Table Of ContentRDeain Oiegl aJw. Ma ollura
MEdaittothr ew P. Lungren
Michael R.B. Evans
Editors
Clinical Medicine
Covertemplate
Total Scar Management
FSruobmtit Llea sfeorrs to Surgery for Scars, Keloids,
aCnlindi cSacla Mr Ceodnictrinaect Cuorevesrs T3_HB
Second Edition
112323
Total Scar Management
Rei Ogawa
Editor
Total Scar Management
From Lasers to Surgery for Scars, Keloids,
and Scar Contractures
Editor
Rei Ogawa
Department of Plastic, Reconstructive and
Aesthetic Surgery
Nippon Medical School
Tokyo
Japan
ISBN 978-981-32-9790-6 ISBN 978-981-32-9791-3 (eBook)
https://doi.org/10.1007/978-981-32-9791-3
© Springer Nature Singapore Pte Ltd. 2020
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Contents
Part I B asic Science of Scars
1 Wound Healing and Scarring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Adriana C. Panayi, Chanan Reitblat, and Dennis P. Orgill
2 Burn Wound Healing and Scarring Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . 17
Haig A. Yenikomshian and Nicole S. Gibran
3 Cellular and Molecular Mechanisms of Hypertrophic Scarring . . . . . . . . . . . . . . 25
Antoinette T. Nguyen, Jie Ding, and Edward E. Tredget
4 Genetics of Scars and Keloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Chao-Kai Hsu, Hsing-San Yang, and John A. McGrath
5 Local, Systemic, and Genetic Risk Factors for Keloids and
Hypertrophic Scars and the Reset Concept of Pathological Scar Therapy . . . . . . 55
Rei Ogawa
Part II C linical Plactice of Scars
6 Scar Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Satoko Yamawaki
7 Clinical and Pathological Diagnosis of Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Chenyu Huang, Longwei Liu, Zhifeng You, Zhaozhao Wu, Yanan Du,
and Rei Ogawa
8 Acne Scars: How They Form and How to Undo Them . . . . . . . . . . . . . . . . . . . . . . 97
Mi Ryung Roh and Kee Yang Chung
9 Pediatric Burns and Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .105
Mark Fisher
10 Dermal Substitutes and Negative- Pressure Wound Therapy for
Burns and Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121
J. Genevieve Park and Joseph A. Molnar
11 Surgery and Radiation Therapy for Keloids and Hypertrophic Scars . . . . . . . . .139
Rei Ogawa
12 Steroids for Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151
Ioannis Goutos
v
vi Contents
13 Intralesional Cryosurgery for the Treatment of
Hypertrophic Scars and Keloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .165
Yaron Har-Shai and Lior Har-Shai
14 Laser Therapy for Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .173
Timothy A. Durso, Nathanial R. Miletta, Bart O. Iddins,
and Matthias B. Donelan
Part I
Basic Science of Scars
Wound Healing and Scarring 1
Adriana C. Panayi, Chanan Reitblat, and Dennis P. Orgill
1.1 Introduction 1.2 Mammalian Response to Injury
From the dawn of man to the present day, traumatic injuries “Healing is not a science, but the intuitive art of wooing
nature”—W.H. Auden [6]
have persisted as a major cause of morbidity and mortality.
Even as recently as the Civil War in the United States, up to
24% of upper extremity amputations and 88% of amputa-
tions just below the hip resulted in death [1]. Over the last 1.2.1 Basic Concepts in Homeostasis, Growth
150 years, however, there have been tremendous advances in Adaptation, and Injury
both the understanding and treatment of wounds that have
resulted in fewer amputations and dramatically lowered The survival of a living organism depends on its ability to
fatality rates [2, 3]. Despite these strides, chronic wounds maintain a stable internal environment, known as homeosta-
and scars left in the wake of trauma continue to physically sis. When homeostasis is perturbed by environmental
and emotionally devastate millions of people around the changes, also known as “stressors,” complex biological sys-
world [4, 5]. Increased insight into the cellular and molecular tems within the organism work in tandem to reestablish equi-
mechanisms underpinning wound healing holds promise for librium via the process of growth adaptation [7].
improving the lives of these individuals and driving the As a homeostatic regulatory response, growth adapta-
development of new therapies. Accordingly, in this chapter tion depends on the type of stressor, its magnitude, and the
we will focus attention on understanding the mammalian type of cell, tissue, or organ affected. Take, for example, the
response to injury, basic mechanisms of healing, local and response of skeletal muscle to mechanical stress in the form
systemic factors affecting healing, and recent advances in the of strength training. As the mechanical stress increases,
management of chronic wounds and scars. muscle cells respond in kind by increasing the number of
contractile proteins, myofibrils, and energy stores leading
to an overall growth in cell size known as hypertrophy [8].
The aggregate effect of cellular hypertrophy can be seen on
the tissue level as an enlarged muscle belly now better
suited to handle heavier mechanical loads. This is in con-
trast to hyperplasia, the process by which the number of
A. C. Panayi cells increases via induction of stem cells in response to
The Wound Care Center, Brigham and Women’s Hospital,
increased stress. A classic example is that of liver hyperpla-
Boston, MA, USA
sia to compensate for cell loss after hepatic necrosis or
e-mail: [email protected]
resection [9]. The response to increased stress need not be
C. Reitblat
binary, however, as seen in the gravid uterus which under-
Harvard Medical School, Harvard Business School,
Boston, MA, USA goes both hypertrophy and hyperplasia in response to
e-mail: [email protected] mechanical and hormonal stimuli in order to better accom-
D. P. Orgill (*) modate a growing fetus.
The Wound Care Center, Brigham and Women’s Hospital, In contrast to the above processes, tissues experiencing a
Boston, MA, USA
decrease in stress diminish in size, or atrophy, due to disuse
Harvard Medical School, Harvard Business School, or withdrawal of trophic factors such as oxygen, nutrients,
Boston, MA, USA
and hormonal stimulation. Mechanisms of atrophy include a
e-mail: [email protected]
© Springer Nature Singapore Pte Ltd. 2020 3
R. Ogawa (ed.), Total Scar Management, https://doi.org/10.1007/978-981-32-9791-3_1
4 A. C. Panayi et al.
decrease in cell size or number. The former occurs via inflammation due to persistent acid reflux, however, epithe-
autophagy (Ancient Greek for “self-eating”), in which cyto- lial stem cells are reprogrammed into mucus-secreting
plasmic contents are enzymatically degraded and recycled columnar cells like those seen in the small intestine which
within lysosomes, as well as the ubiquitin-proteosome path- are better able to withstand an acidic environment. Although
way which targets short-lived (and often damaged) proteins this may be beneficial in the short term, this process of cel-
for destruction [10]. A decrease in cell number, on the other lular reprogramming can be maladaptive if the inciting expo-
hand, can be achieved by an organized program of cell death sure is not resolved. With time, cellular growth and
known as apoptosis or the chaotic destruction of large groups proliferation becomes disordered, known as dysplasia, form-
of cells in response to injury as seen in necrosis. ing premalignant lesions at increased risk of neoplastic
External changes in mechanical stress can lead to changes transformation. In the case of reflux esophagitis, 0.5–1% of
in cell size or number, while certain environmental expo- patients with Barrett’s esophagus develop esophageal adeno-
sures can induce metaplasia, a reversible transformation of carcinoma, a highly lethal cancer [11].
one differentiated cell type into another type better suited to Taken together, these adaptations represent but a small
handle this exposure. The most common forms of metaplasia fraction of the armamentarium that has evolved to combat
involve changes in surface epithelium. A classic example is injury and maintain homeostasis. Yet, despite an organism’s
the alteration in the lining of the lower esophagus in the set- impressive resilience, adaptive measures can also be over-
ting of persistent reflux esophagitis, known as Barrett’s whelmed. Cells can be damaged in a number of ways, includ-
esophagus. The typical lining of the esophagus is squamous ing hypoxia, inflammation, nutritional imbalances, physical
epithelium which can slough off without damaging underly- trauma, genetic derangements, and infectious agents, to
ing layers and is, therefore, ideal for overcoming the mechan- name a few, all of which can cause irreversible injury and
ical friction of a food bolus. When there is chronic eventual cell death (Fig. 1.1).
Hyperplasia Hypertophy
Increase in
Normal tissue trophic factors
Injury
Cannot adapt
to injury
Dysplasia Metaplasia Cell death
Decrease in
atrophic factors
Adaptations
to cell stress
Atrophy Resilience stress
Fig. 1.1 Cells can undergo adaptation when exposed to different factors or injury. When the cells are no longer able to adapt, they undergo cell
death via necrosis or apoptosis
1 Wound Healing and Scarring 5
1.2.2 Mechanisms of Wound Healing 1.2.3.1 Hemostasis (Immediate)
Immediately following tissue injury and damage to capillary
Wound healing describes the restoration of normal anatomi- blood vessels, platelets adhere to subendothelial collagen on
cal relationships and physiological integrity of tissues dis- exposed vessel walls forming a weak hemostatic plug. The
rupted by injury. This essential response to injury proceeds primary purpose of the plug is to stem blood loss. Circulating
via a combination of regeneration and repair, defined as the coagulation factors subsequently stabilize the plug via an
complete restitution of devitalized tissue or replacement with enzymatic cascade that drives platelet aggregation and the
fibrous scar, respectively. Often occurring simultaneously, formation of a nascent fibrin scaffold. In addition to serving
the balance between these two processes is dynamic and as the chief effector cells of hemostasis, activated platelets
depends on the proliferative capacity of the tissue involved, within the fibrin scaffold secrete growth factors necessary for
as well as the nature and extent of injury. wound healing. The most well-studied are platelet-derived
Tissues can be categorized into three basic groups based growth factor (PDGF) and transforming growth factor-β,
on their ability to replace damaged tissue with healthy tissue potent mitogens responsible for the recruitment and prolif-
via the proliferation of stems cells: labile, stable, and perma- eration of inflammatory cells that orchestrate subsequent
nent. Labile tissues such as bone marrow and the epithelial phases of the healing process. Platelets also aid in the revas-
lining of the skin are constantly replicating and produce cularization of the wound by releasing vascular endothelial
robust regenerative responses to injury. Less robust are sta- growth factor (VEGF), a proangiogenic factor which facili-
ble tissues which comprise stems cells that spend a majority tates blood flow by restoring the integrity of damaged ves-
of their life spans in quiescence but can be induced to prolif- sels. Acting in concert, the aforementioned factors lay the
erate. Examples include hepatocytes which regenerate after necessary groundwork for the initiation of the second phase
resection and the epithelium of kidney tubules which divide of wound healing, inflammation.
rapidly following acute kidney injury. Permanent tissues
such as cardiac myocytes are terminally differentiated and 1.2.3.2 Inflammation (Days 0–5)
show little to no regenerative capacity. Instead, these tissues As hemostasis is achieved, the rudimentary plug is trans-
heal via repair, explaining why very little cardiac muscle can formed into a complex extracellular matrix (ECM) com-
be regenerated following myocardial infarction. posed of extracellular proteins and carbohydrates that
When repair is the dominant wound healing process, as provide physical scaffolding and biochemical support to
seen in injury to permanent tissues, but also, injury that the healing wound. Among these molecules are chemoat-
results in the loss of stem cells, as in the case of severe burns, tractants derived from platelets, arachidonic acid metabo-
the injured tissue is replaced with fibrous scar. Deep within lites, complement system, and bacterial degradation
the wound, repair proceeds via the formation of granulation products that attract circulating leukocytes into the wound
tissue which serves to fill the tissue defect, protect the wound in a process known as inflammation. Neutrophils are first to
bed from further trauma and infection, and lay the ground- arrive on scene, phagocytosing invading bacteria as well as
work for scar formation. Bright red and granular in appear- necrotic and foreign debris. Neutrophil levels peak within
ance, granulation tissue is composed of new blood vessels, 24 h, at which point macrophages migrate into the ECM
fibroblasts, and myofibroblasts that serve to provide nutri- and become the dominant mediators of inflammation dur-
ents, deposit structural proteins needed for reconstruction, ing days 2–5. While macrophages also fight infection, and
and contract the wound, respectively. On the surface, epithe- remove debris via phagocytosis, their primary function is to
lial cells at the wound margin rapidly proliferate and migrate recruit the effector cells of repair into the wound bed. This
inwards in order to protect the nascent healing cascade is accomplished by binding to integrin receptors in the
(Fig. 1.2). ECM such as tumor necrosis factor-α and interleukin-1,
enabling the secretion of cytokines which attract fibro-
blasts, the workhorses of wound healing seen in the prolif-
1.2.3 Phases of Wound Healing and Beyond erative phase.
Wound healing is a complex process that begins immediately 1.2.3.3 Proliferation (Days 5–10)
following tissue injury and proceeds via a well-described With the arrival of fibroblasts by day 5, wound healing
sequence of highly regulated and overlapping phases that transitions into the proliferative phase and typically con-
include hemostasis, inflammation, proliferation, and remod- tinues until day 10 post-injury. The hallmark of this phase
eling (Fig. 1.3). is the formation of granulation tissue comprising
