Luc Téot Thomas A. Mustoe Esther Middelkoop Gerd G. Gauglitz Editors Textbook on Scar Management State of the Art Management and Emerging Technologies 123 Textbook on Scar Management Luc Téot • Thomas A. Mustoe • Esther Middelkoop Gerd G. Gauglitz Editors Textbook on Scar Management State of the Art Management and Emerging Technologies Editors Thomas A. Mustoe Luc Téot Division of Plastic and Reconstructive Department of Burns, Wound Healing and Surgery Reconstructive Surgery Northwestern University School of Medicine Montpellier University Hospital Chicago, Illinois, USA Montpellier, France Gerd G. Gauglitz Esther Middelkoop Department of Dermatology and Allergy Amsterdam UMC, Vrije Universiteit Ludwig Maximilian University Munich Amsterdam, Department of Plastic, Munich, Germany Reconstructive and Hand Surgery, Amsterdam Movement Sciences, Amsterdam, The Netherlands Association of Dutch Burn Centers, Red Cross Hospital Beverwijk, The Netherlands This book is an open access publication. ISBN 978-3-030-44765-6 ISBN 978-3-030-44766-3 (eBook) https://doi.org/10.1007/978-3-030-44766-3 © The Editor(s) (if applicable) and The Author(s) 2020 Open Access This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. 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Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland V Foreword The interest in wound healing goes back to the beginning of history and has not dimin- ished throughout the centuries also because practical implications of wound healing studies have remained very relevant for public health. During the last century, much progress has been made in the understanding of basic mechanisms of skin wound heal- ing, and it has been realized that healing processes evolve similarly in various organs. It has been established that fibrotic diseases are regulated by analogous mechanisms, albeit less controlled, compared to those regulating wound healing. Moreover, many advances, such as the use of antiseptics and, later, of antibiotics, as well as the intro- duction of skin transplants have facilitated the treatment of wounds. It has been shown that wound healing evolution depends on several factors including the type of injury causing the damage, the tissue and/or organ affected, and the genetic or epigenetic background of the patient. This Compendium has the merit of discussing a broad spectrum of topics, including the general biology of wound healing, modern diagnostic approaches, and therapeutic tools, applied to many different clinical situations. It should be of interest to teachers, students, and clinicians working in different aspects of wound healing biology and pathology. I am sure that it will rapidly become an important reference book in these fields. Giulio Gabbiani Emeritus Professor of Pathology University of Geneva Geneva, Switzerland Preface Scars represent the indelible cutaneous signature of aggression, surgery, traumas, and other events occurring during life. Most of them cause no problem, but some of them become sources of social exclusion, especially in a world where beauty is glorified. The psychosocial aspects surrounding culture, religion, and uses may be determinant. Even a transient redness may become source of suffering. Paradoxically, major keloids or massive contractures cause definitive loss of function or social problems leading to exclusion in developing countries, whereas simultaneously, we assist a rapid extension of laser technology indications for minor scar problems in the same countries. When we founded the Scar Club in 2006 together with Prof. Tom Mustoe, the aim was and still is the diffusion of knowledge and the development of all types of mechanical devices and antiscarring drugs. Important financial support for researches in the field of growth factors and antis- carring agents was recruited, aiming at controlling cell proliferation and secretion using chemical compounds, but the results were modest. Mechanical control of keloids or hypertrophic scars is proposed and reimbursed in some countries, applying medical devices capable to exert forces over the suture during the post-operative period or over post-burn scars. This small group formed the Scar Club, composed of passionate colleagues who attracted surgeons and dermatologists, researchers, and physiotherapists, becoming an upmost scientific biannual rendezvous attracting colleagues from all over the world. The Scar Club group is built like a club, focusing on researches, new organizations and collaborations, new strategies, and development of guidelines. The need for a larger educational initiative appeared since 2015 and the GScarS was founded in 2016. In October 2018, the first GScarS meeting was held in Shanghai with a successful event, grouping more than 600 colleagues. The idea came from the Board to provide an educational book free of charge, open source, and downloadable from anywhere. Patients and caregivers suffer most of the time from an insufficient profes- sional training, and scar science is poorly represented in teaching courses at universi- ties. Most of the proposed treatments are still based on cultural or anecdotal medicine. It is time to propose a structuration of the scar knowledge based on evidence-based medicine, consensus, guidelines, and key opinion leaders’ expertise. This Compendium on scar management proposes a synthesis of the basic principles in scar management, including the large armamentarium of medical devices having proven efficacy and considered as the standards of care, and also the most recent tech- niques accessible in scar management, provided by the most prominent specialists com- ing from all over the world. It will be completed by a series of illustrations, schematic strategies, and clinical cases accessible on the Springer website. Luc Téot Montpellier, France VII Contents I Biology and Scar Formation 1 Fetal Wound Healing ............................................................ 3 Magda M. W. Ulrich 1.1 Background ........................................................................ 4 1.2 Inflammation ....................................................................... 4 1.3 Extracellular Matrix ................................................................. 5 1.4 Angiogenesis ....................................................................... 5 1.5 Keratinocytes....................................................................... 6 1.6 Fibroblasts.......................................................................... 7 1.7 Mechanical Forces .................................................................. 7 1.8 Remodeling ........................................................................ 8 1.9 Skin Appendix Formation ........................................................... 8 1.10 Conclusions......................................................................... 8 References.......................................................................... 9 2 Mechanobiology of Cutaneous Scarring....................................... 11 Rei Ogawa 2.1 Background ........................................................................ 12 2.2 Role of Mechanobiology in Cutaneous Scarring ...................................... 12 2.3 Cellular and Tissue Responses to Mechanical Forces .................................. 12 2.4 Role of Mechanobiology in the Development of Pathological Scars.................... 13 2.5 A Pathological Scar Animal Model that Is Based on Mechanotransduction ............. 16 2.6 Mechanotherapy for Scar Prevention and Treatment.................................. 16 2.7 Conclusion.......................................................................... 17 References.......................................................................... 17 3 Scar Formation: Cellular Mechanisms.......................................... 19 Ian A. Darby and Alexis Desmoulière 3.1 Background ........................................................................ 20 3.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.3 General Mechanisms of Scar Formation .............................................. 20 3.4 Morphological and Biochemical Characteristics of Myofibroblast Phenotype .......... 21 3.5 Cellular Origins of Myofibroblasts.................................................... 21 3.6 Regulation of Myofibroblast Phenotype.............................................. 22 3.7 Role of Myofibroblasts in Pathological Scarring and Fibrosis .......................... 22 3.8 The Role of Mechanical Tension...................................................... 23 3.9 Role of Innervation in Skin Healing .................................................. 24 3.10 Therapeutic Options ................................................................ 25 3.11 Conclusion.......................................................................... 25 References.......................................................................... 26 II Epidemiology of Scars and Their Consequences 4 The Epidemiology of Keloids.................................................... 29 Chenyu Huang, Zhaozhao Wu, Yanan Du, and Rei Ogawa 4.1 Background ........................................................................ 30 4.2 Demographic Risk Factors That Shape Keloid Rates................................... 30 4.3 Genetic Risk Factors That Shape Keloid Rates......................................... 32 4.4 Environmental Risk Factors That Shape Keloid Rates.................................. 32 V III Contents 4.5 Conclusion.......................................................................... 34 References.......................................................................... 34 5 Epidemiology of Scars and Their Consequences: Burn Scars................. 37 Margriet E. van Baar 5.1 Burn Injuries and Their Treatment.................................................... 38 5.2 Prevalence of Burn Scars and Their Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.3 Factors Predicting Scar Outcome After Burns......................................... 41 5.4 Clinical Relevance................................................................... 42 5.5 Conclusion.......................................................................... 42 References.......................................................................... 43 6 Scar Epidemiology and Consequences......................................... 45 M. El Kinani and F. Duteille 6.1 Introduction and Background ....................................................... 46 6.2 Reminder of the Spectrum of Scars .................................................. 46 6.3 Hypertrophic Scars.................................................................. 46 6.4 Basic Epidemiology ................................................................. 46 6.5 Keloid Scars......................................................................... 47 6.6 Specific Situation: The Burnt Patient Healing ......................................... 47 6.7 Impact of Scars ..................................................................... 48 6.8 Conclusion.......................................................................... 48 References.......................................................................... 48 7 Other Scar Types: Optimal Functional and Aesthetic Outcome of Scarring in Cleft Patients.......................................... 51 Wouter B. van der Sluis, Nirvana S. S. Kornmann, Robin A. Tan, and Johan P. W. Don Griot 7.1 Background ........................................................................ 52 7.2 Objectives of Cleft Lip Surgery....................................................... 52 7.3 Treatment Protocol.................................................................. 52 7.4 Cleft Lip Reconstruction: Surgical Techniques ........................................ 52 7.5 Secondary Cleft Lip Reconstruction.................................................. 55 7.6 Evaluation of Aesthetic Outcome .................................................... 55 7.7 Conclusion.......................................................................... 56 Further Reading .................................................................... 57 III Hypertrophic and Keloid Scar: Genetics and Proteomic Studies 8 Genetics of Keloid Scarring ..................................................... 61 Alia Sadiq, Nonhlanhla P. Khumalo, and Ardeshir Bayat 8.1 Background ........................................................................ 62 8.2 HLA Immunogenetics ............................................................... 62 8.3 Linkage............................................................................. 63 8.4 Large-Scale Population Single-Nucleotide Polymorphism (SNP)....................... 64 8.5 Gene Expression .................................................................... 65 8.6 MicroRNAs (miRNA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 8.7 Long noncoding RNA (lncRNA)....................................................... 65 8.8 Small Interfering RNA (siRNA)........................................................ 65 8.9 Microarray Analysis ................................................................. 70 8.10 Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 8.11 Mutations .......................................................................... 72 8.12 Copy Number Variation ............................................................. 72 IX Contents 8.13 FISH (Fluorescence In Situ Hybridization)............................................. 72 8.14 Conclusions......................................................................... 72 Further Readings/Additional Resources.............................................. 73 IV International Scar Classifications 9 International Scar Classification in 2019....................................... 79 Thomas A. Mustoe 9.1 Immature Scar ...................................................................... 80 9.2 Mature Scar......................................................................... 80 9.3 Atrophic Scar ....................................................................... 82 9.4 Linear Hypertrophic Scar............................................................ 82 9.5 Widespread Hypertrophic Scar ...................................................... 82 9.6 Keloid .............................................................................. 83 Bibliography........................................................................ 84 V Scar Symptoms 10 Scar Symptoms: Pruritus and Pain.............................................. 87 Osama Farrukh and Ioannis Goutos 10.1 Pain: Definition and Subtypes ....................................................... 88 10.2 Pain Pathway ....................................................................... 88 10.3 Conclusion.......................................................................... 97 References.......................................................................... 98 11 Scar Symptom: Erythema and Thickness....................................... 103 Yating Yang, Xiaoli Wu, and Wei Liu 11.1 Mechanisms of Erythema in Scar..................................................... 104 11.2 Contributions of Erythema to Scar Development and Associated Clinical Symptoms ... 105 11.3 Scar Erythema and Scar Thickness ................................................... 105 11.4 Clinical Measurement of Scar Redness and Thickness ................................. 105 11.5 Clinical Relevance................................................................... 106 11.6 Clinical Treatment for Thick Scar ..................................................... 107 11.7 Conclusion.......................................................................... 107 References.......................................................................... 107 12 Scar Symptoms: Pigmentation Disorders...................................... 109 A. Pijpe, K. L. M. Gardien, R. E. van Meijeren-Hoogendoorn, E. Middelkoop, and Paul P. M. van Zuijlen 12.1 Pathophysiology and Epidemiology ................................................. 110 12.2 Measurement Techniques ........................................................... 111 12.3 Therapies........................................................................... 112 12.4 Conclusion.......................................................................... 115 References.......................................................................... 115 13 Scar Contractures................................................................ 117 Marguerite Guillot Masanovic and Luc Téot 13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 13.2 General Features.................................................................... 118 13.3 Contractures of the Neck ............................................................ 118 13.4 Axillar Contractures................................................................. 119 13.5 Hand Contractures.................................................................. 119 X Contents 13.6 Other Anatomical Sites of Scar Contractures.......................................... 120 13.7 Rehabilitation Programs............................................................. 120 13.8 Surgical Strategies .................................................................. 121 13.9 Z Plasties ........................................................................... 121 13.10 Skin Grafts.......................................................................... 121 13.11 Dermal Substitutes.................................................................. 121 13.12 Flaps ............................................................................... 121 13.13 Conclusion.......................................................................... 122 References.......................................................................... 122 VI Scar Assessment Scales 14 Scar Assessment Scales.......................................................... 125 Michelle E. Carrière, Annekatrien L. van de Kar, and Paul P. M. van Zuijlen 14.1 Background ........................................................................ 126 14.2 Domains............................................................................ 126 14.3 Scar Assessment Scales.............................................................. 126 14.4 Measurement Properties/Clinimetrics................................................ 127 14.5 Conclusion.......................................................................... 131 References.......................................................................... 131 15 Japan Scar Workshop (JSW) Scar Scale (JSS) for Assessing Keloids and Hypertrophic Scars ......................................................... 133 Rei Ogawa 15.1 Background ........................................................................ 134 15.2 JSW Scar Scale (JSS) 2015............................................................ 1 34 15.3 Classification Table.................................................................. 134 15.4 Evaluation Table .................................................................... 134 15.5 Clinical Suitability and Usefulness of the JSS ......................................... 136 15.6 Conclusion.......................................................................... 136 References.......................................................................... 140 VII Objective Assessment Technologies (Cutometer, Laser Doppler, 3D Imaging, Stereophotogrammetry) 16 Objective Assessment Technologies: General Guidelines for Scar Assessment ............................................................. 143 Julian Poetschke and Gerd G. Gauglitz 16.1 Background ........................................................................ 144 16.2 Choosing the Right Tools for Each Scar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 16.3 Optimizing the Measurement Process................................................ 144 16.4 Interpreting Therapeutic Success with Objective Scar Assessment Technologies ....... 146 16.5 Conclusion.......................................................................... 146 References.......................................................................... 147 17 Objective Assessment Tools: Physical Parameters in Scar Assessment...... 149 M. E. H. Jaspers and P. Moortgat 17.1 Clinimetrics......................................................................... 150 17.2 Color ............................................................................... 151 17.3 Elasticity............................................................................ 153 17.4 Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 17.5 Conclusion.......................................................................... 157 References.......................................................................... 157