Cosmetic Dermatology: Products and Procedures, [2nd Edition.] 9781118655580, 1118655583

1,019 106 41MB

English Pages [563] Year 2015

Report DMCA / Copyright


Polecaj historie

Cosmetic Dermatology: Products and Procedures, [2nd Edition.]
 9781118655580, 1118655583

Table of contents :
Cosmetic Dermatology Products and Procedures
Part I Basic Concepts
Section 1: Skin Physiology Pertinent to Cosmetic Dermatology
Chapter 1 Epidermal Barrier
Structural components of the epidermal barrier
Proteins of the cornified envelope
Lamellar granules and inter‐corneocyte lipids
Lipid–protein cross‐links at the cornified envelope
Desmosomes and corneodesmosomes
Keratohyalin granules
Functions of epidermal barrier
Water evaporation barrier (epidermal permeability barrier)
Mechanical barrier
Antimicrobial barrier and immune protection
NMF and skin hydration/moisturization
Protection from environmental toxins and topical drugs penetration
Desquamation and the role of proteolytic enzymes
Melanin and UV barrier
Oxidative stress barrier
Regulation of barrier homeostasis
Corneocyte maturation
Lipid synthesis
Environmental and physiological factors
pH and calcium
Coordinated regulation of multiple barrier functions
Methods for studying barrier structure and function
Physical methods
Instrumental methods
Biological methods
Relevance of skin barrier to cosmetic product development
Topical products that influence barrier functions
Cosmetics that restore skin barrier properties
Skin irritation from cosmetics
Summary and future trends
Chapter 2 Photoaging
Photoaged versus chronically aged skin
Cutaneous microvasculature
Molecular mechanisms of photoaging
How does UV irradiation stimulate photoaging?
Reactive oxygen species
UV radiation inhibits procollagen production: TGF‐β/Smad signaling pathway
UV‐induced matrix metalloproteinases stimulate collagen degradation
Fibroblasts regulate their own collagen synthesis
Elastosis and cathepsins
UVA induces the aging‐associated progerin
Evolving data
Ethnic skin: photoaging
Primary prevention
Secondary prevention
Inherent defense mechanisms
Failure of prevention: immunosuppression
Chapter 3 Pigmentation and Skin of Color
Natural sun protective factor in skin of color
Skin of color
Transepidermal water loss
Skin reactivity
Intrinsic skin aging in ethnic skin
Extrinsic aging (photoaging) of ethnic skin
Chapter 4 Sensitive Skin and the Somatosensory System
Peripheral nervous system
Sympathetic nerves
The central projections
Spinal cord
Chapter 5 Novel, Compelling, Non-invasive Techniques for Evaluating Cosmetic Products
Commonly used non-invasive bioinstrumentation methods in cosmetic studies
Use of digital photography as a non-invasive technique for assessing skin features
Review of terminology in clinical photography
Visible light photography
Raking light photography
Polarized photography
UV reflectance photography
UV fluorescence photography
Use of raking light optical profilometry (RLOP) to detect improvements in periocular fine lines and wrinkles
A non-invasive method for assessing the antioxidant protection of topical formulations in humans
Use of image analysis for assessing a variety of skin conditions
Emerging technology for skin imaging and assessment
Chapter 6 Contact Dermatitis and Topical Agents
Pathophysiology and clinical presentation
Irritant contact dermatitis
Allergic contact dermatitis
Phototoxic dermatitis
Contact urticaria
Foreign body reactions
Common irritants and allergen groups
Specific cosmetic products
Cleansing agents
Skin bleaching agents
Topical corticosteroids
Hair dyes and bleaches
Nail products
Cosmetic application devices
Local anesthetics
Section 2 Delivery of Cosmetic Skin Actives
Chapter 7 Percutaneous Delivery of Cosmetic Actives to the Skin
The basics
Skin physiology
Active composition
Fick’s law
Vehicle effect
Delivery of actives from emulsions
Formulation strategies
Penetration enhancers
Chemical enhancers
Physical enhancers
Penetration enhancement vectors
Solid lipid nanoparticles
Devices for penetration enhancement
Ultrasound waves
In vitro and in vivo delivery assessment
Franz cell
Tape stripping
Confocal Raman microspectroscopy
Conclusions and future trends
Chapter 8 Creams and Ointments
Definitions of creams (and lotions) and ointments
Creams (and lotions)
Composition of a cream and an ointment
Oil-in-water cream
Part II Hygiene Products
Section 1 Cleansers
Chapter 9 Bar Cleansers
Cleansing bars – historical perspective
Formulation technology of cleansing bars
Continuous processing
Batch processing
Soap bars
Impact of cleansing bars on skin structure and function
Surfactant interaction with the skin–stratum corneum
Soap bar interactions with the stratum corneum
Synthetic detergent bar interactions with the stratum corneum
The role of pH
Cycle of dryness
Studies comparing mildness properties of soap and syndet cleansing bars
Controlled exposure trials
Normal usage trials
Benefits of mild cleansing for ashy skin
Benefits of mild cleansing for photodamaged skin
Practical implications of mild cleansing for patients with common skin disease
Benefits of mild cleansing for adults and children with mild atopic dermatitis
Benefits of mild cleansing for acne and rosacea patients
The future of cleansing bars
Further reading
Chapter 10 Personal Cleansers: Body Washes
Types of body wash
Major formula components of body washes
Skin benefit agents
Other ingredients
In‐use performance considerations for body washes
Cleansing ability
Consumer understanding and need for moisturizing body washes
Moisturization from body washes
Who will benefit from using body washes?
Ashy skin
Atopic dermatitis
Chapter 11 Facial Cleansers and Cleansing Cloths
A brief history of facial cleansing
How facial cleansers work
Chemistry of cleansing
Physical cleaning
Types of facial cleanser
Lathering cleansers
Emollient (oil-based) cleansers
Cleansing milks
Substrate cleansers
Guide to selecting facial cleansers
Selection based on skin type
Selection based on cleanser form/cleansing ritual
Selection based on skin problems
Chapter 12 Hand Cleansers and Sanitizers
Hand microbiota
Hand hygiene guidelines
Hand Hygiene Techniques and Compliance
Antimicrobial handwash and hand sanitizer formulations
Efficacy of antimicrobial handwashes and hand sanitizers
In vitro assays for potency and spectrum of activity
In vivo models with artificial inoculate to mimic transient flora
In vivo models with artificial inoculate to mimic resident flora
Clinical studies to demonstrate efficacy in reducing the burden of hand microbiota
Effectiveness of antimicrobial hand washes and hand sanitizers in institutional and community settings
Impact on nosocomial infections
Effectiveness of hand hygiene in the community setting
Handwash and hand sanitizer safety
Irritation associated with handwashes and hand sanitizers
Safety concerns specific to alcohol-based hand sanitizers
Development of microbial resistance to antimicrobial agents
Long-term effects on the skin microbiota
Future directions
Chapter 13 Shampoos for Normal Scalp Hygiene and Dandruff
Product and formulation technology overview
Unique attributes of scalp care products
Retention of active on scalp
Spatial distribution of deposited active
Chemical bio-availability
Advantages and disadvantages of the use of therapeutic shampoos
Effective use of products
Benefits of use of scalp care shampoos
Section 2 Moisturizers
Chapter 14 Facial Moisturizers
Dry facial skin
Facial moisturization
Facial moisturizer formulation
Moisturizer ingredients and function
Photoprotection and facial moisturizers
Facial moisturizer testing
Use of facial moisturizers in common inflammatory dermatoses
Further reading
Chapter 15 Hand and Foot Moisturizers
Moisturization needs of the hand and foot
Moisturizing formulations and technologies
Natural moisturizing factors
Ultrastructural effects
Clinical demonstrations of product efficacy of sodium lactate and urea formulations
Hand care
Improvements in urea content
Improvement in eczema and xerosis
Foot care
The future: Next‐generation moisturizers
Enhanced glycerol derivatives
Chapter 16 Sunless Tanning Products
Sunless tanning products
Active ingredients
Mechanism of action of DHA
Alternate actives
Formulation challenges
pH and buffers
Processing and storage of DHA
Nitrogen-containing compounds
Delivery vehicles
Creams and lotions
Gels and gelees
Regulatory considerations
Product attributes
Trends in sunless tanning
Daily use moisturizers/glow
No-rub mists
Sunless tanning spray booths
Sunless tanning products with UV protection
Chapter 17 Sunscreens
Regulatory status of sunscreens
Sunscreen classification
Approved UV filters
Development of sunscreens
Organic UV filters
Inorganic UV filters
Steps toward more efficient sunscreens
Formulation of sun protection products
Criteria and methods for evaluating the efficacy of sunscreen products
Determination of the sun protection factor (SPF)
SPF labeling
Determination of UVA protection level
UVA protection criteria
Section 3 Personal Care Products
Chapter 18 Antiperspirants and Deodorants
Sweat glands and how they work
Wetness and odor control and testing
Chemistry and formulation of antiperspirants
Delivery systems
Dermatologic concerns
Strengths and weakness of antiperspirants
Chapter 19 Blade Shaving
Hair biology basics
The pilosebaceous unit
Hair growth cycle
Properties of hair – impact on shaving
Shaving and the razor explored
Evolution of the system razor
Cutting edge technology
The shaving process
Challenges within male blade shaving
Part III Adornment
Section 1 Colored Facial Cosmetics
Chapter 20 Facial Foundation
Complexion makeup – an ancient practice
Ancient Mesopotamia (2500 bc)
Ancient Egypt (3rd millennium bc)
Ancient Greece
Ancient Rome
From the Middle Ages to the 19th century
20th century: the industrial era and diversification
Formulation diversity
Variety of formulations
Fluid foundations: emulsions
Compact foundations
Color creation
Pigments and coverage
Importance of fillers
When color and skincare combine
Facial foundation application
Emphasis on quality, safety and confirmed performance
Design stage
Formulation stage
Performance stage
Conclusions and prospects
Chapter 21 Camouflage Techniques
Camouflage makeup application procedures
Other camouflage therapies
Medical indications for camouflage makeup
Beginning a camouflage clinic
The camouflage therapist
Camouflage makeup and quality of life
Chapter 22 Lips and Lipsticks
Lip anatomy
Labial epidermis
Lip dermis and lamina propria
Lip topology
Sensitivity of lips to the environment
Aging of the lips
Lip plumpness and cheilitis
Defects of lip pigmentation
Lipstick formulation
Waxy pastes
Texturing agents
Antioxidants and preserving agents
Active ingredients
Lip glosses and brilliances
Chapter 23 Eye Cosmetics
Eye cosmetic history
Eyelash physiology
Mascara composition
Mascara applicator technology
Other eyelash treatments
Product application
Safety and regulatory considerations for eye area cosmetics
The future of eye cosmetics
Long wear
Pushing the applicator envelope
Lash conditioners and growers
Section 2 Nail Cosmetics
Chapter 24 Nail Physiology and Grooming
Introduction: Nail physiology
Nail unit anatomy
Nail matrix
Nail folds
Nail bed
Other structures
Nail growth
Physical properties of nails
Nail composition
Nail flexibility
Nail thickness
Nail grooming principles
Nail care
Nail trimming
Nail buffing and filing
Nail painting
Care for brittle nails
Adverse effects from nail grooming
Allergic reactions to nail cosmetic ingredients
Irritant reactions
Nail cosmetic procedures
Further reading
Chapter 25 Colored Nail Cosmetics and Hardeners
Application techniques
Lacquers, topcoats, and basecoats
Thixotropic agents
Color stabilizers
Minor ingredients
Antifungal agents
Nail hardeners
Formaldehyde issues
UV gel “lacquers” (aka UV gel polish)
Nail lacquer removers
Conclusions and future developments
Chapter 26 Cosmetic Prostheses as Artificial Nail Enhancements
Liquid and powder
UV gels
Nail wraps
Artificial nail removal
Gel manicure/polish
Adverse reactions
Nail damage and infection
UV nail lamp safety
Section 3 Hair Cosmetics
Chapter 27 Hair Physiology and Grooming
Hair follicle
Product of the hair follicle: the hair fiber
Human hair keratins
Shampoos: formulations and diversity
Chapter 28 Hair Dyes
Product subtypes
Temporary dyes
Semi-permanent dyes
Demi-permanent and permanent dyes
Natural hair pigmentation
Permanent hair dyes
Melanin bleaching
Oxidative dye formation
Advantages and disadvantages
Product choice and application
Impact of hair dyes on hair structure
Recent technology strategies to minimize fiber damage
Caring for colored hair
Safety and regulatory considerations
Key hair dye allergens
Allergy prevalence of hair dye allergy
Are children at higher risk to develop hair dye allergic reactions?
Allergy Alert Test
Permanent hair dyes with reduced allergy risk
Chapter 29 Permanent Hair Waving
Hair physiology
Permanent wave hair relevant properties
Hair geometry
Hair and water interaction
Hair aging
Hair chemical structure
Chemophysical principles of hair waving
Perm products and types
Role of permanent waving product ingredients
Different product types
Regulatory aspects of permanent hair waving
Perming practice – how to achieve a perfect curl
Safety of and adverse reactions to perm products
Chapter 30 Hair Straightening
Thermal processing
Reducing agents
Ammonium thioglycolate
Hydroxide straighteners
Chemistry of relaxing
Effect of relaxers on hair
Thiol procedure with heat
Chapter 31 Hair Styling: Technology and Formulations
Polymer formulations
Wax and emollient formulations
Product forms, application, and uses
Hairsprays and liquid settings
Gels and spray gels
Creams, pomades, and emulsions
Waxes and clays
Silicone serums and sprays
Products designed for African hair types
Protecting the hair structure with styling aides
Considerations for consultations with patients about hair styling
Future of hair styling aids – trends and technologic development
Part IV Anti-aging
Section 1 Cosmeceuticals
Chapter 32 Botanicals
Factors affecting concentration and quality of active ingredients
Mechanism of action
Cosmeceutical products
Specific herbs to treat or prevent photoaging
Charentais cantaloupe
German chamomile
Golden fern
Green tea
Milk thistle
Maitake mushroom
Shiitake mushroom
Swiss apple
Date palm fruit
Mountain rose
Recent herbal clinical trials
Chapter 33 Antioxidants and Anti-inflammatories
Antioxidants, free radicals and reactive oxygen species (ROS)
ROS effects on signaling pathways
ROS and glycation: effects on skin aging
Antioxidants protect cells from free radicals, ROS, and glycation
Antioxidants as anti-inflammatories: effects on cell signaling pathways
Biology of the skin inflammatory process
Topical formulation of antioxidants
Prescription medicines for inflammation and mechanism of action
Topical antioxidant anti-inflammatories
Designing effective anti-inflammatory and anti-aging topicals targeting three key mediators: TNF-alpha, IL-1, and PGE-2
Chapter 34 Peptides and Proteins
Amino acids
Biological functions of peptides and proteins in the skin
Obstacles to peptide use in cosmetic formulation
Antioxidant peptides
Skin elasticity
Proteolytic enzymes
T4 endonuclease V
Superoxide dismutase and catalase
Chapter 35 Cellular Growth Factors
Skin aging and wound healing
Role of cellular growth factors in skincare
Unique attributes
Advantages and disadvantages
Clinically proven benefits in reversal of skin aging and post-procedure healing
Risks associated with growth factors
Maintaining activity of growth factors through product shelf-life
Natural growth factors
Growth factors secreting stem cells
Synthetic growth factors
Related products
Alternate delivery methods
Chapter 36 Topical Cosmeceutical Retinoids
Biological concepts
Therapeutic and cosmeceutical retinoids
Epidermal vitamin A
The intracrine pro-ligand concept
Hyaluronan as a partner for cosmeceutical retinoids
Specific profiles of cosmeceutical retinoids
Retinol and retinyl esters
Chapter 37 Topical Vitamins
Vitamin A
Topical effects
Formulation challenges
Vitamin B3
Topical effects
Formulation challenges
Vitamin B5
Topical effects
Formulation challenges
Vitamin C
Topical effects
Formulation challenges
Vitamin E
Topical effects
Formulation challenges
Other vitamins
Vitamin D
Vitamin K
Vitamin P (flavonoids)
Chapter 38 Clinical Uses of Hydroxyacids
Chemical categorization and natural occurrence of hydroxyacids
Polyhydroxy acids
Aldobionic acids or bionic acids
Aromatic hydroxyacids
Physicochemical and biological properties distinguishing HAs
Water binding properties/gel matrix formation
Antioxidant properties
Antiglycation effects of PHA and bionic acids
Sun sensitivity
Sensory responses
MMP inhibition effects of bionic acids
Effects of HAs on skin – similarities and differences
Stratum corneum and epidermis
Clinical uses of HAs
Dry skin and hyperkeratinization
Keratoses and dyspigmentation
Wrinkles and photoaging
Uses as a peeling agent
Synergy with topical drugs
Chapter 39 The Contribution of Dietary Nutrients and Supplements to Skin Health
Nutrients and their role in protecting against UV-induced damage
Nutrients and their role in improving skin appearancwe
Nutrients shown to provide additional skin benefits
Nutrients and their potential in improving dermatologic disorders and wound healing
Section 2 Injectable Anti-aging Techniques
Chapter 40 Botulinum Toxins
Mechanism of action
Neurotoxin physical characteristics
Product stability
Safety and contraindications
Standard injection techniques
General considerations
Treatment of the upper face
Treatment of the mid-face
Treatment of the lower face
Combination of botulinum toxin with fillers
Complications and management
Upper face
Lower face
On the horizon
Chapter 41 Hyaluronic Acid Fillers
Chemical composition and properties of hyaluronic acid fillers
Injection techniques
Treatment optimization: persistence of dermal fillers and in vivo collagen stimulation
Chapter 42 Calcium Hydroxylapatite for Soft Tissue Augmentation
Physiology and pharmacology
Indications and techniques
Chapter 43 Autologous Skin Fillers
Platelet-rich plasma
Preparation of platelet-rich plasma
Techniques for PRP injection
Adverse reactions
Autologous fibroblast cell therapy
Techniques for autologous fibroblast injection
Adverse reactions
Adipose-derived stem cells
Techniques for adipose-derived stem cell injection
Adverse reactions
Chapter 44 Polylactic Acid Fillers
Advantages and disadvantages
Standard injection techniques
Advanced techniques
PLLA compared with other fillers
Section 3 Resurfacing Techniques
Chapter 45 Superficial Chemical Peels
Depth of peel
Histologic changes
Alfa-hydroxy acids (glycolic, lactic, malic, oxalic, tartaric, and citric acid)
Pyruvic acid (alfa-keto acid)
Jessner’s solution (resorcinol 14%, lactic acid 14%, and salicylic acid 14% in alcohol)
Trichloroacetic acid
Salicylic acid (ortho-hydroxybenzoic acid)
Tretinoin peel
Resorcinol (m-hydroxybenzene)
Solid carbon dioxide (dry ice)
Advantages and disadvantages
Standard technique
Initial consult
Peel procedure
Advanced techniques/specific uses
Depth controlled TCA peel
Fluor-hydroxy pulse peel
Chemical reconstruction of skin scars
Treatment of acne vulgaris
Treatment of post-inflammatory hyperpigmentation/melasma
Chapter 46 Medium Depth Chemical Peels
Trichloracetic acid
Advantages and disadvantages
Standard technique
Jessner’s TCA peel procedure after Monheit
Informed consent
Patient preparation
Analgesia and sedation
Application technique
Long-term care
Chapter 47 CO2 Laser Resurfacing: Confluent and Fractionated
CO2 laser resurfacing
Fractionated CO2 laser resurfacing
Active and Deep FX-Lumenis
Fraxel Re:Pair – Solta Medical
MiXto SX – Lasering USA
Mosaic eCO2™ – Lutronic
Pixel CO2 – Alma Lasers
SmartXide DOT – DEKA, Italy
CO2RE – Syneron–Candela
SmartSkin – Cynosure
ProFractional and ProFractional-XC – Sciton
Pixel 2940 – Alma
Lux 2940 – Cynosure
Xeo Pearl Fractionated – Cutera
Technique and procedures for fractionated laser treatment (Active/Deep FX)
Identification and management of complications
Further reading
Chapter 48 Nonablative Lasers
Nonablative modalities
Potassium titanyl phosphate (KTP) 532 nmlaser
Pulse dye laser (PDL) 585 nm or 595 nm
Intense pulsed light (IPL)
1320 nm Neodymium yttrium aluminium garnet (Nd:YAG)
Q-switched (QS) Nd:YAG 1064 nm laser
Erbium:glass 1540 nm
1450 nm diode laser
Infrared light devices (1100–1800 nm)
Radiofrequency devices (RF)
Advanced approaches
Chapter 49 Dermabrasion
Definition and history
Mechanism of action
Advantages and disadvantages
Patient selection and preoperative consultation
Standard technique
Advanced technique
Postoperative wound care
Section 4 Skin Modulation Techniques
Chapter 50 Laser-assisted Hair Removal
Biology of hair follicles
Basic concepts of laser-assisted hair removal
Preoperative management
Description of techniques
Long pulsed 694 nm ruby laser
Long pulsed 755 nm alexandrite laser
Long pulsed 800 nm diode laser
1064 nm Nd:YAG laser
Intense pulsed light
Radiofrequency combinations
Other removal methods for non-pigmented hair
Postoperative management
Future directions
Chapter 51 Radiofrequency Devices
Radiofrequency devices
Monopolar radiofrequency
Future directions
Bipolar radiofrequency and light
Bipolar radiofrequency and vacuum
Unipolar and bipolar radiofrequency device
Subdermal radiofrequency
Further reading
Chapter 52 LED Photomodulation for Reversal of Photoaging and Reduction of Inflammation
Clinical applications
Anti-inflammatory effects
Photodynamic therapy
References [CH3]
Section 5 Skin Contouring Techniques
Chapter 53 Liposuction: Manual, Mechanical, and Laser Assisted
Introduction: history of liposuction with tumescent local anesthesia
Physiology: what skin contour problem does the procedure address and how does this procedure alter the contour problem?
Advantages and disadvantages
Indications for tumescent liposuction, by anatomic site
Hips, outer thighs, and buttocks
Neck and jowls
Female breast
Male chest
Anesthesia technique
Standard and advanced operating technique
Preoperative phase
Intraoperative phase
Postoperative phase
Conclusions and future directions
Laser-assisted liposuction
Liposuction with TLA for lipedema
Chapter 54 Liposuction of the Neck
Aesthetic considerations
Patient selection
Consultation and physical examination
Anesthesia and infiltration
Liposuction: standard operative techniques
Postoperative course
Advanced and ancillary operating techniques
Chapter 55 Hand Recontouring with Calcium Hydroxylapatite
Physiology of the hand
Advantages of calcium hydroxylapatite for treatment of the aging hand
Technique of injection of CaHA into the hand
Preparing the Radiesse-lidocaine mixture
Where to inject
How to inject
Post-injection hand massage
Post-treatment care
Adverse events
Section 6 Implementation of Cosmetic Dermatology into Therapeutics
Chapter 56 Anti-aging Regimens
Vitamin C
Vitamin E (d-α-tocopherol)
Vitamin C with vitamin E
Vitamin C with vitamin E and ferulic acid
Other antioxidants
Chapter 57 Over-the-counter Acne Treatments
Soaps and syndets
Benzoyl peroxide
Alpha-hydroxy acids
Salicylic acid
Polyhydroxy acids
Triclosan and triclocarban
Cleansing cloths
Mechanical treatments
Essential oils
Oral vitamins
Chapter 58 Rosacea Regimens
Physiology of rosacea
Rosacea flare
Rosacea skincare: available OTC products
Cleansing and moisturizing
Available prescription agents
Oral antibiotic therapy
Topical therapy
Other treatment modalities
Light-based therapies
Natural actives
Chapter 59 Eczema Regimens
Moisturizer mechanism of action
Moisturizer goals in eczema
Moisturizer delivery systems
Moisturizing emulsions
Moisturizing serums
Moisturizing liposomes and niosomes
Multivesicular emulsions
Moisturizing nanoemulsions
Developing a moisturizer regimen
Chapter 60 Psoriasis Regimens
Role of OTC medications
Psoriasis education
Role of self-treating
OTC products recommended by physicians
Compliance in psoriasis treatment
Moisturizers and keratolytics
Other OTC products
Ultraviolet light (UV) therapy
Combination regimens

Citation preview

Cosmetic Dermatology Products and Procedures

Cosmetic Dermatology Products and Procedures Edited by

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

Second Edition

Editorial offices:

Registered office:

This edition first published 2016 © 2016 by John Wiley & Sons, Ltd © 2010 by Blackwell Publishing, Ltd John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 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 The right of the author to be identified as the author of this work has been asserted in accordance with the UK 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. 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. 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 health science practitioners 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 (Draelos) Cosmetic dermatology : products and procedures / edited by Zoe Diana Draelos.—Second edition. p. ; cm. Includes bibliographical references and index. ISBN 978-1-118-65558-0 (cloth) I. Draelos, Zoe Kececioglu, editor. II. Title. [DNLM: 1. Cosmetics. 2. Dermatologic Agents. 3. Cosmetic Techniques. 4. Dermatologic Surgical Procedures. 5. Skin Care—methods. QV 60] RL87 646.7′2—dc23 2015030110 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Cover images: background © Getty Images/Ian Hooton/SPL; middle © Getty Images/Renee Keith Set in 9.5/12pt Minion Pro by Aptara Inc., New Delhi, India 1



10 Personal Cleansers: Body Washes, 96

Contributors, viii

Keith Ertel and Heather Focht

Foreword, xii

12 Hand Cleansers and Sanitizers, 110

Duane Charbonneau

13 Shampoos for Normal Scalp Hygiene and Dandruff, 124

James R. Schwartz, Eric S. Johnson, and Thomas L. Dawson, Jr.

1 Epidermal Barrier, 3

Section 1: Skin Physiology Pertinent to Cosmetic Dermatology, 3

Thomas Barlage, Susan Griffiths-Brophy, and Erik J. Hasenoehrl

Part I: Basic Concepts, 1

11 Facial Cleansers and Cleansing Cloths, 103

Preface, xiii

Section 2: Moisturizers, 132 14 Facial Moisturizers, 132

3 Pigmentation and Skin of Color, 23

Teresa M. Weber, Andrea M. Schoelermann, Ute Breitenbach, Ulrich Scherdin, and Alexandra Kowcz

4 Sensitive Skin and the Somatosensory System, 33

Section 2: Delivery of Cosmetic Skin Actives, 65

Section 3: Personal Care Products, 160

18 Antiperspirants and Deodorants, 160

David E. Cohen, Alexandra Price, and Sarika Ramachandran

Dominique Moyal, Angelike Galdi, and Christian Oresajo

Eric S. Abrutyn

19 Blade Shaving, 166

6 Contact Dermatitis and Topical Agents, 52

17 Sunscreens, 153

Evaluating Cosmetic Products, 42 Thomas J. Stephens, Christian Oresajo, Lily I. Jiang, and Robert Goodman

Angelike Galdi, Peter Foltis, and Christian Oresajo

5 Novel, Compelling, Non-invasive Techniques for

16 Sunless Tanning Products, 148

Francis McGlone and David Reilly

Kevin Cowley, Kristina Vanoosthuyze, Gillian McFeat, and Keith Ertel

7 Percutaneous Delivery of Cosmetic Actives to

15 Hand and Foot Moisturizers, 139

Jasmine C. Hollinger, Chesahna Kindred, and Rebat M. Halder

Yohini Appa

Kira Minkis, Jillian Havey Swary, and Murad Alam

2 Photoaging, 13

Sreekumar Pillai, Megan Manco, and Christian Oresajo

8 Creams and Ointments, 75

the Skin, 65 Sreekumar Pillai, Surabhi Singh, and Christian Oresajo

Part III: Adornment, 175

Irwin Palefsky

Section 1: Colored Facial Cosmetics, 175

9 Bar Cleansers, 83

Sylvie Guichard and Véronique Roulier

21 Camouflage Techniques, 186

Anne Bouloc

22 Lips and Lipsticks, 193

Anthony W. Johnson, K.P. Ananthapadmanabhan, Stacy Hawkins, and Greg Nole

Section 1: Cleansers, 83

20 Facial Foundation, 177

Part II: Hygiene Products, 81

Catherine Heusèle, Hervé Cantin, and Frédéric Bonté




Sarah A. Vickery, Robyn Kolas, and Fatima Dicko

39 The Contribution of Dietary Nutrients and Supplements

23 Eye Cosmetics, 199

to Skin Health, 357 Helen Knaggs, Steve Wood, Doug Burke, Jan Lephart, and Jin Namkoong

Section 2: Nail Cosmetics, 207

J. Daniel Jensen, Scott R. Freeman, and Joel L. Cohen

41 Hyaluronic Acid Fillers, 375

Mark S. Nestor, Emily L. Kollmann, and Nicole Swenson

26 Cosmetic Prostheses as Artificial Nail Enhancements, 226

Paul H. Bryson and Sunil J. Sirdesai

42 Calcium Hydroxylapatite for Soft Tissue

Douglas Schoon

40 Botulinum Toxins, 364

25 Colored Nail Cosmetics and Hardeners, 217

Section 2: Injectable Anti-aging Techniques, 364

Anna Hare and Phoebe Rich

24 Nail Physiology and Grooming, 207

Augmentation, 380 Stephen Mandy

Section 3: Hair Cosmetics, 234

Annette Schwan-Jonczyk, Gerhard Sendelbach, Andreas Flohr, and Rene C. Rust

45 Superficial Chemical Peels, 395

M. Amanda Jacobs and Randall Roenigk

31 Hair Styling: Technology and Formulations, 270

Thomas Krause and Rene C. Rust

46 Medium Depth Chemical Peels, 402

Harold Bryant, Felicia Dixon, Angela Ellington, and Crystal Porter

Section 3: Resurfacing Techniques, 395

30 Hair Straightening, 262

Kenneth R. Beer and Jacob Beer

Gary D. Monheit and Virginia A. Koubek

47 CO2 Laser Resurfacing: Confluent and Fractionated, 412

29 Permanent Hair Waving, 251

44 Polylactic Acid Fillers, 390

Rene C. Rust and Harald Schlatter

Amer H. Nassar, Andrew S. Dorizas, and Neil S. Sadick

28 Hair Dyes, 239

43 Autologous Skin Fillers, 385

Maria Hordinsky, Ana Paula Avancini Caramori, and Jeff C. Donovan

27 Hair Physiology and Grooming, 234

Mitchel P. Goldman and Ana Marie Liolios

48 Nonablative Lasers, 429

Adam S. Nabatian and David J. Goldberg

Part IV: Anti-aging, 281

49 Dermabrasion, 437

Christopher B. Harmon and Daniel P. Skinner

Section 1: Cosmeceuticals, 283

50 Laser-assisted Hair Removal, 445

Keyvan Nouri, Voraphol Vejjabhinanta, Nidhi Avashia, and Jinda Rojanamatin

33 Antioxidants and Anti-inflammatories, 295

Section 4: Skin Modulation Techniques, 445

Carl R. Thornfeldt

32 Botanicals, 283

Bryan B. Fuller

35 Cellular Growth Factors, 318

Rahul C. Mehta and Richard E. Fitzpatrick

51 Radiofrequency Devices, 451

Vic Narurkar

52 LED Photomodulation for Reversal of Photoaging and

Karl Lintner

34 Peptides and Proteins, 308

Reduction of Inflammation, 456 David McDaniel, Robert Weiss, Roy Geronemus, Corinne Granger, and Leila Kanoun-Copy

36 Topical Cosmeceutical Retinoids, 325

Olivier Sorg, Gürkan Kaya, and Jean H. Saurat

38 Clinical Uses of Hydroxyacids, 346

Barbara A. Green, Eugene J. Van Scott, and Ruey J. Yu

Section 5: Skin Contouring Techniques, 463 53 Liposuction: Manual, Mechanical, and Laser

Donald L. Bissett, John E. Oblong, and Laura J. Goodman

37 Topical Vitamins, 336

Assisted, 463 Anne Goldsberry, Emily Tierney, and C. William Hanke


56 Anti-aging Regimens, 492

Karen E. Burke

57 Over-the-counter Acne Treatments, 501

Emmy M. Graber and Diane Thiboutot

Zoe D. Draelos

60 Psoriasis Regimens, 522

Section 6: Implementation of Cosmetic Dermatology into Therapeutics, 492

Joseph Bikowski

Kenneth L. Edelson

59 Eczema Regimens, 517

Kimberly J. Butterwick

55 Hand Recontouring with Calcium Hydroxylapatite, 485

58 Rosacea Regimens, 509

54 Liposuction of the Neck, 476

Laura F. Sandoval, Karen E. Huang, and Steven R. Feldman

Index, 529



Eric S. Abrutyn

Kimberly J. Butterwick

Murad Alam

Hervé Cantin

K.P. Ananthapadmanabhan

Ana Paula Avancini Caramori

TPC2 Advisors Inc., Boquete, Chiriqui, Republic of Panama

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Unilever HPC R&D, Trumbull, CT, USA

Yohini Appa

Johnson & Johnson, New Brunswick, NJ, USA

Cosmetic Laser Dermatology, San Diego, CA, USA

LVMH Recherche, Saint Jean de Braye, France

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

Duane Charbonneau

Procter and Gamble Company, Health Sciences Institute, Mason, OH, USA

Nidhi Avashia

Boston University School of Medicine, Boston, MA, USA

Thomas Barlage

Procter & Gamble Company, Sharon Woods Technical Center, Cincinnati, OH, USA

Jacob Beer

Department of Dermatology, University of Pennsylvania, PA, USA

Kenneth R. Beer

General, Surgical and Esthetic Dermatology, West Palm Beach, FL, USA

David E. Cohen

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA

Joel L. Cohen

AboutSkin Dermatology and DermSurgery, Englewood, and Department of Dermatology, University of Colorado at Denver, Aurora, CO, USA

Kevin Cowley

Gillette Innovation Centre, Reading, UK

Thomas L. Dawson, Jr.

Joseph Bikowski

Bikowski Skin Care Center, Sewickley, PA, USA

Agency for Science, Technology and Research (A*STAR), Institute for Medical Biology, Singapore

Donald L. Bissett

Fatima Dicko

Procter & Gamble Beauty Science, The Procter & Gamble Co., Sharon Woods Innovation Center, Cincinnati, OH, USA

Procter & Gamble Cosmetics, Hunt Valley, MD, USA

Frédéric Bonté

L'Oréal Institute for Ethnic Hair and Skin Research, Chicago, IL, USA

Felicia Dixon

LVMH Recherche, Saint Jean de Braye, France

Anne Bouloc

Jeff C. Donovan

Division of Dermatology, University of Toronto, Toronto, Canada

Vichy Laboratoires, Cosmétique Active International, Asnières, France

Ute Breitenbach

Andrew S. Dorizas

Sadick Dermatology, New York, NY, USA

Beiersdorf AG, Hamburg, Germany

Harold Bryant

Kenneth L. Edelson

Icahn School of Medicine at Mount Sinai and Private Practice, New York, NY, USA

L'Oréal Institute for Ethnic Hair and Skin Research, Chicago, IL, USA

Paul H. Bryson

OPI Products Inc., Los Angeles, CA, USA

Doug Burke

Nu Skin and Pharmanex Global Research and Development, Provo, UT, USA

Karen E. Burke

The Mount Sinai Medical Center, New York, NY, USA


Angela Ellington

L'Oréal Institute for Ethnic Hair and Skin Research, Chicago, IL, USA

Keith Ertel

Procter & Gamble Co., Cincinnati, OH, USA

Steven R. Feldman

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


Richard E. Fitzpatrick (deceased)

C. William Hanke

Andreas Flohr

Anna Hare

Heather Focht

Christopher B. Harmon

Peter Foltis

Erik J. Hasenoehrl

Scott R. Freeman

Jillian Havey Swary

Bryan B. Fuller

Stacy Hawkins

Angelike Galdi

Catherine Heusèle

Roy Geronemus

Jasmine C. Hollinger

Department of Dermatology, UCSD School of Medicine, San Diego, CA, USA

Wella/Procter & Gamble Service GmbH, Darmstadt, Germany

Procter & Gamble Co, Cincinnati, OH, USA

L'Oréal Research, Clark, NJ, USA

Sunrise Dermatology, Mobile, AL, USA

DermaMedics LLC, Oklahoma City, OK, USA

L'Oréal Research and Innovation, Clark, NJ, USA

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

David J. Goldberg

Mount Sinai School of Medicine, New York, NY, and Skin Laser and Surgery Specialists of New York and New Jersey, USA

Mitchel P. Goldman

Cosmetic Laser Dermatology and Volunteer Clinical Professor of Dermatology at the University of California, San Diego, CA, USA

Anne Goldsberry

Laser and Skin Surgery Center of Indiana, Carmel, IN, USA

Laura J. Goodman

Procter & Gamble Beauty Science, The Procter & Gamble Co., Sharon Woods Innovation Center, Cincinnati, OH, USA

Robert Goodman

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

Emmy M. Graber

Boston University School of Medicine, Boston, MA, USA

Corinne Granger

Director of Instrumental Cosmetics, L'Oreal Research, Asnieres, France

Laser and Skin Surgery Center of Indiana, Carmel, IN, USA

Emory School of Medicine, Atlanta, GA, USA

Surgical Dermatology Group, Birmingham, AL, USA

Procter & Gamble Company, Ivorydale Technical Center, Cincinnati, OH, USA

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Unilever HPC R&D, Trumbull, CT, USA

LVMH Recherche, Saint Jean de Braye, France

Howard University College of Medicine, Washington, DC, USA

Maria Hordinsky

Department of Dermatology, University of Minnesota, Minneapolis, MN, USA

Karen E. Huang

Center for Dermatology Research, Wake Forest University School of Medicine; Winston-Salem, NC, USA

M. Amanda Jacobs

Division of Dermatology, Geisinger Health Systems, Danville, PA, USA

J. Daniel Jensen

Scripps Clinic, Bighorn Mohs Surgery and Dermatology Center, La Jolla, CA, USA

Lily I. Jiang

Thomas J. Stephens & Associates Inc., Texas Research Center, Richardson, TX, USA

Anthony W. Johnson

Unilever HPC R&D, Trumbull, CT, USA

Eric S. Johnson

Procter & Gamble Beauty Science, Cincinnati, OH, USA

Leila Kanoun-Copy

L'Oréal Research, Chevilly Larue, France

Barbara A. Green

NeoStrata Company, Inc., Princeton, NJ, USA

Gürkan Kaya

Department of Dermatology, Geneva University Hospital, Geneva, Switzerland

Susan Griffiths-Brophy

Procter & Gamble Company, Sharon Woods Technical Center, Cincinnati, OH, USA

Chesahna Kindred

Sylvie Guichard

Helen Knaggs

L'Oréal Research, Chevilly-Larue, France

Rebat M. Halder

Howard University College of Medicine, Washington, DC, USA

Howard University College of Medicine, Washington, DC, USA

Nu Skin and Pharmanex Global Research and Development, Provo, UT, USA

Robyn Kolas

Procter & Gamble Cosmetics, Hunt Valley, MD, USA




Emily L. Kollmann

Amer H. Nassar

Virginia A. Koubek

Mark S. Nestor

Center for Clinical and Cosmetic Research, Aventura, FL, USA

Total Skin and Beauty Dermatology Center, PC, and Departments of Dermatology and Ophthalmology, University of Alabama, Birmingham, AL, USA

Alexandra Kowcz

Beiersdorf Inc, Wilton, CT, USA

Thomas Krause

Wella/Procter & Gamble Service GmbH, Darmstadt, Germany

Jan Lephart

Sadick Dermatology, New York, NY, USA

Center for Clinical and Cosmetic Research, Aventura, FL, USA

Greg Nole

Unilever HPC R&D, Trumbull, CT, USA

Keyvan Nouri

University of Miami Miller School of Medicine, Miami, FL, USA

John E. Oblong

Nu Skin and Pharmanex Global Research and Development, Provo, UT, USA

Procter & Gamble Beauty Science, The Procter & Gamble Co., Sharon Woods Innovation Center, Cincinnati, OH, USA

Karl Lintner

Christian Oresajo

KAL'IDEES SAS, Paris, France

Ana Marie Liolios

Private Practice, Fairway, Kansas, MO, USA

Megan Manco

L'Oréal Recherche, Clark, NJ, USA

Stephen Mandy

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

David McDaniel

McDaniel Institute of Anti Aging Research, Virginia Beach, VA, Eastern Virginia Medical School, Norfolk VA and Old Dominion University Norfolk VA, USA

Gillian McFeat

Gillette Innovation Centre, Reading, UK

Francis McGlone

School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, UK

L'Oréal Research, Clark, NJ, USA

Irwin Palefsky

Cosmetech Laboratories, Inc., Fairfield, NJ, USA

Sreekumar Pillai

L'Oréal Research, Clark, NJ, USA

Crystal Porter

L'Oréal Institute for Ethnic Hair and Skin Research, Chicago, IL, USA

Alexandra Price

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA

Sarika Ramachandran

The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA

David Reilly

Unilever Research, Colworth Science Park, Sharnbrook, Bedford, UK

Rahul C. Mehta

Phoebe Rich

SkinMedica, Inc, An Allergan Company, Carlsbad, CA, USA

Oregon Health and Science University, Portland, OR, USA

Kira Minkis

Randall Roenigk

Department of Dermatology, Weill Cornell Medical College, New York, NY, USA

Department of Dermatology, Mayo Clinic, Rochester, MN, USA

Gary D. Monheit

Jinda Rojanamatin

Total Skin and Beauty Dermatology Center, PC, and Departments of Dermatology and Ophthalmology, University of Alabama, Birmingham, AL, USA

Institute of Dermatology, Bangkok, Thailand

Dominique Moyal

L'Oréal Research, Chevilly-Larue, France

Véronique Roulier

La Roche-Posay Laboratoire Dermatologique, Asnières sur Seine, France

Adam S. Nabatian

Rene C. Rust

GSK/Stiefel, Brentford, Middlesex, UK

Albert Einstein College of Medicine, Bronx, NY, USA

Jin Namkoong

Neil S. Sadick

Nu Skin and Pharmanex Global Research and Development, Provo, UT, USA

Sadick Dermatology, New York, NY and Department of Dermatology, Weill Medical College of Cornell University, New York, NY, USA

Vic Narurkar

Laura F. Sandoval

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

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


Jean H. Saurat

Nicole Swenson

Ulrich Scherdin

Diane Thiboutot

Harald Schlatter

Carl R. Thornfeldt

Andrea M. Schoelermann

Emily Tierney

Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland

Beiersdorf AG, Hamburg, Germany

Procter & Gamble German Innovation Centre, Schwalbach am Taunus, Germany

Beiersdorf AG, Hamburg, Germany

Douglas Schoon

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

Annette Schwan-Jonczyk Private Practice, Darmstadt, Germany

James R. Schwartz

Procter & Gamble Beauty Science, Cincinnati, OH, USA

Gerhard Sendelbach Darmstadt, Germany

Surabhi Singh

L'Oréal Research, Clark, NJ, USA

Sunil J. Sirdesai

OPI Products Inc., Los Angeles, CA, USA

Daniel P. Skinner

Surgical Dermatology Group, Birmingham, AL, USA

Olivier Sorg

Swiss Centre for Applied Human Toxicology, University of Geneva, Geneva, Switzerland

Thomas J. Stephens

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

Center for Clinical and Cosmetic Research, Aventura, FL, USA

Private Practice, Boston, MA, USA

Episciences, Inc., Boise, ID, USA

Department of Dermatology, Tufts University School of Medicine, Boston, MA, USA

Eugene J. Van Scott

Private Practice, Abington, PA, USA

Kristina Vanoosthuyze

Gillette Innovation Centre, Reading, UK

Voraphol Vejjabhinanta

Institute of Dermatology, Bangkok, Thailand

Sarah A. Vickery

Procter & Gamble Cosmetics, Hunt Valley, MD, USA

Teresa M. Weber

Beiersdorf Inc, Wilton, CT, USA

Robert Weiss

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

Steve Wood

Nu Skin and Pharmanex Global Research and Development, Provo, UT, USA

Ruey J. Yu

Private Practice, Chalfont, PA, USA



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 has 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

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. Dr. 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 Anti-aging, which includes cosmeceuticals, injectable anti-aging 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



treasure trove of information on the subject, without which anyone interested in the topic would be sorely lacking. Use it as a reference text, dip into chapters or sections from time to time, or if you really want to know this subject, read it from cover to cover. Enjoy and treasure this work. Jeffrey S. Dover Boston, April 2015 ­

Who better to author and edit a textbook on cosmeceuticals than Zoe Draelos. She is the recognized leader in the field, having done most of the premier studies and written many of the definitive articles on the topic over the last decades. In her first edition, Dr. Draelos set the standard for comprehensive texts on the subject of cosmeceuticals. With this second edition, she has raised the bar even further, producing a near encyclopedic, comprehensive tome on the subject. It is a


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, non‐foaming, 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, anti‐inflammatories, 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 addressed 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 nonablative. Other rejuvenative devices affecting 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. 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 knowledge base. This is no longer the case. Cosmetic dermatology has become a field unto itself. Zoe D. Draelos Durham, NC

Part I

Basic Concepts

Skin Physiology Pertinent to osmetic Dermatology C

Sec tion 1:

pidermal Barrier C

Sreekumar Pillai, Megan Manco, and hristian




Cha ter 1


L’Oréal Research, Clark, NJ, USA


Con e ts c



• The outermost structure of the epidermis is the stratum corneum (SC) and it forms the epidermal permeability barrier which prevents the loss of water and electrolytes. • Understanding the structure and function of the stratum corneum and the epidermal barrier is vital because it is the key to healthy skin. • Novel delivery systems play 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. • Cosmetic companies will exploit this new knowledge in developing more efficacious products for strengthening the epidermal barrier and to enhance the functional and aesthetic 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, dermis and the hypodermis. Epidermis is the outermost structure and it is a multi‐layered epithelial tissue divided into several layers. The outermost structure of the epidermis is the stratum corneum (SC) and it forms the epidermal permeability barrier which prevents the loss of water and electrolytes. Other protective/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 stratum corneum and the epidermal barrier is vital because it is the key to healthy skin and its associated social ramifications.


tructural components of the epidermal barrier

The outer surface of the skin, the epidermis, mostly consists of epidermal cells, known as keratinocytes, that are arranged in several stratified layers – the basal cell layer, the spinous cell layer and the granular cell layer whose differentiation eventu-

ally produces the stratum corneum (SC). Unlike other layers, SC is made of anucleated cells called corneocytes that are derived from keratinocytes. 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. SC is a structurally heterogeneous tissue composed of non‐nucleated, flat, protein‐enriched corneocytes and lipid‐enriched 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 stratum corneum 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 play important roles in the protective barrier of the skin. A list of the different structural as well as functional components of the stratum corneum 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 contains 70% water as do most tissues, yet the SC contains 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

Cosmetic Dermatology: Products and Procedures, Second Edition. Edited by Zoe Diana Draelos. © 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.



BASIC CONCEPTS  Skin Physiology Pertinent to Cosmetic Dermatology

Keratohyalin and lamellar granules of the stratum granulosum

Stratum corneum Stratum granulosum


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.

leaving a proteinaceous core containing keratins, other structural proteins, free amino acids and amino acid derivatives, and melanin particles that 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 cornified cell envelope, formed from cross‐linked cytoskeletal proteins [3].

Proteins of the cornified envelope 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

Table 1.1  Structural and functional components of the stratum corneum Components



Stratum corneum (SC)


Topmost layer of epidermis

Cornified envelope (CE)

Resiliency of SC

Outer surface of the SC

Cornified envelope Precursor proteins

Structural proteins that are cross‐linked to form CE

Outer surface of the SC

Lamellar granules (LG)

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 bilayers

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

Natural Moisturizing Factor (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

1. Epidermal Barrier

protease inhibitors. The cross‐linking is promoted by the enzyme transglutaminase that 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. Lamellar granules and inter‐corneocyte lipids Lamellar granules or bodies (LG or LB) are specialized lipid carrying 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 stratum corneum, 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 sulphate, respectively. These enzymes include: lipases, phospholipases, sphingomyelinases, glucosyl ceramidases, and sterol sulphatases [8,9]. The lipids fuse together in the stratum corneum 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 [4,21]. 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 SC to release the omega hydroxyl ceramide that gets cross‐ linked to the amino groups of the cornified envelope proteins. 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 [5,21]. 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. Desmosomes and corneodesmosomes Desmosomes are specialized cell structures that provide cell‐ to‐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 stratum corneum. Corneodesmosomes have to be degraded by specialized proteases and glycosidases, mainly serine proteases, for the skin to shed in a process called desquamation [6]. Keratohyalin granules Keratohyalin granules are irregularly shaped granules present in the granular cells of the epidermis, thus providing these cells the 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 stratum corneum. 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 [7,8].

Functions of epidermal barrier Water evaporation barrier (epidermal permeability barrier) Perhaps the most studied and the most important function of SC is the formation of the epidermal permeability barrier [1,7,8]. SC limits the transcutaneous movement of water and electrolytes, a function that is essential for terrestrial survival. Lipids, particularly ceramides, cholesterol, and free fatty acids, together form lamellar membranes in the extracellular spaces of the SC that 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 [9,11,12]. 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.


BASIC CONCEPTS  Skin Physiology Pertinent to Cosmetic Dermatology

Table 1.2  Barrier functions of the epidermis

Table 1.3  Antimicrobial components of epidermis and stratum corneum


Localization/components involved


Class of compound


Water and electrolyte permeability barrier

SC/corneocyte proteins and extracellular lipids

Free fatty acids

Mechanical barrier

SC/corneocytes, cornified envelope

Microbial barrier/immune function

SC/lipid components/viable epidermis



Protection from environmental toxins/drugs

SC/corneocytes, cornified envelope


Stratum corneum

Glucosyl ceramides Lipid

Stratum corneum



Stratum corneum



Stratum corneum










Nucleic acid



SC/epidermis/proteases and glycosidases

RNAse 7 Low pH


Stratum corneum

UV barrier

SC/melanins of SC/epidermis

Protein signaling molecules


Oxidative stress barrier

SC, epidermis/antioxidants

“Toll‐like” receptors Proteases


Stratum corneum and epidermis

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 stratum corneum. One such protein, trichohyalin is a multi‐functional cross‐bridging protein that forms intra and inter protein cross‐ links between cell envelope structure and cytoplasmic keratin filament network [13]. Special enzymes called transglutaminases, some present exclusively in the epidermis (transglutaminase 3), catalyzes this cross‐linking reaction. In addition, adjacent corneocytes are linked by corneodesmosomes, and many of the lipids of the stratum corneum 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. Microflora that normally inhabit human skin can contribute to the barrier defenses by competing for nutrients and niches that more pathogenic organisms require, by expressing antimicrobial molecules that kill or inhibit the growth of pathogenic microbes and by modulating the inflammatory response [32]. Desquamation that 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. 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. They contain common secondary structures that vary from α helical to β sheets, and their unifying characteristic is the ability to kill microbes or inhibit them from growing. Pathways that generate and regulate the antimicrobial barrier of the skin are closely tied to pathways that modulate the permeability barrier function. Expression of endogenous AMPs coincides with the presence of a number of epidermal structural components that may become part of the permeability barrier. For instance, murine cathelin‐related antimicrobial peptide CRAMP and mBD‐3 are essential for permeability barrier homeostasis. In addition, acute and chronic skin barrier disruption lead to increased expression of murin β‐defensins (mBDs)‐1, ‐3, and ‐14 and this increase in expression is diminished when the barrier is artificially restored [32]. NMF and skin hydration/moisturization Natural moisturizing factor (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 corneocyte. Many of the components of the NMF are derived from the hydrolysis of filaggrin, a histidine‐ and glutamine‐ rich basic protein of the keratohyalin granule. SC hydration level controls the protease that hydrolyze filaggrin and histidase that converts histidine to urocanic acid. As NMF is water soluble and can easily be washed away from 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, SC also acts to provide hydration and moisturization to skin. NMF components absorb and hold water allowing the outermost layers of the stratum corneum to stay hydrated despite exposure to the harsh external environment. Glycerol, a major component of the NMF, is an important humectant present in skin that contributes skin hydration. Glycerol is produced


% levels

Amino acids and their salts (over a dozen)


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






Glucosamine, creatinine, ammonia, uric acid Cations (sodium, calcium, potassium) Anions (phosphates, chlorides)

1–2 10–11 6–7



Citrate, formate


locally within 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 [14]. Other humectants in the NMF include urea, sodium and potassium lactates and PCA [7]. Protection from environmental toxins and topical drugs penetration The SC also has the important task of preventing toxic substances and topically applied drugs from penetrating the skin. SC acts as a protective wrap due to 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. 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 [6]. In addition, SC also contains protease inhibitors that keep these proteases in check and the balance of protease – protease inhibitors play 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 epidermal‐specific 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 play specific roles in the desquamatory process at different layers of the epidermis. Melanin and UV barrier Although melanin is not typically considered a functional component of 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 melanin, depending on the composition and the color. The darker eumelanin is most protective to UV than the lighter, high sulphur 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 ultraviolet radiation is very damaging to proteins, lipids and nucleic acids and cause oxidative damage to these macromolecules. The SC absorbs some ultraviolet 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 (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 UV‐damaged cells play a critical role in the decreased photocarcinogenesis seen in individuals with darker skin [15]. In addition to melanin, trans‐urocanic acid (tUCA), a product of histidine deamination produced in the stratum corneum, also acts as an endogenous sunscreen and protects skin from UV damage. xidative stress barrier The stratum corneum has been recognized as the main cutaneous oxidation target of UV and other atmospheric oxidants such as pollutants and cigarette smoke. Depletion of atmospheric “ozone layer” allows most energetic UV wavelength of sun radiation, i.e. UVC and short UVB to reach earth level. This high energy UV radiation penetrates deep into papillary dermis. UVA radiation in addition to damaging 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 [16]. In addition to its effects on SC, UV also initiates and activates a complex cascade of biochemical reactions O

able 1.4 Approximate composition of skin Natural Moisturizing Factor C


1. Epidermal Barrier


BASIC CONCEPTS  Skin Physiology Pertinent to Cosmetic Dermatology

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 [17]. 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 [18]. Skin naturally uses antioxidants to protect itself from photodamage. UV depletes antioxidants from outer stratum corneum. A gradient in the antioxidant levels (alpha‐tocopherol, Vitamin C, glutathione and urate) with the lowest concentrations in the outer layers and a steep increase in the deeper layers of the stratum corneum protects the SC from the oxidative stress [19]. Depletion of antioxidant protection leads to UV induced barrier abnormalities. Topical application of antioxidants would support these physiological mechanisms and restore a healthy skin barrier [20,21].

Regulation of barrier homeostasis Epidermal barrier is constantly challenged by environmental and physiological factors. Since 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. Continuous renewal process is balanced by desquamation that removes individual corneocytes in a controlled manner by degradation of desmosomal constituent proteins by the stratum corneum proteases. The protease activities are under the control of protease inhibitors that are co‐localized 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 sulphate also regulate desquamation by controlling the activities of the SC proteases [22]. Corneocyte maturation 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. 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 that 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 / ligands for the nuclear hormone receptors (example: PPAR – peroxisome

proliferation activator receptor and vitamin D receptor) that influence keratinocyte terminal differentiation are endogenous lipids synthesized by the 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 free fatty acids (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, as explained in the previous section, many of the hormonal regulators of corneocyte maturation are lipids or lipid intermediates synthesized by the epidermis. Stratum corenum lipid synthesis and lipid content are also altered with various skin conditions such as inflammation and winter xerosis [23,24]. Environmental and physiological factors Barrier homeostasis is under control of environmental factors such as humidity variations. High humidity (increased SC hydration) downregulates barrier competence (as assessed by barrier recovery after disruption) whereas low humidity enhances barrier homeostasis. Physiological factors can also have influence on barrier function. High stress (chronic as well as acute) increases corticosteroid levels and causes disruption of barrier homeostasis. During periods of psychological stress the cutaneous homeostatic permeability barrier is disturbed, as is the integrity and protective function of the stratum corneum. Many skin diseases, including atopic dermatitis and psoriasis are precipitated or exacerbated by psychological stress [34]. Circadian rhythmicity also applies to skin variables related to skin barrier function. Significant circadian rhythmicity has been observed in transepidermal water loss, skin surface pH, and skin temperature. These observations suggest skin permeability is higher in the evening than in the morning [35]. 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/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

1. Epidermal Barrier

ligands are endogenous lipids control barrier homeostasis. These liporeceptors include peroxisome proliferator activator receptor (PPAR alpha, beta and gamma) and Liver X receptor (LXR). The activators for these receptors are endogenous lipids and lipid intermediates or metabolites such as certain free fatty acids, 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. H

p and calcium Outermost stratum corneum pH is maintained in the acidic range, typically in the range of 4.5–5.0 by a variety of different mechanisms. This acidity is maintained by formation of free fatty acids 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, plays a major role in maintaining the acid pH of the stratum corneum. Maintenance of an acidic pH in the stratum corneum is important for the integrity/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 stratum corneum such as the thiol proteases and cathepsins are more active in the acidic pH, whereas the SCCE and SCTE present in the lower stratum corneum are more active at the neutral pH. Under conditions 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 intra‐epidermal calcium gradient, with peak concentrations of calcium in the granular layer and decreasing all the way up to the stratum corneum [10]. 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 lamellar bodies, 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 co‐ordinated. For example, epidermal permeability barrier, antimicrobial barrier,


mechanical protective barrier and UV barrier are all co‐localized in the stratum corneum. A disruption of one function can lead to multiple barrier disruptions, and therefore, multiple barrier functions are coordinately regulated. Disruption of permeability barrier leads to activation of cytokine cascade (increased levels of primary cytokines, interleukin‐1 and tumor necrosis factor‐ alpha) which in turn activates the synthesis of antimicrobial peptides of the stratum corneum. 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 that release the free amino acids that form the NMF (histidine, glutamine arginine and their biproducts) and trans‐urocanic acid (deamination of histidine) that serves as UV barrier.

Methods for studying barrier structure and function Physical methods Stratum corneum integrity/desquamation can be measured using tape stripping methods. Under dry skin conditions, when 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 SC using cyanoacrylate glue. These physical methods provide a clue to the binding forces that hold the 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 or 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 epidermal barrier (TEWL) after barrier disruption using physical methods (e.g.: tape strips) or chemical methods (organic solvent washing) provide valuable information on the epidermal barrier properties [26]. Skin hydration can be measured using Corneometer®. The measurement is based on capacitance of a dielectric medium. Any change in the dielectric constant due to skin


BASIC CONCEPTS  Skin Physiology Pertinent to Cosmetic Dermatology

surface hydration variation alters the capacitance of a precision measuring capacitor. The measurement can detect even slightest changes in the hydration level. Another important recent development in skin capacitance methodology is using SkinChip®. Skin capacitance imaging of skin surface can be obtained using SkinChip. This method provides information regarding skin microrelief, level of stratum corneum 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 the Magnetic Resonance Imaging (MRI) can provide useful information on internal structures of SC/epidermis and its improvements with treatment. MRI has been successfully used to evaluate skin hydration and water behavior in aging skin [29]. Biological methods Ultrastructural details of SC and the intercellular spaces of the SC can be visualized using transmission electron microscopy (TEM) 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 bilayers within the SC can be visualized by EM after fixation using ruthenium tetroxide. The existence of corneodesmosomes in the SC, and their importance in desquamation can be measured by Scanning electron microscopy (SEM) 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 detergent solution. The suspension so obtained can be analyzed by microscopy, biochemical or immunological techniques. Punch or shaved biopsy techniques can be combined with immunohistochemistry using specific SC/epidermis specific antibodies to quantify the SC quality. Specific antibodies for keratinocyte differentiation specific proteins, desmosomal proteins or specific proteases can provide answers relating to skin barrier properties.

Relevance of skin barrier to cosmetic product development Topical products that influence barrier functions The human skin is constantly exposed to hostile environment. These include 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 [7,8]. 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. Moisturizers affect the SC architecture and barrier homeostatsis, that is, topically applied ingredients are not as inert to the skin as one might expect. A number of different mechanisms behind the barrier‐influencing effects of moisturizers have been suggested, such as simple deposition of lipid material outside the skin. Ingredients in the moisturizers may also change the lamellar organization and the packing of the lipid matrix and thereby change skin permeability [33]. 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 either or 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 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/ nonessential free fatty acids (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 [20,21]. Topically applied substances may penetrate deeper into the skin and interfere with the production of barrier lipids and

1. Epidermal Barrier




Major advances have been made in the last several decades in understanding the complexity and functions of the stratum corneum. Extensive research by several groups has elucidated the metabolically active role of the SC and have characterized the major components and their importance in providing protection for the organism 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 in 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 into barrier homeostasis mechanisms. Novel delivery systems play an increasingly important role in the development of effective skin care products. Delivery

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 Elias PM. (1996) Stratum corneum architecture, metabolic activity and interactivity with subjacent cell layers. Exp Dermatol 5, 191–201. 5 Uchida Y, Holleran WM. (2008) Omega‐O‐acylceramide, a lipid essential for mammalian survival. J Dermatol Sci 51,77–87. 6 Harding CR, Watkinson A, Rawlings AV, Scott IR. (2000) Dry skin, moisturization and corneodesmolysis. Int J Cosmet Sci 22, 21–52. 7 Schaefer H, Redelmeier TE, eds. (1996) Skin Barrier. Principles of Percutaneous Absorption. Basel: Karger. 8 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. 9 Elias PM (2005). Stratum corneum defensive functions: an integrated view. J Invest Dermatol 125, 183–200. 10 Menon GK, Grayson S, Elias PM. (1985) Ionic calcium reservoirs in mammalian epidermis: Ultrastructural localization by ion‐capture cytochemistry. J Invest Dermatol 84, 508–512. 11 Elias PM, Menon GK. (1991) Structural and lipid biochemical correlates of the epidermal permeability barrier. Adv Lipid Res 24, 1–26. 12 Elias PM, Feingold KR. (1992) Lipids and the epidermal water barrier: metabolism, regulation, and pathophysiology. Semin Dermatol 11, 176–82. 13 Steinert PM, Parry DA, Marekov LN. (2003) Trichohyalin mechanically strengthens the hair follicle: multiple cross‐bridging roles in the inner root shealth. J Biol Chem 278, 41409–19. 14 Choi EH, Man M‐Q, Wang F, Zhang X, Brown BE, Feingold KR, Elias PM. (2005) Is endogenous glycerol a determinant of stratum corneum hydration in humans. J Invest Dermatol 125, 288–93. 15 Yamaguchi Y, Takahashi K, Zmudzka BZ, Kornhauser A, Miller SA, Tadokoro T, Berens W, Beer JZ, Hearing VJ. (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. 16 Sander CS, Chang H, Salzmann S, Muller CSL, Ekanayake‐Mudiyanselage S, Elsner P, Thiele JJ. (2002) Photoaging is associated with protein oxidation in human skin in vivo 118, 618–25. 17 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, 213–16.


ummary and future trends



kin 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 skin 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 due to its increased penetration into deeper layers of the skin.

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.

the maturation of corneocytes. Creams may influence the desquamatory proteases and change the thickness of the SC. The increased understanding of the interactions between topically applied substances and epidermal biochemistry will enhance the possibilities to tailor skin care products for various SC abnormalities [33].



BASIC CONCEPTS  Skin Physiology Pertinent to Cosmetic Dermatology

18 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 inflammation‐induced matrix degradation. Int J Cosmet Sci 27, 17–34. 19 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. 20 Pinnell SR. (2003) Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 48, 1–19. 21 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. 22 Madison KC. (2003) Barrier function of the skin: “La Raison d'Etre” of the epidermis. J Invest Dermatol 121, 231–41. 23 Chatenay F, Corcuff P, Saint‐Leger D, Leveque JL. (1990) Alterations in the composition of human stratum corneum lipids induced by inflammation. Photoderamtol Photoimmunol Photomed 7, 119–22. 24 Saint‐Leger D, Francois AM, Leveque JL, Stoudemayer TJ, Kligman AM, Grove G. (1989) Stratum corneum lipids in skin xerosis. Dermatologica 178, 151–5. 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 Research 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, Leveque JL. (1993) Characterization of skin in vivo by high resolution magnetic resonance imaging: water behavior and age‐related effects. J Invest Dermatol 100, 705–709. 30 Corcuff P, Fiat F, Minondo AM. (2001) Ultrastructure of human stratum corneum. 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. 32 Gallo R, Borkowsk, A. (2011) The coordinated response of the physical and antimicrobial peptide barriers of the skin. J Invest Dermatol 131, 285–7. 33 Loden M. (2012) Effect of moisturizers on epidermal barrier function. Clin Dermatol 30, 286–96. 34 Slominski A. (2007) A nervous breakdown in the skin: stress and the epidermal barrier. J Clin Invest 11, 3166–9. 35 Yosipovitch G, Xiong G, Haus E, Sackett‐Lundeen L, Ashkenzai I, Maibach H. (1998) Time‐dependent variations of the skin barrier function in humans: transepidermal water loss, stratum corneum hydration, skin surface pH, and skin temperature. J Invest Dermatol 1, 20–23.


Chapter 2


Kira Minkis,1 Jillian Havey Swary,2 and Murad Alam2 2

Weill Cornell Medical College, New York, NY, USA Feinberg School of Medicine, Northwestern University, Chicago, IL, USA



Con epts c


• 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.


hotoaged 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 sun‐exposed 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, sun‐protected skin is characterized by dryness, fine wrinkles, skin atrophy, homogeneous pigmentation, and seborrheic keratoses [6]. Extrinsically aged skin, on the contrary, is characterized by roughness, dryness, fine as well as 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. P

Skin, the largest human organ, is chronically exposed to UV radiation from the sun. The skin is at the frontline of defense of the human body against the harmful effects of UV exposure. Chronic absorption of UV radiation leads to potential injuries to the skin which includes 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.

tissue. Loss of connective tissue, interstitial 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]. The significance of photoaging lies in both the cosmetic and medical repercussions, i.e. in the demand for agents that can prevent or reverse the cutaneous signs associated with photoaging and its strong association with cutaneous malignancies.



Definition Photoaging is the leading form of skin damage caused by sun exposure, occurring more frequently than skin cancer. Photoaging describes clinical, histologic, and functional changes that are characteristic of older, chronically sun‐exposed skin. Photoaging culminates from a combination of predominantly chronic UV radiation superimposed on intrinsic aging of the skin. 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

Cosmetic Dermatology: Products and Procedures, Second Edition. Edited by Zoe Diana Draelos. © 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.



Basic Concepts  Skin Physiology Pertinent to Cosmetic Dermatology

While the pathophysiology of photoaged and photo‐protected 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, 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.


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 penetrates deeper into the skin, with ~50% of UVA penetrating into the skin in a fair‐skinned individual (versus  retinaldehyde > retinol >>> retinyl esters.

Biological concepts Therapeutic and cosmeceutical retinoids Retinoids define a class of substances comprising vitamin A (retinol) and its naturally 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 [1,2]. Retinol can be oxidized into retinaldehyde, and then into retinoic acid, the biologically active form of vitamin A. Retinol may be also 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 [3,4] (Figure 36.1). 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. ≈1  nmol/g [5]. Retinoic acid is catabolized either by phase I or phase II enzymes, giving rise to retinoyl glucuronide or 4-oxoretinoic acid [6,7]. 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 [810], and exert some of the retinoid-like activities in mouse in vivo [11]. 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 RAR-response element (RARE) DNA sequence, resulting in the modulation of the expression of genes involved in cellular differentiation and proliferation [4,12–14] (Figure 36.1). As biologically active agents given to humans, retinoids can be divided into therapeutics and cosmeceuticals. Therapeutic 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 oncological diseases such as acute promyelocytic leukemia, cutaneous T-cell lymphoma, and squamous or basal cell carcinoma [15]. 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 therapeutic retinoids [16,17] (Figure 36.2A). 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 OTC products; and constitute the group of topical cosmeceutical retinoids [4] (Figure 36.2B). Epidermal vitamin A Vitamin A is present in the epidermis as free and esterified retinol at an average concentration of 1–2  nmol/g [5,18]. Retinol and retinyl esters may be oxidized to retinaldehyde and then to

Cosmetic Dermatology: Products and Procedures, Second Edition. Edited by Zoe Diana Draelos. © 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.



ANTI-AGING  Cosmeceuticals

Figure 36.1  Biochemical pathways from dietary provitamins A to biological responses. Abbreviations: ARAT, acyl-coenzyme A:retinol acyltransferase; BCO,

β-carotene-15,15’-monooxygenase; CAR, β-carotene; CYP26, cytochrome P450 26; LRAT, lecithin:retinol acyltransferase; oxoRA, all-trans-4-oxoretinoic acid; oxoRAL, all-trans-4-oxoretinal; 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.

retinoic acid cis/trans isomers within keratinocytes [19–21]. An epidermal hypovitaminosis A may be the consequence of nutritional deficiency [22,23], acute or long term UV exposure [24], oxidative stress [18,25] and aging [26]. A deficiency of vitamin A manifests in the skin as a follicular hyperkeratosis known as phrynoderma, characterized by rough, hyperkeratotic, follicular papules on the skin of elbows and knees [27]. Vitamin A deficiency is also a risk factor for the development of skin cancers [28–32]. Retinoids increase the expression of the tumor-preventive transcription factor p53 [31,33] and decrease that of AP-1 and NF-κB [34,35], transcription factors linked to proliferation and inflammation, two events involved in tumor formation [36,37]. This defines the biochemical foundation for the use of retinoids in cancer treatment and prevention [32,38–43]. The intracrine pro-ligand concept Chronological aging and photoaging are not only a question of aesthetics that is often accompanied by psychological problems, they also constitute the background for the development of precancerous and cancerous skin lesions, as well as severe functional skin fragility now called dermatoporosis [44,45]. 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 [46]. 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 long-term 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 supraphysiological 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 “pro-ligands” are then converted in a controlled process into active ligands [47]. 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 [5,48–52]. This might be a convenient definition of cosmeceutical topical retinoids.

36. Topical Cosmeceutical Retinoids


Figure 36.2  Molecular structures. The molecular structures of therapeutic (A) and cosmeceutical (B) retinoids are indicated. Notes: (1) “R” in retinyl esters represents an acyl radical; (2) 4-oxoretinoids are indicated, because they have been shown to have a “soft” retinoid action [11]; however, to our knowledge, they haven’t yet been added in topical formulations; (3) OGG is not a retinoid, but, as mentioned in the text, is a potential cosmeceutical retinoid partner.


ANTI-AGING  Cosmeceuticals

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 biological effects [53-55]. 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 hydrolysed to retinol, which is oxidized to retinaldehyde, which is in turn oxidized to retinoic acid. On the other hand, probably for the same reason, the tolerance ranking order is the opposite: retinyl esters > retinol ≥ retinaldehyde >> retinoic acid.

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 matrix metalloproteinase [56,57], oxidative stress and the degradation of extracellular matrix [58]. In particular, retinoids are known to inhibit keratinocyte differentiation and to stimulate epidermal hyperplasia [11,59,60]. 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 [61]. 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 [62]. 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 to an increase in epidermal and dermal HA and with increased expression of the HA synthases 1, 2 and 3 [63]. These observations indicate that the HA system is associated to the HB-EGF paracrine loop, with the transcriptional up-regulation of CD44 and HA synthases. Thus, retinaldehydeinduced in vitro and in vivo proliferative response of keratinocytes is CD44-dependent and requires HB-EGF, its receptor ErbB1, and matrix metalloproteinases [64].

Non-genomic effects

There is some evidence that retinoids might exert a biological activity independently of their binding to nuclear receptors [11,65], thus confirming the concept of cosmeceutical retinoids. Such indirect effects have been well documented, and clinical manifestations have been observed. In particular, isotretinoin (13-cis-retinoic acid), is the only retinoid active at inducing sebaceous gland atrophy, whereas it does not bind itself to nuclear retinoid receptors; for this reason, it is the best therapeutic treatment for severe acne [66,67].

Photobiology of topical retinoids Owing to their side chain containing multiple double bonds, retinoids strongly absorb UV light, with molar extinction coefficients of ≈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-cisretinaldehyde into all-trans-retinaldehyde is the first step in the biochemical cascade leading to the generation of nervous influx from the optic nerve to the visual cortex [68-70]. This property also enables retinoids to act as UV filters when applied topically [71]: topical retinoids have been shown to load the skin with supraphysiological epidermal concentrations [5,18,19,72]. 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 [73]. In mice, retinoic acid, retinaldehyde, retinol and retinyl palmitate were efficient in preventing UVBinduced apoptosis and DNA photodamage [71]. The similar potencies of these retinoids indicate a physical action mediated by their spectral properties rather than a biological action mediated by the binding to nuclear receptors. This also implies that sun exposure induces significant vitamin A depletion in the epidermis [18], which significance in term of photoaging has not been fully analysed. In particular, hypovitaminosis A is known to induce a follicular hyperkeratosis known as phrynoderma [27], and is a risk factor for cancer development [31,32]. On the other hand, the biological effects of photodegradation of vitamin A and other retinoids are less 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 [74,75]. The balance between positive, filter-like properties, and possible damage to biomolecules is difficult to assess, and might depend on several factors [76-79]. For this reason, it is still recommended to avoid UV exposure when using topical retinoids. Antibacterial activity of retinaldehyde Aldehydes represent a relatively unstable intermediate state of oxidation between alcohols and carboxylic acids [80-83]. Retinaldehyde may thus exert a direct biological 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 [84]. The putative anti-infective property of vitamin A had already been observed in the 1920s, although its mechanism of action was not understood [85]. Retinoic acid has been shown to protect dendritic cells in mice [86] and topical retinaldehyde, owing to its better tolerance profile than retinoic acid, was successfully applied to a long period of time to patients with inflammatory dermatoses [55]. Retinaldehyde has been successfully used against Gram-positive bacteria of the cutaneous flora: two weeks of treatment with topical retinaldehyde 0.05% displayed a significant decrease in counts of viable Propionibacterium acnes,

36. Topical Cosmeceutical Retinoids

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 [87,88]. Topical cosmeceutical retinoids as antioxidants Oxidative stress is considered to be the cornerstone of the biochemical pathways leading to both intrinsic (chronological) and extrinsic aging (photoaging) [14,89-93]. 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 [94,95]; however, in the case of chronic or severe oxidative stress, this endogenous antioxidant network reaches its limit and irremediable tissue damage is unavoidable [93,96-100]. According to the free radical theory of aging, oxidative stress increases with age, whereas during the same time the endogenous antioxidant systems become less efficient [101-104]. It thus seems logical to provide the skin with exogenous antioxidants in order to slow the natural process of skin aging. Although many clinical trials failed to demonstrated a benefit for the use of antioxidants, this concept is still actual when analysing these studies in detail and unveiling the reasons for such a misconception about cosmeceutical antioxidants [105]. Retinoids have been shown to exert a free radical scavenging activity in vitro [18,106-110]. This property is most probably due to 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 therapeutic 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 to play 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% [109]. 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 α-tocopherol 1.1% [111]. Effects of topical cosmeceutical retinoids on pigmentation It has been observed for a long time that retinoic acid had a lightening property on human skin, and for this reason it has been used, alone or in combination with hydroquinone, to treat hyperpigmented lesions [112,113]. 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 [114–117]. This suggests that the observed in vivo depigmenting effect of retinoic acid, and retinoids in general, may be due to the increased rate of epidermis “turnover” rather than to a direct effect on melanin content or melanocyte growth [117,118]. 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 [54,55]. 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 retinaldehyde was not solely due to its bioconversion to retinoic acid, but also to a retinoid receptor-independent mechanism [118-120]. 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 [121]. Retinyl esters, in particular retinyl palmitate, are widely used in cosmetics. According to the pro-ligand concept discussed above, in order to exert a retinoid-like activity, retinyl esters have first to be hydrolysed to retinol, and then oxidized to retinoic acid, a process being less effective compared to retinol and retinaldehyde, since it requires the activation of the hydrolysing enzymes acyl:retinol acyltransferase (ARAT) and lecithin:retinol acyl transferase (LRAT) [49,52,122,123]. 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 topical retinol 0.05% and retinyl palmitate 0.05% loaded the epidermis with similar amounts of epidermal retinoids, i.e. a ten-fold increase compared to vehicle [71]. Thus, retinyl esters seem to deliver the skin with similar amounts of retinoids and have less genomic effects than retinol, suggesting that they should have similar depigmenting properties to retinol. Hyaluronan as a partner for cosmeceutical retinoids Hyaluronan (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 N-acetyl-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 ≈8 MDa. In normal skin, HA is synthesized essentially by dermal


ANTI-AGING  Cosmeceuticals

fibroblasts and epidermal keratinocytes. Due to its negatively charged residues, HA can accommodate many water molecules, which help to maintain the normal hydration and viscoelasticity of the skin [124–126]. 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 [44,45,127]. Dermatoporosis is principally due to chronological aging and long-term and unprotected sun exposure, but it 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 of dermatoporosis, and may be a target for intervention [128]. Cleavage of the high molecular weight HA polymer during tissue remodelling gives rise to lower molecular weight fragments that elicit a variety of CD44-mediated cellular responses, including proliferation, migration, HA synthesis, and cytokine synthesis [125,126]. The cellular responses elicited by topical application of HA, and specifically HA synthesis by keratinocytes, depend on the size of the HA oligosaccharides [129–131]. Topical retinoids are known to stimulate epidermal hyperplasia through the activation of a RAR-dependent HB-EGF paracrine loop [61,132]. HA production is also selectively stimulated by retinoids in mouse and human skin [133,134]. In mouse skin, topical retinaldehyde increases HA content, the expression of CD44 and HA synthases [63], and prevents UV-induced depletion of HA and CD44, an effect also observed with topical retinol and retinoic acid, although to a lesser extent [135]. In humans, topical retinaldehyde has been shown to restore the epidermal thickness and CD44 expression in lichen sclerosus and atrophic lesions [136]. 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) [64,137,138]. 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 [138,139]. Thus topical retinoids, in particular retinaldehyde, can restore epidermal functions by stimulating HA synthesis and biological functions.

Specific profiles of cosmeceutical retinoids 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 on long periods of time: in particular, retinaldehyde produced significant improvement in fine and deep wrinkles [140]. Retinaldehyde does not bind to nuclear retinoid receptors and selectively delivers low

concentrations of retinoic acid at the cellular level [54,132]; this prevents an excess of retinoic acid in the skin, a condition that contributes to cutaneous irritation [5,47] and confers to retinaldehyde the required properties for the intracrine concept discussed above [18,47]. The association of retinaldehyde and δ-tocopheryl-gluco-pyranoside, a vitamin E-like precursor, improved the protection against the generation of free radicals – a condition leading to aging – as well as the skin elasticity [141]. Retinaldehyde, which possesses an aldehyde functional group, exerts direct receptor-independent biological actions not shared by other retinoids. This explains the usefulness of topical retinaldehyde 0.05% against P. acnes and Staphylococcus spp. [87,88]. As discussed above, retinaldehyde shares with other retinoids a high absorption power in the UVA range, and may decrease the fluence received in this window significantly [71]. As compared to other retinoids, retinaldehyde loads the skin with natural retinoids very efficiently, probably due to its better penetration profile through the skin, and its ability to be reduced to retinol or oxidized to retinoic acid very rapidly [142–146]. 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, since the production of small quantities of hydrogen peroxide has been considered to be an essential step of the melanogenesis [147]. 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% [118]. Owing to these properties, retinaldehyde should be considered as a key partner in topical depigmenting preparations. For instance retinaldehyde, combined to the tyrosinase inhibitor 4-(1-phenylethyl)-resorcinol and the antioxidant precursor δ-tocopherylglucopyranoside, was shown to have a good depigmentation and tolerance profile in murine melanocytes and in a three-dimensional human reconstructed epidermis [148]. 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 [142,149,150], 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 [151]. It seems that the retinol concentrations required to induce a measurable biological action similar to that of retinoic acid (0.05%) induce a similar irritant dermatitis [121]. Thus, to avoid high concentrations of retinol or retinyl esters in topical formulation, the best way would be to combine them at moderate concentrations

36. Topical Cosmeceutical Retinoids

with other topical agents such as tocopherols, ascorbate and derivatives, flavonoids or other biological antioxidants [152-154]. 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 [71,73]. 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 [49]. Associations

Association with 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 hyaluronate fragments of defined size (HAFi) on cell renewal and de novo hyaluronate synthesis [63,138,139,155]. Accordingly, the topical application of HAFi was found to have repairing action in dermatoporosis [137]. Therefore the combination of HAFi with a retinoid is highly promising as preventive treatment in early phases of dermatoporosis. High molecular weight HA, that does not show the topical activities of HAFi, has been widely used in cosmetic preparations [156]. Application of high molecular weight HA-containing cosmetic products to the skin is reported to moisturize and restore elasticity [157]. HA-based cosmetic formulations or sunscreens may also be capable of protecting the skin against ultraviolet irradiation due to the antioxidant properties of HA [158]. 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.

Association with glycylglycine oleamide

Glycylglycine oleamide (OGG, Figure 36.2B) is a small amphiphilic molecule designed to protect the connective tissue of the skin from glycation and elastosis [159]. Its ability to potentiate the esterification of retinol by retinaldehyde might make OGG a new retinoid partner in cosmeceutical formulations aimed at preventing cutaneous hypovitaminosis A [18]. In particular, a lotion containing 0.1% retinaldehyde, 0.1% OGG and 0.05% δ-tocopherylglucopyranoside improved the antioxidant capacity and decreased the lipoperoxidation in a clinical trial (manuscript in preparation).

Summary The novelty in retinoid cosmeceutics clearly consists in the association of a retinoid with middle-size HA fragments, tyrosinase inhibitors or antioxidant precursors. Such an association seems to


act synergistically to stimulate the targets of the retinoid partners, while optimizing the tolerance profile due to a decreased retinoid concentration in combined formulations. Current laboratory and clinical data indicate that retinaldehyde is the retinoid of choice for this association.

References 1 Castenmiller JJM, West CE. (1998) Bioavailability and bioconversion of carotenoids. Annu Rev Nutr 18,19–36. 2 Vogel S, Gamble MV, Blaner WS. (1999) Biosynthesis, absorptiom, metabolism and transport of retinoids. In: Nau H, Blaner WS, eds. Retinoids The biochemical and molecular basis of vitamin A and retinoid action. Berlin: Springer. 3 Roos TC, Jugert FK, Merk HF, Bickers DR. (1998) Retinoid metabolism in the skin. Pharmacol Rev 50, 315–33. 4 Sorg O, Antille C, Kaya G, Saurat JH. (2006) Retinoids in cosmeceuticals. Dermatol Ther 19, 289–96. 5 Saurat JH, Sorg O, Didierjean J. (1999) New concepts for delivery of topical retinoid activity to human skin. In: NauH, BlanerWS, eds. Retinoids The Biochemical and Molecular Basis of Vitamin A and Retinoid Action. Berlin: Springer-Verlag, pp. 521–36. 6 Sass JO, Forster A, Bock KW, Nau H. (1994) Glucuronidation and isomerization of all-trans- and 13-cis-retinoic acid by liver microsomes of phenobarbital- or 3-methylcholanthrene-treated rats. Biochem Pharmacol 47, 485–92. 7 Taimi M, Helvig C, Wisniewski J, et al. (2004) A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid. J Biol Chem 279, 77–85. 8 Achkar CC, Derguini F, Blumberg B, Langston A, Levin AA, Speck J, et al. (1996) 4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors. Proc Natl Acad Sci USA 93, 4879–84. 9 Blumberg B, Bolado J, Jr., Derguini F, Craig AG, Moreno TA, Chakravarti D, et al. (1996) Novel retinoic acid receptor ligands in Xenopus embryos. Proc Natl Acad Sci USA 93, 4873–8. 10 Ross SA, De Luca LM. (1996) A new metabolite of retinol: all-trans-4-oxo-retinol as a receptor activator and differentiation agent. Nutr Rev 54, 355–6. 11 Sorg O, Tran C, Carraux P, Grand D, Barraclough C, Arrighi JF, et al. (2008) Metabolism and biological activities of topical 4-oxoretinoids in mouse skin. J Invest Dermatol 128, 999–1008. 12 Fisher GJ, Voorhees JJ. (1996) Molecular mechanisms of retinoid actions in skin. FASEB J 10, 1002–13. 13 Napoli JL. (1996) Retinoic acid biosynthesis and metabolism. FASEB J 10, 993–1001. 14 Sorg O, Antille C, Saurat JH. (2004) Retinoids, other topical vitamins, and antioxidants. In: RigelDS, WeissRS, LimHW, DoverJS, eds. Photoaging. New York: Marcel Dekker, pp. 89–115. 15 Dawson MI. (2004)Synthetic retinoids and their nuclear receptors. Curr Med Chem Anticancer Agents 4, 199–230. 16 Sorg O, Kuenzli S, Saurat JH. (2007) Side effects and pitfalls in retinoid therapy. In: VahlquistA, DuvicM, eds. Retinoids and Carotenoids in Dermatology. New York: Informa Healthcare, pp. 225–48. 17 Kuenzli S, Saurat JH, Retinoids. (2003) In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. London: Mosby, Chapter 127, pp. 1991–2006.


ANTI-AGING  Cosmeceuticals

18 Sorg O, Saurat JH. (2014) Topical retinoids in skin aging: A focused update with reference to sun induced epidermal vitamin A deficiency. Dermatology (in press). 19 Duester G. (2000) Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem 267, 4315–24. 20 Jurukovski V, Simon M. (2000) Epidermal growth factor signaling pathway influences retinoid metabolism by reduction of retinyl ester hydrolase activities in normal and malignant keratinocytes. J Cell Physiol 183, 265–72. 21 Kurlandsky SB, Xiao JH, Duell EA, et al. (1994) Biological activity of all-trans retinol requires metabolic conversion to all-trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes. J Biol Chem 269, 32821–7. 22 Johnson KA, Bernard MA, Funderburg K. (2002) Vitamin nutrition in older adults. Clin Geriatr Med 18, 773–99. 23 Miller SJ. Nutritional deficiency and the skin. (1989) J Am Acad Dermatol 21, 1–30. 24 Andersson E, Rosdahl I, Törmä H, Vahlquist A. (1999) Ultraviolet irradiation depletes cellular retinol and alters the metabolism of retinoic acid in cultured human keratinocytes and melanocytes. Melanoma Res 9, 339–46. 25 Ihara H, Hashizume N, Hirase N, Suzue R. (1999) Esterification makes retinol more labile to photolysis. J Nutr Sci Vitaminol (Tokyo) 45, 353–8. 26 Torras H. (1996) Retinoids in aging. Clin Dermatol 14, 207–15. 27 Maronn M, Allen DM, Esterly NB. (2005) Phrynoderma: a manifestation of vitamin A deficiency?… The rest of the story. Pediatr Dermatol 22, 60–3. 28 Levine N. (1998) Role of retinoids in skin cancer treatment and prevention. J Am Acad Dermatol 39, S62–S6. 29 Marks R. (1991) Retinoids in Cutaneous Malignancy. Oxford: Blackwell Scientific. 30 Moon TE, Levine N, Cartmel B, Bangert JL. (1997) Retinoids in prevention of skin cancer. Cancer Lett 19;114, 203–5. 31 Einspahr JG, Bowden GT, Alberts DS. (2003) Skin cancer chemoprevention: strategies to save our skin. Recent Results Cancer Res 163, 151–64; discussion 264–6. 32 Fields AL, Soprano DR, Soprano KJ. (2007) Retinoids in biological control and cancer. J Cell Biochem 102, 886–98. 33 Mrass P, Rendl M, Mildner M, et al. (2004) Retinoic acid increases the expression of p53 and proapoptotic caspases and sensitizes keratinocytes to apoptosis: a possible explanation for tumor preventive action of retinoids. Cancer Res 64, 6542–8. 34 Darwiche N, Bazzi H, El-Touni L, Abou-Lteif G, Doueiri R, Hatoum A, et al. (2005) Regulation of ultraviolet B radiationmediated activation of AP1 signaling by retinoids in primary keratinocytes. Radiat Res 163, 296–306. 35 Fanjul A, Dawson MI, Hobbs PD, et al. (1994) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation. Nature 372, 107–11. 36 Bayon Y, Ortiz MA, Lopez-Hernandez FJ, et al. (2003) Inhibition of IkappaB kinase by a new class of retinoid-related anticancer agents that induce apoptosis. Mol Cell Biol 23, 1061–74. 37 Na SY, Kang BY, Chung SW, et al. (1999) Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. J Biol Chem 274, 7674–80. 38 Camacho LH. (2003) Clinical applications of retinoids in cancer medicine. J Biol Regul Homeost Agents 17, 98–114.

39 Carr DR, Trevino JJ, Donnelly HB. (2011) Retinoids for chemoprophylaxis of nonmelanoma skin cancer. Dermatol Surg 37, 129–45. 40 Ralhan R, Kaur J. (2003) Retinoids as chemopreventive agents. J Biol Regul Homeost Agents 17, 66–91. 41 Saurat JH. (2001) Skin, sun, and vitamin A: from aging to cancer. J Dermatol 28, 595–8. 42 So PL, Lee K, Hebert J, et al. (2004)Topical tazarotene chemoprevention reduces Basal cell carcinoma number and size in Ptch1+/– mice exposed to ultraviolet or ionizing radiation. Cancer Res 64, 4385–9. 43 Zusi FC, Lorenzi MV, Vivat-Hannah V. (2002) Selective retinoids and rexinoids in cancer therapy and chemoprevention. Drug Discov Today 7, 1165–74. 44 Kaya G, Saurat JH. (2007) Dermatoporosis: a chronic cutaneous insufficiency/fragility syndrome. Clinicopathological features, mechanisms, prevention and potential treatments. Dermatology 215, 284–94. 45 Saurat JH. Dermatoporosis. (2007) The functional side of skin aging. Dermatology 215, 271–2. 46 Stratigos AJ, Katsambas AD. (2005) The role of topical retinoids in the treatment of photoaging. Drugs 65, 1061–172. 47 Saurat JH, Sorg O. (1999) Topical natural retinoids. The “Pro-ligand-non-ligand” concept. Dermatology 199, 1–2. 48 Duell EA, Derguini F, Kang S, et al. (1996) Extraction of human epidermis treated with retinol yields retro-retinoids in addition to free retinol and retinyl esters. J Invest Dermatol 107, 178–82. 49 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. 50 Schaefer H. (1993) Penetration and percutaneous absorption of topical retinoids. Skin Pharmacol 6, 17–23. 51 Tran C, Kasraee B, Grand D, et al. (2005) Pharmacology of RALGA, a mixture of retinaldehyde and glycolic acid. Dermatology 210, 6–13. 52 . Tran C, Sorg O, Carraux P, et al. (2001) Topical delivery of retinoids counteracts the UVB-induced epidermal vitamin A depletion in hairless mouse. Photochem Photobiol 73, 425–31. 53 Didierjean L, Sass JO, Carraux P, et al. (1999) Topical 9-cis-retinaldehyde for delivery of 9-cis-retinoic acid in mouse skin. Exp Dermatol 8,199–203. 54 Didierjean L, Tran C, Sorg O, Saurat JH. (1999) Biological activities of topical natural retinaldehyde. Dermatology 199,19–24. 55 Saurat JH, Didierjean L, Masgrau E, et al. (1994) Topical retinaldehyde on human skin : biological effects and tolerance. J Invest Dermato 103, 770–4. 56 Fisher GJ, Datta SC, Talwar HS, et al. (1996) Molecular basis of sun-induced premature skin aging and retinoid antagonism. Nature 379, 335–9. 57 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. 58 Griffiths CE, Russman AN, Majmudar G, et al. (1993) Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 329, 530–5. 59 Ponec M, Weerheim A, Havekes L, Boonstra J. (1987) Effects of retinoids on differentiation, lipid metabolism, epidermal growth factor, and Low-density lipoprotein binding in squamous carcinoma cells. Exp Cell Res 171, 426–35.

36. Topical Cosmeceutical Retinoids

60 Saurat JH. How do retinoids work on human epidermis? A breakthrough and its implications. (1988) Clin Exp Dermatol 13, 350–64. 61 Xiao JH, Feng X, Di W, et al. (1999) Identification of heparinbinding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors. EMBO J 18,1539–48. 62 Yu WH, Woessner JF, Jr., McNeish JD, Stamenkovic I. (2002) CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 16, 307–23. 63 Kaya G, Grand D, Hotz R, et al. (2005) Upregulation of CD44 and hyaluronate synthase by topical retinoids in mouse skin. J Invest Dermatol 124, 284–7. 64 Kaya G, Tran C, Sorg O, et al. (2005) Retinaldehyde-induced epidermal hyperplasia via heparin binding epidermal growth factor is CD44-dependent. J Invest Dermatol 124, A32. 65 Clifford JL, Menter DG, Wang M, et al. (1999) Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl)retinamide in F9 embryonal carcinoma cells. Cancer Res 59, 14–8. 66 Layton A. (2009) The use of isotretinoin in acne. Dermatoendocrinol 1, 162–9. 67 Wiegand UW, Chou RC. (1998) Pharmacokinetics of oral isotretinoin. J Am Acad Dermatol 39, S8–S12. 68 Nakanishi K. (2000) Recent bioorganic studies on rhodopsin and visual transduction. Chem Pharm Bull (Tokyo) 48, 1399–409. 69 Blomhoff R, Blomhoff HK. (2006) Overview of retinoid metabolism and function. J Neurobiol 66, 606–630. 70 Schoenlein RW, Peteanu LA, Mathies RA, Shank CV. (1991) The first step in vision: femtosecond isomerization of rhodopsin. Science 254, 412–5. 71 Sorg O, Tran C, Carraux P, et al. (2005) Spectral properties of topical retinoids prevent DNA damage and apoptosis after acute UVB exposure in hairless mice. Photochem Photobio 81, 830–6. 72 Kang S, Duell EA, Fisher GJ, et al. (1995) Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristics of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol 105:549–56. 73 Antille C, Tran C, Sorg O, et al. (2003) Vitamin A exerts a photoprotective action in skin by absorbing UVB radiations. J Invest Dermatol 121(5):1163–7. 74 Dillon J, Gaillard ER, Bilski P, et al. (1996) The photochemistry of the retinoids as studied by steady-state and pulsed methods. Photochem Photobiol 63:680–5. 75 Fu PP, Xia Q, Yin JJ, et al. (2007) Photodecomposition of Vitamin A and Photobiological Implications for the Skin. Photochem Photobiol 83, 409–24. 76 Ferguson J, Johnson BE. (1989) Retinoid associated phototoxicity and photosensitivity. Pharmacol Ther 40, 123–35. 77 Fu PP, Cheng SH, Coop L, et al. (2003) Photoreaction, Phototoxicity, and Photocarcinogenicity of Retinoids. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev 21, 165–97. 78 Kligman LH. (1987) Retinoic acid and photocarcinogenesis. A controversy. Photodermatol 4, 88–101. 79 Fisher D, Lichti FU, Lucy JA. (1972) Environmental effects on the autoxidation of retinol. Biochem J 130, 259–70. 80 Becker TW, Krieger G, Witte I. (1996) DNA single and double strand breaks induced by aliphatic and aromatic aldehydes in combination with copper(II). Free Radic Res 24, 325–32.


81 Witz G. (1989) Biological interactions of alpha,beta-unsaturated aldehydes. Free Radic Biol Med 7, 333–49. 82 Esterbauer H, Schaur RJ, Zollner H. (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11, 81–128. 83 Feron VJ, Til HP, de Vrijer F, et al. (1991) Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat Res 259, 363–85. 84 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. 85 Green HN, Mellanby E. (1928) Vitamin A as an anti-infective agent. Br Med J II, 691–6. 86 Halliday GM, Ho KKL, Barnetson RSC. (1992) Regulation of the skin immune system by retinoids during carcinogenesis. J Invest Dermatol 99, 83S–6S. 87 Péchère M, Germanier L, Siegenthaler G, et al. (2002) The antibacterial activity of topical retinoids: the case of retinaldehyde. Dermatology 205, 153–8. 88 Péchère M, Pechere JC, Siegenthaler G, et al. (1999) Antibacterial activity of retinaldehyde against Propionibacterium acnes. Dermatology 199, 29–31. 89 Wenk J, Brenneisen P, Meewes C, et al. (2001) UV-induced oxidative stress and photoaging. Curr Probl Dermatol 29, 83–94. 90 Yaar M, Gilchrest BA. (1998) Aging versus photoaging: postulated mechanisms and effectors. J Investig Dermatol Symp Proc 3, 47–51. 91 Pinnell SR. (2003) Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 48, 1–19; quiz 20–2. 92 Nishigori C, Hattori Y, Arima Y, Miyachi Y. (2003) Photoaging and oxidative stress. Exp Dermatol 12, 18–21. 93 Sorg O, Kaya G. (2007) Oxidative stress in human pathology. Adv Gene Mol Cell Ther 1, 56–67. 94 Sies H, Stahl W. (2004) Nutritional protection against skin damage from sunlight. Annu Rev Nutr 24, 173–200. 95 Thiele JJ, Schroeter C, Hsieh SN, et al. (2001) The antioxidant network of the stratum corneum. Curr Probl Dermatol 29, 26–42. 96 Halliwell B. (1994) Free radicals and antioxidants : a personal view. Nutr Rev 52, 253–65. 97 Jacob RA, Burri BJ. (1996) Oxidative damage and defense. Am J Clin Nutr 63, 985S–90S. 98 Kohen R, Gati I. (2000) Skin low molecular weight antioxidants and their role in aging and in oxidative stress. Toxicology 148, 149–57. 99 Sorg O. Oxidative stress : a theoretical model or a biological reality? (2004) CR Biol. [review] 327, 649–62. 100 Halliwell B, Gutteridge JMC. (1999) Free Radicals in Biology and Medicine, 3th edn. HalliwellB, GutteridgeJMC, eds. Oxford: Oxford University Press. 101 Berr C. (2000) Cognitive impairment and oxidative stress in the elderly: results of epidemiological studies. Biofactors 13, 205–9. 102 Barja G. (2004) Free radicals and aging. Trends Neurosci 27, 595–600. 103 Harman D. (2001) Aging: overview. Ann NY Acad Sci 928, 1–21. 104 Crastes de Paulet A. (1990) [Free radicals and aging]. Ann Biol Clin 48, 323–30. 105 Bast A, Haenen GR. (2013) Ten misconceptions about antioxidants. Trends Pharmacol Sci 34, 430–6. 106 Singh DK, Lippman SM. (1998) Cancer chemoprevention. Part 1: Retinoids and carotenoids and other classic antioxidants. Oncology (Williston Park) 12, 1643–53, 57–58; discussion 59–60.


ANTI-AGING  Cosmeceuticals

107 Tsuchiya M, Scita G, Freisleben HJ, et al. (1992) Antioxidant radical-scavenging activity of carotenoids and retinoids compared to alpha-tocopherol. Methods Enzymol 213, 460–72. 108 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. 109 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. 110 Sorg O, Kuenzli S, Kaya G, Saurat JH. (2005) Proposed mechanisms of action for retinoid derivatives in the treatment of skin aging. J Cosm Dermatol 4, 237–44. 111 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. 112 Kligman AM, Willis I. (1975) A new formula for depigmenting human skin. Arch Dermatol 111, 40–8. 113 Griffiths CE, Finkel LJ, Ditre CM, et al. (1993) Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol 129, 415–21. 114 Hoal E, Wilson EL, Dowdle EB. (1982) Variable effects of retinoids on two pigmenting human melanoma cell lines. Cancer Res 42, 5191–5. 115 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. 116 Fligiel SE, Inman DR, Talwar HS, et al. (1992) Modulation of growth in normal and malignant melanocytic cells by all-trans retinoic acid. J Cutan Pathol 19, 27–33. 117 Yoshimura K, Tsukamoto K, Okazaki M, et al. (2001) Effects of alltrans retinoic acid on melanogenesis in pigmented skin equivalents and monolayer culture of melanocytes. J Dermatol Sci 27, S68–S75. 118 Sorg O, Kasraee B, Salomon D, Saurat JH. (2013) The Potential Depigmenting Activity of Retinaldehyde. Dermatology 227, 231–7. 119 Kasraee B, Tran C, Sorg O, Saurat JH. (2005) The depigmenting effect of RALGA in C57BL/6 mice. Dermatology 210, 30–4. 120 Ortonne JP. (2006) Retinoid therapy of pigmentary disorders. Dermatol Ther 19, 280–8. 121 Yoshimura K, Momosawa A, Aiba E, et al. (2003) Clinical trial of bleaching treatment with 10% all-trans retinol gel. Dermatol Surg 29, 155–60. 122 Kurlandsky SB, Duell EA, Kang S, et al. (1996) Auto-regulation of retinoic acid biosynthesis through regulation of retinol esterification in human keratinocytes. J Biol Chem 271, 15346–52. 123 Ross AC. (2003) Retinoid production and catabolism: role of diet in regulating retinol esterification and retinoic acid oxidation. J Nutr 133, 291S–6S. 124 Fraser JR, Laurent TC. (1989) Turnover and metabolism of hyaluronan. Ciba Found Symp 143, 41–59. 125 Laurent TC. (1987) Biochemistry of hyaluronan. Acta Otolaryngol Suppl 442, 7–24. 126 Laurent TC, Fraser JR. (1992) Hyaluronan. FASEB J 6, 2397–404. 127 Kaya G, Jacobs F, Prins C, et al. (2008) Deep dissecting hematoma: an emerging severe complication of dermatoporosis. Arch Dermatol 144, 1303–8. 128 Kaya G, Rodriguez I, Jorcano JL, et al. (1997) Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate

129 130

131 132












144 145

146 147

metabolism in the skin and impairs keratinocyte proliferation. Genes Dev 11, 996–1007. Forrester JV, Balazs EA. (1980) Inhibition of phagocytosis by high molecular weight hyaluronate. Immunology 40, 435–46. West DC, Hampson IN, Arnold F, Kumar S. (1985) Angiogenesis induced by degradation products of hyaluronic acid. Science 228, 1324–6. Wiest L, Kerscher M. (2008) Native hyaluronic acid in dermatology–results of an expert meeting. J Dtsch Dermatol Ges 6, 176–80. Didierjean L, Carraux P, Grand D, et al. (1996) Topical retinaldehyde increases skin content of retinoic acid and exerts biological activity in mouse skin. J Invest Dermatol 107, 714–9. Margelin D, Medaisko C, Lombard D, et al. (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. Tammi R, Ripellino JA, Margolis RU, et al. (1989) Hyaluronate accumulation in human epidermis treated with retinoic acid in skin organ culture. J Invest Dermatol 92, 326–32. Calikoglu E, Sorg O, Tran C, 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. 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. Kaya G, Tran C, Sorg O, et al. (2006) Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med 3, e493. Barnes L, Tran C, Sorg O, et al. (2010) Synergistic effect of hyaluronate fragments in retinaldehyde-induced skin hyperplasia which is a CD44-dependent phenomenon. PLoS One 5, e14372. Kaya G, Tran C, Sorg O, et al. (2006) Synergistic effect of retinaldehyde and hyaluronate fragments in skin hyperplasia. J Invest Dermatol 126, 33. Creidi P, Vienne MP, Ochonisky S, et al. (1998) Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol 39, 960–5. 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. 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. Kishore GS, Boutwell RK. (1980) Enzymatic oxidation and reduction of retinal by mouse epidermis. Biochem Biophys Res Commun 94, 1381–6. Napoli JL, Race KR. (1988) Biogenesis of retinoic acid from b-carotene. J Biol Chem 263, 17372–7. 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. Sorg O, Didierjean L, Saurat JH. (1999) Metabolism of topical natural retinoids. Dermatology 199, 13–7. Kasraee B. (2002) Peroxidase-mediated mechanisms are involved in the melanocytotoxic and melanogenesis-inhibiting effects of chemical agents. Dermatology 205, 329–39.

36. Topical Cosmeceutical Retinoids

148 Sorg O, Kasraee B, Salomon D, Saurat JH. (2013) The combination of a retinoid, a phenolic agent and an antioxidant improves tolerance while retaining an optimal depigmenting action in reconstructed epidermis. Dermatology 227, 150–6. 149 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. 150 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. 151 Connor MJ. (1988) Oxidation of retinol to retinoic acid as a requirement for biological activity in mouse epidermis. Cancer Res 48, 7038–40. 152 Bruce S. (2008) Cosmeceuticals for the attenuation of extrinsic and intrinsic dermal aging. J Drugs Dermatol 7, s17–s22. 153 Burgess C. (2008) Topical vitamins. J Drugs Dermatol 7, s2–s6.


154 Picardo M, Carrera M. (2007) New and experimental treatments of cloasma and other hypermelanoses. Dermatol Clin 25, 353–62. 155 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. 156 Manuskiatti W, Maibach HI. (1996) Hyaluronic acid and skin, wound healing and aging. Int J Dermatol 35, 539–44. 157 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. 158 Trommer H, Wartewig S, Bottcher R, et al. (2003) The effects of hyaluronan and its fragments on lipid models exposed to UV irradiation. Int J Pharm 254, 223–34. 159 Bel A, Fort-Lacoste L, Ginestar-Gonzales J, Navarro R, inventors. (1999) Glycylglycine oleamide in dermo-cosmetology. France.

Chapter 37

Topical Vitamins Donald L. Bissett, John E. Oblong, and Laura J. Goodman Procter & Gamble Beauty Science, The Procter & Gamble Co., Sharon Woods Innovation Center, Cincinnati, OH, USA

BASIC CONCEPTS • Vitamins are commonly used as topical active agents in skincare products designed to improve aging skin appearance. • With appropriate selection of vitamin form and concentration, many vitamins (e.g., A, B3, B5, C, E) can be safely applied topically for skin improvement effects. • Appropriate formulation and packaging of vitamins is required to prevent loss of activity through processes such as light inactivation or oxidation and to achieve aesthetically acceptable products.


Vitamin A

Vitamins are organic compounds required in small quantities for normal skin function and are typically obtained from the diet. Many materials have been described as vitamins [1]. A few have been used in topical cosmetic products, and certainly there is technical rationale for such use, in particular based on the skin consequences in individuals consuming deficient diets. For example, vitamin B3 deficiency leads to the medical condition pellagra, which encompasses a broad range of symptoms from dermatitis to dementia to death. Since vitamins are essential nutrients, several of them functioning in a wide array of biochemical processes, they have potential to provide beneficial effects across a wide spectrum of skin problems, even in people who are nutritionally sufficient. Also, since they are well studied due to their importance in nutrition, their mechanisms and toxicology are often well understood. Additionally, with topical application and subsequent delivery into skin, they are more likely to have local meaningful effects vs. oral intake with the consequent limited delivery via the circulation to the specific skin site of interest (e.g., facial skin). Since there are so many vitamins, this review is necessarily selective, focusing on a few, with particular emphasis on those materials for which there are available well-controlled in vivo human studies to illustrate skin care effects. Selected literature citations are provided to give the reader some references that can serve as a starting point to probe deeper into the available technical data.

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 37.1). Mechanisms Since 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/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 chronological and environmental influences such as chronic

Cosmetic Dermatology: Products and Procedures, Second Edition. Edited by Zoe Diana Draelos. © 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.


37. Topical Vitamins

CH 2






Retinyl palmitate


Retinol (vitamin A)

Alcohol dehydrogenase





Aldehyde dehydrogenase

C OOH All-trans-retinoic acid

9-cis Retinoic acid C OOH Figure 37.1  Conversion of retinyl ester into trans-retinoic acid in the skin.

13-cis Retinoic acid

sun exposure). Some specific changes induced by retinoid that are likely relevant to skin appearance effects are those that result in increased production of epidermal ground substance (glycosaminoglycans or GAGs which bind water, increasing epidermal hydration); increased dermal production of extracellular matrix components such as collagen (to increase dermal thickness and restructure the matrix); and thicker and “restored” epidermis, e.g., increased epidermal proliferation and differentiation (increased epidermal thickness and epidermal turnover). These effects would be expected to contribute to improvements in the appearance of fine lines, wrinkles, and roughness [3]. 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. And while retinoids will stimulate production of ground substance (GAGs) in epidermis, they have the opposite effect in dermal


tissue, specifically inhibiting production of excess ground substance in the upper dermis of photoaged skin. While a low level of GAGs are 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 [4]. Removal of the excess dermal GAGs has been shown to be associated with improved matrix structure and reduced skin wrinkling. Since at least some of the epidermal effects of topical retinoid (e.g., epidermal thickening and turnover) occur relatively rapidly (days) after initiation of treatment, some skin surface effects (e.g., diminution of roughness and fine line appearance) can potentially be realized quickly. The dermal effects likely occur on a much longer time frame (weeks to months) such that reduction in skin problems via this mechanism will require much longer time frames (weeks to months).


ANTI-AGING  Cosmeceuticals

In addition to the fine line, wrinkle, and roughness effects of retinoids, they are also well known as agents to improve hyperpigmentation (e.g., hyperpigmented spots, post-inflammatory hyperpigmentation, solar lentigos, melasma), with the effect being achievement of lighter and more uniform skin color. The mechanisms by which retinoids affect the skin’s pigmentary system have not been completely identified. Yet it is known that retinoids stimulate epidermal turnover, which simply could be interpreted as exfoliating pigmented stratum corneum cells from the skin surface. Retinoids also inhibit UV-induced pigmentation via reducing tyrosinase activity and melanin synthesis, by regulatory action on transcription processes in the epidermis (in melanocytes and keratinocytes) [5]. These effects would reduce hyperpigmentation, leading to lighter skin color (time frame of at least several weeks). Topical effects While much of the substantial literature on the improvement of skin fine lines, wrinkles, roughness, and hyperpigmentation by topical retinoids is focused on trans-retinoic acid, there are also data available on the vitamin A compounds that are used cosmetically. Since retinoids are irritating to skin, defining skintolerated concentrations 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 the widely used retinol and retinyl acetate (Table 37.1) [6]. Since 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, placebocontrolled facial testing (12-week duration), both retinol and retinyl propionate have been shown to be significantly effective in reducing facial hyperpigmentation and fine lines/wrinkles across the study (Figure 37.2). Determination of treatment effects was based on quantitative computer image analysis and blinded expert grading of high-resolution digital images [6]. There are also clinical studies published on other retinoids. Retinyl palmitate has very low irritation potential and has been reported to be effective if tested at a very high dose, such as 2%. There are also a few studies revealing the clinical efficacy of retinaldehyde, typically at a dose of 0.05%. However, retinaldehyde has irritation potential similar to retinol [7]. 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

Table 37.1  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 were: 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)

Expert Grader Cumulative Irritation Scores

Significance of Expert Grader Cumulative Scores*

Chromameter “a” Measure (day 21)

Significance of chromameter “a” measure*

Emulsion control





0.09% Retinyl propionate





0.086% Retinyl acetate





0.075% Retinol





*Treatments with the same letter codes are not significantly different from each other (p