picked up and processed in one of many ways. Peptides perform many important biologic functions. The word hormone comes from Greek and means messenger. Hormones can be classified as peptide hormones or steroid hormones. Both steroids and peptides act in similar fashion. Some disturbance, either internal or external, leads to the release of a small amount of peptide in a cell, blood, gland, or in some other organ. The peptide then travels in the body until it interacts with a target receptor either on the cellular surface or within the cell nucleus after having penetrated the cell wall. This interaction triggers further

Primary protein structure is sequence of a chain of amino acids

Amino acids

Phe Leu Ser

Amino group NH2 H

Cys

COOH Acidic

Figure 36.2 A protein chain composed of amino acids.

R carboxyl R group group Amino acid

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activity at the site, destined to respond and correct the initial disturbance. This mechanism of action is usually characterized by three items: 1 Peptides circulate and act at their target sites at extremely low concentration levels, generally in the nanomolar (10−9 mol/L) level. 2 Each peptide sequence has, at its rather specific target, a highly specific binding affinity and carries a specific message such that its activity is quite specific. The highly simplified concept of “key” and “lock” (i.e. peptide and receptor) interaction is used to explain this potency and specificity. 3 Peptides have short lifespans in the organism because proteolytic enzymes break them down quickly in order to avoid overload at the target site. Well-known biological activities of peptides in the human body are, for instance: regulation of blood sugar concentration (insulin); blood pressure regulation (angiotensin, bradykinin, calcitonin gene-related peptide [CGRP]); lactation and birthing (oxytocin); diuresis (vasopressin); pain repression (endorphins, enkephalin); tanning (α-MSH); radical scavenging (glutathione); other peptides include vasointestinal peptide (VIP), substance P, the inflammatory undekapeptide, and hundreds more. The ubiquitous nature of these peptides and their myriad activities clearly indicate their importance. The relevance of some of the peptides in skin and skincare is of interest. As the term “antiaging” is not defined, it is interpreted here in a rather broad way to represent anything that helps the skin look younger. The rest of this chapter focuses on peptides for antiaging purposes.

Antioxidant peptides Glutathione (γ-glutamyl-cysteyl-glycine) This tripeptide GSH is one of the “oldest” members of the peptide family, with respect to its discovery, analysis, and confirmatory synthesis. It contains an –SH bearing, cystein amino acid which confers antioxidant activity to the molecule (Figure 36.3). The level of glutathione concentration in the body decreases notably with age, which may be a cause and a symptom of aging both at the same time [4]. The less GSH that is present, the more damage generated by free radicals; hence less glutathione reductase may be present to regenerate GSH. Besides affording this protective, antioxidant activity, for which there is in vitro but very little documented clinical evidence of skin benefits (for a medical

HO NH2

N H

H N O

Figure 36.3 Glutathione (γ-Glutamyl-cysteyl-glycine).

294

O OH

study, see [5]), GSH may also have so-called “skin whitening” effects, as described by Villarama and Maibach [6].

Carnosin (β-alanyl-L-histidine) This dipeptide also contains an unusual structure, in that β-alanine is used instead of the standard α-alanine. The histidine moiety in carnosin is of particular interest. Enzymatic breakdown of this peptide can lead to the production of histamine, a potent inflammatory agent, but also useful and necessary in the preparations for wound healing (see below). Carnosin has been proven to scavenge reactive oxygen species (ROS) formed from peroxidation of cell membrane fatty acids during oxidative stress. 4-Hydroxy-2-transnonenal (4HNE) is one of the toxic end products of lipoperoxidation by free radicals. While the reaction of HNE with glutathione (GSH) is a well-recognized pathway of detoxification in biological systems, the quenching ability of carnosin towards HNE was studied by Aldini et al. [7]. Carnosin, although less reactive than GSH, significantly quenched HNE (48.2 ± 0.9% HNE consumption after 1 hour). The results indicate that beside GSH, histidine-containing dipeptides could be involved in the detoxification pathway of reactive species from lipid peroxidation. Carnosin is also shown to be useful to counter the effects of glycation (the non-enzymatic binding of sugars to proteins), leading to cytotoxic advanced glycation end products (AGE). Nagai et al. [8] showed that carnosin may indeed promote wound healing, at least indirectly, as exogenous carnosin is degraded in the body by carnosinase into β-alanine and histidine which is then transformed by histidine decarboxylase to yield histamine. β-Alanine was found to stimulate the biosynthesis of nucleic acids and collagen, whereas histamine is considered to enhance the process of wound healing by stimulating effusion at the initial stage of inflammation.

Neuropeptides The skin and the brain are derived from the same initial embryonic tissues [9]; thus, it is not surprising that many peptides that are found to exist and possess activities in the brain are also found in the skin.

Calcitonin gene-related peptide Calcitonin gene-related peptide (CGRP) contains 37 amino acids presently known to be the most potent vasodilatating substance. Additionally, other activities were discovered, such as stimulation of cyclic adenosine monophosphate (cAMP) levels and sweating, as the peptide is clearly involved in inflammatory response, and has recently been found to contribute to migraine headaches. It is released from nerve cells, including those of the epidermis. Curiously, atopic dermatitis is inversely correlated with CGRP plasma levels. Certain fragments of the peptide, however, have been

36. Peptides and proteins shown to competitively inhibit these activities and may prove to be of interest in skincare applications, such as in anti-redness and antiperspirant products.

Bombesin Bombesin is a 14 amino acid neuropeptide which activates three different G-protein-coupled receptors known as BBR1, BBR2, and BBR3. With respect to skin-related activity, Baroni et al. [10] studied the effect of this neuropeptide on tissue regeneration and wound healing of the skin, on migration, proliferation, and differentiation of keratinocytes in an in vitro experimental model, on a mechanically injured human keratinocyte monolayer. Different mediators involved in wound repair, cell proliferation, and motility, and bombesin’s direct effect on wound repair by observing the wound closure after mechanical injury, were studied. The data suggest that bombesin may have an important role in skin repair by regulating the expression of healing markers. Bombesin also increased cell growth and migration. Other neuropeptides of interest include neuropeptides Y (NPY), PYY, and PP which act on a family of protein G receptors. NPY contains 36 amino acids and is present in the central nervous system. Among other (appetite regulating) activities, NPY acts on adipocytes and favors obesity. NPY inhibitors have been used in cellulite treatment whereas stimulation of NPY in facial skin might be of interest in redensifying the hypodermal layers (lipofilling). Pro-opiomelanocortin Pro-opiomelanocortin (POMC) should be considered as a protein, given its size of 241 amino acids. It is coded for by a gene found in the anterior pituitary gland. It is also secreted by cells of the hypothalamus, some neurons, and by keratinocytes and melanocytes of the skin and scalp. However, this protein does not seem to have a function of its own. Depending on the cell in which it is produced, it is broken down by endopeptidase enzymes into smaller fragments, or peptides, which have specific functions in the target cells. The 241 amino acid chain contains the sequences of the immunomodulatory and inflammation mediating peptide adenocorticotropic hormone (ACTH; corticotropin with 39 amino acids), the melanin synthesis stimulating hormone α-MSH (melanocortin, previously called melanocyte-stimulating hormone with 13 amino acids), and its slight variant called β-MSH as well as the lipolytic peptide β-lipotropine (90 amino acids) which contains within its sequence βendorphin (31 amino acids), and the pentapeptide enkephalin (Tyr-Gly-Gly-Phe-Met) which constitutes the first five amino acids of endorphin. Of interest in skincare are the fragments α-MSH and its derivatives or analogs, as this peptide may be used to help even out skin tone by either stimulating melanogenesis (tanning) or by reducing the amount of pigmentation (skin “whitening”). β-Endorphin and particularly its N terminal

pentapeptide fragment enkephalin may have skin soothing activities, as these molecules can be detected in the epidermis, localized close to nerve endings. A particularly interesting neuropeptide is kyotorphin, which has not yet been detected in the skin, but seems to act in similar ways on the skin as it does in the brain [11, and see below].

Matrikines The term matrikines is used to describe fragments of matrix macromolecules endowed with stimulatory, tissue repair activity [12]. Katayama et al. [13] describe the minimum size fragment of procollagen I still able to induce collagen neosynthesis in human lung fibroblasts; the very hydrophilic pentapeptide Lys-Thr-Thr-Lys-Ser is such a molecule. The tripeptide Gly-His-Lys, found in different parts of broken down collagen and in some serum proteins, also stimulates collagen synthesis in human skin fibroblasts, as found by Maquart et al. [2]. The tetrapeptide Arg-Gly-Asp-Ser, a sequence found within the fibronectin structure responsible for the binding affinity of this protein to collagen and to cell membranes, is able to help cells migrate during the wound healing process. In order for this migration to occur, the cells must detach and then move through tissue to where they are needed [14]. This migration is guided by a concentration gradient of peptides, such as Val-Gly-Val-Ala-Pro-Gly, which are fragments of elastin. This migration phenomenon is better known as chemotaxis [15]. Schematically and very simplified, this event is illustrated in Figure 36.4.

Obstacles to peptide use in dermocosmetics The incorporation of peptides in dermocosmetics can be challenging. Some of the hurdles confronted with peptide formulation include: skin penetration, stability, toxicity, analysis, and cost.

Skin penetration The stratum corneum is not the primary target for peptides, as they need viable, living skin to receive their message. It is necessary for a peptide to cross the cutaneous barrier in order to reach the viable epidermis (keratinocytes), the basal layer (melanocytes, nerve cell endings), the dermis (fibroblasts), and even the hypodermis (adipocytes). Even small peptide molecules, such as the dipeptide carnosin, are too hydrophilic and electrically charged to penetrate any further than the first or second layer of the stratum corneum. The larger the peptide (beyond six or seven amino acids), the less likely it is to reach the deeper layers of the skin. Thus, the long peptide sequences mentioned above, such as CGRP, POMC, and similar structures, do not function as active ingredients in cosmetic formulas. Lintner and Peschard [16] have shown that the attachment of a lipophilic chain (fatty acid of sufficient length) to smaller peptides can increase the penetration rate by a factor of 100 or more. Similar effects were confirmed by Leroux

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Repair

Stress, wound

Healthy tissue

Proteolytic enzymes Stimulation of neosynthesis A B D

F H

Chemotaxis

E I

Cell migration E D

et al. [3]. This technique of vectorizing the peptides has its limits because the longer the peptide chain, the less penetration the fatty acid will produce. Another limitation is the interference of biologic activity by acylation of the peptide. The N terminal ionic charge may be of importance for triggering effects at the target site or otherwise interfering with the peptide’s properties. For example, the antioxidant activity of carnosin turns into pro-oxidant activity when the peptide is modified to become palmitoyl-carnosin (F. Vissac, unpublished results). Alternatively, attaching a poly-arginine chain to the peptide can help molecules penetrate the stratum corneum [17]. Liposome formulations may also help carry the peptide through the barrier, but little if anything has been published in this respect.

Stability Unfortunately, peptides have limited chemical stability. In aqueous environments, such as those frequently encountered in cosmetic applications, hydrolysis may occur. Experience shows that the longer the peptide, the more fragile it becomes. The choice of excipients and stabilizers can help overcome this obstacle [18]. However, the question of peptide stability, an increasingly important consideration, must be considered.

Analysis Detecting the presence of a peptide in a formulation 6–12 months after product manufacture can be difficult when the peptide is present in micromolar or less concentrations (p.p.m. level). Special analytical techniques, such as derivatization, mass spectrometry, and fluorescence spectrometry, have to be individually developed for each peptide. This is not always possible and/or very costly and sometimes proves an insurmountable hurdle.

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Breakdown fragments

Figure 36.4 A tissue protein (e.g. collagen, elastin, fibronectin) is broken into fragments by enzymatic hydrolysis, either during normal tissue renewal, or as a consequence of induced damages (free radicals, burning, mechanical wound). The breaking up of the protein does not occur randomly, nor sequentially from one or the other end; various pieces of amino acid strings are generated, which when small enough, are readily available to act as “messengers” in the surrounding tissue, and will act as chemoattractants, transport aids, and stimulants to trigger neosynthesis of the necessary tissue molecules to renew/repair the three-dimensional structure.

Toxicity Generally, the smaller the peptide, the less likely it is to show untoward effects. Peptides, in contrast to proteins, are hardly big enough to elicit allergic reactions, but specific undesirable cellular effects may occur with unknown sequences. It is advisable to use peptides with a biomimetic amino acid sequence, as the likelihood of toxicity is close to nil when the peptide is almost identical to human peptides. Nevertheless, proper safety evaluation of newly developed peptides, especially if the peptide is modified by acylation or esterification, is necessary.

Cost Peptides of defined sequence and high purity (>90%) are expensive to produce; although extraction from some protein hydrolysates is theoretically possible, most peptides used in cosmetic applications are synthetic (i.e. made in a step by step process from the individual amino acid building blocks). It is noteworthy that the amino acids themselves are frequently of natural plant or fermentation origin. However, the very high potency of the peptides compensates for their cost and makes it possible to employ them at efficient level in all types of skincare formulas, because they are used at the p.p.m. level in finished cosmetics. Therefore, in spite of the formulation challenges, peptides have become popular, widely used active ingredients for antiaging skincare products, discussed next.

Examples of concrete applications of peptides in antiaging skincare Numerous peptides are available for incorporation into cosmetic formulations. This section illustrates the manifold possibilities for using peptides in dermocosmetics.

36. Peptides and proteins

Matrikines The best known matrikine peptide used in skin care is the pentapeptide Pal-KTTKS, derived from the Katayama et al. [13] discovery discussed above. A DNA array study on this molecule indicated that mostly genes implicated in the wound healing process were upregulated in cells incubated with the peptide. Furthermore, the palmitoylated peptide stimulates not only the synthesis of collagen I, but also of collagen IV, fibronectin, and glycosaminoglycans in monolayer culture of normal and aged human fibroblasts and in full thickness skin (P. Mondon, unpublished data). This peptide was tested in vehicle controlled clinical trials where it proved to thicken the skin, improve the epidermal–dermal junction, and macroscopically reduce fine lines and wrinkles [19–21]. The peptide Pal-Gly-Gln-Pro-Arg (Pal-GQPR), although technically not a matrikine because it is not derived from a matrix macromolecule, is a fragment of the natural circulating protein IgG and stimulates macromolecule synthesis in cell culture demonstrated in Figure 36.5. This peptide also contributes to the reduction of basal and UV-induced IL-6 release in keratinocytes and fibroblasts, as demonstrated in Table 36.1. The matrikine tripeptide Gly-His-Lys (GHK) has been mentioned as a wound healing and skincare ingredient for dermocosmetic formulas [2], especially when associated with copper ions. In its palmitoylated form (Pal-GHK) it is more active, even in the absence of copper, and can mimic the effects of retinoic acid [16]. The in vitro synergy between the tri- and tetrapeptide (Pal-GHK + Pal-GQPR) [22] led to an investigation of the combination in a clinical, vehicle controlled, blind study on 23 panelists (P. Mondon, unpublished data). Twice daily application of an oil-in-water (O/W) emulsion containing 4 p.p.m. of Pal-GHK and 2 p.p.m.

of Pal-GQPR against placebo showed significant wrinkle reduction, an increase in skin firmness, and visible smoothing after 1–2 months (Figure 36.6). In another formulation, the peptide GHK was coupled to biotin, instead of palmitic acid, in order to strengthen the affinity of the peptide to hair keratin. This biotinyl-GHK peptide was then tested on hair growth in vitro (Figure 36.7) where 2 p.p.m. of the peptide increased hair length by 58% (identical to minoxidil), and 5 p.p.m. achieved 120% increase. The production of the mitotic marker Ki67 and stimulation of collagen IV and laminin 5 syntheses were also investigated. Confirmation of the improved anchoring of the hair to the follicular infundibulum came from a clinical trial to study hair loss in alopecia patients where a significant

Table 36.1 Variation in IL-6 levels in presence of Pal-GQPR. Pal-Gly-Gln-Pro-Arg (ppm)

Decrease of basal IL-6 (% of baseline level)

Decrease of UVB-induced IL-6 (% of baseline)

−15.6 ± 8.2

−33.2 ± 12.8

−20.0 ± 6.6

−37.3 ± 13.0

−24.6 ± 17.6

−60.3 ± 8.5

−70.6 ± 9.8

−85.5*

−86.5*

NT, not tested. * n = 2.

(a)

(b) Figure 36.5 Immunofluorescence staining of collagen I in a normal human skin fibroblast culture after 3-day incubation: (a) control; (b) with 6 p.p.m. of Pal-GQPR.

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(a)

(b) Figure 36.6 Wrinkle improvement after 2 months’ application (twice daily) of a cream containing 4 p.p.m. Pal-GHK and 2 p.p.m. of Pal-GQPR. (a) Before. (b) After.

(a)

(b)

(c)

(d) Figure 36.7 Hair follicles in survival medium, incubated 14 days; (a & b) control; (c & d) 5 p.p.m. Biot-GHK.

298

36. Peptides and proteins improvement of the anagen : telogen ratio was observed, in line with histologic observations on plucked hairs from the panelists [23].

30 days treatment on a panel of 10 human female volunteers [25].

Neuropeptides

Proteins

Neurotensin, VIP, NPY, substance P, and CGRP, although endowed with potent biological activity, are not candidates for cosmetic applications because of their size and irritation potential. This is not the case for the β-endorphin, enkephalin and the kyotorphin peptide complex. The dipeptide Tyr-Arg, which is known as kyotorphin, has been shown to be analgesic via enkephalin release in mouse brain [11]. The modified peptide, also known as N-acetyl-tyr-arghexadecylester, demonstrates improved skin bioavailability and stimulates the release of β-endorphin in keratinocytes. It is also able to reduce skin sensitivity to external thermal, chemical, and mechanical stress. A double-blind, vehicle controlled study using a lie detector established that this peptide, at 300 p.p.m. in an O/W emulsion, was able to diminish skin electrodynamic response to mechanical trauma induced by wiping the skin with sandpaper [24]. Sensitivity of the skin to thermal trauma induced by a heat probe and chemical trauma induced by topical capsaicin is also decreased after application of the peptide [16]. The peptide also inhibits in vitro muscle contraction. Injections of derivatives of the Botulinium neurotoxin have been approved in a number of countries to diminish glabellar wrinkles. To develop a peptide with similar effects, Blanes-Mira et al. [25] synthesized the hexapeptide NAc-Glu-Glu-Met-Gln-Arg-Arg-NH2 (N-Ac-EEMQRR-NH2), a fragment of the SNAP-25 molecule [26]. It is reported to inhibit neurotransmitter release, apparently as a result of interference with the formation and/or stability of the protein complex that is required to drive Ca2+-dependent exocytosis, namely the vesicular fusion known as SNARE complex, similar to what happens with Botulinium neurotoxin injections. The authors also claim that the peptide, formulated at the concentration of 10% = 100 000 p.p.m. in an O/W emulsion, reduced wrinkle depth up to 30% upon

(a)

(b)

Structural proteins are building blocks for the organs and tissues of the human body. Collagen, one of the most abundant protein families, as well as keratin, elastin, fibronectin, actins, together with glycoproteins and proteoglucans, arrange themselves in finely tuned, three-dimensional structures to form muscles and skin. These proteins undergo a constant renewal process, even in the absence of external disturbances. These structural proteins are in contrast to enzymes, which fulfill an entirely different function. Enzymes speed up biochemical reactions, which would otherwise occur too slowly for the body to function. Enzyme function is highly specific. This specificity results from the precise amino acid sequence, which not only aligns the correct atoms and side chains in the right order, but also directs the precise folding pattern of the enzyme protein, thus guaranteeing its biological function. Enzymes are catalysts acting at low concentrations. The most important families of enzymes are proteolytic, lipolytic, antioxidant, DNA repair, and those involved in protein synthesis and gene regulation. A variety of enzymes have been employed in dermocosmetic products.

Proteolytic enzymes Proteolytic enzymes are used as an alternative to α-hydroxy acids for superficial peeling of the skin surface, but care must be taken with the dosage. Figure 36.8 illustrates the proteolytic smoothing effect obtained with these enzymes.

T4 endonuclease V T4 endonuclease V, isolated from Escherichia coli infected with T4 bacteriophage, has been shown to repair UV-induced cyclobutane pyrimidine dimers in DNA. Applied topically, liposomes containing T4 endonuclease V reduced the

(c)

Figure 36.8 Scanning electron microscope (SEM) pictures of skin treated with an occlusive patch for 2 hours; (a) control cream pH 7; (b) cream with AHA to pH 3.5; (c) cream with 2% proteolytic enzyme solution (10 proteolytic units/mL).

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incidence of basal cell carcinomas by 30% and of actinic keratoses by 68% without adverse effects and no evidence of allergic or irritant contact dermatitis. Although the photoprotective effect of T4N5 has been investigated only in xeroderma pigmentosum patients, it may be also be effective for normal skin [27]. Cosmetic products based on this concept are in the current marketplace.

Superoxide dismutase Superoxide dismutase, an antioxidant enzyme, is present at the surface of the skin. Adding this enzyme to cosmetic formulations to strengthen the natural defense system is tempting, although the transmutation of the superoxide anion to hydrogen peroxide, without further detoxification

of the peroxide, is not necessarily sufficient for protecting the skin. Furthermore, the bovine blood, yeast, or biotechnologically derived SOD does not guarantee sufficient stability to survive manufacturing procedures and shelf life in cosmetic consumer products. A novel alternative is based on extremozymes (enzymes produced by extremophile bacteria, such as Thermus thermophilus). Mas-Chamberlin et al. [28] have shown that these enzymes are heat and UV stable, possessing both SOD and catalase mimicking activity protecting the skin against UVinduced free radical damage. A 6-month clinical vehicle controlled blind trial under tropical conditions (Figure 36.9; Tables 36.2 & 36.3) on the island of Mauritius [29] demonstrated the visible and measurable benefits of protecting the skin in preventive manner.

(a)

(b)

Table 36.2 Changes in transepidermal water loss (TEWL) after exposure to tropical climate (25 panelists); group treated with extremozyme formula. (Reproduced with permission of Soap Perfumery and Cosmetics.) Variation (g/m−2/h−1) (mean ± SEM)

% Change (mean)

Significance

Week 4 vs. T0

−1.0 ± 0.7

−6%

NS* (p = 0.192)

Week 12 vs. T0

+0.8 ± 0.9

Week 24 vs. T0

+0.2 ± 0.9

Time

* NS, not significant.

300

+5%

+1%

NS (p = 0.391)

NS (p = 0.855)

Figure 36.9 Scanning electron microscope (SEM) pictures of stratum corneum strippings: skin exposed to 6 months’ tropical climate, treated with moisturizer. (a) Control formula; (b) extremozyme-containing moisturizer. (Reproduced with permission of Soap Perfumery and Cosmetics.)

Table 36.3 Changes in transepidermal water loss (TEWL) after exposure to tropical climate (25 panelists); group treated with placebo formula; clearly the increase in TEWL indicates damaged skin barrier. (Reproduced with permission of Soap Perfumery and Cosmetics.). Time

Change (g/m-2/h-1) (mean ± SEM)

% Change (mean)

Significance

4 weeks vs. T0

+0.9 ± 0.8

+7%

NS (p = 0.258)

12 weeks vs. T0

+1.3 ± 0.7

+10%

NS (p = 0.081)

24 weeks vs. T0

+1.4 ± 0.7

+11%

Borderline (p = 0.057)

36. Peptides and proteins

Conclusions Peptides, more than proteins, have become the “buzz” word of dermocosmetics (sometimes called “cosmeceuticals” or “active” cosmetics) during the last 5 years. This chapter presents some justification for this success. Although the list of peptides naturally occurring in the human body is long, allowing for further biomimetic peptide development for skincare, the possibility to create derivatives, analogs, and other variations on a theme is enormous and exciting. For example, the number of possible pentapeptides based on the 20 proteinogenic amino acids is 205 or 3 200 000. As understanding of cellular mechanisms, gene regulation, receptor activity, and metabolic interactions increases, many new peptides may appear in dermocosmetics.

References 1 Lintner K. (2007) Peptides, amino acids and proteins in skin care? Cosmet Toiletries 122, 26–34. 2 Maquart FX, Pickart L, Laurent M, Gillery P, Monboisse JC, Borel JP. (1988) Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-Llysine-Cu2+. FEBS Lett 238, 343–46. 3 Leroux R, Peschard O, Mas-Chamberlin C, et al. (2000) Shaping up. Soap Perfum Cosmet 12, 22–4. 4 Rizvi SI, Maurya PK. (2007) Markers of oxidative stress in erythrocytes during aging in humans. Ann N Y Acad Sci 1100, 373–82. 5 Enomoto TM, Johnson T, Peterson N, Homer L, Watts D, Johnson N. (2005) Combination glutathione and anthocyanins as an alternative for skin care during external-beam radiation. Am J Surg 189, 627–31. 6 Villarama CD, Maibach HI. (2005) Glutathione as a depigmenting agent: an overview. Int J Cosmet Sci 27, 147–53. 7 Aldini G, Granata P, Carini M. (2002) Detoxification of cytotoxic alpha,beta-unsaturated aldehydes by carnosine: J Mass Spectrom 37, 1219–28. 8 Nagai K, Suda T, Kawasaki K, Mathuura S. (1986) Action of carnosine and beta-alanine on wound healing. Surgery 100, 815–21. 9 Misery L. (2002) Les nerfs à fleur de peau. Int J Cosmet Sci 24(2), 111–6. 10 Baroni A, Perfetto B, Canozo N, Braca A, Farina E, Melito A, et al. (2008) Bombesin: a possible role in wound repair. Exp Dermatol 17, 628. 11 Shiomi H, Ueda H, Takagi H. (1981) Isolation and identification of an analgesic opioid dipeptide kyotorphin (Tyr-Arg) from bovine brain. Neuropharmacology 20, 633–8. 12 Maquart FX, Simeon A, Pasco S, Monboisse JC. (1999) Regulation of cell activity by the extracellular matrix: the concept of matrikines. J Soc Biol 193, 423–8.

13 Katayama K, Armendariz-Borunda J, Raghow R, Kang AH, Sayer JM. (1993). A pentapeptide from type I procollagen promotes extracellular matrix production. J Biol Chem 268, 9941–4. 14 Singer II, ka*wka DW, Scott S, Mumford RA, Lark MW. (1987) The fibronectin cell attachment sequence Arg-Gly-Asp-Ser promotes focal contact formation during early fibroblast attachment and spreading. J Cell Biol 104, 573–84. 15 Long MM, King VJ, Prasad KU, Freeman BA, Urry DW. (1989) Elastin repeat peptides as chemoattractants for bovine aortic endothelial cells. J Cell Physiol 140, 512–8. 16 Lintner K, Peschard O. (2000) Biologically active peptides: from a lab bench curiosity to a functional skin care product. Int J Cosmet Sci 22, 207–18. 17 Lim JM, Chang MY, Park SG, Kang NG, Song YS, Lee YH, et al. (2003) Penetration enhancement in mouse skin and lipolysis in adipocytes by TAT-GKH, a new cosmetic ingredient. J Cosmet Sci 54, 483–91. 18 Ruiz MA, Clares B, Morales ME, Cazalla S, Gallardo V. (2007) Preparation and stability of cosmetic formulations with an antiaging peptide. J Cosmet Sci 58, 157–71. 19 Mas-Chamberlin C, Lintner K, Basset L, et al. (2002) Relevance of antiwrinkle treatment of a peptide: 4 months clinical double blind study vs excipient. Ann Dermatol Venereol 129: Proceedings 20th World Congress of Dermatology, Book II, PO 438, Paris. 20 Robinson LR, Fitzgerald NC, Doughty DG, Dawes NC, Berge BA, Bissett DL. (2005) Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int J Cosmet Sci 27, 155–60. 21 Watson RE, Long SP, Bowden JJ, Bastrilles JY, Barton SP, Griffiths CE. (2008) Repair of photoaged dermal matrix by topical application of a cosmetic “antiageing” product. Br J Dermatol 158, 472–7. 22 US Patent US6,974,799 B2. 23 Mas-Chamberlin C, Mondon P, Lamy F, Peschard O, Lintner K. (2005) Reduction of hair-loss: Matrikines and plant molecules to the rescue. In Proceedings of the 7th Scientific Conference of the Asian Society of Cosmetic Chemists, Bangkok, Thailand. 24 Mas-Chamberlin C, Peschard O, Mondon P, Lintner K. (2004) Quantifying skin relaxation and well-being. Cosmet Toiletries 119, 65–70. 25 Blanes-Mira C, Clemente J, Jodas G, Gil A, Fernández-Ballester G, Ponsati B, et al. (2002) A synthetic hexapeptide (Argireline) with antiwrinkle activity. Int J Cosmet Sci 24, 303–10. 26 Chen YA, Scheller RH. (2001) SNARE mediated membrane fusion. Nat Rev Mol Cell Biol 2, 98–106. 27 Cafardi JA, Elmets CA. (2008) T4 endonuclease V: review and application to dermatology. Expert Opin Biol Ther 8, 829–38. 28 Mas-Chamberlin C, Lamy F, Mondon P, et al. (2002) Heat and UV stable cosmetic enzymes from deep sea bacteria. Cosmet Toiletries 117, 22–30. 29 Mas-Chamberlin C, Mondon P, Lamy F, et al. (2006) Potential preventive performance. Soap Perfum Cosmet 6, 34–6.

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Chapter 37: Cellular growth factors Richard E. Fitzpatrick1,2 and Rahul C. Mehta1 1 2

SkinMedica, Inc, Carlsbad, CA, USA Division of Dermatology, UCSD School of Medicine, San Diego, CA, USA

BAS I C CONCE P T S • Skin aging is like a chronic wound that does not completely heal. • Cellular growth factors have a key role in the wound healing process. • Cellular growth factors that promote wound healing may accelerate reversal of aging. • Preliminary clinical studies show efficacy of products containing multiple growth factors and cytokines.

Introduction This chapter discusses cellular growth factors, which are proteins capable of stimulating cellular growth, proliferation, and cellular differentiation. Growth factors are important for regulating a variety of cellular processes. They have been best studied in wound healing models, but have been adapted as cosmeceuticals for their ability to improve the appearance of aging skin.

Physiology Skin aging and wound healing Extensive research on skin aging in the last decade has resulted in an improved understanding of the pathophysiology of intrinsic (age-related) and extrinsic aging (UVmediated photoaging). Biochemical processes resulting in skin damage following exposure to UV radiation are now being identified and understood [1]. A correlation between biochemical processes following photodamage and creation of wound is emerging. Of specific interest to cosmeceutical manufacturers are the effects of growth factors in the process of wound healing. Figure 37.1 shows the stages of wound healing and role of growth factors in each stage. Growth factors are regulatory proteins that mediate signaling pathways between and within cells. After a wound has been inflicted, a variety of growth factors flood the wound site and interact synergistically to initiate and coordinate each phase of wound healing. They help recruit and activate fibroblast to produce rapid production of extracellular matrix to close the wound followed by stimulation and multiplica-

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tion of keratinocytes to form new epidermis. The overall process is complex and not completely understood [2]. Following skin damage, a variety of pathways are activated. Formation of a wound or UV damage induces inflammation via several pathways including nuclear factor-κB (NF-κB) mediated activation of tumor necrosis factor-α (TNF-α) and interleukins [3]. Reactive oxygen species (ROS) and proteolytic enzymes are generated as a result of inflammation resulting in degradation of extracellular matrix. ROS increase oxidative phosphorylation of cell surface receptors causing activation transcription factors activator protein 1 (AP-1) and NF-κB, two critical components of mitogenactivated protein (MAP) kinase signaling pathway [4]. ROS therefore have a central role in intrinsic and extrinsic aging. AP-1 stimulates transcription of matrix metalloproteinase (MMP) growth factor genes in fibroblast and keratinocytes, and inhibits type 1 procollagen gene expression in fibroblasts [5]. Multiple studies have shown that activation of the MMP secretion as a result of intrinsic and extrinsic aging produces breakdown of dermal matrix [6]. Different subtypes of MMP have different substrate proteins on which they act to produce a break in their primary sequence. MMP-1 (collagenase) produces cleavage at a single site in central triple helix of fibrillar type I and III collagen. The cleaved subunits are further degraded by MMP-3 (stromelysine 1) and MMP-9 (gelatinase). Tissue inhibitors of metalloproteinase (TIMP) decrease activity of MMPs. ROS inactivates TIMP thereby further increasing MMP activity. AP-1 mediated reduction in synthesis of procollagen appears to result from two mechanisms: interference of AP-1 with type 1 and 3 procollagen gene transcription and blocking the profibrotic effects of TGF-β by impairment of TGF-β type 2 receptor–Smad pathway [3]. Activation of NF-κB stimulates transcriptions of proinflammatory cytokine genes including interleukin 1 (IL-1), TNF-α, IL-6, and IL-8 [4]. Inflammation resulting from these cytokines increases secretion of ROS and more cytokines further enhancing the effect of UV exposure.

37. Cellular growth factors

Wound

Hemostasis Platelets induced clotting WBC recruitment TGF-β TNF-α IL-1, IL-6 IL-8, IL-10

Laser procedure Subclinical wound Inflammation

Extrinsic aging UV exposure

ROS mediated ECM degradation

Intrinsic aging Oxidative metabolism

TGF-β, PDGF VEGF, HGF NGF, IGFs FGF2, IL-8 Granulation ECM formation Wound closure

Figure 37.1 Healing and remodeling of skin damaged by the effect of intrinsic aging, extrinsic aging, wound or laser procedures. (From Mehta RC, Fitzpatrick RE. (2007) Endogenous growth factors as cosmeceuticals. Dermatol Ther 20, 350–9.)

TGF-β FGF2 TIMPs MMPs

Inflammation causes protease-mediated degradation of elastin and UV exposure causes formation of abnormal elastin by fibroblasts. UV light is also an inhibition of leukocyte elastase thereby increasing accumulation of elastotic materials [7]. The accumulation of elastotic materials is accompanied by degeneration of surrounding collagenous network. The overall effects of these interlinked biochemical activities is reduction of procollagen synthesis, increase of collagen degradation in the dermal extracellular matrix, and increase in irregular elastin deposition. Successful resolution of damage to skin and wound healing requires a balance between development of inflammation and its rapid resolution which includes involvement of growth factors and cytokines such as TGF-β, TNF-α, platelet-derived growth factor (PDGF), IL-1, IL-6, and IL-10 [8]. Intrinsic aging does not show the inflammatory component seen with healing of acute photodamage and wounds; instead, mitochondrial oxidative metabolism produces some of the key mediators of extracellular matrix degradation including ROS [9]. Transition from inflammatory phase of wound healing to granulation phase is mediated by a variety of growth factors

Remodeling ECM reorganization Strengthening

and cytokines including PDGF, TGF-α, TGF-β, fibroblast growth factors (FGFs), insulin-like growth factor 1 (IGF-1), cerebrospinal fluid (CSF), interleukins and TNF-α [10]. The growth factors and cytokines are derived from macrophages, epidermal keratinocytes, and fibroblasts. Multiple metabolic pathways lead to formation of new collagen and repair of extracellular matrix during the granulation phase. The final stage of wound healing after granulation and wound re-epithelialization or peeling of sunburned skin is the beginning of dermal tissue remodeling. During this stage, low strength, unorganized, type 3 collagen and elastin structures produced during the extracellular matrix production phase are replaced by stronger type 1 collagen and structured elastin fibers to provide strength and resiliency to the dermis. This remodeling phase can last for several months and is the key to reversing the visible effects of skin aging [11]. Most studies have evaluated the role of single growth factors in controlled wound-healing environments. These studies demonstrate the importance of growth factors in the repair of damaged tissue, but research into the phases of wound healing has demonstrated that it is the interaction of multiple growth factors that is vital to tissue regeneration.

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Cosmeceutical manufacturers have taken notice of the positive results of clinical studies showing accelerated wound healing and have begun to include growth factors in products designed to mitigate damage from chronologic aging and sun exposure [11].

Role of cellular growth factors in skincare The use of growth factors and cytokines in skin rejuvenation and reversal of photoaging is emerging as a novel antiaging treatment. Table 37.1 lists some important growth factors and cytokines that affect the proliferation of dermal

Table 37.1 Partial list of growth factors and cytokines identified in active gel and their function in skin [12]. Growth factor/cytokine

Skin-related functions

Fibroblast growth factors: bFGF (FGF-2), FGF-4, FGF-6, KGF (FGF-7), FGF-9

Angiogenic and fibroblast mitogen

Hepatocyte growth factor (HGF)

Strong mitogenic activities; three-dimensional tissue regeneration and wound healing

Platelet derived growth factors: PDGF AA, PDGF BB, PDGF Rb

Chemotactic for macrophages, fibroblasts; macrophage activation; fibroblast mitogen, and matrix production

Insulin-like growth factors: IGF1, IGFBP1, IGFBP2, IGFBP3, IGFBP6

Endothelial cell and fibroblast mitogen

Transforming growth factor: TGF-β1, TGF-β2, TGF-β3

Keratinocyte migration; chemotactic for macrophages and fibroblasts

Tissue inhibitor of metalloproteinases: TIMP1 (MPI1), TIMP2 (MPI2)

Prevent enzymatic degradation of collagen and hyaluronic acid

Vascular endothelial growth factor (VEGF)

Influence vascular permeability and angiogenesis to improve tissue nutrition

Placenta growth factor (PLGF)

Promote endothelial cell growth

Bone morphogenetic protein: BMP7

Promote development of nerve cells in developing tissue

Interleukins: IL-1α, IL-1β

Early activators of growth factor expression in macrophages, keratinocytes, and fibroblasts

Interleukin: IL-2

Enhance epithelial wound healing

Interleukin: IL-6

Mediator of acute phase response to wound and has synergistic effect with IL-1

Interleukin: IL-10

Inhibits pro-inflammatory cytokines to reduce inflammation prevents scar formation

Interleukin: IL-4, IL-13

Stimulate production of IL-6

Interleukin: IL-3, IL-4, IL-5

Leukocyte maturation and degranulation during inflammatory phase

Interleukins: IL-7, IL-8, IL-15

Leukocyte activation and proliferation during inflammatory phase

Leptin

Epidermal keratinocyte proliferation during wound healing

Colony stimulating factors: GCSF, GM-CSF, M-CSF

Stimulate the development of neutrophils and macrophages

GCSF, granulocyte colony stimulating factor; GM-CSF, granulocyte macrophage colony stimulating factor; M-CSF, macrophage colony stimulating factor.

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37. Cellular growth factors fibroblasts and extracellular matrix production [12]. Growth factors, cytokines, and other agents that help rebuild the extracellular matrix are critical in the reversal of the signs of skin aging such as fine lines and wrinkles. Providing a physiologically balanced mixture of these growth factors and cytokines to cells responsible for extracellular matrix production and remodeling may benefit in rejuvenation of aging skin. Several cosmeceutical products containing either a single human growth factor or combination of multiple human growth factors and cytokines are currently marketed for skin rejuvenation. Several clinical studies now show that human growth factors when applied topically provide beneficial effects in reducing the signs of facial skin aging [2].

Unique attributes Growth factors produce antiaging benefits by virtue of their biologic role to maintain healthy skin structure and function. Together with cytokines, growth factors provide constant communication between cells of the immune system, keratinocytes, and fibroblasts throughout the process of wound healing and skin repair and regeneration. During the final remodeling phase of wound healing, a number of different growth factors and cytokines interact with each other and with the surrounding cells in concert to improve the quality of extracellular matrix. Use of individual growth factors is unlikely to duplicate these complex interactions essential for remodeling of skin. Therefore, a mixture of growth factors and cytokines proven to have a role in skin remodeling should provide superior benefits than individual growth factors. Ideal growth factor products should contain this unique mixture obtained from natural sources.

Figure 37.2 Histology of skin before (a) and after 3 months of TNS Recovery Complex (b) showing increase in grenz-zone collagen and epidermal thickness after treatment.

Advantages and disadvantages Clinically proven benefits in reversal of skin aging In one of the first pilot clinical studies with a product containing a natural combination of fibroblast-derived growth factor mixture, 14 patients with Fitzpatrick class II or greater facial photodamage applied TNS Recovery Complex (SkinMedica, Carlsbad, CA, USA) twice daily for 60 days. The results show a statistically significant reduction in fine lines and wrinkles and reduction in periorbital photodamage by clinical grading and by optical profilometry. Figure 37.2 shows an example of a skin biopsy section with increased collagen after treatment with the study product. Measurements of grenz zone collagen and epidermal thickness from the biopsy show a 37% increase in grenz zone collagen and a 30% increase in epidermal thickness [11]. Vehicle controlled studies on cosmeceutical products are very difficult to conduct as topical vehicles can have benefits by virtue of skin hydration, reduced epidermal water loss, or simply providing physical barrier against the environment. Because of these effects, most vehicles cannot be classified as “inactive” and make it more difficult to achieve statistical significance in a vehicle controlled, double-blind study design. In spite of these difficulties, if the product contains any new active combinations, the study must include a reasonably matched vehicle to scientifically validate effects of the new active [13]. In a double-blind study, 60 subjects were randomly assigned to receive either TNS Recovery Complex or vehicle and apply it twice daily for 6 months along with a moisturizing cleanser and sunscreen. Treatment with TNS Recovery Complex for 3 months produced greater reduction in fine

(a)

(b)

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lines and wrinkles than vehicle treatment as measured by optical profilometry and assessment of photographs. The results were either statistically significant (p ≤ 0.05) or trending towards statistical significance (p ≤ 0.1). Figure 37.3 shows improvement in facial photodamage observed in this study. The study demonstrates that even when compared with a treatment with a good moisturizer and sunscreen, the product being tested showed significant benefits of reversal of signs and symptoms of skin aging [12]. In another double-blind study, 18 patients with Fitzpatrick class II or greater facial photodamage applied Bio-Restorative Skin Cream (NeoCutis, Inc, San Francisco, CA, USA) twice daily for 60 days. The results showed that while the average facial roughness did not decrease, a significant improvement was seen in several other parameters of facial wrinkles. The measurements were conducted by a novel three-dimensional surface mapping technique [14].

Risks associated with growth factors Growth factors are key molecules that affect cellular proliferation and differentiation which, if unregulated, can lead to carcinogenic transformation of cells. Presence of receptors for some growth factors in melanoma cells and expression of certain growth factors by cancerous cells [15] has raised concerns about the potential for topically applied growth factors to stimulate the development of cancer. However,

whether presence of receptors or increased expression contributes to tumor growth is uncertain. A recent finding suggests that chronic administration of high concentrations of PDGF directly into debrided diabetic pressure wounds may result in increased mortality from cancer. It is unlikely that growth factors applied topically to intact skin would affect tumor proliferation as the protein molecules are too large to be absorbed in large quantities [12]. In addition, it is unlikely that the levels of growth factors in skin after topical application is significantly higher than those following inflammation-causing event such as chemical peel, lasers, or skin infections.

Ingredients Natural growth factors Human growth factors may be obtained from two major sources: cultured human cells or genetically engineered microorganisms. Human cells cultured in a three-dimensional network secrete a mixture of a large number of growth factors and other proteins capable of promoting wound healing [16]. The composition of the growth factor mixture varies with cell phenotype and environmental variables. Cells growing under conditions resembling a wound are most likely to produce growth factors, cytokines, and matrix proteins that assist in wound healing.

(a)

(b) Figure 37.3 Photograph of periorbital and upper cheek area before (a) and after 6 months of TNS Recovery Complex (b) showing reduction in wrinkles and fine lines after treatment.

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37. Cellular growth factors SkinMedica’s NouriCel-MD is collected from a threedimensional matrix of dermal fibroblasts induced to produce collagen, the same protein they produce during wound healing. The associated combination of growth factors and cytokines naturally secreted during the collagen production phase of the tissue culture therefore represents the most appropriate combination to induce wound healing (Table 37.1). Naturally secreted growth factors can also be obtained from fibroblast and keratinocyte co-cultures. Another method of collecting a mixture of growth factors and cytokines is to lyse fibroblast and collect the intracellular components which include growth factors, cytokines, and other intracellular materials present at the time of cell lysis [17].

Table 37.2 Synthetic growth factors registered as cosmetic ingredients [19]. INCI name

Growth factor

Human oligopeptide-1 Human oligopeptide-2

Epidermal growth factor Insulin-like growth factor-1

Human oligopeptide-3

Basic fibroblast growth factor

Human oligopeptide-5

Keratinocyte growth factor

Human oligopeptide-7

Transforming growth factor-β3

Human oligopeptide-8

Interleukin 10

Human oligopeptide-10

Platelet derived growth factor

Human oligopeptide-11

Vascular endothelial growth factor

Human oligopeptide-12

Fibroblast growth factor 10

Human oligopeptide-13

Acidic fibroblast growth factor

Growth factors secreting stem cells

Human oligopeptide-14

Transforming growth factor-α

Adipose-derived stem cells, a population of pluripotent cells, have been studied for promotion of wound healing by virtue of their ability to secrete growth factors. Preliminary studies show that intradermal injection of adipose-derived stem cell suspension can produce increased collagen production and reduce signs of skin aging. These preclinical results warrant further evaluation in clinical studies after adequate testing and standardization of methods to obtain autologous adipose-derived stem cells [18].

Human oligopeptide-15

Interleukin 4

Human oligopeptide-19

Nerve growth factor

Human oligopeptide-20

Tissue inhibitor of metalloproteinases

Synthetic growth factors Individual growth factors and cytokines can be made via recombinant technology using bacterial or yeast cultures modified to include DNA sequence for growth factors. Many growth factors of cosmeceutical interest are produced by this technique including TGF-β, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), various FGFs, PDGF, and more [19]. Table 37.2 lists various growth factors registered with International Cosmetic Ingredient Dictionary and Handbook as cosmetic ingredients. While clinical studies have shown a marginally beneficial effect for some of the individual growth factors, more studies must be carried out to understand the role of combinations of growth factors in skin rejuvenation. Combinations of growth factors that complement each other’s effects is likely to be more effective as multiple growth factors are involved in most biochemical processes including wound healing [8].

Related products Phytokinins Kinetin, a plant-derived growth hormone discovered almost 50 years ago, has been recently used in several cosmeceutical products as an antiaging ingredient [20]. Kinetin is found in the DNA of almost all organisms tested so far, including human cells. In plants, kinetin regulates cellular differentiation by an endocrine pathway with unknown mechanism;

however, its function in human cells is not known. Kinetin and other cytokinins are products of oxidative metabolism of the cell. Kinetin is formed in the nucleus by reaction of hydroxyl free radicals with DNA whereas reaction of hydroxyl radical with RNA results in formation of zeatin, another cytokinin used in cosmeceutical products. A large number of in vitro and in vivo studies in many species show a number of pharmacologic actions leading to potential antiaging effects of kinetin and other cytokines. However, the effects are not related to the growth factor or hormone related properties but are primarily brought about by their strong intracellular antioxidant properties. A pilot study on 0.1% kinetin showed moisture retention and reduction in appearance of fine wrinkles and pigmentation; however, more controlled studies are required to substantiate the antiaging benefits.

Alternate delivery methods Mesotherapy is the micro-injection of growth factors or other active molecules into the mesoderm with the premise that the active molecules are directly delivered to the target tissue using fine gauge short needles to a 2–5 mm depth of penetration. Multiple, close spaced injections are made to ensure adequate coverage of the treatment area. There are no clinical studies evaluating the efficacy of the procedures and safety remains a concern because of lack of availability of sterile growth factor solutions. A variation of mesotherapy is the use of micro-needle devises to create micro-punctures into the stratum corneum

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before topical application of growth factors with the assumption that reduced barrier will result in greater efficacy. Again, very little clinical evidence exists to show effectiveness of these procedures.

Product quality considerations Cosmeceutical products containing mixtures of natural substances such as cellular growth factors are generally difficult to analyze for concentrations of active ingredient. Even products manufactured with single growth factor are not labeled with growth factor content which makes it difficult to compare product strengths. More analytical efforts are needed to ensure that consumers know that the products they are using have reliable quality standards. In addition, growth factors and other biologically active peptides are inherently unstable in non-physiologic environment, unless they are stored frozen at temperatures below −20 °C. Presence of surface active additives, alcohols, and other protein denaturing excipients further decrease product stability and compromise product efficacy during the claimed shelf-life of the product. A recent study shows presence of high levels of growth factors and cytokines in a commercial product stored at room temperature throughout its 2-year shelf-life [12]. If quantitative analysis is not possible because of the complexity of the formulation, measurement of biological activity should be performed using an appropriate technique to ensure product stability throughout the labeled shelf-life.

Conclusions Studying the role of growth factors in cutaneous wound healing has led to research demonstrating positive cosmetic and clinical outcomes in photodamaged skin. Although the topical use of growth factors is an emerging treatment approach, clinical studies demonstrate that dermal collagen production and clinical improvement in photodamage appearance are significant. Further, the increase in dermal collagen produced by topical growth factors can be measured quantitatively by biopsy. Although the functions of growth factors in the natural wound healing process are complex and incompletely understood, it appears that wound healing is dependent on the synergistic interaction of many growth factors. The most promising research suggests that multiple growth factors used in combination stimulate the growth of collagen, elastin, and glycosaminoglycans leading to reduction in fine lines and wrinkles. The use of a multiple growth factor topical formulation provides a good first line treatment for mild to moderate photodamaged skin.

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References 1 Gilchrest BA. (1989) Skin aging and photoaging: an overview. J Am Acad Dermatol 21, 610–3. 2 Mehta RC, Fitzpatrick RE. (2007) Endogenous growth factors as cosmeceuticals. Dermatol Ther 20, 350–9. 3 Quan T, He T, Kang S, Voorhees JJ, Fisher GJ. (2004) Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling. Am J Pathol 165, 741–51. 4 Fisher GJ, Talwar HS, Lin J, Lin P, McPhillips F, Wang Z, et al. (1998) Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo. J Clin Invest 101, 1432–40. 5 Schwartz E, Cruickshank FA, Christensen CC, Perlish JS, Lebwohl M. (1993) Collagen alterations in chronically sundamaged human skin. Photochem Photobiol 58, 841–4. 6 Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ. (1997) Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 337, 1419–28. 7 Martin P. (1997) Wound healing: aiming for perfect skin regeneration. Science 276, 75–81. 8 Eming SA, Krieg T, Davidson JM. (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127, 514–25. 9 Sohal RS, Weindruch R. (1996) Oxidative stress, caloric restriction, and aging. Science 273, 59–63. 10 Moulin V. (1995) Growth factors in skin wound healing: review article. Eur J Cell Biol 68, 1–7. 11 Fitzpatrick RE, Rostan EF. (2003) Reversal of photodamage with topical growth factors: a pilot study. J Cosmet Laser Ther 5, 25–34. 12 Mehta RC, Smith SR, Grove GL, Ford RO, Canfield W, Donofrio LM, et al. (2008) Reduction in facial photodamage by a topical growth factor product. J Drugs Dermatol 7, 864–71. 13 Draelos ZD. (2007) Exploring the pitfalls in clinical cosmeceutical research. Cosmet Dermatol 20, 556–8. 14 Gold MH, Goldman MP, Biron J. (2007) Human growth factor and cytokine skin cream for facial skin rejuvenation as assessed by 3D in vivo optical skin imaging. J Drugs Dermatol 6, 1018–23. 15 Liu B, Earl HM, Baban D, Shoaibi M, Fabra A, Kerr DJ, et al. (1995) Melanoma cell lines express VEGF receptor KDR and respond to exogenously added VEGF. Biochem Biophys Res Commun 217, 721–7. 16 Mansbridge J, Liu K, Patch R, Symons K, Pinney E. (1998) Three-dimensional fibroblast culture implant for the treatment of diabetic foot ulcers: metabolic activity and therapeutic range. Tissue Eng 4, 403–14. 17 Schütte H, Kula MR. (1990) Pilot- and process-scale techniques for cell disruption. Biotechnol Appl Biochem 12, 599–620. 18 Park BS, Jang KA, Sung JH, Park JS, Kwon YH, Kim KJ, et al. (2008) Adipose-derived stem cells and their secretory factors as a promising therapy for skin aging. Dermatol Surg 34, 1323–6. 19 Gottscha TE, Bailey JE, eds. (2008) International Cosmetic Ingredient Dictionary and Handbook. Washington DC: Toiletry and Fragrance Association, pp. 1170–4. 20 Barciszewski J, Massino F, Clark BF. (2007) Kinetin: a multiactive molecule. Int J Biol Macromol 40, 182–92.

Chapter 38: Retinoids Olivier Sorg, Gürkan Kaya, Behrooz Kasraee, and Jean H. Saurat Department of Dermatology, Geneva University Hospital, Geneva, Switzerland

BAS I C CONCEPTS • Retinoids define a class of substances comprising vitamin A (retinol) and its naturally and synthetic derivatives. • Retinoids are lipophilic molecules that diffuse through plasma membranes or cross the cutaneous barrier when applied topically. Inside the cells, retinoids bind to nuclear receptors (RAR-α, -β, -γ, and RXR-α, -β, -γ), then the ligand–receptor complexes bind to a RAR-response element (RARE) DNA sequence, resulting in the modulation of the expression of genes involved in cellular differentiation and proliferation. • As biologically active agents given to humans, retinoids can be divided into therapeuticals and cosmeceuticals. • The ranking order of retinoid-like activity following topical application is as follows: retinoic acid > retinaldehyde > retinol >> retinyl esters.

Biologic concepts Therapeutical and cosmeceutical retinoids Retinoids define a class of substances comprising vitamin A (retinol) and its natural and synthetic derivatives. Although they were first discovered in the retina as central players of the biology of vision, they function as key regulators of differentiation and proliferation in various tissues. Retinol is produced in the small intestine either by hydrolysis of retinyl esters, or by oxidation of various carotenoids [1]. Retinol can be oxidized into retinaldehyde, and then into retinoic acid, the biologically active form of vitamin A. However, retinol can be esterified with fatty acids to form retinyl esters. Retinoic acid is oxidized to a less active metabolite, 4-oxoretinoic acid, or converted to retinoyl glucuronide, whereas retinol is converted to retinyl glucuronide. Two other vitamin A metabolites, 4-oxoretinol and 4-oxoretinal, are believed to be the products of oxidation of retinol and retinal, respectively, by CYP26-related hydroxylases, although this has not been demonstrated (Figure 38.1) [2,3]. The two predominant endogenous retinoids are retinol and its esters. Retinol and retinyl esters account for more than 99% of total cutaneous retinoids (i.e. approximately 1 nmol/g) [4]. Retinoic acid is catabolized either by phase I or II enzymes, giving rise to retinoyl glucuronide or 4-oxoretinoic acid [5,6]. Although the latter has long been considered an inactive catabolite of retinoic acid, other oxoretinoids (i.e. 4-oxoretinol and 4-oxoretinal) have been shown to be the predominant retinoids in some models of

morphogenesis [7–9], and exert some of the retinoid-like activities in mouse in vivo [10]. As lipophilic molecules, they can diffuse through plasma membranes or cross the cutaneous barrier when applied topically. Inside the cells, they bind to nuclear receptors (RAR-α, -β, -γ, and RXR-α, -β, -γ), then the ligand–receptor complexes bind to a RARE DNA sequence, resulting in the modulation of the expression of genes involved in cellular differentiation and proliferation (Figure 38.1) [3,11–13]. As biologically active agents given to humans, retinoids can be divided into therapeuticals and cosmeceuticals. Therapeutical retinoids are usually RAR or RXR ligands (except for isotretinoin), and are available on medical prescription to treat diseases such as acne, psoriasis, and actinic keratosis, or oncologic diseases such as acute promyelocytic leukaemia, cutaneous T-cell lymphoma, and squamous or basal cell carcinoma [14]. Endogenous active metabolites of retinol (vitamin A) such as all-trans-retinoic acid (tretinoin), 9-cis-retinoic acid (alitretinoin), and 13-cis-retinoic acid (isotretinoin), as well as the synthetic monoaromatic retinoids acitretin and etretinate, and the arotinoids adapalene, tazarotene, and bexarotene, belong to the therapeutical retinoids (Figure 38.2a) [15,16]. Endogenous precursors of retinoic acids (i.e. retinyl esters, retinol, and retinaldehyde), as well as 4-oxoretinoids (4-oxoretinol, 4-oxoretinal, and 4-oxoretinoic acids), do not bind to nuclear retinoid receptors, are found in many overthe-counter (OTC) products, and constitute the group of topical cosmeceutical retinoids (Figure 38.2b).

Chronologic aging and photoaging are not only a question of esthetics which is often accompanied by psychologic problems, they also constitute the background for the

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LRAT

RoDH

RALDH RA

RAL

UGT ROL CYP26 ?

CYP26 ?

CYP26

oxoRAL ?

ROL-Glu

RoDH ?

RALDH ? oxoRA

REH

BCO

UGT RA-Glu

oxoROL

? Biological responses

Gene expression

RARE Figure 38.1 Biochemical pathways from dietary provitamins A to gene expression. BCO, beta-carotene-15,15’-monooxygenase; CAR, betacarotene; CYP26, cytochrome P450 26; LRAT, lecithin–retinol acyltransferase; oxoRA, all-trans-4-oxoretinoic acid; oxoRAL, all-trans-4oxoretinal; oxoROL, all-trans-4-oxoretinol; RA, all-trans-retinoic acid;

RA-Glu, all-trans-retinoyl-β-D-glucuronide; RAL, all-trans-retinaldehyde; RALDH, retinal dehydrogenase; RE, retinyl esters; REH, retinyl ester hydrolase; RoDH, retinol dehydrogenase; ROL, all-trans-retinol; ROL-Glu, all-trans-retinyl-β-D-glucuronide; UGT, UDP-glucuronosyl transferase.

development of precancerous and cancerous skin lesions, as well as severe functional skin fragility now called dermatoporosis [17,18]. Many clinical studies indicate that certain structural changes induced by excessive sun exposure can be reversed, to some extent, by the use of topical retinoids [19]. Although retinoic acid is widely used for topical therapy of several skin diseases and for improvement of skin aging, it induces irritation of the skin, which precludes its longterm use to treat extrinsic or intrinsic aging. Irritation might be explained, at least in part, by an overload of the retinoic acid-dependent pathways with supraphysiologic amounts of exogenous retinoic acid in the skin. It is still not established whether all the therapeutic activities of topical retinoids are mediated by nuclear receptors, and whether irritation is necessary for obtaining some of these activities, although most experts now consider that irritation is not mandatory for activity. To overcome the problems encountered by topical retinoic acid, delivery can be targeted with precursors of biologically active retinoids; these “proligands” are then converted in a controlled process into active ligands [20]. This intracrine concept, in which the active ligand is produced within the targets cells, has been explored to deliver retinoid activity to

mouse and human skin topically with natural retinoids such as retinaldehyde that do not bind to nuclear receptors [4,21– 25]. This might be a convenient definition of cosmeceutical topical retinoids. To validate this intracrine concept, the precursor should penetrate easily through the epidermis by topical application and be metabolized into biologically active retinoids, while the latter should be well tolerated and result in biologic effects [4,26–30]. The ranking order of retinoid-like activity following topical application is as follows: retinoic acid > retinaldehyde > retinol >> retinyl esters; in other words, this corresponds to the metabolic pathways: retinyl esters are hydrolyzed to retinol, which is oxidized to retinaldehyde, which is in turn oxidized to retinoic acid. However, probably for the same reason, the tolerance ranking order is the opposite: retinyl esters > retinol ≥ retinaldehyde >> retinoic acid.

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Genomic effects The genomic effects of topical retinoids are the consequence of the modulation of gene expression following their binding to nuclear RAR or RXR receptors. These effects most probably explain the results obtained in reversing and preventing various hallmarks of skin aging such as the activation of

38. Retinoids

(b)

Figure 38.2 Structure of therapeutical (a) and cosmeceutical (b) retinoids. “R” in retinyl esters represents an acyl radical.

(a)

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matrix metalloproteinase [31,32], oxidative stress, and the degradation of extracellular matrix [33]. In particular, retinoids are known to inhibit keratinocyte differentiation and to stimulate epidermal hyperplasia [10,34,35]. Heparin binding-epidermal growth factor (HB-EGF) activation of keratinocyte ErbB receptors via a RAR-dependent paracrine loop has been proposed to mediate retinoid-induced epidermal hyperplasia [36]. It has been shown that CD44v3, a heparan sulfate-bearing variant of CD44, which is a multifunctional polymorphic proteoglycan and principal cell surface receptor of hyaluronan (HA), recruits active matrix metalloproteinase 7, the precursor of HB-EGF (pro-HB-EGF) and one of its receptors, ErbB4, to form a complex on the surface of murine epithelial cells [37]. We have previously shown that topical application of retinaldehyde increases the expression of CD44 in mouse skin. The increased expression of CD44 accompanying epidermal hyperplasia induced by topical retinaldehyde is associated with an increase in epidermal and dermal HA and with increased expression of the HA synthases 1, 2, and 3 [38]. These observations indicate that the HA system is associated to the HB-EGF paracrine loop, with the transcriptional upregulation of CD44 and HA synthases. Thus, retinaldehyde-induced in vitro and in vivo proliferative response of keratinocytes is CD44-dependent and requires HB-EGF, its receptor ErbB1, and matrix metalloproteinases [39].

Non-genomic effects There is some evidence that retinoids might exert a biologic activity independently of their binding to nuclear receptors [10,40], thus confirming the concept of cosmeceutical retinoids. Such indirect effects have been well documented, and clinical manifestations have been observed.

Photobiology of topical retinoids Owing to their side chain containing multiple double bonds, retinoids strongly absorb UV light, with molar extinction coefficients of approximately 52 000 (M−1/cm−1) at wavelengths ranging from 325 nm for retinol to 385 nm for retinaldehyde. This property is crucial in the retina, where photoisomerization of 11-cis-retinaldehyde into all-transretinaldehyde is the first step in the biochemical cascade leading to the generation of nervous influx from the optic nerve to the visual cortex [41–43]. This property also enables retinoids to act as UV filters when applied topically: topical retinoids have been shown to load the skin with supraphysiologic epidermal concentrations [4,25]. For instance, topical retinyl palmitate 2% was as efficient as a commercial sunscreen with a sun protection factor of 20 to prevent UVB-induced erythema and DNA photodamage in the skin of healthy volunteers [44]. In mice, retinoic acid, retinaldehyde, retinol, and retinyl palmitate were efficient in preventing UVB-induced apoptosis and DNA photodamage [45]. The similar potencies of these retinoids

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indicate a physical action mediated by their spectral properties rather than a biologic action mediated by the binding to nuclear receptors. This also implies that sun exposure induces significant vitamin A depletion in the epidermis, which significance in term of photoaging has not been fully analyzed. However, the biologic effects of photodegradation of vitamin A and other retinoids are less well understood and may be important for sun-exposed tissues, such as the skin. Exposure of retinol or its esters to UV light generates free radicals and reactive oxygen species that can damage a number of cellular targets, including proteins, lipids, and DNA [46,47]. The balance between positive, filter-like properties, and possible damage to biomolecules is difficult to assess, and might depend on several factors [48–50]. For this reason, it is still recommended to avoid UV exposure when using topical retinoids.

Antibacterial activity of retinaldehyde Aldehydes represent an intermediate state of oxidation between alcohols and carboxylic acids [51–54]. Retinaldehyde may thus exert a direct biologic activity by reacting nonenzymatically with many biomolecules on skin surface, as well as on bacterial flora, independently of its conversion to retinoic acid and subsequent activation of nuclear receptors [55]. The putative anti-infective property of vitamin A had already been observed in the 1920s, although its mechanism of action was not understood [56]. Retinoic acid has been shown to protect dendritic cells in mice [57] and topical retinaldehyde, because of its better tolerance profile than retinoic acid, was successfully applied to a long period of time to patients with inflammatory dermatoses [27,28]. Retinaldehyde has been successfully used against Grampositive bacteria of the cutaneous flora: 2 weeks’ treatment with topical retinaldehyde 0.05% displayed a significant decrease in counts of viable Propionibacterium acnes, Staphylococcus aureus, and Micrococcus spp. in healthy volunteers, whereas retinaldehyde showed to be more potent than retinol and retinoic acid when assessing the minimal inhibitory concentration on various bacterial strains [58,59]. Topical cosmeceutical retinoids as antioxidants Oxidative stress is considered to be the cornerstone of the biochemical pathways leading to both intrinsic (chronologic) and extrinsic aging (photoaging) [13,60–63]. The skin, which is exposed to environmental factors and pollutants, possesses an efficient antioxidant system able to counteract the deleterious effects of occasional oxidative stress of moderate magnitude [64,65]. However, in the case of chronic or severe oxidative stress, this endogenous antioxidant network reaches its limit and irremediable tissue damage is unavoidable [66–70]. According to the free radical theory of aging, oxidative stress increases with age, whereas during the same

38. Retinoids time the endogenous antioxidant systems become less efficient [71–74]. It thus seems logical to provide the skin with exogenous antioxidants in order to slow the natural process of skin aging. Retinoids have been shown to exert a free radical scavenging activity in vitro [75–79]. This property is most probably caused by the conjugated double bond structure of the side chain and their cyclohexenyl or aromatic moiety, rather than their ability to bind nuclear retinoid receptors, indicating that topical cosmeceutical retinoids should be as good candidates as therapeutical ones to prevent or improve skin aging. Because the endogenous antioxidants act together in a functional organized network, when supplying any organ with antioxidants, this concept should be followed; this means that if cosmeceutical retinoids have a role in the prevention or improvement of skin aging, they should be considered as partners of other topical antioxidants, rather than as a whole antioxidant system. In mice, the peroxidation of epidermal lipids induced by topical menadione (vitamin K3) was completely prevented by a pretreatment with either 0.25% topical α-tocopherol (vitamin E, a known efficient endogenous cutaneous antioxidant) or topical retinaldehyde 0.05% [78]. In human, topical retinol 0.075% provided a better protection of the stratum corneum against physical (UV) and chemical (sodium lauryl sulfate) threat than a cream containing αtocopherol 1.1% [80].

naldehyde was not solely a result of its bioconversion to retinoic acid, but also to a retinoid receptor-independent mechanism [87,88]. A clinical trial in which retinol 10% and lactic acid 7% replaced tretinoin 0.1% and dexamethasone 0.1% in the formula of Kligman and Willis was successfully applied to patients with hyperpigmented lesions on the face. This new formula was shown to be comparable to that of Kligman and Willis, with the advantage of preventing the steroid-induced skin atrophy [89]. Retinyl esters, in particular retinyl palmitate, are widely used in cosmetics. According to the proligand concept discussed above, in order to exert a retinoid-like activity, retinyl esters have first to be hydrolyzed to retinol, and then oxidized to retinoic acid, a process being less effective than retinol and retinaldehyde, because it requires more enzymatic steps [22,25]. If a non-genomic effect is expected, the total retinoid content of the skin would be determinant. However, very few studies aimed at assessing the penetration of retinyl esters through human skin have been reported. In hairless mice, we found that a 3-day treatment with topical retinyl palmitate 0.05% loaded the epidermis with more retinoids than topical retinol 0.05% (119 ± 4.5, 43.3 ± 6.6, and 1.5 ± 0.2 pmol/g for retinyl palmitate, retinol, and vehicle, respectively; unpublished data). Thus, retinyl esters seem to deliver the skin with more retinoids and have less genomic effects than retinol, suggesting that they should have similar depigmenting properties to retinol.

Effects of topical cosmeceutical retinoids on pigmentation It has long been observed that retinoic acid has a lightening property on human skin, and for this reason it has been used, alone or in combination with hydroquinone, to treat hyperpigmented lesions [81,82]. The mechanism of this effect is not clear. Depending on the cell culture model, retinoic acid inhibits tyrosinase activity – the rate-limiting step of melanogenesis – inhibits cell proliferation, decreases the melanin content, or has no effect on tyrosinase, melanin content, and cell growth; in particular, in monolayer cultures, there is few or no effect with retinoic acid [83–86]. This suggests that the observed in vivo depigmenting effect of retinoic acid, and retinoids in general, may be caused by the increased rate of epidermis “turnover” rather than to a direct effect on melanin content or melanocyte growth [86]. The best depigmenting product containing a retinoid is the formula developed by Kligman and Willis, consisting of 0.1% tretinoin (retinoic acid), 5.0% hydroquinone, and 0.1% dexamethasone, but none of its active ingredients can be used in cosmetic products. Amongst cosmeceutical retinoids, retinaldehyde, the direct precursor of retinoic acid, is well tolerated in human skin and has been shown to have several biologic effects identical to that of retinoic acid [27,28]. In the mouse tail model of depigmentation, topical retinaldehyde 0.05% showed a higher depigmenting effect than retinoic acid 0.05%, indicating that this effect of reti-

Hyaluronan as a partner for cosmeceutical retinoids HA is the major component of the extracellular matrix and is found in high quantities in the skin. HA is a high molecular weight, non-sulfated, linear glycosaminoglycan composed of repeating units of D-glucuronic acid and Nacetyl-D-glucosamine linked together via alternating β-1,4 and β-1,3 glycosidic bonds. HA chains can have as much as 25 000 disaccharide repeats, corresponding to a molecular mass of approximately 8 MDa. In normal skin, HA is synthesized essentially by dermal fibroblasts and epidermal keratinocytes. Because of its negatively charged residues, HA can accommodate many water molecules, which help to maintain the normal hydration and viscoelasticity of the skin [90–92]. With increasing lifespan, the chronic cutaneous insufficiency syndrome now called dermatoporosis is becoming an emerging clinical problem with significant morbidity, which sometimes results in prolonged hospital stays [17,18,93]. Dermatoporosis is principally caused by chronologic aging and long-term and unprotected sun exposure, but may also result from the chronic use of topical and systemic corticosteroids. Experimental evidence suggests that defective function of CD44, a transmembrane glycoprotein that acts as the main cell surface HA receptor, and the corresponding impaired HA metabolism, are implicated in the pathogenesis

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of dermatoporosis, and may be a target for intervention [94]. Cleavage of the high molecular weight HA polymer during tissue remodeling gives rise to lower molecular weight fragments that elicit a variety of CD44-mediated cellular responses, including proliferation, migration, HA synhesis, and cytokine synthesis [91,92]. The cellular responses elicited by topical application of HA, and specifically HA synthesis by keratinocytes, depend on the size of the HA oligosaccharides [95,96]. Topical retinoids are known to stimulate epidermal hyperplasia through the activation of a RAR-dependent HB-EGF paracrine loop [36,97]. HA production is also selectively stimulated by retinoids in mouse and human skin [98,99]. In mouse skin, topical retinaldehyde increases HA content, the expression of CD44 and HA synthases [38], and prevents UV-induced depletion of HA and CD44, an effect also observed with topical retinol and retinoic acid, although to a lesser extent [100]. In humans, topical retinaldehyde has been shown to restore the epidermal thickness and CD44 expression in lichen sclerosus and atrophic lesions [101]. The proliferative response of keratinocytes elicited by either retinaldehyde or intermediate size HA fragments (HAFi) is dependent of CD44 and requires the presence of HB-EGF, its receptor ErbB1, as well as matrix metalloproteinase-7 (MMP-7) [39,102]. In particular, topical application of HAFi in combination with retinaldehyde caused epidermal hyperplasia by specifically stimulating the CD44 platform molecules in the keratinocytes and increased the HA content of epidermis and dermis [103]. Thus, topical retinoids, in particular retinaldehyde, can restore epidermal functions by stimulating HA synthesis and biologic functions.

Specific profiles of cosmeceutical retinoids Retinol and retinyl esters Retinol and retinyl esters (mostly retinyl palmitate) have been incorporated into many skin products. Theoretically, these topical endogenous retinoids, which are natural precursors of cutaneous retinaldehyde and retinoic acids [104– 106], could also be useful in treating skin conditions for which retinoic acid is active. However, although retinol is widely used in cosmetic formulations to improve photoaging, topical retinol has not been demonstrated to be effective to treat any skin condition, maybe because of its slow oxidation into retinaldehyde and retinoic acid [107]. It seems that the retinol concentrations required to induce a measurable biologic action similar to that of retinoic acid (0.05%) induce a similar irritant dermatitis [89]. Thus, to avoid high concentrations of retinol or retinyl esters in topical formulation, the best way would be to combine them at moderate concentrations with other topical agents such as tocopherols, ascorbate and derivatives, flavonoids, or other biologic antioxidants [108–110].

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Another useful property of retinol is its absorption spectrum: it absorbs UV light in shorter wavelengths (325 nm) than retinaldehyde (385 nm) and retinoic acid (345 nm). Therefore, topical retinol could be useful as a filter partner of many cosmetic and cosmeceutical products in the most biologically active solar UV range (290–320 nm), while delivering small amounts of retinoic acid on a relatively long period of time [44,45]. This can be expanded to retinyl esters, which have the same UV spectrum as retinol, have the better tolerance profile among topical retinoids, while being the weaker retinoic acid precursors [22].

Retinaldehyde Retinaldehyde is much less irritant than retinoic acid, which explains its good compliance, and has been shown to be well tolerated and effective in treating photoaging for long periods of time: in particular, retinaldehyde produced significant improvement in fine and deep wrinkles [28,111]. Retinaldehyde does not bind to nuclear retinoid receptors and selectively delivers low concentrations of retinoic acid at the cellular level [27,97]; this prevents an excess of retinoic acid in the skin, a condition that contributes to cutaneous irritation [4,20] and confers to retinaldehyde the required properties for the intracrine concept discussed above [20]. The association of retinaldehyde and δ-tocopherylglucopyranoside, a vitamin E precursor, improved the protection against the generation of free radicals – a condition leading to aging – as well as the skin elasticity [112]. Retinaldehyde, which possesses an aldehyde functional group, exerts direct receptor-independent biologic actions not shared by other retinoids. This explains the usefulness of topical retinaldehyde 0.05% against P. acnes and Staphylococcus spp. [58,59]. Retinaldehyde shares with other retinoids a high absorption power in the UVA range, and may decrease the fluence received in this window significantly [45]. Compared with other retinoids, retinaldehyde loads the skin with natural retinoids very efficiently, probably because of its better penetration profile through the skin, and its ability to be reduced to retinol or oxidized to retinoic acid very rapidly [105,113–116]. Retinaldehyde has been shown to reduce the pigmentation when applied to the skin for a couple of weeks or longer; this could be due in part to a melanosomal dilution resulting from an increase of epidermal turnover, an effect attributable to its conversion to retinoic acid. The depigmenting property of retinaldehyde could also be due to its antioxidant power, because the production of small quantities of hydrogen peroxide has been considered to be an essential step of the melanogenesis [117]. Indeed, topical retinaldehyde 0.05% decreases the melanin content by 80% and the density of active melanocytes by 75% in mouse tail skin, whereas an application of retinaldehyde 0.01% to guinea pig ear skin decreases epidermal melanin by 50% and the density of active melanocytes by 40% (unpublished data). Owing to these properties,

38. Retinoids retinaldehyde should be considered as a key partner in topical depigmenting preparations.

4-Oxoretinoids According to Achkar et al. [7] and Blumberg et al. [8], 4-oxoretinol and 4-oxoretinaldehyde, the least known of endogenous retinoids, exert morphogenic properties and are able to bind and transactivate RARs in vitro. In a mouse model of retinoid activity, topical 4-oxoretinaldehyde 0.05% induced a moderate retinoid-like activity compared with topical retinoic acid 0.05%, as assessed by: 1 Epidermal hyperplasia and metaplasia; 2 Cutaneous inflammation (myeloperoxidase activity); and 3 Depigmentation of the tail. Topical 4-oxoretinol 0.05% was also active, albeit to a lesser extend. Parallel to the action of these 4-oxoretinoids, no retinoic acid could be detected in the skin, indicating that 4-oxoretinoids exerted a direct biologic activity, which was not due to their bioconversion to their non-oxo counterparts [10]. This confirms the in vitro studies mentioned above [7,8], which demonstrated a direct biologic action of 4-oxoretinol and 4-oxoretinal, and suggests a potential benefits for their use as cosmeceuticals. In another study, the 4-oxoderivatives of the biologically active all-trans-, 9-cis- and 13-cis-retinoic acids (although 13-cis-retinoic acid does not bind to retinoid receptors) have been shown to display strong and isomer-specific transcriptional regulatory activities in human keratinocytes and fibroblasts in vitro [118]. These data revive the interest for these oxidative metabolites of endogenous retinoids. Appropriate clinical trials should be performed to determine whether it is possible to use these the 4-oxoderivatives topically at high concentrations to obtain a better response than retinol and its esters, while retaining a good tolerance. Pilot studies in humans already indicate a good tolerance of 4-oxoretinaldehyde 0.5% (unpublished personal observations). Establishing the spectrum of potential activity of topical 4-oxoderivatives, especially on the pigmentary system also deserves specific clinical trials.

Association with topical hyaluronan fragments The molecular mechanisms underlying retinoid-induced epidermal hyperplasia are closely related to CD44-dependent pathways in keratinocytes. It is well demonstrated that retinoids synergize with the activities of HAFi on cell renewal and de novo HA synthesis [38,103,119]. Accordingly, the topical application of HAFi was found to have repairing action in dermatoporosis [102]. Therefore the combination of HAFi with a retinoid is highly promising as preventive treatment in early phases of dermatoporosis. High molecular weight HA, which do not show the topical activities of HAFi, has been widely used in cosmetic preparations [120]. Application of high molecular weight HAcontaining cosmetic products to the skin is reported to

moisturize and restore elasticity [121]. HA-based cosmetic formulations or sunscreens may also be capable of protecting the skin against UV irradiation due to the antioxidant properties of HA [122]. In almost all of these cosmetic formulations, the HA is associated with retinol. Scientific proof that the association of any topical retinoids with high molecular weight HA has some specific synergizing effect is currently lacking.

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38. Retinoids 52 Witz G. (1989) Biological interactions of alpha,beta-unsaturated aldehydes. Free Radic Biol Med 7, 333–49. 53 Esterbauer H, Schaur RJ, Zollner H. (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11, 81–128. 54 Feron VJ, Til HP, de Vrijer F, Wouterson RA, Cassee FR, van Bladeren PJ. (1991) Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat Res 259, 363–85. 55 Ambroziak W, Izaguirre G, Pietruszko R. (1999) Metabolism of retinaldehyde and other aldehydes in soluble extracts of human liver and kidney. J Biol Chem 274, 33366–73. 56 Green HN, Mellanby E. (1928) Vitamin A as an anti-infective agent. Br Med J 2, 691–6. 57 Halliday GM, Ho KKL, Barnetson RSC. (1992) Regulation of the skin immune system by retinoids during carcinogenesis. J Invest Dermatol 99, 83S–6S. 58 Péchère M, Germanier L, Siegenthaler G, Péchère JC, Saurat JH. (2002) The antibacterial activity of topical retinoids: the case of retinaldehyde. Dermatology 205, 153–8. 59 Péchère M, Péchère JC, Siegenthaler G, Germanier L, Saurat JH. (1999) Antibacterial activity of retinaldehyde against Propionibacterium acnes. Dermatology 199 (Suppl 1), 29–31. 60 Wenk J, Brenneisen P, Meewes C, Wlaschek M, Peters T, Blauschun R, et al. (2001) UV-induced oxidative stress and photoaging. Curr Probl Dermatol 29, 83–94. 61 Yaar M, Gilchrest BA. (1998) Aging versus photoaging: postulated mechanisms and effectors. J Investig Dermatol Symp Proc 3, 47–51. 62 Pinnell SR. (2003) Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 48, 1– 19; quiz 20–2. 63 Nishigori C, Hattori Y, Arima Y, Miyachi Y. (2003) Photoaging and oxidative stress. Exp Dermatol 12, 18–21. 64 Sies H, Stahl W. (2004) Nutritional protection against skin damage from sunlight. Annu Rev Nutr 24, 173–200. 65 Thiele JJ, Schroeter C, Hsieh SN, Podda M, Packer L. (2001) The antioxidant network of the stratum corneum. Curr Probl Dermatol 29, 26–42. 66 Halliwell B. (1994) Free radicals and antioxidants: a personal view. Nutr Rev 52, 253–65. 67 Jacob RA, Burri BJ. (1996) Oxidative damage and defense. Am J Clin Nutr 63, 985S–90S. 68 Kohen R, Gati I. (2000) Skin low molecular weight antioxidants and their role in aging and in oxidative stress. Toxicology 148, 149–57. 69 Sorg O. (2004) Oxidative stress: a theoretical model or a biological reality? C R Biol 327, 649–62. 70 Halliwell B, Gutteridge JMC. (1999) Free Radicals in Biology and Medicine, 3th edn. Oxford: Oxford University Press. 71 Berr C. (2000) Cognitive impairment and oxidative stress in the elderly: results of epidemiological studies. Biofactors 13, 205–9. 72 Barja G. (2004) Free radicals and aging. Trends Neurosci 27, 595–600. 73 Harman D. (2001) Aging: overview. Ann N Y Acad Sci 928, 1–21. 74 Crastes de Paulet A. (1990) Free radicals and aging. Ann Biol Clin 48, 323–30.

75 Singh DK, Lippman SM. (1998) Cancer chemoprevention. Part 1: Retinoids and carotenoids and other classic antioxidants. Oncology (Williston Park) 12, 1643–53, 57–8; discussion 59–60. 76 Tsuchiya M, Scita G, Freisleben HJ, Kagan VE, Packer L. (1992) Antioxidant radical-scavenging activity of carotenoids and retinoids compared to alpha-tocopherol. Methods Enzymol 213, 460–72. 77 Tesoriere L, D’Arpa D, Re R, Livrea MA. (1997) Antioxidant reactions of all-trans retinol in phospholipid bilayers: effect of oxygen partial pressure, radical fluxes, and retinol concentration. Arch Biochem Biophys 343, 13–8. 78 Sorg O, Tran C, Saurat JH. (2001) Cutaneous vitamins A and E in the context of ultraviolet or chemically induced oxidative stress. Skin Pharmacol Appl Skin Physiol 14, 363–72. 79 Sorg O, Kuenzli S, Kaya G, Saurat JH. (2005) Proposed mechanisms of action for retinoid derivatives in the treatment of skin ageing. J Cosmet Dermatol 4, 237–44. 80 Goffin V, Henry F, Piérard-Franchimont C, Piérard GE. (1997) Topical retinol and the stratum corneum response to an environmental threat. Skin Pharmacol 10, 85–9. 81 Kligman AM, Willis I. (1975) A new formula for depigmenting human skin. Arch Dermatol 111, 40–8. 82 Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. (1993) Topical tretinoin (retinoic acid) improves melasma: a vehicle-controlled, clinical trial. Br J Dermatol 129, 415–21. 83 Hoal E, Wilson EL, Dowdle EB. (1982) Variable effects of retinoids on two pigmenting human melanoma cell lines. Cancer Res 42, 5191–5. 84 Edward M, Gold JA, MacKie RM. (1988) Different susceptibilities of melanoma cells to retinoic acid-induced changes in melanotic expression. Biochem Biophys Res Commun 155, 773–8. 85 Fligiel SE, Inman DR, Talwar HS, Fisher GJ, Voorhees JJ, Varani J. (1992) Modulation of growth in normal and malignant melanocytic cells by all-trans retinoic acid. J Cutan Pathol 19, 27–33. 86 Yoshimura K, Tsukamoto K, Okazaki M, Virador VM, Lei TC, Suzuki Y, et al. (2001) Effects of all-trans retinoic acid on melanogenesis in pigmented skin equivalents and monolayer culture of melanocytes. J Dermatol Sci 27 (Suppl 1), S68–75. 87 Kasraee B, Tran C, Sorg O, Saurat JH. (2005) The depigmenting effect of RALGA in C57BL/6 mice. Dermatology 210 (Suppl 1), 30–4. 88 Ortonne JP. (2006) Retinoid therapy of pigmentary disorders. Dermatol Ther 19, 280–8. 89 Yoshimura K, Momosawa A, Aiba E, Sato K, Matsumoto D, Mitoma Y, et al. (2003) Clinical trial of bleaching treatment with 10% all-trans retinol gel. Dermatol Surg 29, 155–60. 90 Fraser JR, Laurent TC. (1989) Turnover and metabolism of hyaluronan. Ciba Found Symp 143, 41–59. 91 Laurent TC. (1987) Biochemistry of hyaluronan. Acta Otolaryngol Suppl 442, 7–24. 92 Laurent TC, Fraser JR. (1992) Hyaluronan. FASEB J 6, 2397–404. 93 Kaya G, Jacobs F, Prins C, Viero D, Kaya A, Saurat JH. (2008) Deep dissecting hematoma: an emerging severe complication of dermatoporosis. Arch Dermatol 144, 1303–8.

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94 Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I. (1997) Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissuespecific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev 11, 996–1007. 95 Forrester JV, Balazs EA. (1980) Inhibition of phagocytosis by high molecular weight hyaluronate. Immunology 40, 435–46. 96 West DC, Hampson IN, Arnold F, Kumar S. (1985) Angiogenesis induced by degradation products of hyaluronic acid. Science 228, 1324–6. 97 Didierjean L, Carraux P, Grand D, Sass JO, Nau S, Saurat JH. (1996) Topical retinaldehyde increases skin content of retinoic acid and exerts biological activity in mouse skin. J Invest Dermatol 107, 714–9. 98 Margelin D, Medaisko C, Lombard D, Picard J, Fourtanier A. (1996) Hyaluronic acid and dermatan sulfate are selectively stimulated by retinoic acid in irradiated and nonirradiated hairless mouse skin. J Invest Dermatol 106, 505–9. 99 Tammi R, Ripellino JA, Margolis RU, Maibach HI, Tammi M. (1989) Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture. J Invest Dermatol 92, 326–32. 100 Calikoglu E, Sorg O, Tran C, Grand D, Carraux P, Saurat JH, et al. (2006) UVA and UVB decrease the expression of CD44 and hyaluronate in mouse epidermis which is counteracted by topical retinoids. Photochem Photobiol 82, 1342–7. 101 Kaya G, Saurat JH. (2005) Restored epidermal CD44 expression in lichen sclerosus et atrophicus and clinical improvement with topical application of retinaldehyde. Br J Dermatol 152, 570–2. 102 Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. (2006) Hyaluronate fragments reverse skin atrophy by a CD44dependent mechanism. PLoS Med 3, e493. 103 Kaya G, Tran C, Sorg O, et al. (2006) Synergistic effect of retinaldehyde and hyaluronate fragments in skin hyperplasia. J Invest Dermatol 126, 33. 104 Bailly J, Crettaz M, Schifflers MH, Marty JP. (1998) In vitro metabolism by human skin and fibroblasts of retinol, retinal and retinoic acid. Exp Dermatol 7, 27–34. 105 Siegenthaler G, Saurat JH, Ponec M. (1990) Retinol and retinal metabolism: relationship to the state of differentiation of cultured human keratinocytes. Biochem J 268, 371–8. 106 Boehnlein J, Sakr A, Lichtin JL, Bronaugh RL. (1994) Characterization of esterase and alcohol dehydrogenase activity in skin: metabolism of retinyl palmitate to retinol (vitamin A) during percutaneous absorption. Pharm Res 11, 1155–9.

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107 Connor MJ. (1988) Oxidation of retinol to retinoic acid as a requirement for biological activity in mouse epidermis. Cancer Res 48, 7038–40. 108 Bruce S. (2008) Cosmeceuticals for the attenuation of extrinsic and intrinsic dermal aging. J Drugs Dermatol 7, S17–22. 109 Burgess C. (2008) Topical vitamins. J Drugs Dermatol 7, S2–6. 110 Picardo M, Carrera M. (2007) New and experimental treatments of cloasma and other hypermelanoses. Dermatol Clin 25, 353–62. 111 Creidi P, Vienne MP, Ochonisky S, Lauze C, Turlier V, Lagarde JM, et al. (1998) Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol 39, 960–5. 112 Boisnic S, Branchet-Gumila MC, Nocera T. (2005) Comparative study of the anti-aging effect of retinaldehyde alone or associated with pretocopheryl in a surviving human skin model submitted to ultraviolet A and B irradiation. Int J Tissue React 27, 91–9. 113 Kishore GS, Boutwell RK. (1980) Enzymatic oxidation and reduction of retinal by mouse epidermis. Biochem Biophys Res Commun 94, 1381–6. 114 Napoli JL, Race KR. (1988) Biogenesis of retinoic acid from beta-carotene. J Biol Chem 263, 17372–7. 115 Raner GM, Vaz AD, Coon MJ. (1996) Metabolism of all-trans, 9-cis, and 13-cis isomers of retinal by purified isozymes of microsomal cytochrome P450 and mechanism-based inhibition of retinoid oxidation by citral. Mol Pharmacol 49, 515–22. 116 Sorg O, Didierjean L, Saurat JH. (1999) Metabolism of topical natural retinoids. Dermatology 199 (Suppl), 13–7. 117 Kasraee B. (2002) Peroxidase-mediated mechanisms are involved in the melanocytotoxic and melanogenesis-inhibiting effects of chemical agents. Dermatology 205, 329–39. 118 Baron JM, Heise R, Blaner WS, Neis M, Joussen S, Dreuw A, et al. (2005) Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol 125, 143–53. 119 Tammi R, Pasonen-Seppanen S, Kolehmainen E, Tammi M. (2005) Hyaluronan synthase induction and hyaluronan accumulation in mouse epidermis following skin injury. J Invest Dermatol 124, 898–905. 120 Manuskiatti W, Maibach HI. (1996) Hyaluronic acid and skin: wound healing and aging. Int J Dermatol 35, 539–44. 121 Brown MB, Jones SA. (2005) Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol 19, 308–18. 122 Trommer H, Wartewig S, Bottcher R, Pöppl J, Hoentsch J, Ozegowski JH, et al. (2003) The effects of hyaluronan and its fragments on lipid models exposed to UV irradiation. Int J Pharm 254, 223–34.

Chapter 39: Topical vitamins Donald L. Bissett Procter & Gamble Beauty Science, Cincinnati, OH, USA

BAS I C CONCEPTS • Vitamins are commonly used as active agents in skincare products designed to improve skin appearance. • The antioxidant vitamins A, C, and E can be safely applied topically. • Niacinamide (vitamin B3) and panthenol (vitamin B5) are of the vitamin B family used in moisturizers to improve skin appearance. • Careful formulation is required with vitamins to prevent loss of activity through photoinactivation or premature oxidation.

Introduction Vitamins are organic compounds required in small quantities for normal function and typically obtained from the diet. Many materials are described as vitamins [1]. Some of them have been used in topical cosmetic products, and certainly there is rationale for such use. Because they are essential nutrients, a few of them in a wide array of biochemical processes, they certainly have potential to have beneficial effects across a wide spectrum of skin problems. Also, because they are well studied because of their importance in nutrition, their mechanisms and toxicology are well understood. Additionally, with topical application and subsequent delivery into skin, they are more likely to have local meaningful effects vs. oral intake and the consequent limited delivery via the circulation to the skin site of interest (e.g. facial skin). Because there are so many vitamins, this review is necessarily selective, focusing on a few, with particular emphasis on those materials for which there is available well-controlled in vivo studies to illustrate skincare effects.

Vitamin A Forms Several forms of vitamin A are used cosmetically, the most widely utilized ones being retinol, retinyl esters (e.g. retinyl acetate, retinyl propionate, and retinyl palmitate), and retinaldehyde. Through endogenous enzymatic reactions, all are converted ultimately to trans-retinoic acid, the active form of vitamin A in skin. Specifically, retinyl esters are

converted to retinol via esterase activity. Retinol is then converted to retinaldehyde by retinol dehydrogenase. Finally, retinaldehyde is oxidized to retinoic acid by retinaldehyde oxidase (Figure 39.1).

Mechanisms Because trans-retinoic acid (RA) is the active form of vitamin A in skin, the abundant published literature on the former is applicable to this discussion. RA interacts with nuclear receptor proteins described as retinoic acid receptors (RAR) and retinoid X receptors (RXR), which can form heterodimer complexes. These complexes then interact with specific DNA sequences to affect transcription, to either increase or decrease expression of specific proteins and/or enzymes [2]. Using genomic methodology, work in our laboratories has found that the expression of over 1200 genes is significantly affected by topical retinoid treatment of photoaged human skin (unpublished observations). Many of these changes can be ascribed, at least on some level, as being normalization of the altered skin conditions that occur with aging (induced by both chronologic and environmental influences such as chronic sun exposure). Some specific changes induced by retinoid that are likely relevant to skin antiwrinkle appearance effects are those that result in thicker skin to diminish the appearance of fine lines and wrinkles; for example, increased epidermal proliferation and differentiation (increased epidermal thickness), increased production of epidermal ground substance (glycosaminoglycans [GAGs] which bind water, increasing epidermal hydration and thickness), and increased dermal production of extracellular matrix components such as collagen (increased dermal thickness). In addition to stimulation of events in skin, retinoids also have an inhibitory effect on other tissue components. For example, retinoids are reported to inhibit production of collagenase. Retinoid will stimulate production of ground

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CH2

Palmitate

Retinyl palmitate

Esterase

Retinol (vitamin A)

Alcohol dehydrogenase

Beta-carotene

Retinaldehyde

Aldehyde dehydrogenase

COOH All- trans-retinoic acid

9-cis Retinoic acid C OOH 13-cis Retinoic acid COOH

substance (GAGs) in epidermis, but it will inhibit production of excess ground substance in photoaged dermis. While a low level of GAGs is required in the dermis for normal collagen structure and function, excess dermal GAGs are associated with altered dermal collagen structure and wrinkled skin appearance in the Shar Pei dog and in photoaged skin [3]. Because at least some of the epidermal effects of topical retinoid (e.g. epidermal thickening) occur relatively rapidly (days) after initiation of treatment, some skin effects (e.g. diminution of fine line appearance) can be realized quickly. The dermal effects likely occur on a much longer timeframe (weeks to months) such that reduction in skin problems via this mechanism likely require much longer timeframes (weeks to months).

Topical effects While much of the substantial literature on the improvement of skin wrinkles by topical retinoids is focused on

320

Figure 39.1 Conversion of retinyl ester into trans-retinoic acid in the skin.

trans-retinoic acid, there are also data available on the vitamin A compounds that are used cosmetically. Because retinoids are irritating to skin, defining skin-tolerated doses clinically is a key step in working effectively with these materials. Retinol is better tolerated by the skin than trans-retinoic acid. In our testing we noted that retinyl propionate is milder to skin than retinol and retinyl acetate (Table 39.1). Because retinoids in general tend to be fairly potent, topical doses of less than 1% are generally sufficient to obtain significant effects. At low doses, in double-blind, split-face, placebo-controlled facial testing (12 weeks’ duration), both retinol and retinyl propionate have both been shown to be significantly effective in reducing facial hyperpigmentation and wrinkles across the study (Figure 39.2). Determination of treatment effects was based on quantitative computer image analysis and blinded expert grading of high resolution digital images.

39. Topical vitamins

Table 39.1 Cumulative back irritation measures for retinol and its esters (double-blind, vehicle-controlled, randomized study; daily patching for 20 days, under semi-occluded patch, n = 45; 0–3 irritation grading). Equimolar doses and abbreviations used: 0.09% RP (retinyl propionate); 0.086% RA (retinyl acetate); and 0.075% ROH (retinol). RP and RA were significantly less irritating than ROH, and RP was directionally less irritating than RA. Topical treatment (oil-in-water emulsions) Emulsion control

Expert grader cumulative irritation scores 3.9

Significance of expert grader cumulative scores*

Chromameter “a” measure (day 21)

Significance of chromameter “a” measure*

0.4

0.09% RP

2.7

0.086% RA

3.8

164

7.6

0.075% ROH

* Treatments with the same letter codes are not significantly different from each other (p < 0.05).

Figure 39.2 Retinyl propionate (RP) reduces the appearance of fine lines and wrinkles. A 0.3% Retinyl propionate in a stable skincare emulsion system was applied twice daily for 8 weeks. (a) Baseline; (b) 8 weeks.

(b)

(a)

There are also clinical studies published on other retinoids. Retinyl palmitate has very low irritation potential and is effective if tested at a very high dose such as 2%. There are also several studies revealing the clinical efficacy of retinaldehyde, typically at a dose of 0.05%. However, retinaldehyde has irritation potential similar to retinol [4].

Formulation challenges There are two primary challenges in working with retinoids. One is their tendency to induce skin irritation (as noted above) which negatively affects skin barrier properties. While high doses will provide greater skin aging appearance improvement, the associated irritation tends to define an upper concentration limit where they can be used practically. While the skin may have some capacity to accommodate to retinoid treatment to yield less irritation, it is not completely eliminated even with long-term use, as demonstrated by evaluation of skin barrier function. Mitigation of the irritation may be managed to some extent with appropriate formulation to meter delivery into the skin, use of retinyl esters which are less irritating than retinol (as noted above),

or inclusion of other ingredients (e.g. those with antiirritancy or anti-inflammatory activity) to counter this issue. The second key issue is instability, especially to oxygen and light. Thus, to ensure stability of retinoid in finished product, formulation and packaging must be carried out in an environment that minimizes exposure to oxygen and light. The final product packaging also ideally needs to be opaque and oxygen impermeable, including use of a small package orifice to reduce oxygen exposure once the container is opened. In addition, a variety of other strategies can be employed (e.g. encapsulation of the retinoid and inclusion of stabilizing antioxidants).

Vitamin B3 Forms There are three primary forms of vitamin B3 that have found utility in skin care products: niacinamide (nicotinamide), nicotinic acid, and nicotinate esters (e.g. myristoyl nicotinate, benzyl nicotinate).

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Family of co-factors:

•NAD

NH2

O O

•NADP

N+

CH2

•NADH (antioxidant) •NADPH (antioxidant)

P O-

H H

O NH2

NH2

‡‡‡‡ O

P O-

N Niacinamide (vitamin B3)

CH2

H OH

Mechanisms Vitamin B3 serves as a precursor to a family of endogenous enzyme co-factors (Figure 39.3), specifically nicotinamide adenine dinucleotide (NAD), its phosphorylated derivative (NADP), and their reduced forms (NADH, NADPH) which have antioxidant properties. These co-factors are involved in many enzymatic reactions in the skin, and thus have potential to influence many skin processes. This precursor role of vitamin B3 may thus be the mechanistic basis for the diversity of clinical effects observed for a material such as niacinamide. While precisely how the dinucleotide cofactors might contribute to all these effects has not been elucidated, several specific actions of niacinamide specifically have been described [5,6]. For example, topical niacinamide has the following effects: • Niacinamide inhibits sebum production, specifically affecting the content of triglycerides and fatty acids. This may contribute to the observed reduction in skin pore size and thus improved skin texture (a component of texture being enlarged pores). • Niacinamide increases epidermal production of skin barrier lipids (e.g. ceramides) and also skin barrier layer proteins and their precursors (keratin, involucrin, filaggrin), leading to the observed enhancement of barrier function as determined by reduced transepidermal water loss (TEWL). This improved barrier also increases skin resistance to environmental insult from damaging agents such as surfactant and solvent, leading to less irritation, inflammation, and skin redness (e.g. facial red blotchiness). Because inflammation is involved in development of skin aging problems, the barrier improvement may contribute to the antiaging effects

322

H OH

N Figure 39.3 Niacinamide as precursor to energy co-factors: nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), and their reduced forms NADH and NADPH.

of topical niacinamide. The anti-inflammatory and sebum reduction effects of niacinamide likely contribute to the antiacne effect reported for this material. • Niacinamide has anti-inflammatory properties (e.g. inhibition of inflammatory cytokines). • Niacinamide increases production of collagen which may contribute to the observed reduction in the appearance of skin wrinkling. • Niacinamide reduces the production of excess dermal GAGs. In cell culture testing as noted above for retinyl propionate, 0.5 mmol niacinamide reduced excess GAG production by 15%. • Niacinamide inhibits melanosome transfer from melanocytes to keratinocytes, leading to reduction in skin hyperpigmentation (e.g. hyperpigmented spots). • Niacinamide inhibits skin yellowing. A contributing factor to yellowing is protein oxidation (glycation; Maillard reaction) which is a spontaneous oxidative reaction between protein and sugar, resulting in cross-linked proteins (Amedori products) that are yellow–brown in color. These products accumulate in matrix components such as collagen that have long biological half-lives [7]. Niacinamide has antiglycation effects, likely because of its conversion to the antioxidant NAD(P)H. Because nicotinic acid and its esters are also precursors to NAD(P), they would be expected to provide these same effects to skin. Nicotinic acid and many (if not all) of its esters (following in-skin hydrolysis to free nicotinic acid) also stimulate blood flow, leading to increased skin redness or a flush response. While in some situations this might be a desired effect (e.g. warming sensation for

39. Topical vitamins body skin), it is difficult to manage for the more sensitive facial skin.

Topical effects As representative for the vitamin B3 family of compounds, there are several published reports on the diversity of clinical effects of topical niacinamide. These data were obtained from double-blind, placebo-controlled, left–right randomized studies. For example, topical niacinamide has been shown to reduce skin fine lines and wrinkling. The effect increases over time and is significant after 8–12 weeks of treatment. Topical niacinamide also improves other aspects of aging skin, such as reduction in sebaceous lipids (oil control) and pore size, which likely contribute at least in part to improved skin texture. Additionally, niacinamide improves skin elastic properties as demonstrated for two parameters of skin elasticity. Beyond these effects, there is also improvement in appearance of skin color, in particular reduction in the appearance of hyperpigmented spots (Figure 39.4) and also skin yellowing. Fairly high doses (2–5%) of vitamin B3 have been used to achieve these effects. However, because there is very high tolerance of the skin to niacinamide even with chronic usage, high doses can be used acceptably. In fact, as noted above, because topical niacinamide improves skin barrier, it actually increases the skin’s resistance to environmental insult (e.g. from surfactant) and reduces red blotchiness. Some data on myristoyl-nicotinate have been presented to suggest that a similar broad array of effects occurs with this agent when used topically (1–5% doses). Clinical data for topical nicotinic acid and other esters are not available.

acid. Nicotinic acid, even at low doses, can induce an intense skin reddening (flushing) response. While a little skin redness (increased skin “pinkness”) may be a desired effect for the face, the flushing response among individuals is highly variable in terms of dose to induce it, time to onset of the response, and duration of response. Additionally, the flushing can also have associated issues such as facial burn, sting, and itch, particularly under cold and/or dry environmental conditions. To avoid hydrolysis, formulating in the pH range of 5–7 is preferred. This flushing issue also requires that the purity of the raw material (e.g. niacinamide) be very high to minimize any contaminating free acid. For the nicotinate esters, there are many commercial options. Many of them unfortunately are readily hydrolyzed to nicotinic acid on or in the skin such that flushing responses occur rapidly (within seconds to minutes) even at very low concentrations (<<1%). The longer chain esters (e.g. myristoyl-nicotinate) apparently are more resistant to this hydrolysis and thus appear to be more suitable for use topically.

Vitamin B5 Forms Pantothenic acid is the active vitamin. A precursor is panthenol or provitamin B5 which is also known as pantothenol or pantothenyl alcohol. The widely used D optical isomer of panthenol is termed dexpanthenol. Panthenol is watersoluble, stable, and of low molecular weight (readily penetrates the stratum corneum).

Mechanisms Formulation challenges The key challenge for working with niacinamide and nicotinate esters on the face is avoiding hydrolysis to nicotinic

Figure 39.4 Niacinamide reduces pigment spots. (a) Baseline. (b) After 8 weeks.

Panthenol has been used topically to treat wounds, bruises, scars, pressure and dermal ulcers, thermal burns, postoperative incisions/distention, and dermatoses [8,9]. The specific

(a)

(b)

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mechanisms for these effects are not known. However, dexpanthenol is a precursor to pantothenic acid (vitamin B5). Pantothenic acid is a component of coenzyme A which functions in acyl group transfer during fatty acid biosynthesis and gluconeogenesis. By increasing skin lipid synthesis, improved barrier should occur, resulting in improved wound healing. In addition, panthenol promotes fibroblast proliferation and epidermal re-epithelialization, effects that promote wound healing. Additionally, panthenol has found utility for skin penetration enhancement.

Topical effects Topical panthenol is extremely well tolerated by the skin, leading to wide topical use of this material and many reported skin effects [8,9]. Among those are hydration and the associated improvement in roughness, scaling, and epidermal elasticity; protection against skin irritation and sodium lauryl sulfate (SLS) induced damage; skin soothing; and anti-inflammatory and antipruritic effects.

Hydration Panthenol’s hydration effect likely derives from its hygroscopic properties. Panthenol is an effective moisturizer of stratum corneum and is even more effective when combined with glycerol. In addition, it improves the dryness, roughness, scaling, pruritus, and erythema associated with a wide variety of skin problems such as atopic dermatitis, ichthyosis, psoriasis, and contact dermatitis [8]. It also reduces the cutaneous side effects associated with retinoid therapy [10]. This hydration effect has further led to its use in haircare, promoting improved elasticity, softening, and easier combing.

Barrier and irritation Panthenol protects against irritation via improvement in skin barrier function [8,11]. Topical pretreatment with panthenol was observed to increase skin’s resistance to visible irritation upon subsequent exposure to the surfactant SLS (Table 39.2). Because panthenol is the precursor to pantothenic acid which is a cofactor in barrier layer lipid biosynthesis, this could account for the noted barrier effect. Some consumers are sensitive to specific components (e.g. certain preservatives, fragrances, sunscreen actives) in cosmetic formulations, leading to induction of negative kinesthetic irritation effects such as burn, sting, itch, and tingling. Topical panthenol incorporated into such formulations can reduce those negative effects (Table 39.3). The mechanism for this may be related to the reported soothing or antiinflammatory effect of panthenol [8].

Formulation challenges Panthenol at high concentrations can yield sticky and/or greasy feeling formulations. Thus, doses of greater than approximately 1% may require appropriate formulation adjustment.

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Table 39.2 Prevention of sodium lauryl sulfate (SLS) induced erythema by topical panthenol. Time point post SLS treatment

Erythema score (0–6 scale) for skin treated with: SLS

Panthenol then SLS

2 days

4.0

2.4

3 days

3.4

1.7

4 days

2.7

1.4

Table 39.3 Reduction in negative kinesthetic effects of formulation containing panthenol vs. formula not containing 1% panthenol. Visible or kinesthetic attribute

Reduction in attribute by panthenol (0–6 scale)

Redness

−1.4

Burning

−2.4

Tingling

−5.7

Stinging

−4.9

Itching

−4.9

Warming

−5.7

Vitamin C Forms Of the many forms of this vitamin, some of the more commonly used are ascorbic acid, ascorbyl phosphate (as the magnesium and sodium salts), and other ascorbate derivatives (e.g. ascorbyl palmitate, ascorbyl glucoside).

Mechanisms Vitamin C is well known as an antioxidant and has been utilized as a skin lightener (e.g. via tyrosinase inhibition and/or its antioxidant effect). It also has been reported to have anti-inflammatory properties because it reduces the erythema associated with postoperative laser resurfacing [12]. In addition, ascorbic acid also serves as an essential co-factor for the enzymes lysyl hydroxylase and prolyl hydroxylase, both of which are required for post-translational processing in collagen (types I and III) biosynthesis. Thus, by stimulating these biosynthetic steps, ascorbic acid has the potential to increase the production of collagen which could lead to wrinkle reduction (as discussed above for vitamin A).

39. Topical vitamins While the ascorbic acid derivatives may possess some properties of the free acid (e.g. antioxidant), hydrolysis of the derivatives would be required for the increased collagen production effect because the acid is the active co-factor. Demonstration of the hydrolysis of all these derivatives in skin has not been well documented.

Topical effects There are several published studies discussing the antiaging effect of ascorbic acid, such as reduced UVA-induced oxidation and reduction in skin aging appearance parameters (skin surface replicas, dermatologist grading, algorithmbased facial image analysis, and histological assessment of biopsy specimens of dermal matrix, such as collagen). For example, topical 5% ascorbic acid for 6 months [13] improved photodamaged forearm and upper chest skin based on dermatologist scores, skin surface replicas, and biopsy specimen analysis (specifically improvements in elastin and collagen fiber appearance).

Formulation challenges The key challenge with vitamin C compounds in general is stability (oxygen sensitivity), particularly with ascorbic acid. Not only does oxidation lead to loss of the active material, there is also rapid product yellowing (an esthetic negative for the consumer). Various stabilization strategies can be attempted to address the issue, such as exclusion of oxygen during formulation, oxygen impermeable packaging, encapsulation, low pH, minimization of water, and inclusion of other antioxidants. In spite of all those approaches, in general ascorbate stability remains a challenge, and some of these approaches (e.g. very low pH) can lead to unwanted esthetic skin effects such as irritation. For the ascorbyl phosphates (Mg and Na salts), the resulting high content of salt in product can dramatically impact the thickener system, requiring increased use of thickener ingredients. These ascorbate derivatives are also considerably more expensive than other ascorbate compounds.

skin for maximal activity. Because it is lipid-soluble, its site of action is more likely to be in lipid-rich environments (e.g. cell membranes).

Topical effects While vitamin E is often used as a preservative and/or stabilizer in formulation, at relatively high topical doses it is quite effective in preventing oxidative damage to skin, such as preventing acute and chronic UV radiation damage. For example, in an in vivo model of UV radiation damage, topical tocopherol reduced by approximately 50% the visible skin damage (e.g. skin wrinkling) induced by chronic UV exposure [14]. Because antioxidants are the topic of another chapter in this volume (Chapter 35), this discussion has been kept brief.

Formulation challenges Tocopherol has some oxidative stability concerns, thus esters such as tocopherol acetate are most often used. Both tocopherol and its alkyl esters are oils, so high doses can be greasy/sticky, requiring formulation to address the esthetic impact.

Other vitamins Vitamin D There are several vitamin D compounds, and many synthetic variations. The active vitamin is 1,25-dihydroxyvitamin D3. Dehydrocholesterol (provitamin D) is a cosmetically used material which can be converted into active vitamin D upon exposure to UV. As a result of the effects of vitamin D compounds on epidermal growth and differentiation, there has been discussion of their skin barrier and photodamage mitigation activities, as seen in in vivo model testing [15,16]. Vitamin D compounds, like vitamin A materials, are often very potent, requiring caution in selecting specific compounds and topical doses.

Vitamin K

Vitamin E

This vitamin is also commonly known as tocopherol. There are several isomers based, for example, on number and position of substituents on the phenyl ring. Thus, there are α, β, γ, δ, and ε isomers of tocopherol. There are also several esters. A widely used form of vitamin E is α-tocopherol acetate.

There are several forms of vitamin K, such as phylloquinone and menaquinone. Vitamin K compounds function in blood clotting, and there are data showing effects for mitigating bruising [17], along with much speculation about the use of them in improving other skin problems such as under-eye dark circles. However, there do not appear to have been any controlled studies presented to support that latter use. Oxidative stability is a concern with at least some of the vitamin K compounds.

Mechanism

Vitamin P (flavonoids)

Vitamin E is an antioxidant. The active form is free tocopherol, so topical use of esters such as tocopherol acetate would require enzymatic hydrolysis to the free vitamin on or in

This family of plant-derived and synthetically prepared chemicals encompasses a huge variety of compounds, both natural and synthetic. Some of the types of flavonoids are

Forms

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flavons, isoflavones, flavanones, chalcones, coumarins, and chromones. Activities associated with flavonoids include antioxidant, anti-inflammatory, and phytoestrogen effects [18–20]. They are appearing in cosmetic products, often as components of natural extracts. This is a fertile area for identification of materials active in improving aging skin.

Conclusions While oral vitamins are well studied because of their importance in nutrition, the entire spectrum of possible effects from topical vitamins has not been thoroughly studied for the potential to improve skin. As the information presented here shows, at least some vitamins used topically can provide appearance-improving effects to aging skin, even in nutritionally normal individuals. With the wide array of vitamin materials, additional effects from their topical use are likely to emerge in the future. A vitamin alone is not likely to be highly potent, although the high tolerance by skin for some vitamins provides opportunity to use high topical doses to achieve greater effects. A key to achieving that is development of esthetic formulations to provide elegant product forms containing those high levels. Also, combinations of different vitamins or vitamins plus other effective agents have potential to achieve considerably more dramatic effects. For example, combining a vitamin B3 with a vitamin A or with a peptide leads to greater effects than the individual materials. There is certainly opportunity to continue to explore this avenue.

References 1 Newstrom H. (1993) Nutrients Catalog. McFarland & Company, Jefferson, NC. 2 Varani J, Fisher GJ, Kang S, Voorhees JH. (1998) Molecular mechanisms of intrinsic skin aging and retinoid-induced repair and reversal. J Invest Dermatol Symp Proc 3, 57–60. 3 Kligman AM, Baker TJ, Gordon HL. (1975) Long-term histologic follow-up of phenol face peels. Plast Reconstruct Surg 75, 652–9. 4 Fluhr JW, Vienne MP, Lauze C, Dupuy P, Gehring W, Gloor M. (1999) Tolerance profile of retinol, retinaldehyde, and retinoic acid under maximized and long-term clinical conditions. Dermatology 199S, 57–60. 5 Bissett DL, Oblong JE, Saud A, et al. (2003) Topical niacinamide provides skin aging appearance benefits while enhancing barrier function. J Clin Dermatol 32S, 9–18.

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6 Bissett DL, Miyamoto K, Sun P, Berge CA. (2004) Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin. Int J Cosmet Sci 26, 231–8. 7 Odetti P, Pronzato MA, Noberasco G, Cotto L, Traverso N, Cottalasso D, et al. (1994) Relationships between glycation and oxidation related fluorescence in rat collagen during aging. Lab Invest 70, 61–7. 8 Ebner F, Heller A, Rippke F, Tausch I. (2002) Topical use of dexpanthenol in skin disorders. Am J Clin Dermatol 3, 427–33. 9 Stozkowska W, Piekos R. (2004) Investigation of some topical formulations containing dexpanthenol. Acta Polon Pharm 61, 433–7. 10 Draelos ZD, Ertel KD, Berge CA. (2006) Facilitating facial retinization through barrier improvement. Cutis 78, 275–81. 11 Biro K, Thaci D, Ochsendorf FR, Kaufmann R, Boehncke WH. (2003) Efficacy of dexpanthenol in skin protection against irritation: a double-blind, placebo-controlled study. Contact Derm 49, 80–4. 12 Alster TS, West TB. (1998) Effect of topical vitamin C on postoperative carbon dioxide laser resurfacing erythema. Dermatol Surg 24, 331–4. 13 Humbert PG, Haftek M, Creidi P, Lapière C, Nusgens B, Richard A, et al. (2003) Topical ascorbic acid on photoaged skin: clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Exp Dermatol 12, 237–44. 14 Bissett DL, Chatterjee R, Hannon DP. (1990) Photoprotective effect of superoxide-scavenging antioxidants against ultraviolet radiation-induced chronic skin damage in the hairless mouse. Photodermatol Photoimmunol Photomed 7, 56–62. 15 Mitani H, Naru E, Yamash*ta M, Arakane K, Suzuki T, Imanari T. (2004) Ergocalciferol promotes in vivo differentiation of keratinocytes and reduces photodamage caused by ultraviolet irradiation in hairless mice. Photoderm Photoimmun Photomed 20, 215–23. 16 Reichrath J, Lehmann B, Carlberg C, Varani J, Zouboulis CC. (2007) Vitamins as hormones. Hormone Med Res 39, 71–84. 17 Shah NS, Lazarus MC, Bugdodel R, Hsia SL, He J, Duncan R, et al. (2002) The effects of topical vitamin K on bruising after laser treatment. J Am Acad Dermatol 47, 241–4. 18 Vaya J, Tamir S. (2004) The relation between the chemical structure of flavonoids and their estrogen-like activities. Curr Med Chem 11, 1333–43. 19 Kim HP, Park H, Son KH, Chang HW, Kang SS. (2008) Biochemical pharmacology of biflavonoids: implications for anti-inflammatory action. Arch Pharm Res 31, 265–73. 20 Amic D, Davidovic-Amic D, Beslo D, Rastija V, Lucic B, Trinajstic N. (2007) SAR and QSAR of the antioxidant activity of flavonoids. Curr Med Chem 14, 827–45.

Chapter 40: Clinical uses of hydroxyacids Barbara A. Green1, Eugene J. Van Scott2, and Ruey J. Yu3 1

NeoStrata Company, Inc., Princeton, NJ, USA Private practice, Abington, PA, USA 3 Private practice, Chalfont, PA, USA 2

BAS I C CONCEPTS • Hydroxyacids are low pH substances that have a keratolytic effect on the skin. • The hydroxyacids include alpha-hydroxyacids (AHAs), beta-hydroxyacids (BHAs), polyhydroxy acids (PHAs), aldobionic acids (bionic acids), and aromatic hydroxyacids (AMAs). • Effects of hydroxyacids include increased thickness of epidermis and papillary dermis; improved barrier properties; increased amounts of hyaluronic acid in the dermis and of other dermal glycosaminoglycans which correspond to increased skin thickness measured micrometrically; improved histologic features of dermal collagen; increase in total skin thickness which in turn diminishes clinical wizened appearances; and diminished dyspigmentation. • Hydroxyacids are effective skin peeling agents.

Alpha-hydroxyacids

Introduction Research on aging today is motivated by the belief that innate degenerative processes of aging, and aging itself, can be modulated, prevented, and perhaps reversed. Even though a complete understanding of the mechanisms of aging may not be known, improvement in clinical appearance and function of the skin with antiaging measures is a signal that modulation of aging and/or degenerative processes has probably occurred. After many years of research and clinical use, hydroxyacids (HAs) have been shown to have biologic importance and clinical value for both younger skin and older skin with a variety of hyperkeratotic and aging-related conditions. This chapter covers HAs, including alpha-hydroxyacids (AHAs), beta-hydroxyacids (BHAs), polyhydroxy acids (PHAs), aldobionic acids (bionic acids), and aromatic hydroxyacids (AMAs).

Chemical categorization and natural occurrence of hydroxyacids Hydroxyacids may be divided into five groups based on their chemical structures: AHAs, BHAs, PHAs, bionic acids, and AMAs.

The AHAs are the most widely studied and commercialized ingredients within the HA family. They are the simplest of the HAs, consisting of organic carboxylic acids with one hydroxyl group attached to the alpha position of the carboxyl group. Both the hydroxyl and carboxyl groups are directly attached to an aliphatic or alicyclic carbon atom. As a result, the hydroxyl group in the AHA is neutral and only the carboxyl group provides acidity to the molecule, a property that distinguishes the AHAs from aromatic hydroxyacids such as salicylic acid as described below. Many AHAs are present in foods and fruits, and therefore are called fruit acids (Table 40.1). Glycolic acid, the smallest AHA, occurs in sugar cane and citric acid is found in lemon juice at a concentration of 5–8%. Some AHAs contain a phenyl group as a side chain substituent; this changes the solubility profile of the AHA providing increased lipophilicity over conventional water-soluble AHAs and can be used to target oily and acne-prone skin. Examples include mandelic acid (phenyl glycolic acid) and benzilic acid (diphenyl glycolic acid).

Beta-hydroxyacids The BHAs are organic carboxylic acids having one hydroxyl group attached to the beta position of the carboxyl group. Both the hydroxyl and carboxyl groups are attached to two different carbon atoms of an aliphatic or alicyclic chain rendering the hydroxyl group neutral in nature. Some BHAs are present in body tissues as metabolic intermediates and energy source. For example, β-hydroxybutanoic acid is produced by the liver and utilized by skeletal and cardiac

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Table 40.1 Examples of hydroxyacids. Category

Example

Occurrence/source

Antioxidant

Alpha-hydroxyacid (AHA)

Glycolic Lactic

Sugar cane Sour milk, tomato

No No

Methyllactic

Mango

Citric

Lemon, orange

Yes

Malic

Apple

Yes

Tartaric

Grape

Yes

Beta-hydroxyacid (BHA)

Beta-hydroxybutanoic Tropic

Urine Plant

No No

Polyhydroxy acid (PHA)

Gluconic

Skin, commercially derived from corn Skin, commercially derived from corn

Yes

Gluconolactone

Yes

Aldobionic acid (bionic acid)

Lactobionic Maltobionic

Lactose from milk Maltose from starch

Yes Yes

Aromatic hydroxyacid (AMA)

Salicylic

Ester form in wintergreen leaves

muscle as an energy source. In contrast to the water-soluble β-hydroxybutanoic acid, tropic acid is derived from a plant source, and is a lipid-soluble BHA. For the most part, BHAs have yet to be commercialized in skincare mainly because of a lack of commercial supply and high cost. Some AHAs are also BHAs when the molecule contains two or more than two carboxyl groups. In this case, the hydroxyl group is in the alpha position to one carboxyl group, and at the same time is in the beta position to the other carboxyl group. For example, malic acid (apple acid) containing one hydroxyl and two carboxyl groups is both an AHA and a BHA. In the same manner, citric acid containing one hydroxyl and three carboxyl groups is both an AHA to one carboxyl group and a BHA to the two other carboxyl groups. These ingredients have been commercialized in skincare formulations to adjust pH and to deliver antioxidant and antiaging benefits.

Polyhydroxy acids The PHAs are organic carboxylic acids that possess two or more hydroxyl groups in the molecule. The hydroxyl and carboxyl groups are attached to the carbon atoms of an aliphatic or alicyclic chain. All the hydroxyl groups in the PHA are neutral, and only the carboxyl group accounts for its acidity. Although hydroxyl groups may be attached to several positions of the carbon chain, in order to be both an AHA and PHA it is essential that at least one hydroxyl group be attached to the alpha position.

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Many PHAs are endogenous metabolites or intermediate products from carbohydrate metabolism in body tissues. Both galactonic acid and galactonolactone are derived from galactose, which is an important component of glycosaminoglycans. Gluconic acid and gluconolactone are important metabolites formed in the pentose phosphate pathway from glucose during the biosynthesis of ribose for ribonucleic acid. Gluconolactone is the most widely studied and commercialized skincare ingredient among the PHAs.

Aldobionic acids or bionic acids The aldobionic acids, also called bionic acids, consist of one carbohydrate monomer chemically linked to a PHA via a stable ether linkage; examples are lactobionic acid (galactose/gluconic acid) and maltobionic acid (glucose/gluconic acid) (Figure 40.1). The bionic acid is commonly obtained from its disaccharide through chemical or enzymatic oxidation. For example, lactobionic acid is obtained from lactose and maltobionic acid from maltose. In general, the bionic acids have a larger molecular size and weight than most PHAs because of the additional sugar unit; however, at 358 Da (lactobionic acid and maltobionic acid) these molecules remain small enough to penetrate skin.

Aromatic hydroxyacids AMAs such as salicylic acid and gallic acid are derived from benzoic acid, which has been used in combination with sali-

40. Hydroxyacids

CH2OH

CH2OH O

OH Acid

COOH OH OH

O OH

OH OH

α-Hydroxy

amounts of water, forming a clear gel matrix. The amount of water retention depends on the individual bionic acid. For example, maltobionic acid can form a clear gel film containing 29% water complexed with maltobionic acid molecules. The formation of a gel matrix provides moisturization and may add protective and soothing properties for inflamed skin. PHAs and bionic acids are gentle and non-irritating, and can be used to provide antiaging benefits to sensitive skin, even after cosmetic procedures [8–11].

Antioxidant properties Glucose

Gluconic acid

Figure 40.1 Maltobionic acid, a bionic acid.

cylic acid as Whitfield’s ointment for hyperkeratotic conditions and fungal infections. Salicylic acid is 2-hydroxybenzoic acid and may be called an HA within a broad definition; however, its effects on skin differ from those of the AHAs, BHAs, PHAs, and bionic acids. Salicylic acid is a conventional keratolytic agent which desquamates corneocytes, layer by layer from the top downward [1]. In contrast, AHAs and BHAs appear to act at the innermost layers of the stratum corneum, the stratum compactum, near the junction with stratum granulosum [2,3]. Moreover, AHAs, PHAs, and bionic acids have been shown to stimulate biosynthesis of dermal components and increase dermal skin thickness upon topical application, whereas salicylic acid has been shown to decrease dermal skin thickness [3–7].

Physicochemical and biological properties distinguishing HAs As individual compounds, HAs differ broadly in physicochemical properties. Some HAs are very small molecules such as glycolic acid and lactic acid, and some are larger molecules such as lactobionic acid. Most HAs are white crystalline at room temperature such as glycolic acid, malic acid, tartaric acid, citric acid, mandelic acid, and benzilic acid, but a few are liquid such as lactic acid. Most HAs are soluble in water, but some are also soluble in lipid solvents. Some HAs are soluble only in lipid solvents. Certain physicochemical properties of HAs are discussed herein.

Water binding properties/gel matrix formation In contrast to AHAs and BHAs, PHAs and bionic acids are strongly hygroscopic and can attract and bind water similarly to other polyol compounds such as glycerin. The bionic acids are so strongly hygroscopic that they form a gel matrix when their aqueous solution is evaporated at room temperature. The transparent gel thus obtained retains certain

Most PHAs, bionic acids, and some AHAs and BHAs with one hydroxyl group and two or more vicinal carboxyl groups have been found to be antioxidants. The antioxidant property is readily determined by using any one of the following test methods: prevention or retardation from air oxidation of: (a) anthralin, (b) hydroquinone, or (c) banana peel. A freshly prepared anthralin solution or cream is bright yellow, and an air-oxidized one is brownish or black. A hydroquinone solution or cream is colorless or white color, and an air-oxidized one is brownish or black. A freshly peeled banana peel is light yellow in color, and an oxidized one ranges in color from tan, dark tan, brown to brownish black. Known antioxidants such as vitamin C and N-acetylcysteine may be used as the positive control in these screen tests. Based on these tests, all the PHAs and bionic acids tested are antioxidants, which include ribonolactone, gluconolactone, galactonolactone, lactobionic acid, and maltobionic acid [11]. Among AHAs and BHAs, malic acid, tartaric acid, citric acid, and isocitric acid have been shown to be antioxidants. Another method to determine antioxidant, free radical scavenging properties utilizes an in vitro model of cutaneous photoaging. In this model, compounds are measured for their ability to prevent UV-induced activation of the elastin promoter gene in skin via free radical scavenging activity. An increase in the expression of this gene causes the abnormal production of poorly structured elastin in skin, resulting in the condition known as solar elastosis. Maximum protection by free radical scavengers reduces gene induction by approximately 50%; the remaining 50% of gene activation is reportedly caused by direct UV damage to cells and cellular DNA, and can only be prevented with sunscreens. Results of the study indicate that the PHA gluconolactone provides up to 50% protection against UV radiation. This significant benefit could not be explained by UV screening, and therefore was attributed to gluconolactone’s ability to chelate oxidation-promoting metals and possibly via direct free radical scavenging effects [12]. It is interesting to note that lactobionic acid (a bionic acid) is an important antioxidant chelator in organ transplantation preservation solutions and is used to suppress tissue damage caused by hydroxyl radicals during organ storage and reperfusion. Lactobionic acid reportedly inhibits

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hydroxyl radical production by forming a complex with Fe(II) [13].

(Table 40.2). Because of these effects such compounds may be categorized as eudermatrophic agents (i.e. agents that nourish the skin toward normalcy).

Sun sensitivity AHAs and PHAs have been evaluated to determine whether daily application alters the sensitivity of normal human skin to UVB radiation. A change in UV sensitivity resulting from enhanced transmission of UVB can be monitored by the formation of sunburn cells (SBCs). Treatment with glycolic acid has been shown to increase the formation of SBCs in skin [14]; this effect can be prevented with use of low level sunscreens [14,15]. Importantly, pretreatment with gluconolactone (PHA) does not lead to an increase in sunburn cells following UVB irradiation, presumably because of its antioxidant effects [12].

Sensory responses One of the distinguishing benefits of the PHAs and bionic acids is their gentleness on skin. When compared to glycolic acid and lactic acid, PHAs and bionic acids are non-stinging and non-burning. Product use studies have demonstrated compatibility with sensitive skin, even on rosacea and atopic dermatitis [8–10]. PHAs and bionic acids are gentle enough to be applied to the skin immediately following cosmetic procedures such as microdermabrasion and non-ablative laser procedures, providing complementary antiaging benefits while helping to reduce redness [11,16].

MMP inhibition Matrix metalloproteinase enzymes (MMPs) digest the skin’s extracellular matrix. Naturally occurring inhibitors of MMPs protect the skin from excessive degradation caused by these enzymes. With aging and sun exposure, an increase in MMP activity and a decrease in natural inhibitors contributes to excessive MMP activity and the clinical manifestations of wrinkles, skin laxity, and telangiectasia [17]. Previous work has revealed that the bionic acid lactobionate is an inhibitor of (MMPs) enzymes obtained from human liver effluents during organ transplantation procedures [18]. Similarly, topical lactobionic acid has been shown to inhibit MMPs in skin helping to protect skin against photodamage [5].

Stratum corneum and epidermis The initial response to AHAs on ichthyotic skin is a sheetlike disjunctive desquamation of the thick, compact stratum corneum. With continued daily use of AHA formulations, the stratum corneum becomes histologically more normal in thickness and in appearance, and the hyperplastic acanthotic underlying epidermis returns to more normal thickness [19]. The opposite occurs in the treatment of atrophic skin of the elderly wherein the stratum corneum and epidermis are both thin. After daily applications of AHAs for several weeks, histologic examination reveals both the stratum corneum and keratinocyte layer to have regained more normal thickness [5,20], with a more even distribution of pigmentation [4]. Other studies have shown AHAs to improve barrier function, particularly the PHAs with antioxidant properties [21].

Dermis Significant dermal remodeling occurs with daily application of AHAs to the skin. In studies on forearm skin where AHAs were applied daily, measurable increases in dermal thickness occurred, which was correlated with increased amounts of hyaluronic acid and other glycosaminoglycans (Figure 40.2) [4,5,7,22], and with qualitative improvements in collagen fibers and improved fibrous quality of elastic fibers [4]. Additionally, the papillary dermis increased in thickness, with increased prominence of dermal papillae. Increased thickness of skin without further topical applications persists for months [23]. Consistent with these clinical histologic findings are in vivo and in vitro observations of others showing the AHA glycolic acid to increase fibroblast proliferation and production of collagen [24].

Clinical uses of HAs HA effects on skin morphology and functionality are manifold, spanning all of the skin’s layers. As a result, numerous clinical benefits have been observed with use of HAs as described herein.

Effects of HAs on skin – similarities and differences

Dry skin and hyperkeratinization

Clinical and histologic observations on the biofunctionality of HAs, both in connection with therapeutic performance on numerous skin disorders and in the course of investigative studies on normal skin, confirm that AHAs, PHAs, and bionic acids have favorable effects on the stratum corneum, epidermis, and dermis. All these effects appear to modulate form and function toward more normal or optimal states

Previous studies demonstrated that the stratum corneum of xerotic skin was thicker and more compact than that of nonxerotic controls, and the epidermis often atrophic. Topical use of AHA formulations on xerotic skin restored the stratum corneum and epidermis to a more normal state both clinically and histologically. This restoration was accompanied by substantial reduction of clinically evident xerosis, and upon discontinuance of the topical AHA treatment the skin

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40. Hydroxyacids

Table 40.2 Clinical grading results for subjects treated with maltobionic acid 8% cream: baseline versus week 12. Variable

Grading site

Mean baseline score (n = 28)

Mean 12-week score (n = 28)

Mean change

Standard deviation

Pore size1

Cheek

4.77

4.01

−0.76

0.37

−20.2

Roughness1

Cheek

4.29

1.51

−2.78

1.08

−65.9

Laxity1

Cheek

5.43

4.51

−0.92

0.35

−18.2

Fine lines1

Eye

4.57

3.29

−1.29

0.40

−29.7

Coarse wrinkles1

Eye

5.22

4.12

−1.11

0.40

−22.0

Mottled Pigmentation1

Face

4.54

3.32

−1.22

0.40

−28.1

Sallowness1

Face

3.79

2.60

−1.20

0.34

−33.4

Clarity/radiance1

Face

3.79

7.13

3.35

0.90

92.4

Pinch recoil2

Face

1.66

1.42

−0.24

0.11

−14.2

Erythema3

Face

0.18

0.20

0.02

0.32

Dryness

Face

0.38

0.00

−0.38

0.52

Stinging3

Face

0.00

0.11

0.42

Statistical difference (p < 0.05)4

Change from baseline (%)5

0.6 −12.5

3.6

Visually graded by a trained assessor using an anchored 0–10 point scale with 0.25 point increments. 0 = low extreme, 10 = high extreme. Measurement collected in triplicate by a trained evaluator using a stopwatch in hundreths of a second; a decrease in pinch recoil time indicates an increase in skin firmness. 3 Visually graded by a trained assessor using an anchored 0–3 point scale (none, mild, moderate, severe) with 0.5-point increments. 4 Arrow indicates statistically significant increase or decrease from baseline; ns = not significant. 5 Percent change from baseline, mean calculated on an individual basis and then averaged. 2

(b)

(a) Figure 40.2 Histologic staining for acid mucopolysaccharides/glycosaminoglycans (GAGs): ×400. (a) Specimen shows staining of untreated control forearm skin. (b) Specimen shows staining following topical application of 8% maltobionic acid cream (pH 3.8) for 12 weeks. Increased density of blue colloidal iron stain demonstrates an increase in GAGs. (Reproduced by permission of Elsevier. From Green B, Briden ME. PHAs and bionic acids: next generation hydroxy acids. In: Draelos Z, ed. (2009) Procedures in Cosmetic Dermatology Series: Cosmeceuticals, 2nd edn, figure 33.9.)

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remained relatively normal for up to about 2 weeks when the thick compact stratum corneum again reformed [11]. Today we find that efficacy of HA formulations for problem dry skin conditions is improved by incorporating into the formulation combinations of AHAs, PHAs, and bionic acids selected for their efficiency in restoring and maintaining a more normal stratum corneum and epidermis. The PHAs and bionic acids, because of water-binding capabilities and inherent gentleness to the skin, offer special advantages in this regard. Combination HA formulations are found to have unparalleled efficacy for treating xerosis [25], and for treating otherwise treatment-resistant conditions such as callused fissured plantar and palmar skin (Figure 40.3).

Keratoses and dyspigmentation Markers of advancing years are a variety of localized hyperkeratotic lesions that include seborrheic keratoses, actinic keratoses, lentigines, age spots, and mottled pigmentation. HAs exfoliate hyperkeratotic pigmentation spots and AHAs have been shown to aid in the even disbursem*nt of melanin [4]. PHAs and bionic acids chelate metals such as copper, an essential co-factor in the production of melanin. HAs can be useful alone or in combination of skin lightening agents to lighten dyspigmentation [2,22].

Wrinkles and photoaging AHAs, PHAs, and bionic acids are now used widely as topical antiaging substances. They are used for superficial peeling

(a)

to initiate accelerated epidermal turnover and to initiate dermal regenerative events; they are used in therapeutic formulations under physicians’ guidance; and they are used in a multitude of consumer cosmetic formulations. The reason for this wide use is because of what may be their eudermatrophic properties, demonstrated in studies described earlier herein where effective concentrations applied to human skin have been found to normalize photoaged skin (Table 40.2). Such changes include increased thickness of epidermis and papillary dermis; improved barrier properties; increased amounts of hyaluronic acid in the dermis and of other dermal glycosaminoglycans which correspond to increased skin thickness measured micrometrically; improved histologic features of dermal collagen; increase in total skin thickness which in turn diminishes clinical wizened appearances (Figure 40.4); and diminished dyspigmentation [3–5].

Uses as a peeling agent Several substances have been used to date as peeling agents, these include phenol, trichloroacetic acid (TCA), salicylic acid, and AHAs. Phenol, weakly acidic in aqueous solution is actually phenylic acid and is quite distinct from AHAs, as is TCA. Both phenol and TCA have a long history of use as peeling agents. Both are caustic, corrosive, powerful denaturants. Both cause rapid chemical destruction of skin. Neither are nutritive, and their benefit is the post-injury replacement of destroyed epidermis and upper dermis through

(b)

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Figure 40.3 Hyperkeratotic feet treated once nightly with a cream containing an AHA/PHA/bionic acid blend (20% total) for 3 weeks. (a) Before treatment. (b) After treatment.

40. Hydroxyacids

(a)

(b) Figure 40.4 Periocular wrinkling is reduced on this 49-year-old female following twice daily application of 8% maltobionic acid cream (pH 3.8) for 12 weeks. (a) Before treatment. (b) After treatment.

mechanisms of wound repair. Salicylic acid (SA), 2-hydroxybenzoic acid, a phenolic acid, is in use today as an agent for superficial peeling mainly for acne. Of the HAs, lactic acid and glycolic acid are the most common peeling agents. Many of the AHAs are nutritive and physiologic, giving them an advantage over phenol, TCA, and SA. In high concentrations of up to 70% or greater, lactic or glycolic acid can be applied to the skin for short times to achieve substantial desquamation and initiate accelerated epidermal and dermal renewal. To date, AHAs have been used primarily as superficial peeling agents offering the benefit of safety and effectiveness over the course of a series of peels [6]. AHA peels can also be safely combined with other cosmetic procedures to optimize results including nonablative laser, light treatments, and with injectable fillers and botulinum toxin type A [16,26,27].

Synergy with topical drugs Enhancement of efficacy can be observed in many conditions by the combined presence of AHAs in formulations that contain active drug ingredients for particular treatments. Examples of active ingredients whose efficacy is enhanced include retinoids, antibacterials, antifungals, antipruritics, and corticosteroids. Mechanisms by which HAs complement or amplify the activity of another substance can be suspected in some instances, for example with retinoids and antibacterials in topical treatment of acne where activities of ingredients join to normalize intrafollicular keratinization and allow more efficient access of the antibiotic into the pilosebaceous unit. The HAs also may enhance therapeutic effect of drugs by providing complementary cosmetic effects. For example, concurrent use of the PHA, gluconolactone, with azelaic acid has been shown to improve therapeutic outcomes for rosacea by reducing skin redness and diminishing the appearance of telangiectasia presumably by increasing overall skin thickness, while also improving the tolerability of the medication [28].

Conclusions In the quest to reverse the clinical signs of aging and improve overall skin health, the HAs (AHA, BHA, PHA, and bionic acids) have emerged as important ingredient technologies owing to their eudermatrophic effects. That is, HAs have the unique ability to nourish the skin towards normalcy, imparting meaningful cosmetic and therapeutic benefits in the process. HAs can be used alone or in combination with other topicals to target symptoms of photoaging and the myriad conditions of hyperkeratosis. HAs continue to be a mainstay in dermatology because they offer significant epidermal and dermal benefits while being safe for skin and the body, even following full body application over long periods of time such as when treating ichthyosis. As time marches forward, it is our expectation that more scientific data will lead to greater uses of HAs alone and in combination with cosmetics, drugs, and devices in dermatology.

References 1 Briden ME, Green BA. (2006) Topical exfoliation: clinical effects and formulating considerations. In: Draelos ZD, Thaman LA, eds. Cosmetic Formulation of Skin Care Products. New York: Taylor & Francis Group, pp. 237–50. 2 Van Scott EJ, Yu RJ. (1982) Substances that modify the stratum corneum by modulating its formation. In: Frost P, Horwitz S, eds. Principles of Cosmetics for the Dermatologist. St. Louis: CV Mosby, pp. 70–4. 3 Yu RJ, Van Scott EJ. (2005) α-Hydroxyacids, polyhydroxy acids, aldobionic acids and their topical actions. In: Baran R, Maibach HI, eds. Textbook of Cosmetic Dermatology, 3rd edn. New York: Taylor & Francis Group, pp. 77–93. 4 Ditre CM, Griffin TD, Murphy GF, Sueki H, Telegan B, Johnson WB, et al. (1996) Effects of alpha-hydroxyacids on photoaged skin: a pilot clinical, histologic and ultrastructural study. J Am Acad Dermatol 34, 187–95.

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5 Green BA, Edison BL, Sigler ML. (2008) Antiaging effects of topical lactobionic acid: results of a controlled usage study. Cosmet Dermatol 21, 76–82. 6 Van Scott EJ, Ditre CM, Yu RJ. (1996) Alpha hydroxyacids in the treatment of signs of photoaging. Clin Dermatol 14, 217–26. 7 Bernstein EF, Underhill CB, Lakkakorpi J, Ditre CM, Uitto J, Yu RJ, et al. (1997) Citric acid increases viable epidermal thickness and glycosaminoglycan content of sun-damaged skin. Dermatol Surg 23, 689–94. 8 Bernstein EF, Green BA, Edison B, Wildnauer RH. (2001) Poly hydroxy acids (PHAs): clinical uses for the next generation of hydroxy acids. Skin Aging 9 (Suppl), 4–11. 9 Rizer R, Turcott A, Edison B, et al. (2001) An evaluation of the tolerance profile of a complete line of gluconolactonecontaining skincare formulations in atopic individuals. Skin Aging 9 (Suppl), 18–21. 10 Rizer R, Turcott A, Edison B, et al. (2001) An evaluation of the tolerance profile of gluconolactone-containing skincare formulations in individuals with rosacea. Skin Aging 9 (Suppl), 22–5. 11 Briden ME, Green BA. (2005) The next generation hydroxyacids. In: Draelos Z, Dover J, Alam M, eds. Procedures in Cosmetic Dermatology: Cosmeceuticals. Philadelphia, PA: Elsevier Saunders, pp. 205–12. 12 Bernstein EF, Brown DB, Schwartz MD, Kaidbey K, Ksenzenko SM. (2004) The polyhydroxy acid gluconolactone protects against ultraviolet radiation in an in vitro model of cutaneous photoaging. Dermatol Surg 30, 1–8. 13 Charloux C, Paul M, Loisance D, Astier A. (1995) Inhibition of hydroxyl radical production by lactobionate, adenine, and tempol. Free Radical Biol Med 19, 699–704. 14 (1998) 34th Report of the CIR expert panel: safety of alpha hydroxy acid ingredients. Int J Toxicol 17 (Suppl 1). 15 Johnson AW, Stoudemayer T, Kligman AM. (2000) Application of 4% and 8% glycolic acid to human skin in commercial skin creams formulated to CIR guidelines does not thin the stratum corneum or increase sensitivity to UVR. J Cosmet Sci 51, 343–9. 16 Rendon MI, Effron C, Edison BL. (2007) The use of fillers and botulinum toxin type A in combination with superficial glycolic acid (AHA) peels: optimizing injection therapy with the skinsmoothing properties of peels. Cutis 79 (Suppl 1), 9–12.

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17 Thibodeau A. (2000) Metalloproteinase inhibitors. Cosmet Toil 115, 75–6. 18 Upadhya GA, Strasberg SM. (2000) Glutathione, lactobionate, and histidine: cryptic inhibitors of matrix metalloproteinases contained in University of Wisconsin and histidine/tryptophan/ ketoglutarate liver preservation solutions. Hepatology 31, 1115–22. 19 Van Scott EJ, Yu RJ. (1974) Control of keratinization with α-hydroxy acids and related compounds. Arch Dermatol 110, 586–90. 20 Van Scott EJ, Yu RJ. (1984) Hyperkeratinization, corneocyte cohesion, and alpha hydroxyacids. J Am Acad Dermatol 11, 867–79. 21 Berardesca E, Distante F, Vignoli GP, Oresajo C, Green B. (1997) Alpha hydroxyacids modulate stratum corneum barrier function. Br J Dermatol 137, 934–8. 22 Grimes PE, Green BA, Wildnauer RH, Edison BL. (2004) The use of polyhydroxy acids (PHAs) in photoaged skin. Cutis 73 (Suppl 2), 3–13. 23 Van Scott EJ, Yu RJ. (1995) Actions of alpha hydroxy acids on skin compartments. J Geriat Dermatol 3 (Suppl A), 19–24. 24 Kim SJ, Park JH, Kim DH, Won YH, Maibach AI. (1998) Increased in vivo collagen synthesis and in vitro cell proliferative effect of glycolic acid. Dermatol Surg 24, 1054–8. 25 Kempers S, Katz HI, Wildnauer R, Green, B. (1998) An evaluation of the effects of an alpha hydroxy acid-blend skin cream in the cosmetic improvement of symptoms of moderate to severe xerosis, epidermolytic hyperkeratosis, and ichthyosis. Cutis 61, 347–50. 26 Effron C, Briden ME, Green BA. (2007) Enhancing cosmetic outcomes by combining superficial glycolic acid (AHA) peels with nonablative lasers, intense pulsed light, and trichloroacetic acid peels. Cutis 79 (Suppl 1), 4–8. 27 Briden E, Jacobsen E, Johnson C. (2007) Combining superficial glycolic acid (AHA) peels with microdermabrasion to maximize treatment results and patient satisfaction. Cutis 79 (Suppl 1), 13–6. 28 Draelos ZD, Green BA, Edison BL. (2006) An evaluation of a polyhydroxy acid skincare regimen in combination with azelaic acid 15% gel in rosacea patients. J Cosmet Dermatol 5, 23–9.

Chapter 41: The contribution of dietary nutrients and supplements to skin health Helen Knaggs, Steve Wood, Doug Burke, and Jan Lephart Nu Skin and Pharmanex Global Research and Development, Provo, UT, USA

BAS I C CONCEPTS • Diet and oral supplementation can influence skin appearance. • Nutrients effective in minimizing UV skin damage include carotenoids, vitamin E (tocopherols), flavonoids, vitamin C (ascorbate) and n-3 fatty acids. • Selenium, zinc, and copper protect against UV-induced damage. • Diets containing high amounts of refined sugars may predispose skin to premature aging through the formation of advanced glycation end products (AGEs).

Introduction The skin is the largest organ in the body and is exposed to many environmental factors affecting its appearance and health. Additionally, there are changes occurring over time in skin, determined by our genes and hormones. It is often said that the appearance of the skin can predict overall health or is a window to health inside of the body and there is much interest in maintaining a healthy skin appearance and function. One approach to achieve an optimal skin appearance is through the use of topical products, such as cosmetics. However, there is now a growing body of research indicating that diet and/or oral supplementation can also influence skin appearance as is reviewed in this chapter. Historically, dietary deficiency of many of the essential nutrients (e.g. thiamin, zinc, and vitamins A and C) was first noted as a result of disruption of skin integrity or by a change in the skin’s appearance [1]. Many nutrients are important co-factors in biochemical processes occurring within skin cells and therefore deficiencies are manifested by changes in the skin. For example, vitamin C was first discovered for its role in preventing scurvy and is an important co-factor for collagen synthesis [2]. Another example is riboflavin, which, when deficient, causes cracks in the corner of the mouth (angular cheilitis) as well as reddening and cracking of the lips, tongue, and mouth. Zinc deficiency may be noted in poor wound healing, and niacin and vitamin A deficiencies can cause dry skin or, in more extreme cases, dermatitis.

Conversely, published studies seem to show that supplementation of some of these key nutrients can result in an improvement in skin condition and this has fueled the use of vitamins and other nutrients as benefit agents in cosmetic preparations. There is obvious interest in whether dietary supplementation of these key agents can also provide benefit to skin and how this compares with providing these actives via the topical route. For example, higher intakes of vitamin C have been associated with a lower likelihood of a wrinkled appearance and skin dryness, independent of age, race, education, body mass index (BMI), and supplement use [3,4], while use of vitamin C in topical products is fraught with challenges presented by the instability of the vitamin in skincare formulations. Vitamin C has a number of different biologic roles in skin, including participating in collagen synthesis, skin regeneration, and wound healing [5]. Many nutrients are required by the skin for different functions and this chapter aims to describe some of the key nutrients and discusses the data describing the use of these nutrients when provided orally for skin benefits (Table 41.1). Below is a description of several aspects of skin health and studies of nutrients or dietary supplements that have been shown to improve skin health and appearance.

Nutrients and their role in protecting against UV-induced damage One of the leading consumer skin concerns is skin aging, and products to delay or reverse the signs of aging are in high demand. A major contributing factor to skin aging is UV radiation, mostly from the sun. Both UVA and UVB rays generate harmful free radicals in the skin contributing to

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Table 41.1 Nutrients and their skin health benefits. Nutrient groups

Specific nutrients

Antioxidants

Vitamin C

Vitamin E

Beta-carotene Lycopene

Lutein/zeaxanthin Astaxanthin

CoQ10

α-lipoic acid

Vitamin C is necessary for collagen synthesis, and higher intakes are associated with better skin appearance [3]. Supplemental vitamin C and E for 3 months significantly reduced the sunburn reaction to UVB irradiation and skin DNA damage [44] Vitamin E is a fat-soluble antioxidant that accumulates in skin cells. It protects against free radical damage. However, if cell membranes are oxidized they become more rigid leading to skin wrinkle formation. Studies have shown that supplemental vitamin E reduced levels of malondialdehyde (MDA, a marker of oxidative stress) in the skin upon exposure to UV rays [18]. Skin healing is also affected by supplemental vitamin E. In 57 patients with pressure ulcers, administration of 400 mg/day oral vitamin E promoted faster healing than the placebo [25] Beta-carotene can be used in the body as a source of vitamin A, which is important for skin maintenance and repair. Several studies have also demonstrated that supplemental carotenoids improve skin health Lycopene is depleted from the skin faster than beta-carotene upon UV exposure [4]. Ten weeks of supplementation of tomato paste, high in lycopene, provided protection against erythema formation following UV irradiation [10,11] Supplemental lutein/zeaxanthin has produced decreased UV damage and increased skin hydration and elasticity [16,17] Subjects given astaxanthin have shown significant improvements in elasticity, moisture content, and fine lines/wrinkles [33], and those consuming astaxanthin and vitamin E exhibited significant reductions in fine wrinkles and pimples, and increased moisture levels, after 4 weeks of supplementation [34] An important antioxidant necessary for energy metabolism. Supplementation of 60 mg CoQ10 for 3 months significant reduced wrinkle grade (depth and area of wrinkles) and improved skin properties [38,39] A potent antioxidant that has benefit to water-soluble and fat-soluble portions of cells

Combinations of antioxidants

A number of studies of vitamins E and C have shown additive or synergistic preventive benefits against UVB-induced erythema [45]. Subjects given beta-carotene, lycopene, vitamin E, vitamin C and experienced significant protection from sun damage [46]

Fish oil/omega-3 fatty acids

Eisapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

Dietary consumption of fish oil is known to modulate the lipid inflammatory mediator balance and therefore is valuable in the treatment of inflammatory skin disorders. Consumption of EPA and DHA totaling 3–4 g/day for up to 3 months reduced erythema upon UV exposure in several studies [4]

Polyphenol and flavonoids

Green tea polyphenols

Polyphenols protect against free radical damage. Forty-one women aged 25–75 years given 300 mg (green tea extract containing 97% pure polyphenols) twice daily for 2 years experienced fewer fine wrinkles and telangiectasias and overall less solar damage compared with baseline and the control group [36] When subjects received 100 mg oligomeric proanthocyanidins along with vitamin C and SiO2 and were then exposed to UV rays, they experienced less erythema and increased skin hydration [47]

Grape seed extract and resveratrol Vitamin D

Minerals

Vitamin D is a compound that is formed/activated in the skin upon sun exposure [48]. Unfortunately, there have not yet been any studies on skin health and supplementation Zinc Copper

Negative nutritional components

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Zinc serves as a co-factor for many important enzymes in the body. Some of the best known are important for skin healing [49] Copper is an important co-factor for elastin, the support structure for skin

Selenium

Selenium is a component of the antioxidant enzyme glutathione peroxidase. Supplemental selenium and copper have shown significant protection (versus placebo) against UV-induced cell damage [32]

Diet high in fats and carbohydrates

Diets high in fats and carbohydrates have been shown to increase the likelihood of a wrinkled appearance [3]

41. Dietary nutrients and supplements photodamage, leading to the production of fine lines and wrinkles, and, in extreme cases of sun exposure, sunburn and skin cancers. With sun exposure and no or inadequate sun protection, the skin depends solely on its internal or endogenous defenses such as melanin for protection. Dietary micronutrients which act as antioxidants can help to protect against the free radical formation induced by UV irradiation. Some of the most widely studied nutrients that have been effective in minimizing UV damage occurring within skin include carotenoids, vitamin E (tocopherols), flavonoids, vitamin C (ascorbate), and n-3 fatty acids [6,7]. Currently, there is perhaps the most evidence to support the role of carotenoids in providing skin benefits, especially for UV damage. Topically, vitamin A has been shown to reduce the signs of photodamage and is most effective in the acid form available on prescription as Retin A® (Ortho Dermatologics, USA) (retinoic acid). Beta-carotene, lycopene, lutein, and zeaxanthin are major carotenoids in human blood and tissues, and are highly effective at quenching singlet molecular oxygen formed during photo-oxidative processes. In fact, carotenoids from a normal, unsupplemented diet accumulate in the skin [8] and confer a measurable photoprotective benefit (at least in lightly pigmented Caucasian skin) that is directly linked to tissue concentrations [9]. Dietary intake of tomato paste, which contains a number of carotenoids, including beta-carotene, lycopene, lutein, and zeazanthin, has been shown to provide photoprotective activity [10,11]. Dietary supplementation with 25 mg total carotenoids a day for 12 weeks to healthy volunteers significantly diminished erythema upon UV irradiation given at week 8. This effect was enhanced when the same regimen was given with 335 mg/day (500 IU) RRR-alfa tocopherol [12]. A 12-week supplementation of betacarotene from Dunaliella algae was also effective in suppressing UV-induced erythema given at a dose of 25 mg/day to healthy volunteers [12]. It is thought that other carotenoids such as lycopene act synergistically with beta-carotene to protect the skin from UV irradiation [4]. In humans, it was shown that lycopene is depleted from the skin faster than beta-carotene upon UV exposure [13], suggesting a primary role of lycopene in mitigating oxidative damage in tissues, and an important role in the defense mechanism against adverse effects of UV irradiation on the skin. In fact, when a single UV light exposure of three times minimal erythemal dose (MED) was administered to human skin, lycopene concentrations decreased rapidly but skin beta-carotene concentrations declined slowly. Lutein and zeaxanthin (LZ) are found in dark, leafy, green and yellow vegetables, and there is evidence that they can provide protection against UV-induced damage. The presence of these carotenoids in the skin following dietary and oral supplementation has been demonstrated [14,15], along with a benefit in reducing UV damage. Forty female subjects aged 25–50 years were assigned to receive one of the following:

1 Oral LZ at 5 and 0.3 mg, respectively, and a topical application of 50 p.p.m. lutein and 2 p.p.m. zeaxanthin; 2 Oral LZ as before and placebo topical application; 3 Placebo oral supplement and active topical application; and 4 Placebo for both treatments, twice daily for 12 weeks. All active treatments reduced UV-light induced malondialdehyde (MDA: a measure of lipid peroxidation) production, with the topical and oral and topical treatments producing similar results, and the combined treatment producing the greatest reduction. Other benefits were also noticed in this study – there were measurable increases in skin lipids produced by all treatments, with the oral regimen producing significantly greater increases than the topical treatment. Additionally, hydration was increased similarly by oral and topical treatments, and significantly more with the combination treatment. All differences were significant for all treatments at week 12 compared with placebo, and for all time points after week 2 [16,17]. The benefit of tocopherols in photoprotection has also been studied. Vitamin E is commonly associated with protecting cell membranes from oxidative damage and administration of oral 400 IU/day vitamin E significantly reduced MDA production but not other measures of oxidative stress in the skin or sensitivity to UV damage [18]. The production of sebum containing dietary vitamin E by the sebaceous glands was shown to be the primary delivery route for sources of tocopherols to the skin surface [19]. Vitamin C is an important co-factor for the enzymes involved in collagen synthesis and it has also been shown to provide benefit in protecting against signs of photodamage. Boelsma et al. [4] reviewed studies that supplemented diet with vitamin C and identified four studies demonstrating a photoprotective effect of vitamin C on skin. Using data from the National Health and Nutrition Examination Survey (NHANES I), associations between dietary nutrient intakes and signs of skin aging in 4025 women aged 40–74 years were compared. High dietary intakes of vitamin C were associated with a lower likelihood of senile skin dryness and a reduced wrinkled appearance. In fact, an increase consumption of vitamin C, by 1 log unit, was associated with an 11% reduction in the odds of a wrinkled appearance and a 7% reduction in the odds of senile dryness, independent of age, race, education, BMI, other supplement use, sun exposure, menopausal status, family income, energy intake, or physical activity [3]. This was an important study as it was the first to directly relate dietary intakes, rather than supplementation, of vitamin C with skin aging and showed that a diet high in foods supplying vitamin C can lead to a lower prevalence of an aged appearance. Other dietary factors were also studied: a lower intake of vitamin A, lower protein, and higher thiamine intakes were also linked to a wrinkled appearance. Conversely, higher intakes of fat and carbohydrates were associated with an increased chance of

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wrinkled skin appearance and skin atrophy. Thus, it appears that one’s appearance may be an indicator of overall health status because balanced nutrition is essential, not only to prevent chronic diseases such as cardiovascular disease, certain cancers, and diabetes [20], but also to maintain skin health and ensure normal cellular function. It is a bold statement, but this evidence suggests that looking “old for one’s age” may also reflect and/or be associated with an increased risk of disease and mortality [21,22]. Researchers have found that supplemental flavanoids for 10–12 weeks in humans protects against UV-induced erythema [23], although this is related to dose, with high doses appearing necessary to provide benefits. In one study, a cocoa supplement with 327 mg total flavanols produced an increased microcirculation in the skin, while the same cocoa drink containing 27 mg/day total flavanols had no benefit. Another study compared two groups of women ingesting either a high (326 mg/day) or low (27 mg/day) flavanol cocoa powder dissolved in 100 mL water for 12 weeks. The production of erythema following a 1.25 MED UV ray dose was reduced significantly by 15% and 25% at 6 and 12 weeks, respectively, in the high dose supplemented group. No such benefit was observed for the group receiving the lower dose of flavanols. In addition, in the high dose group, but not the low-flavanol group, increases in blood flow to cutaneous and subcutaneous tissues were observed, as well as increases in skin thickness, skin density, and skin hydration, along with a significant decrease in skin roughness and scaling [24]. Antioxidant combinations can provide added protection beyond single antioxidants alone in preventing UV damage. For example, in healthy volunteers given a carotenoid blend (25 mg/day) for 12 weeks there was a significant decrease in skin reddening following blue light exposure to the skin, whereas combining this with 500 IU vitamin E had an even more dramatic decrease after only 8 weeks of consumption [7]. Interestingly, in healthy individuals on a normal diet, little benefit was shown with individual antioxidants like vitamin E in preventing UV-induced skin damage [25]. Data show that a combination of supplemental antioxidants that most closely mimics a diet rich in antioxidants can provide a photoprotective effect against sun damage [26]. Administration of 1 g vitamin C and 500 mg vitamin E (as δ-alfa tocopherol) for 3 months to human volunteers significantly reduced the sunburn reaction to UVB irradiation as measured by a reduction in thymine dimer formation by 43% indicating a reduction in skin DNA damage, and an increased in MED by 41% [27]. Oral intake of lipids and lipid-soluble vitamins have long proved beneficial for skin. One study observed a photoprotective effect of a diet higher in olive oil on the skin [28]. Some evidence suggests that n-3 fatty acids (FA) may also be effective in protection against UV-induced skin cancers and photoaging, in part brought about by the reduction of

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UV-induced release of cytokines and other inflammatory mediators in a variety of skin cell types [29,30]. In humans, supplemental omega-3 FA have been shown to significantly increase the UVR-mediated erythema threshold and reduce the level of proinflammatory, immunosuppressive prostaglandin E2 levels from UVB irradiation [31]. Fish oil supplements, which provide eicosapentanoic and docosahexanoic acid, have also shown a photoprotective effect [4,6]. Selenium, zinc, and copper have also been shown to provide benefit and protect against UV-induced damage. This could be because these nutrients are critical components for the activity of several enzymes associated with skin repair following UV irradiation (e.g. matrix metalloproteinase) [32]. A combination of 200 μg selenium and 4 mg copper alone, or with 14 mg vitamin E, 3.6 mg niacin, 0.4 mg pyridoxine, 0.12 mg thiamine, 0.08 mg riboflavin plus 9000 IU retinol per day during meals for 3 weeks gave significant protection (versus placebo) against UV-induced cell damage in the form of sunburn cells, but did not reduce UV-induced erythema. This study was performed on 16 healthy Caucasian subjects aged 20–37 years and the combined supplements gave the strongest effect [32].

Nutrients and their role in improving skin appearance The benefit of nutrients in protecting the skin from damage was discussed in the previous section [3–32]. Cumulative photodamage results in the appearance of fine lines and wrinkles on the face, as well as changes in pigmentation and skin dryness and roughness. There is also evidence to support the use of oral nutrients in improving the signs of photodamage, once formed, and in improving overall skin condition. The carotenoid astaxanthin is found in plants and algae and provides pink–orange color to shellfish and salmon. Supplementation of astaxanthin produced significant improvements in pre-existing fine lines and wrinkles, and also improved skin elasticity scores and moisture content [33]. Another study with 16 female subjects (mean age 40 years) with dry skin conditions were given either 2 mg astaxanthin (as 40 mg AstaReal®, Fuji, Toyama, Japan) and 4 mg natural tocotrienols or a control supplement for 4 weeks. Treated subjects exhibited significant reductions in fine wrinkles and pimples, and had increased skin moisture levels. These parameters contributed to the individual assessments that reported reduced swelling under the eyes, improved elasticity, and “better skin feel.” Subjects on the placebo did not improve and generally worsened during this time [34]. Similarly, soy isoflavones have been shown to provide a significant improvement in fine wrinkles and skin elasticity, compared with a placebo group [35] after 12 weeks’ supplementation. This study showed that the benefits were

41. Dietary nutrients and supplements evident in women in their late thirties and early forties. Another study examined the effect of green tea on skin condition. Forty-one women aged 25–75 years were given 300 mg of a proprietary green tea extract containing 97% tea polyphenols or a placebo twice daily for 2 years. At 24 months, fine wrinkles were significantly reduced compared to baseline, and at 12 months, telangiectasias were significantly reduced in the green tea supplemented group, but not the placebo group. At 24 months compared with 12 months, overall solar damage was reduced over time for the green tea supplemented group but not in the placebo group [36]. Sun damage to skin does not need to have been severe for it to respond to oral supplements within a relatively short period of time. Eight weeks is common for topical treatments to produce a noticeable difference in skin condition, which includes an improvement in moderate photodamage with 8 weeks’ supplementation with key nutrients. For example, one study investigated 30 dry-skinned women aged 48–59 years with moderate xerosis and photoaging. The group was randomized to receive either a topical nanocolloidal gel containing 0.5 mg α-lipoic acid and 15 mg melatonin/emblica along with a nutritional supplement containing 3 mg lutein, 2.5 mg α-lipoic acid, 45 mg ascorbic acid, and 5 mg tocopherol. All treatments were given twice daily for 2 months. Dietary supplements, but not the placebo, significantly reduced blood free radical activity compared with baseline. Skin hydration was significantly increased in all groups compared with baseline and placebo. An increase in superficial skin lipids was found for the treatments, with all being significantly different from baseline. Significantly greater effects were seen with the combined versus individual treatments, and all treatments than the placebo. Lipid peroxidation at weeks 2, 4, and 8 on the skin was significantly greater with the control group [37]. A study of topical application of coenzyme Q10 (CoQ10) for 3 months showed reduced depth and area of wrinkles around the eye area of 20 elderly volunteers, compared with the vehicle, which was applied around the opposite eye. There was a 27% reduction in mean peak to valley depth of the skin and a 26% reduction in Rq values measured on the PRIMOS, compared with controls [38]. Similar findings were reported following daily oral supplementation of 60 mg CoQ10 for 3 months [39]. Diets containing high amounts of refined sugars may predispose skin to premature aging through the formation of advanced glycation end products (AGEs). Glycation is a nonenzymatic reaction between amino groups on proteins (i.e. lysine) and reducing sugars (i.e. fructose). This reaction creates cross-links in the skin and once these reactions occur they disrupt normal function and predispose skin to oxidation or premature aging in the extracellular matrix of the dermis. For example the cross-linkages between dermal molecules cause the loss of elasticity or other properties of the dermis observed during aging. Some preclinical studies have

shown that supplemental nutrients such as α-lipoic acid may prevent the detrimental effects AGEs to the skin. Interestingly, some researchers have shown that AGEs may actually be photosensitizers to cause more severe DNA damage to the skin from phototoxicity which ultimately causes accelerated skin aging and increased risk of skin cancer. Future studies will help establish nutritional strategies to prevent the formation and detrimental effects of AGEs. In summary, there is a growing body of literature that demonstrates that oral nutrients not only protect the skin from UV damage and reduce free radical damage, but also can improve skin condition after the effects of sun damage has formed.

Nutrients shown to provide additional skin benefits As well as protecting from UV and improving photodamage, data exist to show that diet and nutritional supplementation can provide many other benefits for skin. Ingestion of 5 mg lutein and 0.3 mg zeaxanthin twice daily for 12 weeks was shown to improve skin moisture and elasticity [16,17] and this may have resulted from an increase in skin lipids which was demonstrated during the study. Increases in skin lipids and improvements in skin smoothness and elasticity have been reported from previous studies of orally ingested antioxidants [37,40]. A combination of nutrients was also found to provide significant skin changes. Thirty-nine healthy people with normal skin were divided into three groups and given 3 mg lycopene, 3 mg lutein, 4.8 mg beta-carotene, 10 mg αtocopherol, and 75 μg selenium per day, a similar supplement with double the amount of lycopene without lutein, or a placebo. A significant increase of skin density and thickness, as determined by ultrasound, along with improved skin surface of decreased roughness and skin scaling (evaluated by Visioscan) was found for both antioxidant groups but not the placebo [7].

Nutrients and their potential in improving dermatologic disorders and wound healing Skin disorders that have an inflammatory component (e.g. psoriasis and eczema) and are manifested by dry and flaky skin have responded to topical omega-3 polyunsaturated fatty acid supplementation [41] and these nutrients may therefore offer a therapeutic benefit when given orally. There is also evidence to show that oral supplementation can assist in healing. In 57 patients with pressure ulcers, administration of 400 mg/day vitamin E provided faster healing of the ulcer compared with placebo. When 10 females with lichen sclerosis took 300–1200 IU/day vitamin

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E, five improved markedly, two moderately, and three slightly [25]. Zinc deficiency has been associated with delayed wound healing and roughness of the skin [26,42]. Mixtures of tocopherol and CoQ10 have proved to be beneficial for skin healing [43].

Conclusions An individual’s appearance has been regarded as an indicator of overall health, well-being, and age. In fact, it might perhaps be an indicator of life expectancy [21,22]. Nutrients provided in the diet or through dietary supplements can provide benefits to overall skin health and appearance, and in some cases can reverse a wrinkled or aged appearance. There is also evidence that providing several nutrients together is more beneficial than providing single nutrients in isolation. The benefits of nutrients, such as carotenoids, flavonoids, CoQ10, α-lipoic acid, minerals, and omega-3 fatty acids are related to their antioxidant potential, but significant other benefits are also provided, for example nutrients often serve as co-factors for key metabolic enzymes in skin (e.g. vitamin C and collagen production).

References 1 Boelsma E, van de Vijver LP, Goldbohm RA, Klopping-Ketelaars IA, Hendriks HF, Roza L. (2003) Human skin condition and its associations with nutrient concentrations in serum and diet. Am J Clin Nutr 77, 348–55. 2 Miller SJ. (1989) Nutritional deficiencies and the skin. J Am Acad Dermatol 21, 1–30. 3 Cosgrove MC, Franco OH, Granger SP, Murray PG, Mayes AE. (2007) Dietary nutrient intakes and skin-aging appearance among middle-aged American women. Am J Clin Nutr 86, 1225–31. 4 Boelsma E, Hendriks HF, Roza L. (2001) Nutritional skin care: health effects of micronutrients and fatty acids. Am J Clin Nutr 73, 853–64. 5 Catani MV, Savini I, Rossi A, Melino G, Avigliano L. (2005) Biological role of vitamin C in keratinocytes. Nutr Rev 63, 81–90. 6 Sies H, Stahl W. (2004) Nutritional protection against skin damage from sunlight. Annu Rev Nutr 24, 173–200. 7 Heinrich U, Tronnier H, Stahl W, Bejot M, Maurette JM. (2006) Antioxidant supplements improve parameters related to skin structure in humans. Skin Pharmacol Physiol 19, 224–31. 8 Darvin, ME, Patzelt A, Blume-Peytavi U, Sterry W, Lademann J. (2008) One-year study on the variation of carotenoid antioxidant substances in living human skin: influence of dietary supplementation and stress factors. J Biomed Optics 13, 44028. 9 Stahl W, Heinrich U, Aust O, Tronnier H, Sies H. (2006) Lycopene-rich products and dietary photoprotection. Photochem Photobiol Sci 5, 238–42. 10 Stahl W, Heinrich U, Wiseman S, Eichler O, Sies H, Tronnier H. (2002) Dietary tomato paste protects against ultraviolet lightinduced erythema in humans. J Nutr 132, 399–403.

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11 Sies H, Stahl W. (2003) Non-nutritive bioactive constituents of plants: lycopene, lutein and zeaxanthin. Int J Vitam Nutr Res 73, 95–100. 12 Stahl W, Heinrich U, Jungmann H, Sies H, Tronnier H. (2000) Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in humans. Am J Clin Nutr 71, 795–8. 13 Ribaya-Mercado JD, Garmyn M, Gilchrest BA, Russell RM. (1995) Skin lycopene is destroyed preferentially over betacarotene during ultraviolet irradiation in humans. J Nutr 125, 1854–9. 14 Wingerath T, Sies H, Stahl W. (1998) Xanthophyll esters in human skin. Arch Biochem Biophys 355, 271–4. 15 Lee EH, Faulhaber D, Hanson KM, Ding W, Peters S, Kodali S, et al. (2004) Dietary lutein reduces ultraviolet radiation-induced inflammation and immunosuppression. J Invest Dermatol 122, 510–7. 16 Palombo P, Fabrizi G, Ruocco V, Ruocco E, Fluhr J, Roberts R, et al. (2007) Beneficial long-term effects of combined oral/topical antioxidant treatment with the carotenoids lutein and zeaxanthin on human skin: a double-blind, placebo-controlled study. Skin Pharmacol Physiol 20, 199–210. 17 Roberts RL, Green J, Lewis B. (2009) Lutein and zeaxanthin in eye and skin health. Clin Dermatol 27, 195–201. 18 Thiele JJ, Ekanayake-Mudiyanselage S. (2007) Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. Mol Aspects Med 28, 646–67. 19 Thiele JJ, Weber SU, Packer L. (1999) Sebaceous gland secretion is a major physiologic route of vitamin E to skin. J Invest Dermatol 113, 1006–10. 20 Willett WC. (2002) Balancing life-style and genomics for disease prevention. Science 296, 695–8. 21 Purba MB, Kouris-Blazos, Wattanapenpaiboon N, Lukito W, Rothenberg E, Steen B, et al. (2001) Can skin wrinkling in a site that has received sun exposure be used as a marker of skin health and biological age. Age Aging 30, 227–34. 22 Christensen K, Iachina M, Rexbye H, Tomassini C, Frederiksen H, McGue M, et al. (2004) Looking old for your age: genetics and mortality. Epidemiology 15, 251–2. 23 Stahl W, Sies H. (2007) Carotenoids and flavonoids contribute to nutritional protection against skin damage from sunlight. Mol Biotechnol 37, 26–30. 24 Neukam K, Stahl W, Tronnier H, Sies H, Heinrich U. (2007) Consumption of flavanol-rich cocoa acutely increases microcirculation in human skin. Eur J Nutr 46, 53–6. 25 Tebbe B. (2001) Relevance of oral supplementation with antioxidants for prevention and treatment of skin disorders. Skin Pharmacol Appl Skin Physiol 14, 296–302. 26 Richelle M, Sabatier M, Steiling H, Williamson G. (2006) Skin bioavailability of dietary vitamin E, carotenoids, polyphenols, vitamin C, zinc and selenium. Br J Nutr 96, 227–38. 27 Placzek M, Gaube S, Kerkmann U, Gilbertz KP, Herzinger T, Haen E, et al. (2005) Ultraviolet B-induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-alpha-tocopherol. J Invest Dermatol 124, 304–7. 28 Purba MB, Kouris-Blazos, Wattanapenpaiboon N, Lukito W, Rothenberg EM, Steen B, et al. (2001) Skin wrinkling: can food make a difference. J Am Coll Nutr 20, 71–80.

41. Dietary nutrients and supplements 29 Jackson MJ, Jackson MJ, McArdle F, Storey A, Jones SA, McArdle A, et al. (2002) Effects of micronutrient supplements on UV-induced skin damage. Proc Nutr Soc 61, 187–9. 30 Rhodes LE, Durham BH, Fraser WD, Friedmann PS. (1995) Dietary fish oil reduces basal and ultraviolet B-generated PGE2 levels in skin and increases the threshold to provocation of polymorphic light eruption. J Invest Dermatol 105, 532–5. 31 Black HS, Rhodes LE. (2006) The potential of omega-3 fatty acids in the prevention of non-melanoma skin cancer. Cancer Detect Prev 30, 224-32. 32 La Ruche G, Cesarini JP. (1991) Protective effect of oral selenium plus copper associated with vitamin complex on sunburn cell formation in human skin. Photodermatol Photoimmunol Photomed 8, 232–5. 33 Geria NM. (2007) Beauty and the beach: wonders from the sea. Happi December. 34 Yamash*ta E. (2002) Cosmetic benefit of dietary supplements containing astaxanthin and tocotrienol on human skin. Food Style 216, 112–7. 35 Izumi T, Saito M, Obata A, Arii M, Yamaguchi H, Matsuyama A. (2007) Oral intake of soy isoflavone aglycone improves the aged skin of adult women. J Nutr Sci Vitaminol (Tokyo) 53, 57–62. 36 Janjua R, Munoz C, Gorell E, et al. (2009) A two-year, doubleblind, randomized placebo-controlled trial of oral green tea polyphenols on the long-term clinical and histologic appearance of photoaging skin. Dermatol Surg 35(7), 1057–65. 37 Morganti P, Bruno C, Guarneri F, Cardillo A, Del Ciotto P, Valenzano F. (2002) Role of topical and nutritional supplement to modify oxidative stress. Int J Cosmet Sci 24, 331–9. 38 Hoppe U, Bergemann J, Diembeck W, Ennen J, Gohla S, Harris I, et al. (1999) Coenzyme Q10, a cutaneous antioxidant and energizer. BioFactors 9, 371–8. 39 Morre DM, Morre DJ, Rehmus W, Kern D. (2008) Supplementation with CoQ10 lowers age-related arNOX levels in healthy subjects. Biofactors 32, 221–30.

40 Segger D, Shonlau F. (2004) Supplementation with Evelle improves skin smoothness and elasticity in a double blind placebo-controlled study with 62 women. J Dermatol Treat 15, 222–6. 41 Henneicke-von Zepelin HH, Mrowietz U, Farber L, BruckBorchers K, Schober C, Huber J, et al. (1993) Highly purified omega-3-polyunsaturated fatty acids for topical treatment of psoriasis: results of a double-blind, placebo-controlled multicentre study. Br J Dermatol 129, 713–7. 42 Lansdown AB, Mirastschijski U, Stubbs N, Scanlon E, Agren MS. (2007) Zinc in wound healing: theoretical, experimental, and clinical aspects. Wound Repair Regen 15, 2–16. 43 De Luca C, Deeva I, Mikhal Chik E, Korkina L. (2007) Beneficial effects of pro-/antioxidant-based nutraceuticals in the skin rejuvenation techniques. Cell Mol Biol 53, 94–101. 44 Placzek M, Gaube S, Kerkmann U, et al. (2005) Ultraviolet B-induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-alpha-tocopherol. J Invest Dermatol 124, 304–7. 45 Cesarini JP, Michel L, Maurette JM, Adhoute H, Bejot M. (2003) Immediate effects of UV radiation on the skin: modification by an antioxidant complex containing carotenoids. Photodermatol Photoimmunol Photomed 19, 182–9. 46 Masaki T, Yoshimatsu H, Chiba S, Sakata T. (2000) Impaired response of UCP family to cold exposure in diabetic (db/db) mice. Am J Physiol Regul Integr Comp Physiol 279, R1305–9. 47 Hughes-Formella B, Wunderlich O, Williams R. (2007) Antiinflammatory and skin-hydrating properties of a dietary supplement and topical formulations containing oligomeric proanthocyanidins. Skin Pharmacol Physiol 20, 43–9. 48 Holick MF, Chen TC, Lu Z, Sauter E. (2007) Vitamin D and skin physiology: a D-lightful story. J Bone Miner Res 22, V28–33. 49 Rostan EF, DeBuys HV, Madey DL, Pinnell SR. (2002) Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol 41, 606–11.

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Part 2: Injectable Antiaging Techniques Chapter 42: Botulinum toxins Joel L. Cohen1 and Scott R. Freeman2 1 2

Department of Dermatology, University of Colorado, Englewood, CO, USA University of Colorado at Denver and Health Sciences Center, Denver, CO, USA

BAS I C CONCE P T S • Botulinum toxins are high molecular weight protein complexes that are secreted by clostridial bacteria. This substance exacts its effects by binding to and cleaving specific proteins in the presynaptic nerve terminus, thus preventing release of acetylcholine and focally preventing nerve conduction. • Currently only one type A botulinum toxin, Botox®, is approved in the USA for cosmetic use, specifically for the glabella. Botox is also approved for the treatment of axillary hyperhidrosis as well as other medical indications. • In many other areas, Botox has a favorable safety profile and is effective in treating the upper, mid, and lower face, as well as several regions of focal hyperhidrosis (axillary, palmar, plantar, facial). • Injection-related complications can largely be avoided with good technique and a detailed understanding of the regional anatomy.

Introduction Botulinum toxins are produced by the Gram-positive, sporeforming anaerobe Clostridium botulinum, and cause chemical denervation by suppressing the release of the neurotransmitter acetylcholine from the axon terminals of peripheral nerves. There are seven distinct subtypes of botulinum toxin (A–G), with types A and B being the only clinically relevant subtypes at this time. Currently, there is one botulinum neurotoxin type A (BoNTA) and one botulinum neurotoxin B (BoNTB) toxin available for human use in the USA. Botox® (Allergan, Inc., Irvine, CA, USA) is the type A toxin, and it is currently US Food and Drug Administration (FDA) approved for several therapeutic indications (including blepharospasm and strabismus). Myobloc® (Solstice Pharmaceuticals, South San Francisco, CA, USA) is currently only approved for the therapeutic treatment of cervical dystonia. Relevant to this chapter, Botox is approved for cosmetic use in the glabella (but is used off-label in various other facial sites as well), and is also approved for axillary hyperhidrosis (but is used off-label for hyperhidrosis of the palms, soles, face, and scalp). Treatment doses are not interchange-

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able for any of the botulinum products (even among other strains of type A toxin) and all references to BoNTA unless otherwise stated in this chapter refer to Botox. Clostridial bacteria secrete high molecular weight protein complexes that include three key proteins: a 150-kDa toxin, a non-toxin hemagglutinin protein, and a non-toxin nonhemagglutinin protein. The non-toxin proteins may provide the toxin complex protection against temperature or enzymatic denaturation [1]. The 150-kDa toxin is cleaved by bacterial proteases to form a di-chain composed of a 100kDa heavy chain and a 50-kDa light chain. Disulfide and non-covalent bonds link the heavy and light chains, and both chains are required for neurotoxicity [1]. In 1987, Canadian ophthalmologist Jean Carruthers recognized the cosmetic potential of BoNTA. While treating patients for benign essential blepharospasm, Dr. Carruthers noted that several patients treated for blepharospasm had significant improvement of dynamic rhytides in the periocular region. Following this observation, the husband and wife team of Drs. Alastair and Jean Carruthers began more systematic studies of BoNTA for cosmetic indications. In 1991, the Carruthers reported their initial findings of cosmetic treatment with BoNTA at North American Dermatology and Ophthalmology meetings. After initiating clinical trials, their first publication on this topic was in 1992, demonstrating the safe and effective treatment of dynamic rhytids in the glabella with BoNTA [2]. After over a decade of off-label cosmetic use in the USA, in 2003 BoNTA (Botox) was

42. Botulinum toxins approved specifically for the treatment of glabellar rhytids. Currently, off-label cosmetic uses continue to expand with regions of treatment encompassing not only the forehead and lateral canthus, but also the lower face and neck. Botox and other BoNTA are also widely used worldwide for medical and therapeutic purposes including the treatment of hyperhidrosis, headaches, spasticity disorders, and depression. This chapter highlights both traditional and newer cosmetic applications of BoNTA.

Mechanism of action The process of chemical denervation requires that the neurotoxin heavy chain bind a specific receptor on the presynaptic nerve terminal. This process leads to toxin–receptor complex endocytosis, and then subsequently to toxin light chain release through vesicle lysis [3]. While binding sites for each toxin have not been clearly defined, all toxins cause chemical denervation by suppressing the release of acetylcholine from the axon terminals of peripheral motor nerves. After vesicle lysis occurs within the axon terminus, toxin light chains ultimately prevent neurotransmission by cleaving specific protein isoforms necessary for the docking, fusion, and release of acetylcholine from this nerve terminus. Toxins A, C, and E cleave synaptosomal associated protein (SNAP-25) and toxins B, D, F, and G cleave vesicle associated membrane protein (VAMP, also known as synaptobrevin) [1]. Muscle paralysis occurs within approximately 3–7 days, and synaptic regeneration reverses the paralytic effect within 3–6 months [3].

Neurotoxin physical characteristics The complex size of Botox is approximately 900 kDa and one vial contains 5 ng (100 units) of toxin. One unit (U) is standardized to equal the median amount necessary to kill 50% of female Swiss-Webster mice after intraperitoneal injection (LD50) [3–5]. Botox is a vacuum-dried product and in addition to 100 U of toxin, each vial contains 500 μg albumin and 900 μg sodium chloride [1,5]. Typical cosmetic doses of Botox range from 10 to 60 units, depending on the number of areas treated in one session. Product characteristics of Botox compared with some of the other neurotoxins used throughout the world are provided in Table 42.1.

Table 42.1 Botulinum toxin comparison.1 Botox3

Dysport4

Myobloc5

Serotype

Molecular weight (kDa)

900

500–900

700

FDA approved for cosmetic use?

Yes

No, pending

Protein weight per vial (ng)

25, 50, or 100

Units per vial (U/mL)

100

500

5000

5.6

SNAP-25

VAMP7

Target

SNAP-25

Dosages are not equivalent between products. Food and Drug Administration. 3 Allergan, Inc., Irvine, CA, USA. 4 Ipsen Ltd, Slough, UK. (This product may be marketed as Reloxin in the USA.) 5 Solstice Pharmaceuticals, South San Francisco, CA, USA. Marketed as Neurobloc outside of the USA. 6 Synaptosomal associated protein (SNAP-25). 7 Vesicle-associated membrane protein (synaptobrevin). 2

patients showed no significant difference in the treatment of canthal lines between those treated with Botox reconstituted with sterile, non-preserved saline immediately prior to injection compared with toxin reconstituted 1 week prior to injection [6]. Further, in one study product reconstitution at times ranging 1–6 weeks prior to injection produced statistically similar results in patients treated for glabellar rhytides compared with product reconstitution 1 day prior to injection [7].

Advantages and disadvantages Botox is a drug with a large margin of safety (LD50 in humans approximately 40 U/kg), making its cosmetic use a relatively safe endeavor [8]. Care should be taken to use the necessary dosing ranges in a given region in order to optimize patient satisfaction and preserve a natural result. Injectors should possess excellent knowledge of facial anatomy, especially considering the close proximity of adjacent musculature that may not be part of the intended area of treatment.

Product stability Indications Once a vial of Botox is reconstituted, the package insert indicates viability for 4 hours (refrigerated), but recent studies suggest that product is viable for much longer when properly handled. A double-blind, randomized study of 30

At the present time, the glabella is the only FDA-approved site for the cosmetic injection of Botox, although it is also used extensively off-label for other facial esthetic areas. The

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Table 42.2 Precautions and contraindications. Precaution

Mechanism

Frontalis

Ciclosporin

Has been reported to cause neuromuscular blockade, possibly through calcium channel blockade

Corrugator supercilii

Large doses can prevent release of acetylcholine from neurons

Procerus

Aminoglycoside antibiotics

D-penicillamine

Contraindication Myasthenia gravis

May cause formation of antibodies targeting acetylcholine receptor

Autoantibodies targeting acetylcholine receptor

Lambert–Eaton syndrome

Paraneoplastic, antibodies targeting calcium channels

ALS

Neurodegenerative disease

Pregnancy or breastfeeding

Insufficient safety data

Allergy to any constituent of BoNTA

Potential for anaphylaxis

ALS, amyotrophic lateral sclerosis.

glabellar region is also the most common site of esthetic BoNTA treatment worldwide, and is a good starting point for the novice injector. Treatment of the glabellar complex frequently results in a high degree of patient satisfaction, and often patient follow-up for additional treatments in this and other areas. Aside from the glabella, other muscle groups in the upper, mid, and lower face and neck can be successfully treated “off-label” with Botox. Contraindications to BoNTA are few and are listed in Table 42.2 along with several precautionary medications [9].

Standard injection techniques General pretreatment tips Prior to treatment, patients should be informed that the typical duration of efficacy is likely to be 3–4 months, and potential side effects should be discussed. The fact that treatment of areas other than the glabella constitutes “off-label” use of Botox in the USA at the present time should be included in the consent. Consent should be in the form of an oral discussion as well as a signed, written document. Pretreatment asymmetries and scars should always be discussed, documented, and photographed prior to treatment.

Treatment of the upper face Photodamage and overactive musculature can cause changes in the upper face that convey a fatigued or angry look that is often discordant with reality. Treatment of the upper face

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Orbicularis oculi

Figure 42.1 Relevant musculature of the upper face. (Adapted from Sommer B, Sattler G, eds. (2001) Botulinum Toxin in Aesthetic Medicine. Blackwell Science, Boston, MA.)

with BoNTA can lead to a more youthful, relaxed, and rested appearance [10,11]. Data also support the use of BoNTA in multiple areas of the upper face in a single treatment session [12].

Forehead The frontalis muscle is contiguous with the galea aponeurotica of the scalp superiorly, and inserts inferiorly into the skin of the brow. Its configuration varies between individuals but it is generally considered to be either a uniform band across the forehead or V-shaped with a relative absence of fibers medially (Figure 42.1). Fibers of the frontalis are oriented vertically, and thus when they contract the brows elevate and horizontal forehead lines become imprinted in the skin over time. The lateral fibers of the orbicularis oculi muscle pull down on the lateral brow, and thus directly oppose the upward forces of the frontalis. This muscular interaction allows for the creation of a neurotoxin lateral brow lift (discussed below). A recent consensus article addressed treatment of horizontal forehead lines caused by the frontalis [13]. Authors recommended ranges of 6–15 U and 6 to >15 U BoNTA for females and males, respectively (Table 42.3), and agreed that doses over 20 U are more likely to lead to complications or patient dissatisfaction (e.g. eyebrow ptosis and patient complaints of immobility and unnatural appearance). Forehead injections of BoNTA are generally placed over 4–9 injection sites. In order to avoid eyebrow ptosis, the injections should generally not be placed any closer than 1–1.5 cm above the bony orbital rim (Figure 42.2). Patients with tall foreheads may benefit from two rows of injections, and patients with wider foreheads may also require more injection sites. Attention to the shape and positioning of the patients baseline brow is essential, and often injection sites in women are performed in an arch to try to preserve the arch of the brow below. Patients with dermatochalasis or

42. Botulinum toxins

Table 42.3 Treatment recommendations by site. Treatment site

Muscles

Typical number of injection points

Typical total units of BoNTA* Women

Men

Upper face 6 to >15

Horizontal forehead lines

Frontalis

4–9

6–15

Glabellar complex

Procerus, depressor supercilii, orbicularis oculi

5–7

10–30

20–40

Crow’s feet

Orbicularis oculi

2–5 per side

10–30

20–30

Narrow palpebral aperture

Pretarsal fibers of orbicularis oculi

1 per side

Lateral brow lift

Superolateral fibers of orbicularis oculi

1–2 per side

8–12

Bunny lines

Nasalis

1 per side

3–5

Gummy smile

Levator labii superioris alaeque nasi

1 per side

1–2

Perioral lines

Orbicularis oris

4–6 per lip

4–12

Dimpled chin

Mentalis

1–2

4–8

Downturned smile

Depressor anguli oris

1–2

6–8

Platysmal bands

Platysma

2–12 per band

20–35

Nerfertiti lift

Platysma

7 per side

28–42

Masseter hypertrophy

Masseter

5–6 per side

50–60

Mid face

Lower face

* BoNTA represents the type A botulinum toxin approved in the USA for cosmetics, Botox. All sites other than glabellar complex are “off-label” currently in the USA.

(b)

(a) Figure 42.2 Horizontal forehead lines before (a) and after (b) Botox injection.

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low-set brows should be evaluated carefully prior to injection as they represent the population most at risk of significant eyebrow ptosis and/or complaints of “heaviness” after treatment. Patients with significant etched-in lines immediately superior to their lateral brows are also patients who may frequently be advised not to have BoNTA treatment as they depend on the baseline action of the lower frontalis fibers to hoist the brow upward and away from their eyelid.

Glabella The glabellar complex (Figure 42.1) represents the site most commonly treated with BoNTA. In the USA, it is the only cosmetic site for which Botox has FDA approval. It is one of the easiest sites to treat and a good place for novice injectors to begin. Both the corrugator supercilii and the depressor supercilii originate on the nose and insert into the midbrow. These muscles draw the brow medially and downward, and thus create vertical lines in the glabella. Treatment of these brow depressors leads to relaxation of these muscles, which usually results in a medial lift of the brow to some extent. The procerus muscle originates on the nasal bridge and inserts into skin of the mid-glabella. Contraction of the procerus also pulls the medial brow down, but with the pure vertical orientation of this muscle a horizontal line becomes etched in the skin with contraction over time. Glabellar doses of Botox typically range 10–30 U in women and 20–40 U in men. Injections are most commonly placed in five specific sites: one injection in the procerus, one in each of the medial corrugators, and one in each of the lateral corrugators (Figure 42.3). Sometimes, in patients who display significant medial recruitment above the mid-brow, 1–2 additional injection sites can be helpful to avoid this central pulling. Toxin should generally not be placed any closer than 1–1.5 cm above the bony orbital rim in the mid-

pupillary line in order to try to avoid lid ptosis. Lid ptosis can occur from migration of the toxin through the orbital septum to the levator palpebrae superioris muscle (which functions to elevate the lid upwards).

Periorbital The orbicularis oculi muscle is a circular, sphincter-like muscle that surrounds the eye and functions in eyelid closure. The circularity of this muscle creates an anatomical structure composed of fibers running in multiple directions. The muscular diversity of the orbicularis oculi creates functional diversity in animation of the periorbital area. For example, the lateral and superolateral fibers of the orbicularis oculi immediately below the brow function as brow depressors. Treatment of the lateral canthal rhytides (commonly described as crow’s feet) is often satisfying for the novice injector and the patient. Because of the presence of many small vessels in the lateral periocular area, it is often recommended to place BoNTA injections superficially (even intradermally) in this region, usually creating a wheal at the injection site. For treatment of lateral, canthal rhytides, the injector typically chooses 2–5 injection points per side, depending on the prominence of the musculature of the area. The reality is that orbicularis oculi muscle prominence varies between patients, making individual assessment of anatomy and patterns of dynamic muscular lines helpful prior to treatment of each patient [14]. Typically, 5–15 units of BoNTA are injected into each side (Figure 42.4). Care should be taken to inject no closer than 0.5–1 cm to the lateral orbital rim in order to avoid migration of toxin causing unintended paralysis of ocular muscles. In a small minority of patients, pretarsal bands of the orbicularis oculi muscle can be hypertrophic at the lower lid. A hyperfunctional, pretarsal orbicularis oculi muscle can cause unsightly bands around the lower eyelid and narrow-

(b)

(a) Figure 42.3 Glabellar frown lines before (a) and after (b) Botox injection.

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42. Botulinum toxins

(a)

(b) Figure 42.4 “Crow’s feet” before (a) and after (b) Botox injection.

ing of the palpebral aperture. If treating this infraorbital, hyperfunctional musculature, it is recommended to first evaluate lower lid laxity with a “snap-test” to ensure lid competency after the muscle is weakened. Typically, 1–2 units of BoNTA are used in this pretarsal area for patients who complain of significant muscle prominence of this area, or those who desire changing the shape of their eye from an almond-type shape to that of a more rounded eye with a widened palpebral aperture. Injections are placed carefully from a lateral approach subdermally, about 3 mm below the ciliary margin in the mid-pupillary line [13]. A lateral approach in this area helps to ensure a superficial injection, and to allow the non-injecting hand to pull down the lower lid and protect the patient from movement.

Lateral brow lift In patients with downturned or ptotic lateral brows, either from dermatochalasis, overactive lateral orbicularis oculi activity pulling down on the tail of the brow, or inadvertent paralysis of the most inferior fibers of the frontalis after aggressive forehead BoNTA treatment, partial correction can sometimes be achieved with a BoNTA chemical brow lift. This lateral brow lift can be obtained by injection into the superolateral fibers of the orbicularis oculi muscle. This technique relaxes the specific aspect of the orbicularis oculi that is pulling the lateral brow downward, and carefully tries to avoid some of the adjacent inferolateral frontalis fibers just superior to the brow – as these frontalis fibers can be helpful to try to pull the lateral brow upward. To accomplish this effect the injector places 4–6 units of BoNTA in a specific spot just below the lateral infrabrow [15]. Identification of this injection site requires that the patient first elevate their brows to find the lateral margin of the frontalis muscle (known as the temporal fusion plane). Second, the patient must close their eyes forcefully in order to localize the area where the orbicularis oculi exerts maximal medial and

Figure 42.5 The lateral bow lift can be obtained by injection into the superolateral fibers of the orbicularis oculi muscle. This technique relaxes the specific aspect of the orbicularis oculi that is pulling the lateral brow downward. (Adapted from Sommer B, Sattler G, eds. (2001) Botulinum Toxin in Aesthetic Medicine. Blackwell Science, Boston, MA.)

downward pull on the lateral brow. The proper injection point is just inferior to the point of maximal pull downward on the brow, but making sure this site is at least 1–1.5 cm inferior to the most lateral fibers of the frontalis muscle (Figure 42.5). Avoiding these trailing lateral frontalis fibers allows for the preservation of the lift the lateral frontalis normally provides at baseline. Patients with more significant brow redundancy can sometimes be improved with a combination of BoNTA in conjunction with small volumes of fillers (e.g. 0.1–0.2 mL of a hyaluronic acid product) placed just below the lateral brow, but clearly those with more severe dermatochalasis can really only be effectively treated with surgical intervention.

Treatment of the mid-face Bunny lines Contraction of the nasalis muscle creates diagonal lines along the proximal nasal sidewall. This area is becoming a more common area of BoNTA treatment. Patients seeking

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treatment of these lines often have experienced the benefits of BoNTA softening the forehead, glabella, and crow’s feet and are looking to extend a more relaxed look to the midface. Identification of the muscle is straightforward and accomplished by having the patient “scrunch” their nose. Some 3–5 units of BoNTA can be placed superficially into the muscle at the medial aspect of the proximal nasal sidewall on each side of the nose. Placement of BoNTA too far laterally can lead to unwanted paralysis of the adjacent levator labii superioris aleque nasi (LLSAN), resulting in elongation or drooping of the upper lip. The final cosmetic result can often be enhanced with concomitant treatment of the procerus in some patients with more significant bunny lines that seem to be most bulky on the proximal nasal dorsum.

Softening of the nasolabial fold or “gummy smile” An overactive LLSAN can be a component of an accentuated or prominent superior nasolabial fold. Treatment of the LLSAN can be an option for young patients looking to soften the superior aspect of the nasolabial fold without using fillers or at a lower cost than fillers. A total of 1–2 units of BoNTA can often achieve a softening of the top of the nasolabial fold, and a 1992 anatomic study by Pessa illustrated that the LLSAN is actually the more important muscle contributing to the prominence of the nasolabial fold. Higher doses (typically 3–5 units) of BoNTA are usually used at the same location for patients with significant gummy smiles. Injection of 3–5 units per side of BoNTA into the belly of LLSAN at the pyriform aperture can elongate the upper cutaneous lip and partially correct the excessive gingival display [16]. Doses of 5–7.5 units of BoNTA in patients with very severe gummy smiles have been reported [16]. In cases of a prominent nasolabial fold or a gummy smile, injection of the LLSAN is primarily a treatment for younger patients who can compensate for the resulting pronounced elongation of the cutaneous lip with other musculature. In addition to the LLSAN, the muscles responsible for the elevation of the upper lip particulary in younger individuals are the levator labii superioris, levator anguli oris, zygomaticus major and minor, and the depressor septi nasi. Older patients seem to be more reliant on primarily the levator labii muscles alone.

Treatment of the lower face Perioral lines The lips are the cosmetic focal point of the lower face and careful, conservative corrections can often dramatically improve aspects of an aging face. Vertical “etched in” lines of the perioral skin are common and are caused by years of contraction of the orbicularis oris muscle, a sphincter-like muscle that encircles the mouth. Etched in lines are preceded by years of vertical muscle columns in women, leading

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eventually to imprinting of the perioral skin. The skin in this area is highly innervated and vascular, and therefore injections into this region are generally associated with more discomfort and can be associated with bruising or swelling. Topical anesthetics and the application of ice-packets can be very beneficial. Tenants of injecting BoNTA into the lips include: use of low doses with frequent follow-up for retreatment, preservation of symmetry utilizing photography and carefully placed injections, treatment of both upper and lower lips at the same time, and avoidance of midline injections to preserve the desirable Cupid’s bow. Injection technique varies depending on individual anatomy, but typical treatments include four superficial injection sites in the upper lip (two points on each side of the upper lip) just above the vermillion border. In patients with more significant vertical muscle columns (taller, bulkier, deeper) sometimes an additional site on each side of the upper lip (often 1 cm above the vermillion border) can be helpful. For the lower lip, usually four superficial injection sites are performed as well (two sites on each side of midline approximately 1.5 cm apart). It is important to inject superficially and use lower dosages, especially for a patient’s first treatment. Follow-up 2 weeks later will typically allow the injector to see if additional units may be helpful. Some have advocated doses for perioral injection to be in a range of 4–5 units [13], but the authors sometimes use a total of 10–12 units for patients with more significant perioral vertical muscle columns.

Dimpled chin The mentalis muscle originates in the incisive fossa and inserts into the skin of the chin. Contraction of this muscle can create a dimpled appearance of the chin that has been termed “pebbled chin,” “golfball chin,” “peau d’ orange chin,” and “apple dumpling chin.” A total of 4–8 U of BoNTA, placed as a single midline injection or in two points 0.5 cm lateral to midline at the bony part of the chin can be very effective. Product placed too far laterally risks paralysis of the depressor labii inferioris and can cause speech problems.

Downturned smile Descent of the lateral commisures of the mouth can result from gravity and volume loss and sometimes from hypertrophy of the depressor anguli oris (DAO) muscle. Injection of BoNTA (3–4 units per side) into the posterior aspect of the DAO in a single injection site can sometimes partially correct this appearance of a downturned smile (Figure 42.6). Complications associated with medial diffusion or injection of BoNTA into the depressor labii inferioris are discussed below. DAO prominence is often associated with volume loss of the lower face, and in our experience combination treatment with fillers and BoNTA is more consistently effective than BoNTA alone.

42. Botulinum toxins

DAO

Figure 42.6 Treatment of a downturned smile is accomplished by injection into the posterior fibers of the depressor anguli oris (DAO) muscles. (Adapted from Sommer B, Sattler G, eds. (2001) Botulinum Toxin in Aesthetic Medicine. Blackwell Science, Boston, MA.)

ment. Local adverse effects included masticatory difficulties (44% of patients) and speech disturbance (16% of patients). All side effects were transient. A study specifically measuring bite force in patients treated with 25 units of BoNTA per masseter (50 units total) reported significant bite-force reduction at 2, 4, and 8 weeks postinjection (p < 0.05) [20]. Difference in bite-force reduction was not statistically significant at the 12-week measurement, and while bite-force measurements trended upward, they still did not achieve preinjection values at the end of 12 weeks. So while injection can beneficially alter the shape of the masseter, it may alter mastication. Further study is needed to better define the duration and significance of the observed bite-force reduction.

Platysmal bands The platysma is a thin, superficial muscle that can create vertical bands in the neck which are displeasing to many patients. Patient selection is key to successful treatment of this condition, and the most appropriate candidates are those with prominent vertical bands at rest. A typical treatment session includes injection of 2–3 bands with 20–35 U of BoNTA total (2–12 injection points per band). Dysphagia is a rare complication that has been reported with cosmetic use of BoNTA for treatment of platysmal bands [17]. Conservative treatment, with low dosages and superficial injections, is recommended in order to avoid this very rare and disturbing complication that can persist for weeks. Marking injection points and pinching the band between the thumb and forefinger can aid in the precise superficial placement of BoNTA. In addition to the treatment of platysmal bands, placement of toxin along the inferior margin of the mandible and in the superior aspect of the posterior platysmal band may redefine the mandibular border. This procedure has been termed the “Nefertiti lift” and was described by Levy in a study of 130 patients [18]. Patients were treated with 2–3 units of BoNTA per injection site, with five sites being along the margin of the mandible and two sites being in the superior aspect of the posterior platysmal band. It was hypothesized that the resultant sharpening of the mandibular border was secondary to partial reversal of the chronic downward pull on the cheeks by the platysma.

Masseter hypertrophy Prominent masseter bulk over the posterior mandible can create a squared-off shape to the face which is not desirable to some people. A study of 45 patients with masseter hypertrophy were treated with BoNTA and followed for 10 months [19]. Twenty-five to 30 units of BoNTA were injected into each masseter in 5–6 injection points. The maximum reduction in masseter thickness as measured by ultrasound was seen at 1 month and CT scan found continued reduction of masseter muscle thickness up to 3 months after treatment. Eighty-two percent of patients were satisfied with the treat-

Combination of BoNTA with fillers While BoNTA treatment works well for dynamic rhytides, resting lines and volume loss are not corrected by neurotoxin placement alone. Combination treatment consisting of hyaluronic acid and BoNTA often yield impressive results and may double the duration of response compared with filler treatment alone in some areas [21]. Combination therapy can be useful in the glabella, periorbital area, perioral, mentalis, and sometimes the nasolabial creases. Placement of filler prior to BoNTA treatment may decrease untoward migration of toxin caused by massage of the filler and the common practice of confirming placement of the filler product after injection. Areas lending themselves to combination treatment as well as injection tips are presented in Table 42.4.

Complications and management Bruising, swelling, and mild asymmetry are commonly encountered issues. Less common is migration of toxin to adjacent but unintended musculature, which can result in significant asymmetry. Eyebrow ptosis can occur from toxin placement too close to the brow in the frontalis muscle, poor patient selection and use of higher dosages in the forehead. In fact, a recent consensus publication recommended using about half the frontalis dose of BoNTA previously suggested in an earlier statement by the same group [13]. Eyelid ptosis is also uncommon (less than 1% of patients in the hands of experienced injectors) and presumably occurs when injecting the lateral corrugator area, with migration of toxin through the orbital septum leading to the paralysis of the levator palpebrae superioris. This is a transient event (generally resolving by 2–3 weeks) and can be treated to some extent, but often not fully, by using ophthalmic drops such as Naphcon (Alcon, Fort Worth, TX, USA) (can be purchased over-the-counter) which exert mild

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Table 42.4 Combination therapy with BoNTA and fillers. Treatment area

Filler tip

Glabella

Prefer non-cross-linked collagen products* placed superficially and hyaluronic acid products with small particle size. Polymethylmethacrylate (Artefill), calcium hydroxylapatite (Radiesse), poly L lactic acid (Sculptra) and silicone should only be used by very experienced injectors in this area

Crow’s feet

Thin skin requires thin product such as non-cross-linked collagen agent* or a hyaluronic acid designed for superficial placement in small aliquots with 32-gauge needle

Perioral lines

Prefer collagen products (type depending on depth of wrinkle) or hyaluronic acid of small particle size. Polymethylmethacrylate (Artefill), calcium hydroxylapatite (Radiesse), poly L lactic acid (Sculptra) and silicone should only be used by very experienced injectors in this area and still should not be placed shallowly

Downturned smile/marionette lines

Correction of downturned smile with BoNTA can be enhanced with filler placement in the marionette lines. Useful agents in this area include collagens, hyaluronic acids, silicone, poly L lactic acid and calcium hydroxylapatite. Choice of filler depends on skill and experience of the injector

Mentalis

Choice of filler depends on skill and experience of the injector

* Zyderm I or II and Cosmoderm I or II.

adrenergic effects, or Iopidine (Alcon, Fort Worth, TX, USA) prescription drops [22]. The mechanism of both treatments is adrenergic stimulation and contraction of the adjacent Mueller’s muscle which can partially raise the eyelid. Iopidine may mask underlying glaucoma so this treatment should be reserved for short periods of treatment such as 3–5 weeks, as the eyelid ptosis is transient in nature [22]. In a double-blind, placebo-controlled, glabellar study, headache occurred in 20% of patients in the placebo group vs. 11.4% in the BoNTA treated group, leading authors to conclude that headache was likely related to trauma from the injection itself [23]. A non-blinded case series of 320 patients treated for cosmetic reasons with BoNTA reported the occurrence of severe, debilitating headaches in 1% of patients treated [24]. In this study, these headaches occurred within 2 days of injection with BoNTA and persisted at a high level for 2 weeks to 1 month after injection. As far as bruising and swelling, it is best to wipe off the patient’s make-up prior to injection (particularly in the lateral canthal area), to best identify little veins in the area

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to better avoid them and to avoid the risk of introducing foreign make-up material into the skin. Ice prior to injection to facilitate vasoconstriction is also very helpful in helping to reduce the mild pain of the injections themselves. If patients are on medications or vitamins for preventive purposes that may have an anticoagulant type of effect, it is certainly helpful if they discontinue these agents a few days prior to injection. An example of such an agent would be the use of aspirin as a preventive measure in patients lacking a history of atherosclerotic disease, stroke, or clot. Immunogenicity to BoNTA has been reported in the literature but is very rare in patients treated with the newer (post-1997) formulation of BoNTA. The newer formulation of Botox has only 20% of the protein content that the older batch had (pre-1997) and presumably has made the product significantly less immunogenic. One case report, however, describes neutralizing antibody formation to the post-1997 formulation of Botox in a patient treated cosmetically for masseter hypertrophy [25]. Presence of neutralizing antibody was supported by two positive mouse protection assays and by ELISA testing [25]. Risks associated with immunogenicity are very large doses of toxin (more frequent in therapeutic uses of BoNTA) and short intervals (less than 3 months) between high-dose injections [1]. Generalized reactions have been reported related to toxicity and include headache, nausea, malaise, fatigue, flu-like symptoms, and rashes distant to injection sites from improper dosages and the use of “experimental strains of botulinum toxin” [26]. In studies measuring complications in patients treated with legitimate BoNTA, adverse events occurred in similar frequencies in both treatment and placebo groups. Most post-injection issues are transient in nature and resolve spontaneously, requiring no intervention other than reassurance.

Upper face Injection into the frontalis muscle can lead to brow ptosis, and patients can develop a quizzical look (raising of the lateral brow because of residual non-treated frontalis fibers pulling upward) if only medial fibers of the frontalis are treated. This “Mr. Spock” look can usually be easily treated with placement of 1–2 units in each side of the lateral functional frontalis. In addition, patients can rarely experience painful electric shock-like sensations if the supraorbital or supratrochlear sensory nerves are inadvertently hit with the injection needle.

Lower face Treatment of the orbicularis oris muscle for correction of vertical lip lines can very rarely lead to drooling or difficulty with phonation. Thus, when treating vertical muscle columns caused by a hyperfunctional orbicularis oris muscle, care should be taken to use lower dosages and avoid overtreatment. In addition, medial placement of these injections

42. Botulinum toxins can help avoid unintended musculature being affected, especially near the oral commissure. Correction of downturned smile is best accomplished with careful BoNTA placement in the posterior aspect of the depressor anguli oris muscle. This posterior placement helps avoid unintended medial migration and effect on the depressor labii inferioris, a complication that can cause slurred speech and drooling and lasts weeks to months [27]. As far as the neck, injection of BoNTA into the neck for softening of platysmal bands has in one report led to prolonged dysphagia secondary to paralysis of the deeper strap muscles requiring placement of nasogastric tube [17]. This event can be best avoided by following the recently revised recommendations presented in this chapter. Even the most experienced of injectors may observe asymmetric treatment effect, despite consistent technique. This unbalanced appearance is usually easily corrected with additional enhancement injections. Finally, temporary strabismus or diplopia are extremely rare and infrequently reported, and likely occur by either large diffusion or direct injection of toxin into the extraocular muscles.

11 12 13

17 18 19

References 1 Huang W, Foster JA, Rogachefsky AS. (2000) Pharmacology of botulinum toxin. J Am Acad Dermatol 43, 249–59. 2 Carruthers JDA, Carruthers JA. (1992) Treatment of glabellar frown lines with C. botulinum exotoxin. J Dermatol Surg Oncol 18, 17–21. 3 Sadick NS, Matarasso SL. (2004) Comparison of botulinum toxins A and B in the treatment of facial rhytides. Dermatol Clin 22, 221–6. 4 Ting PT, Freiman A. (2004) The story of Clostridium botulinum: from food poisoning to Botox®. Clin Med 4, 258–61. 5 Matarasso SL. (2003) Comparison of botulinum toxin types A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg 29, 7–13. 6 Lizarralde M, Gutierrez SH, Venegas A. (2007) Clinical efficacy of botulinum toxin type a reconstituted and refrigerated 1 week before its application in external canthus dynamic lines. Dermatol Surg 33, 1328–33. 7 Hexsel DM, Trindade de Almeida A, Rutowitsch M, et al. (2003) Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to 6 consecutive weeks before application. Dermatol Surg 29, 523–9. 8 Scott AB, Suzuki D. (1988) Systemic toxicity of botulinum toxin by intramuscular injection in the monkey. Mov Disord 3, 333–5. 9 Cote TR, Mohan AK, Polder JA, Walton MK, Braun MM. (2005) Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases. J Am Acad Dermatol 53, 407–15. 10 Cox SE, Finn JC, Stetler L, Mackowiak J, Kowalski JW. (2003) Development of the Facial Lines Treatment Satisfaction

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Questionnaire and initial results for botulinum toxin type A-treated patients. Dermatol Surg 29, 444–9; discussion 449. Finn JC, Cox SE, Earl ML. (2003) Social implications of hyperfunctional facial lines. Dermatol Surg 29, 450–5. Review. Flynn TC. (2006) Update on botulinum toxin. Semin Cutan Med Surg 25, 115–121. Carruthers J, fa*gien S, Matarasso SL, and the Botox Consensus Group. (2008) Advances in facial rejuvenation: botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies: consensus recommendations. Plast Reconstr Surg 121 (Suppl), 5–30S. Kane MA. (2003) Classification of crow’s feet patterns among Caucasian women: the key to individualizing treatment. Plast Reconstr Surg 112(Suppl), 33–9S. Cohen JL, Dayan SH. (2006) Botulinum toxin type A in the treatment of dermatochalasis: an open-label, randomized, dosecomparison study. J Drugs Dermatol 5, 596–601. Kane MA. (2003) The effect of botulinum toxin injections on the nasolabial fold. Plast Reconstr Surg 112 (Suppl), 66–72S; discussion 73–4S. Carruthers J, Carruthers A. (1999) Practical cosmetic Botox techniques. J Cutan Med Surg 3 (Suppl 4), S49–52. Levy PM. (2007) The “Nefertiti lift”: a new technique for specific re-contouring of the jawline. J Cosmet Laser Ther 9, 249–52. Park MY, Ahn KY, Jung DS. (2003) Botulinum toxin type A treatment for contouring of the lower face. Dermatol Surg 29, 477–83. Ahn KY, Kim ST. (2007) The change of maximum bite force after botulinum toxin type a injection for treating masseteric hypertrophy. Plast Reconstr Surg 120, 1662–6. Carruthers J, Carruthers A. (2003) A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg 29, 802–9. Klein AW. (2003) Complications, adverse reactions, and insights with the use of botulinum toxin. Dermatol Surg 29, 549–56. Carruthers JD, Lowe NJ, Menter MA, Gibson J, Eadie N, Botox Glabellar Lines II Study Group. (2003) Double-blind, placebocontrolled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines. Plast Reconstr Surg 112, 1089–98. Alam M, Arndt KA, Dover JS. (2002) Severe, intractable headache after injection with botulinum a exotoxin: report of 5 cases. J Am Acad Dermatol 46, 62–5. Lee S. (2007) Antibody-induced failure of botulinum toxin type A therapy in a patient with masseteric hypertrophy. Dermatol Surg 33 (1 Spec No.), S105–10. Bootleg Botox sentences. New York Times January 27, 2006. Available at: http://query.nytimes.com/gst/fullpage.html?res59 B02EFDB113FF934A15752C0A9609C8B63. Accessed November 26, 2007. Cohen JL. (2007) Botulinum neurotoxin clinical update. Cosmet Dermatol 20, S3.

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Chapter 43: Hyaluronic acid fillers Mark S. Nestor Center for Cosmetic Enhancement, Aventura, FL, and University of Miami Miller School of Medicine, Miami, FL, USA

BAS I C CONCE P T S • Hyaluronic acid fillers are used for 86% of the volume enhancing procedures performed in the USA. • Hyaluronic acid filler are popular because they are non-permanent but long-lasting, have few allergic aspects, minimal side effects, are relatively painless to inject, and can be reversible. • Hyaluronic acid is a polysaccharide, specifically a glycosaminoglycan, that is formed from repeating D-glucuronic acid and D-N-acetylglucosamine disaccharide units. The disaccharide units are linked together in a linear chain forming a large polymer with a total molecular weight of greater than 10 MDa. • The different hyaluronic acid fillers possess various hyaluronic acid concentrations, sizes of particles, gel consistencies, type of cross-linking, degree of cross-linking, and the degree of gel hardness. • Hyaluronic acids are injected in the deep dermis for optimal volume replacement.

Introduction The appearance of the aging face is a compilation of intrinsic aging; influenced by genetics causing the preprogrammed loss of fat, muscle, and bone as well skin elasticity changes, and extrinsic aging; primarily photodamage that affects collagen, elastin, and accelerates the intrinsic aging process [1]. One of the hallmarks of the aging face is the loss of tissue volume and as well as the accentuation of lines and folds [2]. While many procedures can be used to improve the appearance of the aging face, the use of soft tissue, dermal fillers has become one of the most popular ways of filling lines and wrinkles as well as replacing volume in the aging face [3]. According to recent statistics of the American Society of Aesthetic Plastic Surgeons, the use of dermal fillers is only second to Botox® (Allergan, Inc., Irvine, CA, USA) as one of the most popular non-surgical cosmetic procedures performed in 2007. Of all the dermal fillers used in the USA, hyaluronic acid fillers accounted for nearly 86% of fillers used [4]. While hyaluronic acid fillers might not be the “perfect” filler in all aspects, they come very close to what most patients and physicians look for in the ideal filler, namely non-permanent but long-lasting, having few if any allergic aspects, minimal side effects, relatively painless to inject, and safe because of the reversible nature of hyaluronic

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acid fillers. This chapter outlines the science and use of hyaluronic acid fillers including: 1 The chemical composition and physical properties of hyaluronic acid fillers. 2 The indications for the variety of Food and Drug Administration (FDA) approved fillers. 3 Injection techniques, both beginner and advanced. 4 Complications of filler injections and their solutions. 5 Future uses and indications for hyaluronic acid fillers.

Chemical composition and properties of hyaluronic acid fillers At this time, there are nine FDA approved hyaluronic acid fillers used in the USA. These are listed in Table 43.1. All hyaluronic acid fillers are formed from either bacterial-based or animal-based hyaluronic acid. Hyaluronic acid is a polysaccharide, specifically a glycosaminoglycan, that is formed from repeating D-glucuronic acid and D-Nacetylglucosamine disaccharide units. The disaccharide units are linked together in a linear chain forming a large polymer with a total molecular weight of greater than 10 MDa. While both animal-based and bacterial-based hyaluronic acid fillers are on the market, the vast majority of utilized fillers are based on bacterial production. Native hyaluronic acid would break down very quickly if injected into the skin and needs to be altered and stabilized primarily by cross-linking to have a long resident life in the skin. Because the basis of all bacterial-based dermal fillers is the same, the difference of the fillers and their properties depend upon the type and

43. Hyaluronic acid fillers

Table 43.1 Food and Drug Administration (FDA) approved fillers. Allergan Juvéderm™ Ultra/Juvéderm™ Ultra Plus Captique/Hylaform/Hylaform Plus (phasing out) Anika Therapeutics Hydrelle™ Medicis Restylane® Perlane® Mentor Prevelle™ Silk

degree of cross-linking as well as the manufacturing process that forms the ultimate filler [5]. The important chemical and physical properties of the different filler substances include as noted, the type and degree of cross-linking, the total hyaluronic acid concentration, the size of the particle and/or the consistency of the gel, and the degree of gel hardness or G prime.

Cross-linking The most commonly used hyaluronic acid products in the USA use 1, 4-butanediol diglycidyl ether (BDDE) as crosslinking agents. This includes Juvéderm® (Allergan, Inc., Irvine, CA, USA), Perlane®, and Restylane® (Medicis Aesthetics, Inc., Scottsdale AZ, USA), which are the most commonly used hyaluronic acid products in the USA. Hydrelle™ (Anika Therapeutics, Bedford, MA, USA) uses a different cross-linking agent called biscarbodiimide (BCDI). The degree of cross-linking indicates the percentage of hyaluronic acid disaccharide monomer units that are bound to a cross-linking molecule. For hyaluronic acid fillers, some feel that when all factors are equal, a higher degree of a cross-linking agent may translate into a longer persistence of the filler. However, there are questions about the effect that the cross-linking has on biocompatibility, setting the filler as a foreign substance. Therefore there may be an optimal degree of cross-linking that may give the longest term residence in the skin without causing biocompatibility issues.

Hyaluronic acid concentration Total hyaluronic acid concentration refers to the amount of hyaluronic acid per milliliter in a product. It generally measures both cross-linked hyaluronic acid and free hyaluronic acid in a product. Free hyaluronic acid or uncross-linked

hyaluronic acid is generally added in varying amounts to some products to improve lubrication or product flow. The most widely used hyaluronic acid products are of similar concentration but may vary as to the degree of free or uncross-linked hyaluronic acid, gel hardness, and hyaluronic acid gel consistency. The two most popular hyaluronic acid products, Restylane and Juvéderm, are produced by different mechanical means. The Restylane product line is pressed through screens to split the molecules into different size particles. Juvéderm is manufactured in a way that hom*ogenizes the particles in a blender-type apparatus. The different formulations and production strategies yield different gel hardness or G prime to the variety of different products. Clinically, G prime can be thought of both as the amount of force that is necessary to inject a product through a specificsized needle, as well as the lifting capacity of the filler. In general, fillers that are thicker are more difficult to inject through smaller needles, but based on their properties can act to bring in more water and thus cause more tissue lifting in a given area.

Indications Virtually all fillers are FDA approved to fill “moderate to severe lines and folds” such as the nasolabial fold. Historically, fillers such as collagen were used to fill fine lines and wrinkles including those in the perioral and periorbital regions. Collagen fillers were injected in the mid-dermis and usually had a clinical life in the skin of approximately 3–6 months. Hyaluronic acid fillers are generally injected deeper in the skin, most often below the dermis in the superficial subcutaneous layer and traditionally have primarily been indicated for deeper lines and folds [6,7]. Hyaluronic acid fillers cannot be injected very superficially because of a complication known as the Tyndall effect; whereby the filler appears as a blue hue directly under the skin [8]. The majority of hyaluronic acid fillers used to date were initially used in the nasolabial fold, mesiolabial fold, as well as other similar lines and folds in the face. Over the last 3–4 years, the use of hyaluronic acid fillers has also eclipsed into volume replacement. Thicker hyaluronic acid fillers such as Perlane and Juvéderm Ultra Plus are indicated to replace volume in areas such as the midface and lower face to replace volume lost in both the intrinsic and photoaging process. Hyaluronic acid fillers may be used to augment areas such as the lips by both replacing lost volume with aging and enhancing lip volume. Additionally, fillers are used to replace volume in areas such as the hands and resculpt and act as reshaping agents in areas such as the nose and the chin [9,10]. Hyaluronic acid fillers have significant advantage for these indications because of their longevity and overall low incidence of inflammation and significant swelling.

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Injection techniques Fillers in general are injected using three basic techniques: 1 Droplet injection; 2 Linear threading, either antegrade or retrograde; 3 Fanning. As noted, the majority of hyaluronic acid are injected either in the deep dermis or superficial subcutaneous layer and studies have shown that the vast majority of injections are in the subcutaneous layer [7]. Most injectors use a combination of injection techniques depending upon the specific area that is being injected. Studies have shown that slower injection techniques tend to decrease side effects and swelling as well as decrease patient discomfort [11]. Patients are usually prepared by cleansing the area either with alcohol or another anti-infective topical cleansing substance. A topical anesthethic is often used either in the form of topical lidocaine, or compounded topicals that may include lidocaine and benzocaine. Many injectors also use cooling methods to both decrease pain of injection, as well as decrease swelling and bruising. As the injector gets more comfortable, advanced injection techniques, specifically with regard to volume, may utilize the use of large volumes of hyaluronic acid filler to replace and sculpt volume in areas of loss and these injections may take place in the deeper subcutaneous tissue or under the muscle layer. Injection sites that may be under the muscle include the tear troughs and malar regions.

Complications Possible complications of hyaluronic acid fillers include unevenness of the filler substance, inflammation, swelling, and bruising, injection of the hyaluronic acid filler too superficially in the dermis, and, rarely, abscesses, both bacterial and sterile [12]. Swelling and bruising can be thought of by some as complications, but are usually normally associated with any filler injection. Depending upon the injection technique, swelling and bruising may be common but can often be mitigated by the use of ice as well as the use of a slow injection technique. Patients should be warned that they certainly can experience some swelling and bruising for at least the first 48 hours after injection. The most common type of complication is the unevenness of hyaluronic acid fillers. The clinician needs to evaluate a patient and understand very clearly the needs of that patient and proper injection technique to minimize unevenness. Patients are not symmetrical and they often may need differing amounts of hyaluronic acid on one aspect of the face versus the other. It is also very important that the filler is massaged and the clinician can feel whether the various

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areas of the face are even upon completion of the injection of the filler. If a patient comes back in or is referred for unevenness, there are two methods of correcting this complication. The first is to simply inject more filler to correct the imbalance, and the second is the use of hyaluronidase to dissolve the uneven filler. Most unevenness can be adjusted by injecting small amounts of filler in the contralateral side to even; however, when bumps and areas are too apparent or uneven, hyaluronidase, usually in 25–50 units can be injected and within 48 hours the area of unevenness or of bulging can be dissolved. When a filler is injected too superficially and a Tyndall effect occurs, often it can be extruded by making a small puncture with a 25 gauge needle and massaging the filler through the opening. If this fails, hyaluronidase can be used to dissolve the filler. Finally, in those rare cases of sterile abscess or long-term inflammation, topical anti-inflammatories can be used; if they fail, the use of clarithromycin may also be effective.

Treatment optimization: persistance of dermal fillers and in vivo collagen stimulation Hyaluronic acid fillers injected as a single treatment in the nasolabial fold, with or without one touch-up 1–2 weeks later usually just for the initial treatment, persists in a subset of patients for up to 12 months or longer [13]. It has generally been hypothesized that the prolonged efficacy of stabilized hyaluronic acid fillers versus injectable substances such as collagen is attributed to the sustained persistence of the product in the skin because of the effect that cross-linking has on limiting breakdown from in vivo hyaluronidase. However, new data indicate that, in addition to residual product left at each reinjection which provides a base, hyaluronic acid fillers can stimulate collagen synthesis and inhibit collagen breakdown, which can contribute to their persistence and correlates with physician observations that patients require less overall filler over time to retain optimal correction. A landmark study by Narins et al. [14], which is the basis for a new FDA approval for Restylane for up to 18 months, may provide a key piece of evidence to show that full correction followed by a single optimizing treatment can not only optimize longevity and in turn patient satisfaction, but also may enhance the patient’s in vivo collagen stimulation. This paper is an 18-month interim analysis of a 30-month study to evaluate efficacy and persistence of nonanimalized, stabilized hyaluronic acid 100 000 gel particles/ mL filler based on different retreatment schedules. The results in this study seem to indicate initial full correction of the nasolabial folds, followed by an optimizing treatment at an interval between 4 and 9 months, causes improved

43. Hyaluronic acid fillers long-term persistence of the filler and may indicate that full correction followed by retreatment at optimum treatment intervals may enhance the patient’s own in vivo collagen stimulation. This hypothesis is supported by in vivo studies by Wang et al. [15] who demonstrated that NAHSA (non-animal stabilized hyaluronic acid) 100 000 gel particles/mL hyaluronic acid filler can induce synthesis of type I collagen probably by stretching fibroblasts. The effect of optimizing treatments intervals to enhance in vivo collagen stimulation is consistent with Wang et al.’s data and is further supported by data with other types of treatments that cause collagen stimulation in vivo, namely laser, light, and radiofrequency devices. The data by Narins et al., as well as Wang et al., leads to a new paradigm in the use of dermal hyaluronic acid fillers. Up until now, the standard for esthetic correction using hyaluronic acid dermal fillers has been to inject fillers to replace lost volume and to replace the fillers as they slowly degraded. These data may indeed indicate a new treatment approach. Optimizing initial treatment by achieving full correction and thereby stretching fibroblasts and maximally stimulating collagen synthesis, followed by a second optimizing treatment, perhaps at an interval of 4–9 months, may lead to long-term benefit and a continued enhancement effect by the hyaluronic acid filler. It is possible that with each touch-up injection set the product builds up on a base already there, the metabolism of filler degradation decreases, and collagen production is continually stimulated.

Conclusions The use of dermal fillers, and hyaluronic acid fillers specifically, has become a mainstay in the treatment of the aging face. Hyaluronic acid fillers can be used safely and effectively in treating a variety of aspects of the aging face including folds and wrinkles as well as replacing lost volume. Hyaluronic acid fillers can also be used to sculpt areas such as the chin, the nose, tear troughs, and the eyebrows to enhance features in a non-invasive, completely reversible procedure. Over the next 2 years, there will probably be another four or five hyaluronic acid fillers approved in the USA. The near future will bring the addition of lidocaine to fillers that are already approved in the USA to decrease discomfort both upon injection and tenderness in the injection sites post-injection. New hyaluronic acid products will also look to have characteristics that will increase their use and utilization and may also increase their effective time in the skin. Finally, new treatment paradigms such as initial treatment followed by an optimization treatment within 6

months may cause long-term improvements and optimize in vivo collagen synthesis. Hyaluronic acid fillers will continue to be the mainstay of treatment for static folds, lines, wrinkles, and volume replacement in the near future.

References 1 Chung J, Soyun C, Sewon K. (2004) Why does the skin age? Instrinsic aging, photoaging, and their pathophisiology. In: Rigel DS, Weis RA, Lim HW, Dover JS, eds. Photoaging. New York: Marcel Dekker, pp. 1–13. 2 Rohrich RJ, Pessa JE. (2008) The fat compartments of the face: anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg 121, 1061. 3 Brandt FS, Cazzaniga A. (2008) Hyaluronic acid gel fillers in the management of facial aging. Clin Interv Aging 3, 153–9. 4 American Society for Aesthetic Plastic Surgery. (2007) Statistics on Cosmetic Surgery. 5 Tezel A, Fredrickson GH. (2008) The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 10, 35–42. 6 Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. (2003) A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane® versus Zyplast® for the correction of nasolabial folds. Dermatol Surg 29, 588–95. 7 Arlette JP, Trotter MJ. (2008) Anatomic location of hyaluronic acid filler material injected into nasolabial fold: a histologic study. Dermatol Surg 34, S56–63. 8 Narins RS, Jewell M, Rubin M, Cohen J, Strobos J. (2006) Clinical conference. Management of rare events following dermal fillers: focal necrosis and angry red bumps. Dermatol Surg 32, 426–34. 9 Gold MH. (2007) Use of hyaluronic acid fillers for the treatment of the aging face. Clin Interv Aging 2, 369–76. 10 Beer KR. (2006) Nasal reconstruction using 20 mg/ml crosslinked hyaluronic acid. J Drugs Dermatol 5, 465–6. 11 Glogau RG, Kane MA. (2008) Effect of injection techniques on the rate of local adverse events in patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg 34, S105–9. 12 Cohen JL. (2008) Understanding, avoiding, and managing dermal filler complications. Dermatol Surg 34, S92–9. 13 Lupo MP, Smith S, Thomas J, Murphy DK, Beddingfield FC 3rd. (2008) Effectiveness of Juvéderm Ultra Plus dermal filler in the treatment of severe nasolabial folds. Plast Recontr Surg 121, 289–97. 14 Narins RS, Dayan SH, Brandt FS, Baldwin EK. (2008) Persistence and improvement of nasolabial fold correction with nonanimalstabilized hyaluronic acid 100,000 gel particles/mL filler on two retreatment schedules: results up to 18 months on two retreatment schedules. Dermatol Surg 34, S2–8. 15 Wang F, Garza LA, Kang S, Varani J, Orringer JS, Fisher GJ, Voorhees JJ. (2007) In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 134, 155–63.

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Chapter 44: Calcium hydroxylapatite for soft tissue augmentation Stephen Mandy Volunteer Professor of Dermatology, University of Miami, Miami, FL, and Private Practice, Miami Beach, FL, USA

BAS I C CONCE P T S • Calcium hydroxylapatite is a fibroplastic filler in which volume correction is achieved in part through the biologic response of the host. • Calcium hydroxylapatite is approved for correction of moderate to severe wrinkles and folds, treatment of HIV-associated lipoatrophy, and vocal fold insufficiency. • The injectable filler is composed of microspheres of calcium hydroxylapatite suspended in an aqueous carrier gel. • Ideal areas for correction with calcium hydroxylapatite are the malar eminences, center of the cheek, nasolabial and nasojugal (tear trough) folds, prejowl sulcus/marionette, and chin and jawline regions. • Filler duration is documented for as long as 12 months, although some loss of correction may occur.

Introduction Facial volume loss leads to dramatic changes in appearance resulting from aging, disease, or hereditary conditions. The deflation from lipoatrophy causes skin redundancy, which is compounded by loss of elasticity and collagen degeneration from solar radiation and oxidative damage. Skeletal bone resorption further leads to deflation, enlargement of the ocular orbit, and shrinkage of the jaw. These visual signs of aging cannot be corrected by surgical tightening without volumization as this procedure alone leads to a skeletal, windswept appearance. Replacement of volume through soft tissue augmentation can often offer facial rejuvenation with or without surgery. A variety of suitable materials for soft tissue augmentation exists. Natural fillers, such as collagen, hyaluronic acid, and calcium hydroxylapatite (CaHA), are synthesized to mimic, or are derived from biologic materials. Synthetic fillers may be permanent, such as acrylates and silicone, or biodegradable, such as poly-L-lactic acid [1].

Physiology and pharmacology CaHA is a new type of fibroplastic filler in which volume correction is achieved in part through the biologic response of the host. Radiesse® (Bioform Medical, San Mateo, CA,

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USA) is an injectable filler composed of microspheres of 30% CaHA suspended in an aqueous gel consisting of water, glycerin, and sodium carboxymethylcellulose. Once injected, the gel carrier is soon absorbed. The remaining microspheres are 25–45 μm in diameter, which facilitates injection but resists immediate phagocytosis. These bioceramic spheres have no antigenicity, foreign body or giant cell response, and cause a minimal inflammatory reaction. They do not stimulate ossification. Although visible on X-ray images and magnetic resonance imaging scans, they are radiolucent, appearing somewhat like frosted glass, and pose no impediment to radiologic analysis. The CaHA microspheres form a scaffold for the fibroplastic proliferation, which provides the natural tissue feel of the implant. The local fibroplastic response results in the fibrous encapsulation of the particles and their gradual dissolution into calcium and phosphate ions (Figures 44.1–44.3) [2].

Indications and techniques CaHA is a thick, white, clay-like, cohesive material intended for subdermal injection. The density of the material would make intradermal injection difficult because of poor tissue intrusion into the dermal stroma. It is not intended or suitable for fine lines, superficial injection, or injection into highly mobile areas such as the lip or above the orbital rim, where accumulation of material from movement might result in nodule formation. Because of its density the filler is most easily injected through a 27-g standard needle or a 28-g wide bore (Exel®) needle. It is most commonly injected in a linear retrograde fashion following penetration of the

44. CaHA for soft tissue augmentation

Figure 44.1 Calcium hydroxylapatite microspheres, 25–45 μm in diameter. (Illustration courtesy of BioForm Medical.)

Figure 44.2 Gradual dissolution of microspheres. (Illustration courtesy of BioForm Medical.)

(b)

(a) Figure 44.3 (a) Light microscopic section at 1 month post-injection showing microspherules at the dermal subcuticular junction and a slight increase in histiocytes (arrows). (Illustration courtesy of Drs. David J. Goldberg and Ellen Marmur.) (b) Electron microscopic section at 6 months showing both an intact microspherule and one undergoing a

histiocytic derived catabolic process into smaller particles of calcium (black particles). The phosphate ions are not seen because they are dissolved in the processing of tissue for electron microscopy analysis. (Illustration courtesy of Drs. David J. Goldberg and Ellen Marmur.)

dermis at a 45 ° angle and then fully inserting the needle in the subcutaneous plane parallel to the surface. The material is then extruded upon withdrawal of the needle in a threadlike manner. Multiple parallel or layered repeat injections may be utilized to achieve correction of a soft tissue contour. Fanning and cross-hatching are utilized to achieve greater volume by smooth even injections of 0.1–0.2 mL per pass, followed by massage to avoid lumps and irregularities. One of the advantages of CaHA is its immediate “moldability” by massaging the injected area firmly against underlying structures or bimanually between the injector’s fingers.

Supraperiosteal placement is used to correct bony deformity. Several comparative studies have demonstrated that lesser volumes of CaHA are required for full correction than with collagen or hyaluronic acid [3]. Ideal areas for correction are the malar eminences, center of the cheek, nasolabial and nasojugal (tear trough) folds, prejowl sulcus/marionette, and chin and jawline regions. Reinflation of the midface, including the malar, cheek, nasolabial, tear trough areas, yields a facelift-like effect and a far more dramatic rejuvenation than simple “line filling” (Figures 44.4 and 44.5) [4]. CaHA is a structural, volumetric filler analogous to the

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(a)

Figure 44.4 Preinjection (a) and postinjection (b) of 2.6 mL CaHA.

(b)

(a)

(b) 358

Figure 44.5 Preinjection (a) and immediately post-injection (b) of 2.6 mL CaHA.

44. CaHA for soft tissue augmentation concrete foundation of facial restructuring. It is compatible with other more superficial fillers that can be overlaid for fine line smoothing, and with use in conjunction with radiofrequency and laser devices. Preinjection topical anesthesia, 20–30 minutes pretreatment, is very important to insure patient comfort. For large volume injections, injectable regional nerve blocks might be employed. A popular, non FDA-approved (off-label) means of achieving anesthesia is to mix CaHA with lidocaine via sterile syringe transfer [5]. CaHA is transferred via a female– female connector into a syringe containing 0.05–1.0 mL lidocaine and then the two are mixed by repeatedly passing the emulsion back and forth (Figure 44.6). Avoidance of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and other medications or supplements that promote bruising are advisable. Pre- and post-treatment viral prophylaxis is recommended in patients with a history of herpes simplex. The first indication for Radiesse was for vocal fold correction. In 2006, it was approved for correction of moderate to severe facial wrinkles and folds, and restoration or correc-

tion of signs of lipoatrophy in patients with HIV [4]. In comparative studies of nasolabial fold treatment with CaHa versus collagen or hyaluronic acid, implants with CaHA gave significantly greater and more persistent correction with lower volumes at all time points [3,6]. Duration is documented for as long as 12 months, although some loss of correction may occur prior to that. Off label, non-FDA approved applications include correction of nasal defects, chin augmentation, and filling of the hands. Injection of a full syringe (1.3 mL) into each dorsal hand is accomplished through several bolus deposits in the subcutaneous space and between veins and tendons, followed by massage evenly over the entire hand to provide a full, more youthful appearance (Figure 44.7) [5]. All injections are performed percutaneously. Although some authors suggest intraoral approach to the tear trough area, this approach needlessly creates the opportunity to introduce bacteria into the implant with potentially serious consequences [7]. Glabellar injections are probably illadvised because of the risk of vascular occlusion by embolization or compression, which has been reported with nearly all previous fillers.

Complications

Figure 44.6 Radiesse mixed with lidocaine, using a female–female connector.

Edema, erythema, pain, and ecchymosis are the most common complications, comparable to collagen and hyaluronic acid injections. Too superficial an injection can yield a visible white papule or plaque, which is slow to resolve. Too much material in one placement, or failure to massage, can result in palpable or visible nodules. Many of the complications, in the experience of this author, seem to be reduced when lidocaine is mixed with the CaHA prior to injection in the method described earlier.

(b)

(a) Figure 44.7 Preinjection (a) and post-injection (b) of CaHA into the hand.

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Conclusions Substantial facial volume restoration with facelift-like effect can be achieved with the injection of CaHA. Large volume correction can be accomplished in a practical fashion because of the greater volumizing effect of CaHA in contrast to other filling agents. Success is technique-dependent; complications are infrequent and comparable to other agents. Durability of this fibroplastic filler may be up to 1 year.

References 1 Mandy SH. (2008) Fillers that work by fibroplasia: poly-L-lactic acid. In: Carruthers A, Caruthers J, eds. Soft Tissue Augmentation, 2nd edn. Saunders Elsevier, pp. 101–4.

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2 Marmur ES, Phelps R, Goldberg D. (2004) Clinical histologic and electron microscopic findings after injection of calcium hydroxylapatite filler. J Cosmet Laser Ther 6, 223–6. 3 Moers-Carpi MM, Tufet JO. (2007) Calcium hydroxylapatite versus nonanimal stabilized hyaluronic acid for correction of nasolabial folds. Dermatol Surg 34, 210–5. 4 Graivier M, Bass L, Busso M, Jasin ME, Narins RS, Tzikas TL. (2007) Calcium hydroxylapatite for correction of mid and lower face. Plast Reconstr Surg 120:6, 55–66S. 5 Busso M, Applebaum D. (2007) Hand augmentation with Radiesse® (calcium hydroxylapatite). Dermatol Ther 20, 385–7. 6 Smith S, Busso M, McClaren M, Bass LS. (2007) A randomized, bilateral, prospective comparison of calcium hydroxylapatite microspheres versus human-based collagen for the correction of nasolabial folds. Dermatol Surg 33, S112–21. 7 Wolcott R, Ehrlich G. (2008) Biofilms and chronic infection. JAMA 299, 2682–4.

Chapter 45: Skin fillers Neil Sadick1, Misbah H. Khan2, and Babar K. Rao3 1

Weill Medical College of Cornell University, Department of Dermatology, New York, NY, USA Northwestern University and Northwestern Memorial Hospital, Chicago, IL, USA 3 University of Medicine and Dentistry New Jersey, Robert-Wood Johnson Medical School, Somerset, NJ, USA 2

BAS I C CONCEPTS • Collagen fillers were the first introduced into the marketplace to replace volume loss in the aging face. • Collagen fillers can be conveniently divided into: bioengineered human-derived, animal-derived, and bioengineered animal-derived. • Bovine, humanized, and porcine-based collagen fillers are presently in the marketplace. • Collagen may be combined with other fillers to produce the desired volumizing effect in the face and hands.

Introduction

Historical perspectives

Facial beauty and attractiveness continue to appeal. The quest for and maintenance of a youthful visage are well established. Youth equates with vitality, fecundity, and attractiveness; disguising the passage of time etched in the face is not a new phenomenon, although the proportion of people living to old age is. Facial appearance is rapidly perceived and processed by the brain biasing subsequent cognitive processes [1]. Four characteristics emerge as the most important determinants of attractiveness: averageness, sexual dimorphism, youthfulness, and symmetry. As the population continues to age and cosmetic procedures gain more acceptance, adults from all age groups and socioeconomic backgrounds are seeking cosmetic enhancement. This demand is increasing in younger and older adults, in men as well as women. The demand for cosmetic procedures among people aged 50–65 years has doubled in the last 5 years, with 83% of the 11.5 million procedures performed in 2006 being non-surgical and with botulinum toxin and fillers leading the list [2]. The current understanding that volume loss contributes to the aging face appearance has driven the development of new filling products to replace lost subcutaneous fat. The search for the perfect filling material to eradicate rhytides, smooth scars, and fill traumatic defects continues. This chapter discusses those fillers based on collagen, the structural building block of the skin.

Soft tissue fillers have been used for more than a century to improve and enhance facial esthetic units. At present, a popular substance for soft tissue augmentation is injectable bovine collagen. Collagen was first extracted from fresh calf skin in 1958 by Gross and Kirk at Harvard Medical School [3]. They showed that, under physiologic conditions, a solid gel could be produced by gently warming a solution of collagen to body temperature. It was found in the 1960s that selective removal of the non-helical amino and carboxy terminal telopeptides significantly reduced the antigenicity of bovine collagen molecules. A team of investigators at Stanford University in the early 1970s, Perkins, Daniels, Luck, and Knapp, began work on the development of a clinically useful collagen implant material. In 1977, Knapp, Luck, and Daniels reported the successful injection of pepsin-solubilized, telopeptide-poor, purified human rabbit and rat collagen into the subcutaneous tissue of rats. They reported that the collagen implants remained stable and were progressively infiltrated by a matrix of viable host connective tissue. These same investigators later conducted a human trial of bovine collagen in 28 human subjects. Collagen was injected into the dermal and subcutaneous planes to correct depressed acne scars, subcutaneous atrophy, wrinkling, viral pock marks, and other contour defects, with 50–85% improvement that was maintained for 3–18 months. Subsequently, Zyderm collagen was developed by Collagen Corporation. In 1981, Zyderm I® (McGhan Medical, Santa Barbara, CA, USA) became the first Food and Drug Administratiom (FDA) approved xenogenic agent for soft tissue augmentation.

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Following this approval, two other formulations of bovine collagen, Zyderm II® and Zyplast®, were granted FDA approval.

The “potential face” for collagen implants Evaluation of aging face Although an aged face has several contributing factors, collagen implants are mainly used for tissue augmentation brought about by loss of dermal elasticity, volume, and subcutaneous fat [4]. A major component of esthetic disharmony in the aging face is the loss and/or redistribution of subcutaneous fat. The youthful face has an ample amount of volume evenly distributed, which displays a smooth transition from one area to another and confers a well-rounded, three-dimensional topography delineated by a series of arcs and convexities. Viewed frontally, the primary arc of the jaw line, convexities of the temples, and the smaller secondary arcs of the lips are evident [5]. In profile, the lateral cheek projection (the ogee curve) extending as an unbroken convex line from the lower eyelid to the cheek, the arc of the jaw line, and the arc of the forehead are the most definitive features of youth (Figure 45.1). Facial aging is associated with the loss of soft tissue fullness in the periorbital, forehead, glabellar, temporal, malar, and buccal cheek perioral areas, resulting in accumulation of fat in the infraorbital fat pouches, nasolabial and labiomental folds, jowls, and submental areas. The fat pockets become more discernable as separate entities, as do many of the underlying facial structures (i.e. submaxillary glands and bony protuberances). Malar fat slides forward and down to

Figure 45.1 Facial fat partitioned in discrete compartments in facial architecture.

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bulge against the nasolabial crease, and preauricular and buccal fat slides down and forward to create the jowl, disrupting the defining arcs and convexities of a youthful face. This fat accumulates around the peripheral insertion of the orbicularis oris muscle into the overlying skin. Different compartments of facial architecture can age independently and malpositioning of one compartment may lead to a cascade of changes in others. For example, loss of volume in deep midface fat would decrease the support for the medial cheek compartment, resulting in a diminished midface projection and an unmasking of the nasolabial fold and malar mound. The resulting negative vector would then allow excess traction to be placed on the lower eyelid leading to scleral show. Consequently, medial cheek tissue enhancement will improve the lower lid laxity. Just as volume loss may lead to undesirable changes elsewhere, the replacement of volume in one area may possibly lead to desirable changes in another area.

Analysis of “potential face” correctable with collagen fillers Balance and proportions of the face have been measured over time in almost every conceivable way; however, some simple measurements are well-accepted standards (Figure 45.2). Compare changes in these areas between young and aged faces [6]. As the face ages, predictable changes occur in facial proportions. Looking at the face in vertical fifths and horizontal thirds, changes are visible from the so-called “triangle of youth” to the “pyramid of age.” The forehead narrows because of temporal atrophy and elongates because of loss of underlying support, causing the brows to droop as the hairline recedes. The lower face widens as jowls form and shortens as bone is remodeled in the maxilla and mandible. Focusing on the perioral area, the young face shows

Figure 45.2 Horizontal and vertical facial proportions in a youthful face.

45. Skin fillers triple helices contain three identical alfa-1 chains. Collagen molecules then assemble to form fibrils with other noncollageneous molecules. During the embryonic period, type III collagen, “fetal collagen,” outweighs type I collagen in human skin. However, after birth, the ratio changes favoring collagen type I, which remains the predominant type during childhood and early adulthood in non-sun-exposed skin. However, with aging, the proportion of collagen III will increase in human skin. The matrix metalloproteinases, including collagenase, are responsible for degrading collagen. UV radiation has been shown to increase the level of matrix metalloproteinases in vivo, therefore increasing collagen degradation and accounting for aging of the skin. In addition, decreased collagen formation and low levels of types I and III procollagen precursors have been demonstrated in photodamaged skin, correlating with the clinical severity of photoaged skin [7]. Figure 45.3 Potential sites for collagen fillers.

a one-third : two-thirds ratio of upper lip to chin, the socalled “golden mean.” With age this ratio approaches 1 : 1. Finally, most faces exhibit some bilateral asymmetry, which may reflect a developmental instability, accounting for its importance in the assessment of attractiveness. The changes in proportions in the aging face caused by bone loss and soft tissue repositioning cause speculation as to whether these changes could be improved with nonsurgical bony augmentation. Mild asymmetry caused by unequal volume loss can be addressed with collagen fillers. Specific areas of facial volume loss that are amenable to correction with collagen implants are distributed in a rather mask-shaped area (Figure 45.3).

Collagen-based filler materials, alone and in combination Collagen Collagen is the major structural component of the dermis and is responsible for providing strength and support to human skin. Dermal matrix in adult skin is composed of type I (80–85%) and type III collagen (10–15%), in addition to glycosaminoglycans and elastin fibers. Collagen types I and III are synthesized by dermal fibroblasts as alfa-procollagens. Hydroxylation of proline and lysyl residues is performed by prolyl and lysyl hydroxylase in the presence of copper and ascorbic acid (vitamin C). The alfa chains form the triple helix and are then secreted into the extracellular space, where the protocollagen N-proteinase and protocollagen C-proteinase cleave the amino and carboxy terminal domains of the propeptides. Collagen type I triple helices comprise two alfa-1 and one alfa-2 chains and collagen III

Filler materials A recent survey among plastic surgeons and dermatologists (Professional Education Panel Meeting, Berlin, Germany, 2005) revealed that the ideal filler material should be biodegradable but demonstrate longevity of at least 12 months and no more than 2 years. Although most collagen fillers do not satisfy the longevity criteria, these have been very popular as a dermal replacement filler since their inception. Collagen fillers can be conveniently divided into: bioengineered human-derived, animal-derived, and bioengineered animal-derived (Table 45.1).

Bioengineered human-derived collagen fillers Human-based collagen implants include Cosmo-Derm I, CosmoDerm II, and CosmoPlast (Inamed Corporation, Santa Barbara, CA, USA). These products, which were approved by the FDA in March 2003, contain types I and III human collagen. Dermal fibroblasts harvested from bioengineered human skin cells are placed into a three-dimensional mesh and cultured in a bioreactor simulating the human body. Dermal fibroblasts, supported nutritionally by the medium, produce collagen and extracellular matrix proteins. CosmoDerm I contains 35 mg/mL human-based collagen dispersed in a phosphate-based saline solution and 0.3% lidocaine. The collagen concentration in CosmoDerm II is about twice as much as that found in Cosmoderm I. CosmoPlast has the same ingredients as CosmoDerm I, but is cross-linked by glutaraldehyde, making it more resistant to degradation, allowing for deeper placement of the injectable implant. No skin testing is required for any of the human-derived collagen products, and adverse reactions are limited to bruising, erythema, and swelling. CosmoDerm is used in more superficial furrows, whereas CosmoPlast is ideal for deeper lines and the vermillion border of the lip. These products require refrigeration.

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Table 45.1 Collagen filler products, their advantages and disadvantages. Product

Components

Type and duration

Advantages/disadvantages

Zyderm I and Zyderm II

Bovine collagen 0.3% lidocaine

Xenograft 3 months

Long history of use Commonly used Allergic reactions 1% Requires pretesting Requires refrigeration

Zyplast

Bovine collagen 0.3% lidocaine

Xenograft 3 months

Long history of use Commonly used Allergic reactions 1% Requires pretesting Requires refrigeration Possible vascular necrosis

Cosmoderm I and II

Human-derived collagen 0.3% lidocaine

hom*ograft 4 months

Commonly used Does not require pretesting No allergic reactions reported Requires refrigeration Shorter duration of action

Cosmoplast

Human-derived collagen 0.3% lidocaine

hom*ograft 4–7 months

Commonly used Does not require pretesting Lasts longer than cosmoderm No allergic reactions reported Requires refrigeration Possible vascular necrosis

Cymetra

Cadaveric human Dermal matrix

hom*ograft 4–18 months

Lasts longer Requires pretesting Allergic reactions reported Edema High cost

Artecoll and Artefill

Bovine collagen encapsulated in PMMA

Xenograft Semi-permanent

Semi-permanent Might cause allergic reaction Permanent granulomatous reactions Cannot be used for fine lines Requires refrigeration

Resoplast

Bovine collagen encapsulated in PMMA

Xenograft Semi-permanent

Semi-permanent Might cause allergic reaction Permanent granulomatous reactions Cannot be used for fine lines Requires refrigeration

Isologen

Cultured autologous fibroblasts

3 mm punch of patient’s skin Cryo-preserved

Semi-permanent No allergic reactions Costly, effort to harvest skin

Autologen

Autologous collagen, large piece of patient’s skin

Dermalogen

Human-based collagen and elastin

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No allergic reactions Cost of shipping and handling Not currently available Cadaveric skin

Stored at room temperature No longer available Allergic reactions

45. Skin fillers

Table 45.1 Continued Product

Components

Type and duration

Advantages/disadvantages

Evolence

Porcine-collagen cross-linked in ribose sugar

Porcine 8–12 months

Skin pretesting not required Lasts up to 12 months Less edema Can be used for lip augmentation Requires refrigeration Can cause allergic reactions in porcine-sensitive patients Nodules Possible granulomatous reactions

PMMA, polymethyl methacrylate microspheres.

The cosmetic effects of CosmoDerm and CosmoPlast are immediate and last about 4–7 months, depending on the area of treatment, injection technique, and amount of collagen filler. It is believed that the collagen in the product contains platelet-aggregating effects that may decrease the risk of bruising [8]. Additionally, they contain lidocaine. CosmoPlast has a slightly stiffer consistency than hyaluronic acid-containing fillers, which make it ideal for use in the vermillion border of the lip, the bridge of the nose, and to elevate the corners of the mouth. It is often injected in medium to deep wrinkles alone or, in combination with hyaluronic acid. Contraindications to CosmoDerm and CosmoPlast include hypersensitivity to these products and allergy to lidocaine. Alloderm (LifeCell Corp., Branchburg, NJ, USA) is an acellular allograft human dermal matrix derived from cadaveric skin. The freeze–drying process eliminates the cellular component of human skin leaving behind collagen, laminin, elastin, and proteoglycans. Immunohistochemical staining has failed to show class I or II histocompatibility antigens. Alloderm has the capacity to incorporate into the surrounding tissue and support rapid revascularization, decreasing the risk of infection and rejection [9]. This product is manufactured as sheets and may be used for treating fullthickness burns, surgical defects, and acne scars. Cymetra (Lifecell Corp., Branchburg, NJ, USA), available since 2000, is the injectable form of Alloderm, containing micronized cadaveric-derived collagen. The product is prepared in powdered form and needs to be rehydrated and mixed with lidocaine. The mixing process needs to be carried out properly and takes about 10 minutes. Cymetra has been used for soft tissue augmentation and has been shown to have more durability than Zyderm in lip augmentation [10]. Alloderm and Cymetra are both provided by the American Association of Tissue Banks after appropriate screenings for infectious agents and teratogenicity have been performed. These products are contraindicated in patients with infection

of the treated site, allergy to gentamicin, and collagen vascular disease. Autologen (Collagenesis Corporation, Beverly, MA, USA) is an autologous collagen suspension, made of a patient’s own tissue, containing 3.5% collagen. The process, which takes 6–8 weeks, includes harvesting skin from the patient, usually from mammoplasty or abdominoplasty, which is then sent to the laboratory for culture and processing. About 2 inches of donor skin is needed to produce about 1 mL of Autologen. The advantages of this type of autologous injectable is that there is no risk of hypersensitivity to this product, and the correction may last up to 18 months – considerably longer than with other types of collagen. The disadvantages include the delays in harvesting and processing the skin as well as the need for a relatively large skin specimen and the cost of culture and processing. Autologen can be used for lip augmentation in addition to scars and furrows. However, it is no longer available in the USA. Isologen (Isologen Technologies Inc., Paramus, NJ, USA) is composed of cultured autologous fibroblasts. A 3-mm punch biopsy is obtained from the patient and sent to the laboratory as a frozen specimen. In about 6 weeks the living cultured fibroblasts with extracellular matrix are sent back to the physician for treatment. Injections should be placed within 24 hours of receiving the product. There is a minimal risk of hypersensitivity to this product and therefore a 2-week pretreatment skin allergy test is required prior to injection. It is of note that the fibroblast culture may be cryo-stored and used for additional injections. Disadvantages to this product are cost, processing time, and pain with injections. Also, because the fibroblasts require time to produce collagen, immediate correction is usually not observed with this product, making it dissatisfying to certain patients.

Animal-derived collagen fillers There are three types of bovine-derived collagen products: Zyderm I (Inamed Aesthetics, Santa Barbara, CA, USA),

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Zyderm II, and Zyplast. Zyderm I, FDA-approved in 1981, is composed of 3.5% bovine dermal collagen, suspended in physiologic phosphate-buffered sodium chloride solution and 0.3% lidocaine. Zyderm II differs from Zyderm I by containing 6.5% bovine dermal collagen and was approved by the FDA in 1983. Zyplast, approved by the FDA in 1985, contains 3.5% bovine dermal collagen cross-linked with 0.0075% glutaraldehyde, which strengthens the collagen fibers and extends the duration of action. Each of these products contains 95% type I collagen and 5% type III collagen. All three products are manufactured in 0.5–1.5 mL preloaded syringes and must be kept refrigerated. Zyderm I and II are used for correction of the superficial lines of the skin including glabellar lines, horizontal forehead lines, crow’s feet, fine perioral lines, and scars [11]. Zyderm II has more collagen and therefore is more effective in moderate to deep wrinkles. Zyplast is more valuable in treating deeper lines such as nasolabial folds, deep acne scars, and the vermilion border of the lip. The cosmetic correction with bovine collagen products usually lasts about 3 months, as the product becomes degraded by collagenase. However, there are reports of bovine collagen lasting for up to 18 months. Zyplast tends to lasts longer than Zyderm. In addition, the amount of the filler, area of treatment, and injection techniques are important factors in the longevity of the correction. It is of note that because Zyderm and Zyplast contain lidocaine, the treatment area will be partially anesthetized; therefore additional numbing agents are usually not required. However, if a patient experiences pain, topical lidocaine, and, rarely, nerve blocks may be used to reduce the pain of injection. Patients treated with bovine collagen implants are at risk of developing allergic reaction to the foreign material. Therefore, two consecutive skin tests are recommended (6 and 2 weeks) prior to treatment. The skin test contains 0.3 mL of Zyplast I in a prefilled tuberculin syringe and is injected subcutaneously on the volar aspect of the forearm. About 3% of the general population is sensitive to bovine collagen [12]. It is generally safe to treat a patient with injectable bovine collagen if there is no reaction with the two skin tests. The risk of allergy remains 1.3–6.2% after one negative test, 0.5% after two negative tests, and rarely may occur after multiple treatments. The patient should then be instructed to check the site between 48 and 72 hours after placement and then again at 4 weeks by the treating physician. Patients with hypersensitivity reactions to bovine collagen may be reassured that it usually resolves within 4–24 months. However, if needed, topical, intralesional, or a brief course of systemic corticosteroids may be used to treat these reactions. It has been proposed that there may be a triggering effect of an autoimmune process, particularly dermatomyositis, in patients with the use of bovine collagen [13]. However, in

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a study performed by Hanke et al. [14] the incidence rate of polymyositis and/or dermatomyositis in patients who received bovine collagen was not higher than the controlmatched population. Studies have indicated that the possibility of patients developing autoimmune disease is unlikely.

Bioengineered animal-derived collagen fillers Artecoll (Canderm Pharma Inc., St-Laurent, QC, Canada) is a solution that contains polymethyl methacrylate microspheres (PMMA) suspended in bovine collagen and lidocaine. PMMA is non-biodegradable; therefore it results in durable augmentation after the collagen is absorbed. This product is bovine-derived, a pretreatment skin test is required prior to injection. Artecoll has been used for facial furrows, lip, chin, and malar augmentation. Patients treated with Artecoll may have treatment effects lasting for up to 12 months [15]. Artefill is another form of bioengineered bovine collagen, encapsulated in PMMA microspheres, recently approved for use in the USA for nasolabial folds. Limited data are available in the USA regarding the safety and efficacy of this filler. However, it shares very similar chemical properties to Artecoll, with 80% by volume of bovine collagen in 0.3% lidocaine. Evolence® (ColBar LifeScience Ltd., Herzliya, Israel) is a new dermal filler manufactured specifically to closely resemble the composition of the collagen matrix found in human skin. Evolence is produced by means of a novel cross-linking process that uses a natural sugar ribose to cross-link porcine collagen, which mimics the natural cross-linking pathway of collagen in the body known as glycation. The safety and longevity of Evolence (30 mg/mL formulation) have initially been assessed in an appropriate animal model (rabbit ear assay), and the filler has been compared with two currently available bovine collagen treatments. Evolence has been shown to be safe with no significant degradation at 1, 6, 12, and up to 18 months after injection. It has demonstrated shape preservation and longevity superior to those of the bovine collagen filler, Zyplast [16]. In this study, both histologic and clinical findings supported the conclusion that there were no abnormal or hypersensitivity reactions in any of the study subjects. The immune response in humans to xenogeneic porcine dermal collagen is very reserved and of low frequency compared with bovine collagen because collagen has been well conserved during evolution with little change in basic amino acid composition among mammalian species.

Techniques for collagen filler injections Collagens are still used as the sole dermal-filling agent, but now even more often in a layering fashion with other

45. Skin fillers dermal and subcutaneous fillers. As with most dermal fillers, injection techniques will vary between injectors. When using any injectable, it is important to make the patient as comfortable as possible for the procedure. This will allow the injection process to be easier for both patient and physician. In most cases it is best to have the patient sitting upright in order to delineate the areas of wrinkling and/or dermal defects. In the reclined position, most of these defects will be minimized, resulting in undercorrection and patient dissatisfaction. Pain control is also important. As a result of the addition of lidocaine in the most commonly used, collagen-containing dermal fillers, most patients are able to tolerate injection of these agents without regional anesthesia. In the author’s practice, a topical anesthetic alone is typically used. When using collagen in combination with one of the other fillers, such as the hyaluronic acids, the collagen product is injected first, as this provides additional anesthesia, making the hyaluronic acid injection relatively painless. After visually delineating the areas to be corrected, the depth of the defect is determined in order to decide which agent to use. Very superficial epidermal and dermal defects are best corrected with either Cosmoderm or Zyderm. These agents are injected into the papillary dermis using a serial puncture or serial threading techniques (Figure 45.4). A slight, temporary blanching of the skin is noted at the time of injection, which represents accurate placement of the needle in papillary dermis. When using Zyderm, slight overcorrection is necessary as the product causes slight swelling which abates after 24 hours. Cosmoderm causes less swelling. Artecoll/Artefill, Evolence30, and, sometimes, Cosmoplast and Zyplast are used for deeper dermal defects when placed in mid–deep dermis. Injections should be placed at 45 ° angle with a 30-gauge needle using a linear threading technique (Figure 45.5). Other techniques such as fanning and cross-hatching can be used when combining collagen fillers with more fillers for deeper defects such as hyaluronic acid, fat, calcium hydroxylappatite, and poly-L-lactic acid. Collagen-based filler can be used after the placement of a deeper filler to fill in the more superficial defects such as for fine, perioral lines after lip augmentation with hyaluronic acid (Figure 45.6).

Facial augmentation Approach to the upper third of the face The primary objective in the management of aging in the upper third of the face is to attenuate wrinkles while maintaining patient facial animation. Collagen fillers are used for correction of fine lines, alone and in combination with botulinum toxin type A (Figure 45.6) [17]. Collagen fillers such

Figure 45.4 Various injection techniques.

as Cosmoderm or Zyderm can be used to correct rather superficial rhytids of the glabella and forehead. Linear threading technique is used for this purpose. Deeper injections of collagen fillers such as Cosmoplast and Zyplast, Artecoll/Artefill, and Evolence are generally avoided for the correction of deeper glabellar complex because of the seriousness of adverse effects (see below). Fine lines in the periorbital area can be corrected with more superficially placed fillers such as Cosmoderm I/II or Zyderm I/II. Serial threading or serial puncture techniques are best used. Pretreatment of the rhytids with botulinum toxin A significantly increases the longevity of soft tissue fillers.

Approach to the middle third of the face The middle third of the aging face is primarily treated with dermal fillers. Dermal fillers are useful for correction of the

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(a)

(b)

(c)

(d) Figure 45.5 Techniques for injecting into the nasolabial folds and lower lip vermilion border (a–d).

(b)

(a) Figure 45.6 Correction of perioral rhytids and lip augmentation using a combination of dermal fillers and botulinum toxin type A. (a) Before. (b) After.

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45. Skin fillers midface ptosis and volume loss, especially in patients who are considering non-surgical treatment modalities. The nasolabial folds are best treated with Zyplast or Cosmoplast, alone or in combination with hyaluronic acid fillers. The collagen fillers are placed using a 30-gauge needle at a 45 ° angle in a cross-hatching or fanning technique (Figure 45.5). As in the correction of the upper one-third of the face, synergism between filler and chemodenervation with botulinum toxin type A is still applicable. Bioengineered animal-derived collagens such as Artecoll/ Artefill and Evolence can also be used for correction of nasolabial folds. These fillers are ideal for patients who seek lasting results. The fillers are placed using cross-hatched or fanning techniques.

Approach to the lower third of the face Dermal fillers are widely used for lower face augmentation, most notably lips. Three aspects of lip augmentation are: 1 Definition of vermilion border; 2 Fullness; and 3 Poutiness. Non-cross-linked human collagen is usually used to highlight the vermilion border, injected by serial puncture technique. Fullness is achieved by creating tubercles (three sites for upper lip and two sites for lower lip). To achieve poutiness, collagen is injected above the gingivolabial sulcus to create eversion of the upper and lower lips. Perioral lines are optimally treated with specifically human-derived collagen for fine lines and bovine collagen for deeper rhytids (Figure 45.5d). Marionette lines are also amenable to collagen fillers. Zyplast or Cosmoplast can be used in a cross-hatched or linear threading technique. The irregular contours of the chin (i.e. “peau d’orange” or “cobblestoning”) may benefit from fillers, as these irregularities are a result of dermal and subcutaneous atrophy. Cross-linked bovine or human collagens are the fillers of choice. Additionally, the contraction of mentalis can exacerbate the “peau d’orange” appearance. This can be minimized by augmenting the lower third of the face with botulinum toxin type A.

Figure 45.7 Linear threading technique for injecting into the dorsal hand for hand rejuvenation using collagen dermal filler.

Although collagen fillers are better tolerated than hyaluronic acid fillers, their longevity has been of concern. Work carried out by Man et al. [18] clearly shows significantly higher patient satisfaction regarding longterm results for the hyaluronic acid treated sites versus collagen. Nonetheless, collagen fillers can be used for patients seeking temporary correction for volume loss and dermal atrophy.

Adverse reactions to collagen dermal fillers The occurrence of adverse reactions relates to both the inherent properties of the product and to inappropriate delivery or dilution of the filler, which may lead to harmful sequelae. Although injectable substances are subject to approval by the FDA, most are classified as class III devices. Thorough training of specialist physicians (dermsurgeons), including appropriate product selection, preparation, and injection techniques, is required to minimize avoidable adverse tissue responses.

Hand rejuvenation with collagen fillers

Evaluating adverse reactions

Resurgence in the examination of the aging hand is occurring, both in delineating the esthetics of the hand and in volumetric options for the intrinsic aging. The use of dermal fillers for hand rejuvenation is a new concept. Collagen fillers can be used to correct for volume loss and dermal atrophy of the dorsal hands and to “give it altitude.” Patients seem to tolerate collagen fillers better than the more popular hyaluronic acid derivatives [18] as far as pain is concerned. Collagen fillers can be injected using the linear threading technique followed by a gentle massage (Figure 45.7).

Most adverse reactions are mild and transient; however, responses of greater significance can occur, demanding anything from a short course of medication to surgery. By definition, patients undergo intervention to improve some aspect of their appearance; therefore, any risk of disfigurement from a filler is unacceptable. Some products may induce adverse events because of their inherent properties, such as their ability to elicit hypersensitivity reactions. Some reactions occur immediately after treatment, whereas some have a delayed onset [19], as summarized in Table 45.2.

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Table 45.2 Adverse effects associated with collagen implants. Early adverse reactions (occurring up to several days post-treatment) Injections site reactions Erythema Edema Pain/tenderness Bruising Itching Infection Erythema Edema Pain/tenderness Acne papule formation Nodule Hypersensitivity Erythema Edema Pain/tenderness Non-fluctuant nodules Lumps Poor technique Discoloration Redness Whiteness Hyperpigmentation Local tissue necrosis Vascular occlusion Delayed adverse reactions occurring from weeks to years post-treatment Infection (atypical mycobacterial) Erythema Edema Pain/tenderness Nodule Systemic manifestations Granuloma formation Subclinical Large disfiguring nodules Hypersensitivity Sterile abcesses Persistent discoloration Scarring

Early injection-related events Temporary swelling and bruising With all injectable fillers, the injection itself can initiate tissue response. The intensity is proportional to the degree of tissue injury. With some injectable collagen fillers such as 370

Figure 45.8 Bovine collagen adverse effect. Ecchymosis after injecting Zyplast into the nasolabial folds in a patient on anticoagulants.

Zyderm/Zyplast, CosmoDerm/CosmoPlast, Artecoll, and Evolence this reaction manifests itself as a temporary swelling and/or erythema which resolves within a day. Bruising can occur in patients on anticoagulants. Temporary makeup can be used to camouflage the erythema (Figure 45.8). Newer, bioengineered collagen fillers have also been reported to cause temporary reactions. Acute post-injection swelling and bruising have been reported with the use of Artecoll. Evolence has been associated with lesser tissue swelling and post-procedure erythema.

Skin discoloration Skin discoloration of esthetic significance can occur at the site of treatment; such reactions typically occur immediately after injection and generally resolve within a few weeks. Redness occurs as a result of the inflammatory response, whereas whiteness at the injection site can be attributed to overcorrection and the color of the injected substance. Product-specific training and rigorous adherence to the manufacturer’s instructions should minimize the risk of discoloration occurring (e.g. correct depth of injection).

Hypersensitivity reactions Hypersensitivity reactions to fillers can be severe and cases of severe anaphylaxis have also been reported. Autologous collagen fillers such CosmoDerm and CosmoPlast do not cause a reaction. However, bovine-derived collagen fillers have been shown to cause reactions. Fortunately, potential allergenicity to injectable collagen is reliably determined by skin testing. A positive skin test (seen in 3.0–3.5% of patients), characterized by a change in the contour of the injected implant, erythema, edema, itching, and, occasionally, an indurated papule or inflamed dermal nodule, is a definite contraindication to treatment. Because 1–3% of patients with one negative skin test sub-

45. Skin fillers

(b)

(a) Figure 45.9 Bovine collagen adverse effect. (a,b) Formulation of nodules in the mucosal lip after lip augmentation.

sequently develop a reaction at the treatment site, double skin testing is advocated. Of note is the fact that allergy to bovine collagen does not contraindicate the use of humanderived collagen (CosmoDerm or CosmoPlast). Although Artecoll/Artefill has denatured bovine collagen encapsulated in microspheres of PMMA it also possesses an allergic risk. Skin testing prior to injection is therefore advised. Evolence however has not been shown to cause hypersensitivity reactions. This is partly because it is derived from porcine collagen which resembles very closely to human collagen and does not elicit an allergic reaction.

Vascular compromise with collagen dermal fillers There has been at least one case report of blindness from retinal artery thrombosis following an injection of Zyplast into the glabellar complex [20]. This is believed to be exceedingly rare and an idiosyncratic event. It is therefore recommended to inject glabellar complex rather superficially and with fillers such as Cosmoderm and Zyderm.

Late adverse reactions Nodule formation Nodules can arise from a number of causes and are not uncommon in soft tissue augmentation. Non-erythematous nodules can form immediately after injection as a result of the uneven distribution of product. Such nodules are distinct from the inflammatory responses that are to be expected early following injection, whether as a reaction to injury (which should disappear within days) or infection. Clinical presentation of infection can include single or multiple nodules with inflammatory signs. Nodules may present subcutaneously or in the dermis and may or may not be painful. Nodules may be transient inflammatory granulomatous reactions, although some have suggested that they are the result of the development of a fibrous reaction as a response to the presence of the implant.

Lip nodules are common with thicker collagen fillers such as Zyplast or Cosmoplast, especially when used for lip augmentation (Figure 45.9). If these fillers are injected into the superficial dermis a visible white, yellow, or blue discoloration may persist at the injection site [20].

Granuloma formation Foreign body reactions can occasionally precipitate the appearance of lumps and bumps by leading to granulomatous inflammation. However, without histologic examination, a definite diagnosis of granuloma is impossible. Patients with granulomas usually present with non-fluctuant lumps felt under the skin. Granulomas occur less frequently after injection of resorbable implants compared with more permanent products. The risk of granuloma is reduced following the implantation of products containing microspheres with smooth surfaces, such as PMMA containing filler (Artecoll/Artefill) and Evolence, compared with particles with irregular surfaces. Clinically significant granuloma can be treated successfully by the administration of local or systemic corticosteroids, although the therapeutic role of these agents in the treatment of cosmetic orofacial granulomas has yet to be extensively studied. For well-circ*mscribed nodular lesions, surgical excision is a very effective approach to eradication. However, where lesions are widespread, surgery may lead to scarring and fistulae [19].

Infections Recovered bacterial microorganisms associated with cosmetic procedures usually include common skin and soft tissue pathogens, such as Streptococcus aureus. Patients usually present with single or multiple erythematous and/or fluctuant nodules, which can be treated with a short course of appropriate antibiotics. However, presentation of a new lesion more than 2 weeks post-procedure strongly suggests atypical infection, with mycobacteria being a possible culprit [19]. As a response to infection, patients may also 371

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experience systemic reactions, such as fever, leukocytosis, weight loss, and fatigue. In such cases, lesions should be aspirated or a biopsy should be performed, and the specimens should be sent for bacterial, fungal, and acid–fast stains and culture. Atypical or non-tuberculous mycobacterial organisms are commonly found in the soil and water. In normal healthy individuals, the organisms tend to be associated with low pathogenicity, the exceptions being Mycobacterium chelonae and Mycobacterium fortuitum, which represent more serious strains. Such infections are related to poor surgical technique and inadequate sterilization of the instruments and syringes used for injections. Such infections, if suspected, should be treated promptly with appropriate antibiotics.

Conclusions There are many causes for cutaneous defects, with a correspondingly wide range of techniques for addressing them. Dermal fillers are only one means to improve tissue and volume loss associated with aging. There is no single filler appropriate for all defects. That is partly because aging is a multifactorial process with a slowly progressive change in the three-dimensional facial anatomy, affecting essentially all components of the human face. Dermal fillers can provide temporary but adequate replacement for tissue volume, dermal elasticity, and support by enhancing subcutaneous fat. However, just like any other procedure, these have limitations. Additionally, serious side effects can occur if the practioner is not familiar with their use and potential adverse effects. Finally, regardless of the choice of dermal filler, it is the combination of clinical judgment, realistic expectations, meticulous preparation, and surgical skills that provide optimal results.

References 1 Olson IR, Marshuetz C. (2005) Facial attractiveness is appraised in a glance. Emotion 5, 498–502. 2 American Society for Aesthetic Plastic Surgery. (2007) 2005 Cosmetic Surgery National Data Bank Statistics. pp. 1–20. http:// www.cosmeticplasticsurgerystatistics.com/index.html 3 Klein AW, Elson ML. (2000) The history of substances for soft tissue augmentation. Dermatol Surg 26, 1096–105. 4 Glogau RG. (1994) Chemical peeling and aging skin. J Geriatr Dermatol 2, 30–5.

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5 Donofrio LM. (2000) Fat distribution: a morphologic study of the aging face. Dermatol Surg 26, 1107–12. 6 Azizzedeh B, Murphy MR, Johnson CM. (2006) The aging face consultation. In: Master Techniques in Facial Rejuvenation. Elsevier, pp. 1–16. 7 Baumann L, Kaufman J, Saghari S. (2006) Collagen fillers. Dermatol Ther 19, 134–40. 8 Perret S, Eble JA, Siljander PR, Merle C, Farndale RW, Theisen M, et al. (2003) Prolyl hydroxylation of collagen type I is required for efficient binding to integrin alpha-1 and beta-1 and platelet glycoprotein VI but not to alpha-2 and beta-1. J Biol Chem 278, 29873–8. 9 Menon NG, Rodriguez ED, Byrnes CK, Girotto JA, Goldberg NH, Silverman RP. (2003) Revascularization of human acellular dermis in full-thickness abdominal wall reconstruction in the rabbit model. Ann Plast Surg 50, 523–7. 10 Sclafani AP, Romo T, Jacono AA III. (2002) Rejuvenation of the aging lip with an injectable acellular dermal graft (Cymetra). Arch Facial Plast Surg 4, 252–7. 11 Baumann L. (2002) Soft tissue augmentation. In: Baumann L, ed. Cosmetic Dermatology, Principals and Practice. New York: McGraw-Hill, pp. 155–72. 12 Stegman SJ, Chu S, Armstrong RC. (1988) Adverse reactions to bovine collagen implants: clinical and histological features. J Dermatol Surg Oncol 14, 39–48. 13 Cukier J, Beauchamp RA, Spindler JS, Spindler S, Lorenzo C, Trentham DE. (1993) Association between bovine collagen dermal implants and a dermatomyositis or a polymyositis-like syndrome. Ann Intern Med 118, 920–8. 14 Hanke CW, Thomas JA, Lee WT, Jolivette DM, Rosenberg MJ. (1996) Risk assessment of polymyositis and dermatomyositis after treatment with injectable collagen. J Am Acad Dermatol 34, 450–4. 15 Cohen SR, Holmes RE. (2004) Artecoll: a long-lasting injectable wrinkle filler material: report of a controlled, randomized, multicenter clinical trial of 251 subjects. Plast Reconstr Surg 114, 964–76. 16 Monstrey S, Pitaru S, Hamdi M, Van Landuyt K, Blondeel P, Shiri J, et al. (2007) A two-stage phase I trial of Evolence collagen for soft-tissue contour correction. Plast Reconstr Surg 120, 303–11. 17 Wise JB, Greco T. (2006) Injectable treatments for aging face. Facial Plast Surg 22, 140–6. 18 Man J, Rao J, Goldman M. (2008) A double-blind, comparative study of nonanimal-stabilized hyaluronic acid versus human collagen for tissue augmentation of dorsal hands. Dermatol Surg 34, 1026–31. 19 Lowe NJ, Maxwell A, Patnaik R. (2005) Adverse reactions to dermal fillers. Dermatol Surg 31, 1616–25. 20 Alam M, Gladstone H, Kramer EM, Murphy JP Jr, Nouri K, Neuhaus IM, et al. (2008) ASDS guidelines of care: injectable fillers. Dermatol Surg 34, S115–48.

Chapter 46: Polylactic acid fillers Kenneth R. Beer Clinical Volunteer Professor of Dermatology, University of Miami, Miami, FL, and Palm Beach Esthetic, West Palm Beach, FL, USA

BAS I C CONCEPTS • Polylactic acid fillers (PLLA) is a volume stimulator rather than a direct volume replacement. • PLLA is best suited for areas that are concave. • PLLA results are dependent on techniques such as dilution and injection. • Complications from PLLA are different from those from fillers and include subcutaneous papule formation. • PLLA results (both good and bad) may last for years.

Introduction Poly-L-lactic acid is the active ingredient found in Sculptra® (also known as New-Fill; Sanofi-Aventis, Paris, France). Each bottle of material also contains sodium carboxymethylcellulose (USP) and non-pyrogenic mannitol [1]. The sodium carboxymethylcellulose and mannitol act to stabilize the PLLA and have no biologic effect on the volume stimulation. The material comes as a freeze-dried powder that must be reconstituted with sterile water [2]. At the present time, Sculptra is the only product of its kind and as such is unique. Although the amount of PLLA in a bottle of Sculptra is fixed at 367.5 mg, the methods of reconstitution are variable. The ability to add different amounts of water and/or lidocaine is one opportunity for physicians to vary the use of this material and may contribute to varying reports of success and complications. Initial reports of product use in Europe utilized dilutions of 3 mL per bottle [3]. The duration of reconstitution for these early studies was 4 hours. The package insert for the product recommends a reconstitution time of 4 hours; however, many PLLA injectors advocate longer periods, with some recommending that water imbibe for at least 24 hours with longer periods of up to 3 weeks also touted. At the present time, there is no uniform consensus nor clinical trial to suggest what is the optimal dilution or reconstitution time. This author recommends using at least 4 mL water for at least 24 hours, with longer periods of time being preferable. In addition to the 4 mL water, various anesthetic agents are added to the mixture. The anesthetic added to the

product varies depending on injector preferences and experiences. Among the alternatives used, 1% lidocaine with 1 : 100 k epinephrine added is perhaps the most frequently used. Lidocaine without epinephrine (1%) and 2% lidocaine are also used. Volumes of anesthetic added to the reconstituted material also vary based on the location of each injection and the experience of the injector. At the present time, many skilled injectors utilize 4 mL water for at least 24 hours and immediately before injection add 3–4 mL of 1% lidocaine with epinephrine. When injecting areas such as the back of the hands or the tear trough under the eye, this dilution may require additional water and the total reconstitution volume for these areas is 9 mL for many injectors. For the 9-mL dilution, the author uses 4 mL water and 5 mL 1% lidocaine with 1 : 100 000 epinephrine. Once reconstituted, the bottle should be signed and dated and the material should be stored in a refrigerator. Before injection, it should be left out so that it can warm to room temperature. Whether or not gently heating it to body temperature before injecting to improve outcomes is another area of controversy. At the present time, it seems reasonable to inject material that is at room or body temperature but not to heat the product beyond these temperatures.

Advantages and disadvantages PLLA has many unique properties and strengths and weaknesses. Among the strengths of the product are its longlasting nature, ability to correct large volume losses, and ease of injection. Weaknesses of the product include the formation of subcutaneous papules, multiple injection visits, expense, and, most importantly, there is no way to predict the degree of improvement that will result from any given injection. This latter point means that unlike the hyalurons,

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collagens, or calcium hydroxylapatite, there is no way for a physician to correct a given area with a 1 1 defect to product replacement ratio. Instead, the injector must wait to see the extent to which new collagen will form. One of the advantages of this product is its ability to produce collagen, providing a correction that lasts for more than 1 year [4]. Unlike any of the fillers, except for the permanent ones such as silicone or Artefill, once PLLA has attained a volume correction it will last for a prolonged amount of time. In addition, when the correction is diminishing, it can be enhanced with a touch up injection. Despite the initial high cost of injection, the degree and duration of the PLLA correction makes it cost effective. Volume replacement for moderate lipoatrophy costs $3000–4000. When compared with the cost of other fillers for the same time interval, PLLA correction is reasonably priced. PLLA is technically easy to inject. In fact, the difficulty associated with this product lies more with poor patient selection, inappropriate and inadequate volume reconstitution. The very nature of the product as it is injected (it is a suspension rather than a solution or gel) means that even with the best technique, particles of PLLA will migrate following injection. In addition, density differences both in the syringe and in the patient as the PLLA particles settle provide non-hom*ogeneous product dispersion even with the best technique.

Standard injection techniques Beginners should not have technical problems injecting this product as long as they select the right patients and locations to treat. The most common problem encountered by novice injectors is clogging of material in the needle, resulting in sporadic injections of product under high pressure and placement of the product at the wrong plane.

Rapid injection is the best technique for injecting PLLA. This avoids needle clogs producing high pressure injections and areas of high and low concentration product placement. Injection needles should be either 25 or 26 gauge and 0.5 inch in length. Smaller bore and longer needles may result in difficulty extruding the product into the tissue. Injections of PLLA require deep product placement. Thus, the needle should be at the level of the deep dermis or dermal–subcutaneous junction. Superficial placement will increase the probability of visible papule formation. Various methods of injecting including serial puncture, linear threading, and fanning have been described and espoused. Standard injection techniques should try to include aspects of each because the goal of the injection is to obtain a hom*ogeneous distribution of product at the plane where it will do the most good. Which technique predominates for a given individual depends on the area being injected and the amount of product being placed. Following any technique, it is essential to massage the product vigorously to distribute it. When massaging, deep pressure adequate to move product from discrete pearls into a contiguous plane is required. The most frequently injected areas are the cheeks, jawline, and temples. For the cheeks, it is helpful to inject half a bottle (3.5 mL) per session into each cheek. Each injection should be accomplished such that approximately 0.05 mL is inserted and the space between injections is about 0.5 cm. Serial puncture and fanning may be combined to produce a spoke-like network of injections (Figure 46.1). Typical injection schedules for the cheeks include three injections spaced at least 1 month apart. Patients with severe lipoatrophy may require more injections and it is acceptable to continue injections until full volume restoration is accomplished. However, it is not advisable to decrease the time interval between sessions. Correction of jawline volume loss may be required following loss of subcutaneous tissue and bone resorption. PLLA

1 3

5 4 7 9 6 8

(b)

(a)

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Figure 46.1 Serial puncture and fanning techiques. (a) Fan technique. (b) Cross-hatching technique.

46. Polylactic acid fillers injections may be performed to stimulate collagen in this area with outstanding results. Standard injection techniques for this area are serial puncture and fanning. Needle insertion for this location should be at the level of the deep tissue (subcutaneous or just above the periosteum). As with other locations, deep massage is necessary to move the product into a hom*ogeneous plane. Needle orientation for the jawline is typically at 45 ° to the skin. Moderate volume loss may be treated with 2–3 mL of the 7-mL dilution of PLLA and can be completed in three visits for many patients. Severe volume loss may be treated with four or more injection sessions. Temporal wasting is one of the hallmarks of facial aging. Although other products may be used to treat this, PLLA is exceptionally well suited for this application. Injections in this location have several potential pitfalls that need to be avoided. The plethora of blood vessels in this area provides one potential pitfall for injection of any product and the particulate nature of PLLA is no exception. When injecting the temples with PLLA, it is important to aspirate prior to inserting product. Needle placement should be deep and at the level just superficial to the periosteum. Placement at this level will help avoid formation of visible subcutaneous papules. Average injection volume per side is 2–3.5 mL using the 7-mL volume dilution. The technique for injecting PLLA in this area is predominantly the fanning method but serial puncture is also used.

Advanced techniques Perhaps the most important consideration when performing advanced techniques is to change the dilution and volume to accommodate the different areas being treated. Advanced techniques for injecting PLLA may be utilized to treat areas such as the tear troughs and the dorsum of the hands. When treating these areas, it is worthwhile to dilute each bottle with 9 mL of total volume rather than with 7 mL. Tear troughs are one of the most difficult areas to treat with any injection and PLLA is no exception. There are some additional considerations for this material that warrant special consideration. Unlike standard techniques, this area is one that should be treated only by injectors with advanced skills and experience. Whereas half of the bottle is used for each side of each location treated with simple techniques, it is recommended that about 1–2 mL of the 9-mL diluted product be used for each side of the tear trough. When treating the tear trough, using the non-dominant hand to palpate the margin of the infraorbital rim will help to protect the eye and make certain that the injections remain outside of the globe. As with injections into the temple, aspiration of the syringe is essential prior to the injection. The multitude

of vessels in this area require caution when injecting and although blindness has not yet been reported with PLLA injections, it is a theoretical possibility that needs to be remembered when injecting. Placement of the needle for treatments of the tear trough are at the level immediately superficial to the periosteal plane. Orientation of the needle is either perpendicular to the skin or at 45 ° to the skin and directed medially. When injecting the tear troughs, never point the needle towards the globe as this may result in inadvertent punctures. Each injection should place a small amount of material (about 0.05 mL). Injections should be about 3–5 mm apart. Following placement, each should be massaged to avoid discrete nodule formation. Despite perfect technique, injections of PLLA may result in the delayed formation of nodules and patients should be aware of this possibility prior to treatment [5]. Dorsal hand lipoatrophy and photoaging are hallmarks of aging that are frequently left untreated because of the lack of effective modalities. The use of PLLA for this location is a technique utilized by advanced injectors with very good results. As with injections of the tear trough, the dorsal hands are covered with skin that is typically thin and translucent. Thus, dilution of each bottle of Sculptra with 9 mL liquid is appropriate. Longer needles such as 1 inch may be used to treat the dorsal hands. The needle may be inserted proximally and advanced parallel to the tendons and material inserted as the needle is withdrawn. Photoaged hands typically have prominent veins and care must be taken to avoid injections into these structures. Each hand will require about half a bottle per treatment session and approximately 9–10 injection sites to cover the entire hand.

Complications The most common complications related to injections of PLLA are injection site related [2]. These include bruising, erythema, and site-related discomfort. More serious complications include nodule formation known as subcutaneous papules. These nodules are typically foreign body type granulomas mixed in with collagen matrix [6]. The subcutaneous nodules may be treated with injections of intralesional cortisone and it is reasonable to begin treatments with 2.5– 5 mg/mL triamcinolone acetonide. Injections may be performed on a monthly basis until the nodule resolves. In the event that the nodule does not resolve after multiple injections it is possible to remove it surgically using a small incision. More serious complications are possible with injections of PLLA (or any material) and these include necrosis of the skin. This could result from intravascular injection of PLLA and it is wise to aspirate prior to injections near major

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vascular structures. Inadvertent excursions of the needle into the globe may also occur with PLLA injections (or those of any product) when the periorbital area or tear troughs are injected. The injector should take care to use the non-dominant hand to palpate the infraorbital ridge and to orient the needle away from the eye so that if the patient makes a sudden movement, the needle will not jab them.

PLLA compared with other fillers With the advent of porcine collagen, calcium hydroxylapatite, and new forms of hyaluronic acid, one question asked by some physicians is when PLLA should be used and what patients should be treated with it. PLLA is not a direct volume replacement material and instead causes the body to replace collagen. Thus, it is not a substitute product for the various fillers. Many patients that need discrete line filling will have volume loss associated that can be treated with PLLA. Patients that only require volume replacement of the malar, temporal, or jaw areas may also obtain optimal results with PLLA. Deciding where PLLA fits into one’s practice is as much a patient selection issue as a technical one. Patients who have the temperament and budget to accept a gradual volume replacement should be treated with this product. Patients demanding a single visit correction should not. In addition, because there is no way to anticipate fully how any given individual will manufacture collagen, patients who will not tolerate a treatment program should be avoided.

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Conclusions PLLA is a unique molecule capable of restoring significant amounts of subcutaneous volume for long periods of time. It causes the body to make collagen and other extracellular matrix proteins. Unlike other products used in cosmetic dermatology, PLLA cannot produce exactly predictable results and it requires multiple treatment sessions to achieve its planned correction. Used judiciously, it can correct deficits that would otherwise be difficult to correct. PLLA has some unique complications that should be understood before it is used and patient selection is perhaps more important with this product than any other. However, its unique properties offer cosmetic dermatologists unique opportunities and this product should be embraced by injectors who understand its strengths and weaknesses.

References 1 Beer K. (2007) Optimizing patient outcomes with collagenic stimulators. J Drugs Dermatol Suppl 6. 2 Sculptra Package Insert. Bridgewater, NJ: Sanofi-Aventis. 3 Vleggar D, Bauer U. (2004) Facial enhancement and the European experience with Sculptra. J Drugs Dermatol 3, 542–7. 4 Burgess C, Quiroga R. (2005) Assessment of the safety and efficacy of poly-L-lactic acid for the treatment of HIV associated facial lipoatrophy. J Am Acad Dermatol 52, 233–9. 5 Beer K. (2009) Delayed formation of nodules from PLLA injected in the periorbital area. Dermatol Surg 35 Suppl 1, 399–402. 6 Lombardi T, Samson J, Plantier F, Husson C, Küffer R. (2004) Orofacial granulomas after injection of cosmetic fillers: histopathologic and clinical study of 11 cases. J Oral Pathol Med 33, 115–20.

Part 3: Resurfacing Techniques Chapter 47: Superficial chemical peels M. Amanda Jacobs and Randall Roenigk Department of Dermatology, Mayo Clinic, Rochester, MN, USA

BAS I C CONCEPTS • Chemical exfoliating agent causes destruction of the epidermis (to varying degrees) with subsequent repair and rejuvenation. • Factors that influence the depth of a peel. • Specific peeling agents, chemical action, and results. • Standard and advanced techniques for superficial chemical peels. • Complications.

Depth of peel

Definition Superficial chemical peels involve the application of a chemical peeling agent to the skin, resulting in destruction of the epidermis. The peel may have effects anywhere from the stratum corneum to the basal cell layer. There are many factors that affect the depth of the peel including the peeling agent and the technique of application. Chemical peels create a controlled wound which the body then heals. Permanent histologic changes can be seen after a series of superficial peels.

Multiple factors influence the depth of a given peel, including chemical agent selection and technique of application (Table 47.1). Each of these factors should be considered when selecting a superficial peel for a patient.

Histologic changes Superficial chemical peels injure and rejuvenate the epidermis; however, histologic changes can also be seen in the dermis, including collagen formation in the papillary dermis. Repeated application of alfa-hydroxy acids to the skin surface resulted in a 25% increase in epidermal thickness as well as increased acid mucopolysaccharides and increased density of collagen in the papillary dermis [2].

Physiology Indications Superficial chemical peels are generally safe and can be used on all Fitzpatrick skin types. The peeling agent only affects the epidermis and so this procedure is only indicated for superficial processes such as mild photoaging, superficial dyschromias (melasma, lentigines, post-inflammatory hyperpigmentation [PIH]), acne, and actinic keratoses [1]. Typically, a series of peels is required for the best clinical response.

Formulation In a superficial peel, chemical agents are applied to the skin to create a wound by destroying the epidermis. There are multiple different chemicals that fall into this category (Table 47.2).

Alfa-hydroxy acids (glycolic, lactic, malic, oxalic, tartaric, and citric acid) These acids have been used on the skin for centuries. Ancient Egyptian women would bathe in sour milk (containing lactic acid) to smooth the skin [3,4]. They are naturally occurring in sugarcane, sour milk, and various fruits. When applied to the skin, they decrease corneocyte adhesion above the granular layer, reduce the number of desmosomes, and result in

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desquamation [2,4]. The application is typically painless, although some mild stinging may occur. These acids require neutralization with sodium bicarbonate or dilution with water. Prolonged contact with the skin may result in uneven penetration and deeper peel depths being achieved [1].

Pyruvic acid (alfa-keto acid) This product has keratolytic, antimicrobial, and sebostatic properties. It is a small molecule with a low pKa which

allows deep penetration in the skin. Typical formulations fall into the category of medium depth peels. This potent acid carries a high risk for scarring. Application is associated with an intense burning sensation and neutralization is required with a 10% sodium bicarbonate solution [1,3]. Berardesca et al. [3] describe the efficacy of a 50% pyruvic acid preparation with dimethyl sulfone. This buffered solution has a lower pH value. The overall result is a superficial peel with mild burning on application and mild erythema following the peel.

Jessner’s solution (resorcinol 14%, lactic acid 14%, and salicylic acid 14% in alcohol)

Table 47.1 Variables that affect the depth of a superficial peel.

The penetration of this solution is limited to the epidermis. The peel results in separation of the stratum corneum and upper epidermal edema [1]. Application is best with a sable hair brush. Wrung-out gauze pads may also be used. Typically, two to three coats are applied. The skin will first become erythematous and then a white, powdery appearance will emerge. This is caused by precipitation of the

Peeling agent and concentration Technique of application (number of coats and pressure of application) Duration of contact with the skin (prior to neutralization) Anatomic location Pretreatment regimen

Table 47.2 Characteristics of various chemical peeling agents. Peeling agent

Activity

Neutralization

Frosting

Unique properties

Alfa-hydroxy acid

Diminishes corneocyte adhesion/desquamation

−

Pyruvic acid

Keratolytic, sebostatic, antimicrobial

−

Intense burning with application

Jessner’s solution

Stratum corneum separation, dermal edema

−

−*

Intense burning with application 2–3 coats applied

TCA (10–25%)

Coagulation of epidermal proteins

−

True frost forms, intensity correlates with depth of injury

Burning with application Erythema for several days

Salicylic acid

Keratolytic, comedolytic, desquamation of upper SC Enhances other peeling agents

−

−*

Burning with initial application, then acid becomes an anesthetic

Transient salicylism may occur

Tretinoin

Not destructive Increases cell turnover

−

Painless Discolors skin (yellow) Must remain on skin for 6 hours Decomposed by UV light

Produces strong erythema Fine white flakes with peeling

Resorcinol

Weakens hydrogen bonds of keratin

−

Daily application for 3 days Time consuming

Irritant or contact allergy possible Continued use associated with thyroid dysfunction

Solid carbon dioxide

Freezes and destroys epidermis

Block of dry ice dipped in acetone/ethanol solution Used to treat acne

Cold sensitivity

Deeper peel may be achieved with prolonged skin contact

* White precipitate can occur as vehicle evaporates, does not represent true frost.

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Side effects

Newer formulation used for superficial peels

47. Superficial chemical peels chemical compounds onto the skin with vehicle evaporation. This is not equivalent to a “frost” which indicates depth of peeling in a trichloroacetic acid (TCA) peel. Complications are rare with this type of peel because of the limited penetration of the peeling solution.

Trichloroacetic acid TCA is a much stronger acid than alfa-hydroxy acid (AHA), and higher concentrations produce medium and deep peels. Superficial peels can be achieved using concentrations of 10–25%. TCA is an inorganic compound that occurs naturally in the crystalline form. It is dissolved in distilled water to form an aqueous solution of the desired concentration. It is stable for a long time (23 weeks) and is not heat or light sensitive. Use and storage may affect the concentration of the solution and care should be taken to handle appropriately [1]. Cotton tip applicators and debris can contaminate the solution. The mechanism of action for TCA is coagulation of epidermal proteins and necrosis of the cells. The skin gradually turns whitish gray, creating a “frost” as the epidermal proteins coagulate and precipitate (Figure 47.1) [5]. This is a self-neutralizing acid. Histologically, the epidermis and upper papillary dermis are destroyed along with new collagen deposition [1,4,6]. TCA must be applied in a controlled setting. Analgesia and/or sedation are typically required. Cotton-tipped applicators are dipped in a container with TCA solution and rolled on the edge to prevent dripping of solution. The acid is then painted on the skin, typically along cosmetic units until the desired level of frosting is achieved [6]. Multiple coats may be needed and depth of the peel correlates to the intensity of the frost. Cool compresses can be used to ease burning sensation, but do not neutralize the solution. Patients should expect several days of erythema followed by desquamation over 7 days.

Figure 47.1 White frost seen with a trichloroacetic acid (TCA) peel indicating epidermal protein coagulation. The intensity of the frost corresponds with the peel depth.

This peel is operator dependent and potential for error and complications are high. The greatest risk exists for peeling more deeply than originally intended.

Salicylic acid (ortho-hydroxybenzoic acid) This is a beta-hydroxyl acid. It is a lipophilic acid that allows desquamation of the upper layers of the stratum corneum without inflammation [1,6]. This peeling agent can be safely used on all skin types, even those prone to PIH. This agent also has keratolytic and comedolytic qualities making it ideal for acne patients. It also enhances the penetration of other acids and is often used in combination peels (such as Jessner’s solution). A mild–moderate burning sensation occurs on application. Typically, this is easily managed with a cool fan. The acid causes superficial anesthesia and so this quickly dissipates after a minute or more. The acid should be left on the skin for about 3–5 minutes. This is a self-neutralizing acid, but is typically washed off the skin after 5 minutes with plain water. A white precipitate will be seen on the skin after about 1 minute from evaporation of the vehicle (Figure 47.2). This is not a true frost and does not indicate depth of penetration. Desquamation will begin 2–3 days after the peel and continue for 7 days [1,4,6]. Salicylism is possible with this peel, although unlikely. Care should be taken to avoid peeling large areas at the same time. Patients may experience tinnitus, dizziness, and headache. The symptoms are transient and self-resolving [7]. Increased water intake may improve symptoms more quickly.

Figure 47.2 White discoloration of the skin seen during a salicylic acid peel caused by evaporation of the vehicle and precipitation of salicylate on the skin.

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Tretinoin peel Tretinoin applied in high concentration (1–5%) in propylene glycol is used for peeling. The solution is canary yellow and discolors skin on application. Tretinoin decomposes on UV exposure and should be applied late in the day. The application is painless and the peeling agent must be left on the skin at least 6 hours. This is a safe peel and the desquamation consists only of fine white flakes. It typically produces strong erythema and the risk for prolonged erythema is increased with this type of peel [6]. Tretinoin cream is typically used as part of a pre-peeling regimen to help improve penetration of peeling agent and improve healing time. Most practices advocate at least 2 weeks of pretreatment prior to the peel [7].

Resorcinol (m-hydroxybenzene) Resorcinol is structurally and chemically related to phenol and acts as a potent reducing agent. It disrupts the weak hydrogen bonds of keratin and is therefore a keratolytic. It remains stable in water, ethanol, and ether. Typically, the peeling agent is applied as a paste in concentrations of 10–50%. It is applied daily for 3 consecutive days and the skin contact time is slowly increased daily [1,7]. The paste is then wiped off the skin. Water and creams must be avoided for up to 1 week. Rescorcinol is not typically used as a peeling agent. The process is time-consuming and the results can be achieved by other methods. It also can cause a non-specific irritant reaction or contact allergy. Additionally, there are reports of thyroid dysfunction with continued use (over months to years) [7]. More recent reviews indicate no danger when used in the standard fashion (as described above) [8].

Solid carbon dioxide (dry ice) This modality has been used to treat acne for over 60 years. Brody describes a technique using a block of dry ice wrapped in a hand towel and dipped in a 3 : 1 solution of acetone and alcohol. Acetone dissolves sebum and lowers the temperature of the carbon dioxide. Individual lesions or segments of the face can be treated then using slow even strokes. The depth of injury is modified with pressure of application. Brody reports 5–8 seconds of moderate pressure as sufficient to freeze comedones. This is less destructive than liquid nitrogen which is more than twice as cold (−186 °C) compared to dry ice (−78 °C) [7].

Advantages and disadvantages Superficial chemical peels are generally very safe procedures with a minimal risk profile. They can safely be performed on all Fitzpatrick skin types [4]. Patient discomfort is typically minimal and local anesthesia is not typically needed.

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Patients usually tolerate the erythema and desquamation following the peel quite well. Appropriate management of patient expectations is critical with superficial peels. Patients must be aware that a series of peels is required for maximum benefit. In addition, patients should be selected appropriately, based on the degree of skin disease to ensure a successful peel candidate.

Standard technique Initial consult The initial consult is essential. This allows the treating physician to determine if the patient is an appropriate candidate for a chemical peel. They should have a dermatologic condition that is amenable to this therapy. A history of recent isotretinoin use, hypertrophic scarring, facial radiation, or significant psychologic disorder may make the patient a less desirable candidate. Also, a history of oral contraceptive use or hormonal agents should be noted as this may increase the chance of PIH [4]. Photographs should be obtained at this visit. Perhaps the most important aspect of this consult is managing the patient’s expectations and preparing him or her for the procedure. The peel is superficial in nature and the need for serial treatments should be emphasized. Also, adherence to priming and post-treatment recommendations is essential to treatment success.

Priming Pretreatment is important for peeling. It allows for melanocyte suppression, uniform penetration of the peeling agent, and increased healing time. Ideally, priming occurs for 2–3 weeks prior to the peel procedure. The regimen can be customized to the patient but often includes glycolic acid products (around 10%), tretinoin, hydroquinone, and sunscreen on a regular basis. The regimen (except sunscreen) should be discontinued 3 days prior to the procedure [4,5].

Peel procedure The depth of the chemical peel is determined by multiple variables; however, the key factors are amount and concentration of peeling agent used, pressure used with application, and duration of contact with the skin. Basic peel protocol is similar for all types of superficial peels (Table 47.3). The procedure begins with cleansing and defatting the skin. Defatting is achieved by applying acetone or isopropyl alcohol to remove excess oil and sebum and allow for even penetration of the peeling agent. Occlusive ointment can be used to protect the lips and eyes; hair should be tied back away from face. Ideally, the office should be equipped with an eyewash station or have access to water for flushing [9].

47. Superficial chemical peels

(b)

(a) Figure 47.3 (a) Typical tray set-up for a salicylic acid peel. (b) Excess peel solution is removed from sponge prior to application.

Table 47.3 Standard procedure for a superficial peel. Initial consult Includes pre-peel photographs Priming 2–3 weeks prior to peel

Post-care Post-peel care includes gentle cleansing. Light moisturizing lotions can be used 24 hours after the peel procedure (Figure 47.5). Sun protection (avoidance or sunscreen) is essential for 1 month following the peel. It is critical in the first week after the peel.

Pre-treatment with glycolic acid, tretinoin, hydroquinone, sunscreen Peel Degreasing with acetone or alcohol

Advanced techniques

Application of peeling agent

Depth controlled TCA peel

Desired exposure to skin

Consistent results with TCA peels can be difficult to achieve and potential complications can occur more frequently depending on physician skill level and patient selection. A recent product, the TCA Blue Peel, offers a depth controlled TCA peel with more standardization in acid absorption [10]. The fixed concentration (15% or 20%) of TCA is mixed with the Blue Peel base (glycerin, saponins, and a non-ionic blue color). This base increases the surface tension of the solution and results in slower penetration of TCA into the skin. The blue color allows the physician to easily identify the areas that have been treated. Frosting occurs more slowly which allows the physician to control the depth of peel more consistently. Several coats may be applied depending on the desired depth of peeling.

Rinse skin or neutralize with appropriate material Application of sunscreen and possibly anti-inflammatory agent Post-peel Cool compresses Sunscreen/sun avoidance Creams/lotions as recommended

All of the materials needed should be gathered prior to beginning. This includes a neutralization solution if needed. Patients may be more comfortable with a fan blowing cool air during the peel. Applications with either cotton-tip applicators or gauze are typically used (Figures 47.3 and 47.4). There are inherent errors that can occur with peeling and care should be taken to avoid these situations. One error is incorrect formulation, either secondary to error in compounding or incorrect storage leading to evaporation of alcohol/water vehicle. The latter results in a stronger peeling solution than intended. Careful labeling and storage of peeling agents is essential. If greater than one strength is being used at a time, it is recommended that only one solution be on the tray at any given time and this should be clearly marked with concentration [8].

Fluor-hydroxy pulse peel This peel combines 5-flurorouracil with glycolic acid (70%) peels to treat actinically damaged skin. The two agents appear to have synergistic effects. One randomized study showed this combination cleared 91% of actinic keratoses, compared with 19% when treated with glycolic acid alone. The peel was repeated once weekly for 8 weeks [11].

Chemical reconstruction of skin scars Chemical reconstruction of skin scars (CROSS) is a technique to address acne scars while minimizing the risks of

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(b)

(a)

(d)

(c)

deeper peels (such as scarring and pigmentary changes). The CROSS technique involves focal application or high concentration TCA (65–100%) to atrophic acne scars. Each scar is pressed firmly with a sharpened wooden applicator. Variable improvement can be seen with this technique but typically it requires a series of treatments [12].

Complications Complications arising from superficial chemical peels are relatively rare (Table 47.4) [9]. Post-inflammatory hyperpig-

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Figure 47.4 Standard peel procedure for a salicylic acid peel. (a) Face is degreased with acetone; (b) peel solution is applied; (c) erythema and white precipitate form on skin; (d) patient rinses face with water.

mentation can occur, particularly in darker skin types. Technical errors (dripping of acid in the eyes) or incorrect formulation must also be avoided.

Conclusions Superficial chemical peels wound the epidermis with destruction or desquamation. This leads to increased epidermal thickness and new collagen formation in the papillary dermis with repeated application. They are indicated for superficial processes such as superficial dyschromias, mild

47. Superficial chemical peels

(a)

(b)

(c)

Figure 47.5 (a) Pre-peel; (b) immediately post-peel; (c) 24 hours after a salicylic acid peel.

Table 47.4 Potential complications associated with superficial peels. Pigmentary changes Infection Reactivation of herpes Prolonged erythema/pruritus Contact dermatitis Lines of demarcation Transient textural changes (enlarged pores) Milia Cold sensitivity (CO2)

photoaging, acne, and actinic keratoses. They can safely be performed on all skin types and complications are rare. A series of peels is often required for the best clinical outcome.

References 1 Zakopoulou N, Kontochristopoulos G. (2006) Superficial chemical peels. J Cosmet Dermatol 5, 246–53. 2 Ditre CM, Griffin TD, Murphy GF, Sueki H, Telegan B, Johnson WC, et al. (1996) Effects of alpha-hydroxy acids on photoaged skin: a pilot clinical, histologic, and ultrastructural study. J Am Acad Dermatol 34, 187–95.

3 Berardesca E, Cameli N, Primavera G, Carrera M. (2006) Clinical and instrumental evaluation of skin improvement after treatment with a new 50% pyruvic acid peel. Dermatol Surg 32, 526–31. 4 Roberts WE. (2004) Chemical peeling in ethnic/dark skin. Dermatol Ther 17, 196–205. 5 Roenigk RK. (1998) Facial chemical peel. In: Baran R, Maibach HI, eds. Textbook of Cosmetic Dermatology, 2nd edn. Malden, MA: Blackwell Science, pp. 585–94. 6 Landau M. (2008) Chemical peels. Clin Dermatol 26, 200–8. 7 Brody HJ. (1992) Superficial peeling. In: Chemical Peeling. St. Louis, MO: Mosby Year Book, pp. 53–73. 8 Brody HJ. (2001) Complications of chemical resurfacing. Dermatol Clin 19 (3). 9 Drake LA, Dinehart SM, Goltz RW, Graham GF, Hordinsky MK, Lewis CW, et al. (1995) Guidelines of care for chemical peeling. Guidelines/Outcomes Committee: American Academy of Dermatology. J Am Acad Dermatol 33, 497–503. 10 Obagi ZE, Obagi S, Alaiti S, Stevens MB. (1999) TCA-based blue peel: a standard procedure with depth control. Dermatol Surg 25, 773–80. 11 Marrero GM, Katz BE. (1998) The new fluor-hydroxy pulse peel: a combination of 5-fluorouracil and glycolic acid. Dermatol Surg 24, 973–8. 12 Lee JB, Chung WG, Kwahck H, Lee KH. (2002) Focal treatment of acne scars with trichloroacetic acid: chemical reconstruction of skin scars method. Dermatologic Surgery 28, 1017–21.

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Chapter 48: Medium depth chemical peels Gary D. Monheit1 and Jens J. Thiele2 1 Total Skin & Beauty Dermatology Center, PC, and Departments of Dermatology and Ophthamology, University of Alabama, Birmingham, AL, USA 2 Dermatology Specialists, Inc., Oceanside, CA, USA

BAS I C CONCE P T S • Indicated both for therapeutic field treatments of precancerous skin lesions and for various cosmetic indications. • Induce controlled chemical damage through the epidermis and variable portions of the dermis. • Pretreatments including even cleansing, degreasing, and subsequent application of Jessner’s solution will open the epidermal barrier for more even and deep penetration of trichloracetic acid. • Affords the patient a single procedure with healing time within 1 week to 10 days. • Are considered safe and effective when used by experienced dermatologists.

Introduction A number of acidic and basic chemical agents have been used to produce the varying effects of light, medium, or deep chemical peels, mediated by differences in their ability to penetrate and damage epidermal and dermal skin components. The level of penetration, destruction, and inflammation determines the level of peeling. The stimulation of epidermal growth through the removal of the stratum corneum without necrosis characterizes light superficial peels. Through exfoliation, it thickens the epidermis with qualitative regenerative changes. Destruction of the epidermis defines a full superficial chemical peel inducing the regeneration of the epidermis. Further destruction of the epidermis and induction of inflammation within the papillary and upper portions of the reticular dermis constitutes a medium depth peel. Further inflammatory response in the medium reticular dermis induces new collagen production and ground substances constituting a deep chemical peel [1].

Formulations Trichloracetic acid Trichloracetic acid (TCA) has become the gold standard of chemical peeling agents, based on its long history of usage, its versatility in peeling, and its chemical stability. Its first documented use for skin rejuvenation dates back as far as

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1882, when German dermatologist Paul Gerson Unna described the properties of salicylic acic, resorcinol, phenol, and TCA [1]. TCA has since been used in many concentrations because it has no systemic toxicity and can be used to create superficial, medium, or even deep wounds in the skin. TCA is naturally found in crystalline form and is mixed weight-by-volume with distilled water. It is not light sensitive, does not need refrigeration, and is stable on the shelf for over 6 months. The standard concentrations of TCA should be mixed weight-by-volume to assess the concentration accurately. TCA crystals weight 30 g are mixed with 100 mL distilled water to give an accurate 30% weight-byvolume concentration. Any other dilutional system – volume dilutions and weight-by-weight – are inaccurate in that they do not reflect the accepted weight-by-volume measurements cited in the literature. Because TCA, at concentrations of 50% or above, has a high potential to be scarring, the use of higher concentrations has fallen out of favor [2]. Therefore, combined applications using an initial modifying treatment followed by a 35% TCA formula were developed to better control the level of damage and minimize the risk of side effects [3]. Brody [4] first developed the use of solid CO2 applied with acetone to the skin as a freezing technique prior to the application of 35% TCA. The preliminary freezing appears to break the epidermal barrier for a more even and complete penetration of the 35% TCA. Monheit [5] then introduced the use of Jessner’s solution prior to the application of 35% TCA (Table 48.1). The Jessner’s solution was found to be very effective in destroying the epidermal barrier by breaking up individual epidermal cells. This allows a deeper penetration of the 35% TCA and a more even application of the peel solution. Similarly, Coleman and Futrell [6] have demonstrated the use of 70% glycolic acid prior to the applica-

48. Medium depth chemical peels

Table 48.1 Jessner’s solution (Combes’ formula).

Table 48.3 Major indications for medium depth chemical peels.

Resorcinol

14 g

Salicylic acid

14 g

85% Lactic acid

14 g

95% Ethanol (q.s.ad.)

100 mL

Destruction of premalignant epidermal lesions – actinic keratoses Resurfacing moderate to advanced photoaged skin (Glogau Levels II, III) Improving pigmentary dyschromias Improving mild acne scars Blending laser, dermabrasion, or deep chemical peeling in photoaged skin (transition from treated to non-treated area)

q.s.ad, a sufficient quantity up to.

Table 48.2 Agents used for medium depth chemical peeling. Agent

Comment

40–50% TCA

Not recommended

Combination 35% TCA + solid CO2 (Brody)

The most potent combination

Combination 35% TCA + Jessner’s solution (Monheit)

The most popular combination

Combination 35% TCA + 70% glycolic acid (Coleman)

An effective combination

88% phenol

Rarely used

tion of 35% TCA. Its effect has been very similar to that of Jessner’s solution. All three combinations have proven to be as effective as the use of 50% TCA; however, with a greater safety margin. The application of acid and resultant frosting are better controlled with the combination so that the “hot spots” with higher concentrations of TCA can be controlled, creating an even peel with less incidence of dyschromias and scarring (Table 48.2).

Advantages and disadvantages The advantages of chemical peeling compared with other modalities used to treat photoaging or precancerous lesions include the low cost, the ease of a single application, the ability to be performed in a routine treatment setting without the need for specialized equipment, and reliable efficacy. Additionally, chemical peeling may be performed in any office setting with routine dermatologic supplies such as 2 × 2 or 4 × 4 inch gauze pads and cotton-tipped applicators, and does not require special equipment (Figure 48.1). When performed properly on the correctly chosen patient, a medium depth peel will reliably improve the appearance of photoaged skin and produce sustained clearing of most precancerous skin lesions for a period of several months to several years.

Figure 48.1 Standard setup for Jessner’s and trichloracetic acid (TCA) combination peel. The standard setup includes a facial cleanser such as Septisol, acetone, Jessner’s solution, 35% TCA, cotton-tipped applicators, 2 × 2 inch and 4 × 4 inch gauze pads, and cool-water soaks for patient comfort.

Indications While very light and light peels may improve conditions such as acne and skin texture, and deep peels may help improve moderate rhytids and acne scarring, current indications for medium depth chemical peeling include Glogau type II photoaging, epidermal lesions such as actinic keratoses, pigmentary dyschromias, acne scarring, and also to blend the effect of deeper resurfacing procedures (Table 48.3) [7]. Several contraindications exist when choosing a medium depth chemical peel (Table 48.4). Because patient compliance during the recovery period is essential to avoiding permanent negative sequelae, a medium depth peel should not occur in the setting of a poor physician–patient relationship. Likewise, a frank discussion of what the peel can and cannot accomplish is necessary, and unrealistic expectations on the part of the patient must be recognized. Furthermore, poor general health and nutritional status will compromise wound healing and should dissuade a procedural approach.

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Table 48.4 Contraindications to medium-depth chemical peeling.

tion or hypopigmentation, types III–VI are at greater risk for these complications [8].

Absolute contraindications Poor physician–patient relationship Unrealistic expectations

Standard technique

Poor general health and nutritional status Isotretinoin therapy within the last 6 months Complete absence of intact pilosebaceous units on the face Active infection or open wounds (e.g. herpes, excoriations, or open acne cysts) Relative contraindications Medium depth or deep resurfacing procedure within the last 3–12 months Recent facial surgery involving extensive undermining, such as a rhytidectomy History of abnormal scar formation or delayed wound healing History of therapeutic radiation exposure

Jessner’s TCA peel procedure after Monheit: 1 The skin should be cleaned thoroughly with Septisol® (Vestal Laboratories, St. Louis, MO, USA) to remove oils. 2 Acetone or acetone alcohol is used to further débride oil and scale from the surface of the skin. 3 Jessner’s solution is applied. 4 35% TCA is applied until a light frost appears. 5 Cool saline compresses are applied to dilute the solution. 6 The peel will heal with 0.25% acetic acid soaks and a mild emollient cream.

History of certain skin diseases (e.g. rosacea, seborrheic dermatitis, atopic dermatitis, psoriasis, or vitiligo) or active retinoid dermatitis

Informed consent

Moreover, isotretinoin therapy within the previous 6 months has been associated with increased risk of scarring, and a medium depth chemical peel should be delayed until the patient is beyond 6 months of finishing a course of isotretinoin. Additionally, active infections or open wounds such as herpes simplex vesicles, excoriations, or open acne cysts should postpone the treatment until such conditions resolve. All patients with a history of herpes simplex virus I of the facial area should be premedicated with an antiviral agent such as acyclovir or valacyclovir and remain on prophylactic therapy for 1 week. While not absolute contraindications, patients with overly sensitive, hyperreactive, or koebnerizing skin disorders such as atopic dermatitis, seborrheic dermatitis, psoriasis, or contact dermatitis may find their underlying disease exacerbated by a chemical peel. In particular, patients with rosacea typically develop an exaggerated inflammatory response to the peeling agents, which serves as a trigger factor for symptoms. A history of keloid formation should be screened for prior to chemical peeling. Likewise, patients with a recent history of extensive or major facial surgery, or those who have recently had a medium depth peel in the preceding months should be evaluated closely with regard to risks and benefits. The collagen remodeling phase of wound healing due to prior treatments is still underway in such patients, and an altered wound healing response may occur. Another important relative contraindication is a history of radiation therapy to the proposed treatment area. An absence of pilosebaceous units should serve as a harbinger that the area does not have the reserve capacity of follicular epidermal cells with which to repopulate. While Fitzpatrick skin types I and II are at low risk for post-resurfacing hyperpigmenta-

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A thorough pretreatment discussion is imperative. It allows the opportunity to discuss the risks and benefits, as well as to educate the patient on the expected timeframe and course of recovery. It also allows the surgeon to assess the patient’s goals and expectations so that the procedure is performed only on appropriate candidates. Those who are not willing to tolerate an acute event followed by 7–10 days of desquamation and 2–3 weeks of erythema are best served by other treatments. The patient must fully understand the potential benefits, limitations, and risks of the procedure, and an informed consent form must be signed. Pretreatment photographs are also highly recommended to allow for posttreatment comparison.

Setup All necessary reagents for a Jessner’s + 35% TCA medium depth peel may be obtained in bulk for multiapplication use from leading dermatologic suppliers. When ordering TCA, one must ensure that the strength of the acid is as intended by the physician. While both weight-to-weight and volumeto-volume methods of calculating acid concentration may be used, the authors prefer the more common method of weight-to-volume calculations. When changing vendors or ordering new products, the distributor’s method of calculation should be confirmed so as to avoid application of a more highly concentrated or less highly concentrated than intended product. The standard setup includes a facial cleanser such as Septisol, acetone, Jessner’s solution, TCA, cotton-tipped applicators, 2 × 2 inch and 4 × 4 inch gauze pads, and cool-water soaks for patient comfort (Figure 48.1).

48. Medium depth chemical peels

Patient preparation All patients with a history of oral or facial herpes simplex virus (HSV) infection should be pretreated with antiherpetic agents such as aciclovir or valcyclovir to prevent herpetic activation during the post-peel period. Because a negative history of HSV infection does not always correspond with actual prior exposure, and because antiviral medications are extremely safe, it is prudent to place all patients undergoing medium depth peels on a post-procedural course of medication. All antiherpetic agents act by inhibiting viral replication in the intact epidermal cell, such that the skin must be reepithelialized before the agent has its full effect. Thus, the antiviral agent must be continued after a medium depth peel for at least 10 days. Routine antiviral agents are not necessary in light or superficial chemical peeling, as the injury pattern usually is not enough to activate the HSV.

Analgesia and sedation Medium depth peels may be performed without anesthesia, with preceding topical anesthesia, with local nerve blocks, with mild preoperative sedation, or anxiolytic medications, or a combination of any of the above. For full-face peels in anxious patients, it is useful to give preoperative sedation (5–10 mg diazepam orally) along with mild analgesia in the form of 50 mg meperidine (Demerol, Winthrop, New York, USA) and a mild sedative such as 25 mg hydroxyzine hydrochloride intramuscularly (Vistaril, Lorec, New York, USA). The discomfort from this peel is not long-lasting, so shortacting anxiolytics and analgesics are all that are usually recommended [8].

Application technique Vigorous cleansing and degreasing of the skin prior to application of the active peeling agent represents a crucial and often overlooked step in the protocol. The removal of skin surface lipids deriving from sebum and epidermal lipids, scale and thickened stratum corneum is particularly important for even penetration of the solution. The face is first washed with an antibacterial cleanser in glycerin (Septisol) applied with 4 × 4 inch gauze pads, then rinsed with water. Acetone is then applied with 4 × 4 inch gauze pads to remove residual oils and debris. The skin is thus débrided of stratum corneum and excessive scale. The necessity for thorough degreasing in order to achieve reliable and even penetration cannot be overemphasized. Prior to application of the active peeling agent, one should assess the thoroughness of degreasing. If oil or scale is felt, the degreasing step should be repeated. Particular attention should be focused on the

hairline and nose. Thorough and uniform degreasing conditions the skin to ensure an even peel over the entire face. Next, Jessner’s solution is evenly applied, either with cotton-tip applicators or 2 × 2 inch gauze pads. Jessner’s solution alone constitutes a very light peel, and thus will open the epidermal barrier for a more even and more deeply penetrating TCA application. Only one coat of Jessner’s solution is usually necessary to achieve a light, even frosting with a background of erythema. The expected frosting is much lighter than that produced by the TCA. The face is treated in sequential segments progressing inferiorly from the hairline. Even strokes are used to apply the solution to the forehead first then each cheek, the nose, and the chin. The perioral area should follow, and the eyelids are treated last, creating the same erythema with blotchy frosting. As with the application of Jessner’s solution, cosmetic units of the face are then peeled sequentially with TCA from forehead to temple to cheeks, and finally to the cutaneous lips and eyelids. The 35% weight-to-volume TCA is applied evenly with 1–4 cotton-tipped applicators rolled over different areas with lighter or heavier doses of the acid. Four well-soaked cotton-tipped applicators are used with broad strokes over the forehead and the medial cheeks. Two mildly soaked cotton-tipped applicators can be used across the lips and chin, and one damp cotton-tipped applicator on the eyelids. The amount of acid delivered is thus dependent upon both the saturation of an individual cotton-tipped applicator and the number of cotton-tipped applicators used. In this manner the application is titrated according to the cutaneous thickness of the treated area. The white frost from the TCA application, which represents the keratocoagulated endpoint, should appear on the treated area within 30 seconds to 2 minutes after application (Figure 48.2). An even application should eliminate the need for a second or a third pass, but if frosting is incomplete or uneven, the solution should be reapplied. TCA takes longer to frost than a deep phenol peel, but less time than the superficial peeling agents. After a single application to an area, the surgeon should wait at least 3–4 minutes to ensure that frosting has reached its peak. The thoroughness of application can then be analyzed, and a touch up, or less commonly another pass, can be applied as needed. Areas of poor frosting should be retreated carefully with a thin application of TCA. The physician should seek to achieve a level II–III frosting. Level II frosting is defined as white-coated frosting with a background of erythema [9]. A level III frosting, which is associated with penetration to the reticular dermis, is solid white enamel frosting with no background of erythema. A deeper level III frosting should be restricted only to areas of heavy actinic damage and thicker skin. Although heavily damaged actinic skin may require a level III frosting, most medium depth chemical peels should strive to obtain no more than a level II frosting. This is especially true over

387

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Figure 48.2 Frosting observed immediately after combined Jessner’s and TCA peel. Typical opaque white frosting with mild erythema observed 2 minutes after TCA application.

tip against the rim of the bottle or onto a dry gauze pad before using it for application. The patient should be positioned with the head elevated at 30 ° and the eyelids closed. The applicator is then rolled gently on the lids and periorbital skin within 2–3 mm of the lid margin. Never leave excess peel solution on the lids, because the solution can roll into the eyes. Dry tears with a separate, dry cotton-tipped applicator during peeling because they may wick peel solution to the puncta and eyes by capillary attraction. The patient will experience an immediate burning sensation as the TCA is applied, but this subsides as frosting is completed. A circulating fan may be placed beside the patient for comfort. Cool saline or water compresses also offer symptomatic relief for a peeled area. The compresses are placed over the face for 5–6 minutes after the peel until the patient is comfortable. The burning subsides fully by the time the patient is ready to be discharged. At that time, most of the frosting has faded and a brawny desquamation is evident.

Post-procedure eyelids and areas of sensitive skin. Those areas with a greater tendency to scar formation, such as the zygomatic arch, the bony prominences of the jawline, and chin, should only receive up to a level II frosting. Overcoating TCA with multiple passes or highly saturated cotton-tipped applicators will increase its penetration, so that a second or third application will create further damage. One must be extremely careful to retreat only areas where the amount of solution taken up was not adequate or the skin is much thicker. One should never overcoat a fully frosted area. Certain facial features require special attention. Careful feathering of the solution into the hairline and around the rim of the jaw and brow conceals the line of demarcation between peeled and non-peeled areas. The perioral area has fine, radial rhytids that require a complete and even application of solution over the lip skin to the vermilion border. This is best accomplished with the help of an assistant who stretches and fixates the upper and lower lips as the peel solution is applied. Alternatively, the TCA may be applied along the rhytid to the vermilion border with the wooden end of a cotton-tipped applicator. It should be noted that deeper furrows such as expression lines will not be eradicated by a medium depth peel and thus should be treated like the remaining skin. Thickened keratoses should stand in contrast to the frosted background because they do not pick up peel solution evenly and thus do not frost evenly. Additional applications rubbed vigorously into these lesions may be needed for penetration. Eyelid skin must be treated delicately and carefully. A damp, rather than saturated, applicator should be used. This is accomplished by draining the excess TCA on the cotton

388

Postoperatively, edema, erythema, and desquamation are expected. With periorbital peels and even forehead peels, eyelid edema can be severe enough to close the lids. For the first 2–4 days, the patient is instructed to soak four times a day with a 0.25% acetic acid compresses made of 1 tablespoon white vinegar in 1 pint warm water. A bland emollient is applied to the desquamating areas after soaks. After 4 days, the patient can shower and clean gently with a mild facial cleanser. The erythema intensifies as desquamation becomes complete within 4–5 days. Thus, healing is completed within 7–10 days. At this time the bright red color has faded to pink and has the appearance of a sunburn (Figure 48.3). This erythema may be covered by cosmetics and will fade fully within 2–3 weeks.

Complications Many of the complications seen in peeling can be recognized early on during healing stages. The cosmetic surgeon should be well acquainted with the normal appearance of a healing wound in its timeframe for medium depth peeling. Prolongation of the granulation tissue phase beyond 1 week may indicate delayed wound healing. This could be the result of viral, bacterial, or fungal infection, contact irritants interfering with wound healing, or other systemic factors. A red flag should alert the physician that careful investigation and prompt treatment should be instituted to forestall potential irreparable damage that may result in scarring. Thus, it is critically important to understand the stages of wound healing in reference to medium depth peeling. The

48. Medium depth chemical peels

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 48.3 Sequential exfoliation, granulation, and re-epithelialization after Jessner’s and TCA combination medium depth peel. (a) Postoperative day 1: inflammation with edema, erythema; (b) day 2: early epidermal separation with hyperpigmentation; (c, d) day 3 morning; and (e, f) day 3 afternoon: dermal inflammation with granulation tissue and early re-epithelialization; (g, h) days 5 and 6, respectively: full desquamation with regeneration of new epidermis and beginning dermal remodeling. 389

ANTIAGING

Resurfacing Techniques

(b)

(a)

Figure 48.4 Jessner’s TCA peel performed for photoaging skin and actinic keratoses. (a) Preoperative; (b) 5 weeks postoperative; (c) 10 weeks postoperative.

(c)

physician then can avoid, recognize, and treat any and all complications early (Figure 48.4).

Long-term care Long-term care of peeled skin includes sunscreen protection for up to 6 months along with reinstitution of medical treatment such as low strength hydroxy acid lotions and topical tretinoin formulations. Repeeling areas should not be performed for 6 months from the previous peel. If any erythema or edema persists, the peel should not be performed as the reinjury may create complications. Medium depth peels should not be performed on undermined skin such as facelift or flap surgery performed up to 6 months prior to the peel [10].

390

Conclusions The evolution of medium depth chemical peeling has changed the face of cosmetic surgery. It has introduced new techniques into the armamentarium of the cosmetic surgeon to treat problems that previously have been approached with tools inadequate to obtain the results for moderate photoaging skin or with overly aggressive treatment using deep chemical peeling agents. The combination peels have provided some of the more popular tools needed to approach a burgeoning population with photoaging and photocarcinogenesis. The presented medium depth peel will produce excellent results for a variety of skin conditions, including actinic keratoses (Figure 48.5). A comparison study of the efficacy

48. Medium depth chemical peels

Figure 48.5 Jessner’s 35% TCA peel for actinic keratoses. (a & b) Preoperative diffuse actinic keratoses and seborrheic keratoses; (c & d) 9 months postoperative.

(a)

(b)

(c)

(d)

of Jessner’s solution plus 35% TCA with 5-fluorouracil documented superior effectiveness of this single procedure over 5-fluorouracil, with a significant reduction in morbidity [11]. Medium depth combination peels thus provide an effective, safe, and simple single procedure that can be used as both a therapeutic and cosmetic procedure to counteract cutaneous photodamage.

References 1 Brody HJ, Monheit GD, Resnik SS, Alt TH. (2000) A history of chemical peeling. Dermatol Surg 26, 405–9.

2 Brody HJ. (1989) Variations and comparisons in medium depth chemical peeling. J Dermatol Surg Oncol 15, 960–3. 3 Monheit GD. (2004) Chemical peels. Skin Ther Lett 9, 6–11. 4 Brody HJ. (1997) Chemical Peeling and Resurfacing. Mosby, p. 110. 5 Monheit GD. (1989) The Jessner’s + TCA peel: a medium depth chemical peel. J Dermatol Surg Oncol 15, 945. 6 Coleman WP, Futrell JM. (1994) The glycolic acid + trichloroacetic acid peel. J Dermatol Surg Oncol 20, 76–80. 7 Glogau RG. (1994) Chemical peeling and aging skin. J Geriatr Dermatol 2, 30–5. 8 Monheit GD. (1995) The Jessner’s trichloracetic acid peel. Dermatol Clin 13, 277–83.

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9 Rubin M. (1995) Manual of Chemical Peels. Philadelphia, PA: Lippincott, pp. 120–1. 10 Monheit GD. (1994) Advances in chemical peeling. Facial Plast Surg Clin North Am 2, 7–8.

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11 Lawrence N, Cox SE, co*ckerell CJ, Freeman RG, Cruz PD Jr. (1995) A comparison of efficacy and safety of Jessner’s solution and 35% trichloracetic acid vs. 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol 131, 176–81.

Chapter 49: CO2 laser resurfacing: Confluent and fractionated Mitchel P. Goldman Volunteer Clinical Professor of Dermatology/Medicine, University of California, San Diego and Dermatology/Cosmetic Laser Associates of La Jolla, Inc., San Diego, USA

BAS I C CONCEPTS • Fractionated laser resurfacing with ablative lasers gives better results than with non-invasive lasers. • Confluent ablative laser resurfacing gives better results than fractionated laser resurfacing. • More “down-time” correlates with better results. • Cold air cooling and advanced topical anesthesia provides optimal pain control. • Fractionated ablative resurfacing has minimal adverse effects.

Introduction Carbon dioxide (CO2) lasers are currently available in two forms: confluent and fractionated. The differences between the results, adverse effects, and down-time are compared and contrasted in this chapter.

CO2 laser resurfacing The modern era of CO2 laser resurfacing began in 1994 with the development of the UltraPulse CO2 laser by Coherent Medical (now Lumenis, Inc., Santa Clara, CA, USA). This laser delivers peak fluences above the ablation threshold of cutaneous tissue (5 J/cm2) with tissue dwell times shorter than the 1 ms thermal relaxation time of the epidermis. These new generation CO2 lasers limited tissue dwell time by either shortening the pulse duration (i.e. UltraPulse) or using scanning technology to rapidly sweep a continuous wave CO2 laser beam over the tissue such that the laser beam does not remain in contact with any particular spot on the tissue for longer than 1 ms (i.e. SilkTouch, Sharplan Laser Corporation, now Lumenis Inc., Santa Clara, CA, USA). These high peak-power, short-pulsed, and rapidly scanned CO2 laser systems allow laser surgeons to precisely and effectively ablate 20–30 μm of skin per pass while leaving in its wake a considerably smaller residual zone of thermal damage (up to 150 μm) than left behind by the

previous generation of continuous wave CO2 lasers (up to 600 μm). Clinically, this technologic advancement translates into superior clinical results and a much more favorable safety profile than seen previously with the continuous wave CO2 lasers. The thermal effect of the CO2 laser acts on dermal collagen stimulating neocollagenesis and tightening of facial skin. Successful ablation maximizes thermal stimulation of the dermis while limiting non-specific thermal damage. Another method used to decrease thermal damage is to follow a session of CO2 laser ablation with the erbium:yttrium aluminum garnet (Er:YAG) laser. With this technique, the residual non-specific thermal damage left from the CO2 laser is vaporized by subsequent passes with an Er:YAG laser which leaves little if any non-specific thermal damage. Given the impressive clinical results achieved with the high peak power, short pulsed, and rapidly scanned CO2 lasers, they quickly replaced chemical peels and dermabrasion as the treatment of choice for cutaneous resurfacing. However, the impressive results achieved with these new generation CO2 lasers were not without drawbacks. Reepithelialization can take 5–14 days and postoperative erythema and/or post-inflammatory hyperpigmentation can last 1–6 months depending on the depth of laser ablation, amount of residual non-specific thermal damage, and patient’s skin type. Finally, there is a risk of fungal, viral, and bacterial infections on the denuded skin as well as permanent hypopigmentation from destruction of melanocytes and resultant scarring. Minimizing these potential adverse effects requires excellent postoperative care and is timeconsuming for both the patient and physician. These side effects, as well as the significant “down-time” typically associated with CO2 laser resurfacing and extensive postoperative care, are unacceptable to many patients and

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(a)

(b) Figure 49.1 (a) Two passes of CO2 laser at 7 J/cm leaves approximately 70 μm of residual thermal necrosis. (b) Two passes of Er:YAG laser at 10 J/cm results in removal of approximately 50 μm of this necrotic tissue. (From Carcamo AS, Goldman MP. (2006) Skin resurfacing with ablative lasers. In: Goldman MP, ed. Cutaneous and Cosmetic Laser Surgery. London: Mosby-Elsevier, figure 7.44, p. 234.) 2

significantly dampened the initial enthusiasm associated with their use. Because the CO2 laser typically operates near its tissue ablation threshold (5 J/cm2) in most resurfacing applications, a large fraction of its energy is invested in heating rather than ablating tissue. Consequently, the CO2 laser produces relatively large residual thermal damage zones and causes significant desiccation of the target tissue after only a few passes. With each subsequent pass, the amount of vaporized tissue decreases while thermal damage increases and a “plateau” of ablation is typically reached after the fourth pass. Non-specific thermal damage has a negative impact, not only on the CO2 laser’s ablative capacity, but also on its side effect profile. Our research suggests that the relatively large thermally induced residual zone of necrosis (up to 150 μm) left behind by the CO2 laser is one of the main factors contributing to its adverse sequelae including prolonged erythema, postoperative pain, delayed healing, infection, hypopigmentation, and scarring. To minimize the issues resulting from a large residual thermal zone the Er:YAG laser was introduced for resurfacing. While it was successful in reducing thermal damage it was unable to penetrate beyond papillary dermis as a result of poor hemostatic properties. A multimode Er:YAG system, the Tunable Resurfacing Laser (TRL), was developed (Sciton, Inc., Palo Alto, CA, USA) which allows the user to blend a variety of ablation and thermal coagulation depths by extending the pulse duration of the Er:YAG laser which is typically less than 0.5 ms. Extending the pulse duration to 4–10 ms allowed for less flash vaporization and more prolonged thermal heating to occur. The TRL can be tuned for pure ablation or CO2-like thermal injury, or any point in between. Modifications of technical protocols have continued to improve clinical outcomes. Combination therapy with CO2 immediately followed by Er:YAG lasers allow cosmetic sur394

geons to capitalize on the unique benefits of each laser system and to minimize their disadvantages. Er:YAG laser treatment can be used to bypass the ablation “plateau” characteristic of CO2 resurfacing to ablate deeper into the dermis. Improved postoperative healing can also be attained when the short-pulsed Er:YAG laser is used to remove the residual zone of thermal necrosis left behind after CO2 resurfacing (Figures 49.1 and 49.2). Additionally, the ablative lasers have turned out to be extremely versatile therapeutic tools. Cosmetic surgeons now regularly combine ablative laser resurfacing with other problem-specific non-ablative technologies to address multiple cosmetic concerns for the patient in a single treatment session. The efficacy of Q-switched lasers in the treatment of pigmented lesions is enhanced when these lasers are used after ablative resurfacing. Treatment of vascular lesions with the pulsed dye laser or other vascular lasers has been shown to be extremely successful when performed prior to skin resurfacing with an ablative laser. Despite early reports advising against it, full-face laser resurfacing is now safely being combined with rhytidectomy and autologous fat transfer to achieve a more comprehensive approach to facial rejuvenation. Pretreatment and post-treatment protocols have also improved. Although some controversy remains surrounding the topic of antibiotic prophylaxis, a number of studies in the last decade have provided relevant information on common pathogens, effective antibiotic prophylaxis regimens, and clinical situations at increased risk for infection after cutaneous laser resurfacing. Improved laser wound care regimens have reduced recovery time and decreased morbidity after laser skin resurfacing. The benefits of occlusive dressings in accelerating laser wound healing have been well established in a number of studies. Timely institution of topical medications in the postoperative period is now allowing surgeons to effectively address a number of

49. CO2 laser resurfacing

(a)

(b)

(d)

(e)

(c)

Figure 49.2 Combination UltraPulse CO2 (UPCO2) and Er:YAG laser (patient’s right side) showing improvement equal to left side treated with UPCO2 alone. (a) Before treatment; (b) immediately after treatment; (c) 7 days after laser resurfacing; (d) 3 weeks after laser resurfacing; (e) 2 months after resurfacing. (From Carcamo AS, Goldman MP. (2006) Skin resurfacing with ablative lasers. In: Goldman MP, ed. Cutaneous and Cosmetic Laser Surgery. London: Mosby-Elsevier, figure 7.37 p. 225.)

expected postoperative symptoms and complications including postoperative erythema and edema, pruritus, and postinflammatory hyperpigmentation.

Fractionated CO2 laser resurfacing Because of the prolonged and meticulous postoperative care in addition to potential adverse effects, as well as the

advancement in minimally invasive procedures with rapid healing times, confluent CO2 and/or Er:YAG ablative resurfacing is rarely necessary. Physicians and patients find it easier to have minimally invasive procedures performed even at the expense of minimal results. The current consensus among patients is to embrace a treatment modality that delivers maximum results with minimal down-time. Unfortunately, the promises by most laser companies who have developed and are promoting these minimally 395

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invasive, non-ablative lasers have not lived up to their stated efficacy in improving photodamage. The development of fractionated lasers that treat a percentage of the skin while leaving the intervening areas untreated, allows for the more dramatic results of a variety of laser wavelengths including the 10 640 nm CO2 laser to be associated with quicker healing times and fewer postoperative sequelae. Initially, fractional lasers were introduced in a non-ablative format. This technology was developed to overcome the hom*ogeneous thermal damage typically created after treatment with standard CO2 and/or Er:YAG lasers and instead create microscopic thermal wounds which spares the tissue surrounding each wound. A 2.1% linear shrinkage of periorbital rhytids was noted at 3 months with this non-ablative fractionated laser which is much less than that achieved with standard ablative CO2 and/or Er:YAG laser resurfacing. It did not take long for fractional photothermolysis to be applied to ablative lasers, allowing for a more aggressive treatment option. My recommendation is that non-ablative fractionated lasers be reserved for patients who can not accept any “down-time” and are willing to wait at least 6 months and have 4–6 treatments to see definite improvement in wrinkles and/or scarring.

Interestingly, physicians have had the ability to perform fractionated CO2 laser resurfacing since the development of the scanning UltraPulse hand-piece in 1995. This scanner was developed to deliver precisely overlapped laser pulses that occurred in a Gaussian distribution uniformly to ablate and/or vaporize the epidermis. Recognition that one could use this scanner with a negative 10% overlap along with the development of smaller laser spot sizes (0.1 and 1.2 mm) produced the first fractionated CO2 laser. There are an ever-increasing variety of both fractionated CO2 and Er:YAG lasers to assist in facial rejuvenation. Table 49.1 summarizes the available lasers by company, wavelength, spot size, treatment area, density, speed, power, and maximal depth (if known). The remaining portion of this chapter discusses the available systems at the time of this writing (Fall 2008). Because I have not been able to test each system and very little if anything is currently available in the peer-reviewed medical literature, I am thankful to my friends and colleagues for sharing their experience.

Active and Deep FX Lumenis The Active and Deep FX fractionated CO2 laser delivers the equivalent of 240 W to the tissue compared to the other 30

Table 49.1 Summary of available lasers by company, wavelength, spot size, treatment area, density, speed, power, and maximal depth. Company

Product

Wavelength (nm)

Lumenis

Deep FX

10 600

120

7×7

Lumenis

Active FX

10 600

1300

9×9

Reliant

Fraxel re:pair

10 600

120

15 × 15

Alma

Pixel CO2

10 600

Lasering

Mixto SX Slim E30

10 600

300

20 × 20

MedArt

MedArt FrX

10 600

300

Deka/Cynosure

SmartXide DOT/Affirm

10 600

350

Lutronic

Mosaic eCO2

10 600

Wavelight

Paxel

2 940

Palomar

Lux 2940

2 940

300

Cutera

Fractionated Pearl

2 940

300

Sciton

Profractional

2 940

250

20 × 20

1500

1.5–60%

Sciton

Profractional XC

2 940

430

20 × 20

1500

5.5 or 11%

Alma

Pixel

2 940

11 × 11

<300

49 or 81

MTZ, microthermal zone.

396

Spot size (μm)

Treatment area (mm)

Max Depth (μm)

Frequency (Hz)

Power (W)

5–45%

300

55–100%

600

1600

10–70%

2100 MTZ/s

Any

10 × 10

120, 300, 1000

Density

15–20%

500

20–100%

10 × 10

1660

7–20%

15 × 15

350

5–100%

5–100

14 × 14

2400

5–130%

200

3 × 10 600 200–1000 2.3 cm2/s

49. CO2 laser resurfacing pulse (Figure 49.4). The Deep FX is used to treat individual scars and/or wrinkles. This is followed by the Active FX which is used to treat the entire face, rejuvenating the epidermis. We have evaluated the histologic and clinical effects of varying pulse energies and densities on ex vivo tissue as well as in vivo with the fractionated CO2 laser (UltraPulse Encore Active FX™, Lumenis, Santa Clara, CA, USA). A distinct, stippled gray, fractional epidermolysis pattern is apparent

and 40 W systems. The nature of the 240 W square wave pulse of the UltraPulse makes it about eight times the power of competitive CO2 laser systems. This is said to result in a cleaner ablation. The Active FX hand-piece has a spot size of 1.3 mm and ablates up to 300 μm of tissue (Figure 49.3). The Deep FX hand-piece has a 120 μm diameter spot size which can ablate tissue from superficial to up to 2 mm depending on the power density chosen as well as whether the individual pulses occur as a single, double, or triple

Intact “bridge”

Ablated column

Heat in the dermis

Figure 49.3 Histology of Active FX laser impulse at 100 mJ.

Bridge of in tact tissue

Zone of ablation Lateral coagulation

Figure 49.4 Histology of Deep FX laser impulse at 17.5 mJ. Zones of ablation are created, leaving bridges of intact tissue to aid in regeneration. Lateral and vertical coagulation stimulate a tissue regeneration response between the ablated columns.

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(a)

(b) Figure 49.5 Forty-year-old female treated with Active FX fractionated CO2 laser with a 1.3 mm diameter spot size, density 2, 100 mJ: (a) before; (b) two months after treatment.

during the procedure followed by erythema. Erythema lasts for about 3 days for patients treated with −10% overlap and increases by approximately 1 day for each increased density setting. Edema persists for a little more than 1 day (Figure 49.5). The level of satisfaction at 1 month is relatively high, averaging 6 on a 1–10 scale. We find that it may take three separate treatments with the fractionated CO2 laser to achieve the same results as non-fractionated CO2 laser resurfacing (Figures 49.6 and 49.7). The advantage of the fractionated approach is that the procedure can be performed entirely under topical anesthesia supplemented with cold air cooling as opposed to standard CO2 laser resurfacing which requires general anesthesia or the use of a large number of nerve blocks and/or tumescent anesthesia. In addition, postoperative healing is far easier with the fractionated approach. Patients do not require a Silon TSR dressing (Bio Med Sciences, Inc., Bethlehem, PA, USA) and do not have to be as diligent with vinegar water soaks. There is minimal serous exudate or crusting. Finally, patients are able to wear make-up 3–4 days post-procedure and are usually completely healed and look good without make-up within 5–7 days (Figure 49.8).

398

Weiss has conducted a split-face study to evaluate the efficacy of the Active FX Fractionated Laser compared to the 1550 nm Fraxel Er:YAG laser (Reliant Technologies, Mountain View, CA, USA). The Active FX was used at 80 mJ for a depth of 300 μm and the 1550 Fraxel was used at a final depth of 800 μm per microthermal zone (MTZ) with a density of 1000 MTZ/cm2. The entire face is pretreated with topical anesthesia for 30 minutes and cold air cooling was used during treatment. Pain was higher with the 1550 nm side. Erythema lasted 1–2 days on the 1550 nm side and 4–6 days on the CO2 side. The CO2 side had an average of 75% improvement while the 1550 nm side had an average improvement of 25%. We and others have not seen post-inflammatory hyperpigmentation (PIH) with the Active FX even in Asian patients and patients with type 4 and 5 skin. PIH has been reported with the fractionated 1550 nm lasers.

Fraxel Re:Pair – Reliant The second-generation fractionated resurfacing laser from Reliant used a CO2 laser instead of the 1550 nm Er:YAG laser. The spot size is 120 μm with a large treatment area of

49. CO2 laser resurfacing

(a)

(b)

(d)

(e)

(c)

Figure 49.6 Forty-year-old female (same as in Figure 49.5) treated with Deep FX at 17.5 mJ density 1, 1 pass 3 months after Active FX treatment as above. (a) Immediately before; (b) immediately after treatment; (c) 1 day after treatment; (d) 2 days after treatment; (e) 2 months after treatment.

399

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Figure 49.7 Fifty-one-year-old women treated with Deep FX at 15 mJ, density 1, 1 pass in the periorbital and perioral area followed by Active FX to the entire face at 100 mJ, density 2, 1 pass. Before and 2 months after treatment.

15 × 15 mm. Depth of laser effects has been reported to be 1.6 mm. At the time of this writing, there are no published papers on this system.

Mixto SX – Slim Evolution – Lasering

Figure 49.8 Forty-year-old patient (same as in Figure 49.5 with same laser parameters) treated with fractionated CO2 laser: on day 3 before and after make-up application.

400

This low-powered fractionated CO2 laser is usually used at a power between 8 and 15 W. This low-energy system has the advantage of causing only 1 day of erythema and fine, pinpoint crusting lasting for up to a week. No topical anesthesia or concurrent cold air cooling is recommended, and pain is minimal and “easily tolerated” with one pass (Figure 49.9). A split-face study comparing the Mixto SX with a microfractional Er:YAG laser (Dermablade MCL 30, Aeslepion, Jena, Germany), with both systems using an energy density of 15 J/cm2 without any anesthesia, showed a slightly higher improvement (15%) with the CO2 as opposed to the Er:YAG systems without any difference in satisfaction scores. Microcrusting lasted 1 day less with the Er:YAG system. This laser can also be used in a continuous mode at 30 W for cutting. In fractional mode, the scanner is delivered

49. CO2 laser resurfacing

(a)

(b)

(c)

(d)

(e)

(f)

Figure 49.9 Patient treated with the SLIM E30 Mixto SX fractionated CO2 laser. (a) Before treatment; (b) 1 day after treatment; (c) 3 days; (d) 7 days; (e) 2 weeks; (f) 8 weeks. (Courtesy of Dr. Jeffery Hsu.)

alternatively into four quadrants to produce thermal relaxation between impact spots.

Pixel CO2 – Alma Lasers The Pixel CO2 fractionated laser (Alma Lasers Ltd., Caesarea, Israel) is a 30-W laser that fractionates the continuous duration CO2 laser beam through a patented Pixel® microoptics lens array that divides the energy to 49 250 μm spots with a spacing of 1600 μm. The micro-injury sites are about 15– 20% of the treatment area. Thermal effect goes approximately 300 μm deep at maximal energy. A burning sensation on the skin is said to last 1–3 hours. Re-epithelialization

requires 8–10 days and patients may remain erythematous for 6 weeks to 3 months. The Pixel® CO2 OMNIFIT hand-piece is a separate device that can fit on to nearly any existing CO2 laser designed for skin ablation or resurfacing. It converts any pulsed or continuous wave CO2 laser into a fractionated skin resurfacing laser.

MedArt FrX – MedArt, Denmark This 20-W CO2 laser equipped with a scanner performs fractionated resurfacing with 36, 64, or 100 μm microthermal zones/cm2. One study on the perioral area treated three

401

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times using a 0.5 mm spot size and 12 W with a single pass produced histologic evidence of increased collagen without any noticeable improvement in wrinkles in 9 of 11 patients. Crusting lasted up to 15 days with erythema lasting 1–3 days.

SmartXide DOT – Deka, Italy, Novel Micro Ablative Affirm CO2 Cynosure The SmartXide DOT/Affirm CO2 is the same fractionated laser sold by two subsidiaries of the company EIEn. While power up to 30 W accounts for depth of ablation of approximately 300–350 μm, dwell time (0.2–2.0 ms in microablative mode; 0.2–20.0 ms in standard mode) controls the width of the thermal pulse that is delivered directly after the microablation occurs. A third setting space between laser impacts can be adjusted from 0.0 to 2.0 mm in order to change the laser from fractionated to fully ablative. The scan mode defines how each of the spots are laid out on the scanned surface. The “normal” option will sequentially place each spots. The “interlaced and autofill” options are especially programmed to minimize tissue overheating. In the interlaced mode, odd lines are scanned first followed by the even ones. In the autofill mode, the spots are randomly placed on the scanned area. Like the Lumenis Active/Deep FX, the Affirm CO2 user has the flexibility of selecting one of the six possible shape options (rectangle, triangle, hexagon, parallelogram, line, and point) to fit to the patient’s anatomy. In addition, each

shape can be modified in size (maximum scan area: 15 × 15 mm) and ratio (width/height). Finally, the Affirm CO2 operates without any consumables and comes with the option of a hand-piece that can be used for excision and ablation. As of this writing there are no published or unpublished investigations on this product but excellent results have been presented (Figure 49.10).

Mosaic Lutronic – eCO2™ New Jersey – imported from Korea The Lutronic eCO2 is a multifunctional microfractional CO2 laser with the ability to target the superficial epidermis or remodel collagen deep within the reticular dermis. The eCO2 allows the user to select between several scan shapes and sizes, a sequential beam pattern or a non-linear randomized microbeam delivery pattern (known as Lutronic’s Controlled Chaos Technology™ – a spray paint-like approach). The Controlled Chaos Technology minimizes thermal damage by spacing each beam further apart to reduce the collateral thermal effect of the laser beams and creates a more natural post-treatment look by non-sequentially placing the beams. There are dual operation modes, the Static Mode (a pulsed operating mode) and the Dynamic Mode (a continuous operating mode) used to “feather” the treatment to reduce the “checkerboard” appearance that is common with currently available fractional CO2 devices (Figure 49.11). A Multiple Repetition Mode (also on the Lumenis Deep FX) enables even deeper penetration (successive shots of two to five) to create subdermal damage without the superficial

(a)

(b) Figure 49.10 Patient treated with the Affirm CO2 laser. (a) Before treatment; (b) 6 weeks after treatment. (Courtesy of Dr. Bruce Katz.)

402

49. CO2 laser resurfacing

Figure 49.11 The Controlled Chaos Technology minimizes thermal damage by spacing each beam further apart to reduce the collateral thermal effect of the laser beams.

damage for greater skin tightening ability. The eCO2 laser has a variable microbeam delivery speed, skin sensing treatment tips (safety feature that prevents laser firing without skin contact), and user-friendly treatment interfaces that enable real-time tracking of microbeam delivery (automatic total density counter) in dynamic mode. There are three interchangeable treatment tips (120, 300, and 1000 μm), which include a pinpoint beam tip for traditional ablative skin resurfacing. The 120 μm beam size has a deep penetration depth (up to 2.4 mm) (Figure 49.12). There are no consumable tips for the eCO2 laser. Patients are usually healed within 3–5 days post-treatment at 140 mJ of pulse energy (Figure 49.13).

Sciton ProFractional and ProFractional-XC – Sciton Sciton’s ProFractional 2940 nm wavelength allows the user to optimize treatment depth, area coverage, and the ratio of ablation and thermal zone. The ProFractional module can selectively treat – in a single pass – from 1.5 to 60% of the skin area and from 25 to 1500 μm in depth. ProFractionalXC provides the same treatment depths and two fixed densities – 5.5 and 11% – and offers two additional features: superfast treatment speed and user-controlled thermal coagulation for increased collagen production. Thermal coagulation is achieved by using a long, low-power pulse that heats but does not vaporize tissue, immediately following a short, high-energy pulse for tissue ablation. ProFractional-XC allows the user to select and control the degree of the thermal damage independent of the ablation depth. With

200 μm

×40

Figure 49.12 The 120 μm beam size has a deep penetration depth (up to 2.4 mm).

this tunable flexibility the user can adjust settings for different skin types and patient expectations and can emulate the thermal profile of CO2 or other lasers (Figures 49.14–49.16).

403

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Resurfacing Techniques

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 49.13 (a) Before treatment; (b) 1 day after treatment; (c) 2 days; (d) 3 days; (e) 4 days; (f) 5 days; (g) 1 week; (h) 4 weeks.

Ablation threshold Ablation Coagulation

Pulse width

Energy Pulse width

Coag level 3

Energy

Coag level 2

Coag level 1

Energy

No coag

Pulse width

Figure 49.14 Diagramatic representation of non-specific thermal damage by controlling the pulse width of the Sciton Er:YAG laser. (Courtesy of Sciton, Inc.)

404

49. CO2 laser resurfacing

(a)

(b) Figure 49.15 Patient treated with the Sciton Profractional at 150 μm, 1.9%. (a) Before; (b) 4 weeks after treatment. (Courtesy of Dr. Michael Gold.)

(b)

(a) Figure 49.16 Patient treated with the Sciton Profractional-XC at 100 μm, 11%, 2 passes. (a) Before treatment; (b) 4 weeks after three treatments. (Courtesy of Dr. Kent Remington.)

Pixel 2940 – Alma This fractionated Er:YAG laser delivers the laser beam via a hand-piece that splits the beam into various microbeams 150 μm in diameter using the same technology as the Pixel CO2 laser. The 7 × 7 matrix with 49 microbeams with 150 μm in diameter yields energy density of up to 51 mJ/pulse per

pixel in an area of 11 × 11 mm2. The 9 × 9 matrix produces 81 microbeams 150 μm in diameter, with 31 mJ/pulse per pixel which covers 11 × 11 mm2. The laser operates at energy of up to 2500 mJ/pulse and multiple passes are required to produce epidermal ablation and dermal effects. The degree of thermal effects is determined by the number of stacks

405

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Resurfacing Techniques

(stationary technique) or passes (non-stationary technique). No Zimmer or other cooling means is required during the procedure. An unpublished study found that erythema lasts 2–10 days (mean 3.6 days). An evaluation of 28 patients treated 1–4 times demonstrated excellent (21) and good (7) results.

Lux 2940 – Palomar This fractionated Er:YAG laser splits the laser beam into micobeams 300 μm in diameter through a microlens array hand-piece. Biopsy demonstrates ablated columns extending 600 μm below the epidermis with an approximate 20 μm coagulation area. Re-epithelialization occurs by 12 hours

with a mild inflammatory response persisting for 1 month (Figure 49.17).

Paxel – Wavelight, Germany This fractionated, heated, punch ablation Er:YAG laser has recently been introduced. A 300 × 1000 μm grid is treated with 64–128 mJ/mm2. Skin texture has been noted to occur with an increase in hyaluronic acid production in a limited unpublished study.

Fractionated Pearl – Cutera This is the newest fractionated Er:YAG laser at the time of this writing. There is very limited experience with this

(b)

(a)

Figure 49.17 Patient treated with the Palomar fractionated 2940 nm Er:YAG laser 6 mm diameter spot, 300 μm depth, 120 μm crater diameter, 40–60% coverage. (a) Before treatment; (b) immediately after treatment; (c) 3 months after treatment. (Courtesy of Dr. E. Vic Ross.)

(c)

406

49. CO2 laser resurfacing device. Ross notes that 300 μm holes can ablate 200–1000 μm depending on the energy fluence used.

Technique and procedures for fractionated laser treatment (Active/Deep FX) Preoperative Our experience with full-face ablative laser resurfacing has proven that preoperative treatment with topical retinoids, glycolic or depigmenting agents such as hydroquinones are not required to enhance treatment efficacy. At best, by pretreating the skin, both patient and physician can determine what products are easily tolerated and/or irritating to the skin. This may be beneficial if and when the physician prescribes the medical creams post-laser to treat hyperpigmentation or an acniform eruption. It does make sense to ensure that patients have adequate nutrition and vitamin stores to enhance healing and promote new collagen formation. I regularly recommend oral antioxidants and a multivitamin. No controlled clinical studies have yet to be performed to demonstrate the efficacy of this recommendation. We have found that treating areas of hyperactive muscle movement, such as the lateral canthus, with a botulinium toxin neuromodulator 1 week before laser treatment will allow for uniform lamellar collagen deposition to occur. We do not recommend performing these injections at the same time as laser treatment because the resulting inflammation and edema from the laser may inactivate and/or promote migration of the neuromodulator from the intended site of injection. Before treatment, patients wash their faces with a neutral cleanser. A topical anesthetic cream (2.5% lidocaine and 2.5% prilocaine (Pligalis, Galderma, Dallas TX, USA) is applied to the face for 30 minutes and wiped off just before treatment. We use the UltraPulse Encore™ Fractional CO2 Laser System (Active/Deep FX, Lumenis Inc., Santa Clara, CA, USA), which emits a wavelength of 10 600 nm, with spot sizes of 1.25 and 0.12 mm in diameter. We always treat the face with a 5 °C cold air cooler (Zimmer) set at maximum flow. We initially use the Deep FX hand-piece with its 120 μm spot size at 15–25 mJ to treat areas of skin laxity and/or wrinkles and scars at a density of 1–2 with one to two passes. The entire face is then treated with one pass of the Active FX hand-piece with its 1.25 mm spot size at a fluence of 125 mJ, frequency of 100 Hz, pattern of 3 (square), size 7 mm, and density of 2. We always used the Cool Scan setting, which produces a randomized spot pattern allowing for extra cooling to occur between laser impacts and a repeat delay of 0.3 Hz. The mean duration for the entire procedure is 10–15 minutes.

Postoperative Patients apply cold, wet compresses immediately post-treatment. They use Aquaphor healing ointment for 3 days until

epithelial healing is complete and then a bland moisturizer such as Cetaphil cream (Galderma, Fort Worth, TX, USA) or Pryatine-6 cream (Senetek, Napa, CA, USA) four times a day until erythema has resolved. Patients wear a broadspectrum, zinc oxide containing sunscreen during the day under a mineral based make-up. At 3–4 weeks, when epidermal regeneration is complete with formation of an intact epidermal barrier, patients then use a topical antioxidant growth factor cream (2.5% CRS SpaMD Vitaphenol cream, Avidas Pharmaceuticals, Doylestown, PA, USA) to further stimulate fibroblastic formation of new collagen and elastic fibers. Sun protection with UVA and UVB blockers is continued. Patients are seen 1 day, 1 week, and 1 month after the procedure and then every 3 months. A botulinium toxin neuromodulator is recommended to relax hyperactive muscles and allow continued collagen deposition every 3–4 months. If patients do not achieve the degree of improvement they would like, repeat treatments are scheduled every 6 months. Histologic studies of non-fractionated CO2 and Er:YAG laser resurfacing patients demonstrated continued collagen production and improvement lasting up to 2 years after treatment. It is not know how long fibroblastic stimulation occurs after fractionated laser resurfacing, but 6 months seems to be a reasonable estimate.

Identification and management of complications We recently performed a retrospective evaluation of 373 consecutive patients treated with the Active/Deep FX in our office. We found 4.6% incidence of an irritant reaction to postoperative topical therapy, 2.5% with acne lesions secondary to postoperative ointment, 1% incidence of erythema lasting > 4 days, 1% incidence of herpes simplex in patients not prophylactically treated with an antiviral that cleared with antiviral treatment, and importantly no patient with either postoperative hyperpigmentation or hypopigmentation. A recent split-face study on Chinese patients confirms our adverse effects profile as well as the lack of post-laser pigmentary alterations. Of note is that unlike fully ablative, non-fractionated CO2 laser resurfacing, we have yet to see any patients with hypopigmentation. This could either be that we do not yet have long enough follow-up on a large enough patient group, or that fractionating epidermal and dermal ablation has a protective effect on epidermal melanocytes.

Conclusions In our clinic from 2004–2007, we performed on average 75 full-face CO2: Er:YAG laser resurfacing/year, 75 one pass Er:YAG laser resurfacings/year, and 150 Active/Deep FX

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fractionated CO2 laser resurfacings/year. In 2008 those numbers have changed with only 25 full-face CO2: Er:YAG laser resurfacings, 35 one pass Er:YAG laser resurfacings/ year, and 225 Active/Deep FX fractionated CO2 laser resurfacings. Our advice to patients is to choose the procedure based on how much time they can take off from work and/ or social events vs. the number of treatments that they are willing to undergo to achieve the expected results. Patients with severe acne scarring or those with extensive photodamage, actinic keratoses, and/or acne scarring do best with deeper, non-fractionated laser resurfacing and do not achieve satisfactory results with less invasive procedures. We have found that severe acne scarring may require 2–3 treatments every 6 months to achieve optimal results. Full face CO2: Er:YAG laser resurfacing usually gives excellent results for up to 10 years before patients request additional cosmetic procedures. Full-face Er:YAG laser resurfacing procedures have a more rapid healing and are best reserved for patients who need limited skin tightening but have extensive superficial photodamage. Full-face Er:YAG resurfacing can also be combined with spot Deep FX fractionated laser resurfacing over wrinkled areas or in areas that require skin tightening. Optimal results last approximately 5 years. Fractionated CO2 laser resurfacings are usually given twice within a year to achieve optimal results. At this time our limited experience over 3 years of use does not allow an accurate prediction for the longevity of this procedure, but 5 years seems like a reasonable estimate. Future advances in fractionated CO2 laser resurfacings will incorporate a variety of spot size and energy densities in one hand-piece to allow for more rapid treatment with variation of laser depths as well as differing widths and depths of both flash vaporization and non-specific thermal damage. Incorporation of different laser wavelengths including but not limited to 2940 nm Er:YAG, 1064, 1320, 1440, and 1550 nm separately or together may also increase efficacy.

Further reading Cassuto DA, Sadick NS, Scrimali L, Sirago P. (2008) An innovative device for fractional CO2 laser resurfacing: a preliminary clinical study. Am J Cosmet Surg 25, 97–101.

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Christiansen K, Bjerring P. (2008) Low density, non-ablative fractional CO2 laser rejuvenation. Lasers Surg Med 40, 454–60. Fitzpatrick RE, Goldman MP, Satur NM, Type WD. (1996) Pulsed carbon dioxide laser resurfacing of photoaged skin. Arch Dermatol 132, 395–402. Goldman MP. (2006) Carbon dioxide and erbium:YAG laser ablation. Cutaneous and Cosmetic Laser Surgery. Mosby-Elsevier, p. 162. Goldman MP. (2006) Laser–tissue interactions. Cutaneous and Cosmetic Laser Surgery. Mosby-Elsevier. p. 5. Goldman MP, Manuskiatti W, Fitzpatrick RE. (2000) Combined laser resurfacing with the ultrapulse carbon dioxide and Er:Yag lasers. In: Fitzpatrick RE, Goldman MP, eds. Cosmetic Laser Surgery. St. Louis: Mosby. Goldman MP, Marchell N, Fitzpatrick RE, Tse Y. (2000) Laser resurfacing of the face with the combined CO2/Er:YAG laser. Dermatol Surg 26, 102–4. Greene D, Egbert BM, Utley DS, Koch RJ. (1999) The validity of ex vivo laser skin treatment for histological analysis. Arch Facial Plast Surg 1, 159–64. Hantash BM, Bedi VP, Chan KF, Zachery CB. (2007) Ex vivo histological characterization of a novel ablative fractional resurfacing device. Lasers Surg Med 39, 87–95. Hobbs ER, Bailin PC, Wheeland RG, Ratz JL. (1987) Superpulsed lasers: minimizing thermal damage with short duration, high irradiance pulses. J Dermatol Surg Oncol 13, 9. Lapidoth M, Odo MEY, Odo LM. (2008) Novel use of erbium (2,940-nm) laser for fractional ablative photothermolysis in the treatment of photodamaged facial skin: a pilot study. Dermatol Surg 34, 1048–53. Lowe NJ, Lask G, Griffin ME. (1995) Skin resurfacing with the UltraPulse carbon dioxide laser: observations in 100 patients. Dermatol Surg 21, 1025–9. Manstein, D, Herron GS, Sink, RK, Tanner, H, Anderson RR. (2000) Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med 320, 2026–38. Trelles MA, Velez M, Mordon S. (2008) Correlation of histological findings of single session Er:YAG skin fractional resurfacing with various passes and energies and the possible clinical implications. Lasers Surg Med (in press).

Chapter 50: Non-ablative resurfacing David J. Goldberg1 and Katie Rossy2 1

Mount Sinai School of Medicine, New York, and Skin Laser & Surgery Specialists of New York and New Jersey, New York, NY, USA 2 New York Medical College, New York, NY, USA

BAS I C CONCEPTS • Non-ablative resurfacing produces an injury requiring less recovery time than ablative resurfacing. • Non-ablative lasers have been used to successfully treat rhytides, dyspigmentation, vascular changes, skin texture, laxity, and scarring. • Non-ablative rejuvenation systems are composed of lasers, light sources, and radiofrequency devices. • Each non-ablative system targets a different chromophore in the skin to produce different clinical results.

Introduction In recent years there has been a progressive movement towards non-surgical interventions for facial rejuvenation. Ablative resurfacing with CO2 and erbium:yttrium aluminum garnet (Er:YAG) lasers were first used to treat photodamaged skin in the 1980s and remain the gold standard today [1–5]. Yet, despite their effectiveness in treating photoaging, there has been a recent push for non-ablative treatment modalities with less down-time and fewer side effects. Non-ablative lasers have been used to successfully treat rhytides, dyspigmentation, vascular changes, skin texture, laxity, and scarring [1,5,6]. The main goal of these systems is to selectively induce dermal damage, resulting in collagen remodeling and production while sparing the epidermis [1,3,6–8]. Many different systems have been used with this endpoint in mind (Table 50.1), and these are discussed in detail below.

Pathophysiology Non-ablative rejuvenation systems are composed of lasers, light sources, and radiofrequency devices. Laser systems use energy in the infrared or near-infrared spectrum to target specific dermal chromophores, such as water, melanin, and

hemoglobin. In contrast, radiofrequency devices produce heat in the dermis and subcutaneous tissue as a result of resistance to current flow through the tissue. Although the mechanisms of action are different, the end result is the same. Both the light sources and radiofrequency devices effectively heat the dermis eliciting a wound healing response without disturbing the integrity of the epidermis [1,5,9–11]. One of the main effects of photodamage and aging is a reduction in dermal collagen, and this is the target of nonablative rejuvenation. It has been proven that thermalinduced injury to the dermis causes local release of inflammatory cytokines leading to the proliferation of fibroblasts which results in collagen synthesis [7,12–15]. In vivo mouse studies have been performed to evaluate collagen composition after treatment with various lasers, and they have all demonstrated a significant change in collagen and extracellular matrix [7,13]. A study by Liu et al. [7] compared the dermal collagen composition after treatment with various laser systems. This study confirmed that collagen I production is predominantly increased after non-ablative treatment with the pulse dye laser (PDL), 1320 nm neodymium:yttrium aluminum garnet (Nd:YAG) laser, and the long pulsed 1064 nm Nd:YAG laser. However, collagen type III was more significantly increased in those treated with the Q-switched 1064 nm Nd:YAG laser. These results not only support the theory of neocollagenesis, but also provide specific data on collagen composition and differences in laser systems. This study suggests that because of the predominant increase in collagen type III after treatment with the Q-switched Nd:YAG laser, it may be more effective in increasing the elasticity of the skin and giving a more youthful appearance.

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Table 50.1 Lasers for facial rejuvenation. Laser type

System name

Pulsed KTP

Gemini (Laserscope) Aura (Laserscope) Versapulse (Coherent/Lumenis) Diolite (Iridex)

Pulsed dye 585 nm

Cbeam (Candela) SPTL-1B (Candela) Photogenica V (Cynosure)

595 nm

Cynosure V-star (Cynosure-585/595) V-beam (Candela)

Intense pulse light

Quantum SR (Lumenis) Palomar Starlux (Palomar) Vasculight (Lumenis) Estelux/Medilux (Palomar) Aurora DS/Aurora SR (Syneron)

1320 nm Nd : YAG

Cool Touch I, II, and III (Cooltouch)

1064 nm QS Nd : YAG

Medlite IV Continuum (Biomedical) VersaPulse VPC (Lumenis)

1450 nm diode

Smoothbeam (Candela)

Er:glass 1540 nm

Aramis-Quantel (Quantel Medical)

Infrared light (1100–1800 nm)

Titan (Cutera Inc.)

Radiofrequency devices Monopolar

Thermacool TC (Thermage)

Unipolar and bipolar

Accent (Alma Laser)

KTP, potassium titanyl phosphate.

Non-ablative modalities Many non-ablative systems have been evaluated for efficacy in facial rejuvenation. Results have been variable and often require multiple treatments in order to appreciate clinical improvement. The most effective treatment regimens are still being determined for facial rejuvenation, and the corresponding studies for each laser are discussed below. The most common lasers and parameter settings used today are outlined in Table 50.2.

Potassium titanyl phosphate 532 nm laser The 532 nm potassium titanyl phosphate (KTP) laser is one of the many modalities used in facial rejuvenation (Figure 50.1). It is absorbed more intensely by melanin and hemoglobin, and so it is thought that fewer treatments are needed

410

when targeting these components of photodamaged skin [2]. This laser has been shown to effectively target vascular and pigmentary change, skin texture, tightening, acne scars, and rhytides [5,15]. Lee [15] performed a 150 person study to compare the efficacy of the KTP laser alone, the long pulsed Nd:YAG alone, or the two modalities combined on collagen enhancement and photorejuvenation. After 3–6 treatments, all three groups showed statistically significant improvement in rhytides, skin toning and texture, reduction in redness, and improvement in dyschromia. Overall, the KTP laser-treated patients showed more improvement than the long pulsed Nd:YAG laser, but the combined treatment group was superior to either group alone. The combined group had a 70– 80% improvement in redness and pigmentation, 40–60% improvement in skin texture, tone, and tightening, and a 30–40% improvement in rhytides. In addition to these findings, it was also noted that collagen remodeling continues for up to 6–12 months post-treatment, with slow regression in benefit thereafter. Although further studies are necessary, these results suggest that combined modalities may be superior at targeting various factors involved in photodamage and more effectively stimulate collagen production.

Pulse dye laser 585 or 595 nm The PDL is a yellow light that targets oxyhemoglobin and melanin (Figure 50.2). It has been used to treat vascular changes and induce new collagen formation. It has been hypothesized that wavelengths targeting hemoglobin disrupt vascular endothelial cells resulting in cytokine release and subsequent collagen remodeling and production [5,16,17]. A group of 10 female patients, Fitzpatrick types I–IV, were treated in the periorbital area with the 595 nm flash lamp PDL [17]. One side of the face was treated with the following laser settings: 1.5 ms pulse, fluences of 5–6 J/cm2, and a spot size of 7 mm. The contralateral side was treated with a 40 ms pulse duration, fluences of 8–11 J/cm2, and a 7 mm spot size. Cryogen cooling was administered for 30 ms with a delay of 30 ms before treatment. Subjects were treated 1–2 times, and at their 6-month follow-up 70% treated had mild to moderate improvement overall. Sixty percent had equal improvement on both sides despite the different settings. Histologic and electron microscopic evaluation showed a significant increase in papillary dermal collagen, mainly type I. Another study performed by Bernstein [16] evaluated the effects of treatment of sun-damaged skin with a 595 nm long pulse duration PDL. Ten subjects were treated with 10 ms pulse duration, fluences of 8–10 J/cm2, and a 10 mm spot size. Improvements were evaluated 8 weeks after treatment with photograph comparison. Blinded physician evaluation of before and after treatment photographs rated improvement in wrinkles in 50%, facial veins improved in 82%,

50. Non-ablative resurfacing

Table 50.2 Non-ablative lasers. Laser type

Wavelength (nm)

Fluences (J/cm2)

Pulse duration

Spot sizes (mm)

Target

KTP (pulsed)

532

7–15

20–50 ms

2, 4, 10

Hemoglobin, melanin

PDL

585 595

3–6.5 6–12

350, 450 μs 6–10 ms

5, 7, 10 7, 10

Hemoglobin, melanin

IPL

550–1200

25–28

2.4, 4.0 ms

Nd:YAG

1320

17–22

200 or 350 μs

6, 10

Water

Nd:YAG (QS)

1064

2.5–7

5 ns

Hemoglobin, melanin, water

Diode

1450

8-14

160-260 ms

4, 6

water

Er:glass

1540

Up to 126

3.3

4, 5

water

Infrared light

1100–1800

30–40

170–200 pulses

RF, monopolar

RF bipolar current

61.5–63.5 (adjusted for pain)

300–400 pulses

RF, unipolar

RF electromagnetic radiation

50–250

RF, bipolar

RF bipolar current

40–100

Hemoglobin, melanin, water (weak)

–

Radiofrequency 0.25, 1.0, 1.5, 3 cm

–

IPL, intense pulse light; KTP, potassium titanyl phosphate; RF, radiofrequency; QS, Q-switched; PDL, pulsed dye laser.

Figure 50.1 Potassium titanyl phosphate laser. Figure 50.2 Pulsed dye laser.

overall redness improved 80%, pigmentary change 61.4%, and a 25% improvement in pore size. A small clinical trial was performed on 10 patients comparing the efficacy of a long pulse PDL (LPDL) with an intense pulsed light (IPL) on photodamaged facial skin [18]. When compared with the IPL, the LPDL showed greater

improvement in lentigines (81% versus 62%), no significant difference in wrinkle reduction between the two groups, and fewer treatments were needed with the LPDL when compared with the IPL (three versus six). In addition to using the PDL laser as a single agent in photorejuvenation, recent trends have shown effective

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combination with aminolevulinic acid (ALA) in treatment of photodamaged skin. It is believed that PDL at 595 nm activates protoporphyrin IX, a photosensitizer, which accumulates in photodamaged cells, causing destruction of the cells, release of cytokines, and collagen repair [1]. This is a new and exciting area of research that offers another effective treatment modality for photorejuvenation.

Intense pulsed light The IPL system emits light, with wavelengths of 550– 1200 nm, which effectively targets melanin, hemoglobin, and water, to a lesser degree (Figure 50.3). The IPL device has been used in photorejuvenation to target vascular changes, pigmentary alteration, and mild rhytides [1,2,5,18,19]. Filters may be used with the IPL to target specific chromophores. Rapid improvement in overall appearance after IPL treatment is secondary to rapid and effective improvement of vascular and pigmentary change, rather than improvement in wrinkles [5]. As per Weiss et al. [2], shorter pulse duration and lower cutoff filters when using the IPL system result in significant improvement in pigmentary alteration. Although not thought to be the most effective treatment modality for rhytides, some studies using the IPL have shown improvement [1,3,4,18,19]. Goldberg [3] and Goldberg and Cutler [19] evaluated the treatment of facial rhytides with an IPL system using a 645 nm cutoff filter. Thirty patients, skin types I–III, were treated 1–4 times over a 10-week period. Treatments were delivered using fluences

Figure 50.3 Intense pulsed light.

412

of 40–50 J/cm2, through bracketed cooling device with triple 7 ms pulses, and interpulse delay of 50 ms. At 6 months’ follow-up, approximately 53% showed some improvement, 30% showed substantial improvement, and 17% showed no improvement. Hedelund et al. [4] performed a study looking at the efficacy of IPL treatment for perioral rhytides in comparison with CO2 ablative resurfacing. Twenty seven females, skin type II, with perioral rhytides were randomly treated with 3-monthly IPL sessions or one CO2 laser ablation. The results showed a higher degree of patient satisfaction and significant improvement in rhytides with CO2 laser resurfacing when compared with IPL rejuvenation. In addition to the more dramatic improvement seen with CO2 resurfacing, side effects were also found to be significantly higher in this group. Patients treated with the CO2 laser experienced milia, dyspigmentation, and persistent erythema, while the IPL group was not noted to have any side effects. Both groups showed long-term improvement in skin elasticity, although no significant improvement in wrinkles was seen in the IPL treatment group. Many physicians today advocate 3–6 treatments for significant improvement, which implies that the treatment course may not have been sufficient to produce notable results.

1320 nm Nd:YAG One of the first laser systems to be developed for nonablative rejuvenation was the Nd:YAG 1320 nm laser (Figure 50.4) [20]. At this wavelength, energy is able to penetrate into the papillary and mid-reticular dermis, and it is absorbed by water associated with dermal collagen. There is a high water absorption and strong scattering in the dermis which allows for extensive dermal wounding [20]. The surface

Figure 50.4 1320 nm neodymium:yttrium aluminum garnet (Nd:YAG) laser.

50. Non-ablative resurfacing cooling systems are present to protect the epidermis from involvement. The 1320 nm Nd:YAG laser has been used to target acne scarring, photoaging, and rhytides with variable results [1– 3,20,21]. As a result of its poor absorption by melanin, it can be used in all skin types without fear of pigmentary change [21]. When treating mild rhytides or acne scars, Weiss et al. [2] recommends using a fluence of 17–19 J/cm2, a total of 25 ms of cooling (pre and post cooling at 10 ms and midcooling at 5 ms), with a fixed pulse duration of 50 ms, and 2–3 passes. When treating acne scars with this regimen, 30–50% improvement has been observed in about four of five patients, while 20% show no significant response. According to a study performed by Rogachefsky et al. [21], the 1320 nm Nd:YAG laser is an effective modality to treat atrophic and mixed pattern facial acne scars. After treating 12 patients with 3-monthly sessions, optimal improvement was noted in atrophic acne scars; however, mixed acne scars also showed softening of sclerotic and shallow pitted scars. Sadick and Schecter [20] also confirm significant improvement in acne scars after treatment with the 1320 nm Nd:YAG, but they propose that six sessions is more effective than three laser sessions.

Q-switched Nd:YAG 1064 nm laser The Q-switched (QS) Nd:YAG 1064 nm laser has not only proven to be successful for treatment of tattoos, vascular, and pigmented lesions, but it has recently been used to treat rhytids, photodamage, and acne scars (Figure 50.5) [3,8,11,22]. This laser system is poorly absorbed by water, making deeper collagen damage more likely when compared with systems with other wavelengths [22]. It has been hypothesized that when compared with other non-ablative systems, the 1064 nm QS Nd:YAG laser is able to cause the most severe dermal damage and thus produce the greatest amount of collagen remodeling. This was confirmed in a mouse study which showed greatest improvement in skin elasticity after treatment with the QS Nd:YAG 1064 nm laser [13]. Another small study involving eight patients was performed to evaluate the effects of the QS 1064 nm Nd:YAG laser on facial wrinkles [22]. Treatments were performed monthly, for a total of 3 months, with a fluence of 7 J/cm2, a 3 mm spot size, and two passes, with petechiae as the desired endpoint. In the end, six of the eight subjects demonstrated clinical improvement in rhytides. The QS 1064 nm Nd:YAG laser has also been used to treat atrophic acne scars with notable success. In 11 patients who completed five treatment sessions with the QS 1064 nm Nd:YAG laser, significant improvement in facial acne scars was demonstrated [8]. After completing all five treatments, improvement was seen as early as 1 month, the greatest

Figure 50.5 1064 nm Q-switched Nd:YAG laser.

percentage improvement was noted at 3 months, and improvement had reached a plateau at 6 months. Another similar study used three-dimensional topography to quantify the efficacy of five QS 1064 nm Nd:YAG treatments on facial wrinkles and acne scars [11]. At 3 months post-treatment, a 61% improvement in surface topography was recorded, and it was maintained at the 6-month follow-up. These results, and others, have suggested that collagen remodeling and repair continues to occur for an extended period of time following the last treatment [1,3,8,11].

Erbium:glass 1540 nm The erbium:glass (Er:glass) 1540 nm laser has been used to treat perioral and periorbital rhytides with mild to moderate end results [1,3,12,23]. Fournier et al. [23] studied the effects of the Er:glass laser on 42 patients treated at 6-week intervals for a total of five sessions. Profilometry, ultrasound, and photography were used to rate clinical improvement after the final treatment. All patients reported improvement in quality and appearance of their skin at 6 months. Notable findings showed an increase in dermal thickness by 17%, a reduction of anisotropy by 44.8%, and an overall improvement in clinical appearance. An additional 35-month study was conducted to assess the long-term benefits of treatment with the Er:glass 1540 nm laser on facial rhytides [12]. Eleven patients with periorbital and perioral rhytides were treated with a series

413

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Resurfacing Techniques

of five treatments at 6-week intervals. Approximately half of the patients also received two additional maintenance treatments at 14 and 20 months. Treatments were performed with settings of 8 J/cm2, three stacked pulses at 2 Hz repetition rates for periorbital and five stacked pulses for perioral sites, and a 4 mm spot size. It was demonstrated that for all 11 patients treated, the improvement in collagen anisotropy measurements showed a reduction in rhytides of 51.7% at 14 months, and 29.8% at 35 months. Overall patient satisfaction was 70% at approximately 2.5 years. Based on both of the aforementioned studies, the Er:glass 1540 nm laser appears to effectively stimulate collagen remodeling with long-term results.

In addition to wrinkles, the 1450 nm diode has been used to treat atrophic acne scars with minimal side effects. Tanzi et al. [24] performed a comparison study treating 20 patients with mild to moderate atrophic acne scars with the 1320 nm Nd:YAG on half of the face and the 1450 nm diode laser on the contralateral side. Three-monthly treatments were performed, and only modest improvement in facial scarring was seen among both groups at 6 months. Yet, greater overall clinical improvement and patient satisfaction was seen in the 1450 nm diode laser sites. Increase in dermal collagen and improvement in skin texture was found in both groups. Minimal side effects were reported.

Infrared light devices (1100–1800 nm) 1450 nm diode laser The 1450 nm diode laser targets water-containing tissue to stimulate collagen remodeling and production. It has been used to treat periorbital and perioral rhytides, and facial acne scars (Figure 50.6) [1–3,24,25]. A previous study was performed with the 1450 nm diode laser to assess the efficacy of treatment on facial rhytides and the associated side effects [25]. Twenty patients underwent 2–4 monthly treatment sessions focusing on perioral and periorbital wrinkles. Each session consisted of treatment of one side of the face with laser and cryogen and the other side with cryogen alone. The laser settings were: frequency of 0.5–1.0 Hz, pulse width of 160–260 ms, pre, post, and intermediate cryogen cooling of 40–80 ms total, and a 4 mm spot size. At 6 months after the final treatment, 13 of the 20 laser/cryogen treated sites showed some improvement, while none of the cryogen only sites showed any improvement. It also showed that periorbital wrinkles showed greater improvement when compared with the perioral sites.

Figure 50.6 1450 nm diode laser.

414

A new, non-ablative, broad spectrum infrared device, emitting wavelengths 1100–1800 nm, has been recently introduced for the treatment of photoaged skin. Improvement in skin laxity and rhytides is believed to result from volumetric heating of water in the dermis which leads to tissue contraction [1,26,27]. A large component of facial aging is the development of skin laxity. With this in mind, a study was conducted to evaluate the efficacy of a filtered infrared light device in the treatment of skin laxity with ptosis of the lower face and neck [27]. Thirteen females, with a mean age of 64 years, were treated from the nasolabial folds to the preauricular area, and from the malar prominence to the clavicle. The parameters used were fluences of 30–36 J/cm2, 230–440 pulses per session, pulse duration up to 11 s, a spot size of 1.5 × 1.0 cm, and cooling of the epidermis to 40 °C. Treatments were administered monthly for a total of two treatments. Improvement was seen clinically in 11 of 12 patients who completed the study. Significant improvement in submental and submandibular definition was noted. The most dramatic improvement was seen in those with loss of definition because of excess skin hanging separately from deeper soft tissue. Continued improvement was noted beyond the 1 month follow-up visit. Mild erythema was the only side effect seen, and it resolved within 30 minutes after treatment. A recent small study was performed on nine women, skin types III–IV, with variable photodamage [26]. Half of the subjects received a one time treatment to the face, while the other group had two monthly treatments. The laser parameters were: fluences of 30–40 J/cm2 and 170–200 pulses. Overall, both subjects’ and investigators’ assessments of preprocedural and post-procedural appearances found significant improvement in elasticity, pore size, dyschromia, wrinkles, and overall texture. Also, the improvement in elasticity, rhytides, and skin texture were more evident in the group treated twice. This study showed promising results but was limited to an 8-week timespan and small study

50. Non-ablative resurfacing

Table 50.3 Advanced non-ablative resurfacing. Laser/RF device

Treatment locations

Fluence

Pulse duration/pulse number

Spot size

1320 nm Nd:YAG

Photodamaged dorsal hands

13–18 J/cm2

50 ms macropulse (stacked 350 μs micropulses)

10 mm

Infrared light device (1100–1800 nm)

Neck skin laxity

30–36 J/cm2 (adjusted for pain level)

11 s Total pulses 230–440

1.5 cm

Monopolar RF (Thermacool)

Upper arm skin laxity

Unipolar RF device (Accent XL)

Upper thigh, buttocks, abdominal cellulite

3 cm 150–170 W

30 s

RF, radiofrequency.

population. More studies will need to be performed to determine the role of new infrared light devices in the field of facial rejuvenation.

Table 50.4 Side effects of non-ablative laser resurfacing. Transient erythema and edema (most common) Pain/discomfort Purpura (KTP and PDL)

Radiofrequency devices

Temporary hyperpigmentation Petechiae/pinpoint bleeding (1064 nm QS Nd : YAG)

Radiofrequency (RF) devices have become another widely accepted method of non-ablative rejuvenation. The Food and Drug Administration (FDA) has approved the RF devices for the treatment of periorbital rhytides [9,10].

Burning and vesiculation (rare) Crusting Edematous papules, 1–7 days (1450 nm diode) KTP, potassium titanyl phosphate; PDL, pulse dye laser; QS, Q-switched.

Advanced approaches In addition to facial rejuvenation, several of these devices have also been evaluated for use in photoaging and tightening of other anatomic sites (Table 50.3) [26,28,29,31]. Early studies and preliminary results have suggested that nonablative resurfacing may play a significant part in non-facial rejuvenation and tightening. Yet, further results are necessary to determine how important they will be in this rapidly growing field. For example, a small case series was performed using the 1320 nm Nd:YAG laser to treat photoaging hands [29]. After six monthly treatments, four of the seven patients showed mild to moderate improvement in smoothness, reduced wrinkles, and more even pigmentation. Subjective improvement was reported by six of the seven patients at 6 months. Although this study was small, the results showed statistically significant, although mild, improvement in photoaged hands. RF and infrared light devices have also been used in an attempt to treat skin laxity in non-facial areas with variable findings [27,30,31]. Although non-ablative tightening results may not be as effective as surgical interventions, significant improvement has been found. A small trial using

an infrared light device showed improvement in neck contour and excess skin in 11 of the 12 patients who completed the study [27]. Early results from the use of a monopolar radiofrequency device on upper arm contouring have shown improvement in circumferential size of 36 of 70 patients treated at a 4-month follow-up [31]. Further longterm results are still expected to follow. Other trials are underway looking at the use of RF devices on tightening of thighs and enhancement of gluteal definition.

Complications One of the major benefits of all non-ablative rejuvenation modalities is the low risk of potential complications involved with treatments. The most common side effect found among all non-ablative lasers, light devices, and RF devices is mild transient erythema and edema which commonly resolves within hours to days [1–3,6,8–10, 12,16,17,20,23–25]. Although complications are rare, temporary side effects have been recorded and are listed in Table 50.4.

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Resurfacing Techniques

Conclusions Non-ablative rejuvenation is a relatively new and exciting field in esthetic dermatology. Many different devices are currently being used to treat changes associated with photoaging, such as rhytides, skin laxity, vascular changes, and pigmentary alterations. Although ablative resurfacing and surgical intervention remain the gold standard, non-ablative systems offer an alternative option with less down-time and risk of complications. These devices selectively target the dermis, inciting a wound healing response locally, while sparing the epidermis from harm. Dermal collagen remodeling, production, and repair are upregulated as a result of this selective targeting. Multiple lasers, light sources, and RF devices have been used to induce significant neocollagenesis with measurable success. Yet despite the significant histologic changes noted, the clinical enhancement is often subtle with mild to moderate improvement over time. As a result, it is important to give patients realistic expectations when performing non-ablative rejuvenation. The most effective devices and treatment parameters for photorejuvenation have yet to be determined, but continued enthusiasm in this field gives hope for continued research and success.

References 1 Alexiades-Armenakas MR, Dover JS, Arndt KA. (2008) The spectrum of laser skin resurfacing: nonablative, fractional, and ablative laser resurfacing. J Am Acad Dermatol 58, 719–37. 2 Weiss RA, Weiss MA, Beasley KL, Munavalli G. (2005) Our approach to nonablative treatment of photoaging. Lasers Surg Med 37, 2–8. 3 Goldberg DJ. (2003) Lasers for facial rejuvenation. Am J Dermatol 4, 225–34. 4 Hedelund L, Bjerring P, Egekvist H, Haedersdal M. (2006) Ablative versus non-ablative treatment of perioral rhytides: a randomized controlled trial with long-term blinded clinical evaluations and non-invasive measurements. Lasers Surg Med 38, 129–36. 5 Sadick NS. (2003) Update on non-ablative light therapy for rejuvenation: a review. Lasers Surg Med 32, 120–8. 6 Bosniak S, Cantisano-Zilkha M, Purewal BK, Zdinak LA. (2006) Combination therapies in oculofacial rejuvenation. Orbit 25, 319–26. 7 Liu H, Dang Y, Wang Z, Chai X, Ren Q. (2008) Laser induced collagen remodeling: a comparative study in vivo on mouse model. Lasers Surg Med 40, 13–9. 8 Friedman PM, Jih MH, Skover GR, Payonk GS, Kimyai-Asadi A, Geronemus RG. (2004) Treatment of atrophic facial acne scars with the 1064 nm Q-switched Nd:YAG laser. Arch Dermatol 140, 1337–41. 9 Bogle MA, Ubelho*r N, Weiss RA, Mayoral F, Kaminer FS. (2007) Evaluation of the multiple pass, low fluence algorithm for radiofrequency tightening of the lower face. Laser Surg Med 39, 210–7. 10 Narins DJ, Narins RS. (2003) Non-surgical radiofrequency facelift. J Drug Dermatol 2, 495–500.

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11 Friedman PM, Skover GR, Payonk G, Kauvar AN, Geronemus RG. (2002) 3D in vivo optical skin imaging for topographical quantitative assessment of non-ablative laser technology. Dermatol Surg 28, 199–204. 12 Fournier N, Lagarde JM, Turlier V, Courrech L, Mordon S. (2004) A 35-month profilometric and clinical evaluation of nonablative remodeling using a 1540 nm Er:glass laser. J Cosmet Laser Ther 6, 126–30. 13 Dang Y, Ren Q, Li W, Yang Q, Zhang J. (2006) Comparison of biophysical properties of skin measured by using non-invasive techniques in the KM mice following 595 nm pulsed dye, 1064 nm Q-switched Nd:YAG and 1320 nm Nd:YAG laser nonablative rejuvenation. Skin Res Technol 12, 119–25. 14 Keller R, Belda Junior W, Valente NY, Rodrigues CJ. (2007) Nonablative 1064 nm Nd:YAG laser for treating atrophic facial acne scars: histologic and clinical analysis. Dermatol Surg 33, 1470–6. 15 Lee MW. (2003) Combination 532-nm and 1064-nm lasers for noninvasive skin rejuvenation and toning. Arch Dermatol 139, 1265–76. 16 Bernstein EF. (2007) The new-generation, high-energy, 595 nm, long pulse-duration pulsed-dye laser improves the appearance of photodamaged skin. Lasers Surg Med 39, 157–63. 17 Goldberg DJ, Sarradet D, Hussain M, Krishtul A, Phelps R. (2004) Clinical, histologic, and ultrastructural changes after nonablative treatment with a 595-nm flashlamp-pumped pulsed dye laser: comparison of varying settings. Dermatol Surg 30, 979–82. 18 Kono T, Groff WF, Sakurai H, Takeuchi M, Yamaki T, Soejima K, et al. (2007) Comparison study of intense pulsed light versus a long-pulse pulsed dye laser in the treatment of facial skin rejuvenation. Ann Plast Surg 59, 479–83. 19 Goldberg DJ, Cutler KB. (2000) Nonablative treatment of rhytids with intense pulsed light. Lasers Surg Med 26, 196–9. 20 Sadick NS, Schecter AK. (2004) A preliminary study of utilization of the 1320-nm Nd:YAG laser for the treatment of acne scarring. Dermatol Surg 30, 995–1000. 21 Rogachefsky AS, Hussain M, Goldberg DJ. (2003) Atrophic and a mixed pattern of acne scars improved with a 1320-nm Nd:YAG laser. Dermatol Surg 29, 904–8. 22 Goldberg DJ, Silapunt S. (2000) Q-switched Nd:YAG laser: rhytid improvement by non-ablative dermal remodeling. J Cutan Laser Ther 2, 157–60. 23 Fournier N, Dahan S, Barneon G, Rouvrais C, Diridollou S, Lagarde JM, et al. (2002) Nonablative remodeling: a 14 month clinical ultrasound imaging and profilometric evaluation of a 1540 nm Er:glass laser. Dermatol Surg 28, 926–31. 24 Tanzi EL, Alster TS. (2004) Comparison of a 1450-nm diode laser and a 1320-nm Nd:YAG laser in the treatment of atrophic facial scars: a prospective clinical and histologic study. Dermatol Surg 30, 152–7. 25 Goldberg DJ, Rogachefsky AS, Silapunt S. (2002) Non-ablative laser treatment of facial rhytides: a comparison of 1450-nm diode laser treatment with dynamic cooling as opposed to treatment with dynamic cooling alone. Lasers Surg Med 30, 79–81. 26 Ahn JY, Han TY, Lee CK, Seo SJ, Hong CK. (2008) Effect of a new infrared light device (1100–1800 nm) on facial lifting. Photodermatol Photoimmunol Photomed 24, 49–51.

50. Non-ablative resurfacing 27 Goldberg DJ, Hussain M, Fazeli A, Berlin AL. (2007) Treatment of skin laxity of the lower face and neck in older individuals with a broad-spectrum infrared light device. J Cosmet Laser Ther 9, 35–40. 28 Sadick NS, Alexiades-Armenakas M, Bitter P Jr, Hruza G, Mulholland RS. (2005) Enhanced full-face skin rejuvenation using synchronous intense pulsed optical and conducted bipolar radiofrequency energy (ELOS): introducing selective radiophotothermolysis. J Drugs Dermatol 4, 181–6. 29 Sadick N, Schecter AK. (2004) Tilization of the 1320-nm Nd:YAG laser for the reduction of photoaging of the hands. Dermatol Surg 30, 1140–4.

30 Alexiades-Armenakas M. (2006) Rhytides, laxity, and photoaging treated with a combination of radiofrequency, diode laser, and pulsed light and assessed with a comprehensive grading scale. J Drugs Dermatol 5, 731–8. 31 Goldberg DJ, Hussain M, Fazeli A, et al. (2007) Monopolar radiofrequency tightening of upper arm skin laxity: a multicenter study. Laser Surg Med (Suppl 19), 19.

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Chapter 51: Microdermabrasion Pearl Grimes Vitiligo and Pigmentation Institute of Southern California, and University of California – Los Angeles, Los Angeles, CA, USA

BAS I C CONCE P T S • Microdermabrasion is a superficial resurfacing procedure that utilizes a particulate to remove the stratum corneum. • Microdermabrasion has been used to improve acne, scarring, photodamage, textural changes, stretch marks, and hyperpigmentation. • All Fitzpatrick skin types can be treated with microdermabrasion. • The primary advantage of microdermabrasion is the minimal post-procedure down-time. • Contraindications to microdermabrasion include impetigo, herpes simplex, verruca plana, or other skin infections.

Introduction Microdermabrasion is a superficial skin resurfacing procedure, in which the stratum corneum is partially or completely removed by light abrasion, to correct or improve skin imperfections [1]. This non-invasive procedure is used to treat a variety of skin conditions including acne, acne scars, hyperpigmentation, striae, photodamage, and texturally rough skin (Table 51.1) [2–7]. Microdermabrasion can be used on young and mature skin and is safe for all Fitzpatrick skin types. It is used to treat a variety of anatomic skin sites including the face, neck, chest, back, arms, elbows, knees, and hands. It is sometimes used in combination with chemical peels, non-ablative resurfacing, or other skin rejuvenation procedures. First developed in Italy in 1985, it has become an extremely popular form of resurfacing. In 2007, it was one of the top five esthetic procedures performed in the USA; 829 658 microdermabrasion procedures were performed [8]. Despite the popularity of microdermabrasion there is a dearth of well-designed studies documenting the short-term and longterm efficacy of microdermabrasion.

Microdermabrasion units Multiple microdermabrasion units are available throughout Europe and the USA, with a wide range of features for physician-directed use. Despite the diversity of units, there are several common components to most systems: a pump, tubing, wand, vacuum, and crystals (Table 51.2).

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Different methods of microdermabrasion include mechanical abrasion from jets of aluminum oxide or zinc oxide crystals, fine organic particles, or wands with a roughened surface. Some newer machines include more than one method. Aluminum oxide is the most commonly used abrasive in microdermabrasion. It is a relatively chemically inert abrasive that does not cause allergic skin reactions, such as eczema or itching. Other crystals can also be used for microdermabrasion and these include sodium chloride, sodium bicarbonate, and magnesium oxide crystals [9]. Generally, these alternative particles are not as abrasive as aluminum oxide. Instead of crystals, some newer techniques use diamond-tipped devices that abrade the skin. Such devices have tips made of diamond chips of varied size and coarseness for different types of skin and varied levels of resurfacing.

Procedure During the microdermabrasion procedure microcrystals are deposited on the skin via short, rapid strokes of the wand. A tube contained within the wand simultaneously aspirates the crystals and skin debris. Particle flow rate and vacuum pressure determine the volume of particles impacting the skin. The depth of the treatment is determined by several factors, including the strength of the flow of crystals, speed of movement of the wand, and the number of times the device passes over the treatment area [10]. Slower movement of the wand (allowing longer contact of the abrasive crystals with the skin) and more passes increase the depth of microdermabrasion. The treatment is typically performed in a series of 4–12 weekly or biweekly visits taking 20–30 minutes. The series can be significantly longer, particularly for acne scarring.

51. Microdermabrasion

Table 51.1 Indications for microdermabrasion. Acne Hyperpigmentation Melasma Post-inflammatory Oily skin Enlarged pores Photodamage Texturally rough skin Wrinkles

Table 51.2 Components of microdermabrasion units. Pump

To generate a high pressure stream of non-absorbable crystals

Tube

To deliver the crystals to the wand (hand-piece)

Wand

To contain the crystals

Vacuum

To remove the spent crystals

Crystals

For exfoliating

microdermabrasion showed an increase in stratum corneum hydration after 24 hours, which increased significantly by day 7 on the sodium chloride-treated side. No difference was seen in pH or sebum production. The results suggested that changes in TEWL and hydration enhance lipid barrier function. Such barrier alterations may result in the improved texture and overall appearance of microdermabraded skin. Davari et al. [11] also demonstrated changes in skin barrier function. Their study evaluated the extent of skin barrier function changes in relation with the number of microdermabrasion passes. A series of six microdermabrasion treatments using aluminum oxide crystals were performed in 10 patients. One side of the face was treated with two passes of microdermabrasion and the other side was treated with three passes, randomly. Stratum corneum hydration, sebum secretion, and skin pH were measured before and after the procedure for all sessions, and also at 1 and 4 weeks after the last treatment. Significantly higher sebum content and stratum corneum hydration were observed on the side of the face treated with three passes, suggesting that the higher number of passes has a significant effect on lipid barrier restoration. In addition, significant increases in ceramide levels in the stratum corneum have been observed following the first and second microdermabrasion session. By the third or fourth treatment levels returned to normal [12]. The increase in activating protein 1 (AP-1) and NF-κB following microdermabrasion may also influence ceramide levels via cell signaling pathways [13].

Molecular effects

Skin physiology and histopathology Several studies have assessed the physiologic changes, barrier function, and histopathologic alterations induced by microdermbrasion. In general, most of these studies have been performed in small numbers of patients. In spite of the differences in methodologies, protocols, machines, pressures, number of passes, and biopsy sites, data suggest physiologic and histologic trends [1].

Epidermal barrier function Epidermal barrier changes induced by aluminum oxide and sodium chloride microdermabrasion were initially reported by Rajan and Grimes [9]. Eight patients were treated in a split-face study. One side of the face was treated with aluminum oxide and the other side with sodium chloride microdermabrasion. Transepidermal water loss (TEWL), stratum corneum hydration, skin pH, and sebum production were measured at baseline, 24 hours, and 7 days after treatment. At 24 hours, TEWL increased for both aluminum oxide and sodium chloride microdermabrasion. After 7 days, there was a decrease in TEWL values to less than baseline (p < 0.05), suggesting improved epidermal barrier function. In addition, both aluminum oxide and sodium chloride

It has been suggested that microdermabrasion activates dermal remodeling or the wound healing cascade. Karimipour et al. [13] assessed the molecular alterations following a single microdermabrasion treatment to buttock skin. They reported that transcription factors (AP-1 and NF-κB), primary cytokines (interleukin 1β [IL-1β] and tumor necrosis factor α [TNF-α]) and matrix metalloproteinases (interstitial collagenase, stromelysin-1, and gelatinase B) increase rapidly after a single microdermabrasion treatment. However, no significant alterations in stratum corneum structure were noted. The authors suggested that the increase in matrix metalloproteinases could: 1 Result in matrix remodeling and new collagen deposition; or 2 Remove damaged collagen and allow skin to regain its normal tension.

Histopathologic effects Histologic changes have been observed in both the epidermis and dermis (Table 51.3). The most significant change is an increase in the thickness of the epidermis. In a series of six microdermabrasion treatments in 10 patients, Freedman et al. [3] showed that after three passes, the epidermal thickness increased from 45 ± 4 μm to 62 ± 10 μm (p < 0.01), and

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to 65 ± 7 μm (p < 0.01) after an additional three passes. In the Hernandez-Perez and Ibiett [14] study, the epidermal thickness increased from 0.01 to 0.06 mm in some patients, and to 0.01 mm in one patient. Other studies also demonstrated an increase in the epidermal thickness [7,15]. Other epidermal alterations improved by microdermabrasion include polarity of cells, basal cell liquefaction, horny plugs, and atropic changes [14]. In addition, more regular distribution of melanosomes, less melanization, flattening of the rete pegs, and basal cell hyperplasia had been reported (Figure 51.1) [3,7]. Dermal changes include an increase in papillary dermal thickness, as demonstrated by Freedman et al., from 81 ± 8 μm to 108 ± 11 μm (p < 0.01) after three treatments and to 114 ± 9 μm after an additional three. The treated areas showed hyalinization of the collagen fibers in the papillary

dermis; the fibers were thicker, more tightly packed, and orientated horizontally. An increase in elastic fibers was seen at the junction of the reticular and papillary dermis after three treatments. After six treatments, the density of the elastic fibers in the reticular dermis increased. These new fibers were more vertically orientated and of normal caliber. After treatment, the blood vessels appeared ecstatic with the presence of a perivascular infiltrate. Fibroblasts were more conspicious, larger, and more densely distributed within the dermis, especially around the dermal capillaries. Recent interest in the impact of topical antioxidants on the skin has shown that the addition of a polyphenolic antioxidant serum to a facial microdermabrasion regimen also enhances clinical and histologic changes [16].

Contraindications Table 51.3 Histologic changes caused by microdermabrasion. Epidermal Increased thickness Decreased melanization

Relative contraindications to the use of microdermabrasion include rosacea and telangiectasia, which may be exacerbated. Absolute contraindications include active infections such as impetigo, flat warts, and herpes simplex [17–19]. The active use of isotretinoin is also contraindicated.

Alteration of rete ridges Variable epidermal changes Decreased liquefaction of basal cells Improved polarity Variable dermal changes Increased dermal thickness Increased collagen Increased elastin Mononuclear infiltrates Vascular ectasia

Indications for microdermabrasion Acne Microdermabrasion is most effective when treating superficial skin conditions such as acne (Figure 51.2). In a study by Lloyd [2], the role of microdermabrasion in the treatment of patients with acne was studied. Twenty five patients with grade II–III acne received eight microdermabrasion treatments (Parisian Peel microdermabrasion unit used at a pressure of 26.67 mmHg initially and then increased as tolerated)

(b)

(a) Figure 51.1 (a) Baseline biopsy. (b) Biopsy after a series of four microdermabrasion treatments performed at 1 week intervals. Note: No change in thickness of the stratum corneum; however, marked improvement in the polarity of epidermal cells, some increase in epidermal thickness and improvement in dermal collagen.

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(b)

(a) Figure 51.2 Patient with moderate acne treated with a series of five microdermabrasions in combination with oral antibiotics. Treatments at 2-week intervals.

at weekly intervals. Throughout the treatment, patients continued taking their oral antibiotics and topical acne treatment. Photographs were taken before and after treatment, and evaluated for clinical improvement. Twenty-four patients completed the study: 38% (9 of 24) achieved excellent results, 34% (8 of 24) had good results, 17% (4 of 24) had fair results, and 12% (3 of 24) had poor results. Ninetysix percent of patients were pleased with their results. The most prominent improvement was noted with postinflammatory acne changes and the overall skin quality. No adverse effects were noted during the procedure. The treatment was well tolerated. The only side effect was erythema, which resolved within 24 hours. No controls were included in this investigation.

Scars The effectiveness of this technique in the treatment of facial scarring was first demonstrated in 1995 by Tsai et al. [5]. They treated 41 patients with facial scarring with an average of 9.1 treatments. Facial scars included acne, burns, varicella, and post-traumatic scars. A Harvey 91 microdermabrasion unit with a pressure setting of 76 mmHg was used. All patients had “good to excellent” improvement. The study showed that patients with acne scars require longer treatment (mean, 15.19 times) than those with traumatic or surgical scars (mean, 4 times) to achieve clinical improvement (p < 0.001). Multiple passes and numerous treatments are often needed. This is probably because most

acne scars are depressed and surgical and traumatic scars are elevated – depressed lesions are more difficult to treat than elevated ones.

Hyperpigmentation Albeit commonly used to treat disorders of hyperpigmentation, only a few published reports describe the use of microdermabrasion in the treatment of hyperpigmentation [4,7,20]. Cotellessa et al. [4] evaluated the efficacy of microdermabrasion alone or in combination with 15% trichloroacetic acid (TCA) for treatment of patients with multiple hyperpigmented macules of the face. A total of 20 patients were treated. Eight (40%) had complete clearing of the pigmentation after four to eight treatments; 10 (50%) had partial clearance; and two patients (10%) had no improvement after eight treatments. When patients were treated with both TCA peels and microdermabrasion, fewer treatments (four to six) were required to clear or partially clear pigmentation, 50% and 40%, respectively. No serious side effects were observed. Other studies have also reported improvement in mottled and diffuse hyperpigmentation [1,7,21]. Data from the Vitiligo and Pigmentation Institute suggest that microdermabrasion is an effective and well-tolerated treatment for disorders of hyperpigmentation in all racial ethnic groups (Figure 51.3). Conditions treated included melasma, postinflammatory hyperpigmentation, and the dyschromias of photoaging.

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(b)

(a)

Photodamage Microdermabrasion is well suited for patients with early photodamage, especially those with Glogau photaging classes I and II. In a study to evaluate the effect of microdermabasion on photodamaged skin, 10 patients with Fitzpatrick skin types I–III and photodamage (Glogau scale II and III) were treated once a week for five to six treatments using a Parisian Peel [6]. The face was treated with four passes at a pressure of 30 mmHg, while the periorbital skin received two passes at a pressure of 15 mmHg. Clinical responses, skin surface roughness, topography, elasticity, stiffness, compliance, temperature, sebum content, and histology were analyzed. Nine patients completed at least five treatments. Clinical analysis showed mild improvement in the majority of patients. Immediately after treatment, skin temperature increased and sebum content decreased. There was a temporary increase in skin roughness. Dynamic skin analysis showed a decrease in skin stiffness and increase in skin compliance. The authors suggest that the observed changes in skin characteristics are consistent with increased blood flow and mild abrasion. Biopsies showed slight orthokeratosis and flattening of rete ridges and a perivascular mononuclear cell infiltrate, edema, and vascular ectasia in the upper reticular dermis. There was no change in collagen or elastin content. Other studies addressing photodamage have also shown improvements in skin roughness, mottled pigmentation, and

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Figure 51.3 Patient with melasma and textural changes treated with four microdermabrasions and hydroquinone 4%. (a) Before. (b) After.

overall global improvement in the treated skin areas [7,21]. Hernandez-Perez and Ibiett [14] treated seven women, six with Glogau’s photoaging class II and one with Glogau’s photoaging class III. Five microdermabrasion treatments were carried out on each patient, at weekly intervals, three complete passes per treatment. Clinical parameters assessed were oily skin, dilated pores, fine wrinkles, thick skin, and general appearance. Skin biopsies were taken before and after treatment. All patients showed clinical and histopathologic improvements in all parameters assessed. Clinical improvement was considered ‘good to excellent.’ Patients also reported improved self-esteem.

Striae Microdermabrasion is occasionally used to treat striae. However, patients should be advised that this treatment is aggressive in order to reach the level of the papillary dermis and can cause erythema and hyperpigmentation.

Comparison of microdermabrasion and chemical peeling Chemical peeling and microdermabrasion are both popular resurfacing procedures that exfoliate the skin. While microdermabrasion works well on superficial skin imperfections, chemical peels may be more effective on skin defects such

51. Microdermabrasion as deeper scars and wrinkles. The aftercare and down-time are also longer with more aggressive peeling agents. Unlike microdermabrasion, the depth of wounding induced by chemical peeling is determined by the strength of the peeling agent. Superficial peels target the stratum corneum to the papillary dermis. They include glycolic acid, salicylic acid, Jessner’s solution, and trichloroacetic acid (TCA) 10–30%. Medium depth peels penetrate to the upper reticular dermis and the protype is TCA 35–50%, whereas deeper peels penetrate to the mid-reticular dermis (phenol). Glycolic acid peels were compared with microdermabrasion in a right–left controlled assessment [20]. Ten patients were enrolled in this split-face, unblinded, randomized trial. One side of the face was treated with a series of 20% glycolic acid peels on a weekly basis, and the opposite side was treated simultaneously with microdermabrasion. Patients’ self-analysis revealed that seven patients perceived greater improvement on the side treated with microdermabrasion. Physician investigator ratings found no differences between microdermabrasion or the side with glycolic acid. Furthermore, photographic comparisons by investigators did not reveal treatment-related differences. The investigators could not differentiate pre- and post-treatment photographs. However, both procedures were well tolerated. The efficacy and safety of microdermabrasion followed by a 5% retinoic acid peel was compared with the effects of a 5% retinoic acid peel alone in six patients with photodam-

Figure 51.4 Patient with mottled pigmentation, oily skin, and textural changes treated with a series of five microdermabrasions. (a) Before. (b) After.

age. The authors reported improvement in texture, pigmentation, and overall skin appearance. The combination group showed slightly greater improvement [22]. A recent study compared the immunohistologic and ultrastructural changes induced by chemical peeling and microdermabrasion [23]. Fifteen patients were treated by weekly microdermabrasion for 2 months while 15 were treated with weekly chemical peeling using either glycolic acid 70% or Jessner’s solution. Biopsies were pereformed 1 week before treatment and 1 week after treatment. Skin treated with both chemical peels and microdermabrasion showed an increase in epidermal thickness, dermal vascular ectasia, and densely arranged collagen fibers compared with untreated skin. Skin changes were very similar but milder in the group treated by microdermabrasion [23].

Advantages and disadvantages There are several microdermabrasion benefits. One of the most noteworthy is that there is no “down-time” after treatment, unlike chemical peels. Microdermabrasion is a relatively painless and safe procedure; the patient perceives immediate improvement in skin tone, texture, and pigmentation (Figure 51.4). Retinoids and other exfoliation therapies can be continued up to the day of the procedure without incurring significant irritation. However, the effectiveness of microdermabrasion is limited for deeper skin conditions,

(b)

(a)

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such as deep wrinkles and scars, which are currently best treated with other resurfacing techniques. Deeper injury increases complications and recovery time along with effectiveness. Microdermabrasion can be combined with other skin resurfacing procedures or chemical peels [4].

Complications and side effects Although microdermabrasion is considered a safe procedure with few reported side effects [2,5,6,7,14], complications can occur. The most common include mild erythema and increased sensitivity, but these are transient and resolve within a few hours [6,7]. Post-inflammatory hyperpigmentation and streaking can occur from intense pressure of the hand-piece. Petechia and purpura are also complications of aggressive treatment. Post-treatment hyperpigmentation has also been reported and is more likely with aggressive treatment on patients with higher Fitzpatrick skin types (IV–VI) [5]. Ocular complications can occur if microcrystals enter the eye. These include eye irritation, chemosis, photophobia, and punctate keratitis [24]. Patients must wear protective eyewear during the procedure. Cross-contamination can occur when using mircrodermabrasion equipment. Shelton reported that bloody material was present on the wand after performing microdermabrasion on a patient with acne scaring, indicating that it is not sufficient to sterilize the distal cap of the wand or to use disposable caps. The operator must therefore ensure that cross-contamination does not occur. An unusual case of a severe urticarial reaction immediately following aluminum oxide microdermabrasion has been reported [25].

Conclusions Microdermabrasion is considered a safe, non-invasive procedure for resurfacing the skin and is used to treat a variety of skin problems and is suitable for all skin types. However, despite its popularity by patients and physicians alike, there remains a dearth of robust scientific evidence about the efficacy and long-term safety of this procedure. However, the few studies published suggest that both patients and physicians have reported benefits from microdermabrasion: improved texture, pigmentation, improvement in acne scarring, photodamage, and appearance of treated skin as well as improved self-esteem. Most studies were performed on small patient groups where protocols and the variety of units used differed. Further, multicentered, randomized studies are needed to confirm the long-term benefits of this popular and widely used procedure for skin rejuvenation.

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References 1 Grimes P. (2005) Microdermabrasion. Dermatol Surg 31, 1160–5. 2 Lloyd J. (2001) The use of microdermabrasion for acne: a pilot study. Dermatol Surg 27, 329–31. 3 Freedman BM, Rueda-Pedraza E, Waddell SP. (2001) The epidermal and dermal changes associated with microdermabrasion. Dermatol Surg 27, 1031–4. 4 Cotellessa C, Peris K, Fargnoli M, Mordenti C, Giacomello RS, Chimenti S. (2003) Microabrasion versus microabrasion followed by 15% trichloroacetic acid for treatment of cutaneous hyperpigmentations in adult females. Dermatol Surg 29, 352–6. 5 Tsai RY, Wang CN, Chan HL. (1995) Aluminum oxide crystal microdermabrasion. Dermatol Surg 21, 539–42. 6 Tan MH, Spencer JM, Pires LM, Ajmeri J, Skover G. (2001) The evaluation of aluminum oxide crystal microdermabrasion for photodamage. Dermatol Surg 27, 943–9. 7 Shim E, Barnette D, Hughes K, Greenway HT. (2001) Microdermabrasion: a clinical and histopathologic study. Dermatol Surg 27, 524–30. 8 American Society for Aesthetic Plastic Surgery. (2007) Procedure Survey, Dermasurgery Trends and Statistics. Available from http://www.surgery.org/press/statistics.php 9 Rajan P, Grimes P. (2002) Skin barrier changes induced by aluminum oxide and sodium chloride microdermabrasion. Dermatol Surg 28, 390–3. 10 Grimes P. (2008) Aesthetics and Cosmetic Surgery for Darker Skin Types. Lippincott Williams and Wilkins. 11 Davari P, Gorouhi F, Jafarian S, Dowlati Y, Firooz A. (2008) A randomised investigator-blind trial of different passes of microdermabrasion therapy and their effects on skin biophysical characteristics. Int J Dermatol 47, 508–13. 12 Lew Bl, Cho Y, Lee MH. (2006) Effect of serial microdermabrasion on the ceramide level in the stratum corneum. Dermatol Surg 32, 376–9. 13 Kamimipour DJ, Kang S, Johnson T, Orringer JS, Hamilton T, Hammerberg C, et al. (2006) Microdermabrasion with and without aluminum oxide crystal abrasion: a comparative molecular analysis of dermal remodeling. J Am Acad Dermatol 54, 405–10. 14 Hernandez-Perez E, Ibiett EV. (2001) Gross and microscopic findings in patients undergoing microdermabrasion for facial rejuvenation. Dermatol Surg 27, 637–40. 15 Rubin M, Greenbaum S. (2000) Histological effects of aluminum oxide microdermbrasion on facial skin. J Aesthet Dermatol 1, 237–9. 16 Freedman B. (2009) Topical antioxidant application enhances the effects of facial microdermabrasion. J Dermatolog Treat 20, 82–7. 17 Clark C. (2001) New directions in skin care. Clin Plast Surg 28, 745–50. 18 Bernard R, Beran S, Rusin L. (2000) Microdermabrasion in clinical practice. Clin Plast Surg 27, 571–7. 19 Warmuth I, Bader R, et al. (1999) Herpes simplex infection after microdermabrasion. Cosmet Dermatol 12, 13. 20 Alam M, Omura N, Dover J, Arndt KA. (2002) Glycolic acid peels compared to microdermabrasion: a right–left controlled trial of efficacy and patient satisfaction. Dermatol Surg 28, 475–9.

51. Microdermabrasion 21 Hexsel D, Mazzuco R, Dal’Forno T, Zechmeister D. (2005) Microdermabrasion followed by a 5% retinoid acid chemical peel vs a 5% retinoid acid chemical peel for the treatment of photoaging: a pilot study. J Cosmet Dermatol 4, 111–6. 22 Hussein MR. (2008) Chemical peeling and microdermabrasion of the skin: comparative immunohistological and ultrastructural studies. J Dermatol Sci 52, 205–22.

23 Cotellessa C, Peris K, Onorati M. (1999) The use of chemical peelings in the treatment of different cutaneous hyperpigmentations. Dermatol Surg 25, 450–4. 24 Morgenstern K, Foster J. (2002) Advances in cosmetic oculoplastic surgery. Curr Opin Ophthalmol 13, 324–30. 25 Farris P, Rietschel R. (2002) An unusual acute urticarial response following microdermabrasion. Dermatol Surg 13, 324–30.

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Chapter 52: Dermabrasion Christopher Harmon and Chad Prather Total Skin and Beauty Dermatology Center, Birmingham, AL, USA

BAS I C CONCE P T S • Dermabrasion involves mechanically removing the epidermis and papillary dermis, creating a newly contoured open wound to heal by second intention. • The most common indications for dermabrasion are for the improvement of cystic acne scarring, post-surgical scar revision, and enhanced contouring of partial thickness Mohs defects. • Patients must have realistic expectations of the anticipated improvement, possible side effects, and potential complications of dermabrasion prior to treatment. • Proper technique is paramount in order to avoid intraoperative complications. • Vigilance during the postoperative period is important in order to recognize complications at an early stage and prevent long-term sequelae.

Introduction Dermabrasion involves mechanically resurfacing the skin with an abrasive tip driven by a high-speed rotary hand engine. Either a wire brush or diamond fraise may be used as the abrading tip to create an open wound that will heal by second intention. An irregular or scarred cutaneous surface may be surgically abraded in order to achieve a more regular plane, or a more gradual transition between different planes, thereby improving skin contour. This chapter discusses the dermabrasion technique.

complex, wound healing response is triggered, involving transforming growth factor β (TGF-β) driven myofibroblastic deposition of new type I and III collagen and subsequent remodeling in the dermis [2]. Additionally, TGF-β, keratinocyte growth factor (KGF), and epidermal growth factor (EGF) stimulate re-epithelialization from both underlying skin appendages and adjacent epithelialized skin [2]. When properly performed, the irregularly contoured or actinically damaged epidermal and papillary dermal layers are removed, and second intention wound healing occurs. The clinical result is a smoother, more evenly contoured surface, with fewer irregularities in the form of acne scars, rhytides, keratoses, or step-off transitions.

Mechanism of action Indications Fundamentally, the skin can be subdivided into three layers: epidermis, dermis, and subcutaneous tissue. The dermis is further subdivided into the more superficial papillary dermis, containing both a finely woven meshwork of collagen interdigitating with the epidermal rete as well as the superficial vascular plexus, and the deeper reticular dermis, composed of thick bundles of predominantly type I collagen [1]. Resurfacing, by definition, involves iatrogenic removal of one or multiple layers of the skin to create a cutaneous wound. Dermabrasion mechanically removes the epidermis and papillary dermis, creating a partial thickness wound to heal by second intention. The well-characterized, yet

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The most common indications for dermabrasion are desired improvement of acne scars, traumatic and surgical scars, rhinophyma, deep rhytides, and partial thickness Mohs defects [3]. However, dermabrasion is also indicated for improvement of actinic keratoses, seborrheic keratoses, angiofibromas, syringomas, solar elastosis, epidermal nevi, and tattoo removal [4]. With regard to acne scarring, even in the era of laser devices, fractionated delivery approaches, and non-invasive “tissue-tightening” procedures, dermabrasion remains an important tool in the combination approach to the improvement of cystic acne scarring. While the shallow and wide, undulating, or “rolling” type acne scars are better treated with subcision, dermal grafts, fillers, or fractionated laser devices, the slightly deeper and narrower “box-car” type

52. Dermabrasion acne scars that demonstrate step-off vertical borders respond best to mechanical dermabrasion. Additionally, the deepest and narrowest “ice-pick” type acne scars respond best to dermabrasion subsequent to punch excisions, punch grafts, or trichloroacetic acid (TCA) cross-destruction. For traumatic and surgical scars, the thickness, contour, and overall appearance is routinely improved with postoperative dermabrasion. Also known as “scar abrasion,” this procedure is best performed 6–8 weeks after the initial surgery or wounding event [5]. When performed during this 6–8 week window, the late proliferative and early remodeling phases of wound healing are interrupted and partially “reset,” resulting in an improved final cosmetic result. While several modalities, including wire loop electrosurgery and CO2 laser resurfacing, have been described for the treatment of rhinophyma, dermabrasion remains unmatched in the operator’s ability to re-establish the complex contour of the many cosmetic subunits of the nose. Furthermore, although CO2 resurfacing, erbium:yttrium aluminum garnet (Er:YAG) resurfacing, and deep chemical peels may improve facial rhytides, dermabrasion proves as efficacious or more efficacious at removal of both fine and moderate facial rhytides, with a slightly lower risk of permanent hypopigmentation. Finally, dermabrasion proves to be an incredibly useful technique in the armamentarium of the Mohs surgeon. Thin carcinomas in cosmetically sensitive or high-risk areas can often be completely removed with a shallow Mohs layer to the level of the superficial reticular dermis. After clearance, these partial thickness defects, particularly on the nose and scalp, may lend themselves to healing by second intention rather than primary closure, yet with slightly increased risk of an evident contour discrepancy or sharp pigmentary transition. Dermabrasion of the edges surrounding the partial thickness Mohs defect greatly improves the final contour by replacing the steeply beveled wound edge with a more gradual slope. Additionally, dermabrading the remainder of an involved cosmetic subunit of the nose results in a less obvious scar by placing the pigmentary demarcation lines at the less perceptible subunit boundaries.

Advantages and disadvantages Compared with fully ablative resurfacing with the CO2 and Er:YAG lasers, dermabrasion demonstrates similar or greater efficacy for the treatment of scars, rhytides, and precancerous lesions, with less postoperative erythema and more rapid re-epithelialization. While newer, fractionated delivery protocols result in even less erythema and quicker reepithelialization than dermabrasion, their efficacies for the improvement of scars, rhytides, and precancerous lesions do not currently match that seen with mechanical dermabrasion. Dermabrasion has also been shown to be more

efficacious than 5-fluorouracil for the treatment of actinic keratoses [6]. The major disadvantage of dermabrasion compared with the above modalities is that it is much more operatordependent. Unlike laser and light devices, the depth of penetration is not preprogrammed. Successful treatment relies not only on the physician’s knowledge of the modality and application settings, but also on his or her skilled execution. In the novice’s hands, dermabrasion exhibits a narrower window or buffer between effective treatment depth and inappropriate scarring depth. However, this is quickly overcome with experience.

Patient selection and preoperative consultation The most important components of the preoperative consultation are determining the patient’s specific motivation for resurfacing and establishing realistic expectations regarding the treatment outcome. The ultimate goal of any resurfacing treatment should be an improvement of the given defect rather than a complete eradication. Dermabrasion consistently achieves 30–50% improvement in the appearance of deep acne scars and rhytides, but the patient who seeks and expects the elimination of all scars and rhytides will rarely be satisfied. Reviewing before and after photographs with the patient during consultation, particularly when considering full cosmetic unit or full-face dermabrasion, may foster realistic expectations for improvement. The preoperative consult should also include a complete history addressing bleeding disorders, prior herpes simplex infection, impetigo, keloidal or hypertrophic scarring, koebnerizing conditions, prior isotretinoin therapy, and immunosuppression. The risk:benefit ratio of an iatrogenically induced wound is unfavorable in patients who are immunosuppressed, who have a history koebnerizing conditions such as lichen planus and psoriasis, or who demonstrate a propensity towards keloidal or hypertrophic scar formation. Because of an increased risk of scarring in patients on isotretinoin, dermabrasion should be delayed until 6 months after finishing an oral retinoid course [7]. Caution should also be exercised when planning to dermabrade patients who have recently undergone extensive procedures involving the area to be dermabraded, such as a facelift, as a robust blood supply is necessary for appropriate wound healing. Many surgeons prefer to wait 6 months after a facelift before subsequent dermabrasion. Antiviral prophylaxis should be instituted in those with a history of herpes simplex outbreak in the area to be spot dermabraded or in those who are undergoing full-face or multiple cosmetic unit dermabrasion. The antiviral agents acyclovir or valcyclovir may be used, and patients should remain on prophylactic therapy for 10 days after the

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procedure (50 mg valacyclovir b.i.d. for 10 days). Similarly, antibacterial prophylaxis with an antistaphylococcal agent should be instituted in those with a history of impetigo. Particular attention should also be paid to the Fitzpatrick skin type of the patient. Fitzpatrick skin types IV, V, and VI are much more prone to both postoperative hyperpigmentation and permanent, clinically significant hypopigmentation, the latter of which may not appear for several months following the procedure. Preoperative photographs are highly recommended, and should include a frontal view, 45 ° and 90 ° views from both sides, and a close-up view of the areas to be treated. Additionally, all preoperative and postoperative expectations should be discussed. The patient should particularly be made aware of the nature of the postoperative recovery routine, which includes extensive facial dressings with multiple changes over several days, and clinically apparent erythema for several weeks.

Instrumentation With mechanical dermabrasion, a diamond fraise or wire brush abrading tip is driven by a handheld engine at speeds of 15 000–30 000 rotations per minute. Current hand engines include the Osada, Ram, and Urawa Kohgyo Acrotorque hand-pieces. The classic Bell hand engine is no longer available from the manufacturer, but may occasionally be found as a refurbished item through select vendors. Diamond fraises come in a range of shapes and sizes, such as pears, cones, bullets, and wheels, and also vary in coarseness from fine to extra coarse. Alternatively, the wire brush is a 3.0–5.0 mm wide × 17.0 mm diameter wheel with steel bristles radiating from the center in a clockwise fashion when viewed from the shaft (Figure 52.1). The wire brush is the most aggressive type of end piece and can be more

Figure 52.1 Wire brush abrading wheel with steel bristles radiating from the center in a clockwise fashion.

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technically difficult to master, yet it is considered more efficacious by those experienced with its use. The microlacerations created with the wire brush are the most efficient means of removing the nodules of rhinophyma, the thick plaques of hypertrophic scars, and deep acne scars.

Standard technique Treating surgical scars, rhinophyma, and partial thickness Mohs defects provides an excellent point of entry into the practice of dermabrasion prior to practicing advanced techniques such as full-face dermabrasion. If the treatment area is limited in size, local anesthesia (1% lidocaine with epinephrine 1 : 100 000) or tumescent technique is adequate. When treating the entire nose, a ring block may achieve an appropriate degree of anesthesia. Prior to abrasion, the area to be treated is cleansed with a 4% chlorhexidine solution. The body of the hand engine is grasped in the palm of the dominant hand with four fingers, allowing the thumb to project along the neck for stabilization (Figure 52.2). Finger position is similar to a “thumbs-up” sign or to that seen when gripping a golf club, yet the hand and instrument are pronated, with the palm facing downward. Freon 114 refrigerant spray (Frigiderm, Delasco, Council Bluffs, IA, USA) is applied to the treatment area in an amount necessary to achieve a 5–10 s thaw time, during which time abrasion is performed on the frozen area. Refrigerant spray accomplishes two important functions: decreasing pain by cryoan-

Figure 52.2 Dermabrasion of multiple cosmetic subunits of the nose showing operator hand position and three-point retraction by physician’s non-dominant hand and two hands of assistant.

52. Dermabrasion

Figure 52.3 Female patient after two stages of Mohs micrographic surgery for removal of basal cell carcinoma of the nasal tip. Tumor has been cleared and defect depth remains in the superficial reticular dermis. Surgical marking notes superior border of nasal supratip subunit.

Figure 52.4 Same patient as in Figure 52.3 after wire brush dermabrasion of the remaining nasal tip and surrounding cosmetic subunits. Area will now heal with improved contour and pigment match.

esthesia and a providing a firm substrate upon which to achieve recontouring. Immediately after freezing, three-point retraction is obtained by the two hands of the surgical assistant and the non-dominant hand of the surgeon. The frozen skin is thus stabilized by retraction, and the lesion is recontoured with the wire brush rotating in a counter-clockwise direction (with the angle of the radiating bristles) as determined from the point of view of the body of the hand engine. The wire brush is passed over the treatment area in an arciform motion with the long axis perpendicular to the rotating hand-piece (parallel to the body of the hand engine). Counter-clockwise rotation of the wire brush offers a less aggressive technique of wire brush surgery that is especially well suited for spot dermabrasion of Mohs defects or surgical scars without cryoanesthesia (Figures 52.3 and 52.4). With counter-clockwise rotation, the radiating bristles are less prone to gouge unfrozen skin. This counter-clockwise direction of rotation is also useful when dermabrading free margins of the face such as the lips and nasal alae, in order to prevent the inadvertent “grabbing” of tissue by the rotating wire brush when dermabrading from the right side with the dominant right hand. Regular pinpoints of bleeding signal abrasion to the level of the papillary dermis. As depth increases to the reticular dermis, the bleeding foci become larger, and frayed collagen bundles become apparent. Surgical scars will frequently disintegrate upon abrasion, which is a desirable endpoint. Contouring should often include “feathering” or graduating

zones of treatment around the central scar to provide a smooth transition between different planes and improved pigment transition. Alternatively, the treatment zone may be stopped at the border of a cosmetic unit or carried to an inconspicuous endpoint such as 1.0 cm beyond the mandible.

Advanced technique While local or tumescent anesthesia may be adequate for scar or spot dermabrasion, full-face abrasion of acne scarring or rhytides is best accomplished with a combination of oral (p.o.) or intramuscular (i.m.) light sedation, nerve blocks, and cryoanesthesia. A standard regimen consists of 50–75 mg meperidine i.m., 25 mg hydroxyzine i.m., and 5–10 mg diazepam p.o. or sublingual 30–60 minutes prior to the start of the procedure. After a chlorhexidine prep, nerve blocks to the supratrochlear, supraorbital, infraorbital, and mental nerves may also be performed. In contrast to the counter-clockwise rotation typically utilized for less aggressive dermabrasion, more experienced practitioners may opt to use a clockwise rotation of the abrasive wire brush. Rotation in a clockwise direction occurs against the angle of the radiating wire bristles and causes the tip to pull away from the thumb rather than driving toward it. Deeper planing and recontouring are possible with clockwise rotation, but this direction is much less forgiving. Additionally, clockwise rotation utilized by a

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dominant right hand increases the risk that free margins of the face, such as lips and nasal alae, will be “grabbed” by the rotating bristles rather than brushed away, resulting in unintentional, deeper abrasion in these areas. When performing full-face dermabrasion, beginning at the periphery of the cheek or mandible and working toward the center of the face allows the practitioner to avoid gravity dependent bleeding as the procedure progresses. A surgical towel, surgical cap, or petrolatum may also be used to help prevent entanglement of hair at the periphery of the treatment area. Surgical towels are also preferable to cotton gauze as sponges on the surgical field, as gauze becomes more easily entangled in the wire brush and hand engine.

Postoperative wound care Gauze soaked with 1% lidocaine with 1 : 100 000 epinephrine may be immediately applied to the post-abraded area for a period of 5–10 minutes to assist with hemostasis. A closed technique, layered bandage is then applied, composed of a semi-permeable hydrogel dressing (Vigilon, CR Bard, Inc., Covington, GA, USA, or Second Skin, Spenco Medical Corp., Waco, TX, USA) in contact with the wound, a nonadherent dressing (Telfa™, Covidien, Mansfield, MA, USA) above, and paper tape or surgical netting to secure the bandage in place. Semi-permeable hydrogel dressings provide two important advantages over other types of dressings: decreased patient discomfort in the postoperative period and decreased time to re-epithelialization by up to

40% [8]. The dressing should be changed daily for 3–5 days. If full-face dermabrasion has been performed, it is usually most convenient to have the patient return to the office for dressing changes during this period. For smaller areas, the patient may change the bandage at home. After 3–5 days, the patient begins an open wound care technique at home. 0.25% Acetic acid soaks (1 tablespoon white vinegar into 1 pint of warm water) are followed by topical petrolatum ointment until re-epithelialization is complete, usually 7–10 days after the procedure. Strict adherence to this regimen reduces the risk of both secondary infection and scarring. If full-face dermabrasion is performed, a short course of oral or intramuscular steroids may also be given immediately after the procedure to help reduce facial swelling. Swelling is an anticipated consequence of full-face dermabrasion and may be expected to resolve over several weeks to a few months. All previously prescribed antivirals and antibacterials should be instituted or continued, and patients should be given a prognosis and expected recovery timeframe. Once re-epithelialization has occurred, sunscreens and sun avoidance should be strictly adhered to for several weeks in order to minimize post-procedure pigment alteration. Makeup may be used to cover erythema after re-epithelialization.

Complications The most common complications encountered after dermabrasion are milia and acne flares (Table 52.1). These minor

Table 52.1 Complications of dermabrasion with suggested treatment. Complication

Comment

Treatment

Milia and acne flare

Most common

Expression, topical retinoids, oral antibiotics

HSV “breakthrough” infection

Intensely painful erythematous lesions at 7–10 days

Increase antiviral dose (1 g valcyclovir t.i.d. for 7–10 more days)

Bacterial infection

Persistently painful erythematous lesions

Culture and begin empiric therapy with antistaphylococcal antibiotic

Fungal infection

Persistently painful erythematous lesions

Culture and begin empiric therapy with anticandidal agent

Hyperpigmentation

Usually transient

4–8% hydroquinone for 4–8 weeks

Hypopigmentation

Delayed onset, usually permanent

Camouflaging makeup, possibly 308 nm excimer laser

Scarring

Persistent erythema in the absence of infection

Treat early and repeatedly Topical steroids Intralesional steroids Pulsed dye laser

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52. Dermabrasion side effects should be anticipated, and may be treated by comedone expression, topical tretinoin, and oral antibiotics. Infection, pigment alteration, and scarring are the more portentous complications that may be encountered after dermabrasion. Vigilance in the immediate postoperative period is necessary to identify these complications at an early stage and institute treatment. Herpes simplex infection may still occur while the patient is on a prophylactic antiviral dose, and clinically manifests as painful (out of proportion to healing phase), erythematous lesions 7–10 days postprocedure. Larger doses of antiviral medications are then necessary for treatment (1 g valcyclovir t.i.d. for 7–10 more days). Bacterial and fungal infections may likewise produce persistently painful, erythematous lesions. Lesions should be cultured and empiric therapy with an antistaphylococcal or anticandidal agent, or both, should be implemented as warranted by clinical suspicion. Transient, postoperative hyperpigmentation is a common complication, usually beginning 4–6 weeks after dermabrasion. 4–8% Hydroquinone, or formulations containing hydroquinone, tretinoin, and a mild steroid, should be implemented at the earliest signs of hyperpigmentation and continued for 4–8 weeks. A more difficult complication to treat is hypopigmentation. While not quite as common as with fully ablative CO2 laser resurfacing, nearly one-third of patients will develop permanent hypopigmentation after full-face wire brush dermabrasion. Furthermore, such hypopigmentation often does not develop until several months post-procedure. Female patients may camouflage such hypopigmentation with makeup, but male patients have fewer options for improvement. The 308 nm excimer laser has been shown to improve hypopigmented scars and vitiligo, and may be an option for improvement after dermabrasion [9]. True hypopigmentation should be differentiated from the pseudo-hypopigmentation seen when resurfaced skin without actinic damage simply appears lighter than the surrounding actinically damaged skin. Finally, persistent erythema in the absence of infection is the harbinger of scar formation. Scars should be treated early and proactively in order to minimize sequelae. Flat, erythematous scars may be managed by topical steroids, or steroid-impregnated tape (Cordran, Aqua Pharmaceuticals, LLC, West Chester, PA, USA) worn nightly. However, indurated scars also require intralesional corticosteroid injections and/or pulsed dye laser treatments on a regular basis. These may be repeated every few weeks until stabilization and improvement occur.

Conclusions With the armamentarium of resurfacing modalities increasing, mechanical dermabrasion remains an important dermasurgical procedure, particularly for the improvement of cystic acne, post-surgical scars, and partial thickness Mohs defects. Selecting appropriate patients and establishing realistic treatment goals are prerequisites. Small areas may be easily and safely treated with proper technique, and these demonstrate a rapid recovery. Although experience and skill are necessary in order to avoid serious complications with full-face dermabrasion, its efficacy for the treatment of acne scarring and deep rhytides currently remains unmatched for the patient who is willing to endure the resultant recovery period. Close follow-up during the postoperative period is important in order to recognize and treat the most serious potential complications of infection and scarring at the earliest stages. While new technologies continue to emerge, mechanical resurfacing will likely remain an essential and unmatched modality for scar improvement into the foreseeable future.

References 1 Murphy GF. (1997) Histology of the skin. In: Elder D, Elenitsas R, Jaworsky E, Johnson BL, eds. Lever’s Histopathology of the Skin, 8th edn. Philadelphia, PA: Lippincott, pp. 42–3. 2 Kirsner RS. (2008) Wound healing. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd edn. Spain: Elsevier, pp. 2147–58. 3 Campbell RM, Harmon CB. (2008) Dermabrasion in our practice. J Drugs Dermatol 7, 124–8. 4 Roenigk HH Jr. (1977) Dermabrasion for miscellaneous cutaneous lesions (exclusive of scarring from acne). J Dermatol Surg Oncol 3, 322–8. 5 Yarborough JM Jr. (1988) Ablation of facial scars by programmed dermabrasion. J Dermatol Surg Oncol 14, 292–4. 6 Coleman WP 3rd, Yarborough JM, Mandy SH. (1996) Dermabrasion for prophylaxis and treatment of actinic keratoses. Dermatol Surg 22, 17–21. 7 Rubenstein R, Roenigk HH Jr, Stegman SJ, Hanke CW. (1986) Atypical keloids after dermabrasion of patients taking isotretinoin. J Am Acad Dermatol 5, 280–5. 8 Pinski JB. (1987) Dressings for dermabrasion: new aspects. J Dermatol Surg Oncol 13, 673. 9 Alexiades-Armenakas MR, Bernstein LJ, Friedman PM, Geronemus RG. (2004) The safety and efficacy of the 308-nm excimer laser for pigment correction of hypopigmented scars and striae alba. Arch Dermatol 140, 955–60.

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Part 4: Skin Modulation Techniques Chapter 53: Laser-assisted hair removal Keyvan Nouri1, Voraphol Vejjabhinanta1,2, Nidhi Avashia1, and Rawat Charoensawad3 1

University of Miami Miller School of Medicine, Miami, FL, USA Suphannahong Dermatology Institute, Bangkok, Thailand 3 Rawat Clinic and Biophile Training Center, Bangkok, Thailand 2

BAS I C CONCE P T S Current options for hair removal include shaving, epilation, depilatories, electrolysis, and, more recently, lasers. • Lasers are fast, safe, and effective when used appropriately. • Selective photothermolysis is the key concept in laser hair removal. • By varying specific parameters such as wavelength, pulse duration, and fluence, certain specific chromophores may be targeted while protecting other tissues. • Melanin is the main endogenous chromophore in hair follicles. • In permanent hair reduction, heat from the laser must spread from the hair shaft to the bulb and the bulge of the hair. • Adverse effects reported after laser-assisted hair removal include erythema, perifollicular edema, crusting, vesiculation, hypopigmentation, and hyperpigmentation.

Introduction The use of lasers for hair removal, or photoepilation, is becoming increasingly popular. According to the American Society for Aesthetic Plastic Surgery (ASAPS), nearly 11.7 million cosmetic surgical and non-surgical procedures were performed in the USA in 2007. ASAPS, which has been collecting multispecialty procedural statistics since 1997, notes the number of cosmetic procedures has increased 457% [1]. Laser hair removal is one of the top, non-surgical, cosmetic procedures with 1 412 657 performed in 2007. Hair removal is of great interest because excess hair, especially in those with hypertrichosis or hirsutism, can be socially and psychologically troubling [2]. The psychosocial importance of hair is great, as noted by patient distress over both hair loss and excess hair [3]. Current options for hair removal include shaving, epilation, depilatories, electrolysis, and, more recently, lasers [4]. All of these hair removal methods possess side effects, yet lasers are fast, safe, and effective when used appropriately. The concept of laser hair removal was defined in 1998 by the US Food and Drug

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Administration (FDA). Following this, manufacturers were given permission to use the term “permanent hair reduction” in their materials. The FDA definition of permanent hair reduction included “long-term, stable reduction in the number of hairs regrowing after a treatment regimen.” Thus, permanent hair removal does not imply the total elimination of hairs [5], but rather a significant reduction in growth rate. Complete hair loss is defined as a lack of regrowing hairs, which can be temporary or permanent. However, permanent hair loss is defined as lack of regrowing hair indefinitely. Hair removal with lasers produces complete but temporary hair loss for 1–3 months [6].

Biology of hair follicles Hair is a skin appendage, present on the entire body except for the palms and soles. There are approximately 5 million hair follicles on the adult body with a density of 40–800/ cm2. They are made of keratin fibers supported by specialized dermal structures. Hair is formed from the matrix epithelial cells at the base of the hair follicle. The hair matrix is contained in the hair bulb, which is the deep bulbous portion of the hair follicle that surrounds the dermal papilla. The bulge of the hair is the reservoir for hair stem cells. In permanent hair reduction, heat from the laser must spread

53. Laser-assisted hair removal

Table 53.1 Hair cycles for various body sites. Body site

Anagen (%)

Telogen (%)

Anagen duration (months)

Telogen duration (months)

Follicular depth (mm)

Scalp

24–72

3–4

3–5

Upper lip

3–4

1–2

Axillae

3–4

2–3

3–4

Arms

2–4

2–3

Legs

5–7

3–6

3–4

Bikini area

1–3

2–3

3–4

from the hair shaft to the bulb and the bulge of the hair. Heating only the hair matrix is not sufficient for permanent hair reduction. There is no formation of new hair follicles throughout life, so, as the body expands, the density decreases. Hair changes throughout our lifetime. A single follicle can form several different types of hairs ranging from lanugo in preterm newborns to vellus hairs in children to terminal hairs in adults. Lanugo is fine, non-pigmented hairs present at birth. Vellus hairs are fine, short, non-pigmented hairs known as “peach fuzz.” Terminal hairs are the thick, usually pigmented, hairs of the scalp and secondary sexual areas. Terminal hairs are the targets of photoepilation. Hair does not grow continuously, but instead grows in three phases: anagen, catagen, and telogen. The anagen phase is known as the growth phase. Catagen is the transition phase. Telogen is the resting phase. The cycle for scalp hairs is not only asynchronous but lasts 3–5 years. The duration of the hair cycle varies depending on body location (Table 53.1). Photoepilation is most effective during certain phases of the hair growth cycle. The regulation of hair growth is influenced by genetic factors and hormones, particularly androgens. The function of hair, while primarily psychosocial, serves to protect from mechanical, thermal, and UV damage [3]. Thus, hair removal is important for appearance and not functional reasons. The basic concepts of laser-assisted hair removal are discussed next.

Basic concepts of laser-assisted hair removal Selective photothermolysis is the key concept in laser hair removal, known as photoepilation. Photoepilation causes thermal destruction of the hair follicle and its associated stem cells at the hair bulge. By varying specific parameters such as wavelength, pulse duration, and fluence, certain

specific cutaneous chromophores may be targeted while protecting other tissues [7]. Whether the hair is in telogen at the time of removal is important, because only anagen hairs are sensitive to photothermolysis. Because melanin is the main chromophore in hair follicles, the corresponding wavelength spectrum would range from UV to near-infrared light. Longer wavelengths are preferred, because the chromophore lies deep in the skin and the penetration of light increases with wavelength. The specific target in laser hair removal is melanin and the light emitted must be within the absorption spectrum of melanin, which is 250–1200 nm [8]. Melanin is an endogenous chromophore found in the hair bulb, bulge, and shaft. Thus, in the range of 600–1100 nm, deep dermal melanin absorption may be used for selective photothermolysis of hair follicles [9]. A drawback to the use of lasers for hair removal, especially in those with darker skin, is that melanin resides in the epidermis. This is problematic because epidermal melanin can interfere with photoepilation by distracting the laser energy, but can also lead to certain side effects, such as epidermal damage and pigmentation. Thus, proper preoperative management is essential to achieving superior results.

Preoperative management Discrepancy can exist between patient expectations for laser-assisted hair removal and the actual effects of such a treatment. Open communication must exist between the care provider and the patient. Preoperative management for laser hair removal consists of three main steps: history and physical examination, counseling, and preparatory instructions (Table 53.2). First, an accurate patient history must be taken focusing on patient’s expectations, current medications, scarring risk, and local infection including history of herpes virus infection in the area of treatment. Along with a complete history, a thorough physical examination is vital.

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Table 53.2 Preoperative and postoperative procedures for hair removal. History

Preoperative care (4 weeks prior to treatment)

Preoperative care (day before treatment)

Day of treatment

Postoperative care

Conditions that may cause hypertrichosis: hormonal, familial, drug, tumor

Sunscreen application

Shave area to be treated

Clean and remove make-up from area to be treated

Ice packs

History of HSV perioral and genitalis

Bleaching cream (hydroquinone) to those with darker skin

When indicated, start prophylactic antiviral

Apply topical anesthetic cream to treatment area 1–2 h prior to treatment

Avoid sun exposure and trauma

History of keloids/hypertrophic scarring

No plucking, waxing, or electrolysis

When indicated, start prophylactic oral antibiotic

Previous treatment modalities

Shaving or depilatory creams may be used

Mild topical steroid creams (if necessary) Prophylactic antiobiotics/antivirals completed

Current medications HSV, herpes simplex virus infection.

Table 53.3 Step-by-step technique for hair removal. Skin preparation

Visibility

Treatment fluence

Technique

Cooling

Remove anesthetic cream, makeup

Treatment grid or Seymour light in order to prevent skipped areas and double treatment

Ideal treatment parameters individualized for each patient, increase fluence carefully while monitoring for adverse effects

Slightly overlapping laser pulses are delivered with a predetermined spot size and highest tolerable fluence to obtain best results

Cooling gel applied prior to pulses if device is not equipped with cooling feature

The physical examination should assess the aspects of the patient’s skin color, health condition, hair color, hair diameter, and hair density. Following the workup of the patient, a counseling session is necessary. The patient must be advised that 4–6 weeks prior to laser treatment no plucking or other hair removal methods can be used in the treatment areas. Shaving and depilatory creams may be used as these methods do not remove the hair root, which is targeted by the laser. In addition, sun exposure and tanning should be limited. Bleaching of the skin with retinoic acid or hydroquinone can lighten the skin prior to laser treatment. Topical anesthetic creams or cryogenic sprays may be applied to the treatment area to reduce discomfort during the procedure. Cold compresses are also effective in reducing discomfort, erythema, and edema at the treatment area. The skin surface must be thoroughly cleansed of all makeup, anesthetic creams, and other applicants immediately prior to laser treatment. This may be done with a gentle cleanser, followed by a cloth, and should be allowed to dry completely. 434

Laser systems are dangerous hazards to the eye. Because there are high concentrations of melanin in the iris and in the retina, these areas are highly susceptible to damage by laser light. Every person in the room during laser treatment should wear protective eyewear that is certified for the wavelength of the laser in use. Because the patient usually lies supine, he or she may require full occlusive eye protection to prevent laser light from entering underneath a sunglasses or goggle type of protective eyewear [6].

Description of techniques Long pulsed 694 nm ruby laser The long pulsed ruby laser was the first widely used laser for hair removal (Table 53.3). This laser has the shortest wavelength at 694 nm of all the available lasers for hair reduction. It is absorbed the best by melanin but has the shortest penetration depth. Thus, this would mean that the ruby laser is the most effective at hair removal, but has the greatest potential for epidermal injury. A cooling hand-

53. Laser-assisted hair removal piece is used concomitantly during treatment to reduce the risk of injury by lowering the skin’s temperature. This laser is ideal for those with light skin and dark hair, and penetrates the skin by only 1–2 mm. This laser is not recommended in darker skin types. In a study demonstrating the efficacy of the ruby laser, 48 areas of unwanted facial and body hair from 25 patients with blonde, brown, or black hair were treated with the long pulsed ruby laser at fluences of 10–40 J/cm2. Hair regrowth was measured at 4 weeks after the first treatment, 4 weeks after the second treatment, 4 weeks after the third treatment, and 16 weeks after the third treatment by counting the number of terminal hairs compared with baseline pretreatment values. The mean percent of regrowth after the first treatment was 65.5%, 41% after the second treatment, and 34% after the third treatment. Overall, regardless of skin type or targeted body region, patients who underwent three treatment sessions demonstrated an average 35% regrowth in terminal hair count [10].

neodymium:yttrium aluminum garnet (Nd:YAG) laser for treating patients with darker skin types. The diode laser is more effective for laser-assisted hair removal in patients with dark skin because of the higher absorption by melanin than is seen with the Nd:YAG laser. Still, temporary adverse effects have been reported with the use of the diode laser in the form of postinflammatory hyperpigmentation when used on individuals with dark skin. A retrospective study of 313 consecutive laser-assisted hair removal treatments was conducted on a total of 23 patients (22 women, 1 man) with 58 anatomic areas by means of an alexandrite laser. The long pulsed alexandrite system was used at a 755 nm wavelength to deliver fluences ranging 17–25 J/cm2 through a 10 mm spot size. The results showed that patients who undergo more treatment sessions achieve a higher rate of hair reduction; although this may be concomitant with an increase in the incidence of adverse effects. The benefit of more laser treatments should be balanced with the risk of occurrence of side effects in each patient [11].

Long pulsed 755 nm alexandrite laser The long pulsed alexandrite laser has a wavelength of 755 nm. This longer wavelength allows deeper penetration into the dermis with less absorption by epidermal melanin. This causes less adverse side effects such as pigmentation in darker skin patients. This laser is still typically used for patients with lighter skin types, but can also be used in those with darker skin. The adverse effects of this laser, when used on patients with darker skin types, can include blistering, crusting, and alterations of pigment, even when skin cooling devices are used. In patients classified as having the darkest skin, residual hypopigmentation or hyperpigmentation is the rule with the alexandrite laser.

Long pulsed 800 nm diode laser The 800 nm diode laser is comparable to the 755 nm alexandrite laser, and has become more popular along with the

1064 nm Nd:YAG laser The 1064 nm Nd:YAG has the longest wavelength and deepest penetration amongst the aforementioned laser systems available. It is not very well absorbed by melanin, but is sufficient in achieving selective photothermolysis and has superior penetration. This laser is able to penetrate the skin to 5–7 mm, a depth at which most of the target structures lay. Furthermore, the combination of a low melanin absorption and deep penetration leads to less collateral damage to the melanin-containing epidermis. These features make this particular laser the safest method to treat all skin types, especially darker skinned patients (Figure 53.1). Unfortunately, while this laser may be the safest, it is not the most effective. In a study by Bouzari et al. [12], hair reduction by the long pulsed Nd:YAG, alexandrite, and diode lasers were compared. They found

(b)

(a) Figure 53.1 (a) Pretreatment of the right axillary area with coarse hair. (b) Only fine hair exists after 3 months after five treatments with a 1064 nm Nd:YAG laser. 435

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(b)

(a) Figure 53.2 (a) Pretreatment of the upper lip area. (b) Seven weeks after two treatments with intense pulsed light (IPL) system.

that after 3 months, the Nd:YAG was the least effective of the three.

Intense pulsed light The intense pulsed light (IPL) system is not a laser, but has recently entered the hair removal realm as a competent contender. It has been used for virtually all of the same indications as laser systems. IPL systems utilize a xenon bulb as a light source, which produces polychromatic light with wavelengths of 515–1200 nm. This is in contrast to laser light sources, which produce monochromatic light of a specific wavelength. Light emitted by the bulb passes through a filter that excludes shorter wavelengths which may severely damage skin. The ability to “tune” the wavelength of light emitted by these systems gives IPL systems the advantage of versatility. Using different filters, a pulsed light system could mimic any number of laser systems, allowing the operator to treat many different conditions amenable to light therapy, including, of course, the removal of unwanted hair (Figure 53.2).

Radiofrequency combinations Radiofrequency devices have been combined with both IPL and diode lasers to provide optimal hair removal treatments to a wider range of skin types. The combinations are considered safe for patients with darker skin types because the radiofrequency energy is not absorbed by melanin in the epidermis. This technology, termed electro-optical synergy (ELOS) has a dual mechanism of heating the hair follicle with electrical energy (radiofrequency) and heating the hair shaft with optical energy.

which is sprayed on, is selectively absorbed by the hair follicle and not the skin. This in turn gives the follicles a temporary boost of melanin to optimize laser hair removal treatments. Clinical studies in Europe have shown vast permanent hair reduction in patients who used meladine prior to treatment. However, other studies have found meladine to only offer a delay of hair growth as opposed to permanent hair reduction [6]. Another option for non-pigmented hair removal is photodynamic therapy. A photosensitizer such as 5-aminolevulinic acid (5-ALA) is used because non-pigmented hair lacks a natural chromophore. In a study conducted to compare the 6-month hair removal efficacy of a combined pulsed light bipolar radiofrequency device with and without pretreatment using topical 5-ALA, researchers found that an average terminal white hair removal of 35% was observed at 6 months after treatment with the combined pulsed light bipolar radiofrequency device. When pretreatment with topical 5-ALA was provided the average hair removal of terminal white hairs was found to be 48%. This finding can be explained by the fact that light exposure activates the 5-ALA, which leads to the formation of reactive oxygen elements and slows for hair follicle destruction [13].

Postoperative management Postoperative management consists of reducing pain and minimizing edema. This can be done using ice packs. Mild topical steroid creams can also be used to decrease redness. Antibiotics should be given if epidermal injuries occur during the procedure.

Complications Other removal methods for non-pigmented hair Meladine, a topical melanin pigment, has been studied in Europe with interesting results. The liposome solution dye,

436

Although there is no obvious advantage of one laser system over another in terms of treatment outcome (except the Nd:YAG laser, which is found to be less efficacious, but more suited to patients with darker colored skin), laser parameters

53. Laser-assisted hair removal or permanent unless the FDA determines that there are sufficient data to demonstrate such results. Several manufacturers received FDA permission to claim, “permanent reduction,” not “permanent removal” for their lasers. This means that although laser treatments with these devices will permanently reduce the total number of body hairs, they will not result in a permanent removal of all hair. There is a new laser hair removal device that the FDA has approved for at home use and over-the-counter sales. This new device is known as TRIA. SpectraGenics announced clearance from FDA for their patented hand-held laser hair removal device designed for at-home use. The TRIA is the first hair removal laser to enter the US home-based device market, an industry projected to grow exponentially over the next 3 years.

Conclusions Figure 53.3 Blister formation 3 days after treatment with IPL system.

may be important when choosing the ideal laser for a patient. Adverse effects reported after laser-assisted hair removal including erythema and perifollicular edema, which are common, and crusting and vesiculation of treatment site, hypopigmentation, and hyperpigmentation (depending on skin color and other factors) (Figure 53.3). Most complications are generally temporary. The occurrence of hypopigmentation after laser irradiation is thought to be related to the suppression of melanogenesis in the epidermis (which is reversible), rather than the destruction of melanocytes. Methods to reduce the incidence of adverse effects include lightening of the skin and sun avoidance prior to laser treatment, cooling of the skin during treatment, and sun avoidance and protection after treatment. Proper patient selection and tailoring of the fluence used to the patient’s skin type remain the most important factors in efficacious and well-tolerated laser treatment. While it is generally believed that hair follicles are more responsive to treatment while they are in the growing (anagen) phase, conflicting results have also been reported. There is also no consensus on the most favorable treatment sites [14]. In addition, patients should be cautious and not use numbing agents on large areas of their body for prolonged periods of time as this can lead to adverse reactions.

Future directions Laser hair removal is not FDA approved to be marketed as a permanent hair removal treatment. Further, manufacturers may not claim that laser hair removal is either painless

Up to 22% of women in North America have excessive or unwanted facial hair. Men also feel compelled to rid themselves of unwanted body hair, as dictated by popular culture and appearance anxieties. Excessive facial hair can negatively impact on one’s quality of life. Prior options to hair removal have been painful, tedious, resulted in frustrated clients, and caused short-term effects. With the advent of laser technology, laser and light systems have becomes some of the most popular procedures. While this is still not a permanent solution to hair removal, is a safe, fast, and effective method for hair reduction.

References 1 American Society for Aesthetic Plastic Surgery (ASAPS). (2007) ASAPS 2007 Cosmetic Surgery National Data Bank Statistics. http://www.surgery.org/download/2007stats.prf Accessed 2008 Aug 20. 2 Nouri K, Trent JT. (2003) Lasers. In: Nouri K, Leal-Khouri S, eds. Techniques in Dermatologic Surgery. St. Louis: Mosby, pp. 245–58. 3 Rassner G. (2004) Atlas of Dermatology. Philadelphia, PA: Lea & Febiger, pp. 224–6. 4 Olsen EA. (1999) Methods of hair removal. J Am Acad Dermatol 40, 143–55. 5 Food and Drug Administration. (1998) FDA docket K980517. July 21. 6 Dierickx C, Crossman M. (2005) Laser hair removal. In: Golderg DJ, ed. Lasers and Lights, Vol. 2. China: Elsevier-Saunders, pp. 61–76. 7 Anderson RR, Parrish JA. (1983) Selective photothermolysis: precise microsurgery by selective abdorption of pulsed radiation. Science 220, 524–7. 8 Battle EF, Hobbs LM. (2003) Lasers in dermatology: four decades of progress. J Am Acad Dermatol 49, 1–31. 9 Mandt N, Troilius A, Drosner M. (2005) Epilation today: physiology of the hair follicle and clinical photoepilation. J Investig Dermatol Symp Proc 10, 271–4.

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10 Williams R, Havoonjian H, Isagholian K, Menaker G, Moy G. (1998) Clinical study of hair removal using the long-pulsed ruby laser. Dermatol Surg 24, 837–42. 11 Bouzari N, Nouri K, Tabatabai H, Abbasi Z, Firooz A, Dowlati I. (2005) The role of number of treatments in laser-assisted hair removal using a 755-nm alexandrite laser. J Drugs Dermatol 4, 573–8. 12 Bouzari N, Tabatabai H, Abbasi Z, Firooz A, Dowlati Y. (2004) Laser hair-removal: comparison of long-pulsed Nd:YAG, long-

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pulsed aleandrite, and long-pulsed diode alsers. Dermatol Surg 30, 498–502. 13 Goldberg DJ, Marmur ES, Hussain M. (2005) Treatment of terminal and vellus non-pigmented hairs with an optical/ bipolar radiofrequency energy source: with and without pretreatment using topical aminolevulinic acid. J Cosmet Laser Ther 7, 25–8. 14 Liew SH. (2002) Laser hair removal: guidelines for management. Am J Clin Dermatol 3, 107–15.

Chapter 54: Radiofrequency devices Vic Narurkar Bay Area Laser Institute, San Francisco, CA, and University of California Davis Medical School, Sacramento, CA, USA

BAS I C CONCEPTS • Radiofrequency devices have been introduced for non-surgical skin tightening of facial and non-facial skin. • The mechanism of action of these devices involves an initial immediate collagen contraction and a secondary wound healing response producing collagen deposition and remodeling with skin tightening over time. • Radiofrequency devices can be divided into monopolar and bipolar categories. • Monopolar radiofrequency utilizes an electrical current passed from the radiofrequency energy source through a monopolar electrode in the hand-piece and the current continues through the patient to the grounding pad, which completes the circuit. • Bipolar radiofrequency in conjunction with light and vacuum offer more superficial treatments, and, most recently, a combined unipolar and bipolar radiofrequency device has been introduced with control of depths of radiofrequency energies.

Introduction Radiofrequency devices have been introduced for nonsurgical skin tightening of facial and non-facial skin. The mechanism of action of these devices involves an initial immediate collagen contraction and a secondary wound healing response producing collagen deposition and remodeling with skin tightening over time. There has been a great deal of controversy surrounding the use of these devices when they were first introduced for non-surgical skin tightening. With the advent of newer protocols utilizing lower energies and multiple passes, the safety and efficacy of radiofrequency devices is increasing.

Radiofrequency devices Radiofrequency devices can be divided into monopolar and bipolar categories (Table 54.1). Monopolar radiofrequency utilizes an electrical current passed from the radiofrequency energy source through a monopolar electrode in the handpiece and the current continues through the patient to the grounding pad, which completes the circuit. The Thermage device is an example of monopolar radiofrequency. Bipolar radiofrequency devices employ a closed system and are usually combined with other sources. Examples include systems using bipolar radiofrequency and light (electrooptical synergy systems), bipolar radiofrequency and

vacuum, and a combination of unipolar and bipolar radiofrequency to deliver different depths of radiofrequency current to the skin.

Monopolar radiofrequency Monopolar capacitive radiofrequency was the first commercially available device to be introduced for non-surgical skin tightening and is the most widely studied. The generation of heat occurs because of natural tissue resistance to the movement of electrons within a radiofrequency field which creates heat relative to the amount of current and time. The different components of skin (dermis, fat, subcutaneous tissue, muscle, and fibrous tissue) have varying resistance to the movement of radiofrequency energy. For example, the fibrous septa are heated more than the surrounding subcutaneous tissue. Controlled radiofrequency pulses selectively heat zones of the dermis and deeper tissue with the use of cryogen delivery to protect and cool the epidermis. A pressure-sensitive tip prevents the non-uniform application of energy to the skin and the cryogen delivery minimizes epidermal compromise and assists in comfort of the procedure. The initial approach to utilize monopolar radiofrequency for skin tightening employed very high fluencies with one to two treatments. The discharge time was slow and the protocol was to utilize the highest tolerable fluence with a single pass over the entire treated area. With this protocol, the results were modest at best with significant pain. Moreover, the discharge time of the tip was slow at 5–6 seconds. In addition to significant discomfort and high variability in efficacy, infrequent reports of subcutaneous tissue

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Table 54.1 Examples of radiofrequency devices. Device

Mechanism

Thermacool (Solta Medical)

Unipolar radiofrequency

Aluma (Lumenis)

Bipolar radiofrequency

ELOS devices (Syneron)

Bipolar radiofrequency

Accent (Alma lasters)

Unipolar and bipolar radiofrequency

Figure 54.1 Subcutaneous atrophy from unipolar radiofrequency using old protocol with high fluencies.

depressions were reported (Figure 54.1). As a result, the treatment received much skepticism and criticism. The Thermacool device utilizes monopolar radiofrequency energy with a maximal output of 225 J/cm2 with a peak temperature 2–3 mm beneath the surface. Upon activation of the device, a cooling system which uses a cryogen spray is activated and internally precools the electrode. The cryogen continues to be delivered during (parallel cooling) and after (post-cooling) the energy delivery. The initial treatment cycle consisted of 6 seconds but the newer protocol is about 2 seconds. A new protocol was developed to overcome these limitations based on observations and studies demonstrating that low fluence delivery with multiple passes of monopolar radiofrequency can produce a more reproducible clinical endpoint. Histologic correlations to these findings demonstrated greater collagen denaturation at multiple passes using lower energies. In addition, lower energies produced less discomfort and greater patient satisfaction. A consensus panel published these findings with the following criteria: 1 Use of patient feedback about heat sensation as a valid and preferred method for selecting the optimal amount of energy; 2 Use of multiple passes at moderate energy settings to yield consistent efficacy; and

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3 Treatment to a clinical endpoint of visible tightening and contouring for maximizing predictability and long-term results. With the original treatment protocol (single pass and high fluence) 26% of patients showed immediate tightening and 54% showed delayed tightening. With the new protocol, 87% showed immediate tightening and 92% noted tightening after 6 months, with 94% of patients of the patients showing satisfaction. The largest studied areas for monopolar radiofrequency are the midface, lower face, and neck. The technique with the new protocol utilizes a tip that can deliver up to 900 pulses using multiple low fluence passes (typically 450 per each side of the face and neck). Treatments are administered without any topical anesthesia or intravenous sedation, as patient feedback is critical for outcomes. Up to 10 passes are performed using this algorithm. The greatest challenge in all skin tightening modalities is patient selection and setting expectations. Because threedimensional changes are often difficult to capture in twodimensional photography, it is imperative to have a detailed and thorough consultation to set realistic expectations. In our practice, we perform a detailed consultation to discuss the realistic goals of monopolar radiofrequency and emphasize the variability in results. Standardized photography is absolutely critical with standardized lighting and angles to capture subtle changes. Our criteria for patient selection include the following: 1 Patients who are absolutely averse to any surgical procedures for laxity such as rhytidectomy. 2 Patients who have had rhytidectomy and are showing signs of laxity. 3 Patients who are not surgical candidates because of risks associated with surgery. 4 Post-surgical patients who still show some laxity. 5 Off face loose skin, for which there are no other options. We also offer this procedure to candidates who seek subtle body contouring, with emphasis on the word subtle.

Complications Complications with monopolar radiofrequency are rare. With the old protocol, subcutaneous depressions were seen. Common transient side effects include mild erythema and edema. Slight tenderness post-treatments have been reported. Lack of proper contact with the skin can produce burns. With the new protocol, there have been no reports of permanent complications. All skin types can be treated, as radiofrequency is truly color blind and does not compete with melanin chromophores. There have been no reports of postinflammatory hyperpigmentation.

Future directions New directions for monopolar radiofrequency are the introduction of several new tips to address specific areas. These

54. Radiofrequency devices include tips for eyelid rejuvenation and large area body contouring. Eyelid rejuvenation has been one of the most exciting and innovative developments in monopolar radiofrequency tips. A shallow 0.25 cm2 tip is utilized which delivers heat more superficially than the medium depth tips utilized for facial and body areas. Plastic corneoscleral shields are placed prior to treatment. Ideal candidates for eyelid treatment include patients with mild to moderate dermatochalasis and good skin tone and patients who have previously had blepharoplasty and show signs of skin laxity. With low fluence and multiple pass protocol, upper eyelid tightening and reduction of hooding has been seen in over 80% of patients. The newest addition to the tip armamentarium is the large diameter deep tip for large body areas. One of the limitations of treating large body areas has been the amount of time required for treatments. Recently, a 16 cm2 deep tip was introduced which has shortened the treatment time by 50%. This allows for more efficient treatments of large body areas such as abdomen, buttocks, and flanks.

Summary Monopolar radiofrequency, in summary, is the most widely studied modality for non-surgical skin tightening. The initial protocol has been modified with a low energy multiple pass algorithm to reduce discomfort and achieve more predictable outcomes. While midface and lower neck were the initial areas for treatments, the advent of varying depth tips has expanded the use for the treatment of eyelids and off face areas such as the abdomen, buttocks, and flanks. The biggest challenge in treatment outcomes is predictability of results, which are variable. Therefore, a thorough consultation setting realistic patient expectations and “underpromising” results are key for optimal outcomes. It is imperative to emphasize that these procedures are not a subsititute for surgery and will not address severe laxity.

To further enhance outcomes of monopolar radiofrequency treatments, combination therapy approaches are being investigated. Most recently, we have initiated combining non-ablative fractional resurfacing, monopolar radiofrequency, and dermal fillers. Combination therapy is becoming the mainstay of treatments for a variety of non-surgical procedures. The combined non-ablative fractional resurfacing and monopolar radiofrequency procedure has been coined “Thermafrax,” with the fractional resurfacing addressing dyschromia, superficial rhytids, and the monopolar radiofrequency addressing laxity. The treatments can be performed on the same day or as staged procedures. The radiofrequency treatments are performed first, as patient feedback is necessary and anesthesia cannot be used. This is followed by non-ablative fractional resurfacing. Dermal fillers are performed last for any volume depletion. Facial and non-facial skin can be effectively treated with this approach. Hand rejuvenation with combination of monopolar radiofrequency, non-ablative fractional resurfacing, and dermal fillers is becoming increasingly popular, with each modality complementing the other – radiofrequency addressing laxity, fractional resurfacing addressing dyschromia and photodamage, and fillers addressing volume loss (Figure 54.2).

Bipolar radiofrequency and light The second commercially introduced modality for non-invasive skin tightening employed the combination of bipolar radiofrequency and light energy devices (900 nm diode laser in a single pulse or broadband light in the 700–2000 nm wavelength in a single pulse). The theory behind the use of two technologies is the safer delivery of radiofrequency energy, with the optical component enabling the bipolar

(b)

(a) Figure 54.2 (a) Pre-Thermage and Fraxel laser. (b) Post-Thermage and Fraxel laser.

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radiofrequency energy to concentrate where the optical energy has selectively heated the target. Optical energy levels of 30–50 J/cm2 with radiofrequency levels of 80–100 J/ cm2 are utilized in this mode. Three to four passes are usually performed and, unlike monopolar radiofrequency, 3–5 treatment sessions are necessary, as opposed to a single treatment. The main indication for bipolar radiofrequency and light combination devices is diminution of superficial rhytids. There may be some subtle tissue tightening. There is much controversy regarding the synergistic effects of light and radiofrequency energies. The use of lower optical energies makes this a safe device in all skin types. However, because the radiofrequency energy does not penetrate very deep into the skin, tissue arcing can occur with improper technique, resulting in scar formation. The majority of published clinical studies using these devices have focused on the treatment of mild to moderate rhytids with modest improvement. The amount of energy penetration with these devices does not produce deep volumetric heating and subsequent tightening compared with monopolar radiofrequency.

Bipolar radiofrequency and vacuum Bipolar radiofrequency with vacuum was introduced to reduce discomfort associated with radiofrequency devices. The bipolar radiofrequency energy with an accompanying vacuum apparatus allows the tissue into the vacuum and targets the radiofrequency energy to the deep dermis. Less energy is necessary for treatment efficacy, as the vacuum brings the electrodes closer to the dermis, with the additional benefit of reducing pain. The main indications for this technology are subtle improvement of fine rhytids and tissue tightening.

Unipolar and bipolar radiofrequency device Different depths of radiofrequency energy can be delivered to the skin – bipolar for more superficial heating and unipolar for deeper heating. It is a closed system and does not require grounding, as monopolar radiofrequency. Published data are limited and there is some evidence in the reduction of the appearance of cellulite and subtle tissue tightening.

Conclusions Non-surgical tissue tightening has evolved considerably since its first introduction. Monopolar radiofrequency using

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a new treatment algorithm remains the gold standard of radiofrequency, with the largest series of published papers, longest clinical experience, and modifications for optimal outcomes. Bipolar radiofrequency in conjunction with light and vacuum offers more superficial treatments, and, most recently, a combined unipolar and bipolar radiofrequency device has been introduced with control of depths of radiofrequency energies. The greatest challenge in all modalities of radiofrequency treatments is predictability of outcomes. Patient selection with a thorough consultation reviewing realistic expectations is key for successful outcomes. The development of newer algorithms with standardized protocols is allowing for more reproducible outcomes in using these devices for nonsurgical skin tightening.

Further reading Alster TS, Tanzi E. (2004) Improvement of neck and cheek laxity with a nonablative radiofrequency device: a lifting experience. Dermatol Surg 30, 503–7. Biesman B, Baker SS, Carruthers J, Silva JL, Holloman EL. (2006) Monopolar radiofrequency treatment of human eyelids: a prospective multicenter efficacy trial. Lasers Surg Med 38, 890–8. Doshi SN, Alster TS. (2005) Combination radiofrequency and diode laser for treatment of facial rhytids and skin laxity. J Cosmet Laser Ther 7, 11–5. Dover JS, Zelickson BD. (2007) 14 physician multispecialty consensus panel. Results of a survey of 5700 patient monopolar radiofrequency facial skin tightening treatments: assessment of a low energy multiple pass technique leading to a clinical endpoint algorithm. Dermatol Surg 33, 900–7. Emilia del Pino M, Rosado RH, Azuela A, Graciela Guzmán M, Arqüelles D, Rodríguez C, et al. (2006) Effect of controlled volumetric tissue heating with radiofrequency on cellulite and the subcutaneous tissue of the buttocks and thighs. J Drugs Dermatol 5, 714–22. Fitzpatrick R, Geronemus R, Goldberg D, Kaminer M, Kilmer S, Ruiz-Esparza J. (2003) Multicenter study of noninvasive radiofrequency for periorbital tissue tightening. Lasers Surg Med 33, 232–2. Fritz M, Counters JT, Zelickson BD. (2004) Radiofrequency treatment for middle and lower face laxity. Arch Facial Plast Surg 6, 370–3. Gold MH. (2007) Tissue tightening: a hot topic utilizing deep dermal heating. Drugs Dermatol 6, 1238–42. Gold MH, Goldman MD, Rao J, Carcamo JS, Ehrlich M. (2007) Treatment of wrinkles and elastosis using vacuum assisted bipolar radiofrequency heating of the dermis. Dermatol Surg 33, 303–9. Jacobson LG, Alexiades-Armenakis M, Bernstein L, Geronemus RG. (2003) Treatment of nasolabial folds and jowls with a noninvasive radiofrequency device. Arch Dermatol 139, 1371–2. Lack EB, Rachel JD, D’Andrea L, Corres J. (2005) Relationship of energy settings and impedance in different anatomic areas using a radiofrequency device. Dermatol Surg 31, 1668–70.

54. Radiofrequency devices Sadick NS. (2005) Combination radiofrequency and light energies: electro-optical synergy technology in esthetic medicine. Dermatol Surg 31, 1211–7. Weiss RA, Weiss MA, Munavalli G, Beasley KL. (2006) Monopolar radiofrequency facial tightening: a retrospective analysis of effi-

cacy and safety in over 600 treatments. J Drugs Dermatol 5, 707–12. Yu CS, Yeung CK, Skek SY, Tse RK, Kono T, Chan HH. (2007) Combined infrared light and bipolar radiofrequency for skin tightening in Asians. Lasers Surg Med 39, 471–5.

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Chapter 55: LED photomodulation for reversal of photoaging and reduction of inflammation Robert Weiss1, Roy Geronemus2, David McDaniel3, and Corinne Granger4 1

Maryland Laser Skin & Vein Institute, Hunt Valley, MD, and Johns Hopkins University School of Medicine, Baltimore, MD, USA Laser & Skin Surgery Center of New York, NY, and New York University Medical Center, New York, NY, USA 3 Laser Skin & Vein Center of Virginia, and Eastern Virginia Medical School, Virginia Beach, VA, USA 4 L’Oréal Research, Asnières, France 2

BAS I C CONCE P T S • Photomodulation uses of non-thermal light treatments to regulate the activity of cells rather than to invoking thermal wound healing mechanisms. • Photomodulation stimulates cells to perform certain functions using light packets that are low energy and enhance cell metabolism. • LED arrays for photomodulation are useful for collagen stimulation, textural smoothing, and reduction of inflammation.

Introduction Photorejuvenation encompasses many procedures using light or laser-based technology to reverse the effects of photoaging. Photoaging, a huge component of which is dermal collagen degeneration, is compounded by environmental damage including smoking, pollutants, and other insults causing free radical formation. Non-ablative photorejuvenation refers to the controlled use of thermal energy to accomplish skin rejuvenation without disturbance of the overlying epidermis and with minimal to no down-time. Currently employed non-ablative modalities include primarily intense pulsed light (IPL), visible wavelengths including pulsed dye laser (PDL), and 532 nm green light (KTP laser) [1]. Various infrared wavelengths with water as the target are used for remodeling dermal collagen. Because absorption by melanin is negligible, these devices can be used for all skin types and these include 1064, 1320, 1450, and 1540 nm [2,3]. The primary mechanism of action is thermal injury either by heating the dermis to stimulate fibroblast proliferation or by heating blood vessels for photocoagulation [4–6]. The newest way to deliver these wavelengths is by fractionating the dose through microlenses that allow microthermal zones surrounded by normal skin [7]. A non-thermal mechanism, which represents a fundamental change in thinking, is the theory of photomodula-

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tion. This concept involves the stimulation of cells to perform certain functions using light packets that are low energy and stimulate cell metabolism. This novel approach to photoaging uses non-thermal light treatments to regulate activity of cells rather than to invoke thermal wound healing mechanisms [8,9]. This incurs far less risk for patients than other light modalities. The first written report on using photomodulation to improve facial wrinkles was in 2002 [10]. Photomodulation was first discovered from use of LED and low energy light therapy (LILT) in stimulating growth of plant cells [11]. The belief that cell activity can be upregulated or downregulated by low energy light had been discussed in the past, but consistent or impressive results had been lacking [12,13]. Some promise had been shown with wound healing for oral mucositis [13]. Wavelengths previously examined included a 670 nm LED array [13], a 660 nm array [14], and higher infrared wavelengths [15]. Fluence and duration of exposure were variable in these studies with high energy required for modest results [13]. To investigate LED light for rejuvenation purposes, a fibroblast culture model was utilized in conjunction with clinical testing. Particular packets of energy with specific wavelengths combined with using a very specific propriety pulse sequencing “code” were found to upregulate collagen I synthesis in fibroblast culture using reverse transcription polymerase chain reaction (RT-PCR) to measure collagen I [10]. The upregulation of fibroblast collagen synthesis correlated with the clinical observation of increased dermal collagen on treated human skin biopsies [16]. Curiously, both in the fibroblast and clinical model, collagen synthesis was accompanied by reduction of matrix metalloproteinases

55. LED photomodulation (MMP). In particular, MMP-1 (collagenase) was greatly reduced with exposure to 590–870 nm low energy light. Use of very low energy, narrow band light with specific pulse code sequences and durations was termed LED photomodulation by McDaniel et al. [10]. A device that utilizes pulsed code sequences of LED light to induce photomodulation was termed Gentlewaves® (Gentlewaves, Inc., Charlotte, NC, USA) and patented by McDaniel.

Clinical applications LED photomodulation can be used both alone and in combination with a variety of common, non-ablative, rejuvenation procedures in an office setting. Several anti-inflammatory and wound healing applications are also possible. Treatments were delivered using the yellow/infrared light LED photomodulation unit with a full face panel. Energy density was set at 0.15 J/cm2 and 100 pulses were delivered with a pulse duration of 250 ms and an off interval of 100 ms. Treatment time was approximately 35 seconds.

Photorejuvenation This technique was evaluated on 6000+ patients over the last 6 years. Of these treatments, 10% were LED photomodulation alone and 90% were concomitant with a thermal-based photorejuvenation procedure. Using specific pulsing sequence parameters, which are the basis for the LED photomodulation “code,” the original multicenter clinical trial was conducted with 90 patients receiving a series of eight LED treatments over 4 weeks [17–20]. This study

showed positive results, with over 90% of patients improving by at least one Fitzpatrick photoaging category and 65% of the patients demonstrating global improvement in facial texture, fine lines, erythema, and pigmentation. Results peaked at 4–6 months following completion of a series of eight treatments [20]. Another retrospective study, using the same 590–870 nm LED array (Gentlewaves®), demonstrated similar results (Figure 55.1). These results were confirmed by digital microscopy [21]. Most recently, the 590 nm LED array was used in an independent clinical laboratory confirming the findings (data on file, L’Oréal Research, France). An additional clinical trial involving 65 subjects used silicone replica impressions of lateral canthal wrinkles (crow’s feet). These replicas, illuminated by reproducible lighting both parallel and perpendicular to each wrinkle, were analyzed with image-analyzing software (Quantirides, Monaderm, Monaco). The analysis showed a significant reduction in the number of wrinkles 2–4 months after treatment accompanied by a significant reduction in the length of wrinkles at 5 months post-treatment. Subject self-assessment showed significant improvement in skin wrinkles, texture, softness, and radiance. Others have confirmed that additional wavelengths of LED light, using red and infrared wavelengths, may be effective for skin texture improvement. Although these treatments were longer in duration, 36 patients receiving nine treatments over a 5-week period showed improvement in skin softness [22]. Each treatment was administered in continuous mode, without pulsing, with a treatment time of 20 minutes using 633 and 830 nm as an LED array (Omnilux™, Phototherapeutics, Altrincham, Cheshire, UK). Another

(b)

(a) Figure 55.1 Smoothing of the skin seen after eight treatments over 4 weeks of Gentlewaves® photomodulation (Gentlewaves, Inc., Charlotte, NC, USA) (a) Before treatments. (b) Eight weeks after baseline. Reduction in wrinkles, pigmentation and improvement of texture are noted.

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recent report using this system studied 31 subjects with facial rhytids who received nine light therapy treatments using combined wavelengths of 633 and 830 nm. Fluences were relatively high utilizing 126 J/cm2 for 633 nm and 66 J/ cm2 for 830 nm. Improvements to the skin surface were reported at weeks 9 and 12 by profilometry performed on periorbital replicas. Results showed that 52% of subjects showed a 25–50% improvement in photoaging scores [23]. In the USA, the first Food and Drug Administration (FDA) cleared LED device to be used in the reduction of periocular wrinkles was in 2005 (Gentlewave; Figure 55.2). Other devices (Omnilux™, Photo Therapeutics Ltd., Altrincham, Cheshire, UK) then followed.

Figure 55.2 Gentlewaves LED photomodulation device. Array of LEDs.

Anti-inflammatory effects Photomodulation can also be used for the reduction of erythema from a variety of causes. Erythema may be induced from wide ranging skin injuries including but not limited to thermal laser treatments, UV burns, radiation therapy, blunt trauma, and skin disease. Treatment of atopic eczema in patients withdrawn from all topical medications led to resolution with 3–4 treatments over 1–2 weeks (Figure 55.3). Use of LED photomodulation in combination with other laser modalities may results in faster erythema resolution. The enhanced erythema resolution may be a result of the anti-inflammatory effects of LED photomodulation. The mechanism has not yet been elucidated but downregulation of inflammatory mediators from lymphocytes or macrophages is possible. Studies on human skin fibroblasts treated with LED photomodulation have shown a reduction in interleukins IL-1B1 and IL-6 [24]. A recent study looked at whether LED photomodulation therapy could accelerate resolution of post-intense pulsed light (IPL) erythema [25]. Fifteen subjects were randomized to receive LED treatment to one side of the face immediately following a single IPL treatment for photodamage. Results showed mean erythema scores on the first visit were statistically significantly lower on the LED-treated side. This led the authors to conclude that LED photomodulation treatment may accelerate resolution of erythema following IPL treatment [25]. A study on radiation dermatitis examined whether LED photomodulation could alter and improve the outcome of intensity-modulated radiation treatments (IMRT) on overlying breast skin. Nineteen patients with breast cancer were

(b)

(a) Figure 55.3 (a) Before shows flare of eczema following withdrawal of all therapy. (b) Atopic eczema after three treatments with Gentlewave LED photomodulation. The after image (b) shows effects of reduction of inflammation by LED photomodulation within 10 days.

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55. LED photomodulation treated with LED photomodulation immediately after every radiation session. Treatments were administered to postlumpectomy patients receiving a full course of IMRT [26]. Skin reactions were monitored weekly using National Cancer Institute (NCI) criteria for grading. Age-matched controls (n = 28) received IMRT without LED photomodulation. The results of this study showed that LED treatment had a significantly positive effect. Of the LED treated patients, 94.7% (18) had grade 0 or 1 reaction and 5.3% (1) had a grade 2 reaction. Among controls, 4 (14.3%) had a grade 1 reaction and 24 (85.7%) had a grade 2 or 3 reaction. Of the non-LED treated group, 67.9% had to interrupt treatment because of side effects of skin breakdown with moist reactions but only 5% of the LED treated group had interrupted treatment. The authors concluded that not only did LED photomodulation treatments delivered immediately after each IMRT reduce the incidence of adverse NCI criteria skin reactions, but also allowed the full course of treatment and resulted in a final smoother skin texture with improved skin elasticity post-radiation treatment. Additional data indicates an anti-inflammatory effect for LED photomodulation following UV-induced erythema. Using a solar simulator, findings indicate a photoprotective effect when delivered after UV radiation [24]. This concept is a rescue from UV damage even after inadvertant UV radiation has occurred. We have observed a reduction in UV erythema when LED photomodulation was supplied within hours after UV exposure. The use of 590–870 nm LED photomodulation produced significant downregulation of dermal matrix degrading enzymes, which were stimulated by the UV exposure [24]. Additionally, a pilot study with precise CO2 laser epidermal destruction has shown promise with using this device for accelerated wound healing. Parallel to wound healing, use of photomodulation has been extended to a protective or preventative effect following several types of toxic injury. Experiments using LED light to protect the retina against the toxic actions of methanol-derived formic acid in a rodent model of methanol toxicity have been successful. In a recent study, LED treatment protected the retina from the histopathologic changes induced by methanol on mitochondrial oxidative metabolism in vitro and retinal protection in vivo [27]. Photomodulation may enhance recovery from retinal injury and other ocular diseases in which mitochondrial dysfunction is postulated to have a role. Human retinal pigment epithelial (RPE) cells were treated with LED photomodulation produced by acute injury from blue light wavelengths [28]. The results showed reduction of cell death at 24 hours from 94% to 10–20%. Another in vitro test on human RPE cells showed a sevenfold reduction in vascular endothelial growth factor (VEGF) expression at 24 hours post-LED exposure using LED photomodulation at 590–870 nm delivered at 0.1 J/cm2 [29].

Photodynamic therapy LED red light (630 nm) has been used in combination with a sensitizer (levulinic acid) for photodynamic therapy (PDT) [30]. When exposed to light with the proper wavelength, the sensitizer produces an activated oxygen species, singlet oxygen, that oxidizes the plasma membrane of targeted cells. As a result of a lower metabolic rate, there is less sensitizer in the adjacent normal tissue, thus less of a reaction. One of the absorption peaks of the metabolic product of levulinic acid, protoporphyrin, absorbs strongly at 630 nm red. A red LED panel emitting at 630 nm (Omnilux PDT™, Phototherapeutics, Altrincham, Cheshire, UK) has been used for this purpose in Europe and Asia [31]. A full panel 590 nm LED array has also been used for facilitating PDT. This therapy is delivered by application of levulinic acid (Levulan™, DUSA, Wilmington, MA, USA) for 45 minutes and exposure to continuous (non-pulsed) 590–870 nm LED for 15 minutes for a cumulative dose of over 70 J/cm2. The results show reduction in actinic damage including improvement of skin texture and reduction of actinic keratoses [32]. The primary means for photomodulated upregulation of cell activity for collagen synthesis by LED is the activation of energy switching mechanisms in mitochrondria, the energy source for cellular activity. Cytochrome molecules are believed to be responsible for the light absorption in mitochrondria. Cytochromes are synthesized from protoporphyrin IX and absorb wavelengths of light from 562 to 600 nm. It is believed that LED light absorption causes conformational changes in antenna molecules within the mitochrondrial membrane. Proton translocation initiates a pump, which ultimately leads to energy for conversion of adenosine diphosphate (ADP) to adenosing triphosphate (ATP). This essentially recharges the “cell battery” and provides more energy for cellular activity. Others have confirmed that mitochrondial ATP availability can influence cellular growth and reproduction, with lack of mitochrondrial ATP associated with oxidative stress [33]. Cellular aging may be associated with decreased mitochrondial DNA activity [34]. It has been concluded that LED light represents a novel, non-invasive, therapeutic intervention for the treatment of numerous diseases linked to mitochondrial dysfunction [35]. Previous work has also demonstrated rapid ATP production within mitochrondia of cultured fibroblasts exposed to 590–870 nm yellow/infrared LED light only with the proper pulsing sequence [9,36]. New ATP production occurs rapidly after LED photomodulation, triggering subsequent metabolic activity of fibroblasts [19]. There also appear to be receptor-like mechanisms, which result in modulation of the expression of gene activity producing upregulation or downregulation of gene activity as well as wide-ranging cell signaling pathway actions. The choice of photomodulation parameters has a vital role in determining the overall pattern

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of gene upregulation and/or downregulation. In our experience, use of LED yellow/infrared light without the proper pulsing sequence leads to minimal or no consequences on mitochrondrial ATP production.

Conclusions LED arrays for photomodulation are useful for collagen stimulation, textural smoothing, and reduction of inflammation. Pilot wound healing studies show slightly accelerated wound resolution. Cellular rescue from UV damage and other toxic insults has been shown in small studies. Thermal, non-ablative photorejuvenation and non-thermal LED photomodulation have a synergistic effect. LED photomodulation is delivered immediately subsequent to the thermal-based treatment for its anti-inflammatory effects, which may reduce the thermally induced erythema and edema of nonablative treatments. Delivery of LED light immediately before and after thermal injury appears to increase antiinflammatory and protective effects.

References 1 Weiss RA, Weiss MA, Beasley KL, Munavalli G. (2005) Our approach to non-ablative treatment of photoaging. Lasers Surg Med 37, 2–8. 2 Munavalli GS, Weiss RA, Halder RM. (2005) Photoaging and nonablative photorejuvenation in ethnic skin. Dermatol Surg 31, 1250–60. 3 Weiss RA, McDaniel DH, Geronemus RG. (2003) Review of nonablative photorejuvenation: reversal of the aging effects of the sun and environmental damage using laser and light sources. Semin Cutan Med Surg 22, 93–106. 4 Weiss RA, Gold M, Bene N, Biron JA, Munavalli G, Weiss M, et al. (2006) Prospective clinical evaluation of 1440-nm laser delivered by microarray for treatment of photoaging and scars. J Drugs Dermatol 5, 740–4. 5 Weiss RA, Goldman MP, Weiss MA. (2000) Treatment of poikiloderma of Civatte with an intense pulsed light source. Dermatol Surg 26, 823–7. 6 Fatemi A, Weiss MA, Weiss RA. (2002) Short-term histologic effects of nonablative resurfacing: results with a dynamically cooled millisecond-domain 1320 nm Nd:YAG laser. Dermatol Surg 28, 172–6. 7 Bogle MA. (2008) Fractionated mid-infrared resurfacing. Semin Cutan Med Surg 27, 252–8. 8 Weiss RA, McDaniel DH, Geronemus RG. (2003) Review of nonablative photorejuvenation: reversal of the aging effects of the sun and environmental damage using laser and light sources. Semin Cutan Med Surg 22, 93–106. 9 McDaniel DH, Weiss RA, Geronemus R, Ginn L, Newman J. (2002) Light-tissue interactions I: photothermolysis vs photomodulation laboratory findings. Lasers Surg Med 14, 25. 10 McDaniel DH, Weiss RA, Geronemus R, Ginn L, Newman J. (2002) Light-tissue interactions II: photothermolysis vs photomodulation clinical applications. Lasers Surg Med 14, 25.

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11 Whelan HT, Smits RL Jr, Buchman EV, Whelan NT, Turner SG, Margolis DA, et al. (2001) Effect of NASA light-emitting diode irradiation on wound healing. J Clin Laser Med Surg 19, 305–14. 12 Whelan HT, Buchmann EV, Dhokalia A, Kane MP, Whelan NT, Wong-Riley MT, et al. (2003) Effect of NASA light-emitting diode irradiation on molecular changes for wound healing in diabetic mice. J Clin Laser Med Surg 21, 67–74. 13 Whelan HT, Connelly JF, Hodgson BD, Barbeau L, Post AC, Bullard G, et al. (2002) NASA light-emitting diodes for the prevention of oral mucositis in pediatric bone marrow transplant patients. J Clin Laser Med Surg 20, 319–24. 14 Walker MD, Rumpf S, Baxter GD, Hirst DG, Lowe AS. (2000) Effect of low-intensity laser irradiation (660 nm) on a radiationimpaired wound-healing model in murine skin. Lasers Surg Med 26, 41–7. 15 Lowe AS, Walker MD, O’Byrne M, Baxter GD, Hirst DG. (1998) Effect of low intensity monochromatic light therapy (890 nm) on a radiation-impaired, wound-healing model in murine skin. Lasers Surg Med 23, 291–8. 16 Weiss RA, McDaniel DH, Geronemus RG, Weiss MA, Beasley KL, Munavalli GM, et al. (2005) Clinical experience with light-emitting diode (LED) photomodulation. Dermatol Surg 31, 1199–205. 17 Weiss RA, McDaniel DH, Geronemus RG, Weiss MA. (2005) Clinical trial of a novel non-thermal LED array for reversal of photoaging: clinical, histologic, and surface profilometric results. Lasers Surg Med 36, 85–91. 18 McDaniel DH, Newman J, Geronemus R, Weiss RA, Weiss MA. (2003) Non-ablative non-thermal LED photomodulation: a multicenter clinical photoaging trial. Lasers Surg Med 15, 22. 19 Geronemus R, Weiss RA, Weiss MA, McDaniel DH, Newman J. (2003) Non-ablative LED photomodulation: light activated fibroblast stimulation clinical trial. Lasers Surg Med 25, 22. 20 Weiss RA, McDaniel DH, Geronemus R, Weiss MA, Newman J. (2004) Non-ablative, non-thermal light emitting diode (LED) phototherapy of photoaged skin. Lasers Surg Med 16, 31. 21 Weiss RA, Weiss MA, Geronemus RG, McDaniel DH. (2004) A novel non-thermal non-ablative full panel led photomodulation device for reversal of photoaging: digital microscopic and clinical results in various skin types. J Drugs Dermatol 3, 605–10. 22 Goldberg DJ, Amin S, Russell BA, Phelps R, Kellett N, Reilly LA. (2006) Combined 633-nm and 830-nm led treatment of photoaging skin. J Drugs Dermatol 5, 748–53. 23 Russell BA, Kellett N, Reilly LR. (2005) A study to determine the efficacy of combination LED light therapy (633 nm and 830 nm) in facial skin rejuvenation. J Cosmet Laser Ther 7, 196–200. 24 Weiss RA, McDaniel DH, Geronemus RG, Weiss MA. (2005) Clinical trial of a novel non-thermal LED array for reversal of photoaging: clinical, histologic, and surface profilometric results. Lasers Surg Med 36, 85–91. 25 Khoury JG, Goldman MP. (2008) Use of light-emitting diode photomodulation to reduce erythema and discomfort after intense pulsed light treatment of photodamage. J Cosmet Dermatol 7, 30–4. 26 DeLand MM, Weiss RA, McDaniel DH, Geronemus RG. (2007) Treatment of radiation-induced dermatitis with light-emitting diode (LED) photomodulation. Lasers Surg Med 39, 164–8.

55. LED photomodulation 27 Eells JT, Henry MM, Summerfelt P, Wong-Riley MT, Buchmann EV, Kane M, et al. (2003) Therapeutic photobiomodulation for methanol-induced retinal toxicity. Proc Natl Acad Sci U S A 100, 3439–44. 28 Eells JT, Henry MM, Summerfelt P, Wong-Riley MT, Buchmann EV, Kane M, et al. (2003) Therapeutic photobiomodulation for methanol-induced retinal toxicity. Proc Natl Acad Sci U S A 100, 3439–44. 29 McDaniel DH, Weiss RA, Geronemus R, Weiss MA. (2006) LED photomodulation ‘reverses’ acute retinal injury. Annual meeting of the American Society for Laser Medicine and Surgery, Boston, MA, April 6, 2006. 30 Tarstedt M, Rosdahl I, Berne B, Svanberg K, Wennberg AM. (2005) A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp. Acta Derm Venereol 85, 424–8. 31 Chen HM, Yu CH, Tu PC, Yeh CY, Tsai T, Chiang CP. (2005) Successful treatment of oral verrucous hyperplasia and oral

leukoplakia with topical 5-aminolevulinic acid-mediated photodynamic therapy. Lasers Surg Med 37, 114–22. Weiss RA, McDaniel DH, Geronemus RG, Weiss MA, Beasley KL, Munavalli GM, et al. (2005) Clinical experience with light-emitting diode (LED) photomodulation. Dermatol Surg 31, 1199–205. Zhang X, Wu XQ, Lu S, Guo YL, Ma X. (2006) Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles. Cell Res 16, 841–50. Sorensen M, Sanz A, Gomez J, Pamplona R, Portero-Otin M, Gredilla R, et al. (2006) Effects of fasting on oxidative stress in rat liver mitochondria. Free Radic Res 40, 339–47. Desmet KD, Paz DA, Corry JJ, Eells JT, Wong-Riley MT, Henry MM, et al. (2006) Clinical and experimental applications of NIRLED photobiomodulation. Photomed Laser Surg 24, 121–8. Weiss RA, Weiss MA, McDaniel DH, Newman J, Geronemus R. (2003) Comparison of non-ablative fibroblast photoactivation with and without application of topical cosmeceutical agents. Lasers Surg Med 15, 23.

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Part 5: Skin Contouring Techniques Chapter 56: Liposuction: Manual, mechanical, and laser assisted Emily Tierney1,2 and C. William Hanke3 1

Laser and Skin Surgery Center of Indiana, Carmel, IN, USA Department of Dermatology, Boston University School of Medicine, Boston, MA, USA 3 University of Iowa, Carver College of Medicine, Iowa City, IA, and Indiana University School of Medicine, Indianapolis, IN, USA 2

BAS I C CONCE P T S • The safety profile for liposuction is significantly improved when tumescent local anesthesia technique is employed. • Tumescent local anesthesia utilizing lidocaine with epinephrine allows the removal of large volumes of fat with minimal associated blood loss and postoperative morbidity. • Liposuction is a procedure for patients who are either at or approaching their goal weight, to achieve a more esthetic figure, contour, and shape in conjunction with a diet and exercise regimen. • Preoperative consultation, setting realistic patient expectations for improvement, establishing patients’ overall health status and past medical history and discussion of risks and benefits of the procedure are critical to the success of the procedure. • Laser-assisted tumescent liposuction has been purported to result in mechanical cavitation of fat, resulting in greater ease of suction and greater skin retraction; however, additional studies are needed to confirm these results.

Introduction: history of liposuction with tumescent local anesthesia The early history of liposuction begins with Fischer’s description of hollow cannula liposuction in 1976 [1]. Shortly thereafter, Ilouz, a Frenchman trained in obstetrics and gynecology, and Fournier, a general surgeon, began practicing liposuction using the “wet technique,” involving injection of hypotonic saline and hyaluronic acid into the fat prior to suction [2]. Fournier pioneered the “criss-cross” technique and syringe liposuction and became a teacher of the technique [3]. Shortly thereafter, in 1977, an American dermatologist, Lawrence Field, visited Paris and learned about liposuction and published his experience with the technique in 1984. Jeffrey Klein, an American dermatologist, was the first to publish a report of liposuction using exclusively tumescent local anesthesia (TLA) in 1987 [4]. Prior to this point, the pain associated with liposuction had necessitated the procedure be performed under general anesthesia.

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In 1988, Hanke and Bernstein published a report on the safety of the TLA technique for liposuction, reporting the results of 9478 patients treated by dermatologists [5]. Shortly after attending Fournier’s liposuction course in Paris, William Hanke, the editor-in-chief of the Journal of Dermatologic Surgery and Oncology, commissioned an issue of the dedicated to liposuction. Further innovations to the field evolved with the publication by Hanke and colleagues documenting the safety of TLA in 15 336 patients in 1995 [6]. Additionally, while initial reports by Klein established the safety of tumescent liposuction using a lidocaine dose of 35 mg/kg in 1990 [4], Ostad et al. [7] reported the safety at a total dose of 55 mg/kg. In 2000, Klein published a book entitled Tumescent Technique [8], highlighting many of his important contributions to the field including: TLA technique, the Klein microcannula, Klein infiltration pumps, multihole Klein Capistrano cannulas, and specific techniques for treating all body areas. Since Klein’s introduction of the technique of TLA for liposuction in 1987, it has revolutionized the technique among dermatologic surgeons and surgeons of all specialties performing the procedure. Liposuction with TLA facilitates the removal of large volumes of fat with minimal blood loss or postoperative morbidity, excellent esthetic results, and a remarkably superior safety profile to general anesthesia.

56. Liposuction

Table 56.1 Appropriate liposuction candidate selection. Does the patient have realistic expectations of the procedure? Is the patient at or near goal body weight? Is the patient in good health in the absence of anticoagulant therapy? Does the patient have localized fat deposits on the body that are diet and exercise resistant for which they are seeking treatment? Does the patient have good or adequate skin tone?

Physiology: what skin contour problem does the procedure address and how does this procedure alter the contour problem? Liposuction is a procedure that can assist patients to achieve a more idealized and balanced body contour (Table 56.1) [9–12]. It is designed for individuals at their ideal body weight who seek correction of a single or multiple anatomic sites with focal excess adiposity and laxity [9–12]. The ideal liposuction patient is a patient of ideal body weight with focal disproportionate adiposity, resulting in contour deformity [9–12]. Importantly, liposuction is not a weight loss procedure, and it should be emphasized that patients seeking the goal of weight loss are not good candidates for the procedure (Table 56.1) [9–12]. In initial patient consultations, it is important to set realistic patient expectations for the results of the procedure. The results of liposuction in all anatomic sites are limited by the existing bony structure, the texture and quality of the skin, the tone and build of muscle, and the pre-existing adiposity in areas not amenable to liposuction. Liposuction can help to achieve a more idealized and balanced body contour, and patients will largely vary in seeking correction of a single area or multiple anatomic sites to achieve their own personal optimal correction.

Advantages and disadvantages Liposuction with TLA allows the removal of large volumes of fat with minimal blood loss or postoperative morbidity, excellent cosmesis, and a remarkable safety profile. TLA techinique with the use of a dilute epinephrine and anesthetic achieves the aims of hemostasis and anesthesia at the surgical site [13–17]. The advantages of the technique include improved safety, precision, and patient convenience [13–17]. These advances have contributed to the enhanced safety profile and widespread growth in the popularity of the liposuction technique [13–17]. TLA can be utilized for any anatomic site treated with liposuction, from the neck to the ankles.

Figure 56.1 A 2-L liposuction cannula, filled with liposuction aspirate.

Advantages of the TLA technique include a significant reduction in blood loss attributed to the vasoconstrictive effects of epinephrine. This can be quantified by comparing the aspirate from TLA (containing 1–3% whole blood) with that from the procedure performed under general anesthesia (40% whole blood) [15]. Improved hemostasis results in both decreased blood loss as well as decreased bruising and discomfort for the patient in the postoperative phase [15]. In addition, the anesthetic and vasoconstrictive effects of the TLA are directed towards the sites being treated, resulting in prolonged anesthesia of several hours’ duration as a result of the reservoir effect of TLA [12–15]. This results in decreased reliance upon postoperative narcotics. The TLA solution also results in a hydrodissection effect, whereby the pressure of the solution allows easier and more uniform penetration and removal of adipose tissue by the cannula (Figures 56.1 and 56.2) [4–8, 12–15]. Tumescent fluid enlarges, magnifies, and lifts targeted fat, allowing for more precise removal of fat [4–8, 12–15]. With proper technique for infusion of the tumescent fluid, TLA can be performed without ancillary sedation and intravenous or general anesthesia [14,15]. With TLA, patient convenience is significantly enhanced during the perioperative recovery period where there is more rapid recovery [14–24]. In contrast, the recovery is much more prolonged after general anesthesia, both as a result of the after-effects of the anesthetic and from the increased bruising and discomfort associated with the procedure [14–24]. Complications with the TLA technique include discomfort, swelling, bruising, temporary loss of sensation, postinflammatory hyperpigmentation, and minimal scarring at the

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incision sites but these are significantly less than those associated with the procedure performed under general anesthesia [14–24]. Potential risks of liposuction under general anesthesia are significantly greater and include deep venous thrombosis or pulmonary embolus, abdominal or other organ perforation, infection, and bleeding [21,23].

Figure 56.2 Blanching of skin visible after infusion of tumescent anesthesia with tumescent local anesthesia (TLA) technique.

Indications for tumescent liposuction, by anatomic site Abdomen Patient selection has a significant role in liposuction surgery of the abdomen. Patients should be within 10–25 lb (5– 12 kg) of their ideal body weight and should have good to excellent skin tone which will assist with skin contraction after the procedure [25]. The overall body shape of the patient should be examined during the preoperative physician examination [25]. The patient should be marked while standing to identify the larger areas of fatty deposition in the abdomen [25]. Incision sites are made in the following locations: two to three in the suprapubic region, one at the umbilicus, and two on the lateral portions of the umbilical fat depositions [25]. The patient should be lying on his or her back for the procedure; however, towards the end of the procedure, it is helpful if the patient lies in both lateral decubitus positions to identify pockets of fat as they fall away from the rectus muscle [25]. The goal of abdominal liposuction should be to reduce the deeper fatty layers while preserving a superficial, even layer of fat attached to the skin [25]. Oversuction can lead to dimpling of the skin, uneven fat deposits, and dermal necrosis [25]. Patients in group 1 (Table 56.2), lower abdomen only, are typically thin patients with a localized fatty deposition in the lower abdomen alone (Figure 56.3) [25]. These patients tend to respond very well to liposuction with high patient satisfaction.

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Figure 56.3 Lower abdomen, anterior view: (a) pretreatment; (b) post-treatment.

56. Liposuction Patients in group 2 (Table 56.2), requiring liposuction of both the upper and lower abdomen, must be carefully evaluated (Figure 56.4) [25]. This group may also be relatively thin; however, if suction of the lower abdomen alone is performed, they may have a protuberant overhanging upper abdomen [25]. Therefore, it is important to perform liposuction on both segments of the abdomen to ensure a proportionate appearance. Patients requiring liposuction of the upper and lower abdomen in addition to the hips, waist, and back (group 3; Table 56.2; Figure 56.5) tend to be older postmenopausal women or those on hormone replacement therapy with a history of weight gain [25]. Men requesting liposuction of the abdomen may require more widespread liposuction to ensure a proportionate appearance as fat deposits in men in the abdomen are usually accompanied by excess fat on the chest, flanks, and back [25]. Many men are not good candidates for abdominal liposuction as much of the fat deposits are behind the rectus abdominus and thus are not accessible to suction during the liposuction procedure [25]. Table 56.2 Five groups of patients: abdominal liposuction. 1. Liposuction: lower abdomen 2. Liposuction: upper and lower abdomen 3. Liposuction: hourglass abdomen; upper and lower abdomen, hips, waist, and back 4. Liposuction and skin excision: mini-abdominoplasty with or without umbilical translocation 5. Complete abdominoplasty

Figure 56.4 Lower abdomen and hips liposuction, lateral view: (a) pretreatment; (b) post-treatment.

The fourth group of patients (Table 56.2) demonstrate atrophic, stretched skin from pregnancy, advancing age, and rapid fluctuations changes in weight [25]. More extensive liposuction is needed in these patients and liposuction alone is often not satisfactory. Waiting 3–4 months after the procedure will allow the physician to assess if liposuction alone is sufficient or if the patient will require abdominoplasty procedure to address skin redundancy [25].

Hips, outer thighs, and buttocks Evaluation of patients for liposuction in these anatomic sites requires a three-dimensional and universal approach to all anatomic site, otherwise a disproportionate appearance can result with more noticeable enlargement in the unsuctioned areas after suction of localized fat deposits. For the hips, outer thigh, and buttocks, it is important to observe review carefully with the patient all changes in underlying musculature, cellulite, and inelastic skin, none of which can be improved with liposuction. For the hips, the patient should be placed in the lateral decubitus position. For the thighs, the patient should also be in the lateral decubitus position with a pillow placed between the legs, which mimics the standing position and allows the femur to be directed anteriomedially [20]. The end result of suctioning should be that a region is flat, not concave [25]. Suctioning should also be equal on both sides and careful steps should be taken to monitor that relatively equivalent amounts of fat are removed from either side [25]. Liposuction of the buttocks must be performed carefully, with special consideration to the inferolateral gluteal crease, where a banana roll, comprised of a defined infragluteal fat

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Figure 56.5 Lower abdomen, hips, and lateral thigh liposuction, lateral view: (a) pretreatment; (b) post-treatment.

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(a) Figure 56.6 Arm, anterior view: (a) pretreatment; (b) post-treatment.

pocket, may worsen or lead to an atrophic buttock in the event of oversuction [25]. Physical examination must focus on bony and muscular prominences and asymmetry. Realistic expectations must be established with the patient as liposuction will not assist with underlying bony asymmetry, the presence of large or asymmetrical muscle masses, or skin laxity. Conservative buttock suction is recommended with removal of no more than 30–50% of fat from the middle and deep fat layers [25]. Superficial suctioning of the buttocks should be avoided as it is likely to result in undesirable dimpling.

Arms Liposuction of the arms is performed in women with laxity of the proximal arm musculature and who have a pendulous fatty protuberance of the posterior, lateral, or anterior upper arm (Figure 56.6). The fat distribution in the arms is best visualized when the arms are extended at 90 ° from the body. Avoiding oversuctioning is critical for the arms and

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gentle liposuction should only be performed in the medial and posterior (extensor arms). As skin redundancy often contributes significantly to laxity of the arms, patients need to be advised that the goal is to decrease the convexity of the arms as opposed to complete removal of all redundancy of skin and soft tissue. Excessive tumescent solution should be avoided in the upper arm region as there is a small risk for creation of “compartment syndrome” whereby a functional tourniquet develops distal to the infused region, brought about by fluidinduced compression of neural, vascular, and lymphatic structures in the area. One position for the procedure is to lay the patient’s arms entirely flat with palms facing down over the hips with the body in a lateral decubitus position, which will serve to maximally expose the posterior portion of the arm. The other position that is helpful is for the patient to be in a supine or lateral decubitus position with a hand brought behind the head, forearm flexed, and elbow pointing out,

56. Liposuction which also exposes the posterior portion of the arm. Liposuction to the axilla should be avoided given the risks of damage to the branches of the brachial plexus in this area.

Neck and jowls The goal of liposuction of the neck and jowls is to give improved definition of the cervicomental angle and jawline [26–30]. Aging in this region can be caused by a multitude of factors, including ptosis of fatty tissue and decreased elastic tissue. These changes in the subcutaneous tissue of the neck allow the anterior margins of the platysma to slide forward and result in protrusion of the submental and submandibular fat [26–30]. Patients with excess laxity in this area may benefit from a spectrum of procedures, including facelifts, chin implants, platysmal plication, and CO2 laser resurfacing, and thus optimal selection of patients who will benefit from liposuction in this area is critical (Figure 56.7) [26–30]. Fullness in the neck and jowls can be attributed to a variety of factors, including redundant skin, muscle, or a low

or anteriorly positioned hyoid bone (creating an obtuse cervicomental angle) [26–30]. Patients with low set or anteriorly placed hyoid bones are unlikely to benefit form liposuction alone. The ideal candidate should have a hyoid positioned at the level of the C3–C4 vertebrae, excellent skin elasticity, and a palpable submental fat pad [26–30]. In order to mark the neck liposuction patient, the anatomic boundaries must be distinguished, including the mandibular border, the jowls, the submental fat pad, the anterior borders of the sternocleidomastoid, platsyma band, and the thyroid cartilage (Figure 56.8) [26–30]. The patient should be seated with the head gently extended posteriorly and the chin raised with the small supportive pillow for neck support [26–30]. For liposuction of the neck and jowls, entry points should be along the submental crease, just below or lateral to the jowls [26–30]. If extensive lateral neck fat is present, additional insertion sites can be made in a neck fold behind the earlobes [26–30]. The suctioning plane should begin just above the platysma muscle, with subsequent suction with

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(a) Figure 56.7 Neck, lateral view: (a) pretreatment; (b) post-treatment.

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(a) Figure 56.8 Neck liposuction markings: (a) anterior view; (b) lateral view.

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small (1.5–2 mm) cannulae [26–30]. The cannula should be delicately applied in this area to suction above the platsyma in order to avoid placing the cannula through the platsyma [26–30]. In addition, the marginal mandibular branch of the facial nerve is located in this area (below the angle of the mandible at the anterior border of the masseter muscle), and care must be taken to avoid trauma to the nerve [26–30]. The nerve becomes increasingly superficial and more likely to be injured along or posterior (up to two fingerbreadths) to the posterior border of the sternocleidomastoid muscle [26–30]. The cannula can be used to elevate the subcutaneous fat away from the underlying structures in these areas to avoid injury to underlying structures [26–30]. Also, it is important to avoid oversuctioning cheeks and along the jowl–cheek margin, as an undesirable hollowed appearance results from oversuctioning in this area [26–30].

Female breast Traditional breast reduction in women, reduction mammoplastly, requires general anesthesia with significant associated risks, including, seroma, hematoma, scarring, skin loss, and fat necrosis [31,32]. The procedure involves making a T-shaped incision extending from the areola to the inframammary folds, which in the majority of cases leaves an unattractive scar [31,32]. Liposuction as a means to decrease breast size is a relatively new procedure and when utilized alone to decrease breast size has only been described in the literature in a handful of cases [31,32]. For women with moderate to severe breast enlargement, liposuction may not be sufficient given that it may not address issues of excess skin and soft tissue [31,32]. A preoperative breast weight should be taken to establish the optimal amount of fat reduction and then calculate the percentage fat reduction after the procedure [31,32]. The patient should be positioned supine with the ipsilateral arm behind the head or with the arm posteriorly displaced in order to bring the breast flat against the chest wall [31,32]. Two incisions for suctioning should be made, one in the lateral axillary line and one in the mid-inframammary crease [31,32]. Suctioning should focus in the mid to deep plane of the lateral and inferior quadrants of the breast [31,32]. It is less desirable for suction in the superior quadrant to preserve the natural contour of the breast, as the upper quadrants typically flatten with age [31,32]. The surgeon determines the amount of fat removed, calculated as a percentage of total fat, based upon preoperative measurement [31,32]. It is currently recommended that less than one-third of the measured total breast volume be removed in one session [31,32]. Breast reduction in female breasts by liposuction alone represents a promising new application of this technology and presents significant advantages relative to traditional reduction mammoplasties, including less risk

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associated with general anesthesia, as well as benefits of decreased infection and scarring risks.

Male chest A careful history and physician examination should be performed in men before attempting liposuction in the male chest, with specific attention to the palpation of the gynecomastia and regional lymph nodes [31–33]. Several authors also recommend palpation of the testes to evaluate for testicular tumors [31,32]. While rare, breast tumors do occur in men and thus all masses with suspicion for malignancy (asymmetry, firm, or fixed) should undergo mammogram, ultrasound, and/or biopsy [31,32]. Etiologies for male breast enlargement include fatty deposition, glandular deposition, medications (estrogen, spironolactone, digitalis, diazepam, phenytoin and clomiphene), alcoholism, hypogonadism, and hormone-secreting tumors of the pituitary, adrenal gland, and testis [31,32]. As the male breast is one of the most vascular sites for TLA, care must be taken to ensure the vasoconstrictive effect of epinephrine has taken effect prior to the procedure and that the pectoralis muscle is not traumatized during the anesthesia infusion or liposuction [31,32]. The male breast is also one of the most fibrous sites in which liposuction is performed, with significant variability in the content of glandular and fatty tissue present [31,32]. Incision sites for the liposuction cannula are placed along the periphery of the breast and in the inframammary crease to allow for complete infiltration and criss-cross suction of adipose tissue [31,32]. Suction is started with microcannulae, allowing for easier tissue penetration, such as the 16gauge Capistrano cannula for initial tunneling with transition to a larger 14-gauge cannula [31,32]. The subareolar breast tissue can be gently suctioned with the use of a 16-gauge short (5 or 7 cm) Capistrano cannula [31,32].

Anesthesia technique Tumescent solution should be prepared on the day of the procedure utilizing 0.9% sodium chloride solution (normal saline) [4–9]. The anesthetic is lidocaine, available in 1% or 2% solution. Epinephrine and sodium bicarbonate are added to aid in vasoconstriction and buffering, respectively [4–9]. The range of doses utilized for TLA range from conservative doses of 30–35 mg/kg to as high as 55 mg/kg [4–9]. Doses at the lower end of the range can be utilized when patients are taking medications that inhibit cytochrome P450, specifically the CYP3A4 isoenzyme, responsible for the clearance of lidocaine [4–9]. In particularly smaller individuals, lidocaine concentrations should be limited to 0.05–0.075% as the total dose is limited by weight [4–9]. Higher concentrations are generally advised on more sensitive areas, such as the chest, waist, and periumibilical area [4–9]. Epinephrine

56. Liposuction is added to the solution at a concentration of 1 : 1 000 000 (1 mg 1 : 1000 epinephrine in 1 L solution of saline) [4–9]. Finally, bicarbonate is added in the amount of 10 mEq in 1 L [4–9]. Before mixing, the saline should be warmed to enhance the comfort of the patient during the infiltration process [4–9]. TLA should be administered once the patient has been comfortably positioned for the procedure. Insertion sites should be anesthetized with 1% lidocaine with epinephrine (usually at a dilution of 1 : 100 000) [4–9]. The incisions are created using a No. 11 blade through the dermis to allow entry of the blunt-tipped infiltration cannula into the subcutaneous tissue [4–9]. The infiltration cannula should be inserted and the infiltration rate should be appropriately adjusted for the anatomic site [4–9]. The infiltration rates should be less than 100 mL per minute to minimize patient discomfort [4–9]. Gentle advancement of the cannula should occur prior to infiltration of the tumescent solution [4–9]. Anesthesia should be performed using a fanned approach from the entry site with care taken not to put excessive strain on the entry site [4–9]. If the patient experiences excessive pain, slowing the rate of infiltration can improve patient comfort [4–9]. The infiltration endpoint is reached when the edges of the field become firm and indurated and the area of infiltration is blanched (secondary to vasoconstriction effect of epinephrine) [4–9].

Standard and advanced operating technique After infiltration of the TLA is complete and after allowing 15–20 minutes for full epinephrine effect to occur, fat suction can begin [4–9]. Suction can be performed through the same sites of insertion of the TLA [4–9]. More aggressive thinner cannulas should be used first to break up the fibrous setae and to create tunnels for subsequent removal of fat with larger (3 mm), less aggressive cannulae [4–9]. Suction movement should proceed in a linear and vertical fashion with little horizontal movement in the creation of subcutaneous tunnels [4–9]. The cannula should be directed so that the aperture is facing downwards or opposite the dermis [4–9]. Both deep and superficial tunneling should be performed so that the physician’s free or “smart hand” monitors the motion and position of the cannula tip [4–9]. Initially during the suctioning, the area is tense from the infiltration of TLA; however, as the suctioning proceeds, the area becomes more flaccid and techniques are needed to maintain the cannula in a uniform plane to ensure uniform suctioning [4–9]. One helpful technique is to have the assistant gently grasp the flaccid skin adjacent to the suction area and roll in such a way to flatten the suctioned area [4–9]. Another helpful technique is to have an assistant flatten the

region by placing counter traction of the skin while the surgeon continues suction guided by their “smart hand” [4–9]. The endpoint of fat suction is determined by a number of factors, such as the observation that the aspirate has become increasingly bloody and devoid of suctionable fat and palpation of the area revealing minimal persistence of fat pockets and even distribution of the remaining fat [4–9]. When this occurs, suctioning should stop in this area and the cannula should be repositioned. Localized pockets of fat should be sought out and removed by lacing the cannula (with the suction apparatus off) into tunnels and gently pulling back and up against the dermis. Pockets of fat may become more pronounced with this maneuver and further suctioning of these well-defined areas helps create a more even result. The total volume of fat removed in a single procedure should not exceed 4500 mL. This equates to 6000–8000 mL of total aspirate, assuming 50–60% of the aspirate of fat. If the patient possesses areas of fat where the estimated loss is greater than 4500 mL, treatments should be planned over multiple visits [4–9].

Equipment The fundamental equipment needed to perform liposuction includes an aspiration pump, liposuction cannulae, the infiltration pump, a sterile field, syringes with 1% lidocaine with or without epinephrine (to anesthetize the cannula insertion sites), a No. 11 blade, gauze, and clamps to secure tubing and drapes in place [34]. Various infiltration pumps for administration of the tumescent solution are available, the most optimal of which allow adjustment of the rate of administration of the TLA solution [34]. The infiltration pump is connected directly to the tumescent solution via intravenous tubing which is threaded through the power pump and connected directly to the tumescent solution through an infusion cannulae or needle [34]. The aspiration pump is an electrically powered device which is designed to create negative pressure and collect fatty tissue throughout the procedure [34]. There are a variety of machines available, the ideal of which are those with a closed collection system, overflow trap, and disposable air filter with efficient and uninterrupted suction [34]. The liposuction cannulae are comprised of stainless steel, aluminum, deldrin, or brass [34]. The shape, diameter, hole placement, and size determine the ease of fat removal as well as the relative injury to the tissue [34]. Easier fat removal is achieved with cannulae with several holes and a large-diameter tapered end (usually 3 mm), where the holes are located distally on the tip (e.g. Capistrano, Pinto, Cobra, Becker, and Eliminator cannulae; Wells Johnson Company,

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Tucson, AZ, USA) [34]. Cannulae with smaller diameters (less than 3 mm), blunted ends, fewer holes, or holes placed more proximally relative to the tip are less aggressive and gentler to the tissue (e.g. Klein, Fournier, Standard cannulae; Wells Johnson Company, Tucson, AZ, USA) [34]. In fibrous tissue, it is best to begin with a cannula with an aggressive tip and a small diameter [34]. As the fibrous tissue is diminished, a less aggressive cannula with a larger diameter tip can be utilized [34]. In areas where the fat is soft, such as the inner thigh, smaller cannulae can be utilized to avoid oversuction. Per the guidelines of the American Academy of Dermatology regarding liposuction, the cannula diameter should be no greater than 4.5 mm in diameter [34]. As most liposuction cannula utilized are between 2 and 3 mm in size, they comply with this recommendation [34].

ing bleeding complications with prior deliveries or surgeries may elicit a history of bleeding which gives an indication for further work-up [16]. A review of medication intake, both prescription and over-the-counter, is essential to the safety and success of the TLA procedure [16]. Intake of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is contraindicated before surgery, because of inhibition of platelet activity and subsequent increased perioperative bleeding [16]. Aspririn should be discontinued 7–10 days prior to surgery [16]. Ibuprofen and other NSAIDs should be discontinued 4–7 days prior to surgery [16]. The discontinuation of vitamins and herbal supplements, such as vitamin E, chondroitin, glucosamine, Ginkgo biloba, and ginseng is encouraged because of the anticoagulant effects of these agents [16].

Intraoperative phase

Complications Long-term experience has shown that the complications associated with liposuction under the TLA technique are minor and significantly less than those associated with complications with liposuction performed under intravenous or general anesthesia [18–24]. The most common complications of liposuction using TLA include bruising, swelling, soreness, inflamed incision sites, and postoperative fatigue [18–24].

Preoperative phase Obtaining informed consent from each patient prior to the procedure and reviewing the risks of the procedure, especially of skin contour abnormalities in areas of poor skin elasticity, will allow the patient to be more accepting of the final results [16]. It should be emphasized that there are limitations to the procedure. Safety dictates the amount of fat that can be removed [16]. Additionally, as a body contouring procedure, liposuction will not assist with pre-existing scars, pigmentary variation, cellulite, indentations, and skin textural changes [16]. Finally, it should be emphasized to the patient that his or she adopts and/or continues a regular exercise routine in order to assist with improved skin contraction and maintenance of results [16]. Preoperative assessment should also include assessment for possible abdominal wall hernias [16]. Blood tests should be performed to ensure the patient does not have an underlying bleeding tendency or liver transaminitis, which could also potentially affect clotting factor synthesis [16]. At a minimum, a full blood count with platelets, liver function tests, and a prothrombin time/partial thromboplastin time (PT/PTT) should be checked [16]. Additional studies to undergo with an underlying bleeding abnormality include: a bleeding time, von Willebrand’s factor, factor V Leiden level, or hemophilia screen [16]. Detailed questions regard-

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The key to achieving a smooth end result with liposuction involves performing the suction from multiple angles and directions in a criss-cross motion. During the procedure, sterile technique must be emphasized, with the use of antiseptic washes to the area the night before and immediately prior to the surgery. Superficial infections, usually around incision sites, are typically culture positive for staphylococcus and streptococcus. However, deeper infections which occur in a delayed fashion several months after the procedure occur with atypical mycobacterial species (Mycobacterium abscessus, M. chelonae, M. fortuitum) and have been associated with improper cleaning and sterilization of surgical instruments. During liposuction, the surgeon should always use the non-dominant hand or “smart hand” to assess the position of the liposuction cannula at all times. Elevating the skin with the “smart hand” and then passing the cannula along the adipose tissue horizontally will preserve the integrity of the abdominal wall. Superficial placement of the cannula in this area is recommended to maximize the amount of fat removed, induce skin contraction, and allow a safe layered approach to fat removal. One of the significant advantages of liposuction using the TLA technique is that it minimizes blood loss. However, often surgeons will fail to wait long enough after infiltration of the TLA solution until the vasoconstrictive effects of epinephrine (15–20 minutes after infiltration of TLA solution) have taken effect. During the procedure, the surgeons should keep a close eye on the aspirate, directing the cannula away from areas where there are greater volumes of blood relative to fat in the aspirate. Selecting the appropriate cannula size (4 mm should be the largest utilized) and blunt tip style will have a significant role in the decreased tendency for bleeding and hematoma formation. To decrease the risk of bleeding and hematoma formation, larger procedures such as high volume abdominal liposuction, should be considered in two stages.

56. Liposuction During TLA, the maximum dosage of lidocaine used should be 55 mg/kg [4]. The lowest dose of lidocaine that provides complete local anesthesia should be utilized. The normal saline utilized should contain lidocaine in concentrations of 0.05–0.1% [4]. The peak plasma concentration of lidocaine occurs 12–18 hours postoperatively, given the slow systemic absorption of lidocaine from the adipose tissue [4]. Patients, family, and staff taking care of the patient should be aware of the symptoms and signs of lidocaine toxicity.

Postoperative phase Postoperative compression garments will both enhance skin contraction and assist with more rapid removal of local tumescent solution. The compression garment is also critical in order to minimize or eliminate bleeding, hematoma and seroma formation, and to speed wound healing. Patient comfort after the procedure is also greatly improved by wearing compression garments. In general, it is recommended that the garment be worn around the clock for the first week and be worn half-time for the subsequent 2–3 weeks. Any signs of infection should be evaluated and cultured as soon as possible. With atypical mycobacterial infections, it is important to obtain the culture medium requirements of the laboratory and to notify the laboratory that special processing of the specimen is needed. A rare case of necrotizing fasciitis has been reported with liposuction and thus any patient presenting with severe pain out of proportion to examination, surface blistering, and tenderness should be promptly evaluated for possible débridement and started immediately on broad-spectrum antibiotics and supportive care. Lidocaine, epinephrine, and bicarbonate utilized in the tumescent solution have all been proven to have antimicrobial effects on a diverse range of pathogens (bacteria, fungi, viruses) and thus the large dilute volume of anesthetic solution with the tumescent technique may further have a role in the low rates of infection associated with this procedure. In addition, using fine cannulas (4 mm or less) will assist with deep bruising and seroma formation and infection risk. Leaving the cannula sites open to drain leads to decreased hematoma and seroma formation. If significant hematomas form, they will usually spontaneously resolve or can be evacuated once they have liquefied. Large hematomas can be very uncomfortable for the patient and can prevent him or her from returning quickly to usual routines. Seromas need to be drained, sometimes repeatedly with recurrence, with subsequent compression applied to the area (Figure 56.9).

Figure 56.9 Adverse complication of liposuction: skin dimpling and scarring in medial thighs after overly aggressive liposuction procedure.

with a documented safety record, longevity of results, and high levels of patient satisfaction. Liposuction using TLA only in the office setting has a documented superior safety profile which has been documented in a number of studies in the dermatologic surgery literature by Bernstein, Hanke, Coleman and Housman (Table 56.3). Several of largest studies to date, the first by Hanke et al. in 1995 [6], reported data on 44 014 body areas treated with liposuction. There were no serious complications of death, emboli, hypovolemic shock, perforation of thorax or peritoneum, thrombophlebitis, seizures, or toxic reactions to drugs. Subsequently, in 2002, Housman et al. [24] reported data on 66 570 liposuction procedures. No deaths were reported and the serious adverse event ratio was low at 0.68 per 1000. In 2004, Hanke surveyed 39 tumescent liposuction centers and 688 patients treated with the tumescent technique to examine liposuction practice and safety [35]. The overall complication rate was 0.7%, with a minor complication rate of 0.57% and a major complication rate of 0.14% (1/688 patients). Patient satisfaction was very high among the surveyed population, where 91% of patients surveyed were positive about their decision to have liposuction. In contrast, in the plastic surgery literature (Table 56.3) the case fatality and complication rates were significantly higher for liposuction. In the largest study to date among plastic surgeons by Grazer and de Jong in 2000 [36] evaluating data on 496 245 procedures, the fatality rate was 19.1/100 000; where the most common causes of death included thromboembolism (23.1%), abdomen/viscus perforation (14.6%), anesthesia/sedation/medication (10%), fat embolism (8.5%), cardiorespiratory failure (5.4%), massive infection (5.4%), and hemmorhage (4.6%).

Conclusions and future directions Laser-assisted liposuction Liposuction with local TLA is a procedure that was designed and developed by dermatologic surgeons. It is a procedure

Current studies are undergoing evaluating the ability to liquefy or rupture fat cells using various lasers [37–43]. The

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Table 56.3 Liposuction safety studies. Study/author

Year

Number of procedures

Specialty

Newman, Dolsky [45]

1984

5 458

Cosmetic surgeons (derm, ENT, etc.)

1/38 426

Bernstein, Hanke [5]

1988

9 478

Dermatologic surgeons

Temourian, Rogers [46]

1991

112 756

Plastic surgeons

Dillerud [47]

1991

3 511

Plastic surgeons

Hanke et al. [6]

1995

15 336

Dermatologic surgeons

ASPRS Task Force on Liposuction [48]

1998

24 295

Plastic surgeons

20.6/100 000

Jackson, Dolsky [49]

1997

200 000

Cosmetic surgeons (derm, ENT, etc.)

2.4/100 000

Grazer, De Jong [36]

2000

496 245

Plastic surgeons

19.1/100 000

Hughes [50]

2001

94 159

Plastic surgeons

Not stated

1/47 415 (lipo only) 17 314 (lipo and other procedures) 1/3281 (lipo and abdominoplasty

Housman et al. [24]

2002

66 570

Dermatologic surgeons

Hanke et al. [35]

2004

688

Dermatologic surgeons

laser devices most widely utilized to assist with liposuction include a helium-neon laser (635 nm), a diode laser (600– 800 nm), and, most recently, a 1064 nm neodymium:yttrium aluminum garnet (Nd:YAG) laser [37–43]. The studies with a 635 nm diode laser utilized to release fat from adipocytes demonstrated changes in the adipose structure utilizing electron microscopy and magnetic resonance imaging (MRI) [37–44]. Six minutes of exposure to the 635 nm diode laser at 1.2 J/cm2 resulted in a transitory pore in the cell membrane with resultant release of the fat into the interstitial space [37–44]. Recent studies have evaluated both the clinical and histopathologic effects of the 1064 nm Nd:YAG laser and 980 nm diode laser in laser-assisted lipolysis [37–44]. A recent study by Mordon et al. [37] demonstrated both enhanced lipolysis and skin contraction with the laser-assisted devices. Using an optimal thermal modeling approach, the authors demonstrated that increased heat generated by the laser in the deep reticular dermis may result in collagen and elastin synthesis and resultant skin tightening which they observed clinically after laser lipolysis. Goldman demonstrated skin contraction and enhanced lipolysis with the use of the 1064 nm Nd:YAG laser for submental liposuction [39]. Clinical results of tissue tightening were correlated with histologic analysis confirming laser-induced rupture of the adipocyte membrane. Kim et al. [38] reported the results of 29 patients treated with

460

Number of fatalities

Fatality rate

12.7/100 000

laser lipolysis with the 1064 nm Nd:YAG device and demonstrated clinical improvement (at 3 months, average of 37%) as well as decreased adiposity as measured by MRI (average of 17% reduction in volume). Greater improvement was noted in smaller volume areas, such as the submentum, in both clinical outcome and dermal tightening. However, several other recent comparative trials evaluating laserassisted liposuction with the 1064 nm Nd:YAG laser have shown equivocal results with laser-assisted liposuction relative to liposuction alone [42–44]. Laser-assisted liposuction has been purported to result in both mechanical cavitation of fat resulting in greater ease of suction and greater skin retraction after the procedure resulting in enhanced tightening. However, further studies are highly needed to evaluate scientifically the benefits of pretreatment with lasers for ease of adipose removal and enhanced cosmesis [37–43].

References 1 Fischer G. (1990) Liposculpture: the correct history of liposuction, part I. J Dermatol Surg Oncol 16, 1087–9. 2 Ilouz Z. (1983) Body contouring by lipolysis: a 5 year experience with over 3000 cases. Plast Reconstr Surg 72, 591–7. 3 Fournier P. (1987) Body Sculpting Through Syringe Liposuction and Autologous Fat Re-injection. Corona del Mar: Samuel Rolf International.

56. Liposuction 4 Klein JA. (1990) Tumescent technique for regional anesthesia permits lidocaine doses of 35–55 mg/kg for liposuction. Peak plasma levels are diminished and delayed for 12 hours. J Dermatol Surg Oncol 16, 248–63. 5 Bernstein G, Hanke CW. (1988) Safety of liposuction: a review of 9478 cases performed by dermatologists. J Dermatol Surg Oncol 14(10), 1112–4. 6 Hanke CW, Bernstein G, Bullock S. (1995) Safety of tumescent liposuction in 15,336 patients: national survey results. Dermatol Surg 21, 459–62. 7 Ostad A, Kageyama N, Moy R. (1995) Tumescent anesthesia with a lidocaine dose of 55 mg/kg is safe for liposuction. Dermatol Surg 22, 921–7. 8 Klein JA. (2000) Tumescent Technique: TLA and Microcannular Liposuction. St. Louis, MO: Mosby. 9 Hanke CW. (1999) State-of-the-art liposculpture in the new millennium. J Cutan Med Surg 3 (Suppl 4), S36–42. 10 Pasman WJ, Saris WH, Westerterp-Plantenga MS. (1999) Predictors of weight maintenance. Obes Res 7, 43–50. 11 Brownell KD, Rodin J. (1994) Medical, metabolic and psychological effects of weight cycling. Arch Intern Med 154, 1325–30. 12 Ozgur F, Tuncali D, Guker Gursu K. (1998) Life satisfaction, self-esteem and body image: a psychosocial evluation of aesthetic and reconstructive surgery candidates. Aesthetic Plast Surg 22, 412–9. 13 Mann MW, Palm MD, Sengelmann RD. (2008) New advances in liposuction technology. Semin Cutan Med Surg 27, 72–82. 14 Hanke CW. (1989) Liposuction under local anesthesia. J Dermatol Surg Oncol 15, 12. 15 Lillis PJ. (1988) Liposuction surgery under local anesthesia. Limited blood loss and minimal lidocaine absorption. J Dermatol Surg Oncol 14, 1145–8. 16 Butterwick J. (2003) Liposuction consultation and preoperative considerations. In: Narins RS, ed. Safe Liposuction and Fat Transfer. New York: Marcel Dekker. 17 Jacob CI, Kaminer MS. (2003) Tumescent anesthesia. In: Narins RS, ed. Safe Liposuction and Fat Transfer. New York: Marcel Dekker. 18 Hanke CW, Coleman WP. (1999) Morbidity and mortality related to liposuction: questions and answers. Dermatol Clin 17, 899–902. 19 Coleman WP 3rd, Hanke CW, Lillis P, Bernstein G, Narins R. (1999) Does the location of the surgery or the specialty of the physician affect malpractice claims in liposuction? Dermatol Surg 25, 343–7. 20 Landry GL, Gomez JE. (1991) Management of soft tissue injuries. Adol Med 2, 125–40. 21 Klein JA. (2000) Miscellaneous complications. In: Klein JA, ed. Tumescent Technique, Tumescent Anesthesia and Microcannular Liposuction. St. Louis, MO: Mosby. 22 Narins RS, Coleman WP. (1997) Minimizing pain for liposuction anesthesia. Dermatol Surg 23, 1137–40. 23 Klein JA. (2000) Thrombosis and embolism. In: Klein JA, ed. Tumescent Technique, Tumescent Anesthesia and Microcannular Liposuction. St. Louis, MO: Mosby. 24 Housman TS, Lawrence N, Mellen BG, George MN, Filippo JS, Cerveny KA, et al. (2002) The safety of liposuction, results of a national survey. Dermatol Surg 39, 971–8.

25 Narins RS. (2003) Abdomen, hourglass abdomen, flanks and modified abdominoplasty. In: Narins RS, ed. Safe Liposuction and Fat Transfer. New York: Marcel Dekker. 26 Jacob CI, Kaminer MS. (2003) Surgical approaches to the aging neck. In: Narins RS, ed. Safe Liposuction and Fat Transfer. New York: Marcel Dekker. 27 Goddio AS. (1992) Suction lipectomy: the gold triangle at the neck. Aesth Plast Surg 16, 27–32. 28 Kamer FM, Minoli JJ. (1993) Postoperative platysmal band deformity: a pitfall of submental liposuction. Arch Otolaryngol Head Neck Surg 119, 193–6. 29 Key D. (2008) Efficacy of skin tightening and contour correction of the lower face and jowl using 1320 nm laser lipolysis: a comparison evaluation of lipolysis without aspiration, lipolysis with aspiration and aspiration without lipolysis. Abstract presented at American Society of Laser Medicine and Surgery Conference, Kissimmee, FL. 30 Goddio AS. (1992) Suction lipectomy. The gold triangle at the neck. Aesth Plast Surg 16 27–32. 31 Samdal F, Kleppe G, Amland PR, Abyholm F. (1994) Surgical treatment of gynecomastia. Scan J Plast Recontstru Hand Surg 28 123–30. 32 Matarasso A, Courtiss EH. (1991) Suction mammoplasty, the use of suction lipectomy to reduce large breasts. Plast Reconstr Surg 87, 709–10. 33 Gray LN. (1988) Liposuction breast reduction. Aesthetic Plast Surg 22, 159–62. 34 Bernstein G. (1999) Instrumentation for liposuction. Dermatol Clin 14, 735–49. 35 Hanke W, Cox SE, Kuznets N, Coleman WP 3rd. (2004) Tumescent liposuction report performance measurement initiative: national survey results. Dermatol Surg 30, 967–77. 36 Grazer FM, de Jong RH. (2000) Fatal outcomes from liposuction: census survey of cosmetic surgeons. Plast Reconstr Surg 105(1), 436–46. 37 Mordon SR, Wassmer B, Reynaud JP, Zemmouri J. (2008) Mathematical modeling of laser lipolysis. Biomed Eng Online 7, 10. 38 Kim KH, Geronemus RG. (2006) Laser lipolysis using a novel 1,064 nm Nd:YAG Laser. Dermatol Surg 32, 241–8. 39 Goldman A. (2006) Submental Nd:YAG laser-assisted liposuction. Lasers Surg Med 38, 181–4. 40 Ichikawa K, Miyasaka M, Tanaka R, Tanino R, Mizukami K, Wakaki M. (2005) Histologic evaluation of the pulsed Nd:YAG laser for laser lipolysis. Lasers Surg Med 36, 43–6. 41 Morton S, Wassmer B, Reynaud P, Zemmouri J. (2008) Mathematical modeling of laser lipolysis. Abstract presented at American Society of Laser Medicine and Surgery Conference, Kissimmee, FL. 42 Dressel T, Zelickson B. (2008) Laser liposuction a work in progress. Abstract presented at American Society of Laser Medicine and Surgery Conference, Kissimmee, FL. 43 Weiss R, Weiss M, Beasley K. (2008) Laser lipolysis: skin contraction effect of 1320 nm. Abstract presented at American Society of Laser Medicine and Surgery Conference, Kissimmee, FL. 44 DiBernardo B, Goldman M, Saluja R, Woodhall K, Reyes J. (2008) Mulicenter study evaluation of sequential emission of lasers for the treatment of fat with laser assisted lipolysis.

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Abstract presented at American Society of Laser Medicine and Surgery Conference, Kissimmee, FL. 45 Dolsky RL, Newman J, Fetzek JR, Anderson RW. (1987) Liposuction. History, techniques, and complications. Dermatol Clin 5(2), 313–33. 46 Teimourian B, Rogers WB 3rd. (1989) A national survey of complications associated with suction lipectomy: a comparative study. Plast Reconstr Surg 84(4), 628–31. 47 Dillerud E, Håheim LL. (1993) Long-term results of blunt suction lipectomy assessed by a patient questionnaire survey. Plast Reconstr Surg 92(1), 35–42.

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48 ASPRS Task Force on Liposuction, available at http://www. plasticsurgery.org/Medical_Professionals/Publications/PSN_ News_Bulletins/ASPS_urges_members_to_exercise_caution_in_ lipoplasty_procedures_Task_Force_report_calls_for_scrutiny_ of_training_large_volume_removals.html, accessed August 2, 2009. 49 Dolsky RL. (1997) State of the art in liposuction. Dermatol Surg 23(12), 1192–3. 50 Hughes CE 3rd. (1999) Patient selection, planning, and marking in ultrasound-assisted lipoplasty. Clin Plast Surg 26(2), 279–82; ix.

Chapter 57: Liposuction of the neck Kimberly J. Butterwick Dermatology/Cosmetic Laser Associates of La Jolla, San Diego, CA, USA

BAS I C CONCEPTS • Neck liposuction is used to remove excess fat from the neck area and minimize skin sagging. • Small cannulas and multiple entry sites are necessary to achieve even fat removal without ridging or deformity. • Tumescent anesthesia is key to reducing pain and bruising while facilitating fat removal. • Proper selection of patients with fat in front of the platysma muscle can ensure a successful outcome. • Overremoval of fat on the lower neck should be avoided.

Introduction One of the first signs of aging that prompts patients to seek cosmetic treatment is the sagging neck. Tumescent liposuction of this area often dramatically rejuvenates the neckline and is one of the most common body areas treated with this modality. Although this area may seem complicated to the novice surgeon, liposuction of the neck is relatively quick, safe, and readily learned. It is also well tolerated by patients with rapid healing in 3–4 days. With careful selection of patients and good technique, this is a very rewarding area for patients and surgeon alike.

Anatomy The primary goal of liposuction of the neck is restoration of the cervicomental angle (CMA). This is the angle formed by the horizontal plane of the submental region and the vertical plane of the neck (Figure 57.1) [1]. The ideal angle is generally considered to be 90–100 ° or more, up to 135 ° [1–3]. Other anatomic features of a youthful neck include definition of the inferior mandibular border, subthyroid depression, a thyroid notch visible as a gentle indentation, and a visible anterior border of the sternocleidomastoid muscle [1]. The face should be distinct from the neck such that a shadow should be cast on to the upper neck by the mandible. With aging and/or genetics, there may be accumulation of submental fat leading to blunting of the CMA or a “double chin.” Other anatomic factors may also contribute to an obtuse CMA such as a low-lying hyoid bone, microgenia, or

retrognathia. Ideally, the hyoid bone should be positioned at the C3–C4 level [4]. Lateral to the submental region, there may be loss of definition of the submandibular region leading to an unattractive continuum between the face and the neck. Further contributing to fullness in this area may be ptotic submandibular glands located along the inferior midportion of the mandibular ramus. Other stigmata of aging in the lower third of the face may need to be addressed such as the presence of jowls and the development of a depression just medial to the jowl called the prejowl sulcus [5]. The platysma muscle is the thin layer of muscle just deep to the submental fat pad arising from the cervicopectoral fascia inferiorly and attaching to the depressor anguli oris, risorius, and mentalis muscles superiorly with a varying degree of decussation at the midline [6]. Approximately 75% of the time, the fibers interlace 1–2 cm below the chin but separate in the suprahyoid region. Less often, the fibers decussate all the way down to the thyroid cartilage or not at all [7]. With aging, the medial fibers of the platysma muscle may hypertrophy into thick visible bands. Deep to the platysma, there may be a collection of fat that is midline and submental. While the preplatysmal fat pad is accessible to tumescent liposuction, the retroplatysmal fat pad is not and requires direct excision for removal. Having the patient clench his or her teeth tightens the platysma and aides in distinguishing pre- or retroplatysmal fat [3]. The amount of submental retroplatysmal fat has been estimated to vary between 30% and 57% of the total amount [8]. Also deep to the platysma is the marginal mandibular branch of the facial nerve, which is vulnerable to trauma during liposuction of this area. This motor nerve runs along the mandible, parallel to the ramus and is typically most superficial at the anterior border of the masseter muscle (Figure 57.2). However, the position of this nerve is variable, and it can be found 3–4 cm inferior to the ramus. Caution

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must be exercised when suctioning this region because repeated pressure and rubbing from the cannula may result in temporary neuropraxis. While this typically lasts only 4–6 weeks, the distorted appearance is very distressing to the patient. To minimize injury to this nerve, patients should be asked to clench their teeth and the anterior edge of the massester should be marked where the nerve is likely to be found, at or just below the level of the ramus. Other techniques to minimize potential injury to this nerve are described below. Another structure less vulnerable to injury is the external jugular vein which passes over the sternocleidomastoid muscle. The vessel could be injured from inadvertent deep penetration by the cannula from a lateral position.

Esthetic considerations To the novice surgeon, liposuction of the neck entails simply removing fat in the submental area. However, there are

some esthetic principles and proportions that should be considered for optimal esthetic results (Figure 57.1) [9,10]. When evaluating the cervicomental angle, one should evaluate the entire profile of the head and neck. The ideal profile should be viewed with the head held in the Frankfurt horizontal plane. This is the horizontal plane, parallel to the floor, in which a horizontal line can be drawn through the highest point of the ear canal meatus and the lowest point of the orbital rim [10]. In this position, the chin is at the proper level for assessing the CMA and for uniformity of preoperative and postoperative photographs. It is said that in this position, the glabella, nasal root, lip projection, and mentum should ideally align in a vertical facial plane. Utilizing this proportion enables the surgeon to assess the relative strength of the chin and the adequacy of volume in the face. The face should be divisible by thirds from the midline frontal scalp to glabella, the glabella to the infranasal area, and the infranasal area to the mentum. Often, the lower third of the face is reduced in volume because of bone loss, aging, genetics, or other factors.

Patient selection

Frankfurt plane

CMA 105°

Facial plane Figure 57.1 The youthful neck with a cervicomental angle of 100 °. The facial and Frankfurt plane are shown with glabella, subnasale, and chin in alignment.

Potential candidates for submental liposuction fall into three groups: correction of genetic traits, rejuvenation for mild to moderate aging, and restoration of more advanced aging. The latter two groups may also have some pre-existing hereditary factors. All groups should be assessed systematically and all determinates to the aging neck evaluated (Table 57.1). The first group of patients tends to be relatively young, typically less than 30 years, and usually of normal weight, although this deposit makes them look heavier or older than they are. Although the skin quality is excellent, the profile is obscured by submental fat. There are often contributing factors to the obtuse CMA, such as microgenia or a low-lying

Facial artery and vein Parotid gland

Sternocleidomastoid muscle

Marginal mandibular branch of the facial nerve Submandibular gland

Platysma muscle

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Figure 57.2 Marginal mandibular branch of the facial nerve and other relevant anatomy.

57. Liposuction of the neck

Table 57.1 Preoperative assessment. 1 Cervicomental angle 2 Degree of submental fat 3 Platysma banding 4 Degree of subplatysma fat 5 Hyoid position 6 Presence of jowls 7 Position of submandibular glands 8 Adequacy of chin profile 9 Skin thickness 10 Skin laxity

hyoid bone. These limitations should be addressed at the time of the consultation. Patients in this age group may also have quite full cheeks, but with age cheek hollows often become more marked. Removal of fat may then retrospectively be seen as inappropriate. The next group of patients is typically 35–50 years old with some skin laxity brought about by photoaging, facial volume loss, and a genetic tendency towards submental fat accumulation. They are often mildly overweight, but even at ideal weight, the problem persists. The last group is over 55 years old and has submental fat but in addition significant skin redundancy, bone and volume loss, platysma banding, and photoaging. Many in this group would fare better with reconstructive surgery, but at times the risk : benefit ratio – that is, the improvement offered by liposuction alone – will satisfy those wishing to avoid the risks of a more invasive surgical procedure. These patients should be carefully assessed, as liposuction alone could significantly worsen the appearance of the skin, platysma bands, or expose ptotic submandibular glands. In all three groups, males may show relatively less improvement than females. Their thickened, bearded skin retracts less readily than that of females. Even thinner females with little submental fat often show good benefit because of marked skin retraction after liposuction.

Consultation and physical examination The consultation is a key step in communicating expected risks and benefits. In our practice, patients initially voice their concerns to a practice consultant. The consultant reviews treatment options and helps patients develop and prioritize their beauty wish list. Patients often pull back the neck tightly and, in the same breath, state they would never want a facelift. If liposuction alone is being considered, it is helpful to grasp the submental fat and tuck it up under the chin. This maneuver essentially “removes” the fat from view

Figure 57.3 Grasping and tucking the submental fat to demonstrate expected results of submental liposuction without upward posterior retraction seen in rhytidectomy.

without pulling up on the jowls (Figure 57.3). If the patient has lax, photoaged skin, the surgeon should bunch it up a little and show the patient that it could look more wrinkled after the procedure. The surgeon should pull the skin back and demonstrate the probable result of a rhytidectomy to help the patient visualize the different results of different procedures. Any contributing factors to the blunted neck angle are reviewed with the patient at this point and additional corrective measures and alternative treatments are discussed. Platysma bands can be identified by having the patient grimace. An overview of the risks is also part of the consultation. At this point, the surgeon typically leaves the room, and the consultant answers additional questions, reviews the fee quote, and offers to schedule the procedure. Should the patient decide to proceed, he or she returns for a second visit for a preoperative examination. At this visit, the patient has a modified physical examination, reads and signs consents forms, and is given written preoperative and postoperative instructions. Preoperative laboratory studies and photographs are completed. Typical preoperative laboratory studies include: full blood count, chemistry panel, prothrombin time/partial thromboplastin time (PT/PTT), international normalized ratio, and viral titers. A prescription for preoperative antibiotics is given to start the night before surgery for a total of 10 days.

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Procedure Markings The preoperative markings are summarized in Table 57.2. With the patient in an upright position, the edge of the mandible is outlined and a circle is drawn around the perimeter of the main accumulation of fat in the submental area (Figure 57.4). An “X” is then marked on the most visible mound within that circle. An additional circle may be drawn just inferior to the submental area if indicated, or concentric circles may be drawn around the main deposit of fat. The jowls are outlined as they extend both superior and inferior to the mandibular border. Again, the fullest aspects of the jowl are marked with an “X.” Laterally, fullness superior to the mandible is outlined. Inferior to the mandible, small “X’s” or a line should be drawn where maximum definition is desired. This is the area where a linear shadow should be cast. The patient is then instructed to clamp down on the back teeth. The edge of the masseter is then palpated and an “X”

is placed at the probable location of the marginal mandibular nerve, preferably in a different color. The platysma is assessed during this maneuver and the bands may be outlined in another color. Other landmarks that may be highlighted include the anterior border of the sternocleidomastoid muscle, the hyoid bone, and the inferior border of the neck. Parallel vertical lines are drawn from the immediate submental area down the remainder of the neck to the base of the neck. Fat is rarely removed from the lower two-thirds of the neck because the skin here is often so thin that it will look more aged and wrinkled if underlying fat is removed. The long vertical lines remind the surgeon not to remove fat but rather to tunnel through, without suction. Tunneling is thought to create tissue injury that will then stimulate some neocollagenesis and perhaps thicken or tighten the skin to some degree. On rare occasion if the patient has horizontal rhytids of the lower two-thirds of the neck and excessive fat, very conservative liposuction of the lower neck will significantly improve fat bulges and horizontal furrows.

Anesthesia and infiltration Table 57.2 Preoperative marking. 1 Mark border of mandible 2 Encircle submental fat and place “X” on apex 3 If present, outline jowl and excess fat in lower lateral cheek 4 Make a line or “X’s” where submandibular concavity desired 5 Mark likely position of marginal mandibular nerve 6 Dot in platysma bands if indicated 7 Draw parallel vertical lines to base of neck

Figure 57.4 Preoperative markings.

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Patients undergoing liposuction of the neck do not require general anesthesia and many of them could undergo the procedure without any sedation at all. However, most patients prefer to have some anxiolysis and are typically given 1 mg lorazepam p.o. prior to the procedure. Alternatively, if a surgicenter is utilized, an intravenous line may be started and the patient given 1.0 mg midazolam IV along with 25 μg fentanyl IV as a one-time dose. Intravenous medications are often preferred because the patient will feel instantly relaxed and will be nearly fully awake when the procedure is over. One must be careful with intravenous medicationss to avoid excessive sedation and apnea; however, the low doses utilized above result in mild sedation with appropriate responsiveness. The patient is then positioned in a supine position with a neck roll partially under the shoulders so that the head rolls back comfortably in an extended position. After prepping with benzalkonium chloride antiseptic (Zephiran™, SanofiAventis, Bridgewater, NJ, USA), the patient is draped with sterile towels, including a sterile turban (Figure 57.5). A lap sponge is placed over the patient’s eyes for comfort and protection. Tumescent anesthesia of the neck is the next step. Superficial blebs of tumescent lidocaine are first made in five sites, corresponding to the entry sites for the cannula. Dilute lidocaine consisting of Klein’s standard formula with lidocaine 0.1% is infiltrated into the subcutaneous space with the aid of an infusion pump [11]. A 25-gauge spinal needle is used initially in a fan-like motion, introduced through five blebs, until the entire surgical field has been partially infused. The tumescent fluid is warmed, the infusion rate is low, and the needle gauge is small, assuring that there is minimal

57. Liposuction of the neck

Figure 57.5 Operative position with chin extended. Three of the five entry sites are denoted with circles and typical fanning pattern shown.

Table 57.3 Standard technique. 1 Debulk in midline submental region from three entry sites 2 Turn head laterally, suction lateral cheek/submandibular region 3 Avoid rasping mandible 4 Conservative suction of the jowl 5 Repeat steps 2 and 3 on contralateral side 6 Return head to central position. Tunnel inferiorly 7 Palpate all areas for smoothness 8 Apply French tape

discomfort for the patient. Approximately 50–100 mL is utilized at this point. The spinal needle is then changed to 20gauge, at a faster infusion rate, so that very quickly, within 5–15 minutes, the entire surgical field is tumesced. The patient may feel a bit anxious at this point because the neck will feel taut. Reassure patients that they can still breathe and swallow and that the tightness will loosen within a few minutes of starting the liposuction. It should be noted that it is not necessary to infiltrate the lower half of the neck. While the procedure is underway, the solution will drift inferiorly to the sternal notch, so that at the end of the procedure, when tunneling the lower neck may be desired, the lower neck will have adequate anesthesia. Typical volumes of infiltrated solution are 400–500 mL.

Liposuction: standard operative techniques The standard liposuction procedure utilizes five entry sites and a thorough suction with small cannulae (Table 57.3). The submental area is approached through three small stab incisions with an 11 blade. Although it may be tempting to perform the entire procedure through one site, the most thorough and smooth result requires criss-crossing through

multiple sites. In addition, one avoids a depression which is commonly seen under a single incision site. Only small cannulae are utilized, such as the Klein 14 and 16 gauge Finesse, to avoid ridges or troughs in thin-skinned patients. In patients with thicker skin, a slightly more aggressive cannula is sometimes needed such as a 12-gauge Klein Finesse or the multi-holed Klein Capistrano, gauge 14. These smaller cannulas also preserve connective tissue strands throughout the fat and are thought to maximize retraction of the skin. A thorough fanning technique is utilized through all three incisions with the cannula attached to the suction device. An assistant may anchor the skin at the entry site and elsewhere to minimize skin buckling, thereby facilitating long smooth strokes of the cannula. This is the area to be aggressive, from the submental crease to the superior edge of the thyroid cartilage, approximately 8–9 cm caudal to the submental crease. The end point in this area is a thin pinch of the skin. When lifting up a cannula under the skin, the overlying skin should be palpated and free of lumps. A thin layer of fat, approximately 3–5 mm in thickness should be left to prevent surface irregularities [12]. The cannula may be visible beneath the skin. The patient’s head is then turned to the side and a fourth incision site is made. If indicated by the preoperative examination, very conservative liposuction of the lower cheek is performed. Usually, less than 10 strokes of the cannula are needed in order to taper the face. One must be careful not to overressect this area and to feather (tunnel without suction) into the cheek immediately superior to the treated area in order to avoid a shelf or step-off. It is also important that fat is left behind. A strong, smooth, mandibular border is a youthful feature so it is rarely necessary to remove fat immediately overlying the mandible. The cannula is then directed approximately 3–4 cm below the ramus. This is a key area for removing fat to optimize definition between the head and the neck. Thorough removal is performed along this region. The surgeon must be mindful not to rasp against the ramus while performing liposuction with the head turned because of the proximity of the marginal mandibular nerve. In this position, the nerve may be located 3–4 cm below the mandible and become more superficial. Although it is deep to the platysma, this muscle is very thin and could be punctured by a small cannula [13]. If liposuction is needed near the ramus, one should pinch up the skin off the ramus and avoid deep fat. Special attention is then directed toward the jowl. If the jowl is large, a separate stab incision is made with an 18gauge No-Kor needle, at the most caudal extension of the jowl (Figure 57.6). A 16-gauge Klein Finesse cannula is then utilized to very conservatively remove less than 30% of the fat. Excessive removal in this area is not necessary as the skin will redrape nicely and overresection will result in deepening of the adjacent marionette fold. These same steps are then repeated on the contralateral side.

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Figure 57.6 Liposuction of the jowl with a 16-gauge Klein Finesse cannula. The skin is pinched up by the non-dominant hand to avoid rasping the cannula against the mandible.

After liposuction of both sides, the head is then returned to a central position. A 14-gauge Klein Finesse cannula is passed through the three central incisions sites to check for remaining fat deposits. Sometimes there are stubborn deposits inferior to the lowermost extension of the jowls and this area is specifically checked. Tunneling or feathering without suction is then performed with the cannula passing through the entire surgical field, down to the sternal notch without suction. Some surgeons recommend “windshield wiping” at this point in order to gain maximal skin retraction. In the author’s opinion this is not necessary and may have a negative effect in the development of delayed and unattractive adherence of the skin to underlying fascia. If platysma bands were visible at the preoperative examination, it may be helpful to take a spatula-tipped cannula and tunnel underneath them to reduce cutaneous attachments. Others prefer a closed neck V-shaped neck dissector to release tethering fibrous bands [14]. At the end of the procedure, three pieces of French tape are applied as shown in Figure 57.7. This helps to minimize pooling of tumescent fluid and free floating adipocytes in the submental area and minimizes postoperative bruising. It is removed 23–48 hours after the procedure.

Figure 57.7 French tape with two shorter pieces applied with traction to the midline and a third piece across entire area. This helps to decrease central pooling.

and can be covered with clothing or scarves. During the first 2 weeks postoperatively, the submental area swells and patients will note increasing induration. There may be small focal areas of induration appearing as lumps or areas of stiff skin that crease unnaturally with movement. Patients should be advised ahead of time because induration always develops as an expected, temporary condition that resolves over a period of 4–8 weeks. Lymphatic massage may be helpful as the induration most likely represents a localized interstitial edema. Rarely, a larger nodule develops that is unsightly. Low doses of 2.5 mg/mL Kenalog (Bristol-Myers Squibb Princeton, NJ, USA) may be injected to reduce the edema more quickly. After the healing process, expected benefits of liposuction of the neck and jowls include reduction of adipocities, and skin retraction leading to elevation of the submental area, flattening of the jowls, and a reduced cervicomental angle (Figures 57.8 and 57.9). The capacity of the skin of the neck to retract and redrape in this area is outstanding and remarkable even compared to liposuction in other areas [15]. The very small incision sites (3 mm or less) heal readily and essentially ensure a scarless procedure. Avoiding both surgical scars and general anesthesia are key aspects of this procedure that factor into the patient’s choice over more invasive options.

Postoperative course In addition to French tape, patients wear a chin strap 24 hours a day for 3–4 days. The strap is then worn 2–4 hours per day for another 3 weeks. Immediately after the procedure, patients experience minimal to no discomfort. Mild discomfort may last 2–4 days. Patients may return to work after the initial few days at home. Purpura is typically minimal. If it develops, it tends to drift below the collar line

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Complications Submental liposuction has a very low rate of complications with proper careful technique. Immediate potential complications include bleeding or hematoma. With tumescent liposuction and blunt-tipped cannulas the risk of significant

57. Liposuction of the neck

(b)

(a) Figure 57.8 Before (a) and 3 years after (b) removal of 50 mL of supranatant fat.

(b)

(a) Figure 57.9 Before (a) and 1 month after (b) removal of 100 mL of supranatant fat. CoolLipo laser applied at 15 W, 40 Hz for 625 pulses with simultaneous suction. After suction, skin tightening was performed at 5 W, 50 Hz for 93 pulses.

bleeding is very low. Postoperative compression further minimizes this risk. Temporary injury to the marginal mandibular nerve is probably the most common complication. It is important to be aware of the likely position of this nerve, anterior to the masseter muscle and at the level of the ramus or 3–4 cm inferior to the border. The nerve is most vulnerable when

the head is turned to the side. It is also prone to injury if one attempts to treat the jowl from a medial, submental incision site. Avoidance of brushing against the mandible in any position and avoidance of penetrating the thin platysma muscle is essential. In addition, approaching the jowl from the previously described inferior position should nearly eliminate this potential risk. If paresis develops, it presents

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(b)

(a) Figure 57.10 Small platysma bands unmasked after submental liposuction (b).

not as ipsilateral weakness, but rather hyperkinesis of the contralateral side. This side effect is temporary, rarely lasting beyond a few weeks, but it may last for 2–3 months. If troublesome to the patient, a few units of botulinum toxin may be placed in the contralateral, hyperkinetic, depressor labii inferioris. Permanent injury to the marginal mandibular nerve has not been reported after tumescent liposuction because there is no sharp instrumentation. Sensory nerves may also be temporarily affected. Reassurance that the numb feeling will resolve within 4–6 weeks generally consoles the patient. Postoperative edema has been mentioned previously. One more troubling aspect of this is the development of a submental fold. This is most likely caused by the compression garment loosening in this area. Patients with larger necks, low hyoid bones, and who frequently flex their neck for work or hobbies (i.e. needlepoint) seem to be at risk for this complication, which presents as a ridge, just posterior to the submental crease. Careful taping with French tape and admonition to elevate the chin regularly will mitigate this risk. Overresection is an avoidable complication. Overressection in the submental area leads to a “cobra” neck in which there is an actual depression under the chin with flaring of the sides because of the relative overabundance of adjacent fat [16]. The jowls are another danger zone in which the surgeon may be overly aggressive and cause a depressed, aged appearance. If patients are thin-skinned and/or elderly, overresection will lead to increased wrinkling of the skin. Conservative liposuction, leaving a thin blanket of fat, is best in these patients.

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Although it may not be a result of overresection, performing liposuction of the neck may unmask platysma bands and ptotic submandibular glands (Figure 57.10). A thorough preoperative examination should help to detect these patients. In one study of 301 patients, submental obesity and the anatomic pattern non-decussating platysma fibers were found to be significant correlates in the development of the postoperative platysmal banding [17]. The bands may be treated with botulinum toxin A (Allergan, Inc., Irvine, CA, USA) after surgery or adjuvant procedures such as platysmaplasty at the time of surgery. Excessive defatting in a patient with a round face, without tapering the lower face, can result in a “lollipop” appearance. Tapering of the lower face will prevent this appearance; however, care must be given to feather superiorly to avoid a shelf or step off. Infection is very rare with tumescent liposuction of any area. Patients are advised of this low risk, which is further reduced by preoperative antibiotics, and sterile procedures during surgery.

Advanced and ancillary operating techniques Submental liposuction is an excellent stand-alone procedure but it also lends itself to the addition of other procedures. At times, these procedures are essential for an acceptable outcome. Examples include platysmaplasty for thick, pronounced platysma bands that are present at rest or with mild animation [14,18]. A mini or full rhytidectomy may be added for excessively lax skin and jowls [11]. The use of

57. Liposuction of the neck

Figure 57.11 Before (a) and 6 months after (b) submental liposuction (25 mL) combined with fat augmentation to cheeks and chin (21 mL).

(b)

(a)

various lasers and devices to melt fat and/or tighten skin has been touted by some, but at this point, clinical data are lacking. At other times, procedures may be added to enhance an otherwise good outcome. With photoaged skin, for example, one may perform a resurfacing procedure to the face and neck immediately following the liposuction procedure. A typical procedure would add a fractionated laser versus a more invasive laser to avoid the oozing and discomfort from more aggressive laser procedures while wearing the chin strap. If the chin is recessed and/or the chin height short, chin implants may be inserted through a submental incision [19]. Alternatively, autologous fat transfer may be easily added to the procedure (Figure 57.11) [20]. Fat may be utilized from the neck, but it is usually difficult to obtain enough fat through a hand-held syringe, particularly if the fat is to be centrifuged as well. Another donor site may be necessary. Other areas of the face in which volume restoration will enhance the neckline include the prejowl sulcus, marionette fold, or mandibular border. Full-face volume restoration if indicated will elevate the cheeks and jowls and often lift the submental area.

Conclusions Liposuction of the neck is a procedure that is straightforward, takes 1 hour or less, and is rapidly healing with few complications. It is often a stand-alone procedure or it can be combined with other procedures that may be indicated in the aging patient or those with pre-existing anatomic factors. Proper patient selection and good technique that avoids overresection are key elements for achieving optimal results. Because aging of the neckline and drooping jowls

are often the first major complaint of the aging patient, it is incumbent of the dermasurgeon to achieve mastery of this technique as it is likely to become one of his or her favorite procedures to perform.

References 1 Prendiville S, Kohoska MS, Hollenbeak CS, et al. (2002) A comparative study of surgical techniques on the cervicomental angle in human cadavers. Arch Facial Plast Surg 4, 236–42. 2 Ellenbogen R, Karlin J. (1980) Visual criteria for success in restoring the youthful neck. Plast Reconstr Surg 66, 826. 3 Jacob CI, Berkes BJ, Kaminer MS. (2000) Liposuction and surgical recontouring of the neck: a retrospective analysis. Dermatol Surg 26, 635–2. 4 Moreno A, Bell WH, Zhi-Hao Y. (1994) Esthetic contour analysis of the submental cervical region. J Oral Maxillofac Surg 52, 704–13. 5 Mittelman H. (1994) The anatomy of the aging mandible and its importance to facelift surgery. Facial Plast Surg Clin N Am 2, 301–10. 6 de Castro CC. (1980) The anatomy of the platysma muscle. Plast Reconstr Surg 66, 680–3. 7 Hoefflin SM. (1998) Anatomy of the platysma and lip depressor muscles: a simplified mnemonic approach. Dermatol Surg 24, 1225–31. 8 Lambros V. (1992) Fat contouring in the face and neck. Clin Plast Surg 19, 401–14. 9 Powell N, Humphreys B. (1984) Proportions of the Aesthetic Face. New York: Thieme-Stratton. 10 Farkas LG, Sohm P, Kolar JC, Katic MJ, Munro IR. (1985) Inclination of the facial profile: art versus reality. Plast Reconstr Surg 75, 509–19. 11 Klein JA. (1990) Tumescent technique for regional anesthesia permits lidocaine doses of 35 mg/kg for liposuction. J Dermatol Surg Oncol 16, 248–63.

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12 Watson D. (2005) Submentoplasty. Facial Plast Surg Clin N Am 13, 459–67. 13 Langdon RC. (2000) Liposuction of neck and jowls: five-incision method combining machine-assisted and syringe aspiration. Dermatol Surg 26, 388–91. 14 Jacob CI, Kaminer MS. (2002) The corset platysma repair: a technique revisited. Dermatol Surg 28, 257–62. 15 Goddio AS. (1992) Suction lipectomy: the gold triangle at the neck. Aesth Plast Surg 16, 27–32. 16 Fattahi TT. (2004) Management of isolated neck deformity. Atlas Oral Maxillofacial Surg Clin N Am 12, 261–70.

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17 Kamer FM, Minoli JJ. (1993) Postoperative platysmal band deformity. Arch Otolaryngol Head Neck Surg 119, 193–6. 18 Knipper P, Mitz V, Maladry D, Saad G. (1997) Is it necessary to suture the platysma muscles on the midline to improve the cervical profile? An anatomic study using 20 cadavers. Ann Plast Surg 39, 566–71. 19 Newman J, Dolsky RL, Mai ST. (1984) Submental liposuction extraction with hard chin augmentation. Arch Otolaryngol 110, 445–57. 20 Butterwick KJ. (2003) Enhancement of the results of neck liposuction with the FAMI technique. J Drug Dermatol 2, 487–93.

Chapter 58: Hand recontouring with calcium hydroxylapatite Kenneth L. Edelson Mount Sinai School of Medicine and Private Practice, New York, NY, USA

BAS I C CONCEPTS • The aging hand is a common area of concern for patients. • Adequate treatment solutions were hampered by injection pain and the absence of treatment longevity. • The soft tissue filler calcium hydroxylapatite is effective for rejuvenating aging hands. • Calcium hydroxylapatite combined with lidocaine reduces pain of injection, improves product rheology of the procedure, and deposits the product in the correct metacarpal spaces. • The volume of injected calcium hydroxylapatite varies with physician preference.

Introduction This chapter begins with a description of the aging hand, then identifies various cosmetic hand treatment products used by physicians for the past 20 years. Calcium hydroxylapatite is then introduced as an alternative to past dermal fillers. A discussion of how to add anesthesia to the calcium hydroxylapatite follows. The author then leads the reader through a step-by-step instruction of injection of the product into the aging hand. The chapter closes with a summary and a discussion of the various volumes of product and possible durability effects that have been used by various physicians.

Physiology of the hand The great Irish playwright Oscar Wilde once said that “a woman who tells you her age will tell you anything.” Well, in his day she did not have to; one could just examine her hands. Today, with the technology of hand recontouring, her secret is safe. The hands have always been problem areas for physicians to rejuvenate and a myriad of applications and techniques have been used, both surgical and non-surgical with limited success. Until recently, no gratifying procedure has been

successful in producing the effect of Botox on wrinkles or intense pulsed light (IPL) and lasers on vessels. Signs of the aging hand include: a textural, crepe-like appearance, dryness, dyscromia, increased skin laxity, and volume loss giving the sunken appearance highlighting bones, tendons, and veins. A combination of both fractional non-ablative, or ablative laser resurfacing to address the epidermal defects, and the ideal subdermal filling agent to correct the loss of skin elasticity, volume, and wrinkling, is needed to address the aging hand. Both men and women can benefit from volume restoration and can attain a plumper, more youthful hand appearance with the proper technique and product. A panoply of dermal fillers exists in the esthetic marketplace. These have been well described in the 2008 American Society for Dermatologic Surgery (ASDS) guidelines publication [1]. Zyderm® collagen (Collagen Corp., Palo Alto, CA, USA), the original filler since 1982 and the gold standard for more than two decades, and Zyplast® (Collagen Corp., Palo Alto, CA, USA), followed by Cosmoderm® and Cosmoplast® (Allergan, Irvine, CA, USA) did not produce optimal results because of its consistency and flow characteristics, as well as lack of longevity. The filler was injected into the atrophic area, but did not cover objectionable structures. Collagen and hyaluronic acid fillers also did not flow well, yielding lumps and bumps. Harvested fat has also been used by some physicians. However, the large-bore needles required for injection often leave unsightly puncture marks. More importantly, the results were modest at best, and short-lived, requiring a second surgical procedure to harvest the fat.

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Advantages of calcium hydroxylapatite for treatment of the aging hand

Technique of injection of CaHA into the hand

In 2007, Florida dermatologists Mariano Busso (Coconut Grove) and David Applebaum (Boca Raton) reported offlabel clinical experiences using calcium hydroxylapatite (CaHA; Radiesse, BioForm Medical, San Mateo, CA, USA) for hand recontouring [2]. Their idea involved addition of lidocaine to the existing Radiesse compound. (Radiesse was approved in later 2006 for treatment of severe lines and wrinkles of the face such as nasolabial folds as well as treatment for HIV-associated facial lipoatrophy.) As a result, pain of treatment was reduced to nearly none, with immediately pleasing results to patients in one treatment session. Radiesse consists of CaHA microspheres, 25 μm to 45 μm in diameter, in a carboxymethyl cellulose carrier gel. The CaHA is identical to the component found in human bone. The carrier gel disperses within weeks, leaving behind the calcium microspheres. It does not induce osteogenesis when placed in tissue but laboratory studies show neocollagenesis extending out to 72 weeks [3]. Hand recontouring required a substance that could not only fill atrophic areas of the dorsal hand, but could also conceal the vein and tendon color. Radiesse is white, opaque, possesses the proper viscosity, and flows smoothly with a low extrusion force (Table 58.1).

Contrary to the technique developed for collagen injection in 1982, CaHA hand recontouring requires a different injection technique : bolus injection, followed by vigorous massage, allowing the CaHA to fill where needed. It is a new technique, not predicated on line filling, but rather on steady vigorous massage to deliver the material to required atrophic areas (Table 58.2).

Preparing the Radiesse-lidocaine mixture Prior to injecting CaHA into the hands, it is hom*ogenized with 0.5 mL of 2% plain lidocaine. The 1.5 mL CaHA LuerLok syringe is attached via a Rapid Fill Luer-Lok to Luer-Lok connector (Baxa, Englewood, CO, USA) to a 3-mL Luer-Lok syringe containing 0.5 mL lidocaine (Figure 58.1) The use of a 3-mL Luer-Lok syringe is ideal for the hom*ogenization process, because a high extrusion pressure is generated to mix the two liquids. The Baxa connector should be filled with lidocaine prior to making the connection, otherwise the CaHA will not flow. Instead, the plunger will move down without product emerging from the needle tip, the result of air in the mixture. The CaHA is first injected into the syringe containing the lidocaine and mixed back and forth for 10 passes until the filler–lidocaine mixture is

Table 58.1 Representative treatment products for the aging hand. Product category

Duration of effect*†

Advantages

Disadvantages

Autologous fat

Widely variable, from 4 months to more than 12 months

Biocompatibility, potential neovascularization

Harvesting required, not amenable to patients with lipodystrophy, does not conceal structures

Calcium hydroxylapatite (Radiesse®)

Approximately 12–15 months

Biocompatibility, collagen proliferation, immediate correction, no overcorrection needed, minimal pain

Time required for mixing with lidocaine

Collagen [bovine] (Zyderm®, Zyplast®) CosmoDerm®, CosmoPlast® (human)

Approximately 2–3 months

Long history of use in US esthetics No testing required

Skin testing for hypersensitivity reactions, does not conceal structures

Hyaluronic acids (Juvederm™, Restylane®, Perlane®)

Approximately 6–9 months

Wide variety of products available

Visibility of papules, color not easily blended into skin of dorsum, tindall effect, does not conceal structures

Poly-L-lactic acid (Sculptra®)

Approximately 18–24 months

Sustained collagenesis after a few weeks post-injection

Multiple treatments often necessary, does not conceal structures

* Facial areas (scant literature on longevity in hand). ASDS Guidelines.

†

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58. Hand recontouring

Table 58.2 Steps of in-office procedure for treatment of the aging hand. (Adapted from Busso M, Applebaum D. (2007) Hand augmentation with Radiesse® (calcium hydroxylapatite. Dermatol Ther 20, 315–17.) 1 Combine Radiesse with lidocaine, using a Luer-Lok connector for the Radiesse syringe and a 3-mL syringe containing 0.5 mL of 2% plain lidocaine 2 Identify the areas of treatment, usually between the second and fifth metacarpals, from the dorsal crease of the wrist to the metacarpophalangeal joints 3 Isolate the area of treatment with skin tenting between thumb and forenger of non-injecting hand, or forceps 4 Using a 27-gauge, 0.5-inch needle, inject the boluses of CaHAlidocaine mixture into the areolar plane between the subcutaneous layer and superficial fascia of the hand as needed 5 Have the patient make a fist of the injected hand, then firmly massage mixture to disperse 6 Schedule follow-up with patient in 2–4 weeks; repeat treatment for any areas missed during initial visit

Figure 58.2 Radiesse–lidocaine mixture with 1.5 mL Radiesse and 0.5 mL 2% plain lidocaine.

be modified depending on the injector’s judgment regarding the location of the defects to be filled.

How to inject

Figure 58.1 Radiesse with lidocaine using the Baxa connector.

smooth and without bubbles (Figure 58.2) [4]. The addition of the anesthetic changes the viscosity and filler extrusion force, delivering a more malleable mixture which is less viscous and therefore requires a smaller extrusion force.

Where to inject Careful injection site selection can considerably limit the amount of bruising. Before injecting, carefully examine the hand to ensure selection of an area devoid of veins or tendons. The imaginary line of bolus injection(s) is midway between the dorsal crease of the wrist and the metacarpophalangeal joints, bound laterally by the fifth metacarpal and medially by the second metacarpal. This boundary can

The patient should be comfortably seated on an examination table with the hands extended in front of them, preferably resting on a Mayo stand covered with a soft pillow, adjusted to the height of the patient’s knees, allowing gravity to have the desired effect on the defects to be corrected. The skin must be tented in order to separate it from the underlying veins and tendons (Figure 58.2). Entry is into the areolar plane, which is located between the superficial fascia and the subcutaneous fat. The thumb and forefinger of the noninjecting hand are used to lift the skin and create the entry point in the center of the tent (Figure 58.3). With a 27-gauge by 0.5 inch needle (or the new 28-gauge with 27-gauge inner lumen) attached to the prefilled CaHA syringe, inject 2–4 boluses of product across the previously described area of the dorsum of the hand, refilling the syringe when necessary. The average bolus amount is about 0.2–0.5 mL CaHA emulsion (Figures 58.4–58.6).

Post-injection hand massage At this point, massaging – the quintessential element of relocating the CaHA – is begun (Figure 58.7). Have the patient make a tight fist. To relieve friction and enhance the process, apply a liberal amount of Aquaphor (Beiersdorf Inc., Wilton, CT, USA) or white petrolatum to the dorsum. Begin pushing the boluses, one at a time, distally, laterally and medially, so that the bolus is flattened and spread as far as possible. Care should be taken not to encroach upon the metacarpophalangeal joints or the medial and lateral dorsopalmar junctions; product is not intended for these areas.

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Figure 58.3 Tenting of the skin technique.

Figure 58.6 Injected bolus prior to closed-fist massage.

Figure 58.4 Injecting and forming bolus of Radiesse mixture (0.5 mL bolus) in the areolar plane.

Figure 58.7 Partial massage of bolus into the dorsum.

After completing treatment of the first hand, have the patient sit on that hand while you treat the other hand. It will help in the smoothing out process as well as add to hemostasis if needed. In the event of a hematoma, have the patient hold pressure firmly for 5–10 minutes, and proceed to begin treating the contralateral hand. When the other hand is completed, go back and complete the “bruised” hand. Each hand usually requires between one and two 1.5-mL syringes. CaHA is also available in 0.3 mL and 0.8 mL syringes, should a full 1.5-mL syringe not be needed for the second syringe.

Post-treatment care

Figure 58.5 Injected bolus prior to closed-fist massage.

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After treatment is completed apply ice packs to the hands. The patient leaves the office with the disposable pack, using it for as long as it stays cool. Use of the ice pack will help reduce some of the possible swelling. The patient should be told to carry on with normal activities beginning the follow-

58. Hand recontouring ing day. Schedule the patient for follow-up in 2 weeks, and if at this time there are skip areas noticed, fill them in using the 0.3-mL CaHA syringe mixed with 0.12 mL of 2% lidocaine.

Adverse events Because it is a compound identical to that found in bone, CaHA has high biocompatibility and low adverse event risks. Adverse events in published studies have been few and of short duration [5–8]. They include ecchymosis, erythema, and occasional edema, when used in facial applications other than the lips. In general, the diluted product described for off-label use in the hands is even more forgiving. Clinical experiences with treatment of the aging hand suggest that adverse events in this area are infrequent and not severe. Anecdotal reports, however, have noted hand edema persist for 5–7 days post injection.

Figure 58.9 Same patient 2 weeks post-treatment with 1.5 mL mixture in each hand.

Results Figures 58.8–58.11 represent a 45-year-old female patient who received 1.5 mL CaHA mixture per hand during the initial visit, and did not have a touch-up performed. Figures 58.12–58.16 represent a 58-year-old female patient who also received 1.5 mL of CaHA mixture in each hand, and returned for a touch-up of the left hand only with 0.3 mL CaHA at week 8.

Discussion As with every new technique in surgery, refinements and modifications are the rule as time goes on. New approaches

Figure 58.10 Same patient 8 weeks post-treatment.

Figure 58.8 45-year-old female patient prior to treatment.

Figure 58.11 Same patient 12 weeks post-treatment.

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Figure 58.12 58-year-old female patient pretreatment (pianist).

Figure 58.15 Same patient at 20 weeks after initial treatment.

Figure 58.13 Same patient 2 weeks post-treatment with 1.5 mL Radiesse mixture for each hand.

Figure 58.16 Same patient at 28 weeks after initial treatment.

Figure 58.14 Same patient 8 weeks post-treatment with a touch-up using 0.3 mL Radiesse mixture for only left hand performed at 4 weeks after initial treatment.

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to the same technique give rise to slight revisions and adjustments leading to a better outcome. The original technique described by Busso was a single, voluminous bolus of an entire syringe of Radiesse and lidocaine, which was then spread out over the hand. Some physicians prefer the largevolume bolus approach; others believe it is less advantageous than the multiple, smaller-volume bolus approach. The volume of lidocaine remains an open question. The original volumes of lidocaine with the single bolus injection were much smaller (0.10 mL per 1.5 mL CaHA) than the volumes found in many clinical settings today (0.23–2.0 mL per syringe). In many personal communications, the author has determined that a larger volume of lidocaine is preferred for optimum results. These volumes have ranged 0.12– 2.0 mL lidocaine per 1.5-mL syringe of CaHA. A mixture of 0.5 mL of 2% lidocaine per 1.5-mL CaHA syringe and 0.12 mL for the 0.3-mL CaHA syringe appear optimal. There are several reasons why these two volumes are the volumes

58. Hand recontouring of choice. In the first place, considerably less hand swelling occurs when 0.5 mL lidocaine is used than using 2.0 mL. In addition, this volume enhances product flow and makes massage of injected mixture relatively easy. However, the most important reason is longevity and the convenience issue for the patient. Much less product is used with higher dilutions, and therefore the correction may not endure as long as with smaller dilutions. Busso’s recent paper states “physicians have reported that they see no significant decrease in durability for media diluted with lidocaine” [4]. At this point, controlled clinical trials are needed to determine that dilution with lidocaine does not negatively affect longevity of CaHA correction, not only in the hands, but for all applications. This issue of higher dilutions and possible decreased durability can easily be addressed, but it means more procedures at the 2-week follow-up than necessary. Follow-up sessions should address the missed areas that are inevitable, not retreating areas where the “excess” lidocaine has been absorbed. Another refinement that is helpful is the use of a smooth forceps to create the subsequent tents that might be needed. Once the emollient has been applied to the skin, a gloved hand on greasy skin will not be able to create the tent.

Conclusions Past experiences with products for treating the aging hand have met with limited success. These products – harvested fat, collagen, and hyaluronic acids – have disadvantages for placement in the hands for contouring enhancements. Foremost among these is the short duration, usually less than 3 months, and the inability of all of the other fillers to conceal the objectionable structures of the aging hand. CaHA appears well-suited for consideration as a product for recontouring of the hand, with a duration of effect of 6 months or longer. Unlike other areas, where there is not a

lot of muscle activity, the hand’s muscles and tendons are constantly moving, creating the friction that accelerates product breakdown. This is in contrast to more static treatment areas where there is greater longevity of correction. Perhaps the single most important and unique characteristic of CaHA that makes it ideal for hand recontouring is its opacity, the trait that enables the concealment of the undesirable structures of the aging hand. CaHA is also clinically unchanged by the addition of lidocaine, enabling painless treatment.

References 1 Alam M, Gladstone H, Kramer EM, Murphy JP, Nouri K, Neuhaus I, et al. Guidelines Task Force. (2008) American Society for Dermatologic Surgery (ASDS) Guidelines of Care: Injectable Fillers. Dermatol Surg 34, 115–48. 2 Busso M, Applebaum D. (2007) Hand augmentation with Radiesse® (calcium hydroxylapatite). Dermatol Ther 20, 315–7. 3 Berlin AL, Hussain M, Goldberg DJ. (2008) Calcium hydroxylapatite for facial filler rejuvenation: a histologic and immunohistochemical analysis. Dermatol Surg 34, 64–S67. 4 Busso M, Voigts R. (2008) An investigation of changes in physical properties of injectable calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lidocaine/epinephrine. Dermatol Surg 34, 16–24. 5 Tzikas TL. (2008) A 52-month summary of results using calcium hydroxylapatite for facial soft tissue augmentation. Dermatol Surg 34, 9–15. 6 Carruthers A, Liebeskind M, Carruthers J, Forster BB. (2008) Radiographic and computed tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial lipoatrophy and correction of nasolabial folds. Dermatol Surg 34, 78–84. 7 Moers-Carpi M, Vogt S, Martinez Santos B, Planas J, Rovira Vallve S, Howell DJ. (2007) A multicenter, randomized trial comparing calcium hydroxyalaptite to two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg 33, 144–51. 8 Sadick NS, Katz BE, Roy D. (2007) A multicenter, 47-month study of safety and efficacy of calcium hydroxylapatite for soft tissue augmentation of nasolabial folds and other areas of the face. Dermatol Surg 33, 122–7.

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Part 6: Implementation of Cosmetic Dermatology into Therapeutics Chapter 59: Antiaging regimens Karen E. Burke The Mount Sinai Medical Center, New York, NY, USA

BAS I C CONCE P T S • The appearance of aging skin can indeed be reversed without invasive treatments by daily skin care using scientifically proven techniques and products. • Proper cleansing and exfoliation smooth the skin’s surface to decrease pore size and wrinkles within days. • Sun protection by application of ample amounts of high-SPF, UVA-protective, highly water-resistant sunscreen is essential to protect from photoaging and to enhance natural repair. • Topical retinoids as well as topical antioxidants such as vitamins C and E, selenium, genestein, and coenzyme Q10 not only protect from but also reverse photoaging if the correct molecular forms and concentrations are applied.

Introduction In her book, Survival of the Prettiest, Etcoff [1] synthesizes literature and research from anthropology, biology, psychology, and archeology to show that indeed appreciation of one’s own and others’ beauty is hard-wired in human brains. Etcoff concludes, “Flawless skin is the most universally desired feature of beauty.” This chapter presents a basic skin regimen to protect from photodamage and reverse the appearance of aging. The four necessary steps are cleansing, exfoliation, protection, and treatment. Helpful techniques and scientific research proving efficacy of specific ingredients are presented.

Cleansing Proper cleansing is an essential component of skincare. The face accumulates endogenous and exogenous soils.

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Sebaceous gland size and density are greatest on the face, upper back, and chest. The natural oils, sweat, and sebum secretions create a hydrolipid film on the skin surface that, in addition to applied cosmetics, traps and accumulates environmental pollutants such as dust, airborne irritants, and compounds from cigarette smoke. Care must be taken to accomplish thorough cleansing without irritation or drying. Therefore, a gentle, effective cleanser is of utmost importance. Surfactants are the ingredients that bind to dirt and oil for removal. These surfactants are classified by their charge on the surface-active moiety as anionic (negatively charged, for good foaming and lathering), cationic (positively charged), amphoteric (both positive and negative, considered to “condition” skin while helping to foam), and non-ionic (which are used in baby products to suppress foam) [2]. Components of surfactants can bind to the stratum corneum proteins, decreasing the skin’s ability to bind and hold water. With continued, frequent use, surfactants can damage the skin barrier. New synthetic surfactants improve cleansing with less irritation. Other components of cleansers include polypeptides and synthetic polymers to make the product smooth and to soften skin, polymers to moisturize, preservatives, opacify-

59. Antiaging regimens

Figure 59.1 To treat wrinkles while washing, gently rub upward horizontally across the upper lip and “up and out” on the rest of the face – perpendicular to the direction of wrinkles.

ing agents, and fragrance. With frequent washing, these ingredients can cause sensitivities or contact allergy in certain individuals. Because cleansers are rinsed off, their contact time with the skin is reduced causing less contact allergy. Newer cleansers are less alkaline than older formulations, so they are less drying. In recent years, antibacterial agents (e.g. triclosan and triclocarban) have been added to hand cleansers. Surprisingly, these agents are rarely skin irritants. However, some physicians voice concern, fearing development of bacterial resistance to these antibiotics with frequent use. Originally, triclosan was thought to kill bacteria by a “broad-based” mechanism, similar to alcohol and peroxide. However, recent research demonstrated that triclosan acts at a specific gene site in Escherichia coli to inhibit replication, so resistant strains could evolve [3]. Thorough washing with gentle cleansers removes dirt and has been shown to be as effective as using these antibacterial compounds. Cleansing the face should be accomplished with lukewarm water and the fingertips. The face and neck should be washed with upward, outward motions. On the face, one should always rub perpendicular to the direction of those wrinkles that could develop later. On the forehead, cheeks, chin and neck, rub up and out; above the upper lip and under the eyes, the strokes should be first horizontal, then upward at the edges, as illustrated in Figure 59.1. Sunscreen, moisturizer, or other treatments should be applied immediately after gently towel-drying.

Exfoliation Exfoliation is the rejuvenation treatment providing the most immediate improvement in appearance. Exfoliation removes

the outer layers of stratum corenum, and thus treats the hyperkeratosis of dry skin. Exfoliative rubbing perpendicular to the direction of wrinkles minimizes small wrinkles because the surface is smoothed (Figure 59.1). Exfoliation can be chemical or mechanical. Chemical exfoliants such as hydroxyacids and retinoic acid remove dead surface cells by keratolysis. Mechanical exfoliants include cleansing grains, waxy creams that adhere to the surface cells, as well as slightly abrasive terry washcloths, non-woven polyester polishing pads, brushes, or loofas which physically “sand” the skin surface by rubbing. Grainy exfoliants with aluminum oxide crystals can be effective, but the user must be careful not to get the grains into the eyes. Exfoliants to be avoided are those with apricot or almond kernels, walnut shells, and pumice – all of which have irregularly shaped particles with sharp edges which can be too rough on delicate skin and dangerous if they get into the eyes. The immediate improvement in small wrinkles by gentle exfoliation can be appreciated in Figure 59.2. Masks are among the oldest face mechanical exfoliants. Masks can “wash off” or “peel off.” Some “wash off” masks are made of clay, which harden and are removed with water rinsing. “Peel-off” masks contain synthetic polymers that are quite safe and effective. Some masks may irritate the skin; it is advisable to test on the inner wrist before treating the face.

Protection The single most effective therapy for aging skin is sun protection [4]. Avoid sun exposure between 10AM and 4PM, and beware of “hidden sun”: UVA is not filtered by glass and neither UVA or UVB are filtered by clouds. People get their worst burns on cloudy days, especially when skiing or when on the beach or in the water. Sunscreen should be applied often and generously. Sunscreens are classified as organic filters (which absorb photons of UV light) or inorganic filters (which reflect or scatter UV radiation) [5]. As shown in Figure 59.3, some organic sunscreen agents block only UVB (p-aminobenzoic acid [PABA] and its esters padamate A and O, the cinnamates, and salicylates); others absorb primarily UVB and some low wavelength UVA (octocrylene, benzophenones, anthranalides). Mexoryl XL or SL blocks UVB as well as most UVA. The UVA absorbing sunscreen avobenzone (Parsol 1789) can degrade with exposure to UV [6], but stabilizing compounds (benzylidene camphor and diphenyl cyanoecrylate derivatives, both UVB filters) can be effectively added [7]. The inorganic filters with microfine titanium dioxide and zinc oxide are total UVB blocks, blocking low wavelength UVA and almost all UVA, respectively. Thus, zinc oxide provides better protection than titanium dioxide [8]. The new technology with microfine particles makes them

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(b)

(a)

(d)

(c)

Padimate-O Sunscreen ingredients

Octyl methoxycinnamate Octyl salicylate Octocrylene Benzophenone Titanium dioxide Avobenzone Mexoryl Zinc oxide

290

320 UVB

340 UVAII

400 UVAI

Ultraviolet spectral coverage Figure 59.3 Ultraviolet spectral coverage of sunscreen ingredients.

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Figure 59.2 Tiny wrinkles and crepy skin can be treated immediately at home by exfoliation. Improvement is seen in this 60-year-old woman’s face after she simply washed with a non-woven polyester polishing pad and used a waxy exfoliant that mechanically “sticks” and removes surface cells. (a) and (c), pre-exfolitaion; (b) and (d), post-exfoliation.

non-opaque and cosmetically appealing. The concentration and the size of the microparticles determine SPF efficacy [5]. The ability of a sunscreen to prevent UVB-mediated erythema is measured by the internationally accepted standard sun protection factor (SPF), the ratio of equivalent exposure by UVB in sunscreen-protected compared with unprotected skin. (An SPF of 30 means that the amount of UB exposure in 10 minutes without sunscreen is equivalent to 10 minutes × 30 = 5 hours of exposure with sunscreen.) The SPF should be at least 25–30. After SPF, the second important criterion for a sunscreen is that it be “highly water resistant,” meaning it is effective for about 90 minutes. Many prefer a different sunscreen for the face than for the body. These criteria are summarized in Table 59.1. Further protection with topical antioxidants and sun protective clothing, hats, and sunglasses are indicated. Sun pro-

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Table 59.1 Criteria of a good sunscreen. 1. 2. 3. 4. 5.

High SPF (SPF 25 or higher) Protection against UVA and UVB Highly water resistant Non-comedogenic Excellent esthetics

SPF, sun protection factor.

tective clothing is rated using UV protective factor (UPF), measured by the amount of UV radiation transmitted through the fabric. A fabric with a UPF of 40–50 transmits only 2.6% of biologically effective radiation, in contrast with normal summer clothing that typically has a UPF of only 4–10, providing a maximum SPF of 30% but often only an SPF of about 2 if wet [9]. New products (such as SunGuard (2,2 ′ - (1,2 - ethenediyl)bis[5 - [[4 - (methylamino) - 6[[4 (methylamino)catonyl]-phenyl]amino]-1,3,5-triazin-2-yl] amino]-, disodium salt)) have recently become available to be added when washing clothes to give a UPF of 30 that lasts 20 washes.

Treatment There are several medical treatments for antiaging purposes. These include retinoic acid, hydroxy acids, and topical antioxidants. Many products are advertised, but their efficacy may not have been demonstrated by rigorous placebocontrolled, double-blind clinical trials.

Hydroxyacids Hydroxyacids (HAs) have been used for centuries. Cleopatra routinely applied HAs and Marie Antoinette washed with red wine, benefitting from tartaric acid. Hydroxyacids were reintroduced to dermatology in 1974 when Van Scott and Yu [10] reported improvement of severe hyperkeratosis and icthyosis. Hydroxyacids are classified by the position of the hydroxyl group attached to the acid moiety: α-hydroxyacids (AHAs) (glycolic acid, lactic acid, and citric acid), β-hydroxyacids (BHAs) (tropic acid, salicylic acid [SA] – called a BHA but actually an αhydroxybenzoic acid), and the “new generation” polyhydroxy acids (PHAs) (gluconolactone or lactobionic acid – a naturally occurring component of skin). AHAs act rapidly (within 2 weeks) to smooth the surface skin by reducing epidermal cornecyte adhesion, first at the innermost level of the stratum corneum (just above the stratum granulosum) [11]. Epidermal damage of photoaging is corrected in 14–16 weeks, resulting in a thinned stratum corneum, epidermal acanthosis, and decreased melanogenesis [12]. An increase

in epidermal intercellular hyaluronic acid improves surface moisturization by water retention. An elegant study demonstrated that epidermal keratolysis is followed by dermal penetration which increases synthesis of glycosaminoglycans and increases fibroblast proliferation and production of collagen and elastin [13]. A 25% increase in skin thickness was measured after 6 months’ treatment with 25% AHAs with no inflammation. SA is unique among the hydroxyacids in that it is lipophilic and is particularly attracted to sebaceous orifices, thereby exhibiting its keratolytic properties not only to smooth surface wrinkles, but also to decrease pore size and prevent acne. As an excellent keratolytic agent, SA solubilizes intercellular cement by disrupting corneocyte adhesion layer by layer, from the surface downward. SA may also be directly bacteriostatic. The PHAs have several advantages. They have larger molecules, so they penetrate the skin gradually and are therefore less irritating than AHAs or SA. PHAs are recommended for patients with sensitive skin, rosacea, or atopic dermatitis [12]. They can even be used in conjunction with retinoic acid without irritation. PHAs also give improved moisturization of the stratum corneum when compared with AHAs. PHAs have anti-inflammatory and antioxidant activity, further enhancing repair of cutaneous photoaging [14]. Three key factors determine HA efficacy: 1 Type of hydroxyacid (described above). 2 Concentration: the higher the concentration, the more effective but the more possible irritation. Concentrations of 8–12% glycolic and lactic acids are available by prescription, as are concentrations of SA greater than 3%. High concentrations are used for medical chemical peels. 3 pH (acidity): the amount of biologically free acid determines the clinical strength [15]. To be effective, the hydroxyacid must be acidic. There is a delicate balance in attaining efficacy without irritation. For each type of hydroxyacid or mixture thereof, the concentration and pH determines the strength and the clinical benefits [15].

Retinoids Retinoids are the “gold standard” for reversing photoaging of the skin. Retinoic acid (tretinoin) has been used for more than 35 years for the treatment of acne. In the late 1980s, the remarkable clinical improvement of wrinkles and solar lentigos after treatment with topical tretinoin was documented [15–17]. UV exposure leads to decreased expression of retinoic acid receptors (RAR) and retinoic X receptors (RXR) (in particular, RAR-α and RXR-γ, the two major nuclear receptors in keratinocytes) with subsequent activation of transcription factors (AP-1 and NF-IF) which increase proliferation and inflammation and activate the matrix metaloproteinases (MMPs) which break down extracellular

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matrix proteins [18]. By binding to these receptors, topical retinoids restore expression, thereby reversing UV-induced damage at all levels of the epidermis and dermis [19,20]. Retinoids increase epidermal proliferation causing epidermal thickening with compaction of the stratum corneum and deposition of glycosaminoglycans intercellularly; with epidermal proliferation, inhibition of excess melanogenesis and shedding of melanin-laden keratinocytes resolves mottled hyperpigmentation; and retinoids directly induce collagen synthesis and reduce collagen breakdown by inhibiting the UV-induced MMPs [21,22], thereby correcting wrinkles. Topical tretinoin also reverses intrinsic aging, perhaps even more significantly in non-sun-exposed than in photoaged skin. A marked increase in epidermal thickness (with a more undulating dermoepidermal junction), in anchoring fibrils, and in dermal angiogenesis with new elastic fibers and glycosaminoglycans was observed [23]. Previously, topical tretinoin was postulated to make the skin more sensitive to UV exposure. Indeed, resolution of unattractive hyperkeratosis may allow more UV to penetrate deeper, but the inhibition of the UV-induced MMPs that break down collagen results in less UV damage with tretinoin treatment. Occasionally, irritation (retinoid dermatitis) can occur, especially when beginning treatment. This can usually be avoided by starting with lower concentrations (0.025% cream instead of 0.05% cream or 0.01% gel), other formulations (microsphere gels, new generic formulations, or different retinoids as described below), and less frequent application. Patients with sensitive skin should begin with a mild formulation, applying initially each 3 days and increasing to daily over several weeks or months. Most of the improvement occurs within the first year, improvement is maintained with continued use, as proven by up to 4-year histologic studies [22]. Other “second generation” retinoids have been proven effective in treating photodamage [22]. Retinaldehyde cream (0.05%) and retinol cream (up to 1.6%) are comparable to tretinoin in efficacy, but are more irritating. Tazarotene (0.5% and 0.1%) may give faster improvement but is also more irritating. Adapalene (0.1% cream and gel) is less irritating but probably less effective than tretinoin.

Antioxidants The skin naturally uses nutritional antioxidants to protect itself from photodamage and topical application has been investigated. The challenge is to make topical antioxidant formulations that are stable and that give percutaneous absorption to deliver high concentrations of the active forms to the dermis as well as the epidermis.

Vitamin C If the retinoids are the “gold standard,” topical vitamin C is the “silver standard” for reversing photoaging of the skin. Vitamin C (L-ascorbic acid) is the body’s major aqueous-

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phase antioxidant. Dietary vitamin C is absolutely required for life. Environmental free-radical stress depletes vitamin C levels in the skin. UV exposure of 1.6 minimal erythema dose (MED) decreases vitamin C to 70% normal, and 10 MED to 54% [20]. Although vitamin C is itself not a sunscreen, topical vitamin C protects against solar damage. As an antioxidant, vitamin C deactivates the UV-induced free radicals, decreasing erythema and sunburn. This protection has been confirmed by histologically: treatment with topical 10% vitamin C decreases the number of abnormal “sunburn cells” by 40–60% and reduces the UV damage to DNA by 62% [24]. The main function of vitamin C is as the essential co-factor for collagen synthesis. When 10% vitamin C was added to in vitro elderly fibroblasts, collagen proliferation and synthesis increased by factors of 6 and 2, respectively [25]. Vitamin C also inhibits tyrosinase, thereby lightening solar lentigos. Formulation is key to optimizing percutaneous absorption of vitamin C. Because L-ascorbic acid is inherently unstable – making it an excellent antioxidant – an effective topical delivery system is crucial. Many products contain stable derivatives, which are not metabolized by the skin (such as ascorbyl-6-palmitate or magnesium ascorbyl phosphate) and therefore have no appreciable cutaneous activity [26]. Other formulations do not result in measurable absorption of vitamin C because they are not at the correct pH. Topical absorption of 10% vitamin C cream was proven by radioactive labeling studies in pigs. After treatment, 8.2% was found in the dermis, and 0.7% was in the blood [27]. The most effective concentration for topical delivery is 20%, giving maximal skin levels after 3 days.

Vitamin E (d-α-tocopherol) Natural vitamin E is the most important lipid-soluble, membrane-bound antioxidant in the body. Natural dietary vitamin E can exist in four methylated forms (α, β, χ, δ); synthetic vitamin E is a mixture of eight (d,l) stereoisomers. The d-α-tocopherol isomer has the greatest biologic efficacy. In order to attain activity through cutaneous application, the natural non-esterified form must be applied in concentrations greater than 2% (5% is optimal) [28]. Most commercial products containing “vitamin E” contain a mixture of 32 synthetic isomers, esterified, and in quite low concentrations. Allergic contact dermatitis has been reported from such formulations, although no adverse reaction has ever been reported with the natural d-α-tocopherol. In a mouse model, topical d-α-tocopherol has been shown to be impressively effective in protecting against all acute and chronic UV-induced damage, and far more effective than the esterified topical d-α-tocopherol succinate [29]. Vitamin E has also been demonstrated to reverse photoaging dramatically. Figure 59.4 shows the dramatic decrease in periorbital rhytides after 4 months of daily application of

59. Antiaging regimens

(b)

(a) Figure 59.4 Correction of periorbital wrinkles after 4 months of once-daily treatment with 0.05% d-α-tocopherol cream. (a) Before. (b) After.

d-α-tocopherol (5%). Histology confirmed this improvement in a mouse model. The UV-induced epidermal hypertrophy and hyperkeratosis, the increased incidence of damaged “sunburn cells” in the basal layer, and the disruption of dermal collagen and elastin were all corrected after 8 weeks of topical treatment (KE Burke, L Riciotti, EG Gross, unpublished observations).

Vitamin C with vitamin E In cells, vitamins C and E interact synergistically to provide antioxidant protection. In membranes, vitamin E is oxidized as it quenches peroxyl free radicals and intracellular vitamin C regenerates the vitamin E activity [30]. Oral vitamin C with E in high doses protects against UV-induced erythema in humans, whereas either vitamin alone is ineffective [27]. Compared to twofold protection for either vitamin alone, topical L-ascorbic acid (15%) with α-tocoperol (1%) gives fourfold protection against UV-induced erythema, decreasing the number of damaged “sunburn cells” seen histologically and decreasing thiamine dimer formation in porcine skin [29]. Fortunately, mixing these hydrophilic and lipophilic antioxidants in a topical formulation stabilizes each.

Vitamin C with vitamin E and ferulic acid Ferulic acid is a potent antioxidant present in the cell walls of grains, fruits, and vegetables. Ferulic acid alone absorbs some UV and therefore is itself a weak sunscreen. When mixed with vitamins C and E, it further stabilizes the formulation and acts synergistically to double the photoprotection from fourfold to eightfold [31]. This triple antioxidant combination has been made into the SkinCeuticals product

C E Ferulic (15% vitamin C, 1% vitamin E, and 0.5% ferulic acid).

Other antioxidants Coenzyme Q10 Coenzyme Q10 (ubiquinone or CoQ10) is a component of the mitochondrial electron transport chain in all plant and animal cells, including human cells, especially in organs with high rates of metabolism such as the heart, liver, and kidney. In the skin, CoQ10 acts as an antioxidant, although the level is naturally relatively low, with 10 times more in the epidermis than the dermis [32]. CoQ10 has been shown to reverse natural intrinsic aging by increasing rates of cell division and increasing natural hyaluronic acid [33]. Decreased wrinkle depth was documented by optical profilometry using 0.3% ubiquinol cream for 6 months [34]. CoQ10 also suppresses UVA destruction of collagen [33].

α-Lipoic acid α-Lipoic acid (αLA), made in cells of all plants and animals, has many impressive antioxidant properties and has been shown to retard aging in heart and brain cells in laboratory studies. However, the evidence for reversal of photoaging in the skin is scant: 33 women applied 5% αLA to half of their faces for 12 weeks and noted some decrease in wrinkles, skin roughness, and fading of dark spots [35]. αLA provides little or no protection against sun damage [33]. Selenium Selenium is a trace mineral essential to human life because it is the required co-factor for the intracellular antioxidant

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Table 59.2 Photoprotection and reversal of photoaging. Treatment agent

Source

Photoprotection

Treatment of wrinkles

Treatment of solar lentigos

α-Hydroxy acids

Sugar cane, milk, fruits*

–

β-Hydroxy acids

Willow or sweet birch bark, wintergreen leaves*

–

Retinoic acid

Vitamin A*

Dermis only

++++

Vitamin C

Citrus fruits, red peppers

+++

++++

Vitamin E (d-α)

Sunflower oil

+++

++++

+++

Ferulic acid

Cell wall of fruits, grains, vegetables

++++

Coenzyme Q10 (ubiquinone)

Fish, shellfish, spinach, nuts

Dermis only

α-Lipoic acid

All plant and animal cells (including humans)*

–

L-selenomethionine

Grains, saltwater fish

++++

Genistein

Soy

+++

+, Minimal effect noted in good studies; ++++, maximal effect (a “gold standard”) ?, not studied. * Produced synthetically for cosmetic products.

enzymes glutathione peroxidase and thiodoxin reductase. Topical L-selenomethionine (0.02–0.05%) has been shown to protect the skin from both acute and chronic UV damage (erythema, pigmentation, and skin cancer) [36]. Application increases MED [37] and delays the onset and decreases the incidence of skin cancer [38]. Furthermore, when applied to sun-damaged skin, topical L-selenomethionine was shown clinically and histologically to reverse photoaging as effectively as retinoic acid – with a decrease in hyperkeratosis and regeneration of collagen and repair of elastic tissue.

Genistein Genistein is a potent antioxidant isolated from soy, which has been proven to protect against UV-induced erythema and skin cancer [38]. As a phytoestrogen, genistein confers the additional benefit of stimulating collagen synthesis, and thus may prove to be an excellent treatment for wrinkles. In Table 59.2, this author has summarized her personal impressions of the clinical efficacy of well-researched topicals for photoprotection and reversal of photoaging. Others include niacinamide (smoothing texture, improving red blotchiness, and dark spots, decreasing yellowing, and improving fine lines, wrinkles, and elasticity – but is only about one-third to one-fifth as effective as retinoic acid), and kinetin (a synthetic plant growth hormone that retards senescence in plants, shown to reverse aging of skin cells in

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the laboratory, but in the author’s experience only minimally helpful in correcting wrinkles).

Conclusions The appearance of aging skin can be treated non-invasively. Strategies include primary prevention (with changes in lifestyle by not smoking, avoiding excessive sun exposure, and assiduous protection when in the sun) and treatment. Some treatments improve the appearance immediately and others act physiologically to inhibit further photodamage and to reverse previous damage at a molecular level. New therapies for photoaging are promoted, but many have not been subjected to large, placebo-controlled, double-blind, clinical trials.

References 1 Etcoff N. (1999) Survival of the Prettiest: The Science of Beauty. New York: Anchor Books, Random House. 2 Rieger MM. (2000) Skin cleansing products. In: Rieger MM, ed. Harry’s Cosmeticology. New York: Chemical Publishing Company, Inc., pp. 485–500. 3 Levy CW, Roujeinikova A, Sedelnikova S, Baker PJ, Stuitje AR, Slabas AR, et al. (1999) Molecular basis of triclosan activity. Nature 308, 383–4. 4 Glaser DA. (2003) Anti-aging products and cosmeceuticals. Facial Plast Surg Clin North Am 11, 219–27.

59. Antiaging regimens 5 Forestier S. (2008) Rationale for sunscreen development. J Am Acad Dermatol 58, S133–8. 6 Roscher NM, Lindeman MKO, Kong SB, et al. (1994) Photodecomposition of several compounds commonly used as sunscreen agents. J Photochm Photobiol A 80, 417–21. 7 Deflandre A, Forestier S, Lang G, et al., inventors; L’Oreal, assignee. (1997) Photostable cosmetic composition containing a UV-A screen and a UV-B screen and a process for stabilizing the UV-A screen with the UV-B screen. US patent US 5605680. February 25. 8 Pinnell SR, Fairhurst D, Gillies R, Mitchnick MA, Kollias N. (2000) Microfine zinc oxide is a superior sunscreen ingredient to microfine titanium dioxide. Dermatol Surg 26, 309–14. 9 Diffey BL. (2001) Sun protection with clothing. Br J Dermatol 144, 449–51. 10 Van Scott EJ, Yu RJ. (1974) Control of keratinization with the alpha hydroxy acids and related compounds. Arch Dermatol 110, 586–90. 11 Van Scott EJ, Ditre CM, Yu RJ. (1996) Alpha-hydroxyacids in the treatment of signs of photoaging. Clin Dermatol 14, 217–26. 12 Grimes PE, Green BA, Wildnauer RH, Edison BL. (2004) The use of polyhydroxy acids (PHAs) in photoaged skin. Cutis 73, 3–13. 13 Ditre CM, Griffin TD, Murphy GF, Sueki H, Telegan B, Johnson WC, et al. (1996) Effects of AHAs on photoaged skin: a pilot clinical, histological and ultra-structural study. J Am Acad Dermatol 34, 187–95. 14 Green B, Briden ME. (2009) PHAs and bionic acids: next generation hydroxy acids. In: Draelos ZD, Dover JS, Alan M, eds. Philadelphia, PA: Elsevier Saunders, In press. 15 Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. (1988) Topical tretinoin improves photodamaged skin: a double-blind, vehicle-controlled study. JAMA 259, 527–32. 16 Kligman AM, Grove GL, Hirose R, Leyden JJ. (1986) Topical tretinoin for photoaged skin. J Am Acad Dermatol 15, 836–59. 17 Burke KE, Graham GF. (1988) Tretinoin for photoaging skin: North Carolina vs. New York. JAMA 260, 3130. 18 Fisher GJ, Wang ZQ, Datta SE. (1997) Pathophysiology of premature skin aging induced by ultraviolet radiation. N Engl J Med 337, 1419–28. 19 Stratigos AJ, Katsambas AD. (2005) The role of topical retinoids in the treatment of photoaging. Drugs 65, 1061–72. 20 Shindo Y, Wit E, Han D, Packer L. (1994) Dose–response effects of acute ultraviolet irradiation on antioxidants and molecular markers of oxidation in murine epidermis and dermis. J Invest Dermatol 23, 470–5. 21 Wang Z, Boudjelal M, Kang S, Voorhees JJ, Fisher GJ. (1999) Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pretreatment. Nat Med 5, 418–22. 22 Bhawan J, Olsen E, Lufrano L, Thorne EG, Schwab B, Gilchrest BA. (1996) Histologic evaluation of the long-term effects of tretinoin on photoaged skin. J Dermatol Sci 11, 177–82.

23 Kligman AM, Dogadkina D, Lauker RM. (1993) Effects of topical tretinoin on non-sun-exposed protected skin of the elderly. J Am Acad Dermatol 39, 25–33. 24 Darr D, Combs S, Dunston S, Manning T, Pinnell S. (1992) Topical vitamin C protects porcine skin from ultraviolet radiation-induced damage. Br J Dermatol 127, 247–53. 25 Phillips CL, Combs SB, Pinnell SR. (1994) Effects of ascorbic acid on proliferation and collagen synthesis in relation to donor age of human dermal fibroblasts. J Invest Derm 103, 228–32. 26 Pinnell SR, Yang HS, Omar M, Monteiro-Riviere N, DeBuys HV, Walker LC, et al. (2001) Topical L-ascorbic acid: percutaneous absorption studies. Dermatol Surg 27, 137–42. 27 Fuchs J, Kern H. (1998) Modulation of UV-light-induced skin inflammation by d-α-tocopherol and L-ascorbic acid: a clinical study using solar simulated radiation. Free Radic Biol Med 25, 1006–12. 28 Burke KE, Clive J, Combs GF Jr, Commisso J, Keen CL, Nakamura RM. (2001) The effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. J Nutr Cancer 38, 87–97. 29 Lin JY, Selim MA, Shea CR, Grichnik JM, Omar MM, MonteiroRiviere NA, et al. (2003) UV photoprotection by combination topical antioxidants vitamin C and E. J Am Acad Dermatol 48, 866–74. 30 Chan AC. (1993) Partners in defense, vitamin E and vitamin C. Can J Physiol Pharmacol 71, 725–31. 31 Lin FH, Lin JY, Gupta RD, Tournas JA, Burch JA, Selim MA, et al. (2005) Ferulic acid dstabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Dermatol 125, 826–32. 32 Hoppe U, Bergemann J, Diembeck W, Ennen J, Gohla S, Harris I, et al. (1999) Coenzyme Q10, a cutaneous antioxidant and energizer. BioFactors 9, 371–8. 33 Pinnell SR, Lin J-Y, Lin F-H, et al. (2004) Alpha lipoic acid is ineffective as a topical photoprotectant of skin. Poster presentation, 62nd Annual Meeting of the American Academy of Dermatology, Washington, DC. 34 Eucerin Q10 Anti-Wrinkle Sensitive Skin Crème. (2003) From Wrinkle Reduction Study 2003. In: Eucerin Q10 Product Compendium. Wilton, CT: Beiersdorf Inc., p. 11. 35 Beitner H. (2003) Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alphalipoic acid related to photoaging of facial skin. Br J Dermatol 149, 841–9. 36 Burke KE, Combs GF, Gross EG, Bhuyan KC, Abu-Libdeh H. (1992) The effects of topical and oral L-selenomethionine on pigmentation and skin cancer induced by ultraviolet irradiation. Nutr Cancer 17, 123–37. 37 Burke KE, Burford RG, Combs GR Jr, French IW, Skeffington GR. (1992) The effect of topical L-selenomethionine on minimal erythema dose of ultraviolet irradiation in humans. Photodermatol Photoimmun Photomed 9, 52–7. 38 Wei H, Saladi R, Lu Y, Wang Y, Palep SR, Moore J, et al. (2003) Isoflavone genistein: photoprotection and clinical implications in dermatology. J Nutrition 133, 3811S–9S.

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Chapter 60: Over-the-counter acne treatments Emmy M. Graber1 and Diane Thiboutot2 1 2

SkinCare Physicians, Chestnut Hill, MA, USA Pennsylvania State University College of Medicine, Hershey, PA, USA

BAS I C CONCE P T S • Over-the-counter cosmeceutical products are frequently used in the treatment of acne. • Topical benzoyl peroxide is one of the most effective over-the-counter acne treatments. • Other active agents in acne products include hydroxy acids, salicylic acid, sulfur, and retinol. • Leave-on products have a more profound effect on acne than cleansers. • Cleansing cloths and scrubs may be used for their sebum removal and keratolytic activity.

Introduction Although acne is one of the most common conditions that a general dermatologist treats [1], most people with acne will first try to self-treat before seeking the assistance of a healthcare professional. A survey carried out in 2000 demonstrated that 75% of acne sufferers waited about 1 year prior to seeking the help of a healthcare professional [2]. Another study estimated that one-third of those battling acne will ever consult a physician regarding their condition [3]. Without the assistance of a physician, patients will often turn to the drugstore shelves to treat their acne. A plethora of over-the-counter (OTC) modalities exists for treating acne. These modalities include topical cleansers, creams, lotions, gels, and masks as well as mechanical treatments, essential oils, and oral vitamins. The non-prescription acne market is one of the fastest growing segments of the dermatologic industry. This OTC market worldwide is estimated to be 2–4 times the size of the prescription market [4]. Estimates from 2001 revealed that consumers spend approximately $100 million per year on OTC antiacne products [5]. The Food and Drug Administration (FDA) is the regulatory agency that presides over the marketing of nonprescription acne products. In the Final Acne Monograph, the FDA states that any product labeled as an “acne drug product” is defined as: “A drug product used to reduce the number of acne blemishes, acne pimples, blackheads and whiteheads.” The FDA defines OTC products that fit this description to include: salicylic acid, sulfur, sulfur combined

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with resorcinol, and benzoyl peroxide [6]. Although products cannot be sold bearing an antiacne label unless they contain one of the above approved ingredients, many other products are marketed towards the acne-prone consumer claiming to “heal,” “purify,” or “cleanse,” the skin and pores. In this chapter we address OTC products that are marketed for the treatment of acne, not just those products that the FDA defines as an “acne drug product.” There are a multitude of OTC products with labeling that implies an acne efficacy. Some of these washes and leave-on products contain benzoyl peroxide, salicylic acid, alfa-hydroxy acids, polyhydroxy acids, retinol, or sulfur. Mechanical treatments exist as well and come in the form of cleansing brushs, adhesive pads, heating devices, and scrubs. Some patients may turn to homeopathic remedies such as tea tree oil or chamomile. Oral vitamins, such as vitamin A, zinc, or nicotinamide are also tried as an OTC acne fix.

Soaps and syndets Studies show that over half of those with acne believe that their condition is caused by poor hygiene and dirt on the skin [7]. This belief often leads patients to alter both how they wash their face and their face washing frequency. While washing the face twice daily is more optimal then washing once or four times daily, the quantity of cleansings probably does not matter as much as the substance that is used to wash the face [8]. A multitude of cleansers exist and can be categorized as either soaps or syndets. Traditional soaps are made of fats and an alkali and have a basic pH of 9–10. This pH, which is higher than the skin’s pH, disrupts the intercellular lipids that hold the stratum corneum together. The disintegration of the intercellular “cement” causes skin irritation. Syndets are made of synthetic deter-

60. Acne treatments 3.0 2.5

Log cm2

2.0 1.5 1.0 Figure 60.1 Reduction in Propionibacterium acnes with topical therapy. Clin-BP, clindamycin and benzoyl peroxide; Ery-BP, erythromycin and benzoyl peroxide. (From Leden JJ. (2001) The evolving role of Propionibacterium acnes in acne. Semin Cutan Med Surg 20, 139–43.)

0.5 0

gents and have a pH of 5.5–7, similar to the skin’s natural pH. Because syndets only contain less than 10% soap, they are much less damaging to the stratum corneum [9]. The benefit of syndet cleansers specifically for acne patients has been demonstrated in studies. One study, looking at 25 patients undergoing acne treatment, were randomized to cleanse with either a soap or a syndet. After 4 weeks, those using the syndet cleanser reported having significantly less acne and less oil. Both patients and dermatologists reported less irritation in those using the syndet cleanser [10]. Although not all-inclusive, some brands of syndet cleansers include Cetaphil, Aveeno, Purpose, Basis, Oil of Olay, and Dove. There are additional cleansers that are marketed specifically for acne use that contain an active antiacne ingredient (e.g. benzoyl peroxide or salicylic acid).

Benzoyl peroxide Benzoyl peroxide is commonly found in OTC antiacne washes, creams, and lotions. In fact, 23% of people aged 13–27 have used an OTC benzoyl peroxide product [11]. Benzoyl peroxide was first utilized in 1917 to bleach flour. In the 1960s, benzoyl peroxide began to have medical applications for treating leg and decubitus ulcers. Several years later, in 1979, it was first used for treating acne. Benzoyl peroxide has antibacterial, anti-inflammatory, and comedolytic properties, which makes it effective in acne treatment. It has antimicrobial properties against Propionibacterium acnes and Staphylococcal aureus. One study demonstrated an almost 2-log10 decrease in P. acnes concentration just after 2 days of 5% benzoyl peroxide use [12]. Another study confirmed this fast-acting effect showing that P. acnes counts reduced by a mean of 2-log10 after applying 10% benzoyl peroxide cream for 3 days. After 7 days, there was no further decline in P. acnes levels [13]. Benzoyl peroxide has greater antimicrobial properties against P. acnes than any of the topical antibiotics alone. However, unlike the antibiotics, benzoyl peroxide will not induce bacterial resistance. Using a topical

Clin-BP

Ery-BP

Benzoyl peroxide

Clindamycin

Erythromycin

Azelaic acid

antibiotic with the addition of benzoyl peroxide will increase the bactericidal effect of the antibiotic (Figure 60.1) [14]. Furthermore, it will also prevent the development of P. acnes resistance when used in combination with a topical or oral antibiotic [15]. Benzoyl peroxide also acts as an anti-inflammatory agent by reducing oxygen free radicals and also by lessening P. acnes density. The reduction of P. acnes has a profound antiinflammatory effect because the bacteria induce monocytes to produce tumor necrosis factor α (TNF-α), interleukin-1β, and interleukin-8 [16,17]. The strong anti-inflammatory and antibacterial effects of benzoyl peroxide can be parlayed into good clinical results, as shown in a large UK study. This study looked at five antimicrobial acne treatments over an 18-week period. Subjects used either oral oxytetracycline, oral minocycline, benzoyl peroxide, separate administration of topical erythromycin and benzoyl peroxide, or a combination product with containing both topical erythromycin and benzoyl peroxide. The 5% benzoyl peroxide used twice daily had similar efficacy to 100 mg minocycline once daily. This study also carried out a cost-effectiveness analysis and found that the least expensive treatment (benzoyl peroxide) was 12 times more cost-effective than minocycline [18]. Besides being an anti-inflammatory, benzoyl peroxide is also comedolytic. One study utilizing the rabbit ear comedogenicity assay showed a 10% reduction of comedones [19]. Another study compared 5% benzoyl peroxide twice daily with 0.05% tretinoin once daily for 8 weeks. Both treatments were “extremely effective” for all acneiform lesions but significantly reduced both open and closed comedones after only 2 weeks [20]. Benzoyl peroxide is available OTC in 2.5–10% strengths and as either washes or leave-on products (e.g. cream, lotion, gel). Leave-on products reduce P. acnes counts more than the washes, although both significantly reduce P. acnes on the skin [14]. There is some indication that gel formulations may be more stable and release benzoyl peroxide more consistently than creams and lotions [21]. Equal reductions of acneiform lesions are seen with benzoyl peroxide strengths of 2.5, 5, and 10%. Increasing the strength of benzoyl

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peroxide seems only to intensify the irritation [22]. Skin irritation to benzoyl peroxide is one of its greatest barriers to use. Redness, stinging, and dryness may be manifestations of irritation. Many patients describe this as an “allergy” to benzoyl peroxide. However, true allergic contact dermatitis to benzoyl peroxide is estimated at only 1–2.5% of patients with acne [23,24]. Patients should be warned about irritation that may result and should also be told of the propensity for benzoyl peroxide to bleach fabrics and hair. In addition to being available OTC, benzoyl peroxide is also available as a prescription. These prescription products may contain different formulations that may enhance penetration and decrease irritation, although no head-to-head trials exist comparing prescription with OTC benzoyl peroxide. Since mouse studies have shown that benzoyl peroxide can produce DNA strand breaks, there has been some question to its carcinogenic potential. However, two case–control studies showed no correlation between benzoyl peroxide use and skin cancer. Additionally, 23 carcinogenicity studies in rodents produced negative results [11]. Epidemiologic evaluations have shown no association between benzoyl peroxide and malignant melanoma [25].

Alfa-hydroxy acids The hydroxy acids are another common OTC antiacne ingredient found in washes and leave-on products. There are two main classes of hydroxy acids that are used for treating acne: alfa-hydroxy acids and beta-hydroxy acids (Table 60.1). The alfa-hydroxy acids are water-soluble, penetrate the epidermis and even into the dermis at higher concentrations. They act by desquamating the stratum corneum (i.e. exfoliation). Specifically, alfa-hydroxy acids disrupt corneocyte adhesion in the upper stratum corneum, possible by chelating calcium [26]. This results clinically in a smoother appearance to the skin, and may also give the illusion of reducing pore size

[27]. Alfa-hydroxy acids also promote epidermolysis, disperse basal layer melanin, and when strong enough to penetrate the dermis they may increase collagen synthesis [28]. These effects may make alfa-hydroxy acids helpful for acne prevention and treatment of postinflammatory hyperpigmentation. The most common OTC alfa-hydroxy acids are glycolic acid (derived from sugar cane) and lactic acid (from sour milk) and are found in less than 10% concentration.

Salicylic acid The only beta-hydroxy acid used in dermatology is salicylic acid. Unlike the alfa-hydroxy acids, it is lipid-soluble allowing it to penetrate not only the epidermis but also the pilosebaceous unit. This added penetration makes it comedolytic, thus giving it superiority over the alfa-hydroxy acids in treating acne [29]. Salicylic acid also exerts anti-inflammatory effects by inhibiting arachidonic acid. Multiple studies exist demonstrating the superiority of salicylic acid to placebo or to benzoyl peroxide. One study examined 49 patients who applied either 0.5% salicylic acid or placebo twice daily for 12 weeks. Those who applied the salicylic acid had significantly reduced inflammatory papules and open comedones, but closed comedones were not diminished [30]. One of the two studies submitted to the FDA during the OTC approval phase was a 12-week, doubleblind investigation of 180 subjects. It compared the efficacy of 2% salicylic acid solution with a vehicle solution and 5% benzoyl peroxide. Of the subjects treated with the salicylic acid, 40% showed a good or excellent response versus 5% in the vehicle group and only 2% in the benzoyl peroxide group. Salicylic acid was better than either vehicle or benzoyl peroxide in improving total lesions, inflammatory lesions, and open comedones, but not closed comedones. The second study submitted to the FDA involved 187 subjects and compared 0.5% and 2% salicylic acid solution with the vehicle solution. Both 0.5% and 2% salicylic acid

Table 60.1 Hydroxy acids. Hydroxy acid

Solubility

Alfa-hydroxy acids

Water soluble

Source

Glycolic acid

Sugar cane

Lactic acid

Sour milk

Beta-hydroxy acid Salicylic acid

490

Lipid soluble

Willow bark, wintergreen, sweet birch

Penetration

Action

Over-the-counter strength

Dermis (at high concentrations)

Exfoliative

Less than 10%

Epidermis and pilosebaceous unit

Exfoliative, comedolytic, anti-inflammatory

0.05–5%

60. Acne treatments were superior to the vehicle in reducing inflammatory lesions, open and closed comedones, and total lesions [31]. There are also several studies that demonstrate the efficacy of salicylic acid formulations other than solution. A cross-over study evaluating a 2% salicylic acid cleanser and a 10% benzoyl peroxide lotion in 30 patients found the salicylic acid cleanser to be superior at improving comedones [32]. Another study demonstrated the efficacy of a 2% salicylic acid scrub in reducing open comedones [33]. Based on these studies, many consider salicylic acid more effective than benzoyl peroxide in treating comedonal acne, but less effective than benzoyl peroxide in treating inflammatory acne [31]. Unlike benzoyl peroxide, salicylic acid does not have the ability to prevent resistance when used in combination with oral or topical antibiotics.

to be comedogenic [39], further studies have not validated this claim [40]. Sulfur is available OTC in concentrations of 3–8% and is often found in combination with resorcinol or resorcinol monoacetate. The malodor and messiness of sulfur limits its use.

Triclosan and triclocarban Triclosan and triclocarban are two antimicrobials that are found in cleansers marketed for acne treatment and are often labeled as “antibacterial” cleansers. Including having effects against P. acnes, both of these antimicrobials are effective against Gram-positive bacteria and triclocarban also is effective against Gram-negative bacteria. Studies are scant, but there is some evidence that these antimicrobials improve acne [41,42].

Polyhydroxy acids A third class of hydroxy acids, polyhydroxy acids, is becoming more popular in OTC dermatologic formulations. Polyhydroxy acids have been shown to be less irritating than alfa-hydroxy acids, but their larger particle size may limit penetration [34]. Lactobionic acid and gluconolactone are polyhydroxy acids most often found in topicals marketed for antiaging purposes but may someday also be found in OTC acne treatments. Although very little of either the topical benzoyl peroxide or hydroxy acids is absorbed systemically, both of these OTC products are pregnancy category C. Like benzoyl peroxide, the hydroxy acids can cause skin irritation marked by dryness, erythema, and flaking. Use of the hydroxy acids can also lead to greater sun sensitivity. Although generally safe, toxic levels of salicylic acid (known as salicylism) can occur if salicylic acid is used on a large body surface area in patients with icthyosis or excoriations. Use of salicylic acid is contraindicated in any patient with an aspirin allergy [35].

Retinols Retinols are a group of vitamin A derivatives that are available topically OTC in various forms such as retinol, retinyl propionate, and retinyl palmitate. Both retinol and retinyl propionate are absorbed by keratinocytes where they are reversibly oxidized into retinaldehyde, wherease retinyl palmitate is inactive. Retinaldehyde is irreversibly converted into all-trans retinoic acid (i.e. tretinoin). Tretinoin is transported into the keratinocyte nucleus where it acts by binding to the hormone response elements. There are no large multicenter trials that evaluate the efficacy of the retinols. In general, the retinols are 20 times less potent than topical tretinoin but exhibit greater penetration than tretinoin [43]. 0.25% Topical retinol induces cellular and molecular changes similar to that observed with 0.025% tretinoin without causing the irritation typical of tretinoin. However, it should be noted that most OTC formulations of retinol come in only 0.04–0.07% [44].

Sulfur

Cleansing cloths

Sulfur is a yellow, non-metallic element that has been used for centuries to treat various dermatologic conditions. A physician in Ancient Rome, Aulus Cornelius Celsus (ca 25 BC – ca 50 BC), wrote De Medicina, a medical text which includes the use of sulfur in mineral baths to treat acne [36]. Sulfur continues to be used today for a variety of conditions because of its antifungal and bacteriostatic properties [37]. It is believed by some to also have a keratolytic effect. Although the precise mechanism of action is not known, sulfur is thought to interact with cysteine in the stratum corneum causing a reduction in sulfur to hydrogen sulfide. Hydrogen sulfide in turn degrades keratin, producing the keratolytic effect of sulfur [38]. Although one study has shown sulfur

Cleansing cloths are disposable, dry towlettes that are impregnated with a cleanser and possibly an antiacne ingredient. Just prior to use, most of them need to be moistened with water. They are manufactured by combining polyester, rayon, cotton, and cellulose fibers through a thermal process. Many cloths are impregnated with triclosan or a hydroxy acid. Their effect on the skin is determined in part by their ingredients but also by the type of weave. The cloths may be either open or closed weave. Cloths with an open weave have 2–3 mm between fibers. This relatively large spacing between the fibers decreases the cloth’s contact area with the skin and in turn lessens irritancy. The closed weave cloths have less space between each individual fiber and

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are more irritating to the skin [45]. There are no known published trials evaluating the efficacy of cleansing cloths against acne.

Mechanical treatments In addition to the above-described antiacne ingredients, there are several OTC treatments designed to mechanically rid the skin of acne. Some of these treatments, such as scrubs and cleansing brushes, physically abrade the skin in an attempt to control acne. There are many abrasive scrubs available OTC that patients will often try to combat acne. Scrubs are topical agents that incorporate particles that mechanically abrade the skin and thin the stratum corneum. In general, three classes of scrubs exist. The most abrasive scrubs are made of aluminum oxide particles and ground fruit pits. These particles are the harshest on the skin, in part because of their irregular shape. The second, and milder, class of scrubs is made of polyethylene beads that are smooth and round particles. The mildest class of scrubs is composed of sodium tetraborate decahydrate granules, which soften and dissolve soon after application [45]. To our knowledge, there is only one published study looking at the effect of scrubs on acne. This study showed that scrubs did not improve comedones, but in fact worsened them. The abrasives also caused peeling and erythema. However, resorption of inflammatory lesions was somewhat augmented by the abrasives [46]. Some scrubs also include benzoyl peroxide or a hydroxy acid in order to target the consumer with acne. In addition to scrubs, another cleansing method designed to thin the stratum corneum is the cleansing brush. Some cleansing brushes (e.g. Sonic™ Skin Care Brush [Pacific Bioscience Labs, Bellevue, MA, USA]) are handheld, battery operator devices with an oscillating brush head while others are simply handheld, coarse pads (Clean and Clear™ Blackhead Eraser [Johnson and Johnson, New Brunswick, NJ, USA]). There are no published trials evaluating the efficacy of either of these devices for removing acne. However, there is a small internally performed study by the makers of the Sonic™ Skin Care Brush demonstrating the brush to remove 2.34 times more foundation than traditional cleansing methods. There are also adhesive pads (Biore™ [Kao Brands Co., Cincinnati, OH, USA]) on the market that are purported “to get rid of pore clogging buildup and blackheads” [47]. These disposable pads are applied to wet skin and left in place for 10 minutes, over which time the pad will stiffen. The active agent of these pads is polyquaternium 37, a cationic hydrocolloid substance that binds to the anionic component of comedonal plugs [48]. Although no studies exist evaluating the pads’ efficacy in treating acne, there is a report of its success in treating trichostasis spinulosa [48]. Besides mechanical agents such as brushes and pads, there is a handheld, electronic heating device (Zeno™ [Zeno 492

Corp., Houston, TX, USA]) designed to speed the resolution of existing acne lesions. The user is directed to apply the device to individual acne lesions for 2.5 minutes, for 2–3 times a day. The device heats to 121°Fahrenheit, killing P. acnes. The exact mechanism by which the delivered heat kills this bacterium is unknown. Data from the manufacturer demonstrates that lesions treated with the Zeno device clear on average 1.3 days faster than those treated with a placebo [49].

Essential oils Patients who are seeking a homeopathic approach to treating acne may seek out essential oils and oral vitamins. Two topical essential oils that can be used are tea tree oil and chamomile. Tea tree oil is derived from the Australian tree Melaleuca alternifolia. The oil contains several antimicrobial substances including terpinen-4-ol, alfa-terpineol, and alfapinene [50]. A comparative study of 5% tea tree oil versus 5% benzoyl peroxide showed that both substances significantly reduce acne. The tea tree oil had a slower onset but was less irritating than the benzoyl peroxide [51]. It should be noted that the majority of tea tree oil available OTC is no more than 1% concentratioon. Chamomile is derived from the German chamomile plant Matricaria recutita. The active ingredient is alfa bisabolol. One study demonstrated that alfa bisabolol has an anti-inflammatory effect in the skin equal to that of 0.25% hydrocortisone [52]. Because of this anti-inflammatory effect, some will try this homeopathic approach to treat their acne.

Oral vitamins Oral vitamins that have been tried for the treatment of acne include zinc, nicotinamide, and vitamin A. Zinc sulfonate was first used as an acne treatment in 1970. Later, in the 1980s, a different formulation of zinc was developed – zinc gluconate. In patients with acne, zinc inhibits chemotaxis, is bacteriostatic against P. acnes, and reduces TNF-α production. In vitro, zinc inhibits type I 5-alpha reductase, a key enzyme in the hormonal impact on acne [53]. A randomized, double-blind study of 332 patients compared 30 mg/ day zinc gluconate with 100 mg/day minocycline. At 90 days, patients treated with either medication had significant reductions of papules and pustules. However, minocyclinetreated subjects had a 17% greater reduction in inflammatory lesions than those treated with zinc [54]. It should be noted that the recommended daily allowance of zinc is 15 mg, half the dose than is often used to treat acne. The most common side effect of zinc supplementation is gastrointestinal upset. Although generally safe at common doses (even safe in pregnancy), side effects can ensue when higher doses are used. In an anecdotal report, a desperate

60. Acne treatments teenage boy with acne self-medicated with 300 mg/day zinc for 2 years. As a result, he developed severe anemia, leucopenia, and neutropenia, which improved upon cessation of the zinc [55]. Another oral vitamin often utilized for acne treatment is nicotinamide (also known as niacinamide), a water-soluble B vitamin. Nicotinamide can improve acne by both inhibiting white blood cell chemotaxis and by inhibiting the release of lysosomal enzymes by white blood cells which damage the follicular wall [56]. Although the recommended daily allowance of nicotinamide is 20 mg, studies showing its beneficial effect for acne have used 750–1000 mg/day [57]. Supplementation is safe up to 3000 mg/day, at which point it may induce reversible elevations of liver function tests. Oral nicotinamide is also available as a prescription in combination with zinc, copper, and folic acid in a product known as Nicomide (DUSA Pharmaceuticals, Inc., Wilmington, MA, USA) and has shown success in treating acne [58]. Topical nicotinamide has not shown benefit in treating acne [59]. Vitamin A is a fat-soluble vitamin that can be used in high doses to treat acne. Interestingly, those with acne tend to have lower plasma levels of vitamin A than controls [60,61]. Vitamin A binds to some of the same nuclear receptors as isotretinoin (13-cis retinoic acid). The recommended daily allowance of vitamin A is 50 000–100 000 IU. It is effective for acne at 300 000 IU/day in females and 400 000–500 000 IU/ day in males [62]. At these high doses most patients experience similar side effects to those who are on isotretinoin (e.g. xerosis and cheilitis). High doses of vitamin A also have the potential to induce liver and kidney damage and to cause pseudotumor cerebri.

Conclusions Because many patients will turn to OTC remedies to treat their acne, it is important that the physician understand what is available to patients. The ability of the physician to speak knowledgeably on OTC remedies instills patient confidence in the physician. Many of these OTC treatments may be used beneficially; however, it is helpful for the physician to advise the patient on both their advantages and shortcomings. Some OTC treatments may enhance the use of prescription medications while others may only cause further irritation. Ultimately, the physician should be educated on merging OTC and prescription acne medications to best help the patient with acne.

References 1 Feldman SR, Fleischer AB Jr. (2000) Role of the dermatologist in the delivery of dermatologic care. Dermatol Clin 18, 223–7. 2 Woodard I. (2002) Adolescent acne: a stepwise approach to management. Top Adv Nurs Pract eJournal 2(2). 3 Malus M, LaChance PA, Lamy L, Macaculay A, Vanasse M. (1987) Priorities in adolescent health care: the teenager’s viewpoint. J Fam Pract 25, 159–62.

4 Bowe WP, Shalita A. (2008) Effective over-the-counter acne treatments. Semin Cutan Med Surg 27, 170–6. 5 Agency for Healthcare Research and Quality. (2001) Management of Acne. March 2001, Contract No. 01-E018. 6 21 CFR Part 333.350(b)(2), 21 CFR (1991). 7 Clearihan L. (2001) Acne: myths and management issues. Aust Fam Physician 30, 1039–44. 8 Choi JM, Lew VK, Kimball AB. (2006) A single-blinded, randomized, controlled clinical trial evaluating the effect of face washing on acne vulgaris. Pediatr Dermatol 23, 421–7. 9 Abbas S, Goldberg JW, Massaro M. (2004) Personal cleanser technology and clinical performance. Dermatol Ther 17 (Suppl 1), 35–42. 10 Subramanyan K. (2004) Role of mild cleansing in the management of patient skin. Dermatol Ther 17, 26–34. 11 Kraus AL, Munro IC, Orr JC, Binder RL, LeBoeuf RA, Williams GM. (1995) Benzoyl peroxide: an integrated human safety assessment for carcinogenicity. Regul Toxicol Pharmacol 21, 87–107. 12 Bojar RA, Cunliffe WJ, Holland KT. (1995) Short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol 132, 204–8. 13 Pagnoni A, Kligman AM, Kollias N, Goldberg S, Stoudemayer T. (1999) Digital fluorescence photography can assess the suppressive effect of benzoyl peroxide on Propionibacterium acnes. J Am Acad Dermatol 41, 710–6. 14 Leyden JJ. (2001) Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol 15 (Suppl 3), 51–5. 15 Berson DS, Shalita AR. (1995) The treatment of acne: the role of combination therapies. J Am Acad Dermatol 32, 31–41. 16 Kim J, Ochoa M, Krutzik S, Takeuchi O, Uematsu S, Legaspi A, et al. (2002) Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 169, 1535–41. 17 Vowels B, Yang S, Leyden J. (1995) Induction of proinflammatory cytokines by a soluble factor of Propionibactreium acnes: implications for chronic inflammatory acne. Infect Immun 63, 3158–65. 18 Ozolins M, Eady EA, Avery AJ, Cunliffe WJ, Po ALW, O’Neill C, et al. (2004) Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet 364, 2188–95. 19 Tucker SB, Flannigan SA, Dunbar M Jr, Drotman RB. (1986) Development of an objective comedogenicity assay. Arch Dermatol 122, 660–5. 20 Belknap BS. (1979) Treatment of acne with 5% benzoyl peroxide gel or 0.05% retinoic acid cream. Cutis 23, 856–9. 21 Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et al. (2003) Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 49 (Suppl), S1–37. 22 Mills OH Jr, Kligman AM, Pochi P, Comite H. (1986) Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 25, 664–7. 23 Balato N, Lembo G, Cuccurullo FM, Patruno C, Nappa P, Ayala F. (1996) Acne and allergic contact dermatitis. Contact Derm 34, 68–9. 24 Morelli R, Lanzarini M, Vincenzi C. (1989) Contact dermatitis due to benzoyl peroxide. Contact Derm 20, 238–9. 493

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25 Cartwright RA, Hughes BR, Cunliffe WJ. (1988) Malignant melanoma, benzoyl peroxide and acne: a pilot epidemiological case–control investigation. Br J Dermatol 118, 239–42. 26 Berardesca E, Distante F, Vignoli GP, Oresajo C, Green B. (1997) Alpha hydroxyacids modulate stratum corneum barrier function. Br J Dermatol 137, 934–8. 27 Bergfeld W, Tung R, Vidimos A, Vellanki L, Remzi B, StantonHicks U. (1997) Improving the cosmetic appearance of photoaged skin with glycolic acid. J Am Acad Dermatol 36, 1011–3. 28 Tung RC, Bergfeld WF, Vidimos AT, Remzi BK. (2000) Alphahydroxy acid-based cosmetic procedures: guidelines for patient management. Am J Clin Dermatol 1, 81–8. 29 Kligman AM. (1997) A comparative evaluation of a novel lowstrength salicylic acid cream and glycolic acid products on human skin. Cosmet Dermatol 11 (Suppl). 30 Shalita AR. (1981) Treatment of mild and moderate acne vulgaris with salicylic acid in an alcohol-detergent vehicle. Cutis 28, 556–8. 31 Chen T, Appa Y. (2006) Over-the-counter acne medications. In: Draelos ZD, Thaman LA, eds. Cosmetic Formulations of Skin Care Products. New York: Taylor & Francis, pp. 251–71. 32 Shalita AR. (1989) Comparison of a salicylic acid cleanser and a benzoyl peroxide wash in the treatment of acne vulgaris. Clin Ther 11, 264–7. 33 Pagnoni A, Chen T, Duong H, Wu IT, Appa Y. (2004) Clinical evaluation of a salicylic acid containing scrub, toner, mask and regimen in reducing blackheads. 61st meeting, American Academy of Dermatology, February 2004, Poster 61. 34 Grimes PE, Green BA, Wildnauer RH, Edison BL. (2004) The use of polyhydroxy acids (PHAs) in photoaged skin. Cutis 73 (Suppl), 3–13. 35 Brubacher JR, Hoffman RS. (1996) Salicylism from topical salicylates: review of the literature. J Toxicol Clin Toxicol 34, 431–6. 36 Thayer B. (2006) Celsus: De Medicina. Available from: http:// penelope.uchicago.edu/Thayer/E/Roman/Texts/Celsus/home. html. 37 Gupta AK, Nicol K, Gupta AK, Nicol K. (2004) The use of sulfur in dermatology. J Drugs Dermatol 3, 427–31. 38 Lin AN, Reimer RJ, Carter DM. (1988) Sulfur revisited [see comment]. J Am Acad Dermatol 18, 553–8. 39 Mills OH Jr, Kligman AM. (1972) Is sulphur helpful or harmful in acne vulgaris? Br J Dermatol 86, 620–7. 40 Fulton JE Jr, Pay SR, Fulton JE 3rd. (1984) Comedogenicity of current therapeutic products, cosmetics, and ingredients in the rabbit ear. J Am Acad Dermatol 10, 96–105. 41 Franz E, Weidner-Strahl S. (1978) The effectiveness of topical antibacterials in acne: a double-blind clinical study. J Intern Med Res 6, 72–7. 42 Lee TW, Kim JC, Hwang SJ. (2003) Hydrogel patches containing triclosan for acne treatment. Eur J Pharm Biopharm 56, 407–12. 43 Duell EA, Kang S, Voorhees JJ. (1997) Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate or retinoic acid. J Invest Dermatol 109, 301–5. 44 Kang S, Leyden JJ, Lowe NJ, Ortonne JP, Phillips TJ, Weinstein GD, et al. (2001) Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized,

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vehicle-controlled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks [see comment]. Arch Dermatol 137, 1597–604. Draelos Z. (2005) Reexamining methods of facial cleansing. Cosmet Dermatol 18, 173–5. Mills OH Jr, Kligman AM. (1979) Evaluation of abrasives in acne therapy. Cutis 23, 704–5. Available from: www.biore.com. Elston DM. (2000) Treatment of trichostasis spinulosa with a hydroactive adhesive pad. Cutis 66, 77–8. Bruce S, Conrad C, Peterson RD, Conrad R, Arambide LS, Thompson J, et al. Significant efficacy and safety of low level intermittent heat in patients with mild to moderate acne. http:// www.myzenoeurope.com/doc/zenowhite.pdf. Raman A. (1995) Antimicrobial effects of tea-tree oil and its major components on Staphylococcus aureus, Staph. epidermidis and Propionibacterium acnes. Lett Appl Microbiol 21, 242–5. Bassett IB. (1990) A comparative study of tea-tree oil versus benzoyl peroxide in the treatment of acne. Med J Aust 153, 455–8. Brown DJ, Dattner AM. (1998) Phytotherapeutic approaches to common dermatological conditions. Arch Dermatol 134, 1401–4. Dreno B, Trossaert M, Boiteau HL, Litoux P. (1992) Zinc salts effects on granulocyte zinc concentration and chemotaxis in acne patients. Acta Derm Venereol 72, 250–2. Dreno B, Moyse D, Alirezai M, Amblard P, Auffret N, Beylot C, et al. (2001) Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Dermatology 203, 135–40. Porea TJ, Belmont JW, Mahoney DH Jr. (2000) Zinc-induced anemia and neutropenia in an adolescent. J Pediatr 136, 688–90. Fivenson DP. (2006) The mechanisms of action of nicotinamide and zinc in inflammatory skin disease. Cutis 77 (Suppl), 5–10. Niren NM. (2006) Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review. Cutis 77 (Suppl), 11–6. Niren NM, Torok HM. (2006) The Nicomide Improvement in Clinical Outcomes Study (NICOS): results of an 8-week trial. Cutis 77 (Suppl), 17–28. Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK. (1995) Topical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris. Int J Dermatol 34, 434–7. Vahlquist A, Michaelsson G, Juhlin L. (1978) Acne treatment with oral zinc and vitamin A: effects on the serum levels of zinc and retinol binding protein (RBP). Acta Derm Venereol 58, 437–42. El-Akawi Z, Abdel-Latif N, Abdul-Razzak K. (2006) Does the plasma level of vitamins A and E affect acne condition? Clin Exp Dermatol 31, 430–4. Kligman AM, Mills OH Jr, Leyden JJ, Gross PR, Allen HB, Rudolph RI. (1981) Oral vitamin A in acne vulgaris. Preliminary report. Int J Dermatol 20, 278–85.

Chapter 61: Rosacea regimens Joseph Bikowski Ohio State University, Columbus, OH, and Bikowski Skin Care Center, Sewickley, PA, USA

BAS I C CONCEPTS • Rosacea is a chronic vascular disorder characterized by flushing, redness, telangiectasias, and inflammatory skin lesions. • Skincare products and cosmetics can improve the skin barrier and also camouflage the underlying erythema. • Cleansers, moisturizers, and sunscreens can impact the appearance of rosacea. • Skincare products can be used in conjunction with prescription medications for optimal redness reduction.

Introduction Rosacea is a chronic vascular disorder affecting the facial skin and eyes which often is characterized by a chronic cycle of remission and flare. Regardless of disease severity (Figure 61.1a–c), there are cosmetic consequences for the patient including flushing, redness, telangiectasia, papules, and/or pustules. Estimates of disease prevalence vary, but it is likely that 14 million people in the USA have rosacea [1]. Because there is no cure for the disease, management consists of the avoidance of disease triggers and the use of both prescription and over-the-counter (OTC) products that work in concert to achieve remission, prevent flare, and camouflage disease manifestations such as flushing and redness.

Physiology of rosacea Rosacea is found most frequently in fair-skinned individuals with Fitzpatrick type I skin who tend to burn rather than tan. UV radiation damages blood vessels and supporting tissue, and sun exposure may be a causative factor in the disease [2]. Rosacea is most often diagnosed in patients between the ages of 30 and 60 years [2] but it also can begin in adolescence, when it is often mistaken for acne vulgaris, or in persons older than 60 years. The etiology and pathogenesis of rosacea have not been established, nor are there any known histologic or serologic markers of the disease. However, rosacea is diagnosed by the presence of one or more primary disease features including flushing (transient erythema), non-transient erythema, tel-

angiectasia, papules, and pustules. Secondary diagnostic features include burning/stinging, plaque formation, dryness, edema, ocular manifestations, peripheral location, and/or phymatous changes [3]. Although these disease features often occur in various combinations, four rosacea subtypes have been classified and agreed upon to assist in the diagnosis and selection of appropriate treatment [4] (Figure 61.2a–d). Subtype 1 is erythematotelangiectatic rosacea (Figure 61.2a), which is characterized by flushing episodes lasting more than 10 minutes and persistent erythema of the central face. Telangiectasia is often present. These patients may also complain of central facial edema, stinging and burning, roughness or scaling, and a history of flushing alone is common. Subtype 2 is papulopustular rosacea (Figure 61.2b), which is characterized by persistent erythema, with transient papules and/or pustules on the central face. Subtype 2 resembles acne, but without comedones; however, acne and papulopustular rosacea can occur simultaneously. Papules and pustules also can occur around the mouth, nose, or eyes, and some patients report burning and stinging. Subtype 3 is phymatous rosacea (Figure 61.2c), which includes thickening skin and nodularities. Rhinophyma, nose involvement, is the most common presentation; however, ears, chin, and forehead may be involved. Patients may also have telangiectasias and/or patulous follicles in the phymatous area. Subtype 4 is ocular rosacea (Figure 61.2d), which should be considered if the patient has one or more of the following ocular signs: watery or bloodshot eyes, foreign body sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectasia of the conjunctiva and lid margin, or lid and periocular erythema. Blepharitis and conjunctivitis are also found commonly in rosacea patients with ocular manifestations. Ocular rosacea can precede cutaneous signs by years, but it is found most frequently along with cutaneous disease.

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(a)

(c)

(b) Figure 61.1 Mild (a), moderate (b), and severe (c) rosacea.

Rosacea flare Beyond these recognized disease stages and presentation, rosacea is characterized by a chronic cycle of remission and flare. Sun avoidance is crucial in avoiding recurrence, but there are numerous other disease triggers. Table 61.1 is only a partial list of flare factors, but it is sufficient to illustrate how challenging flare avoidance is for patients and next to impossible for them to adhere to completely. Because rosacea pathophysiology has not yet been fully described, treatment targets the signs and symptoms of the disease without a full understanding of disease mechanisms. Disease manifestations and treatment-related cosmetic sequelae necessitate the use of OTC and prescription products for long-term treatment and for camouflaging skin redness, flushing, and blemishes.

Rosacea skincare: available OTC products Rosacea patients should be counseled to avoid astringents, soaps, fresheners, toners, facial scrubs, masks, and OTC skin-

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Table 61.1 Potential rosacea flare factors. (Adapted from ‘Factors that may trigger rosacea flare-ups’. National Rosacea Society website, National Rosacea Society. http://www.rosacea.org/patients/materials/ triggers.php. Accessed July 3, 2008.) Heat Hot baths, saunas, excessively warm environments, overdressing

Food Spicy and thermally hot foods Foods high in histamine

Exertion Exercise, lifting

Alcohol Red wine, liquor, beer

Emotions Anxiety, stress, embarrassment

Drugs Vasodilatators, topical steroids

Medical conditions Chronic cough, menopause

Topical products Some cosmetics and hair sprays, especially those containing alcohol; witchhazel or fragrances; hydro-alcoholic or acetone substances

Weather Sun, hot, cold, strong winds, humidity

61. Rosacea regimens

(a)

(b)

(c)

(d) Figure 61.2 Rosacea clinical subtypes: (a) subtype 1; (b) subtype 2; (c) subtype 3; (d) subtype 4.

care programs. However, even though the list of verboten agents is long, there are numerous safe and effective cleansers, moisturizers, sunscreens, and cosmetics available for rosacea patients. Disease management is aimed at achieving synergy between prescription and OTC products to ensure maximum efficacy of active drugs, extend remission, and conceal redness and blemishes. People with rosacea have skin that is extremely sensitive to chemical irritants, so it is important that patients try to avoid all sources of irritation. Furthermore, the skin care regimen of a rosacea patient needs to be simple because the more the skin is specifically manipulated the more opportunity there is for unnecessary irritation.

Cleansing and moisturizing A proper cleansing and moisturizing routine is an important part of rosacea management. Patients should be counseled that daily cleansing is important to rid the skin of surface dirt, makeup, dead skin, and excess oil, but they should

wash with only cool or lukewarm water. The ideal cleanser for rosacea skin is a product that leaves minimal residue, is non-comedogenic and lipid free, and contains non-ionic surfactants with a neutral or slightly acidic pH [4]. Table 61.2 lists some recommended cleansers for rosacea patients. Moisturizing is important in order to maintain the softness and elasticity of the skin, and therapeutic moisturizers devoid of irritants are important adjunctive therapy in rosacea management [5]. A large proportion of rosacea patients have dry skin, and some topical rosacea medications (e.g. topical metronidazole) can cause further drying and irritation. Moisturizers formulated with a combination of emollients and humectants are recommended to help keep the stratum corneum intact to either repair or prevent skin barrier dysfunction. Furthermore, moisturizing dry skin lessens the itchiness and irritation that rosacea patients often experience as a part of their condition. Table 61.3 lists some moisturizers that can be used as part of a rosacea skin care regimen.

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Table 61.2 Recommended over-the-counter cleansers for rosacea skincare.

Table 61.3 Recommended over-the-counter moisturizers for rosacea skincare.

Cleansers

Benefits

Moisturizers

Benefits

Cetaphil® Gentle Skin Cleanser

Lipid-free, neutral pH, soap-free, non-comedogenic, fragrance-free, leaves no residue, non-irritating

Cetaphil® Moisturizing Cream

Eucerin® Gentle Hydrating Cleanser

Lipid-free, soap-free, non-comedogenic, fragrance-free, leaves no residue, non-irritating

Non-greasy, cosmetically appealing, fragrance-free and non-comedogenic. Contains sweet almond oil, which is a source of essential fatty acids

L’Oréal® Plénitude Gentle Foaming Cleanser

Lipid-free, soap-free, non-comedogenic, leaves no residue, non-irritating

Eucerin® Redness Relief Soothing Moisture Lotion SPF 15 or Daily Protecting Lotion SPF 16

Contains licochalcone A; protects from UVA/UVB; fragrance-free, oil-free, non-irritating, noncomedogenic; Daily Protecting Lotion contains green color neutralizers

Purpose® Gentle Cleansing Wash

Lipid-free, soap-free, non-comedogenic, soap-free, non-irritating

Olay® Complete UV Protective Moisture Lotion

Eucerin® Redness Relief Soothing Cleanser

Soap-free gel, non-irritating, non-drying, fragrance-free, non-comedogenic, contains licochalcone A

Color and fragrance-free; contains vitamin E; SPF 15, protects against UVA and UVB

Rosaliac® Anti-Redness Moisturizer

Contains vitamin C to reduce redness and green tint to conceal redness; expensive

All trademarks are property of their respective owner.

(b)

(a)

Cosmetics Cosmetics are used to camouflage disease signs and symptoms, which is an important part of disease management. Rosacea patients should be counseled to avoid products containing menthol, camphor, or sodium lauryl sulfate, as these can be irritating. It is also recommended that rosacea patients avoid the use of waterproof cosmetics and heavy foundations because they are mechanically harder to apply, and their removal often requires the use of irritating solvents.

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Figure 61.3 The effect of green-tinted makeup on reddened skin. (a) Patient with rosacea. (b) Camouflage of patient’s rosacea using green-tinted makeup.

Pigmentation irregularities can be camouflaged by applying foundations of complementary colors [6]. For example, red skin can be camouflaged by applying a green foundation, which is the complementary color to red; the combination of green and red creates a brown tone, and this can be covered further, if desired, by a light foundation that spreads easily. Furthermore, a yellow skin tone will turn brown when complemented with purple foundation. Figure 61.3 (a & b) shows how effective green-tinted makeup can be in camouflaging redness. Fortunately, there are an increasing

61. Rosacea regimens

Table 61.4 Recommended over-the-counter cosmetics for rosacea skincare.

Table 61.5 Recommended over-the-counter sunscreens for rosacea skincare.

Cosmetics

Benefits

Sunscreens

Benefits

Eucerin® Redness Relief Concealer

Smooth formula blends easily into the skin. Fragrance-free, oil-free, non-irritating, non-comedogenic, contains licochalcone A and has green color neutralizers

L’Oréal® Anthelios SX®

Contains ecamsule; expensive

Neutrogena Helioplex™

Contains avobenzone; protects from UVA/UVB

Active Photo Barrier Complex™

Contains avobenzone; protects from UVA

Dermaplex™

Contains avobenzone; protects from UVA

Titanium dioxide/zinc oxide formulations

Effective options for UVA protection. Older formulations made patients look pale, but newer manufacturing techniques have made these effective products cosmetically elegant

Cellex-C Eye Contour Cream with a 5% L-ascorbic acid

Contains L-ascorbic acid and zinc; lightweight; expensive

All trademarks are property of their respective owner.

number of tinted cosmetics and skincare products available to help camouflage rosacea redness, some of which are listed in Table 61.4.

All trademarks are property of their respective owner.

Sunscreens The daily uninterrupted use of sunscreen is a cornerstone in the long-term management of rosacea. Sun exposure is the leading cause of rosacea flares, and patients should be advised to use a sunscreen daily, irrespective of cloud coverage, with a sun protection factor (SPF) of at least 15. However, patients should be advised that a good sunscreen contains both UVB blockers (e.g. octyl methoxycinnamate, hom*osalate), as well as UVA blockers (e.g. avobenzone, ecamsule, titanium dioxide, oxybenzone, sulisobenzone, and zinc oxide) [6]. It is also important that the sunscreen be non-irritating, and patients with rosacea may have better tolerance of products containing dimethicone or cyclomethicone [7]. Furthermore, green-tinted sunscreens have the additional benefit of camouflaging erythema. Examples of some recommended sunscreens for rosacea can be found in Table 61.5. Cleansing, moisturizing, camouflaging, and using sunscreen are the primary features of a rosacea skincare regimen. OTC products that have a green tint or that are cosmetically elegant can be applied during the day, and prescription products used to treat erythema and redness that are less cosmetically elegant can be applied at night. Patients with long-term rosacea often have sensitive skin and can be the most difficult to treat.

Available prescription agents Oral and topical prescription agents are fundamental in the management of rosacea. Mild to moderate rosacea can be treated with topical monotherapy or topical combination therapy with or without an oral antibiotic. Moderate to

severe rosacea necessitates the use of oral antibiotic therapy until remission is achieved, usually for 3–4 months. Remission can often be maintained by continuing the topical therapy alone or in combination with a low-dose oral antibiotic [1]. Because rosacea pathogenesis is so poorly understood, management is focused on treating disease endpoints rather than the underlying disease. In general, inflammation is treated with an anti-inflammatory agent, papules and pustules are treated with antibiotics (with no target organism), flushing is treated with vasoconstrictors, and telangiectasias are treated with light-based therapies.

Oral antibiotic therapy Papular-pustular rosacea responds well to oral antibiotics, although their efficacy likely is brought about bytheir antiinflammatory effects more than their antimicrobial effects [2]. Standard antibiotic agents include tetracyclines (tetracycline, doxycycline, and minocycline), erythromycin, and co-trimoxazole, although the latter is usually reserved for use in Gram-negative rosacea or for patients who have not responded to other therapies [8]. These agents have been used for decades and are associated with a relatively good safety profile [8]. Tetracyclines are the most commonly prescribed oral antibiotics for rosacea, but there is apprehension about antibiotic resistance with the long-term use of these and other antibiotic agents. In response to this concern, an anti-inflammatory dose doxycycline (40 mg delayed-release formulation) has been formulated for the treatment of rosacea. Long-term use of this agent did not alter bacterial susceptibility to antibiotics during a 9-month period [9]. Furthermore, a 16week comparison study showed that both the 40-mg

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delayed-release and the 100-mg formulations in combination with 1% metronidazole topical gel are equally effective for the treatment of moderate to severe rosacea with a similar onset of action, and the delayed-release group had a superior side effect profile including fewer gastrointestinal effects [10].

Topical therapy Topical therapy for rosacea reduces inflammatory lesions (papules and pustules), decreases erythema, improves pruritus, burning and stinging, and reduces the incidence and intensity of flares [1]. Standard topical therapies include sulfacetamide 10%/sulfur 5%, metronidazole, and azelaic acid (AzA), which is the first new therapeutic class of topical agents approved for rosacea in more than a decade. Topical antibiotics erythromycin and clindamycin are second-line agents, but data regarding their efficacy in rosacea treatment are limited [1]. Sulfacetamide-sulfur has anti-inflammatory properties, and the gel comes in a green-tinted formulation, which has the advantage of simultaneously treating inflammation and toning down redness. Sulfacetamide-sulfur also has been combined with avobenzone (UVA filter) and octinoxate (UVB filter) in an SPF 18 formulation, which has shown superior efficacy than topical metronidazole in investigator global severity, percent reductions in inflammatory lesions, and improvement in erythema [11]. Overall, these leave-on products have demonstrated favorable safety and tolerability profiles [1]. Furthermore, sulfacetamide-sulfur cleansers also have demonstrated efficacy as adjunctive therapy in combination with other topical and/or systemic agents [1].

Other treatment modalities Flushing is a challenging treatment aspect of rosacea management and a source of frustration for most patients. Although there are few data supporting the use of vasoconstrictor agents for flushing, anecdotal reports support the use of low-dose beta-blockers, selective serotonin reuptake inhibitors, and clonidine [12].

Light-based therapies Many patients also are frustrated with the poor efficacy of oral and topical therapies in resolving telangiectasia and persistent erythema. However, efficacy has been demonstrated in the improvement of vascular disease features from light-based and laser therapies. Pulsed dye laser can be highly effective in reducing telangiectasia, flushing, and erythema by eliminating hemoglobin within increased dilated vessels in rosacea skin. However, efficacy is inconsistent, and treatment can be limited by the frequent occurrence of purpura, which can be long-lasting and difficult to conceal [13].

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More recently, intense pulsed light (IPL) therapy has been used with success to treat vascular symptoms of rosacea. IPL utilizes selective photothermolysis with a broad spectrum of light to destroy targeted vessels by coagulation while sparing surrounding tissue [1]. IPL is advantageous because it can penetrate the skin more effectively than lasers. Furthermore, variable light durations can target vessels of different sizes at multiple depths, IPL’s increased spot size allows a larger treatment area, and sequential pulsing provides for epidermal cooling between pulses [13].

Natural actives Cosmetic products with natural actives can be useful to soothe irritation associated with rosacea. Vitamin C is an antioxidant with numerous positive effects on the skin including collagen repair, normalization of photodamage, and anti-inflammatory properties. The use of a 5.0% vitamin C preparation demonstrated efficacy in objective and subjective improvement in erythema, which might be because of its anti-inflammatory effects [2]. There are currently three or four anti-redness products available, and the anti-redness moisturizer listed in Table 61.3 also has a green tint, which heals and conceals redness simultaneously. Licochalcone A is a major phenolic constituent of the licorice species Glycyrrhiza inflata which exhibits anti-inflammatory and antimicrobial effects, and improves redness and irritation [14]. The Eucerin® Redness Relief line has an SPF lotion and spot concealer containing licochalcone A with a green-tinted base, which provides both an anti-inflammatory component and redness camouflage. A study assessing the efficacy of this product line in reducing irritation in patients with mild to moderate facial redness showed that a regimen of cleanser, SPF lotion, spot concealer, and night cream containing licochalcone A improved redness and was compatible with daily metronidazole treatment [15]. Chrysanthellum indicum is a plant-based extract containing phenylpropanoic acids, flavonoids, and saponosids with documented effects on vascular wall permeability and on the increase of the mechanical resistance of capillaries [16]. A cream containing C. indicum was recently evaluated in 246 patients with moderate rosacea. Results showed that 12week, twice daily treatment with the C. indicum extractbased cream was significantly more effective than placebo in reducing erythema. Furthermore, this cream has vitamin P properties, which may be responsible for reducing or preventing microcirculation disorders involved in the erythema of rosacea [16]. Alfa-hydroxy acid-based cosmetic peels and at-home regimens also have shown promise for rosacea treatment. A regimen of a daytime cream containing SPF 15 and gluconolactone 8%, and an evening cream with gluconolactone 8% demonstrated significant improvement in texture, fine lines, photodamage, dryness, and erythema, and 80% of patients rated the cosmetic acceptability of these products as

61. Rosacea regimens good to excellent [17]. A polyhydroxy acid skin care regimen (cleanser and moisturizer) also demonstrated good tolerability and efficacy in combination with AzA 15% in patients with sensitive skin conditions [18]. This regimen significantly added to the reduction of facial erythema, did not interfere with the efficacy of AzA 15%, and smoothed the skin, which could further enhance patient satisfaction with the products. Glycolic acid peels and topical glycolic acid products added to an antibacterial regimen also have demonstrated dramatic improvement in skin texture and follicular pores, and in the resolution of comedones, papules, and pustules [17]. An additional benefit of these products and procedures is that they provide a treatment option for pregnant women because glycolic acid products, as well as AzA 15%, are not contraindicated in pregnancy.

Conclusions Management of rosacea includes avoidance of disease triggers and use of oral and topical prescription agents and OTC products to achieve remission, maximize time to flare, and conceal redness. A non-irritating skincare regimen is essential for long-term disease management. A variety of OTC cleansers, moisturizers, sunscreens, and cosmetics are available to keep skin healthy, and an increasing number of OTC products are tinted and/or contain natural anti-redness actives such as vitamin C and licochalcone A, which can be used in combination with prescription agents to maximize response. Although the pathogenesis of rosacea still has not been elucidated, there is hope that future rosacea therapies will target the disease at the genetic level, which is now common for other inflammatory skin disorders such as atopic dermatitis. There is ongoing research on vascular endothelial growth factor (VEGF) antagonists. It would appear that retinoids can modulate VEGF expression in the skin, and topical retinoic acid has demonstrated beneficial effects on vascular components of rosacea, specifically erythema and telangiectasia. Natural actives and botanicals will continue to be evaluated for their positive effects on the skin, and work remains to be done in optimizing light-based therapy in terms of clarifying treatment parameters, optimal treatment frequency, and the utility of adjuvant light-based therapies.

References 1 Del Rosso JQ. (2004) Medical treatment of rosacea with emphasis on topical therapies. Expert Opin Pharmacother 5, 5–13. 2 Cohen AF, Tiemstra JD. (2002) Diagnosis and treatment of rosacea. J Am Board Fam Pract 15, 214–7.

3 Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, et al. (2002) Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol 46, 584–7. 4 Bikowski J. (2001) The use of cleansers as therapeutic concomitants in various dermatologic disorders. Cutis 68 (Suppl), 12–9. 5 Bikowski J. (2001) The use of therapeutic moisturizers in various dermatologic disorders. Cutis 68 (Suppl), 3–11. 6 Draelos ZD. (2007) Cosmetics. Emedicine online journal. Available at: http://emedicine.com/derm/topic502.htm. Accessed June 4, 2008. 7 Nichols K, Desai N, Lebwohl MG. (1998) Effective sunscreen ingredients and cutaneous irritation in patients with rosacea. Cutis 61, 344–6. 8 Del Rosso JQ. (2000) Systemic therapy for rosacea: focus on oral antibiotic therapy and safety. Cutis 66 (Suppl), 7–13. 9 Walker C, Webster G. (2007) The effect of anti-inflammatory dose doxycycline 40 mg once-daily for 9 months on bacterial flora: Subset analysis from a multicenter, double-blind, randomized trial. Poster presented at 26th Anniversary Fall Clinical Dermatology Conference; October 18–27, 2007, Las Vegas, Nevada. 10 Del Rosso JQ. (2008) Comparison of anti-inflammatory dose doxycycline (40 mg delayed-release) vs doxycycline 100 mg in the treatment of rosacea. Poster presented at 8th Annual Caribbean Dermatology Symposium, January 15–19, 2008; St. Thomas, US Virgin Islands. Shalita AR, Dosik JS, Neumaier GJ, et al. (2003) A comparative efficacy study of Rosac® cream with sunscreens (sodium sulfacetamide 10% and sulfur 5%) and MetroCream® (metronidazole 0.75%) in the twice daily treatment of rosacea. Skin Aging Oct (Suppl), 17–22. 11 Baldwin HE. (2007) Systemic therapy for rosacea. Skin Ther Lett 12, 1–5; 9. 12 Bikowski JB, Goldman MP. (2004) Rosacea: where are we now? J Drugs Dermatol 3, 251–61. 13 Kolbe L, Immeyer J, Batzer J, Wensorra U, tom Dieke K, Mundt C, et al. (2006) Anti-inflammatory efficacy of licochalcone A: correlation of clinical potency and in vitro effects. Arch Dermatol Res 298, 23–30. 14 Weber TM, Ceilley RI, Buerger A, Kolbe L, Trookman NS, Rizer RL, et al. (2006) Skin tolerance, efficacy, and quality of life of patients with red facial skin using a skin care regimen containing licochalcone A. J Cosmet Dermatol 5, 227–32. 15 Rigopoulos D, Kalogeromitros D, Gregoriou S, Pacouret JM, Koch C, Fisher N, et al. (2005) Randomized placebo-controlled trial of a flavonoid-rich plant extract-based cream in the treatment of rosacea. J Eur Acad Dermatol Venereol 19, 564–8. 16 Tung RC, Bergfeld WF, Vidimos AT, Remzi BK. (2000) Alphahydroxy acid-based cosmetic procedures: guidelines for patient management. Am J Clin Dermatol 1, 81–8. 17 Draelos ZD, Green BA, Edison BL. (2006) An evaluation of a polyhydroxy acid skin care regimen in combination with azelaic acid 15% gel in rosacea patients. J Cosmet Dermatol 5, 23–9.

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Chapter 62: Eczema regimens Zoe D. Draelos Consulting Professor, Department of Dermatology, Duke University School of Medicine Durham, NC, USA

BAS I C CONCE P T S • Dry skin affected by eczema is characterized by loss of intercellular lipids which results in barrier deficits. • Moisturizers are an important part of eczema treatment as they provide an environment optimal for barrier repair. • Moisturizers function by impeding transepidermal water loss with oily occlusive substances, such as petrolatum, mineral oil, vegetable oils, and dimethicone, and by attracting water to the dehydrated stratum corneum and epidermis with humectants, such as glycerin, sodium PCA, propylene glycol, lactic acid, and urea. • Moisturizing ingredients can be delivered to the skin surface by emulsions, liposomes, and niosomes. • Careful moisturizer selection is key to the treatment and prevention of eczematous skin disease.

Introduction Eczematous skin disease is one of the most commonly treated dermatologic conditions. While topical prescription corticosteroids and calcineurin inhibitors are the mainstay of therapy, cosmeceutical moisturizers are key to the treatment and prevention of disease. Moisturizers enhance the skin barrier, decreasing stinging and burning from a sensory standpoint and improving the look and feel of the skin. Moisturizers can also smooth desquamating corneocytes and fill corneocytes gaps to create the impression of tactile smoothness. This effect is temporary, of course, until the moisturizer is removed from the skin surface by wiping or cleansing. From a functional standpoint, moisturizers can create an optimal environment for healing and minimize the appearance of lines of dehydration by decreasing transepidermal water loss. Transepidermal water loss increases when the “brick and mortar” organization of the protein-rich corneocytes held together by intercellular lipids is damaged. A well-formulated cosmeceutical moisturizer can decrease the water loss until healing occurs.

the use of abrasive substances that induce stratum corneum exfoliation. In some cases, the barrier may be defective because of insufficient sebum production, inadequate intercellular lipids, or abnormal keratinocyte organization. The end result is the induction of the inflammatory cascade accompanied by erythema, desquamation, itching, stinging, burning, and possibly pain. The immediate goal of treatment is to stop the inflammation through the use of topical, oral, or injectable corticosteroids, depending on the severity of the eczema and the percent body surface area involved. In dermatology, topical corticosteroids are most frequently employed with low potency corticosteroids (desonide) used on the face and intertrigenous areas, medium potency corticosteroids (triamcinolone) on the upper chest and arms, high potency corticosteroids (fluocinonide) on the legs and back, and ultra high potency corticosteroids (clobetasol) used on the hands and feet. Newer topical options for the treatment of eczema-induced sensitive skin include the calcineurin inhibitors, pimecrolimus, and tracrolimus. However, the resolution of the inflammation is not sufficient for the treatment of eczema. Proper skin care must also be instituted to minimize the return of the conditions that led to the onset of eczema.

Etiology Moisturizer mechanism of action Eczema is characterized by barrier disruption, which is the most common cause of sensitive skin. The barrier can be disrupted chemically through the use of cleansers and cosmetics that remove intercellular lipids or physically through

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Moisturizers are incorporated into eczema treatment regimens to reduce transepidermal water loss. There are three cosmeceutical ingredient categories that can reduce transepidermal water loss: occlusives, humectants, and hydrophilic matrices [1]. The most common method for reducing transepidermal water loss is the application of an occlusive ingredient to the skin surface. These are oily sub-

62. Eczema regimens

Table 62.1 Occlusive moisturizing ingredients to inhibit transepidermal water loss. 1. Hydrocarbon oils and waxes: petrolatum, mineral oil, paraffin, squalene 2. Silicone oils 3. Vegetable and animal fats 4. Fatty acids: lanolin acid, stearic acid 5. Fatty alcohol: lanolin alcohol, cetyl alcohol 6. Polyhydric alcohols: propylene glycol 7. Wax esters: lanolin, beeswax, stearyl stearate 8. Vegetable waxes: carnauba, candelilla 9. Phospholipids: lecithin 10. Sterols: cholesterol

stances that create a barrier to water evaporation. The more commonly used occlusive ingredients in current formulations and their chemical category are listed in Table 62.1 [2]. The most popular and effective occlusive ingredient is time-tested petrolatum, which blocks 99% of water loss from the skin surface [3]. This remaining 1% transepidermal water loss is necessary to provide the cellular message for barrier repair initiation. If the transepidermal water loss is completely halted, the removal of the occlusion results in failure to repair the barrier and water loss quickly resumes at its preapplication level. Thus, the occlusion does not initiate barrier repair [4]. Petrolatum does not function as an impermeable barrier, rather it permeates throughout the interstices of the stratum corneum allowing barrier function to be re-established [5]. Moisturizers for eczematous disease must contain several occlusive moisturizing ingredients. In addition to occlusive ingredients, a therapeutic moisturizer for eczema must contain humectants. Humectants are substances that attract water to the viable epidermis and stratum corneum from the dermis. They function as a sponge to hold and release water as necessary. Examples of humectants include glycerin, honey, sodium lactate, urea, propylene glycol, sorbitol, pyrrolidone carboxylic acid, gelatin, hyaluronic acid, vitamins, and some proteins [2,6]. Humectants only draw water from the environment when the ambient humidity exceeds 70%. In environmentally controlled spaces, this does not occur, thus humectants pull water from the deeper epidermal and dermal tissues to rehydrate the stratum corneum. A therapeutic moisturizer for eczema must trap the water in the skin with an occlusive film placed on top of the stratum corneum [7]. Humectants also allow the skin to feel smoother by filling holes in the stratum corneum through swelling [8,9]. Therefore, a moisturizer recommended for eczema must combine both occlusive and humectant ingredients for optimal efficacy and patient esthetics. Occlusive and humectant moisturizers are the formulations most beneficial in the treatment of eczema and include the majority of those found in the dermatologic

sample closet (Eucerin Cream and Lotion, Beiersdorf; Norwegian Formula Moisturizers, Neutrogena; Aveeno Cream and Lotion, Johnson & Johnson; Olay Daily Facial Moisturizer, Procter & Gamble, Plentitude, L’Oréal; Cetaphil Cream and Lotion, Galderma; CeraVe Cream and Lotion, Coria). A third type of moisturizing formulation is known as the hydrophilic matrix. Hydrophilic matrices are large molecular weight substances that create a film over the skin surface thereby retarding water evaporation. The first hydrophilic matrix developed was an oatmeal bath (Aveeno Oatmeal Bath, Johnson & Johnson). The colloidal oatmeal created a film that prevented water from leaving the skin to enter the bath water. Newer hydrophilic matrices include peptides and proteins, but they do not provide meaningful skin moisturization in the eczema patient.

Moisturizer goals in eczema The goal of all moisturizing emulsions is to accomplish skin remoisturization, which occurs in four steps: initiation of barrier repair, alteration of surface cutaneous moisture partition coefficient, onset of dermal–epidermal moisture diffusion, and synthesis of intercellular lipids [10]. These steps must occur sequentially in order for proper skin barrier repair. Once the barrier has repaired, there must be some substance that holds and regulates the skin water content. This substance has been termed the natural moisturizing factor (NMF). The constituents of the NMF have been theorized to consist of a mixture of amino acids, derivatives of amino acids, and salts. Artificially synthesized NMF has been constructed from amino acids, pyrrolidone carboxylic acid, lactate, urea, ammonia, uric acid, glucosamine, creatinine, citrate, sodium, potassium, calcium, magnesium, phosphate, chlorine, sugar, organic acids, and peptides [11]. Ten percent of the dry weight of the stratum corneum cells is composed of NMF in well-hydrated skin [12]. Cosmeceutical moisturizing emulsions try to duplicate the effect of the NMF.

Moisturizer delivery systems Another method for optimizing the ability of moisturizers to create an environment for healing in eczema patients is through novel delivery of the ingredients. This has led to the development of delivery systems that can time release substances onto the skin surface and improve product esthetics. For example, petrolatum is the most effective ingredient for skin healing, yet it leaves an easily removed, sticky, greasy film on the skin surface. A delivery system could allow small amounts of petrolatum to be released onto the skin surface avoiding the esthetic drawbacks. Examples of delivery systems relevant to eczema treatment include emulsions,

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serums, liposomes, niosomes, multivesicular emulsions, and nanoemulsions.

Moisturizing emulsions Most moisturizers developed for the treatment of eczema are emulsions [13]. An emulsion is formed from oil and water mixed and held in solution by an emulsifier. Most emulsifiers are surfactants, or soaps, which dissolve the two nonmiscible ingredients. The most common emulsions are oil-in-water, where the oil is dissolved in the water [14]. This emulsion is the most popular among patients because the water evaporates leaving behind a thin film of oily ingredients. If the emulsion can be poured from a bottle, it is considered a lotion. These moisturizing products are popular for eczema treatment, but may make the eczema worse as the repeated wetting and drying of the skin results in further maceration. Cream oil-in-water emulsions are preferred because the environment created for barrier repair is far superior. Water-in-oil emulsions, where the water-soluble substances are dissolved in the oil-soluble substances, are less popular because of their greasy esthetics. Most ointments are water-in-oil emulsions, but they leave the skin feeling warm and sticky. Ointments deliver higher levels of moisturization because the water phase is small, leaving behind a proportionately larger concentration of ingredients capable of retarding transepidermal water loss. Even though their efficacy is greater, most eczema patients prefer more esthetic formulations.

Moisturizing serums A specialized form of emulsion is a serum. Serums are usually low viscosity, oil-in-water emulsions that deliver of

thin film of active ingredients to the skin surface. For example, a high concentration glycerin serum can be placed under a high concentration petrolatum oil-in-water emulsion to provide robust skin moisturization. Sometimes a serum will contain cosmeceutical barrier enhancing ingredients, such as ceramides, cholesterol, and free fatty acids.

Moisturizing liposomes and niosomes Moisturizing ingredients can be incorporated into structures with unique physical properties on the skin, such as liposomes and niosomes (Table 62.2). Liposomes are spherical vesicles with a diameter 25–5000 nm formed from membranes consisting of bilayer amphiphilic molecules, which possess both polar and non-polar ends. The polar heads are directed toward the inside of the vesicle and toward its outer surface while the non-polar, or lipophilic tails, are directed toward the middle of the bilayer. Liposomes are based on the natural structure of the cell membrane, which has been highly conserved through evolutionary change. The name is derived from the Greek word “lipid” meaning fat, and “soma” meaning body. Liposomes are primarily formed from phospholipids, such as phosphatidylcholine, but may also be composed of surfactants, such as dioleoylphosphatidylethanolamine. Their functionality may be influenced by chemical composition, vesicle size, shape, surface charge, lamellarity, and hom*ogeneity. The liposome is an extremely versatile structure. It can contain aqueous substances in its core, or nothing at all. Hydrophobic substances can dissolve in the phospholipid bilayer shell, which allows liposomes to deliver both oilsoluble and water-soluble substances without need for an emulsifier. Thus, the internal moisturizer payload plus the phospholipid membrane can both function as moisturizers.

Table 62.2 Special moisturizer delivery systems. Delivery system

Structure

Advantages vs. disadvantages

Liposomes

Spherical vesicles consisting of bilayer amphiphilic molecules with polar and non-polar ends

Can deliver hydrophilic and hydrophobic substances to the skin surface without an emulsifier

Multivesicular emulsion (MVE)

Liposome within a liposome within a liposome to form concentric liposomes

Deliver multiple moisturizing ingredients (glycerin, dimethicone, sphingolipids, ceramides) simultaneously

Niosome

Liposome composed of non-ionic surfactants, such as ethoxylated fatty alcohols and synthetic polyglycerol ethers

Non-ionic surfactants do not moisturize the skin surface

Nanoemulsions

Emulsions with 20–300 nm droplets

Allow enhanced skin penetration due to small droplet size

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62. Eczema regimens It is unlikely that liposomes diffuse across the stratum corneum barrier intact. The corneocytes are embedded in intercellular lipids, composed of ceramides, glycosylceramides, cholesterol, and fatty acids, which are structurally different from the phospholipids of the liposome. It is postulated that liposomes penetrate through the appendageal structures. They may also fuse with other bilayers, such as cell membranes, to release their ingredients. This is the mechanism by which liposomes can function as moisturizers, supplementing deficient intercellular lipids. Niosomes are a specialized form of liposome composed of non-ionic surfactants. These are detergents, such as ethoxylated fatty alcohols and synthetic polyglycerol ethers (polyoxyethylene alkylester, polyoxyethylene alkylether). These liposomes do not deliver the moisturizing phospholipids to the skin surface.

droplets of 70 nm are transparent. Nanoemulsions offer the ability to deliver highly hydrophobic or lipophilic substances into the skin, which could not otherwise penetrate. The stratum corneum is an excellent barrier to lipophilic ingredients. For example, new nanoemulsions of ubiquinone have been developed. Ubiquinone, also known as coenzyme Q10, is an important antioxidant manufactured by the body and found in all skin cells. It is found in both hydrophilic and hydrophobic cellular compartments, but topical delivery has been challenging. Nanoemulsions have successfully delivered higher concentrations of ubiquinone into the skin with the goal of enhancing the skin’s natural antioxidant capabilities, while leaving beyond a moisturizing film from the other ingredients in the emulsion.

Multivesicular emulsions

Developing a moisturizer regimen

Another variant of the liposome is a multivesicular emulsion (MVE) (Figure 62.1). The MVE is created through a physical mixing technique, which makes them more stable, but also less expensive to produce. An MVE can be thought of as a liposome within a liposome within a liposome. Thus, with the release of each liposome, additional moisturizing ingredients can be deposited on the skin surface. MVEs can deliver glycerin, dimethicone, sphingolipids, and ceramides to the skin surface simultaneously.

Moisturizing nanoemulsions Nanoemulsions are similar to regular emulsions with an oilloving hydrophobic phase and a water-loving hydrophilic, except droplets in these emulsions are on the nano scale of 20–300 nm [15]. If the nano droplets are larger than 100 nm, the emulsion appears white, while nanoemulsions with

This chapter has discussed the goals of moisturization, the various types of moisturizers, and some of the unique moisturizer delivery systems. The biggest challenge for the clinician is adding moisturizers or combining moisturizers as part of a treatment regimen. Patients with eczema require basic hygiene. The face and body must be cleansed. There is no doubt that the synthetic detergent cleansers, also known as syndets, provide the best skin cleansing while minimizing barrier damage. Bars based on sodium cocyl isethionate appear to perform the best (Dove, Unilever; Olay, Procter & Gamble). There are some patients, however, who only require the use of a facial syndet cleanser occasionally, because sebum production and physical activity are minimal. For these patients, a lipid-free cleanser is preferable because it can be used without water

Ceramides

Hyaluronic acid

Phytoshingosine

Glycerin

Dimethicone

Oil Figure 62.1 A multivesicular emulsion can dissolve many ingredients in the concentric lipsomes.

Water

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and wiped away (Cetaphil, Galderma; CerVe, Coria). These products may contain water, glycerin, cetyl alcohol, stearyl alcohol, sodium laurel sulfate, and occasionally propylene glycol. They leave behind a thin moisturizing film and can be used effectively in persons with excessively dry, sensitive, or dermatitic skin. They do not have strong antibacterial properties, however, and may not remove odor from the armpit or groin. Lipid-free cleansers are best used where minimal cleansing is desired. After completing cleansing, the eczema patient requires moisturization. The moisturizer should create an optimal environment for barrier repair, while not inducing any type of skin reaction. For example, the product should not contain any mild irritants that may present as an acneiform eruption in the eczema patient because of the presence of follicular irritant contact dermatitis. The best moisturizers are simple oil-in-water emulsions. The morning moisturizer should provide SPF 30 photoprotection. A variety of sunscreen-containing moisturizers are on the market for this purpose (Olay Complete Defense SPF 30, Procter & Gamble; Neutrogena Daily Defense SPF 30, Johnson & Johnson). If additional hydration is required, a moisturizer can be applied to the face followed by a second sunscreen-containing moisturizer on top. It is possible to layer moisturizers for additive benefit. The sunscreen-containing moisturizer should be applied last, as it does not need to touch the skin to provide optimal photoprotection. The evening moisturizer provides the best opportunity for barrier repair, because the body is at rest. The best ingredient for barrier repair is white petrolatum, but dimethicone and cyclomethicone are commonly added to decrease the greasiness of a simple petrolatum and water formulation. Basic night creams containing these ingredients, in addition to glycerin, are the mainstay of therapeutic eczema moisturizers. It is important to remember that fewer ingredients are preferred, because more ingredient exposure creates added opportunities for sensitization or an adverse event.

Conclusions Eczema treatment requires the use of prescription medications in conjunction with skincare products. Both must be

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judiciously selected to insure optimal results. Thorough resolution of eczema requires alleviation of the disease, the treatment phase, and prevention of recurrence, the maintenance phase. This chapter has discussed those concepts that are key to designing a maintenance phase regimen for eczema patients.

References 1 Baker CG. (1987) Moisturization: new methods to support time proven ingredients. Cosmet Toilet 102, 99–102. 2 De Groot AC, Weyland JW, Nater JP. (1994) Unwanted Effects of Cosmetics and Drugs Used in Dermatology, 3rd edn. Amsterdam: Elsevier, pp. 498–500. 3 Friberg SE, Ma Z. (1993) Stratum corneum lipids, petrolatum and white oils. Cosmet Toilet 107, 55–9. 4 Grubauer G, Feingold KR, Elias PM. (1987) Relationship of epidermal lipogenesis to cutaneous barrier function. J Lipid Res 28, 746–52. 5 Ghadially R, Halkier-Sorensen L, Elias PM. (1992) Effects of petrolatum on stratum corneum structure and function. J Am Acad Dermatol 26, 387–96. 6 Spencer TS. (1988) Dry skin and skin moisturizers. Clin Dermatol 6, 24–8. 7 Rieger MM, Deem DE. (1974) Skin moisturizers II .The effects of cosmetic ingredients on human stratum corneum. J Soc Cosmet Chem 25, 253–62. 8 Robbins CR, Fernee KM. (1983) Some observations on the swelling of human epidermal membrane. J Sos Cosmet Chem 37, 21–34. 9 Idson B. (1992) Dry skin: moisturizing and emolliency. Cosmet Toilet 107, 69–78. 10 Jackson EM. (1992) Moisturizers: What’s in them? How do they work? Am J Contact Derm 3, 162–8. 11 Wehr RF, Krochmal L. (1987) Considerations in selecting a moisturizer. Cutis 39, 512–5. 12 Rawlings AV, Scott IR, Harding CR, Bowser PA. (1994) Stratum corneum moisturization at the molecular level. Prog Dermatol 28, 1–12. 13 Chanchal D, Swarnlata S. (2008) Novel approaches in herbal cosmetics. J Cosmet Dermatol 7, 89–95. 14 Carlotti ME, Gallarate M, Rossatto V. (2003) O/W microemulsions as a vehicle for sunscreen. J Cosmet Sci 54, 451–62. 15 Kaur IP, Agrawal R. (2007) Nanotechnology: a new paradigm in cosmeceuticals. Recent Pat Drug Deliv Formul 1, 171–82.

Chapter 63: Psoriasis regimens Steven R. Feldman1,2,3 and Lindsay C. Strowd1 Center for Dermatology Research, Departments of Dermatology,1Pathology,2and Public Health Sciences,3 Wake Forest University School of Medicine, Winston-Salem, NC, USA

BAS I C CONCEPTS • Psoriasis is a common condition that can be treated with a variety of over-the-counter skincare products. • Over-the-counter skincare products helpful for the treatment of psoriasis include moisturizers, keratolytics, tar, hydrocortisone, salicylic acid, and tanning booth radiation exposure. • Compliance is key in psoriasis therapy, which may be encouraged by over-the-counter skincare products. • Over-the-counter skincare products can be combined with prescription medications for optimal treatment.

Introduction Psoriasis affects an estimated 7.5 million people in the USA and 125 million worldwide. Men and women are affected equally. The disease may occur at any age, most frequently starts in the late teens and early twenties, and is most prevalent in the third through fifth decades of life. Caucasians are twice as likely as African-Americans to be diagnosed with psoriasis [1]. The etiology of psoriasis is not yet fully characterized. There is tremendous variation in individual’s disease presentation and response to treatment, adding to the complexity of psoriasis treatment. Most patients with psoriasis have limited, or so-called “mild,” disease, covering less than 3% of total body surface area [2]. However, the disease burden does not correlate closely with the extent of disease, and even patients with limited areas of psoriasis can experience significant psychosocial stress and depression [3,4]. Only about 1 in 6 people with psoriasis sees a doctor for their disease in any given year. The remaining patients with psoriasis do not seek treatment by a dermatologist. They may be untreated, or they may self-treat with a variety of over-the-counter (OTC) medications. The poor quality of life seen in patients with psoriasis is in part brought about by the cutaneous manifestations of the disease and the treatment regimens. Patients claim physical appearance to be a large negative factor in quality of life. The concern over physical appearance increases as the extent of disease spreads. The treatment regimens can also negatively impact quality of life, as they often require mul-

tiple daily applications, come in messy, greasy vehicles, and can be very expensive. This chapter focuses on the role of OTC medications in psoriasis and describes strengths and weaknesses of different OTC products. We briefly discuss the role of OTC medications as part of a combination treatment regimen. Patient compliance is a major factor affecting the effectiveness of psoriasis treatments, and we discuss the future development of OTC medications.

Physiology Psoriasis is a multifactorial, inherited condition, involving genetics, immune system alterations, and environmental factors. Normal keratinocytes remain in the epidermis for 300 hours, but psoriasis keratinocytes only remain in the epidermis for 36 hours. This shortening of the keratinocyte life cycle is associated with an increased proliferation of keratinocytes and subsequent plaque formation [5]. The pathophysiology behind the shortened keratinocyte life cycle is brought about, at least in part, by a complex immune reaction. This cascade is largely driven by helper T cells and their release of cytokines and tumor necrosis factor α (TNFα) into the dermis. The presence of cytokines in the dermis triggers infiltration and activation of both polymorphonuclear and mononuclear leukocytes [6]. Many different cytokines have been found in the dermis and epidermis of psoriatic skin, including interleukins IL-4, IL-6, IL-12, IL-23, and transforming growth factor β (TGF-β) [5]. The roles of each of these cytokines have yet to be fully understood. Genetics impacts psoriasis, as up to 70% of identical twins both develop this disease [7]. Psoriasis has been associated with certain HLA genotypes, and recently researchers have identified a psoriasis risk allele PSORS1 that codes for HLA-

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Cw6 genotype [8]. However, no single allele can be called the “psoriasis gene” because there are multiple alleles that contribute to the inheritance and risk of developing psoriasis. There are at least seven other genetic loci that have also been identified as psoriasis risk alleles [7]. Complex inherited diseases such as psoriasis require large studies of many affected families in order to begin to identify all the possible genetic loci, a task that has been difficult to achieve. While there is still much debate about the affect of stress on psoriasis, many retrospective studies have found a correlation between stress and psoriasis flares [9,10]. At baseline, patients with psoriasis have high stress levels and poor quality of life [11]. Up to 80% of patients with psoriasis report that a stressful event triggered a flare during the course of their disease. Most of these stress-related flares occur within 2 weeks of the stressful event [12]. Obesity is a risk factor both for developing psoriasis and for increased severity of psoriasis [13]. Streptococcal type A infections have also been reported to cause psoriasis outbreaks. The link between streptococcal infections and psoriasis has been extensively researched, but no single hypothesis has emerged. Some theories posit there exists molecular mimicry between streptococcal antigens and keratinocytes, while other theories blame bacterial superantigens [5]. These genetic, biologic, and environmental factors combine to create the “perfect storm” of psoriasis. The shortened keratinocyte life cycle results in thick scales that accumulate on the surface of the skin. The inflammatory infiltrates cause dysfunction of the skin’s natural barrier. Inflammatory cytokines cause vascular capillary dilatation which results in skin erythema and helps perpetuate the inflammatory process [14]. The end result is dry, cracked, inflamed plaques that can be both painful and pruritic.

Role of OTC medications Psoriasis education The first step in any psoriasis treatment regimen is education. Empowering patients with knowledge about their disease allows them to make informed decisions about their care and creates realistic expectations for treatment outcomes. The National Psoriasis Foundation is a great resource for patients. Foundation members feel more satisfied with their treatment and have less disease burden. The Foundation’s website has an OTC treatment guide that provides information on many products commonly used for psoriasis. The site also provides information to help patients screen out non-prescription remedies that are touted for their efficacy but which are at best unproven.

Role in self-treating vs. dermatology patients Patients who self-treat their psoriasis tend to have mild disease and can achieve a measure of control with OTC

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medications alone. For these patients OTC medications provide symptom relief (reduced pruritus) or improve the skin’s cosmetic appearance [15]. Based on their experiences, some dermatologists may feel OTC medications have little efficacy; such an impression may be based on seeing only the patients who have failed to adequately control their disease with OTC medications. People who do achieve adequate control with OTCs alone would be less likely to feel the need to visit a dermatologist. For those patients who do visit a dermatologist for prescription treatment, OTC medications may still have an important role in reducing symptoms and improving appearance. Additionally, OTC medications such as moisturizers and keratolytics can serve to increase the efficacy of prescription topical corticosteroids and phototherapy.

OTC products recommended by physicians The National Ambulatory Care Survey (NAMCS) provides a representative snapshopt of psoriasis treatment in the USA. Through this survey, prescription and OTC medications prescribed by dermatologists and non-dermatologists are tabulated each year. OTC treatment options for psoriasis are estimated to cost $500 million and to account for 40% of all psoriasis-related expenditures [16]. The NAMCS provides data on the OTC psoriasis treatments most commonly prescribed by physicians. We looked at NAMCS data from 1986 to 2005 and identified the most common OTC prescriptions for psoriasis in each of four 5-year periods. The most popular classes of OTC medications were hydrocortisone and keratolytics. These were followed by moisturizers and tar (Figure 63.1). When the keratolytics were broken down into individual types, salicylic acid, lactic acid, and urea were the three most commonly prescribed keratolytics (Figure 63.2). Urea was the least commonly prescribed keratolytic. While the prescription frequency of tar, urea, and lactic acid have remained relatively constant over time, salicylic acid and moisturizers show a recent increase in prescription. In contrast, OTC hydrocortisone has dropped in prescription frequency in recent years.

Compliance in psoriasis treatment Psoriasis patients are among the worst in terms of compliance with treatment regimens [17]. They have levels of depression and anxiety that are higher than other patients with dermatologic disease [3]. Depression and disease burden can negatively affect the patients’ ability to adhere to treatment. Adherence to topical medications is worse than adherence to oral medications, with the number of daily applications, the chronicity of treatment, and the complexity of the treatment regimen affecting overall compliance [18]. Topicals have traditionally been messy, greasy, and generally unappealing from a cosmetic perspective. When choosing a topical preparation for a patient, that particular patient’s

63. Psoriasis regimens

Figure 63.1 Over-the-counter (OTC) psoriasis medications prescribed by physicians 1986–2005. National Ambulatory Care Survey (NAMCS) data was used to find the prescription frequency of OTC medications prescribed by both dermatologists and non-dermatologists. Yearly data was then grouped in four 5-year time periods. OTC medications were grouped in hydrocortisone, keratolytics, moisturizers, and tar preparations.

Prescription frequency (000)

700 000 600 000 500 000 Hydrocortisone Keratolytics Moisturizers Tar

400 000 300 000 200 000 100 000 0 1986–1990 1991–1995 1996–2000 2001–2005 Time period

Figure 63.2 Over-the-counter (OTC) psoriasis medications prescribed by physicians 1986–2005. National Ambulatory Care Survey (NAMCS) data was used to find the prescription frequency of OTC medications prescribed by both dermatologists and non-dermatologists. Yearly data was then grouped in four 5-year time periods. OTC medications analyzed included hydrocortisone, salicylic acid, lactic acid, urea, moisturizers, and tar preparations.

Prescription frequency (000)

600 000 500 000 400 000

Hydrocortisone Salicylic acid Urea Lactic acid Moisturizer Tar

300 000 200 000 100 000

preferences are critical to consider. While ointments may be said to be more efficacious for psoriasis, they will not be efficacious for patients who find them too messy to use. OTC medications allow patients access to a wide variety of treatment options at relatively low cost. Patients can try out different vehicles and different combinations of products to achieve the best improvement. OTC products give patients the independence to experiment with products until they find one they prefer, rather than having to go through a dermatologist every time they want to switch products or try something new.

Moisturizers and keratolytics Dry skin is often a sign of poor barrier function, as is the case in psoriasis. Symptoms of psoriasis include scaling, itching, and increased sensitivity. Moisturizers can improve the skin’s hydration in two ways. First, the hydrophobic emollients such as petrolatum provide occlusive benefits, meaning they create a physical layer of protection on the surface of the skin which acts to slow epidermal water loss. Second, hydrophilic emollients such as glycerine provide humectant benefits, meaning they attract moisture from the

0 1986–1990 1991–1995 1996–2000 2001–2005 Time period

air and help skin preserve its water content. Some moisturizers only contain either hydrophobic or hydrophilic elements, but most contain both compounds. The net effect of this increase in moisture on psoriatic skin is a decrease in appearance of scale. Factors such as number of applications and thickness of the applied layer impact success. Moisturizers can often make scale completely invisible by changing the refractive index of scale so less light is reflected. Keratolytics differ from moisturizers in that they actually dissolve the scales on the skin’s surface. Keratolytics help decrease the thickness of the hyperkeratotic plaque from the top surface inward by softening the scaly layers allowing for easy removal [19]. Salicylic acid comes in a wide variety of vehicles from shampoo to gels to creams. OTC concentrations approved for psoriasis use range 1–3%. OTC concentrations exist up to 6%, but concentrations above 3% have not been FDA approved for psoriasis [20]. OTC lactic acid products come in 5–12% concentrations. Other OTC keratolytics include phenol (which is often used in scalp preparations) and urea products. OTC urea preparations range 10–25% in concentration and typically are sold as lotions or creams [20]. Keratolytics such as these can be found OTC in single preparations or in OTC combinations with a moisturizer. Combination products allow the scale to be camou-

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flaged by moisturizer as the keratolytics gradually thin the psoriatic plaques. Keratolytics can cause irritant contact dermatitis secondary to their acidic nature. Therefore it is important for patients to find a keratolytic product with a potency that is effective but minimizes irritation.

Tar Tar is one of the oldest treatments for psoriasis, but its exact mechanism of action remains unknown. Tar is believed to exert anti-inflammatory and antimitotic effects on psoriasis skin. It also has antipruritic effects that can provide a great deal of symptom relief [21]. Tar is developed from coal or wood and can be sold as crude or refined tar products. Most tar products for psoriasis treatment are coal tar products, and are available OTC in concentrations of 0.5–5%. OTC formulations are varied and include shampoos, soaps, lotions, creams, and ointments [20]. Tar shampoos and ointments can be very helpful in the treatment of scalp psoriasis [22]. There are several disadvantages to tar products that prevent them from being used more commonly to treat psoriasis. Traditional tar preparations have been messy, malodorous, and stain skin and clothing. This is especially true of crude tar products. Newer products that use refined tar have tried to minimize these unwanted side effects, increasing the esthetic appeal of tar topicals while maintaining the desired efficacy [22,23]. Despite improvements in the vehicle and odor, patient compliance with tar products may be poor. Tar can also cause unwanted skin reactions such as contact irritation and folliculitis, further decreasing patient compliance. Another component of tar therapy that affects patient use is the fear of its carcinogenic properties. While there is no clear evidence showing an increased risk of cancer in humans, several animal studies have demonstrated an increased risk of cancer with topical tar application [24]. All OTC tar products are covered by an FDA monograph that permits marketing and sales of tar products of certain concentrations for an indication of psoriasis [25]. Other ingredients that are generally regarded as safe may also be in the product. Thus, companies can create and market many different products and claim they are effective for psoriasis as long as the product contains the appropriate concentration of tar. Companies can create all manners of fruit and vegetable extracts and claim their product is FDA approved for the treatment of psoriasis by incorporating tar into the product.

Hydrocortisone Topical hydrocortisone cream is available OTC in 0.5% and 1% concentrations and is a low-potency corticosteroid with

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anti-inflammatory and anti-itch properties. In a survey conducted by the National Psoriasis Foundation, psoriasis patients named “scaling,” “itching,” and “skin redness” as their most common symptoms [26]. Topical corticosteroids help relieve these symptoms. Despite their low potency, OTC hydrocortisone treatments can have an important role in psoriasis management. A benefit of low-potency OTC hydrocortisone is that psoriasis patients can use this corticosteroid to self-treat more sensitive areas of their skin, such as the face, axilla, and genital area.

UV light therapy Phototherapy has been a mainstay treatment for psoriasis for millenia. Up until the 1990s, broad-spectrum UVB was the treatment of choice. More recently, narrowband (300– 313 nm) UVB boxes were introduced, as well as devices designed to provide localized therapy to individual lesions [27]. The addition of PUVA (psoralen and UVA) therapy for severe psoriasis in the 1990s further expanded the use of phototherapy for psoriasis [28]. Many patients with psoriasis realize the benefit of UV exposure before any prescription phototherapy is used, through the seasonal variation in their psoriasis and the beneficial effect of outdoor (and sometimes indoor) tanning on their disease. Benefits of non-prescription phototherapy over prescription phototherapy include greater convenience and lower cost, albeit at the expense of less control over dosimetry. Prescription phototherapy requires patients to travel to the dermatologist’s office anywhere from three to five times a week to receive UV treatments. This can be costly and inconvenient to patients, which compromises the overall benefit and accessibility of the treatment. Sun exposure is the least costly way to obtain phototherapy for psoriasis, although it may be inconvenient or inaccessible (depending on geography). Dosimetry is difficult to control. Commercial tanning beds provide another phototherapy option. Although these devices radiate mostly UVA light, the most widely used commercial tanning bulbs have about 5% of the output that is in the UVB range and this may contribute to tanning bed efficacy. Some dermatologists discourage use of tanning beds for treating psoriasis because of the potential and poorly defined risk of skin cancer and premature aging. However, tanning beds can be an option for psoriasis patients who cannot afford or who do not have access to home or dermatologist-administered UVB therapies. Some dermatologists may not think tanning beds are effective based on their experiences with patients who have tried tanning and seen no benefit. Dermatologists should keep in mind that the people who tried tanning and did find it to be effective for clearing their psoriasis may not come to the dermatologist.

63. Psoriasis regimens If tanning bed use is recommended by a dermatologist for a particular patient, guidance for use should be provided and realistic expectations about length of time until improvement should be set. Most patients will require multiple tanning sessions over several weeks before seeing improvement in their skin. To help control the dosimetry, patients should use the same tanning bed for each exposure (not switching between tanning establishments or between beds within a single establishment). Tanning bed operators are familiar with their equipment and will likely recommend a safe starting dose, but starting with half that dose may provide a greater degree of safety, particularly if the tanning bed is used in conjunction with oral retinoid treatment (tanning beds should not be used in conjunction with psoralen as life-threatening burns may result). Sunscreen or protective clothing can be recommended to protect unaffected skin, and eye protection should be worn. These measures help patients avoid burning their skin and minimize the risk of developing skin cancer or cataracts [1]. Psoriasis patients may inquire if OTC tanning is safe to use with other psoriasis medications. Topical corticosteroids are safe to use with phototherapy and may even enhance the UV light’s effect by thinning the psoriatic plaques, although there is concern that corticosteroids reduce the remission periods associated with phototherapy. Systemic retinoids are not only safe to use with phototherapy, they are frequently prescribed in combination with phototherapy because they can improve the efficacy of phototherapy [29]. While methotrexate is safe to use with phototherapy, cyclosporine should not be used with UVB therapy [30]. UV therapy may inactivate topical calcipotriol, so it is recommended for patients to apply calcipotriol after, rather than before, phototherapy sessions [30,31].

Combination regimens Most psoriasis treatment regimens do not rely on only one drug to treat psoriasis effectively. Specific combinations of therapies often produce the best results with the least side effects. The caution with combination treatment regimens is that overly complex regimens can confuse and discourage patients and negatively affect treatment adherence. The goal of a dermatologist should be to develop a streamlined regimen that focuses on the individual patient’s treatment goals and lifestyle. OTC medications have a large role in combination psoriasis therapies. Keratolytics are used to enhance the ability of topical corticosteroids to penetrate the epidermis and target dermal inflammation. Topical corticosteroids can penetrate skin two to three times better with keratolytics than without. This results in better relief of symptoms such as scaling and pruritus [19]. Keratolytics have similar effects with tar prod-

ucts and UV phototherapy. Moisturizers can also enhance the efficacy of topical corticosteroids [32]. When prescribing such combination regimens, however, it is essential to consider that complicating the regimen may reduce treatment adherence, resulting in the loss of any potential gains expected from increased penetration. The classic psoriasis combination therapy is the Goeckerman treatment, which combines topical coal tar and UVB phototherapy. This combination’s success was first described by Dr. Goeckerman in 1925, and continues to be one of the most effective psoriasis treatments in use today. The Goeckerman treatment can induce remission even when the most technologically advanced regimens such as biologics fail [33]. Goeckerman treatment is typically administered by a dermatologist in the inpatient or specialized outpatient psoriasis treatment center. Patients can attempt to mimic the effects of Goeckerman by using outdoor or indoor UV therapy followed by prolonged OTC tar ointment used under plastic wrap or sauna suit occlusion.

Conclusions OTC medications play a large part in the treatment regimen of self-treating patients and those managed by a dermatologist. For the vast majority of people with psoriasis who choose to self-treat their disease, OTC medications provide relief of symptoms such as pruritus, erythema, and dry skin as well as effectively controlling plaque formation. For the minority of patients who require a dermatologist, OTC medications still provide a degree of symptom relief, and are commonly used in combination with prescription medications. The NAMCS data show that dermatologists prescribe OTC hydrocortisone, keratolytics, and moisturizers to supplement prescription psoriasis therapies. The large percentage of psoriasis patients who rely on OTC medications continues to drive the production of new and improved OTC products. New moisturizers are constantly being developed to increase skin’s hydration, and new keratolytics seek to improve the appearance of hyperkeratotic plaques while minimizing skin irritation. Improved vehicles such as foams and sprays for OTC corticosteroids are being developed to increase efficacy and make them more attractive to patients. New tar extracts and derivatives are designed to be less messy and smelly than their older counterparts; by increasing patient adherence such treatments may offer improved efficacy outcomes. Future trends in OTC psoriasis medications can be considered in two different populations. In those people who entirely self-treat and do not see a dermatologist, there will probably be a continued increase in the use of products such as moisturizers, keratolytics, and tar as the products continue to improve. In patients who see a dermatologist, there

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may be a decrease in some OTC use of medications such as keratolytics as more and more topical prescriptions are switching to combination topical products that contain a prescription drug along with an OTC drug. An example of this would be a high-potency topical corticosteroid ointment that also contains salicylic acid. Prescription topicals are now available in new vehicles such as foams and sprays that reduce the messy application process. This movement towards multiple therapies in one product and improved prescription vehicles may result in a decrease in the prescription of OTC topical medications. Biologic agents have revolutionized treatment in a small population of psoriasis patients, inducing rapid and complete remission and thereby reducing their need for complicated combination regimens.

Funding/conflicts of interest The Center for Dermatology Research is supported by an educational grant from Galderma Laboratories, L.P. Dr. Feldman has received research, speaking, and/or consulting support from Galderma, Abbott Labs, Warner Chilcott, Aventis Pharmaceuticals, 3M, Connetics, Roche, Amgen, Biogen, and Genentech. Dr. Strowd has no conflicts of interest to disclose.

References 1 National Psoriasis Foundation. http://www.psoriasis.org. Accessed July 18, 2008. 2 Stern RS, Nijsten T, Feldman SR, Margolis DJ, Rolstad T. (2004) Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc 9, 136–9. 3 Evers AWM, Lu Y, Duller P, van der Valk PJ, Kraaimaat FW, van de Kerkhof PC. (2005) Common burden of chronic skin diseases? Contributors to psychological distress in adults with psoriasis and atopic dermatitis. Br J Dermatol 152, 1275–81. 4 Gupta MA, Gupta AK. (1998) Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 139, 846–50. 5 Nickoloff BJ, Qin JZ, Nestle FO. (2007) Immunopathogenesis of psoriasis. Clin Rev Allergy Immunol 33, 45–56. 6 Linden KG, Weinstein GD. (1999) Psoriasis: current perspectives with an emphasis on treatment. Am J Med 107, 595–605. 7 Valdimarsson H. (2007) The genetic basis of psoriasis. Clin Dermatol 25, 563–7. 8 Nair RP, Stuart PE, Nister I, Hiremagalore R, Chia NV, Jenisch J, et al. (2006) Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 78, 827–51. 9 Buske-Kirschbaum A, Kern S, Ebrecht M, Hellhammer DH. (2007) Altered distribution of leukocyte subsets and cytokine production in response to acute psychosocial stress in patients with psoriasis vulgaris. Brain Behav Immun 21, 92–9.

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10 Berg M, Svensson M, Brandberg M, Nordlind K. (2008) Psoriasis and stress: a prospective study. J Eur Acad Dermatol Venereol 22, 670–4. 11 Misery L, Thomas L, Jullien D, Cambazard F, Humbert P, Dehen L, et al. (2008) Comparative study of stress and quality of life in outpatients consulting for different dermatoses in five academic departments of dermatology. Eur J Dermatol 18, 412–5. 12 Kimyai-Asadi A, Usman A. (2001) The role of psychological stress in skin disease. J Cutan Med Surg 5, 140–5. 13 Azfar RS, Gelfand JM. (2008) Psoriasis and metabolic disease: epidemiology and pathophysiology. Curr Opin Rheumatol 20, 416–22. 14 Joshi R. (2004) Immunopathogenesis of psoriasis. Indian J Dermatol Venereol Leprol 70, 10–2. 15 Proksch E. (2008) The role of emollients in the management of diseases with chronic dry skin. Skin Pharmacol Physiol 21, 75–80. 16 Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E, et al. (2004) Burden of skin diseases. Available at http://www.sidnet.org/pdfs/Burden%20of%20Skin%20 Diseases%202004.pdf. 17 Storm A, Andersen SE, Benfeldt E, Serup J. (2008) One in three prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol 59, 27–33. 18 Carroll CL, Feldman SR, Camacho FT, Manuel JC, Balkrishnan R. (2004) Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial: commonly used methods of measuring adherence to topical therapy overestimate actual use. J Am Acad Dermatol 51, 212–6. 19 Koo J, Cuffie CA, Tanner DJ, Bressinck R, Cornell RC, DeVillez RL, et al. (1998) Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis: a multicenter study. Clin Ther 20, 283–91. 20 National Psoriasis Foundation Treatment Guide. http://psoriasis. org/treatment/guide/otc/. Accessed July 26, 2008. 21 Roelofzen JH, Aben KK, van der Valk PG, van Houtum JL, van de Kerkhof PC, Kiemeney LA. (2007) Coal tar in dermatology. J Dermatolog Treat 18, 329–34. 22 Dodd WA. (1993) Tars: their role in the treatment of psoriasis. Dermatol Clin 11, 131–5. 23 Mefford L. (2008) NeoStrata® announces the launch of Psorent™ Psoriasis Topical Treatment. http://www.reuters.com/ article/pressRelease/idUS169492+04-Feb-2008+PRN20080204. Accessed August 10, 2008. 24 van Schooten FJ, Godschalk R. (1996) Coal tar therapy. Is it carcinogenic? Drug Saf 15, 374–7. 25 Kessler DA. (1991) Food and Drug Administration. Dandruff, seborrheic dermatitis, and psoriasis drug products for over-the-counter human use: final monograph. Federal Register 56, 63554–63569. Available at http://www.fda.gov/cder/ otcmonographs/Dandruff&Seborrheic_Dermatitis&Psoriasis/ dandruff_seborrheic_dermatitis_psoriasis_FR_19911204.pdf. 26 Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. (2001) The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol 137, 280–4. 27 Stein KR, Pearce DJ, Feldman SR. (2008) Targeted UV therapy in the treatment of psoriasis. J Dermatolog Treat 19, 141–5.

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subsequent UV exposure. Photodermatol Photoimmunol Photomed 24, 16–8. 32 Ghali FE. (2005) Improved clinical outcomes with moisturization in dermatologic disease. Cutis 76 (Suppl), 13–8. 33 Soares TF, Davis MD. (2007) Success of Goeckerman treatment in two patients with psoriasis not responding to biological drugs. Arch Dermatol 143, 950–1.

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Index

Note: page numbers in italics refer to figures, those in bold refer to tables

Aα fibers 39, 41 Aβ fibers 39, 41 trigeminal nerve sensory nucleus 44 Aδ fibers 39, 41 dorsal horn entry 44 nociception 42 abdomen, liposuction indications 452–3 Ablative Affirm Carbon Dioxide resurfacing 396, 402 ABS nail tips 216, 217 acetaminophen 287 acetone artificial nail removal 219 nail polish remover 213 acids, strong 56–7 acne adhesive pads 492 alpha-hydroxyacids 490 antimicrobials 491 benzoyl peroxide 489–90, 491 beta-hydroxyacids 490–1 cleansing 488–9 cleansing brushes 492 cleansing cloths 491–2 electronic heating device 492 essential oils 492 gluconolactone 491 isotretinoin 493 lactobionic acid 491 mechanical treatments 492 microdermabrasion 420–1 mild cleansing 84–5, 86 nicotinamide 493 oral vitamins 492–3 over-the-counter treatments 488–93 polyhydroxyacids 491 retinoids 491 salicylic acid 490–1 scarring 426–7 scrubs 492 soaps 488–9 sulfur 491 syndet treatment 488–9 triclosan/triclocarban 491 vitamin A 493

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acneiform eruptions 57 acrylates 217 actinic keratoses, chemical peel 390, 391 activator protein 1 (AP-1) 16, 17, 19 activation by phenolic compounds 283 by retinoic acid receptors 483 corticosteroid mechanism of action 286, 287 MAP kinase signaling pathway 302 microdermabrasion effects 419 Active and Deep FX Lumenis fractionated carbon dioxide laser 396–8, 399, 400 procedures/technique 407 adhesive pads 492 advanced glycation endproducts (AGEs) 339 adverse reactions antiperspirants 154–5 artificial nails 219–20 calcium hydroxylapatite hand recontouring 477 collagen fillers 369–72 cosmetics 55 deodorants 154–5 hair permanent waving 245, 245, 246 nail cosmetic prostheses 219–20 nail grooming 203–4 aerosol sprays, sunscreen vehicles 147 afferent nerves, synapses 43–4 African hair 35, 264 pseudofolliculitis barbae 162 styling aids 263–4 African–American skin aging 31–2 ashy skin 92 self-perceived sensitive skin 24–5 UV irradiation 18 aging African-American skin 31–2 Asian skin 31–2 brow ptosis 31 Caucasian skin 31–2 chronic 13–14 cytokines 304–5 ethnic skin 31–2 face evaluation 362 facial tissue sagging 32

free radical theory 312–13 growth factors 304–5 hair 237–8 hands 473–9 Hispanic skin 32 inflammatory process 286 pathophysiology 409 physiology 302–5 reversal 304–6 see also antiaging products; photoaging; wrinkles alcohol hand sanitizers 108, 111 waterless cleansers 104 aldobionic acids 328 alexandrite laser, long pulsed 435 alkalis, strong 57 alkaloids, plant 272 allergens 56–60 IgE antibodies 60 self-perceived sensitive skin 23 allergic contact dermatitis 55–6 irritant contact dermatitis differential diagnosis 56 allergy/allergic reactions 58–60 antibacterials 111 bovine collagen 366 collagen fillers 60, 370–1 fragrances 111 hair dyes 59, 234 nail cosmetics 203, 204 sensitive skin 23 UV cured nail lacquer 212 Alloderm 364, 365 aloe 275–6 alpha-hydroxyacids (AHA) 327, 328, 329 acne treatment 490 antiaging 483, 486 antioxidant 329 chemical peels 377–8 peels 332–3, 500–1 rosacea 500–1 water binding 329 aluminium compounds, antiperspirants 152, 153 aluminium oxide, microdermabrasion 418 Alzheimer’s disease 154

Index amino acids definition 292 hair 238 protein chain 293 side chains 292, 293 5-aminolevulinic acid (5-ALA) 436 ammonium thioglycolate 250–1 anaesthetics, injectable 59 anagen phase of hair growth 157, 236, 433 anesthesia dermabrasion 428, 429 fractionated carbon dioxide laser resurfacing pretreatment 407 liposuction 450 neck 466–7 polylactic acid fillers 373 angiogenesis 19 antiaging products antioxidants 484–6 botanicals 274 coenzyme Q10 485, 486 cytokines 304–5, 307 ferulic acid with vitamins C and E 485, 486 genistein 486 hyaluronic acid fillers 352–5, 474 hydroxyacids 332, 483, 486 alpha-lipoic acid 485, 486 retinoic acid 483, 486 retinoids 483–4 selenium 485, 486 vitamin C 484, 486 with vitamin E 484–5 vitamin E 484, 486 see also botulinum entries; calcium hydroxylapatite; fillers; growth factors antiaging regimen 480–6 cleansing 480–1 exfoliation 481, 482 protection 481–3 sunscreens/UV light protection 481–3 treatments 483–6 vitamin C 325 see also photoaging antibacterials allergy 111 cleansers 480–1, 491 soap bars 79 antibiotics, rosacea treatment 499–500 antidandruff materials 117 antifungal agents, nail lacquer 209 anti-inflammatory agents 284–90 botanicals 289 cosmeceutical actives 289 topically applied 11 anti-inflammatory techniques, LED photomodulation 446–8

antimicrobial agents acne treatment 491 resistance 111–12 antioxidants 8, 281–4 antiaging 484–6 body washes 90 cell signaling pathways 282 enzymes 8 free radical damage protection 282 hydroxyacids 329–30 lipsticks 188 oral 281 partition coefficient value 284 peptides 294 photoaging prevention 19–20 potency assessment 282 retinoids 312–13 skin health 336 skin penetration 284 topical 11, 281 formulation 283–4 sun protection 482–3 topical formulation protection 52–3, 54 UV damage protection 337 combinations 338 product 53 vitamin C 281, 282, 283, 324 vitamin E 281, 282, 283, 325 topical formulation 284 antiperspirants 150–5 actives 152 adverse effects 154–5 aluminium compounds 152, 153 breast cancer 154–5 chemistry 153 crystal products 153 definition 152 delivery systems 153–4 formulation 153 sweating control 155 Wetness Inhibiting Performance 153 antiwrinkle performance, facial foundation effect measurement 173 apocrine glands 150, 151, 152 apoptosis photoaging 32 UV-induced 7–8 aquaporins 135–6, 137 arbutin 272 arms, liposuction indications 454–5 aromatic hydroxyacids 328–9 arrector pili muscle 157 Artecoll 366, 367 Artefill 366, 367 ascorbic acid see vitamin C ascorbyl phosphates 325 ashy skin, African–Americans 92 Asian hair 33–5, 264

Asian skin 18 aging 31–2 self-perceived sensitive skin 24, 25 aspartate proteases 7 aspirin 287 astaxanthin 338 atopic dermatitis body washes 92, 94 facial 128 mild cleansing 84, 85 moisturizer use 128 topical corticosteroids 128 Autologen 364, 365 avobenzone 147, 148 sunscreen 481, 482 azelaic acid 500, 501 B cells, corticosteroid prolonged use 287 bar cleansers 77–87, 104 barrier function microdermabrasion 418 panthenol effects 323 repair 506 see also epidermal barrier behenyl alcohol 126 benzoyl peroxide 489–90, 491 beta-hydroxyacids (BHA) 327–8, 329 acne treatment 490–1 antiaging 483, 486 antioxidant 329 water binding 329 betaines, facial cleansers 97 bionic acids 328, 329 biotin, brittle nails 203 black henna tattoos 234 black skin dermis 31 dyspigmentation 33 hyperpigmentation 33 irritant contact dermatitis 30 photoaging 33 transepidermal water loss 30 UVA protective factor 29 UVB protective factor 29 see also African–American skin blade shaving see shaving, blade bleaches allergic reactions 59 see also hair bleaches blepharopigmentation 194 body washes 88–94 antioxidants 90 ashy skin 92 atopic dermatitis 92, 94 chelating agents 90 cleansing ability 90 color 90 components 89–90 consumer understanding 90–1

515

Index exfoliation aids 90 fragrances 90 in-use performance 90–2 moisturization from 91–2, 93 moisturizing 88–91 people benefitting 92, 93, 94 regular 88 skin benefit agents 89–90 specialty 89 surfactants 89 syndets 89 types 88–9 water content 89 bombesin 295 botanicals 269–79 antiaging 274 anti-inflammatory 289 emollients 274 lighteners 276 photoprotection 276 studied 273 tighteners 276 Botox 342 advantages 343 complications 350–1 contraindications 344 disadvantages 343 indications 343–4 injection techniques 344, 345, 346–9 lower face treatment 348–9 side-effects 350–1 midface treatment 347 precautions 344 product stability 343 treatment sites 344, 345, 346–9 upper face treatment 344, 345, 346–7 side-effects 350 botulinum neurotoxin type A (BoNTA) 342–3 filler combination 349, 350 immunogenicity 350 upper face treatment 344, 345, 346–7 botulinum neurotoxin type B (BoNTB) 342 botulinum toxin 299, 342–51 allergic reactions 60 fractionated carbon dioxide laser resurfacing pretreatment 407 marginal mandibular branch of facial nerve damage 470 mechanism of action 343 physical characteristics 343 brain activation with self-perceived sensitive skin 25 thalamocortical afferents 44, 45 breast cancer, antiperspirants 154–5 breasts, liposuction 456 brighteners 276

516

bromelain 276 brow lift, lateral 347 brow ptosis 31 bruising Botox 349–50 collagen fillers 370 buffer salts, hair permanent waving 242 bunny lines 347–8 buttocks, liposuction indications 453–4 butyl methoxy dibenzoyl methane (BMDM) 147, 148 caffeine 276–7 calcineurin inhibitors 288 eczema treatment 502 calcitonin gene-related peptide (CGRP) 294–5 calcium gradient, stratum corneum 9 calcium hydroxylapatite 356–60 anaesthesia 359 areas for correction 357 complications 359 hand recontouring 473–9 adverse events 477 injection technique 474–7 lidocaine 474–5, 478–9 post-injection hand massage 475–6 post-treatment care 476–7 results 477, 478 indications 356–7, 358, 359 microspheres 356, 357, 474 pharmacology 356 physical properties 356 techniques 356–7, 358, 359 camouflage makeup 176–83 application 176–8 color matching 177 definition 176 goals 176 indications for 179 melasma 180 neutralizers 177 periorbital hyperpigmentation 179 postsurgical scars 179 quality of life 182–3 removal 178 skin matching 177 telangiectasia 182 texture abnormalities 177 vascular malformation 181 vitiligo 179, 180 camouflage therapists 181–2 camphor 208 cancer risk growth factors 306 hair dyes 234 capsaicin test 23–4 carbomers 73 carbon dioxide, solid 378, 380

carbon dioxide laser resurfacing 393–408 fractionated 394–8, 399, 400–3, 404, 405–7 thermal necrosis 394 carnosine 294, 296 beta-carotene 337, 339 carotenoids antioxidant 281 skin appearance improvement 338 UV damage protection 337 castor oil, lipsticks 187 catagen phase of hair growth 157–8, 433 catalase 8 cationic polymers, shampoo conditioning aids 116 Caucasian hair 33–5, 264 Caucasian skin aging 31–2 self-perceived sensitive skin 24 UV irradiation 18, 29 cell signaling pathways, antioxidants 282 central nervous system (CNS), self-perceived sensitive skin 25 central projections 43–4 ceramides microdermabrasion effects 419 skin barrier building 103 cervicomental angle (CMA) 463, 464 reduced after liposuction 468 C-fibers 23, 39, 41 dorsal horn entry 44 itch 42–3 nociception 42 pleasure sensation 43 self-perceived sensitive skin 25 chamomile, German 277, 492 cheilitis 186 chelating agents, body washes 90 chemical peel, microdermabrasion comparison 422–3 chemical peels advantages 380, 385 combination 384–5 complications 382 contraindications 385, 386 depth 377, 378 disadvantages 380, 385 fluor-hydroxy pulse peel 381 formulation 377–80, 384–5 frosting 388 histologic changes 377 indications 377, 385–6 long-term skin care 390 medium-depth 384–91 analgesia 387 complications 388, 390 granulation 388, 389 long-term skin care 390 patient preparation 387

Index post-procedure 388 sedation 387 set-up 386 technique 386, 387–8 wound healing 388, 389 post-care 381 priming 380 procedure 380–1 scar chemical reconstruction 381–2 superficial 377–83 techniques 380–2, 386, 387–8 chemical reconstruction of skin scars (CROSS) 381–2 chemokines 285 chest liposuction, male 456 chin Botox treatment of dimple 348 implants 471 Chinese herbal medicines, toxicity 271 chromophores 146 UV absorption 14 Chrysanthellum indicum 500 ciclosporin 288 citric acid 483 clays, hair styling aids 262 cleansers allergic reactions 58 antiaging 480–1 antibacterials 480–1, 491 bar 77–87, 104 exfoliants 481 foaming liquid 104 formulation 480–1 fragrances 104 lipid-free 104 low-foam 102–5 mechanisms 104–5 mildness 103–4 production 103 types 102–4 non-foam 102–5 mechanisms 104–5 types 102–4 personal 88–94 preservatives 104 rosacea 497, 498 skin barrier building ingredients 103 skin disease 84–5, 86 types 104 waterless 104 see also body washes; facial cleansers; hand sanitizers; hand washes; shampoos cleansing acne 488–9 antiaging regimen 480–1 body wash ability 90 mechanisms 104–5

procedure 481 skin barrier damage 105 see also facial cleansing cleansing bars 77–87 formulation 77–8 manufacturing processes 78 non-soap detergent 79 preservatives 79 skin structure/function impact 79–81 soap 78–9 see also syndets/syndet bars cleansing brushes 492 cleansing cloths 98–9 acne treatment 491–2 dry lathering 99 wet 99 cleansing milks 98 climbazole 117, 118 Clostridium botulinum 342 C-mechano-heat (CMH) nociceptors 42 coacervate 116 coal tar 118 coenzyme Q10 (CoQ10) 284 antiaging 485, 486 nanoemulsions 505 skin appearance 339 wound healing 340 coffee 276–7 coffeeberry extract 277 cold-sensitive fibers 41, 42 collagen bovine 366 degradation stimulation 16 dermis 31 laser treatment 409 photoaging 15, 409 skin fibroblast 297 stimulation by hyaluronic acid fillers 354–5 synthesis by fibroblasts 16, 17 collagen fibers, photoaging 14 collagen fillers 361–72 adverse reactions 369–72 allergic reactions 60, 370–1 anaesthesia 367 animal-derived 365–6 bioengineered animal-derived 366 cross-hatching 367 facial augmentation 367–9 fanning 367 granuloma formation 371 hand rejuvenation 369 infections 371–2 injection techniques 366–7 injection-related events 370–1 materials 363, 364–5, 365–6 nodule formation 371 ‘potential face’ 362–3 vascular compromise 371

color additives in sunless tanning products 141 appraisal of facial foundation 173, 174 body washes 90 coordinates 177 matching 177 color charts 49 Color Index (CI) number 209 color stabilizers, nail lacquer 209 color standard chips 49 coloration, sunless tanning products 141–2 colored cosmetics camouflage techniques 176–83 facial foundation 167–74 coloring agents lipsticks 187, 188 nail polish 208–9 combination gels, allergic reactions 60 comedones 57 benzoyl peroxide treatment 489 salicylic acid treatment 491 compartment syndrome, risk with liposuction 454 complexion 167 history of makeup 167–9 Complexion Analysis Software 49–50 conditioners (hair) 225 after hair relaxing 253 allergic reactions 58–9 colored hair 234 rinse-off 121 conditioning polymers, hair permanent waving 242 confocal Raman microspectroscopy (CRS) 68–9 consumers facial moisturizer testing 128 understanding of body washes 90–1 contact dermatitis 55–61 diagnosis 60 skin of color 30 treatment 60 see also allergic contact dermatitis; irritant contact dermatitis contact urticaria 56, 57–8 contouring see skin contouring techniques copper, UV damage protection 338 corneocytes 3, 5, 6 cohesion 7 desquamation 8 dry lips 186 lip labial epidermis 185 maturation 8 melanin particles 7–8 visualization 10 corneodesmosomes 5, 7 desquamation 10 Corneometer® 10

517

Index corneometry 127 cornified envelope (CE) 5, 6 lipid–protein cross-links 5 cortex 44, 45 corticosteroids anti-inflammatory action 286–7 eczema treatment 502 mode of action 286 psoriasis 508, 509, 510 topical allergic reactions 59 atopic dermatitis 128 contact dermatitis treatment 60 cosmeceuticals anti-inflammatory actives 289 botanicals 269–79 growth factors 302–8 nutrients 335–40 peptides 296–7, 298, 299 polylactic acid fillers 373–6, 474 product development 273–4 proteins 293, 299–300 see also anti-inflammatory agents; antioxidants; hydroxyacids; retinoids; vitamin(s) cosmetic(s) adverse skin reactions 55 allergic contact reactions 11 hypersensitivity reactions 55–6 product development 10–11 rosacea 498–9 skin irritation 11 cosmetic actives composition 62–3 delivery assessment 68–9 emulsions 63 formulation 63–4 molecular weight 62–3 natural 500–1 occlusion of skin 64 patch formulations 67 penetration enhancement 64–8 percutaneous delivery 62–9 rosacea 500–1 skin barrier 62 skin partition coefficient 64 transepidermal delivery 62 vehicle effect 63–5 cosmetic intolerance syndrome 57 cosmetic product evaluation bio-instrumentation 47–8 non-invasive 47–54 digital photography 48–51 methods 48 cosmetic surgery, lips 186 CosmoDerm 364, 365, 367 hands 473 CosmoPlast 364, 365, 367, 369 hands 473

518

creams 71–4 active ingredients 73 composition 72–3 definition 71 elevated temperature testing 74 oil-in-water 72–3 stability 74 sunless tanning product delivery 140–1 water-in-oil 73 critical wavelength method, UVA radiation 148 cross-linking agents 353 crystal products, antiperspirants 153 C-tactile afferents 43 curcumin 282–3, 284, 289 curl, degree of 248 cuticle remover 200 irritant reactions 203–4 cyanoacrylate monomers 217, 218, 219 cyclomethicone 506 cyclo-oxygenase (COX) 287 cyclo-oxygenase 2 (COX-2) inhibitors 287–8 Cymetra 364, 365 cysteine proteases 7 cytokeratins, lip labial epidermis 184–5 cytokines 285 aging reversal 304–5 anti-aging 307 skin function 304–5 dandruff 115, 116 therapeutic shampoos 117, 120–1 year-round treatment 121 deodorants 150–5 adverse effects 154–5 delivery systems 153–4 odor control 153 soap bars 79 depigmentation niacinamide 323 retinaldehyde 314–15 retinoids 313 vitamin B3 323 dermabrasion 426–31 advanced technique 429–30 advantages 427 complications 430–1 disadvantages 427 Fitzpatrick skin types 428 full-face 429–30 indications 426–7 instrumentation 428 mechanism of action 426 patient selection 427 postoperative wound care 430 preoperative consultation 427–8 preoperative photographs 428 technique 428–30

dermatomyositis, bovine collagen 366 dermis 4 collagen 31 grenz zone 32–3 hydroxyacids effects 329 microdermabrasion effects 420 photoaging 14 skin of color 31 desmosomes 4, 5 desquamation 7, 8, 124 assessment 9–10 corneodesmosomes 10 pathogen protection mechanism 6 detergent bars non-soap 79 stratum corneum interactions 80–2 detergents, synthetic see syndets/syndet bars diathesis factors, sensitive skin 23 dibutyl phthalate 208 diclofenac 287, 288 diet 335–40 deficiency 335 digital photography cosmetic product evaluation 48–50 terminology 50–1 dihydroxyacetone (DHA) mechanism of action 139–40 moisturizers 142 processing 140 stability checks 140 storage 140 structure 140 sunscreen addition 140 sunless tanning products 139 vitiligo camouflage 179 dimethicone 506 dimethyl urea, nail hardening 211 diode laser, long pulsed 435 diode laser 1450 nm 410, 411, 414 dirt, facial cleansing 101 DNA, UV damage 7, 8 dorsal horn 44 double-chin formation 32 Dove bar 79 dry ice peel 378, 380 dry skin cleanser mildness 101 facial 123–4 flaking 124 hydroxyacids use 330, 332 lactic acid treatment 133 lips 186 moisturizer use 91 urea treatment 133 dryness of skin 30 assessment 127 D-squames 127 dyes see hair dyes

Index dyspigmentation 29 black skin 33 hydroxyacids 332 see also hyperpigmentation; hypopigmentation East Asian skin, UV irradiation 18 eccrine glands 150, 151, 152 eczema etiology 502 facial moisturizers 128 hygiene 505–6 moisturizer use 128, 502–6 occupational 60 regimens 502–6 syndet use 505–6 elastic fibers, photoaging 32 elastic recovery time 31 elasticity of skin 31 nutrient effects 339 elastosis 32 elevated temperature testing 74 emollients 11, 73 botanicals 274 cleansers 97 facial moisturizers 125, 126–7 hair styling aids 259, 260 moisturizers 125 emulsification, emollient/lathering cleansers 97 emulsifiers/emulsifying agents 71 cationic 72 creams 72 facial foundation 169 moisturizers 131 facial 125 emulsions 71, 72 cosmetic actives 63 fluid facial foundation 169 hair 261–2, 263 styling aids 259 moisturizers 504, 505 multivesicular 504, 505 oil-in-water 73, 104, 131 sunscreen vehicles 147 water-in-oil 73, 131 enhanced glycerol derivatives 136–7 enkephalin 295 environmental factors irritants 57 sensitive skin 23 environmental toxins, stratum corneum protective function 7 epidermal barrier 3–11 antimicrobial 6 building ingredients in cleansers 103 cosmetic product development 10–11 damage in cleansing 105 disruption 6

functions 5–8, 124 regulation 9 herbal product penetration 271–2 homeostasis 7, 8–9 immune protection 6 mechanical 6 microdermabrasion 418 oxidative stress 8 permeability 5–6 restoration by cosmetics 10–11 self-perceived sensitive skin 25 structural components 3, 4, 5 study methods 9–10 topical products 10 UV barrier 7–8 water evaporation 5–6 epidermal nerves 25 epidermis hydroxyacids effects 329 photoaging 32–3 skin of color 29 thickening with retinoids 483–4 thickness measurement 10 erbium:glass 1540 nm laser 410, 411, 413–14 Er:YAG lasers 394 fractionated 396 erythema intense pulsed light laser 446 laser-assisted hair removal complication 437 UV-induced 447 essential oils, acne treatment 492 ethnic skin see skin of color ethyl acetate, nail polish remover 213 etodolac 287 eumelanin 27, 229 eutectic blends 64 Evolence® filler 365, 366, 367 exfoliants/exfoliation aids body washes 90 chemical 481 mechanical 481 exfoliation antiaging 481, 482 facial cleansers 95, 96, 101 extensibility of skin 31 extracellular matrix (ECM), degradation effects of UV irradiation 19 extremozymes 300 eye(s) microdermabrasion side-effects 424 protection against laser beams 434 eye cosmetics 190–6 history 190–1 microbiological contamination protection 195 safety/regulatory consideration 195

virtual modeling 196 see also mascara eyebrow ptosis with Botox treatment 349 eyelashes ailments 191 curling 195 digital simulation 196 extensions 194 false 193 growth stimulation 194, 196 perming 194 physiology 191 tinting 193–4 transplantation 194 see also mascara eyelids nail cosmetic allergic reactions 204 ptosis with Botox treatment 349–50 rejuvenation 441 tattooing 194 eyeliners 194–5 eyeshadow 194, 195 face ageing evaluation 362 full-face volume restoration 471 tapering of lower 470 facial augmentation, collagen fillers 367–9 facial cleansers 95–101 exfoliation 95, 96, 101 function 96–7 makeup removal 98, 101 mildness 101 pH 96 scrubs 98 selection 99–101 solvents 97 surfactants 96, 97 types 97–9 facial cleansing chemistry 96–7 dirt 101 form 100 friction 97 history 95–6 physical 97 ritual 100 skin problems 100–1 surfactants 96, 97 facial foundation 167–74 antiwrinkle performance measurement 173 application 171–2 color appraisal 173, 174 color creation 170 compact 169–70 coverage 170–1 design 172 fillers 171, 172

519

Index fluid 169 formulation 169–71, 172 history 167–9 iron oxides 170 manufacturing development 169 moisturizing effect measurement 173 performance 172–3 pigments 170–1 powders 170 product categories 171 silicone oils 169 facial moisturizers 123–8 dihydroxyacetone content 142 formulation 125 inflammatory dermatoses 128 ingredients 126–7 testing 127–8 facial nerve, marginal mandibular branch 463–4 damage during liposuction 469–70 facial skin cell differentiation/maturation 124 dry 123–4 water content 124 facial tissue sagging 32 fast adapting (FA) receptors 39 fat transfer, autologous 471 hand recontouring 473, 474 fern, golden 277 ferulic acid with vitamins C and E 485, 486 feverfew 277 fibroblasts collagen I 297 collagen synthesis 16, 17 growth factor source 307 inflammatory mediator release 285 microdermabrasion 420 UV radiation effects 17 fillers allergic reactions 60 botulinum neurotoxin type A combination 349, 350 calcium hydroxylapatite 356–7, 358, 359–60 collagen 60, 361–72 facial foundation 171, 172 following radiofrequency treatment 441 hand 473 hyaluronic acid 352–5 persistence 354–5 polylactic acid 373–6 fish oils, skin health 336 Fitzpatrick skin types, dermabrasion 428 flaking, dry skin 124 flavonoids 272 skin health 336 topical 325–6 UV damage protection 338

520

fluor-hydroxy pulse peel 381 flushing response to vitamin B3 323 rosacea 500 foaming liquid cleansers 104 follicular inflammation 121 follicular plugging 57 foot, moisturization of skin 130–1 foot moisturizers 130–8 commercially available 132 lactate efficacy 133–4, 135 urea efficacy 133–4, 135 forearm controlled application test (FCAT), soap and syndet bars 83, 84 forehead Botox treatment 344, 345, 346 brow ptosis 31 lateral brow lift 347 foreign body reactions 56 formaldehyde 211–12 allergy 58, 211 formalin 211 fractionated carbon dioxide laser resurfacing 394–8, 399, 400–3, 404, 405–7 Ablative Affirm Carbon Dioxide resurfacing 396, 402 Active and Deep FX Lumenis 396–8, 399, 400 anaesthetic 407 botulinum toxin neuromodulator 407 complications 407 Fractionated Pearl 396, 406–7 Fraxil Re:Pair 396, 398, 400 Lux 2940 396, 406 MedArt FrX 396, 401–2 Mixto SX Slim Evolution 396, 400–1 Mosaic Lutronic eCO2 396, 402–3 Paxel 396, 406 Pixel 2940 396, 405–6 Pixel Carbon Dioxide 396, 401 postoperative treatment 407 preoperative treatment 407 procedures 407 Sciton ProFractional resurfacing 396, 403, 404, 405 SmartXide DOT resurfacing 396, 402 technique 407 Fractionated Pearl (Cutera) resurfacing 396, 406–7 fragrances allergic reactions 58 allergy 111 body washes 90 cleansers 104 facial moisturizers 127 lipsticks 188 Frankfurt plane 464 Franz cell 68, 284

Fraxil Re:Pair (Reliant) 396, 398, 400 free radical scavengers retinoids 313 see also antioxidants free radicals 281–2 aging theory 312–13 antioxidant protection against damage 282 friction, facial cleansing 97 gallic acid 328–9 gel fillers 56 gels/gelees hair 258–9, 261, 263 sunless tanning products 141 genistein 486 Gentlewaves® photomodulation 445, 446 German chamomile 277, 492 Ginseng, delivery 271 glabella, Botox treatment 342, 344, 345, 346 glabrous skin 38, 39 low threshold mechanoreceptors 41 structure 40 gluconolactone 483, 491 glutathione 294 glycation 339 glycerin cleanser humectant 103 keratinocyte maturation 128 moisturizer humectant 125, 126 glycerol 7 glycerol monothioglycolate 242 glycolic acid acne treatment 490 antiaging 483 medium depth peel 384–5 microdermabrasion comparison 423 rosacea 501 glycols 73 glycosaminoglycans (GAGs) 319–20, 331 glyoxal, nail hardening 211 Goeckerman treatment for psoriasis 511 golden fern 277 golden mean 363 granulation medium depth chemical peel 388, 389 nail 204, 204 wound healing 303 granuloma formation, collagen fillers 371 grape products 277 green tea, skin appearance 339 grenz zone 32–3 growth factors 302–8 aging reversal 304–5 delivery methods 307–8

Index natural 306–7 product quality 308 risks 306 skincare 304–5 stem cell 307 synthetic 307 wound healing 303–4 hair 33–5, 222–5 African 263, 264 aging 237–8 biology 157–9 bonds 248 care of colored 233 chemical structure 238–9 color 224, 227 natural 229–30 cortex 224 curl 244 degree of 248 retention 258 curliness spectrum 33, 34–5 cuticle 223, 236, 237 ethnic types 264 eyelashes 191 fiber 222–4, 236 water hydrophilicity 237 geometry 236–7 graying 229 grooming 224–5 growth 236, 433 anagen phase 157, 236, 433 catagen phase 157–8, 433 telogen phase 158, 433 hydration 158, 161 keratin 34, 35, 224 loss 121 medulla 224 melanin 224, 229, 230 peptide application 297, 298, 299 physiology 222–4, 236, 256 pigmentation 229–30 properties 158–9 racial differences 33–4 shaft 157 shape 33 stabilization 257 shedding 236 split ends 238 structure 33–4, 248 stabilization 257 terminal 33, 433 thermal behavior 237 water interaction 237 waving 239, 240 weathering 238 wet setting 258 hair bleaches 229, 232 allergic reactions 59

chemistry 230 growth cycle 157–8 hair cosmetics 222 see also conditioners (hair); hair dyes; shampoos hair creams 261–2 hair dyes 227–35 advantages 231–2 allergic reactions 59, 234 application 232–3 cancer risk 234 care of colored hair 233 chemistry 229–31 couplers 231 definition 227 demi-permanent 228, 229, 232 disadvantages 232 fiber damage 233 formulation 231, 232, 233 hair structure 233–4 occupational safety 234 oxidative dye formation 230–1 permanent 59, 228–9, 232 chemistry 230–1 precursors 230 product types 227–9 regulation 234 safety 234 semi-permanent 228 sensitization 233, 234 skin sensitivity test 233, 234 temporary 228 hair emulsions 261–2, 263 hair follicles 157, 222, 223–4 biology 432–3 innervation 158 keratins 222, 223–4 melanocytes 229 peptide application 298 hair gels 258–9, 261, 263 hair mousses 258–9, 261, 263 hair permanent waving 236–46 acidic 243 adverse reactions 245, 245, 246 alkaline perms 243 alkalizing additives 242 buffer salts 242 carriers 242 complexing agents 242 conditioning polymers 242 disulfide cleaving 239, 240 ingredients 240–3 neutral 243 neutralizers 243 opacifiers 243 practise 243–4 products 240–3 reducing agents 240–1 regulatory aspects 243

safety 244–5 solubilizing agents 243 solutions 239 steps 241 sulfite 243 surfactants 242 thermal waves 243 thickeners 243 types 240–3 hair pomades 261–2 hair relaxers 251–5 application 253 effects 253–4 hair removal 156 laser-assisted 432–7 see also shaving hair setting lotions 258–9, 261 hair spray gels 261, 263 hair straightening 248–55 hydroxides 251–2 reducing agents 250–1 relaxers 251–5 sulfites 251 terminology 252 thermal processing 249–50 thiol with heat 255 hair styling 256–65 consultations 264–5 hair styling aids 258 African hair 263–4 applications 259–64 clays 262 curl retention 258 definition 256 emollients 259, 260 emulsions 259 film-forming active ingredients 259 formulations 258–9 polymer formulations 258–9 product forms 259–64 silicone 262–3 silicone pump sprays 262–3 silicone serums 262–3 smoothness improvement 257 technologic developments 265 uses 259–64 volume improvement 257 wax formulations 259 waxes 260, 262, 263 hairdressers, occupational hand eczema 60 hairsprays 258–9, 259–61, 263 aerosol 259–60, 261 formulation 260–1 propellants 260–1 pump 260 spot welds 260 hairy skin 38, 39, 41 structure 40

521

Index hand(s) aging 473–9 microbiota 106–7, 110 moisturization of skin 130–1 pH 108 physiology 473 polylactic acid fillers 375 rejuvenation with collagen fillers 369 skin damage 108 volume restoration 473 washing 108 hand flora 107 resident 110 hand hygiene 107–8 compliance 108 effectiveness in community 110–11 guidelines 107–8 hospital epidemiology nosocomial studies 111 nail cosmetics 206 hand moisturizers 130–8 commercially available 132 lactate efficacy 133, 134 urea efficacy 133, 134 hand recontouring autologous fat 473, 474 calcium hydroxylapatite 473–9 adverse events 477 injection technique 474–7 lidocaine 474–5, 478–9 post-injection hand massage 475–6 post-treatment care 476–7 results 477, 478 hand sanitizers 106–12 alcohol-based 108 safety 111 efficacy 108–10 formulations 112 safety 111–12 skin irritation 111 hand washes 106–12 efficacy 108–10 formulations 112 safety 111–12 skin irritation 111 in vitro measurement 108–9 in vivo models 109 headache, Botox treatment side-effect 350 heating device, electronic 492 heliodermatitis 14 henna, allergic reaction 59 herbal extracts 270 herb-based products 269–79 active ingredients 270 cross-reactivity with other herbs 271 delivery of therapeutic concentration 271 effectiveness 271–2

522

extraction methods 270 mechanism of action 272 quality control 270–1 regulation 269 safety 271 secondary metabolites 272, 273 variability 270 herbs esthetic utility 273–9 wildcrafting 270 herpes simplex virus (HSV) antiviral prophylaxis 427–8 dermabrasion 427–8, 431 pretreatment for medium-depth chemical peel 387 hips, liposuction indications 453–4 Hispanic skin aging 32 self-perceived sensitive skin 24, 25 homeostasis, epidermal barrier 7, 8–9 hom*ogenous gels, allergic reactions 60 humectants 73 cleansers 103 facial moisturizers 125, 126 moisturizers 125, 131, 132 hyaluronic acid fillers 352–5, 474 chemical composition 352–3 collagen stimulation 354–5 complications 354 concentration 353 cross-linking 353 indications 353 injection techniques 354 persistence 354–5 properties 352–3 hyaluronan 313–14, 315 hydration of hair 158, 161 hydration of skin 6–7, 9, 124 measurement 10 microdermabrasion 418 panthenol effects 323 surface 124 hydrocortisone, psoriasis 508, 509, 510 hydrogen peroxide 230, 231 allergic reaction 59 hair structure alteration 232 regulatory aspects 243 hydrophilic substances, delivery through sweat glands 62 hydroquinone, allergic reactions 58 hydroxide hair straighteners 251–2 hydroxyacids 327–33 antiaging 483, 486 antioxidant 329–30 biological properties 329–30 chemical peels 377–8 clinical uses 330, 331, 332–3 efficacy 483 gel matrix formation 329

groups 327–9 matrix metalloproteinase inhibition 330 natural occurrence 327–9 physicochemical properties 329–30 sensory responses 330 skin effects 330, 331 sun sensitivity 330 topical drug synergy 333 water binding 329 wrinkle treatment 332, 333 hyperhidrosis 155 Botox use for palmar 342 hyperkeratinization, hydroxyacids use 330, 332 hyperpigmentation black skin 33 dermabrasion postoperative 431 laser-assisted hair removal complication 437 microdermabrasion 421 side-effects 424 periorbital 179 postinflammatory 29 hypersensitivity reactions 55–6 collagen fillers 370–1 diagnosis 60 immediate (type I) 56, 58 hyponychium 198–9 hypopigmentation dermabrasion postoperative 431 laser-assisted hair removal complication 437 postinflammatory 29 ibuprofen 287 immune protection, epidermal barrier 6 immuno-allergologic pattern of sensitive skin 23 immunoglobulin E (IgE) antibodies, allergens 60 immunomodulators 288–9 immunosuppressants 60 immunosuppression 20 indomethacin 287 nano-encapsulated 66 induration, neck liposuction 468 infections/infectious diseases artificial nails 220 collagen fillers 371–2 epidemiology 106 epidermal barrier for pathogens 6 hand hygiene efficacy 111 nails 204–5, 205 staining 220 transmission 106 inflammation acute 284, 285 chronic 284, 285–6

Index follicular 121 foreign body reactions 56 photoaging 14 pigmentation effects 29 prescription medicines 286–90 process 284–6 proteolytic enzyme release 302 reactive oxygen species release 302 inflammatory mediators 285 inflammatory responses, immune cell-mediated 285 informed consent Jessner’s solution medium depth peel 386 liposuction 458 infrared light devices 410, 411, 414–15 injectables, allergic reactions 60 integrins 16 intense pulsed light (IPL), rosacea treatment 500 intense pulsed light (IPL) laser 410, 411, 412 erythema 446 hair removal 436, 437 intensity-modulation radiation treatments (IMRT) 446–7 intercellular adhesion molecules (ICAM) 285 inter-corneocyte lipids 5 interleukins, skin damage 302 iontophoresis 68 iron oxides, facial foundation 170 irritant contact dermatitis 55 allergic contact dermatitis differential diagnosis 56 keratolytics 510 skin of color 30 irritants 56–7 environmental factors 57 skin barrier function assessment 127–8 irritation antiperspirants 154 benzoyl peroxide-induced 490 cosmetics 11 deodorants 154 hand washes/sanitizers 111 keratolytics 510 nail cosmetics 203–4 panthenol protective effects 323 retinoid induction 310, 321 shaving 158 subjective 57 vitamin A 321 Isologen 364, 365 isopropyl alcohol, waterless cleansers 104 isotretinoin 493 itch 42–3

Jessner’s solution 378–9 medium depth peel 384, 385, 389, 390, 391 informed consent 386 microdermabrasion comparison 423 technique 386 jowling 32 jowls 463 liposuction 467, 468 indications 455–6 jugular vein, external 464 Juvéderm filler 353 keratin hair 34, 35, 224 hair cuticle 223 hair follicles 222, 223–4 nail granulations 204, 204 nail plate 199 keratin chain interactions 257 keratinocytes 3, 5 differentiation 8 epidermal barrier disruption 6 facial skin 123 glycerin in maturation 128 growth factor source 307 immune function 6 inflammatory mediator release 285 psoriasis 507, 508 UV radiation effects 17 pigmentation induction 28 keratohyalin granules 5 keratolysis epidermal 483 exfoliants 481 keratolytics contact dermatitis 510 irritation 510 psoriasis 508, 509, 509–10, 511 keratoses, hydroxyacids 332 ketoconazole 117, 118 ketoprofen 287 kinetin 307 kytorphin 295, 299 labeling, sunless tanning products 141 lactic acid acne treatment 490 antiaging 483 dry skin treatment 133 psoriasis 508, 509, 509 see also sodium lactate lactic acid stinging test 23, 25 lactobionic acid 329–30, 483, 491 lamellar granules (bodies) 5 Langerhans cells 4, 6 photoaging 32 lanolin, moisturizer occlusive 126

lanugo 433 laser techniques fractionated 394–8, 399, 400–3, 404, 405–7 liposuction 459–60 non-ablative 409–16 types 409, 410, 410–15 see also carbon dioxide laser resurfacing laser-assisted hair removal 432–7 complications 436–7 concepts 433 eye protection 434 postoperative management 436 preoperative management 433–4 radiofrequency combinations 436 techniques 434–6 laser-assisted liposuction 459–60 latex, contact urticaria 58 lathering facial cleansers 97 lecithin 72 LED photomodulation 444–8 anti-inflammatory actions 446–8 clinical applications 445–6 retina protection 447 leukocytes, inflammatory process 285 levator labii superioris alequae nasi (LLSAN) 348 licochalcone A 500 lidocaine, calcium hydroxylapatite hand recontouring 474–5, 478–9 light energy device, bipolar radiofrequency 441–2 light therapy, rosacea 500 lighteners botanicals 276 vitamin C 324 lip(s) 184–6 aging 185–6 cheilitis 186 cosmetic surgery 186 dermis 185 dryness 186 histology 185 hyaluronic acid fillers 353 labial epidermis 184–5 lamina propria 185 pigmentation 186 sensitivity to environment 185 topology 185 vermillion zone 184, 185 see also lipstick lip brilliances 188 lip glosses 188 lipid(s) desquamation 8 facial moisturizer emollients 126–7 hair 238 inter-corneocyte 5 nail plate 200

523

Index pH effects 82 sebaceous 115 soap bar use 80 stratum corneum 82 surfactant interactions 105 synthesis 8 topically applied 11 UV damage protection 338 lipid peroxidation 281–2 lipid-free cleansers 104 alpha-lipoic acid 485, 486 liporeceptors 9 liposomes 271 moisturizers 504–5 penetration enhancement 65 liposuction 450–60 advantages 451 complications 451–2, 458–9 disadvantages 451–2 endpoint determination 457 equipment 457–8 fanning 467 feathering 468 history 450 indications 452–6 informed consent 458 intraoperative phase calculations 458–9 jowls 467, 468 indications 455–6 laser-assisted 459–60 neck 463–71 indications 455–6 operating technique 457 postoperative phase complications 459 preoperative phase complications 458 skin contour 451 skin physiology 451 tumescent local anesthesia 450, 451–2 neck 466–7 technique 456–7 tunneling 468 lipstick 184, 186–8 active ingredients 188 antioxidants 187–8 formulation 186–8 oils 187 pigments 187 preservatives 187–8 texturing agents 187 liver X receptor (LXR) 9 local anaesthetics, allergic reactions 59 long pulsed alexandrite laser 435 long pulsed diode laser 435 long pulsed ruby laser 434–5 lotions 71–4 definition 71 sunless tanning product delivery 140–1 low density lipoprotein (LDL), free radical damage 282

524

low threshold mechanoreceptors (LTMs) 39, 41 lutein 337, 339 Lux 2940 (Palomar) resurfacing 396, 406 lycopene 337, 339 lymphoma, immunomodulator association 288 makeup history 167–9 removal facial cleanser selection 101 toners 98 shades 172 skin color 172 see also eye cosmetics; facial foundation; lipstick Malassezia 115, 117 maltobionic acid 329 skin effects 331 structure 329 wrinkle treatment 333 mandibular border redefinition 349 manicure 201–2, 202 practice 206 marginal mandibular branch of facial nerve 463–4 damage during liposuction 469–70 mascara 190–1, 191–3 application 195, 196 applicator technology 192–3, 194, 196 composition 192 masks, peel-off/wash-off 481 masseter muscle, hypertrophy 349 mast cells, skin of color 30 matrikines 295, 297, 298, 299 matrix metalloproteinases (MMPs) 19 activation 483 collagen degradation stimulation 16 inflammatory process 286 inhibition by hydroxyacids 330 LED photomodulation 444–5 skin damage 302 sunscreen regimens 127 mechanoreceptive afferents 39, 41 MedArt FrX laser resurfacing 396, 401–2 Meissner corpuscles 39, 41 meladine, hair removal 436 melanin 7–8, 27 hair cortex 224, 229, 230 laser-assisted hair removal 433 oxidative degradation 230 photoprotection in skin of color 33 postinflammatory hyperpigmentation 29 melanocortin-1 receptor (MC1R) 28 melanocytes 4, 27–8 hair follicles 229

melanocyte-stimulating hormone (MSH) 295 alpha-melanocyte-stimulating hormone (MSH) 28 melanogenesis 28, 295 melanosomes 27–8 melasma, camouflage makeup 180 Merkel disks 39, 41 mesolabial fold, hyaluronic acid fillers 353 mesotherapy, growth factor delivery 307–8 methacrylate polymers artificial nails 215–16 nail resins 208 methyl ethyl ketone (MEK) artificial nail removal 219 nail polish remover 213 methyl methacrylate monomers 220 methylacrylates 217 methylene glycol, allergy 211 metronidazole 500 mexoryl sunscreen 481, 482 microbial resistance 111–12 microdermabrasion 418–24 advantages 423–4 chemical peel comparison 422–3 complications 424 contraindications 420 dermis effects 420 disadvantages 423–4 histopathologic changes 418–19 indications 420–2 molecular effects 419 procedure 418 side-effects 424 skin physiologic changes 418 trichloracetic acid combination 421 microdermabrasion units 418, 419 microdialysis 68, 69 microemulsions 271 microneedles 67–8 microvasculature of skin 15 milk thistle 277–8 minerals, skin health 336 mists, no-rub 142 mitochondrial ATP, photodynamic therapy 447–8 mitogen-activated protein (MAP) kinase signaling pathway 302 Mixto SX Slim Evolution 396, 400–1 Mohs surgery, dermabrasion 427, 429 moisturization of skin 6–7 body washes 91–2, 93 cosmetic products 10–11 facial foundation effect measurement 173 foot 130–1 hand 130–1 sunless tanning products 142 ultrastructural effects 133

Index moisturizers 10–11 after shaving 162 allergic reactions 58 aquaporins 135–6, 137 body washes 89–91 delivery systems 503–5 dihydroxyacetone content 142 dry skin 91 eczema treatment 502–6 emulsifiers 125, 131 emulsions 504 enhanced glycerol derivatives 136–7 facial 123–8, 142 foot 130–8 formulation 131 hand 130–8 liposomes 504–5 mechanism of action 502–3 multivesicular emulsions 504, 505 nanoemulsions 504, 505 next-generation 135–7 niosomes 504, 505 nutrient effects 339 ointments 504 psoriasis 508, 509, 509–10 rosacea 497, 498 serums 504 sunscreen containing 506 technology 131 treatment 505–6 see also sunless tanning products; sunscreens monocytes, inflammatory process 285 Mosaic Lutronic eCO2 resurfacing 396, 402–3 mucilages 272 multivesicular emulsions 504, 505 mushrooms 278 myristoyl-nicotinate 323 nail(s) 197–205 acrylic extensions 200, 215–16 artificial (see nail cosmetic prostheses) brittleness 200, 201, 202, 203 buffing 203 calcium content 199 care 202–3 composition 199–200 cuticle remover 200 irritant reactions 203–4 discoloration 198, 204, 209 dyschromia 198 dystrophy 203 filing 202–3 flexibility 200, 201, 202, 203 grooming 201–2, 202–4 hardening 210–11 infections 204–5, 205 artificial nails 220

keratin granulations 204, 204 manicure 202, 202 painting 207 pedicure 202 physiology 199–200, 201, 202 plasticizers 200 signs 198 staining 209 infections 220 thickness 202 trauma 203 trimming 202–3 nail basecoats 208 nail bed 199 changes 198 nail cosmetic prostheses 215–20 adverse reactions 219–20 equipment 218 infections 220 liquid and powder systems 215–16, 217 nail damage 220 nail surface preparation 216 nail wraps 216, 217–19 rebalancing 219 removal 219 training for technicians 220 UV gels 216–17 nail cosmetics 200 allergic reactions 59, 203, 204 application 206 colored 206–12 (see also nail polish) hygiene 206 irritant reactions 203–4 procedures 204 safe use 205 nail folds 197–8 nail hardener 200, 206, 207, 210–11 nail matrix 197, 198 nail plate 197, 199 lipids 200 surface filing 203 thinnning 204 water content 200 nail polish (lacquer) 200, 206–7, 206–12 antifungal agents 209 brittle nails 203 color stabilizers 209 colorants 208–9 ingredients 206–8, 209 plasticizers 208 preservatives 209–10 solvents 208 thixotropic agents 209 UV curable 207, 212, 213 yellow staining 204 nail polish remover 200, 212–13 irritant reactions 203–4 nail resins 208

nail surface dehydrators 216 adhesion promoters 216 nail topcoats 208, 209 nail unit anatomy 197–9 breaks in integrity 204 lines 198 nail wraps 216, 217–19 nanocapsules 66 nanoemulsions 271, 504, 505 nanosomes 271 naproxen 287 nasolabial fold collagen filler injection 368 hyaluronic acid fillers 353 softening 348 natural actives 500–1 see also cosmetic actives natural moisturizing factor (NMF) 5, 6–7, 131, 133, 503 amino acids 292 composition 131 epidermal barrier 9 Nd:YAG 1064 nm laser hair removal 435 Q-switched 410, 411, 413 Nd:YAG 1320 nm laser 410, 411, 412 neck anatomy 463–4 liposuction 463–71 advanced/ancillary techniques 470–1 anesthesia 466–7 complications 468–70 consultation 463 ethical considerations 464 fat augmentation 471 French tape application 468 indications 455–6 induration 468 overresection 470 patient selection 464–5 physical examination 463 postoperative course 468 preoperative markings 466, 467, 468 procedure 466–8 standard operative techniques 467–8 submental fold development 470 tapering of lower face 470 skin retraction 468 neuropeptides 294–5, 299 neutralizers, camouflage makeup 177 Neutrogena soap bar 78–9 neutrophils, inflammatory process 285 niacinamide (nicotinamide) 321 depigmentation 323 formulation 323 mechanisms of action 322–3 structure 322 topical effects 323

525

Index nicotinamide 493 nicotinate esters 321 formulation 323 nicotinic acid 321 formulation 323 mechanisms of action 322–3 niosomes moisturizers 504, 505 penetration enhancement 65–6 nitrocellulose, nail resins 208 nociception 42–3 non-steroidal anti-inflammatory drugs (NSAIDs) 287–8 nuclear factor of activated T cells (NFAT) 288 nuclear factor-κB (NFκB) 283 corticosteroid mechanism of action 286, 287 microdermabrasion effects 419 skin damage 302 nutrients 335–40 appearance improvement of skin 338–9 dermatological disorder effects 339–40 moisture/elasticity of skin 339 UV-induced damage protection 335, 336, 337–8 wound healing 339–40 oat products 278 occlusion of skin 64 occlusives facial moisturizers 125, 126 moisturizers 125, 131, 132 occupational hand eczema 60 occupational safety, hair dyes 234 octopirox 117, 118 odor control 153 oils, lipsticks 187 ointments 71–4 composition 73–4 definition 71–2 elevated temperature testing 74 moisturizers 504 natural 73–4 psoriasis 509 semi-solid 63 stability 74 omega-3 fatty acids, skin health 336 onycholysis 198, 199, 203, 204 onychomycosis 203 onychorrhexis 198 onychoschizia 198, 204 opacifiers, hair permanent waving 243 optical coherence tomography (OCT) 81 optical profilometry, wrinkles 51–2, 53 oral supplements 335–40 oxidative stress, epidermal barrier 8 4-oxoretinoids 309, 315

526

oxygen radical absorbance capacity (ORAC) assay 282 oxytalan fibers 32 Pacinian corpuscles 39, 41 pain fibers, dorsal horn entry 44 pain primary afferents 44 pain sensation 42–3 panthenol 323–4 pantothenic acid 323 para-toluenediamine (pTD) 234 paronychia 198, 204 patch test antigens, skin of color 30 patch testing, contact dermatitis 60 patches, penetration enhancement 67 pathogens, epidermal barrier 6 Paxel (Wavelight) resurfacing 396, 406 Pears soap 78 pedicure 202 peeling agents hydroxyacids 332–3 see also chemical peels penetration enhancement 64–8 devices 66–8 vectors 65–6 penetration enhancers 65 Penfield’s somatosensory homunculus 45 peptides acylation 296 analysis 296 antiaging applications 296–7, 298, 299 antioxidant 294 biological functions 293–5 cost 296 definition 292–3 lipophilic chain attachment 295–6 mechanism of action 293–4 skin penetration 295–6 stability 296 toxicity 296 use in cosmetics 295–6 percutaneous absorption 64 percutaneous delivery of cosmetic actives 62–9 perfume lipsticks 188 see also fragrances periocular fine lines, assessment 51–2 perioral lines, Botox treatment 348 periorbital injection, Botox 346–7 peripheral nervous system 38–9, 40, 41–3 pain 42–3 pleasure sensation 43 temperature sensing 41–2 touch 38–9, 40, 41 Perlane filler 353 permanent hair dyes 59 peroxisome proliferator activator receptor (PPAR) 9

personal care products antiperspirants 150–5 blade shaving 156–62 deodorants 150–5 personal cleansers 88–94 petrolatum moisturizer occlusive 126, 506 ointments 73, 74 white 506 phagocytes 6 phenolics 272, 283 phenylalanine 293 p-phenylenediamine (PPD) 59, 234 pheomelanin 27, 229 photoaging 13–20 antioxidants in prevention 19–20 definition 13 dermis 14 epidermis 32–3 ethnic skin 18, 32–3 histopathology 32–3 hydroxyacids 332 immunosuppression 20 inherent defense mechanisms 20 mechanism 127 medium depth chemical peel 390 microdermabrasion 422 molecular mechanisms 15–16, 17 neck liposuction 465 pathophysiology 409 physiology 13–15 prevention 18–20, 127 retinoids 19, 483–4 reversal 486 skin microvasculature 15 sun protection 18–19 UV stimulation 14–16, 17 vitamin E in reversal 484 see also antiaging entries photodynamic therapy 447–8 hair removal 436 photoepilation 432–7 photography 48–51 cosmetic product evaluation 48–50 cross-polarized 50, 51 guide 51 polarized 50, 51 UV fluorescence 50–1 UV reflectance 50, 51 visible light 50 photomodulation 444–8 photoprotection botanicals 276 facial moisturizers 127 nutrients 335, 337–8 photorejuvenation 444 LED photomodulation 445–6 photosensitivity reactions, retinoids 57 phototherapy, psoriasis 510–11

Index photothermolysis, laser-assisted hair removal 433 phytokinins 307 phytosomes 271 phytosteroids 272 pigmentation 27–35 dryness of skin 30 hair 229–30 inflammation effects 29 lips 186 melanosomes 28 retinoid effects 313 see also depigmentation; dyspigmentation; hyperpigmentation; hypopigmentation pigments facial foundation 170–1 lipsticks 188 pilosebaceous unit 157 pimecrolimus 288 eczema treatment 502 pineapple 276 Pixel 2940 (Alma) resurfacing 396, 405–6 Pixel Carbon Dioxide (Alma Lasers) 396, 401 plant alkaloids 272 plant extracts, skin barrier building 103 plasticizers, nail lacquers 208 platysma muscle 463, 464 banding 463, 465, 468, 470 Botox treatment 349 platysmaplasty 470 pleasure sensation 43 polyhydroxyacids 328, 329 acne treatment 491 antiaging 483 antioxidant 329 rosacea 501 water binding 329 polylactic acid fillers 373–6, 474 advantages 373–4 anaesthetic 373 complications 375–6 cross-hatching technique 374 disadvantages 373–4 fan technique 374 formulation 373 hands 375 injection techniques 374–5 tear troughs 375 polypeptides, cleansers 480 polyphenolics 283 skin health 336 pomades 261–2 pomegranate 278 pore cleansing, toners 98 postinflammatory hyperpigmentation (PIH) 29 postinflammatory hypopigmentation 29

potassium alum 153 potassium titanyl phosphate (KTP) 532nm laser 410, 411 preservatives allergic reactions 58 cleansers 104 cleansing bars 79 eye cosmetics 195 facial moisturizers 127 lipsticks 188 nail lacquer 209–10 vitamin E 325 prick tests 60 primary sensory afferents 39, 41 procollagen induction by trans-retinoic acid 19 inhibition by UV radiation 16 pro-opiomelanocortin 295 Propionibacterium acnes 489, 492 UV fluorescence photography 50 prostaglandin analogs, eyelash growth stimulation 194 prostaglandin E2 283 NSAID mechanism of action 287–8 skin cancer association 288 protease-activated receptor-2 (PAR-2) 28 proteases desquamation 8 stratum corneum 7 protection of skin antiaging regimen 481–3 see also antiaging products; sunscreens proteins chain 293 cosmetic use 299–300 definition 293 hair 238, 239 hydrolysis 296 proteolytic enzymes 7, 299–300 inflammation 302 pseudofolliculitis barbae 162 psoriasis 507 dermatology patients 508 education 508 flares 508 genetics 507–8 Goeckerman treatment 511 hydrocortisone 508, 509, 510 keratolytics 508, 509, 509–10, 511 lactic acid 508, 509, 509 moisturizers 508, 509, 509–10 nail dystrophy 203 ointments 509 over-the-counter medications 508–9, 511 phototherapy 510–11 physiology 507–8 regimens 507–12 salicylic acid 508, 509, 509

self-treatment 508 stress factors 508 sun exposure 510 tanning beds 510–11 tar 508, 509, 510, 511 topical medication 508–9 treatment compliance 508–9 urea 508, 509, 509 UV light therapy 510–11 pulsed dye laser 410–12 pustular eruptions 57 PUVA (psoralen and UVA) 510 pycnogenol 278 pyramid of age 362–3 pyrithione zinc (PTZ) 117, 118 chemical availability optimization 119 distribution on scalp 118–19 particle size 118, 119 types 118 pyruvic acid chemical peel 378 quality of life, camouflage makeup 182 quercetin 289 radiation dermatitis, LED photomodulation 446–7 Radiesse® filler 356 hands 474–9 indications 359 see also calcium hydroxylapatite radio allergo-sorbent tests (RASTs) 60 radiofrequency bipolar 441–2 and light 441–2 and unipolar 442 and vacuum 442 monopolar 439–41 complications 440 eyelid rejuvenation 441 unipolar 442 radiofrequency devices bipolar 439, 440 monopolar 439, 440 skin tightening 439–42 radiofrequency non-ablative resurfacing devices 410, 411, 415 Raking Light Optical Profilometry (RLOP) 48 wrinkle improvement detection 51–2, 53 razors blade edge 160 blade spacing 160 cutthroat 156 development 157 double-edge 159 electric 157 geometry control 159–60 lubricating strips 160–1 safety 156

527

Index shaving 159–61 skin guard 161 system 159–60 reactive oxygen species (ROS) inflammation 302 photochemical generation 15 UVA-induced 14, 15–16 reactivity of skin, skin of color 30 reducing agents hair permanent waving 241–2 hair straightening 250–1 reducing sugars, sunless tanning products 140 reflectance confocal microscopy (RCM) 30 remodeling of skin 303 resorcinol, sulfur combination 491 resorcinol peel 378, 380 Restylane filler 353, 354 resurfacing carbon dioxide laser 393–408 dermabrasion 426–31 following neck liposuction 471 microdermabrasion 418–24 non-ablative 409–16 see also chemical peels; fractionated carbon dioxide laser resurfacing; peeling agents retina protection, LED photomodulation 447 retinaldehyde 319 acne treatment 491 antiaging 484 antibacterial activity 312 cosmeceuticals 314–15 depigmentation 313, 314–15 structure 320 wrinkle treatment 314, 321 retinoic acid 483, 486 irritation induction 310 all-trans-retinoic acid, structure 320 retinoic acid peel 423 retinoic acid receptors (RAR) 319, 483 retinoic X receptors (RXR) 319, 483 retinoid dermatitis 484 retinoids 309–15 acne treatment 491 antiaging 483–4 antioxidants 312–13 cosmeceutical 309, 314–15 depigmentation 313 epidermal thickening 483–4 formulation 321 free radical scavengers 313 genomic effects 310, 312 hyaluronan 313–14, 315 intracrine proligand concept 309–10, 311, 312–13 irritation 310, 321

528

photoaging prevention 19, 483–4 photobiology 312 photosensitivity reactions 57 pigmentation effects 313 stability 321 structures 311 therapeutical 309 topical effects 320–1 wrinkle treatment 320–1 retinol 309 acne treatment 491 antiaging 484 cosmeceuticals 313 stratum corneum protection 313 structure 320 topical 319 wrinkle treatment 320–1 see also vitamin A retinyl esters 309, 313 cosmeceuticals 314 topical 319, 321 retinyl palmitate 312, 313 acne treatment 491 structure 320 wrinkle treatment 321 retinyl propionate acne treatment 491 wrinkle treatment 320, 321 rhinophyma, dermabrasion 427 rhytidectomy 470 rosacea alpha-hydroxyacids 500–1 antibiotic therapy 499–500 azelaic acid 501 Chrysanthellum indicum 500 cleansers 497, 498 cosmetics 498–9 erythemotelangiectatic 495, 497 flare 496, 499 flushing 500 glycolic acid 501 licochalcone A 500 light therapies 500 mild cleansing 84–5, 86 moisturizers 497, 498 natural actives 500–1 ocular 495, 497 over-the-counter products 496–9 papulopustular 495, 497, 499 phymatous 495, 497 physiology 495, 496 polyhydroxyacids 501 prescription agents 499–500 regimens 495–501 subtypes 495, 497 sun protection 496, 499 sunscreens 499 topical therapy 500 vitamin C 500

ruby laser, long-pulsed 434–5 Ruffini endings 39, 41 safety eye cosmetics 195 occupational for hair dyes 234 salicylic acid 118, 328–9 acne treatment 490–1 antiaging 483 psoriasis 508, 509, 509 salicylic acid peel 378, 379, 382 salicylism 379, 491 sarcosinates, facial cleansers 97 scalp 115, 116 sebaceous lipids 115 scalp care products 118–20 scars abrasion 427 chemical reconstruction 381–2 formation with dermabrasion 431 microdermabrasion 421 postsurgical 179 SciCon ratio 124 Sciton ProFractional resurfacing 396, 403, 404, 405 scrub particles 98 scrubs acne treatment 492 facial cleansers 98 Sculptra® filler 373 sebaceous lipids, scalp 115 sebaceous oil, cleaning of excess 100 seborrheic dermatitis see dandruff secondary metabolites, herb-based products 272, 273 selenium 339 antiaging 485, 486 UV damage protection 338 selenium sulfide 117, 118 L-selenomethionine 485, 486 self-perceived sensitive skin (SPSS) 22–5 barrier functions 25 clinical features 24–5 clinical signs 22 clinical subgroups 22–3 CNS involvement 25 diagnosis 23–4 epidemiology 24 neurogenic origin 25 physiologic mechanisms 25 provocative tests 23–4 sensitive skin 57 allergy 23 clinical signs 22 clinical subgroups 22–3 crisis phases 22 diathesis factors 23 environmental factors 23 hyperreactivity 23

Index immuno-allergologic pattern 23 provocative factors 22 severe 22 somatosensory system 38–45 topical factors 23 sensitization antiperspirants 154 deodorants 154 hair dyes 233, 234 sensory axons 39, 41 serine proteases 7 serums, moisturizers 504 shampoos 115–21, 224–5 allergic reactions 58–9 attributes 118–20 chemical availability optimization 119 colored hair 234 conditioning 121, 225 conditioning aids 116 cosmetic 116 alternating with therapeutic 120 cosmetically-optimized 116, 120 effective use 120–1 formulation 115–18, 224–5 irritation prevention 119–20, 121 products 115–18 rinse-off conditioner 121 surfactants 116–17 therapeutic 116–17 advantages/disadvantages 120 benefit 121 cost 120 effective use 120–1 shaving, blade 156–62 females 156–7, 162 hair properties 158–9 irritation 158 males 156–62 moisturizer use 162 process 161–2 razors 159–61 rinsing skin 162 skin cleansing 161 technology 156 shaving creams 161 shaving gels 161 signal transduction pathway activation 15 silicone allergic reactions 60 hair conditioners 225 hair styling aids 262–3 silicone derivatives, moisturizer occlusive 126 silicone oils, facial foundation 169 skin color 172 discoloration with collagen fillers 370 hairy 38, 39, 40, 41

hyperreactivity 23 pH 96, 108 topography 158–9 type and facial cleanser selection 99, 100 skin barrier building ingredients in cleansers 103 damage in cleansing 105 see also barrier function; epidermal barrier skin benefit agents 89–90 skin cancer immunomodulator association 288 immunosuppression 20 PGE-2 288 skin contouring techniques hand recontouring with calcium hydroxylapatite 473–9 liposuction 450–60 neck 463–71 skin disease nutrient effects 339–40 psychosocial aspects 182 skin modulation techniques laser-assisted hair removal 432–7 LED photomodulation 444–8 radiofrequency devices 439–42 skin of color 27–35 aging of skin 31–2 contact dermatitis 30 dermis 31 dryness 30 epidermis 29 facial cosmetics 167 hair differences 33–4 makeup shades 172 mast cells 30 melanin photoprotection 33 melanosomes 27–8 patch test antigens 30 photoaging 18, 32–3 reactivity 30 self-perceived sensitive skin 24 stratum corneum 29 transepidermal water loss 30 UV irradiation 18 protective factors 29 see also black skin; named racial groups; white skin skin partition coefficient, cosmetic actives 64 skin problems, facial cleansing 100–1 skin tightening expectations 440 monopolar radiofrequency 439–41 patient selection 440 radiofrequency devices 439–42 skincare, growth factors 304–5 slowly adapting (SA) receptors 39

SmartXide DOT resurfacing 396, 402 smile downturned 351 Botox treatment 348, 349 gummy 348 smoking, lip pigmentation 186 soap 57, 77 acne treatment 488–9 basic 78 drying potential on skin 80 pH 81 superfatted 81 transparent 78–9 soap bars 78–9 antibacterial 79 deodorant 79 market share 79 mildness 82–4 skin condition treatment 84–5, 86 stratum corneum interaction 80 superfatted 78 sodium cocyl isethionate 505 sodium lactate, moisturizer clinical efficacy 133–4 sodium laureth sulfate (SLES) 103 sodium lauryl sulfate (SLS) 103 damage protection 323 soft tissue augmentation 361–2 allergic reactions 60 calcium hydroxylapatite 356–60 see also fillers solid lipid nanoparticles (SNP) 66 solvents cosmetic actives 65 facial cleansers 97 irritants 57 nail lacquers 208 nail polish remover 213 somatosensory cortex 44, 45 somatosensory system central projections 43–4 pain 42–3 pathways 45 pleasure sensation 43 sensitive skin 38–45 temperature 41–2 touch 38–9, 40, 41 South Asian skin, UV irradiation 18 South-East Asian skin, UV irradiation 18 soy isoflavones 338–9 spinal cord 43–4 spinal nucleus of V 44 spinothalamic tract 44 stabilizers, vitamin E 325 Staphylococcus aureus 107 Staphylococcus epidermidis 107 status cosmeticus 22 stem cell, growth factors 307

529

Index stinging, burning and itching (SBI) score 24 stratum basale 4 stratum corneum 3, 4, 5 barrier function assessment 127 barrier to cosmetic actives 62 calcium gradient 9 components 4 detergent bar interactions 80–2 environmental toxin protection 7 facial skin 123–4 hydration function 7 maintenance 126 hydroxyacids effects 329 integrity assessment 9–10 intercellular spaces 10 lipids 82 moisturization function 7 pH 9 proteases 7, 8 skin of color 29 soap bar interactions 80 surfactant interaction 80 topical drug penetration protection 7 ultrastructural details 10 urea 133 see also desquamation stratum corneum chymotryptic enzyme (SCCE) 124 stratum granulosum 4 stratum spinosum 4 stress, psoriasis 508 striae, microdermabrasion 422 submandibular glands, ptotic 470 submandibular region 463 submental fat 465 submental fold, development after neck liposuction 470 submicron delivery systems (SDS) 65 substrate cleansers, facial 98–9 sulfacetamide sulfur 500 sulfites hair permanent waving 243 hair straighteners 251 sulfur 118, 491 sun exposure, psoriasis 510 sun protection clothing 482–3 photoaging prevention 18–19 rosacea 496, 499 sun protection factor (SPF) 18–19, 144, 481–2 evaluation 147 sunburn, NSAID use 288 sunscreens 481–3 regulatory status 144–5 sunless tanning products 140 SunGuard 483

530

sunless tanning products 139–42 active ingredients 139 buffers 140 color additives 141 coloration 141–2 creams 140–1 definition 139 delivery vehicles 140–1 evaluation 142 formulation 140 gels/gelees 141 labeling 141 lotions 140–1 moisturization 142 nitrogen-containing compounds 140 no-rub mists 142 pH 140 product attributes 141–2 regulatory aspects 141 sunscreens 140 trends 142 UV protection 142 sunlight, premature aging of skin 32 sunscreens 18, 144–8, 146–7 classification 144–5 development 145–7 efficacy evaluation 147–8 efficiency 146–7 facial moisturizers 127 formulation 147 migration over face 51 moisturizers 506 rosacea 499 UVA protection 144 vehicles 147 superficial musculo-aponeurotic system (SMAS) 32 superoxide dismutase (SOD) 8, 300 supersaturation 64 surfactants body washes 89 cleansers 480 cleansing bars 77–8 facial cleansing 96, 97 groups 96 hair permanent waving 242 hair styling products 262 lipid interactions 105 low-foam cleansers 102–3 mild 103 non-foam cleansers 102–3 pH 96 shampoos 116–17 skin barrier damage 105 skin interactions 80 stratum corneum interaction 80 substrate cleansers 98 waterless cleansers 104 see also soap; syndets/syndet bars

surgical scars, dermabrasion 427 sweat glands 150, 151, 152–3 hydrophilic substance delivery 62 sweating 155 control 155 physiology 151, 153 swelling Botox 349–50 collagen fillers 370 sympathetic nerves 43 synapses, afferent nerve 43–4 syndets/syndet bars 79 acne treatment 488–9 body washes 89 eczema 505–6 mildness 82–4 pH 81 skin condition treatment 84–5, 86 stratum corneum interactions 80–2 synthetic polymers, cleansers 480 T cells, corticosteroid prolonged use 287 T4 endonuclease V 299–300 tacrolimus 288 eczema treatment 502 tactile perception, psychophysical channels 39 tactile primary afferents 43 tanning 139 see also sunless tanning products tanning beds, psoriasis treatment 510–11 tannins 272 tape stripping 68 tar, psoriasis 508, 509, 510, 511 tattooing, medical 179 tattoos, black henna 234 tea tree oil 492 tear troughs, polylactic acid fillers 375 telangiectasia, camouflage makeup 182 telogen phase of hair growth 158, 433 temperature sensing 41–2 temperature-sensitive fibers 41–2 terminal hair 33, 433 terpenes 272 texturing agents, lipsticks 187–8 thalamocortical afferents 44, 45 Thermacool device 440 Thermafrax procedure 441 thermal primary afferents 44 thermosensitive mechanoreceptors 41–2 thickeners 73 thighs, liposuction indications 453–4 thioglycolate hair straighteners 250–1 thioglycolic acid salts 241–2, 243, 245 thiol hair straightening 250–1 with heat 255 thixotropic agents, nail lacquer 209 tighteners, botanicals 276

Index Time and Extent Application (TEA), UV filters 145 tissue inhibitors of metalloproteinase (TIMP), skin damage 302 titanium dioxide 146, 481 sunscreen 482 TNS Recovery Complex 305–6 tocopherol see vitamin E d-alpha-tocopherol, topical 484 tocopherol acetate 325 toluene, nail lacquer solvent 208 para-toluenediamine (pTD) 234 toners, facial cleansers 98 topical drugs, stratum corneum protective function 7 topical factors, sensitive skin 23 topical products antioxidant protection 52–3, 54 epidermal barrier 10 tosylamide/formaldehyde resin 211–12 touch 38–9, 40, 41 touch receptors 39 transepidermal delivery, cosmetic actives 62 transepidermal water loss (TEWL) 10, 124 extremozyme protection 300 microdermabrasion 418 self-perceived sensitive skin 25 skin of color 30 soap bar use 80 stratum corneum barrier function assessment 127 transforming growth factor beta (TGF-beta), collagen production 15 transforming growth factor beta (TGF-beta)/Smad pathway 16 trans-retinoic acid (tRA) 19 trans-urocanic acid (tUCA) 8, 9 trauma, nail dystrophy 203 traumatic scars, dermabrasion 427 tretinoin peel 378, 380 see also retinoic acid triangle of youth 362–3 trichloracetic acid 378, 379 depth-controlled peel 381 medium depth peel 384–5, 389, 390, 391 microdermabrasion comparison 423 techniques 386, 388 microdermabrasion combination 421 triclocarban 491 triclosan 491 trigeminal nerve 44 tropic acid 483 tumescent local anesthesia (TLA), liposuction 450, 451–2 neck 466–7 technique 456–7 turmeric 278–9

Tyndall effect 353 tyrosinase 28 tyrosinase-related protein (TRP) 28 ubiquinone see coenzyme Q10 (CoQ10) ultrasound waves, penetration enhancement 66–7 ultraviolet A (UVA) radiation 14, 144 critical wavelength method 148 protection antiaging 481 level determination 147–8 protective factor in black skin 29 reactive oxygen species induction 14, 15–16 sunscreens 144 ultraviolet B (UVB) radiation 14–15, 144 antiaging protection 481 hydroxyacids 330 protective factor in black skin 29 sunscreens 144 ultraviolet C (UVC) radiation 14 ultraviolet (UV) filters 145 efficiency 146–7 inorganic 146 organic 146 Time and Extent Application 145 ultraviolet (UV) fluorescence photography 50–1 ultraviolet light (UV) 144 angiogenesis of skin 19 erythema induction 447 ethnic skin 18 protective factors 29 exposure 13, 14 extracellular matrix degradation effects 19 fibroblast effects 17 keratinocyte effects 17 pigmentation induction 28 nutrient protection 335, 336, 337–8 photodamage 14–16, 17 protection 481–3 protective antioxidant product 53 psoriasis therapy 510–11 retinol absorption 314 retinyl ester absorption 314 skin damage protection 11 spectrum 14–15 vitamin E protection 325 see also photoaging ultraviolet light (UV) barrier 7–8 sunless tanning products 142 ultraviolet light protection factor (UPF) 18, 483 ultraviolet (UV) reflectance photography 50, 51 urea dry skin treatment 133

moisturizers 131 clinical efficacy 133–4 psoriasis 508, 509, 509 stratum corneum 133 urticaria, contact 56, 57–8 UV gel nails 216–17 vascular cell adhesion molecules (VCAM) 285 vascular compromise, collagen fillers 371 vascular endothelial growth factor (VEGF) 15, 19 vascular malformation, camouflage makeup 181 vellus hair 33 vermillion border, collagen filler injection 368 vibrotactile stimulation 39 VISIA CR® system 49–50 vitamin(s) oral 492–3 topical 319–26 vitamin A acne treatment 493 formulation 321 irritation 321 mechanisms of action 319–20 photodegradation 312 stability 321 structure 320 topical 319–21 UV damage protection 337 see also retinol vitamin B3 321–3 depigmentation 323 forms 321 formulation 323 mechanisms of action 322–3 structure 322 topical effects 323 wrinkle treatment 323 vitamin B5 323–4 vitamin C antiaging effects 325, 484, 486 antioxidant 281, 282, 283, 324 topical formulation 284 collagen synthesis co-factor function 484 forms 324 formulation 325, 484 mechanisms of action 324–5 photodamage mitigation 20 rosacea treatment 500 topical 324–5 UV damage protection 337 with vitamin E 484–5 vitamin D skin health 336 topical 325

531

Index vitamin E antiaging 484, 486 antioxidant 281, 282, 283, 325 topical formulation 284 formulation 325 isomers 484 photoaging reversal 484 skin changes 339 skin diseases 339–40 topical 325 UV damage protection 337 with vitamin C 484–5 wound healing 339–40 vitamin K, topical 325 vitamin P see flavonoids vitiligo, camouflage 179, 180 warm-sensitive fibers 41, 42 water vapor flux measurement 10 waterless cleansers 104 waterpacts 169–70 waxes hair styling aids 259, 260, 262, 263 lipsticks 187

532

waxy pastes, lipsticks 187 wetness control 152–3 Wetness Inhibiting Performance, antiperspirants 153 white petrolatum 506 white skin dermis 31 irritant contact dermatitis 30 photoaging 33 whitening of skin 295 wound healing dermabrasion postoperative 430 granulation 303 growth factors 303–4 inflammatory phase 303 medium depth chemical peel 388, 389 nutrient effects 339–40 physiology 302–5 re-epithelialization 303 wrinkles Botulinum neurotoxin injections 299 facial foundation effect measurement of antiwrinkle performance 173 formation with photoaging 33

hydroxyacids 332, 333 improvement detection 51–2, 53 optical profilometry 51–2, 53 peptide application 298 Raking Light Optical Profilometry 51–2, 53 retinaldehyde treatment 314 retinoid treatment 320–1 skin around lips 186 topical product evaluation 48 vitamin B3 treatment 323 zeaxanthin 337, 339 zinc deficiency 340 UV damage protection 338 zinc oxide 146 microdermabrasion 418 sunscreen 481, 482 zinc sulfonate 492 Zyderm II® filler 362, 364, 365–6, 367 hands 473 Zyplast® filler 362, 364, 365–6, 367, 369 hands 473

Cosmetic Dermatology: Products and Procedures - PDF Free Download (2024)

References