15  
Skin wound healing: Repair biology, wound,
and scar treatment
Ursula Mirastschijski, Andreas Jokuszies, and Peter M. Vogt
SYNOPSIS
 Fast and uneventful wound repair guarantees the integrity of
our body and is essential for survival of all living organisms.
Overlapping wound healing phases reflect adult repair resulting in a
scar in contrast to scar-free fetal skin regeneration.
 Wound healing disorders extend between two extremes: chronic
nonhealing ulcers on one side and excessive healing with
hypertrophic scarring on the other.
 Multifactorial causes lead to and sustain chronic wounds, while
excessive scarring is found predominantly after deep dermal burns.
In both cases, biomolecular processes are still not well delineated
and focus of intensive research.
 Clinical wound management starts with an assessment of wound
type for choosing the appropriate dressing and ends with an
interdisciplinary treatment of the wound and accompanying
co-morbidities.
 Long-term scar treatment is characterized by physiotherapy,
pressure garments and surgical contracture release.
 Innovative therapies for aberrant wound repair are still insufficiently
evaluated and mainly experimental. Clinical phase III studies are
lacking for proof of efficacy and wide-spread clinical use.
Wound repair biology
A human being has approximately 3000 skin injuries
during a lifetime. Small wounds usually heal unevent-
fully. Questions about normal and pathological
©
2013, Elsevier Inc. All rights reserved.
processes in the wound-healing scenario only arise
when wound repair is disturbed.
Fast and uneventful wound closure restoring the
integrity of the outer envelope is a criterion for survival
for all living organisms. From prehistoric times up until
today’s highly developed medicine, the aims of wound
repair have not changed: restoring of the outer surface
to protect the individual from infection and dehy­
dration. Egyptian papyri document the treatment of
wounds and recommend the use of different dressings
depending on wound quality.1 The use of honey as an
antiseptic has an astonishing history dating back more
than 4000 years and has been rediscovered in recent
years for the treatment of chronic wounds.2 Furthermore,
different resins, myrrh, frankincense, and cinnamon
were used for wound treatment. South American tribes
applied antiseptic resins such as copaiba, Tolu or
Peru balm on wounds.3 The oldest wound suture was
detected on an Egyptian mummy dating from the 21st
dynasty, around 1100 BC.1
Four thousand years later, fast and uneventful repair
is still the maxim of skin wound healing, albeit aesthetic
issues around tiny and invisible scars play an increasing
role. Acute wounds that heal within 3 months are dis-
tinguished from chronic nonhealing wounds. The term
“acute” comprises burn wounds, traumatic lesions, or
surgical incisional wounds.
268 • 15 • Skin wound healing: Repair biology, wound, and scar treatment

Major Clot formation Growth factor Collagen deposition Collagen cross-linking

event Haemostasis elaboration
Inflammatory
Repair
Proliferation
phase
Remodeling
Fibroblasts
Cellular Lymphocytes
influx Macrophages
Neutrophils
Vascular
Vasodilation
response
Vasoconstriction Fig. 15.1  The temporal patterns of repair phase, cellular
influx, and vascular response during wound repair. The time
Injury 3d 7d 3 weeks 1-2 years points are approximate, and overlap occurs during these
Time repair events.7

Adult wound repair Epidermis

The repair cascade consists of inflammatory, prolifera-

tive, and remodeling phases (Fig. 15.1). These overlap-
ping phases act in highly coordinated relationships to Blood vessel
heal skin defects. During the inflammatory phase,
hemostasis occurs and an acute inflammatory infiltrate Exposure Dermis
of thromboplastic
ensues. The proliferative phase is characterized by fibro- tissue elements
plasia, granulation, contraction, and epithelialization.
The final phase is remodeling, which is commonly Resident
described as scar maturation. moncyte

Platelet

Inflammatory phase Fibroblast

Inflammation is the first stage of wound healing and
comprises cellular and vascular responses, including
hemostasis. At the injury site, lacerated vessels immedi-
ately constrict. Thromboplastic tissue products, pre-
dominantly from the subendothelium, are exposed.
Platelets adhere, aggregate, and form the initial hemo-
static plug.
The coagulation and complement cascades are initi-
ated. The intrinsic and extrinsic coagulation pathways
lead to activation of prothrombin to thrombin, which
converts fibrinogen to fibrin, subsequently polymerized
into a stable clot. As thrombus is formed, hemostasis in
the wound is achieved (Fig. 15.2). The aggregated plate-
lets degranulate, releasing potent chemoattractants for
inflammatory cells, activation factors for local fibrob-
lasts and endothelial cells, and vasoconstrictors. The
adhesiveness of platelets is mediated by activated
integrin receptors such as GpIIb-IIIa (αIIbβ3) on their
SQ fat
Red blood cell
Fig. 15.2  Hemostasis is stimulated by platelet degranulation and exposure of
tissue thromboplastic agents immediately after tissue injury.7 SQ, subcutaneous.
surface.4,5 Interestingly, under thrombocytopenic condi-
tions, macrophages and T cells at the wound site com-
pensated for lack of platelet-derived growth factors
(PDGFs) and initiation of the inflammatory phase.6
Immediately, the repair processes are initiated. After
hemostasis, local vessels dilate secondary to the effects
of the coagulation and complement cascades. Bradykinin
is a potent vasodilator and vascular permeability factor
that is generated by activation of Hageman factor
in the coagulation cascade.8 The complement cascade

Keratinocytes
Neutrophil
Fibrin matrix
Fibroblast
Fig. 15.3  A neutrophil influx into the wound occurs within 24 hours. The
neutrophils scavenge debris and bacteria and secrete cytokines for monocyte and
lymphocyte attraction and activation. Keratinocytes begin migration when a
provisional matrix is present.7
generates the C3a and C5a anaphylatoxins, which
directly increase blood vessel permeability and attract
neutrophils and monocytes to the wound. These com-
plement components also stimulate the release of hista-
mine and leukotrienes C4 and D4 from mast cells. The
local endothelial cells then break cell–cell contact and
increase permeability, which enhances the margination
of inflammatory cells into the wound site.8
The initial influx of white blood cells in the wound
is composed of neutrophils (Fig. 15.3). This early neu-
trophil infiltrate scavenges cellular debris, foreign
bodies, and bacteria. Activated complement fragments
aid in bacterial killing through opsonization. The neu-
trophil infiltrate is decreased in clean surgical wounds
compared with contaminated or infected wounds.
Within 2–3 days, the inflammatory cell population
begins to shift to one of monocyte predominance.
Circulating monocytes and mast cells are attracted and
infiltrate the wound site.9,10 These monocytes differenti-
ate into macrophages and, in conjunction with the resi-
dent tissue macrophages, orchestrate the repair process.
Macrophages not only continue to phagocytose tissue
and bacterial debris but also secrete multiple peptide
Adult wound repair 269
growth factors. These growth factors activate and attract
local endothelial cells, fibroblasts, and keratinocytes to
begin their respective repair functions. More than 20
different cytokines and growth factors are known to be
secreted by macrophages (Table 15.1).11
Depletion of monocytes and macrophages in combi-
nation with steroid therapy resulted in severe wound-
healing deficiency with poor debridement, delayed
fibroblast proliferation, and inadequate angiogenesis.12
In contradiction to the dogma that inflammation is
essential for skin wound healing, mice deficient in the
hematopoietic ETS family transcription factor PU.1
showed normal wound repair13 despite immunoincom-
petent leukocytes and nonfunctional macrophages.14
Although the growth factor and cytokine pattern was
altered, incisional wounds healed uneventfully and
scar-free with phagocytic fibroblasts clearing the wound
debris. Obviously, attenuated inflammation is beneficial
for wound healing.9
Proliferation phase
Extracellular matrix formation
During fibroplasia, fibroblasts synthesize and deposit
replacement extracellular matrix (ECM) at the wound
site. The proliferative phase begins with degradation of
the initial fibrin–platelet provisional matrix. Three major
classes of proteases are involved in wound repair.
Proteases of the serine, cysteine, and matrix metallopro-
teinase (MMP) family are secreted to facilitate cellular
migration through fibrin clot and provisional matrix.
Both tissue and urokinase plasminogen activator are
expressed to dissolve the blood clot.15 MMPs comprise
endopeptidases such as collagenases, gelatinases, and
stomelysins that can degrade virtually all matrix pro-
teins, activate growth factors, and bind on cell sur-
faces.16,17 Cysteine proteases are present in epithelia
during wound repair and are involved in signaling and
basement membrane protein degradation.18
Macrophages, mast cells, and the adjacent ECM
release growth factors that stimulate fibroblast activa-
tion.9 Local fibroblasts become activated and increase
protein synthesis in preparation for cell division. As
fibroblasts proliferate, they become the predominant
cell type by 3–5 days in clean, noninfected wounds (Fig.
15.4). After cell division and proliferation, fibroblasts
270 • 15 • Skin wound healing: Repair biology, wound, and scar treatment

Table 15.1  A partial list of growth factors present at the wound site*
Growth factor Cellular source Target cells Biologic activity

Activin Fibroblasts, keratinocytes Stromal cells Granulation tissue formation,

scarring
TGF-β1 and TGF-β2 Macrophages, platelets, fibroblasts, Inflammatory cells, keratinocytes, Chemotaxis, proliferation, matrix
keratinocytes fibroblasts production (fibrosis)
TGF-β3 Macrophages Fibroblasts Antiscarring?
TGF-α Macrophages, platelets, keratinocytes Keratinocytes, fibroblasts, Proliferation
endothelial cells
TNF-α Neutrophils, mast cells Macrophages, keratinocytes, Activation of growth factor
fibroblasts expression
PDGF Macrophages, platelets, keratinocytes, Neutrophils, macrophages, Chemotaxis, proliferation, matrix
fibroblasts, endothelial cells, fibroblasts, endothelial cells, production
vascular smooth-muscle cells vascular smooth-muscle cells
FGF-1, FGF-2, FGF-4 Macrophages, fibroblasts, endothelial Keratinocytes, fibroblasts, Angiogenesis, proliferation,
cells endothelial cells, chondrocytes chemotaxis
FGF-7 (KGF-1), FGF-10 Fibroblasts Keratinocytes Proliferation, chemotaxis
(KGF-2)
EGF Platelets, macrophages, keratinocytes Keratinocytes, fibroblasts, Proliferation, chemotaxis
endothelial cells
HB-EGF Macrophages, keratinocytes Keratinocytes, fibroblasts Proliferation, epithelial migration,
synergistic with IGF
IGF-1/Sm-C Fibroblasts, macrophages, platelets Fibroblasts, endothelial cells Proliferation, collagen synthesis
IL-1α and IL-1β Macrophages, neutrophils Macrophages, fibroblasts, Proliferation, collagenase
keratinocytes synthesis, chemotaxis
CTGF/CCN2 Fibroblasts, endothelial cells Fibroblasts Downstream of TGF-β1
VEGF Macrophages, keratinocytes, Endothelial cells Angiogenesis
fibroblasts
*Redundant biologic effects occur through both autocrine and paracrine mechanisms.
TGF-α, transforming growth factor-α; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; PDGF, platelet-derived growth factor; FGF, fibroblast growth fac-
tor; KGF, keratinocyte growth factor; EGF, epidermal growth factor; HB-EGF, heparin-binding EGF, IGF-1, insulin-like growth factor 1; Sm-C, somatostatin C; IL-1, interleukin-1;
CTGF, connective tissue growth factor; VEGF, vascular endothelial cell growth factor.
(Reproduced from Lorenz HP, Longaker MT. Wounds: biology, pathology, and management. New York: Springer-Verlag; 2000.)

begin the synthesis and secretion of ECM products. The
initial fibrin matrix is replaced by a provisional matrix
of fibronectin and hyaluronan, which facilitates fibro­
blast migration. The control of ECM deposition by
fibroblasts is complex and partially regulated by growth
factors and interactions of fibroblast cell membrane
receptors with the ECM. Integrins are regulators of cel-
lular function during repair. They are transmembrane
receptors with extracellular, membrane, and intracellu-
lar protein domains. Integrins are heterodimeric and
composed of α and β subunits that interact to form the
active protein receptor. Ligands to integrins include
growth factors and ECM structural components such as
collagen, elastin, and other cells.19,20 After ligands bind,
phosphorylation occurs in the cytoplasmic domain of
the integrin receptor, which starts a signal transduction
cascade that ultimately changes gene expression, and
new cellular function ensues.
Fibronectin and the glycosaminoglycan hyaluronic
acid compose the initial wound matrix.10 Hyaluronic
acid provides a matrix that enhances cell migration
because of its large water content. Adhesion glycopro-
teins, including fibronectin, laminin, and tenascin, are
present throughout the early matrix and facilitate cell
attachment and migration. Integrin receptors on
cell surfaces bind to the matrix glycosaminoglycans
and glycoproteins. As fibroblasts enter and populate
the wound, they secrete hyaluronidase to digest

Scab
Keratinocyte
migration
Myofibroblast
Fibroblast
Neutrophil
Macrophage
Fig. 15.4  Fibroblasts are activated and present at the wound by 3–5 days after
injury. These cells secrete matrix components and growth factors that continue to
stimulate healing. Keratinocytes migrate over the new matrix. Migration starts from
the wound edges as well as from epidermal cell nests at sweat glands and hair
follicles in the center of the wound.7
the provisional hyaluronic acid-rich matrix, and larger,
sulfated glycosaminoglycans are subsequently depos-
ited. Concomitantly, new collagen is deposited by
fibroblasts on to the fibronectin and glycosaminoglycan
scaffold in a disorganized manner, resulting in scar for-
mation. The major fibrillar collagens composing the
ECM in skin and scar are collagen types I and III. The
ratio of collagen type I to type III is 4 : 1 in both skin and
wound scar. Although type III collagen is initially
deposited in relatively greater amounts in wounds,
its amount is always less than type I collagen in
mature scar.21
At least 28 different types of collagen are currently
known.22 Most collagen types of the ECM are synthe-
sized by fibroblasts; however, some types are synthe-
sized by keratinocytes.23 The collagens share common
characteristics: the basic structural unit is a right-handed
triple helix. Unique structural properties that distin-
guish the different collagen types include segments that
interrupt the triple helix and fold it into other structures
with unique properties.24
The major structural component of wound scar is
collagen. Fibroblasts synthesize and secrete collagens
Adult wound repair 271
through a complex intracellular and extracellular
process. Coordinated transcription of genes on different
chromosomes (2, 6, 7, 12, 13, 17, and 21) occurs. In addi-
tion, several intracellular and extracellular modifica-
tions are required to form the new collagen fiber.
Collagens contain a high fraction of proline amino acid
residues, and this is the basis of its triple helix structure.
With regard to collagens I and III, tropocollagen is
formed in the ECM.24 Tropocollagen molecules aggre-
gate laterally and are covalently cross-linked by the
enzyme lysyl oxidase to form collagen fibrils.25 The
fibrils interact with other fibril types, which then aggre-
gate into fibers. Fibers then aggregate into bundles and
form a collagen-rich scar.
Granulation tissue formation and angiogenesis
Granulation tissue is a dense population of blood
vessels, macrophages, and fibroblasts embedded within
a loose provisional matrix of fibronectin, hyaluronic
acid, and collagen. Granulation tissue is clinically char-
acterized by its beefy-red appearance (i.e., “proud
flesh”) and is present in open wounds. It is a conse-
quence of the rich bed of new capillary networks (neoan-
giogenesis) that form by endothelial cell division and
migration. The directed growth of vascular endothelial
cells is stimulated by tissue hypoxia, and platelet
and activated macrophage and fibroblast products.26
Examples are basic fibroblast and vascular endothelial
growth factor (VEGF), which induce migration and pro-
liferation of endothelial cells.27 A prerequisite for
endothelial sprouting is the expression of the integrin
avβ3 at the leading capillary tip28 and the secretion of
proteases for matrix degradation. Granulation tissue is
a clinical indicator that an open wound is amenable to
skin graft treatment. Wounds that benefit from skin
grafts are of sufficient size such that the healing time
would be decreased after grafting. Because granulation
tissue has a high level of vascularity due to the abun-
dance of new capillary formation, it readily accepts and
supports skin grafts.
Wound contraction
Contraction is the process in which the surrounding
skin is pulled circumferentially toward an open wound
(Fig. 15.5). This phenomenon does not occur with closed
272 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
A B
Fig. 15.5  Wound contraction is the process in which the surrounding tissue is pulled radially toward the wound. The wound size is decreased, which shortens the healing
time. Full-thickness, rat skin wounds on postoperative days 0 (A), 4 (B), 8 (C), 12 (D), and 14 (E) after wounding. Note completely healed wound on postoperative day 14.
surgical incisions. Open wounds after trauma, burns,
and previously closed wounds secondarily opened by
infection are associated with contraction. Wound con-
traction decreases the size of the wound dramatically
without new tissue formation. This repair process
speeds wound closure compared with epithelialization
and scar formation alone. In addition, the area of insen-
sate scar is smaller. Animals have a much greater ca­­
pacity for wound contraction than humans do. Most
mammalian animals (e.g., rodents, cats, dogs, sheep,
and rabbits) have a panniculus carnosus, which is a
myofascial layer between the subcutaneous fat and
musculoskeletal layers. This anatomy results in a plane
of low resistance between two fascial layers, which
allows enhanced skin mobility and therefore contrac-
tion. The amount of contraction is related to both the
size of the wound and mobility of the skin. In humans,
contraction is greatest in the trunk and perineum, least
on the extremities, and intermediate on the head and
neck. Eighty percent to 90% of wound closure can be
due to contraction in the trunk and perineum.29 These
regional differences in contraction are probably due to
relative differences in skin laxity.
It has become accepted that myofibroblasts play a
key role in wound contraction. After wounding, dermal
fibroblasts at wound margins are activated by growth
factors released into the wound. Stimulated by mechan-
ical tension and PDGF, they turn into stress fiber-
expressing protomyofibroblasts. Protomyofibroblasts
are found in early granulation tissue and in normal
connective tissue with high mechanical load.
Approximately 4 days after wounding, myofibroblasts
appear in the wound.30 Mechanical tension, activated
transforming growth factor-β (TGF-β1)16 and the splice
variant ED-A fibro­­nectin trigger protofibroblast differ-
entiation into alpha-smooth-muscle actin-expressing
myofibroblasts.31 Myofibroblasts exert their contractile
C D E
forces by focal adhesion contacts that link the intracel-
lular cytoskeleton to the ECM. Interestingly, intercellu-
lar myofibroblast contacts via connexin-containing
gap junctions are important for contractility because
connexin-43-depleted fibroblasts were incapable to
contract collagen matrices.32 Furthermore, the role of
keratinocytes in wound contraction should not be
neglected. In vitro experiments showed higher contrac-
tile forces of keratinocytes compared with fibroblasts.33
Future research will shed further light on the biology of
skin wound contraction.
Wound contraction must be distinguished from con-
tracture. Clinically, contracture is defined as tissue
shortening or distortion that causes decreased joint
mobility and function. Scar contracture commonly
refers to decreased function in the area, whereas scar
contraction refers to shortening of the scar length com-
pared with the original wound.
Epithelial resurfacing
Morphologic changes in keratinocytes at the wound
margin are evident within hours after injury. Marginal
basal cells dissolve intercellular contacts, e.g., desmo-
somes and adherence junctions, and cell–matrix con-
tacts, e.g., hemidesmosomes. Flattened migratory cells
express cytoplasmatic actin filaments, promigratory
integrins, e.g., α2β1, α5β1, αvβ5, αvβ6, and secrete pro-
teases to enable movement.34 MMP-3 is localized to
wound margin keratinocytes and cleaves the intercel-
lular contact protein E-cadherin.35 MMP-9 cleaves base-
ment proteins, e.g., collagen type IV and VII releasing
keratinocytes from their substratum.36 MMP-1 degrades
native collagen type I and III, smoothing the way for
newly formed matrix. Furthermore, MMP-1 binds to
α2β1 integrin on cell membranes, presumably acting as
a migration promoter.37 Blocking MMP activity with

synthetic broad-spectrum inhibitors abolished epithelial
migration in vitro and in vivo.38,39
In contrast to keratinocytes are fibroblasts able to
adopt an ameboid phenotype and squeeze through the
matrix network in the presence of MMP inhibitors.40
Recently, cysteine proteases, e.g., cathepsin-B, C, K and
L, entered the field of skin wound healing, acting as
endopeptidases involved in the degradation of ECM
proteins.18
After the re-establishment of the epithelial layer,
keratinocytes and fibroblasts secrete laminin and type
IV collagen to form the basement membrane.41 The
keratinocytes become columnar and divide to restore
the layering of the epidermis and reform a barrier to
further contamination and moisture loss. Keratinocytes
can respond to foreign-body stimulation with migration
as well. Sutures in skin wounds provide tracks along
which these cells can migrate. Fibrotic reactions, cysts,
and sterile abscesses centered on the suture can occur.
These are treated by removal of the inciting suture and
epithelial cell sinus track or cyst.
Remodeling phase
The scaffold that supports cells in both the unwounded
and wounded states is the ECM, which is the structural
component of skin that must be repaired after injury.
The ECM is dynamic and is constantly undergoing
remodeling during repair, which can be conceptualized
as the balance between synthesis, deposition, and deg-
radation. Lysyl oxidase is the major intermolecular col-
lagen cross-linking enzyme.25 Collagen cross-linking
decreases its degradation and improves wound tensile
strength. The balance of collagen deposition and degra-
dation is in part determined by the regulation of MMP
activity.42 MMPs are inactivated by tissue inhibitors of
MMPs, α-macroglobulin, and degradation by other pro-
teases.17,43 Except for reduced wound contraction in
MMP-3-deficient mice,44 other MMP knockout mice
have little or no wound-healing disturbances.36
Scar formation is the ultimate outcome of wound
repair in children and adults. The scar has no epidermal
appendages (hair follicles and sebaceous glands), and it
has a collagen pattern that is distinctly different from
unwounded skin. New collagen fibers secreted by
fibroblasts are present as early as 3 days after wound-
ing. As the collagen matrix forms, densely packed fibers
Regulation 273
fill the wound site. The ultimate pattern of collagen in
scar is one of densely packed fibers and not the reticular
pattern found in unwounded dermis.
Wound scar remodeling occurs during months to
years to form a “mature” scar. The early scar appearance
is red due to its dense capillary network induced at the
injury site. When closure is complete, capillaries regress
until relatively few remain. As the scar redness dissipates
during a period of months, the true scar pigmentation
becomes evident. Scars are usually hypopigmented after
full maturation. However, scars can become hyperpig-
mented in darker-pigmented patients and in those
lighter-pigmented patients whose scars receive excess
sun exposure. For this reason, sun protection measures
are recommended for patients with early scars on sun-
exposed areas such as the scalp, face, and neck. During
remodeling, wounds gradually become stronger with
time. Wound tensile strength increases rapidly from 1 to
8 weeks after wounding and correlates with collagen
cross-linking by lysyl oxidase. However, the tensile
strength of wounded skin at best reaches only appro­
ximately 80% that of unwounded skin45 but can be
increased by synthetic MMP inhibitors.46 In addition,
scar is brittle and less elastic than normal skin. It is
readily visible because of color, contour, and texture dif-
ferences compared with unwounded skin. Although
scars can be hidden well with proper surgical planning
and uneventful healing, they may have aesthetically unac-
ceptable appearances in nonelective wounds after trauma
and burns and in wounds with healing problems.
Regulation
Growth factors in skin wound healing
Growth factors are the focal regulatory points of the
repair process. They are polypeptides that are released
by a variety of activated cells at the wound site (Table
15.1). They act in either a paracrine or autocrine fashion
to stimulate or to inhibit gene expression by their target
cells in the wound. In general, they stimulate cellular
proliferation and chemoattract new cells to the wound.
Myriad growth factors are present in wounds and many
have overlapping biologic functions. Most growth
factors exist in several isoforms with several receptor
types present in wounds, which increases the
274 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
complexity of growth factor function. In addition to
growth factor ligands, their signaling receptors are
another locus for regulation of repair. Growth factors do
not have an effect on target cells without a functional
signaling receptor present on the cell surface. The level
of regulation is complex in that the growth factors have
multiple different receptor types to which they can bind
and induce cell signaling. In recent years, the develop-
ment of transgenic and knockout mouse models includ-
ing inducible and cre-lox technologies has generated
new knowledge in the function of many growth factors
in wound healing. Clinical trials applying various
growth factors to chronic nonhealing wounds showed
beneficial effects,47 although treatment efficacy should
be confirmed by larger, randomized, double-blinded
studies.48
Platelet-derived growth factor
PDGF is released from platelet alpha granules immedi-
ately after injury. PDGF attracts neutrophils, macro-
phages, and fibroblasts to the wound and serves as a
powerful mitogen. Macrophages, endothelial cells, and
fibroblasts also synthesize and secrete PDGF in the
wound. PDGF stimulates fibroblasts to synthesize new
ECM, predominantly the noncollagenous components
such as glycosaminoglycans and adhesion proteins and
to contract these matrices.49 PDGF also increases the
amount of collagenase secreted by fibroblasts, indicat-
ing a role for this growth factor in tissue remodeling.
PDGF strongly induces granulation tissue production
and was the first growth factor to be approved for the
treatment of diabetic nonhealing wounds.50
Transforming growth factor-β
The TGF-β family comprises TGF-β1–3, bone morpho-
genic proteins (BMP), and activins. TGF-β1 predomi-
nates in adult wound healing and is a promigratory
and profibrotic growth factor that directly stimulates
collagen synthesis and decreases ECM degradation by
fibroblasts. It is released from all cells at the wound
site, including platelets, macrophages, fibroblasts,
and keratinocytes. TGF-β acts in an autocrine fashion
to stimulate its own synthesis and secretion. TGF-β
also chemoattracts fibroblasts and macrophages to
the wound, promotes granulation tissue formation,
myofibroblast differentiation, and wound contraction.
TGF-β accelerates wound repair when it is applied
experimentally to wounds that have no deficiency in
repair. However, the increase in repair rate is at the
expense of increased fibrosis, which could be a detri-
ment during normal skin healing. In addition, increased
TGF-β activity is associated with pathologic fibrosis in
multiple different organ systems, including heart, lung,
brain, liver, and kidney. TGF-β stimulates ECM synthe-
sis by increasing collagen, elastin, and glycosamino­
glycan synthesis. It increases integrin expression, which
enhances cell–matrix interactions. TGF-β increases
ECM accumulation by decreasing MMP and increasing
tissue inhibitor of MMP expression. Through these
mechanisms, exogenous TGF-β augments fibrosis at
the wound site.51 Interestingly, studies in mice with
a lack of endogenous TGF-β activity demonstrate
accelerated healing with an impaired inflammatory
response.52 In chronic wounds, however, significantly
reduced TGF-β was found leading to clinical trials with
TGF-β treatment that failed showing beneficial effects.53
Activins and BMP are promigratory proteins secreted
by keratinocytes and fibroblasts during wound repair
and promote keratinocyte differentiation.53 These find-
ings underscore the complex effects of TGF-β and other
growth factors during the repair process.
Fibroblast growth factors
The fibroblast growth factors (FGFs) are a group of
heparin-binding growth factors that are secreted into
the ECM, where they remain dormant until activated by
tissue injury. They are bound by heparin and the gly-
cosaminoglycan heparan sulfate. They have a broad
range of biologic functions, specific to each isoform.
FGF-1 (acidic FGF) and FGF-2 (basic FGF) stimulate
angiogenesis.26 Endothelial cells, fibroblasts, and macro-
phages produce FGF-1 and FGF-2. Basement membrane
serves as a storage depot for FGF-2, which is released
on degradation of the heparin components of the base-
ment membrane at sites of injury. FGF-1 and FGF-2
stimulate endothelial cells to divide and form new capil-
laries. They also chemoattract endothelial cells and
fibroblasts. FGF-7 (keratinocyte growth factor 1 (KGF-
1)), FGF-10 (KGF-2), and epidermal growth factor
(EGF) stimulate epithelialization. KGF-1 and KGF-2
are expressed in wound fibroblasts and promote

keratinocyte proliferation and migration in a paracrine
fashion. Decreased expression of KGF-1 occurs in dia-
betic and reduced levels of FGF-2 in aged mouse wounds
with decreased angiogenic response.54,55 In an ischemic
rabbit wound model, exogenous KGF-2 treatment accel-
erates epithelialization without an increase in scar for-
mation.32 Exogenous KGF-2 also increases wound tensile
strength, collagen content, and epidermal thickness in
animal models of normal healing.56 Hitherto, only one
clinical trial has been conducted using recombinant
human KGF-2 for treatment of chronic venous ulcers
and showed accelerated wound healing.57
Vascular endothelial growth factor
VEGF is also a potent angiogenic stimulus.58 It acts in a
paracrine manner to stimulate vascular permeability
and proliferation by endothelial cells after release from
platelets, endothelial cells, neutrophils, macrophages,
fibroblasts, and keratinocytes.59–61 Its expression is
increased in hypoxic conditions, such as those found at
the wound site.62 Intramuscular gene transfer of VEGF
to patients with ischemic ulcers resulted in sprouting
of collateral vessels and limb salvage.63 Despite these
promising results, careful use of VEGF is recommended
because exogenous VEGF administration yielded vas-
cular leakage and malformation.64 Placental growth
factor (PLGF) is also proangiogenic and acts synergisti-
cally to VEGF.65 PLGF is upregulated in migrating kerat-
inocytes and promotes granulation tissue formation and
migration. Unlike VEGF, PLGF does not interfere with
lymphatic vessel formation66 and accelerates wound
healing in diabetic mice.67
Other growth factors and cytokines
Multiple other growth factors affect wound repair.
Epithelialization is also directly stimulated by members
of the EGF family, e.g., EGF, heparin-binding EGF (HB-
EGF), and TGF-α. These mitogens are released by kerat-
inocytes to act in an autocrine fashion. Insulin-like
growth factor 1 (IGF-1) stimulates cell proliferation and
collagen synthesis by fibroblasts and interacts synergis-
tically with HB-EGF, PDGF, and FGF-2 to facilitate
fibroblast proliferation.51 Various cytokines comprising
interleukins (IL), chemokines, and tumor necrosis
factor-α (TNF-α) mediate inflammatory cell functions at
Regulation 275
the wound site and contribute to tissue remodeling and
angiogenesis.51 IL-6 is crucial for initiation of the wound-
healing response68 whereas overexpression leads to
cutaneous scarring. TNF-α and interferon-γ have
been shown to downregulate ECM protein synthesis.
Granulocyte–macrophage colony-stimulating factor
(GM-CSF) is a pleiotropic cytokine stimulating migra-
tion and proliferation during wound repair. Experimental
treatment of diabetic and chronic wounds showed
promising results with faster healing rates.69,70
Although further studies are needed to determine the
precise growth factor combination that is optimal for
specific wound types, therapeutic growth factor appli-
cation has become a reality. The clinical use of PDGF-BB
was approved by the Food and Drug Administration for
chronic ulcers. Further promising candidates are VEGF/
PLGF, FGF-2, and GM-CSF.
Growth factor interactions with
the extracellular matrix
In normal, unwounded conditions, the ECM is a deposi-
tory of growth factors in latent forms. With injury and
matrix destruction, growth factors are released from the
ECM in active form and thereby assist in initiating and
regulating the repair process. For example, TGF-β is
bound in the ECM to the proteoglycan decorin and is
inactive when bound. At sites of injury, TGF-β forms
complexes with its binding protein, latency-associated
protein (LAP), and is released. Under acidic conditions,
such as at sites of hypoxia and tissue injury, LAP disas-
sociates and active TGF-β is formed. LAP can also be
proteolytically cleaved and released by MMPs and other
proteases at the wound site. Active TGF-β immediately
binds to its receptors (RI and RII), which are present on
fibroblasts, macrophages, and endothelial cells.71 The
TGF-β RI and RII receptors form heterodimeric com-
plexes with each other, and TGF-β biologic activity is
initiated in the target cell through the Smad pathway.72
The FGFs are another example of growth factors
bound by the ECM. PDGF and HB-EGF have also been
shown to bind to ECM proteins. Through sequestration
of growth factors with their subsequent release during
injury, the ECM plays a fundamental role in wound
repair by presenting growth factors that regulate the
repair processes.
276 • 15 • Skin wound healing: Repair biology, wound, and scar treatment

intrauterine environment, and fetal serum factors are

Fetal wound repair biology
The therapeutic solution for the reduction and possible
elimination of scar formation may be found in the mech-
anisms responsible for scarless wound healing in the
fetus. The early-gestation fetus can heal skin wounds
with regenerative-type repair and without scar forma-
tion.74,75 In scarless fetal wounds, the epidermis and
dermis are restored to a normal architecture. The col-
lagen dermal matrix pattern is reticular and unchanged
from unwounded dermis. The wound hair follicle and
sweat gland patterns are normal as well (Fig. 15.6) . The
wound is not evident grossly unless a wound edge
contour change is present, and this will cast a light
shadow under appropriate circumstances.73 Scarless
healing by the fetus does not depend on the fetal envi-
ronment. Fetal wounds in marsupials76 or skin graft
wounds heal without scar after transplantation to a
postnatal environment. Thus, amniotic fluid, the
not required for scarless healing. Scarless repair appears
to be inherent to the fetal tissue and probably depends
on factors associated with skin development.75 Notably,
fetal scarless repair in skin is organ-specific with scar-
ring of intestinal wounds at the same gestational age.77
The fetal environment alone cannot induce scarless
healing in adult skin. When adult skin is transplanted
on to a fetus and later wounded at a point in gestation
when fetal skin heals scarlessly, the adult skin grafts still
heal with scar formation.78 The transformation of adult
healing to scarless repair cannot be accomplished simply
by perfusion of adult skin with fetal serum or by immer-
sion in amniotic fluid. Thus, induction of scarless healing
in adult skin will require more than recreation of the
fetal environment. The adult repair processes will likely
have to be modified to recapitulate skin development.
An understanding of the biology of scarless fetal
wound repair will help surgeons develop therapeutic
strategies to minimize scar and fibrosis.

A B

C D

Fig. 15.6  Fetal rat skin wound made at gestational age 16.5 days (term = 21days), stained with hematoxylin and eosin. The hair follicle pattern is normal and there is
no dermal collagen scar formation. Black arrows indicate India ink tattoo made at the time of wounding to locate the scarless wound. (A,C) Healed wounds harvested at
72 hours (×100). The epidermal appendage (developing hair follicles) pattern shows numerous appendages in the healed wound. (B,D) Magnified views of the same
wounds show epidermal appendages (open arrows) within the wound site (×200). No inflammatory infiltrate is present. (Modified from Beanes SR, Hu FY, Soo C, et al.
Confocal microscopic analysis of scarless repair in the fetal rat: defining the transition. Plast Reconstr Surg 2002; 109:160–170.)

Transition from scar-free healing
to scar formation
Both gestational age and wound size determine whether
the fetus will heal a wound without scar.79 As gestation
progresses, a transition from scarless healing to healing
with scar formation occurs before birth. In large-animal
models, such as the fetal lamb and monkey (Fig. 15.7),
this transition occurs during the early part of the third
trimester for incisional, closed wounds. In addition,
wound size affects the temporal occurrence of this tran-
sition. Open, excisional wounds must be made earlier
in gestation than closed, incisional wounds for scarless
healing to occur. Also, larger open wounds must be
made earlier in gestation than smaller open wounds for
scarless healing.79 The exact reasons underlying these
observations remain unknown but probably relate to
whether the wound has healed before a certain thresh-
old in development. The shift from scarless healing
to scar formation is not abrupt but instead occurs
gradually with an intermediate repair outcome that is
neither regeneration nor scar: the transition wound. The
Fig. 15.7  Fetal monkey full-thickness wedge excision lip wound made at the
beginning of the third trimester and harvested 2 weeks later. The cutaneous wound
is identified by the sutures. No scar was present histologically, and the orbicularis
oris muscle reformed across the defect.73 Interestingly, the naris was deformed
compared with the contralateral side.
Fetal wound repair biology 277
transition wound has a normal reticular collagen and
connective tissue matrix pattern but without restoration
of epidermal appendages.73 Thus, it has features of
both scar (no appendages) and scarless (normal ECM)
healing.
Differences between fetal and adult repair
Cellular differences
Because fetal fibroblasts deposit matrix in a scar-free
pattern, they are crucial for scarless repair. A number of
studies have defined the functional differences between
fetal and postnatal dermal fibroblasts. First, fetal fibrob-
lasts synthesize more collagen type III and IV with
simultaneous proliferation, in contrast to their postnatal
counterparts in vitro.80 Fetal fibroblasts failed to respond
to TGF-β stimulation with collagen synthesis compared
to postnatal fibroblasts in vitro.81 Furthermore, higher
gene expression of MMP-1, -2, -3, -9, and -14 is found
during fetal wound healing with virtually absent myofi-
broblasts during early gestation.82,83 Fetal fibro­blasts
also migrate at a faster rate than postnatal fibro­blasts.84
Increased migration velocity during repair is likely to
affect collagen deposition and crosslinking.
In postnatal wounds, epidermal continuity is restored
by proliferating stem cells derived from the epidermal
basement membrane and the hair follicle bulge.85
Because immature fetal skin does not have hair bulges,
the stem cell origin is likely to be different to adult
wound repair. Indeed, a new stem cell was recently
discovered and named dot cell because of its extremely
small size.86 Dot cells are found in basement membranes
and in the blood during fetal development and have a
strong affinity to wounded tissue. After transplantation
of dot cells into adult murine wounds, scarless healing
was noted. Despite their small size, these cells seem to
have a great future in wound repair.
Differences in wound repair
Several parameters of repair are different in fetal wounds
compared with postnatal wounds. The rate of repair for
wounds of equal size is faster in the fetus. The collagen
synthesis rate is greater in fetal wounds. In addition, the
rate of epithelialization is faster in the fetal wound.80
278 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
Fetal wound repair may be more rapid because there is
little or no period of activation for the fetal fibroblast to
synthesize ECM at the wound site.
A key difference between fetal and postnatal tissue
repair is a reduced inflammatory cellular infiltrate in
fetal wound repair.87 Inflammation plays a prominent
role in postnatal repair, but it is not present in signifi-
cant amounts during scarless fetal healing. This may
be due to the immature fetal immune system with
decreased platelet degranulation, PDGF and TGF-β
production.87 However a marked inflammatory cellular
infiltrate occurs later in gestation after the transition
when fetal wounds form scar. The amount of inflam-
mation correlates strongly with the amount of scar
formation.
Growth factor expression in fetal wound repair
Few growth factors associated with adult repair have
increased expression in scarless fetal wounds. This is
likely due to inherent major differences in the regulation
between the two repair systems. Growth factors that
are upregulated in scarless wounds are increased more
rapidly than in postnatal wounds. One example is
VEGF, which is expressed rapidly and threefold higher
after injury in scarless wounds but is delayed in post-
natal wounds.88 The expression of TGF-β isoforms,
receptors, and bioactivity modulators has been ana-
lyzed in fetal wounds. Compared with scarring wounds,
scarless fetal wounds have more TGF-β3, receptor type
II, and fibromodulin expression.89 In contrast, increased
TGF-β1, receptor type I, and decorin expression is asso-
ciated with the transition to scar formation. Thus, the
expression profile of isoforms, receptors, and modula-
tors for a growth factor can be different in scarless and
scarring wounds. By understanding the scarless repair
expression profile for a growth factor, information is
obtained that can permit recapitulation of this profile
during postnatal repair to reduce scar formation.
Exogenous addition of several cytokines to fetal wounds
has also been performed and in every case has resulted
in accelerated scarring. The cytokines tested include
TGF-β1, TGF-β2, PDGF, and BMP-2, each of which has
increased expression during scar formation in postnatal
wounds.90–92 Thus, growth factors with increased expres-
sion in scarring wounds probably modulate scarless
wounds in a similar fashion, and this results in scar
formation.
Differences in gene expression
Because fetal skin is growing and differentiating, genes
associated with development are likely to have an
important role during scarless healing. Their expression
may not occur during adult healing because of inactiva-
tion at the end of development. Homeobox genes are
transcription factors that govern gene expression during
embryogenesis. PRX2 is a homeobox gene that has
increased expression during scarless fetal wound
healing and only weak expression during adult skin
healing.93 New data are available for Wnt proteins
involved in skin maturation, fetal and adult wound
repair.94,95 Wnt signaling is increased in postnatal but not
in fetal murine wound healing with a TGF-β1-like profi-
brotic influence on postnatal but not on fetal fibrob-
lasts.96 Differential signaling in fetal and adult cells in
response to wounding seems to direct the way to either
tissue regeneration or scarring.
Differences in matrix composition
Fetal skin and wound matrix are composed of more
hyaluronic acid than are postnatal skin and scar.
Hyaluronic acid stimulates fibroblast migration and
probably affects the ECM deposition pattern.84 Elastin,
present in adult skin, is absent in fetal dermis, although
no differences were found in basement membrane pro-
teins or vessel formation.97 Fetal skin and wound ECM
have a relatively greater amount of collagen type III,
but how this affects scar formation is not known. The
collagen fiber thickness is increased in scarring fetal
wounds compared with unwounded fetal skin as meas-
ured by confocal microscopy. This distance between
collagen fibers is also greater in scarring fetal wounds,
but the mechanisms causing these earliest changes in
healing associated with scar formation remain to be
elucidated.74 Scarless fetal skin repair is the blueprint
for ideal repair. With regard to TGF-β3, an antiscarring
product was developed98 but failed to prove efficacy
in clinical phase III trials. However, the mechanisms
responsible for scarless repair still remain to be fully
determined and when delineated will likely lead to
innovative antiscarring treatment strategies.

Adult wound pathology
Nonhealing wounds
Chronic or nonhealing wounds are open wounds that
fail to epithelialize and close in a reasonable amount of
time, usually defined as 30 days. These wounds typi-
cally are clinically stagnant and unable to form robust
granulation tissue. Many factors contribute to inhibit
healing in these patients, but no unifying theory can
explain the etiopathogenesis of each individual non-
healing wound (Table 15.2). Medical conditions such as
diabetes, arterial insufficiency, venous disease, lymph-
edema, steroid use, connective tissue disease, and radia-
tion injury inhibit wound healing. Nonhealing wounds
can also be due to pressure necrosis, infection (espe-
cially osteomyelitis), skin cancer, malnutrition, chronic
dermatologic disease, and other metabolic conditions.
In each case, treatment begins with debridement of any
necrotic tissue present.99 However, despite optimal
treatment for each clinical problem, these wounds fre-
quently still do not heal and surgical intervention is
required.
Pressure sores
Wounds that develop over a bone prominence, usually
in the immobile patient, are termed pressure sores. They
are also called decubitus ulcers or bed sores. The sacrum,
ischium, and greater trochanter are the most common
locations affected.100 However, the metatarsal heads,
ankles, heels, knees, and occiput are susceptible under
certain conditions. Another problem is malleolar skin
pressure necrosis due to constricting cast placement.
The amount of tissue pressure necrosis is determined by
both the degree and duration of the pressure. When the
tissue pressure is greater than 25–30 mmHg and capil-
lary perfusion pressure is blocked, microcirculation is
compromised. Necrosis can occur with as little as 2
hours of sustained pressure at this level.101 Skin is more
resistant to pressure necrosis than are underlying fat
and muscle, which explains the common finding of a
small area of skin ulceration overlying a large cavitary
volume of subcutaneous fat and muscle necrosis.
Treatment begins with identification and control of the
factors that lead to increased pressure and subsequent
wound formation. Paralyzed patients require periodic
Adult wound pathology 279
rotation and an air mattress or another type of low-
pressure bed. Wheelchair seat cushions commonly need
to be changed in patients with ischial pressure sore.
Behavior, such as prolonged sitting in wheelchairs
without equal weight distribution, must frequently
be modified. Lower extremity contractures that cause
excessive hip, knee, and ankle pressure may need
release. Tight casts should be removed and replaced.
Improperly fitting lower extremity prostheses can lead
to stump wounds and need modification. Other contrib-
uting factors, such as malnutrition, infection, and dia-
betes mellitus, should be identified and treated. Most
pressure sores will heal with avoidance of pressure over
the involved area. However, they heal with scar, which
is less resistant to trauma than is normal skin. Thus, a
higher incidence of recurrence exists after spontaneous
closure of these wounds than if they are closed surgi-
cally with flaps of normal skin and muscle over the
bony prominence.102,103
Lower extremity wounds
Leg wounds generally arise from either one of two dif-
ferent vascular diseases: arterial or venous insufficiency.
Most (80–90%) result from venous valvular disease
(venous insufficiency).104 The role of impaired lymphatic
drainage is discussed controversially in being a direct
cause of nonhealing wounds or aggravating venous
insufficiency.104a
Venous
Increased venous pressure in the dependent lower
extremity with valvular incompetence leads to localized
edema with plasma extravasation. Fibrinogen leakage
results in formation of a fibrin layer around the capil-
laries that impairs oxygen and nutrient diffusion.105
Leukocytes may be trapped and activated in obstructed
capillaries. Oxygen radicals and proteases may then be
released, which causes tissue necrosis. Postcapillary
obstruction leads to increased perfusion pressure and
hypoxia, with further necrosis. Without treatment, the
wound size can easily continue to grow.
Arterial
Wounds require adequate oxygen delivery to heal.
Ischemic wounds heal poorly and have a much greater
risk of infection.106 Minor trauma, resulting from
280 • 15 • Skin wound healing: Repair biology, wound, and scar treatment

Table 15.2  Factors that may impair normal healing and lead to chronic nonhealing wounds

Etiopathology Examples

Vascular Arterial Arteriosclerosis, arterial aneurysm, fat embolism with arterial obstruction, hypertension (Martorell
ulcer)
Lymphatic Lymphatic edema, lymphangiodysplasia
Venous Chronic venous insufficiency, necrotizing thrombophlebitis
Mixed Combined arteriosclerosis with venous insufficiency, arteriovenous malformations/dysplasia;
arteriovenous steal phenomenon (e.g., arteriovenous shunts, vascular compression/obstruction (due to
tumors, enlarged lymphatic nodes, etc.)
Vasculitis Wegener granulomatosis, Churg–Strauss vasculitis, Henoch–Schönlein purpura, Sneddon
syndrome, systemic lupus erythematosus, rheumatoid arthritis, Felty syndrome, Takayasu
arteriitis, polyarteritis nodosa, Kawasaki syndrome, pyoderma gangrenosum, necrobiosis
lipoidica diabeticorum, thrombangiitis obliterans (Buerger syndrome), allergic reactions
Vasculopathic Raynaud syndrome, systemic scleroderma, CREST, Klippel–Trenaunay syndrome, proteus
syndromes syndrome145,146, CLOVE syndrome,147 Kasabach–Merritt syndrome
Physical, chemical, Pressure Immobility, intra- and postoperative bedding, tight shoes and casts, compression therapy
and biological
causes
Trauma Lacerations, any type of soft-tissue and bone injury, vascular rupture
Thermal Burns / frostbite, electrical injury (electrical current/high voltage/lightning)
Radiation Radiation therapy
Chemical-toxic Extravasation, chemical burns (acids/bases), sclerotherapy
Infections Erysipelas, necrotizing fasciitis, septic cutaneous embolism, osteomyelitis, complications after
cutaneous infection
Herpes simplex, cytomegalovirus, human immunodeficiency virus, syphilis, leprosy, tuberculosis
Tropical ulcers, parasitic and vermicular infections
Neuropathic Posttraumatic Spinal lesions with palsy, peripheral nerve injury
Congenital Spina bifida, syringomyelia, multiple sclerosis, neurological syndromes
Systemic Diabetes mellitus, etyltoxic neuropathy, degenerative central and peripheral neuropathies
neuropathic Poliomyelitis, leprosy, tabes dorsalis
diseases
Hemopathological Systemic diseases Polycythemia vera, sickle-cell anemia, other anemias, thalassemia, thrombocythemia vera,
thrombocytopenic purpura, increased blood viscosity (paraneoplastic, paraproteinemia,
hyperglobulinemia, leukemia), complication after blood transfusion
Disturbed Factor V Leiden syndrome, antiphospholipid syndrome, disturbed fibrinolysis, factor XIII
hemostasiology deficiency syndrome, antithrombin III deficiency, protein C/S deficiency, Marcumar necrosis,
disseminated intravascular coagulation, necrosis due to vitamin K antagonist therapy
Neoplastic Cutaneous tumors Basal and squamous cell carcinoma, melanoma, Bowen syndrome, Marjolin ulcer (scar
diseases carcinoma),148 tumors with cutaneous metastasis or penetration (e.g., Paget syndrome)
Therapeutic Steroids, vaccination ulcer (BCG), cytostatic drugs, NSAIDs, extravasation of various drugs
modalities
Systemic diseases Hepatic and/or renal insufficiency, immunosuppression, sarcoidosis, homocysteinemia,
hemochromatosis
Other causes Alcoholism, obesity, gout, smoking, advanced age, malnutrition (e.g., vitamin, protein, and
micronutrient deficiency, scurvy); psychiatric diseases with self-harming, neglect, intravenous
drug abuse; foreign bodies/ projectiles with fistulas
CREST, calcinosis, Raynaud’s syndrome; esophageal dysmotility, sclerodactyly, and telangiectasia; CLOVE, congenital lipomatous overgrowth, vascular malformations, and
epidermal nevi; BCG, bacillus Calmette-Guérin; NSAIDs, nonsteroidal anti-inflammatory drugs.

scratches and abrasions that would otherwise heal
quickly in a well-vascularized extremity, can progress
to large wounds in ischemic limbs. Necrotizing infec-
tion that is not only limb- but also life-threatening can
develop. A reliable clinical sign of adequate arterial
inflow for healing is the presence of an arterial pulse.
The ankle brachial pressure index (ABPI) represents a
simple noninvasive method to detect arterial insuffi-
ciency within a limb. ABPI is calculated by dividing the
systolic blood pressure measured at the level of the
ankle by the systolic blood pressure measured in the
brachial artery.107 Normal ranges of ABPI were defined
as being 0.91–1.3, whereas ratios of ≤0.4 imply clinically
critical limb ischemia.108 Transcutaneous oxygen meas-
urement is a noninvasive method with 83% accuracy in
predictability of wound closure and 68% in predicting
failure in an ischemic extremity.109,110 To standardize
transcutaneous oxygen measurements, tissue hypoxia
was defined as <40 mmHg in healthy patients and
<30 mmHg in patients with limb ischemia110 with likely
wound-healing disturbances at rates lower than
20 mmHg.99,111 A nonhealing wound in an ischemic
extremity is an indication for revascularization.112
Diabetic
Wound healing is impaired in diabetic patients by
several mechanisms. Neuropathy is frequently present,
which leads to decreased sensation and biomechanical
joint instability. Arterial insufficiency is present in 30–
60% of cases. Studies have implicated an altered expres-
sion profile of growth factors in diabetic wounds.113
Decreased expression of GM-CSF receptor, PDGFs and
their receptors, VEGF and its type II receptor, EGF recep-
tor, IGF-1, and nitric oxide synthase-2 has been demon-
strated in human diabetic foot ulcers.114 Sustained
inflammation is marked by an increase in proinflamma-
tory cytokines115 and cells, e.g., macrophages, B cells,
and plasma cells, but decreased number of T cells in the
wound margin.116 MMP production is deregulated with
dislocation of proinflammatory MMP-9 to the ulcer
bed.117,118 Advanced glycation end-products and inflam-
matory mediators commit fibroblasts and vascular cells
to apoptosis and impair granulation tissue formation.119
Diabetic fibroblasts and keratinocytes have reduced
proliferation rates and collagen production.120 Wound
healing is enhanced if glucose levels are well controlled,121
Adult wound pathology 281
which suggests that many of these impairment mecha-
nisms are partially reversible in diabetic wounds.
Radiation injury
External-beam radiation through skin to treat deeper
disease has both acute and chronic effects on skin.
Acutely, a self-limited erythema may develop that spon-
taneously resolves. The late effect of radiation is a more
significant injury to fibroblasts, keratinocytes, and
endothelial cells. DNA damage to these cells propagates
and impairs the ability of these cells to divide success-
fully. Irradiated tissue usually has some degree of resid-
ual endothelial cell injury and progressive endarteritis,
which results in atrophy, fibrosis, and poor tissue
repair.122 Ultimately, the affected skin may spontane-
ously break down, but usually after repeated mild
trauma.122 When a surgical incision is placed through
irradiated skin on the trunk or extremities, it is not likely
to heal. Although improvement in chronic wound repair
can be achieved with hyperbaric oxygen therapy,123 sur-
gical intervention with resection of the wound to normal,
nonirradiated tissue and coverage with a vascularized
flap are frequently necessary.
Infection
Wound infection is an imbalance between host resist-
ance and bacterial growth.124 Bacterial infection impairs
healing through several mechanisms. At the wound site,
acute and chronic inflammatory infiltrates slow fibro­
blast proliferation and thus slow ECM synthesis and
deposition. Although the exact mechanisms are not
known, sepsis causes systemic effects that also impede
repair. A threshold number of bacteria in the wound is
necessary to overcome host resistance and cause clinical
wound infection. Bacterial contamination results in clin-
ical infection and delays healing if more than 105 organ-
isms per gram of tissue are present in the wound.125 Skin
grafts on open wounds are likely to fail if quantitative
culture shows more than 105 organisms per gram of
tissue, which provides further evidence that bacterial
load has an impact on repair.126 Similarly, well-
vascularized muscle flaps heal open wounds success-
fully if bacterial loads are not greater than 105 organisms
per gram of tissue.127 These studies demonstrate that
high levels of bacteria inhibit the normal healing
282 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
processes. Treatment of the closed infected wound
depends on whether fluid or necrotic tissue is present.
If no fluid is draining or accumulating, the cellulitis can
be successfully treated with appropriate antibiotics. The
wound should be opened and sutures removed; the
wound is irrigated and débrided if pus or necrotic tissue
is present. Administration of appropriate antibiotics
after wound culture treats surrounding cellulitis. Signs
of wound infection include fever, tenderness, erythema,
edema, and drainage.
Malnutrition and obesity
Wound healing is an anabolic event that requires addi-
tional calorie intake.128 However, the precise calorie
requirements for optimal wound healing have to be cal-
culated for each patient individually.129 Large injuries
such as burns greatly increase metabolic rate and nutri-
tional requirements.130 Severely malnourished and
catabolic patients tend to impaired healing131 because
nutrients such as proteins, vitamins, and minerals that
are important for effective wound repair are not substi-
tuted. These nutrients are involved in collagen synthesis
and cross-linking and re-epithelialisation and promote
the inflammatory response in early wound healing.
Wound dehiscence risk is increased in humans with
hypoproteinemia132 and in protein-depleted rats, but
this can be reversed with protein repletion immediately
after wounding.133
Vitamin C (ascorbic acid) deficiency results in
scurvy. In these patients, wound healing is arrested
during fibroplasia. Normal quantities of fibroblasts are
present in the wound, but they produce an inadequate
amount of collagen.134 Vitamin C is necessary for
hydroxylation of proline and lysine residues,135 and
without hydroxyproline, newly synthesized collagen
is not transported out of cells and collagen fibrils are
not cross-linked. Both mechanisms decrease wound
tensile strength.
Vitamin A (retinoic acid) is involved in multiple facets
of repair: fibroplasia, collagen synthesis and cross-
linking, and epithelialization.134 Because vitamin A
requirements increase after injury, severely injured
patients require supplemental vitamin A to maintain
normal serum levels. Animal studies show that vitamin
A also reverses the impaired healing that occurs with
chronic steroid treatment.136 Although it is not proved
conclusively in human studies, most surgeons adminis-
ter vitamin A postoperatively to their patients receiving
steroid therapy. Vitamin A is fat-soluble and can be
taken in toxic doses, so careful administration is essen-
tial. The oral dose is 25 000 IU/day.134
Vitamin B6 (pyridoxine) deficiency impairs collagen
cross-linking.137 Vitamin B1 (thiamine) and vitamin B2
(riboflavin) deficiencies cause syndromes associated
with poor wound repair. Supplementation with these
vitamins does not improve healing unless a pre-existing
deficiency is present. Deficiencies of trace metals such
as zinc and copper have been implicated in poor wound
repair because these divalent cations are cofactors in
many important enzymatic reactions.134 Zinc deficiency
is associated with poor epithelialization and chronic,
nonhealing wounds.138 Trace metal deficiency is now
extremely rare in both enterally and parenterally fed
patients. Excess administration of vitamins and miner-
als can be detrimental and cause toxic effects, especially
by the fat-soluble vitamins. Adequate amounts are
present in today’s enteral feeding solutions and as
supplemental additives to parenteral solutions.
Supplemental administration is necessary only in defi-
ciency states and certain unique clinical situations, as
described before.
Obesity interferes with repair independently of
diabetes.139 Obese patients with diabetes have
impaired wound healing independently of glucose
control and insulin therapy. Poor wound perfusion
and necrotic adipose tissue probably contribute to
impaired healing in both diabetic and nondiabetic
obese patients.
Medical treatment
Both topically applied steroids and pharmacologic
steroid use impair healing, especially during the first 3
days after wounding.140 Steroids reduce wound inflam-
mation, collagen synthesis, and contraction.134 The exact
mechanisms by which steroids impair healing are not
fully understood. Glucocorticoids decrease PDGF and
KGF expression in experimental wounds.141,142 Steroids
stabilize lysosomal membranes and thereby decrease
the release of lysosomes at the repair site, which may
slow repair processes. Because steroids decrease inflam-
mation, they may decrease host bacterial resistance and
thus increase wound infection complications. The entire
 Adult wound pathology 283

Table 15.3  Diagnostic criteria for distinction between most institutions, chemotherapeutic agents are not
hypertrophic scars and keloids157,182 administered until at least 5–7 days postoperatively to
Hypertrophic scar Keloid
prevent impairment of the initial healing events.

Clinical Remain within the Grow beyond the wound

symptoms boundaries of the borders Excessive healing
wound
Rarely more than 1 cm Size variations; growth Normal wounds have “stop” signals that halt the repair
in thickness or width may be widespread, process when the dermal defect is closed and epitheli-
vertical, or both
alization is complete. When these signals are absent or
Form scar contractures No contractures
Less pruritic and painful Pruritic and painful ineffective, the repair process may continue unabated
Occur after injury only: Spontaneous and cause excessive scar formation. The underlying
disruption of skin appearance without molecular mechanisms leading to excessive repair are
continuity, burns skin injury possible still a topic of intensive research. Profibrotic cytokine
Generally arise within 4 Appear within several
overexpression and reduction of collagenase activity
weeks, grow months after initial
intensely for several scar, then gradually were found in skin tissue of burn patients.149 In cell
months, then proliferate indefinitely co-cultures, keratinocytes from hypertrophic scar tissue
regress often within or keloids induced increased proliferation and collagen
1 year
production in dermal fibroblasts.150,151 A lack of pro-
Occur on points with Occur often on the
excessive tensile chest, shoulders, grammed cell death, apoptosis, at the conclusion of
forces: across joint trunk, back of the repair with the continued presence of activated fibrob-
surfaces, sternum, neck and earlobes, lasts secreting ECM components has also been impli-
neck, palm, and rarely on the palms cated.152 Notwithstanding the molecular regulation of
soles after injury or soles
excessive scar formation, there are clinical factors that
Regress spontaneously Do not regress
spontaneously affect scar formation. To minimize visible scar on skin,
Histological Fine and thin collagen Large and thick collagen
elective incisions are least noticeable when they are
features fibers oriented fibers; closely placed parallel to the natural lines of skin tension
parallel to the packed collagen (Langer’s lines). This placement has two advantages:
epidermis fibrils; increased ratio the scar is parallel or within a natural skin crease, which
of type I to type III
camouflages the scar, and this location places the least
collagen
Nodules with increased Increased fibroblast amount of tension on the wound. Wound tension widens
fibroblast density density in enlarging the scar. Sharply defined and well-aligned wound edges
borders, acellular in that are approximated without tension heal with the
keloid center least amount of scar. Infection or separation of the
Presence of α-smooth- Lack of α-smooth-
muscle actin- muscle actin-
wound edges with subsequent secondary intention
expressing expressing healing also results in more scar formation. Hyper­
myofibroblasts is myofibroblasts pigmentation and hypo­pigmentation of the scar increase
typical its contrast with the surrounding skin, making the scar
more visible. Sun protection of all wounds is recom-
repair process is slowed, and risk of dehiscence and mended to prevent scar hyperpigmentation.
infection is increased. Vitamin A administration can
reverse this effect.136,143
Hypertrophic scar
Both radiation and chemotherapeutic agents have
their greatest effects on dividing cells. During the pro- Hypertrophic scars and keloids are unique to humans
liferative phase of repair, numerous cell types are and do not occur in animals for unknown reasons. These
dividing at the wound site. Antiproliferative chemo- pathologic scar types are distinguished on the basis of
therapeutic agents act to slow this process and thus their clinical characteristics. Hypertrophic scars are
retard healing.144 After oncologic surgical procedures, in defined as scars that have not overgrown the original
284 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
wound boundaries but are instead raised. They usually
form secondary to excessive tensile forces across the
wound and are most common in wounds across joint
surfaces on the extremities but also commonly occur on
the sternum and neck. Physical therapy with range-
of-motion exercises is helpful in minimizing hyper-
trophic scar as well as joint contracture in the extremities.
Hypertrophic scar is a self-limited type of overhealing
that can regress with time. These scars generally fade as
well as flatten to the surrounding skin level. No clear
histologic difference between hypertrophic scar and
keloid has been demonstrated. Because of similar histo-
logic findings in both hypertrophic scar and keloid,153
they are more easily differentiated by their clinical char-
acteristics (Table 15.3).154
Hypertrophic scars and keloids are both fibroprolif-
erative disorders of wound repair with excess healing.155
However, because there are no animal models of either
condition, there are few biochemical and molecular
data that distinguish the two entities in direct compari-
son. In addition, most studies analyze either one or the
other, but not both. In general, both keloid and hyper-
trophic scar fibroblasts have an upregulation of colla-
gen synthesis, deposition, and accumulation.154 It may
be that keloid fibroblasts respond to a greater degree
than do hypertrophic scar fibroblasts to the signals
stimulating scar formation. For example, keloid fibrob-
lasts respond to exogenous TGF-β with a much greater
increase in collagen production than do hypertrophic
scar fibroblasts.156
Mast cells and fibrocytes, circulating bone marrow-
derived progenitor cells that differentiate into fibro­
blasts, are proposed to promote tissue fibrosis,
especially in burn patients.157,158 Both cell types are
present in hypertrophic scar tissue and secrete profi-
brotic cytokines. Mast cell histamine enhances collagen
production in fibroblasts159 and is elevated in the
plasma of patients developing hypertrophic scar.160 The
keratinocyte’s regulatory role in this scenario has
gained more interest in the past years. By secreting
various factors, keratinocytes stimulate migration, pro-
liferation, and matrix remodeling in a paracrine and
autocrine way.161 Increased collagen production was
found in normal fibroblasts co-cultured with hyper-
trophic scar-derived keratinocytes.151
Hypertrophic scar fibroblasts produce more con­
nective tissue growth factor (CTGF/CCN2) after TGF-β
stimulation. CTGF stimulates chemotaxis, prolifera-
tion, MMP expression and ECM production.162 The
proteoglycan decorin binds TGF-β and regulates colla-
gen fibrillogenesis by downregulating TGF-β pro­
duction.163,164 In contrast to normal dermal fibroblasts,
hypertrophic scar-derived fibroblasts secrete less
decorin and probably contribute thereby to sustained
TGF-β activity.165 A distinct histological difference
between keloids and hypertrophic scars is the predomi-
nance of myofibroblasts in hypertrophic scar tissue.
Controversial findings exist concerning the persistence
of fibroblasts after accomplished healing. Programmed
cell death is thought to underlie myofibroblast disap-
pearance after wound closure. Whether fibroblast resist-
ance to apoptosis leads to excessive scarring is still
unknown.157
Keloid
Keloids are scars that overgrow the original wound
edges. This clinical characteristic distinguishes keloid
from hypertrophic scar. True keloid scar is not common
and occurs mainly in darkly pigmented individuals
with an incidence of 4.5–16% in African and Asian pop-
ulations compared to less than 1% in Caucasians.166,167
Currently, it is proposed that keloids form in areas of
high skin tension,168 although this does not explain why
palms or soles are unaffected and why there is a high
occurrence rate on tension-free earlobes. Another
hypothesis postulates an immune response to the pilose-
baceous unit after dermal injury and subsequent
cytokine release with fibroblast activation. This is sup-
ported by the fact that keloids preferentially occur on
anatomical sites with high concentrations of sebaceous
glands, such as the chest wall, neck, and pubic area.
Patients with keloids have a positive skin reaction to
sebum antigen and benefit from desensitization with
sebum vaccine.169 A genetic predisposition is the point
of discussion with autosomal-dominant features.170
Certain syndromes are associated with keloid forma-
tion, e.g., Rubinstein–Taybi syndrome,171 scleroderma,172
and Touraine–Solente–Golé syndrome.173 Interestingly,
altered TGF-β regulation of the pro-opiomelanocortin
(POMC) gene expression in keloid-derived fibroblasts
was found.174 A regulatory role of POMC in keloid for-
mation is conceivable considering the fact that hitherto
no human albinos with keloids have been reported.

The keloid scar continues to enlarge past the original
wound boundaries and behaves like a benign skin
tumor with continued slow growth. However, complete
excision with primary closure of the defect results in
recurrence in the majority of cases. Keloid patients may
have excessive start signals or lack the appropriate stop
signals for healing. In the latter instance, the lack of stop
signals results in continued and unchecked repair. A
possible mechanism of keloid formation may be the
presence of persistent signals pushing fibroblasts to
keep “healing” the wound site despite complete cover-
age of the original wound. Studies have looked at apop-
tosis in normal scar, hypertrophic scar, and keloid.
Similar numbers of apoptotic cells at the advancing
wound edge in both normal scar and hypertrophic scar
have been found.175 However, proapoptotic gene expres-
sion is decreased in keloids, suggesting persistence of
activated fibroblasts.176
Keloids consist mainly of collagen and are relatively
acellular in their central portions with fibroblasts present
along their enlarging borders. They do not contain a
significant excess number of fibroblasts. Keloid fibrob-
lasts respond differently than normal wound fibroblasts
to growth factors found at the repair site.177 Keloid-
derived fibroblasts express increased levels of CTGF,178
TGF-β,179 and VEGF180 compared to normal skin fibrob-
lasts and show increased proliferation and collagen pro-
duction compared to normal fibroblasts.181
Clinical wound management
Management is based on the classification of the wound
type. Surgically closed incisions obviously require a dif-
ferent treatment from that of nonhealing open wounds.
Hypertrophic scars and keloids with their excessive
scarring require other different therapeutic approaches.
The treatment options for various wound types are
described below.
Incisional wounds
Incisional wounds closed in layers along tissue planes
heal with primary intention. Deep sutures are placed in
collagen-rich layers such as fascia and dermis. These
strength layers can hold sutures under a high degree of
tension. Fatty tissue layers, such as subcutaneous fat, do
not have significant collagen and cannot hold sutures
Clinical wound management 285
under tension. For this reason, most surgeons do not
close the subcutaneous fat layer, even in morbidly obese
patients. Dead space here is better obliterated with a
short course of closed suction drainage postoperatively,
which can prevent seroma formation and possible infec-
tion. The amount of tissue injury and degree of contami-
nation influence the length and quality of healing. Small,
clean closed wounds heal quickly with less scar forma-
tion, whereas large, open dirty wounds heal slowly with
significant scar. To decrease scar formation and risk of
infection, meticulous hemostasis should be performed.
This limits the amount of hematoma to be cleared and
thus decreases the inflammatory phase and probably
decreases scar formation. Because hematoma is a culture
medium for bacteria, less bleeding also decreases the
risk of infection. By limiting the inflammation with
sterile technique and tight hemostatic control, repair by
activated fibroblasts can begin earlier and shorten the
healing period.
Smaller surgical scars are achieved with meticulous
approximation of corresponding wound edges, no skin
edge trauma, and less resultant inflammation. Forceps
crush injury of the epidermis and dermis should be
avoided by the use of fine forceps and skin hooks to
retract and assist in dermal closure. This decreases the
amount of necrotic tissue at the wound edge and thereby
reduces inflammation. Because suture material is a
foreign body, it generates an immune response and is
susceptible to infection. Some surgeons therefore close
the epidermis with Steri-Strips. There is no suture to
leave a “railroad track” scar or serve as an infection
locus in the skin. Fibrin and other biologic glues and
sealants are also used especially for superficial wounds
in infants without need for anesthesia. Depending on
the wound localization, different suture techniques and
materials are recommended (Table 15.4).183
Closed wounds require less care than open wounds.
Closed wounds should be kept sterile for 24–48 hours
until epithelialization is complete. At this point, water
barrier function has been restored and patients can be
allowed to shower or wash. This has a psychological
benefit during the postoperative recovery period. In
addition, gentle cleansing removes old serum and blood,
which reduces potential bacterial accumulation and
infection risk. Tensile strength of a closed incisional
wound is only 20% that of normal skin at 3 weeks when
collagen cross-linking is becoming significant. At 6
286 • 15 • Skin wound healing: Repair biology, wound, and scar treatment

Table 15.4  Recommended suture materials and techniques for closure of full-thickness skin wounds at various body sites183
Wound localization Suture material Closure technique Suture removal (days)*

Scalp 3-0 or 4-0 nonabsorbable, Simple, narrow stitches 7–12

monofilament
Face 4-0 or 5-0 synthetic absorbable In layers; in case of full-thickness wound: running or 3–5
or 6-0 nonabsorbable, single sutures
monofilament
Eyelid 5-0 or 6-0 nonabsorbable, Single-row stitches or running intracutaneous suture 5
monofilament (secured with Steri-Strip for 10 days)
Lip, oral cavity 4-0 or 5-0 absorbable for In layer: muscle, mucosa, skin; single stitches 3–5
mucosa, muscle, dermis;
6-0 monofilament
nonabsorbable for skin
Neck 4-0 absorbable, 5-0 Double-layered for better cosmetic result; 4–6
nonabsorbable, intracutaneous, running sutures
monofilament
Abdomen, back 3-0 or 4-0 absorbable, 3-0 or Single or multilayered sutures; intracutaneous, 6–12
4-0 nonabsorbable, running sutures
monofilament
Limbs 3-0 or 4-0 absorbable,† 3-0 or Single or multilayered stitches (dermis); running 6–14‡
4-0 nonabsorbable, intracutaneous sutures; splints for joint-crossing
monofilament wounds or wounds with high mechanical tension
Hands and feet 4-0 or 5-0 nonabsorbable, Single layer with simple or Allgöwer / Donati stitches; 7–12
monofil splints for joint-crossing wounds or wounds with
high mechanical tension
Nail bed 6-0 or 7-0 absorbable Meticulous approximation with single stitches Resorption
Use of magnifying glasses is recommended
Nail bed splinting with original or artificial nail to avoid
adhesions

*If nonabsorbable suture material was used.

†
Absorbable, monofilament sutures (e.g., polydioxanone) are more suitable for wounds with high mechanical tension, providing higher wound-breaking strength during
collagen bundle cross-linking.
‡
Nonabsorbable sutures on legs remain for up to 21 days depending on limb perfusion status and skin quality.

weeks, wounds are at 70% of the tensile strength of
normal skin, which is nearly the maximal tensile strength
achieved by scar (75–80% of normal). Therefore, if
absorbable suture is used to close deep structures that
are under significant tension, such as abdominal fascia,
the suture should retain significant tensile strength for
at least 6 weeks before absorption severely weakens the
suture. In addition, heavy activity should be limited for
a minimum of 6 weeks when healing of abdominal
fascial layers is necessary.
Excisional wounds
Open wounds heal with the same basic processes of
inflammation, proliferation, and remodeling as do
closed wounds. The major difference is that each
sequence is much longer, especially the proliferative
phase. There is much more granulation tissue formation
and contraction. This type of healing process is referred
to as secondary intention.
Open wound edges are not approximated but are in­­
stead separated, which necessitates epithelial cell migra-
tion across a longer distance. Before re-epithelialization
can occur, a provisional matrix must be present.
Granulation tissue must form. There are variable
amounts of bacteria, tissue debris, and inflammation
present, depending on wound location and etiology.
Infection, with high protein exudative losses and acute
and chronic inflammation, can dysregulate repair
and transform the healing wound into a clinically

nonhealing wound. The exact molecular mechanisms
causing this shift from healing to a nonhealing wound
with infection remain unknown.
During the proliferative phase of an uncomplicated
course of secondary-intention healing, a bed of granula-
tion tissue will be present. If no infection is present and
the area is of sufficient size that healing will not be
complete for at least 2–3 weeks, placement of a partial-
or full-thickness skin graft should be considered. Grafts
readily adhere to granulation tissue and will quickly
speed the repair process. Partial-thickness skin graft
donor sites can heal in as little as 2 weeks, depending
on graft thickness. When an open wound heals, which
is generally defined as complete epithelialization, the
dermal defect has been filled with collagen that is
covered by epithelium. This scar has less tensile strength
and is more susceptible to trauma than normal skin.
Thus, these scars break down more easily from local
trauma such as pressure.
Wound treatment
Necrotic material should be removed from open wounds
on initial presentation and subsequently as it accumu-
lates. Necrotic tissue serves only as a culture source for
bacteria and does not aid healing. The only exception to
immediate debridement is a dry, chronic, arterial-
insufficiency eschar without evidence of infection. These
types of wound may be best treated by revasculariza-
tion before debridement.
Open wounds heal optimally in a moist, sterile envi-
ronment. Numerous experimental and clinical studies
have demonstrated that a moist environment speeds
healing.184,185 This is thought to occur by preventing des-
iccation at the base of the wound. Desiccation causes
necrosis at the base of the wound until an eschar forms,
which may take several days. During this time, the
wound is enlarging and initiation of the healing process
is delayed. When the wound is kept covered and moist
without infection, desiccation necrosis and healing
delay are prevented.
Chronic open wounds
A team approach for the treatment of chronic wounds
is employed in wound centers. Members include a
plastic surgeon, vascular surgeon, orthopedic surgeon,
Clinical wound management 287
podiatrist, internist, endocrinologist, and specialist in
microbiology. The team leader, usually a plastic surgeon,
diagnoses the cause of the wound, coordinates appro-
priate referrals, and directs overall wound care.
Prosthetists, physical therapists, enterostomal thera-
pists, and clinical nurse specialists complete the team.
Because the etiopathogenesis of chronic wounds is mul-
tifactorial, coordinated care by multiple specialists is
required for optimal results.
To achieve standardized wound management, the
International Wound Bed Preparation Advisory Board
and the Canadian Chronic Wound Advisory Board have
proposed components relevant for wound bed prepara-
tion: tissue debridement, infection/inflammation, and
moisture balance. Even when these factors have been
corrected, some wounds do not heal and have an abrupt
or steep epidermal edge, with no migration of epider-
mal cells across the wound surface. These four com­
ponents of wound bed preparation can easily be
remembered using the mnemonic TIME – tissue,
infection/inflammation, moisture, and edge effect.99
Wound bed preparation is the management of a
wound in order to accelerate endogenous healing or
to facilitate the effectiveness of other therapeutic
measures. Treatment begins with debridement of
necrotic tissue, which removes a potential source of
bacterial infection. Depending on the bacterial load,
systemic antimicrobial treatment adjusted to bacterial
drug resistance is recommended. To provide optimal
healing conditions, wound moisture imbalances
should be corrected with adequate dressing and com-
pression therapy.186 Active medical comorbidities are
aggressively treated. The wound characteristics (size,
depth, infection, necrotic tissue component, edema,
drainage) are documented, and local wound care is
initiated. Care is continued until the wound is clean
and ready for reconstruction or heals by secondary
intention.
Wound dressings
A plethora of wound dressings are available for all types
of wounds. High levels of evidence on clinical efficacy
could not be demonstrated for any type.187 However,
substantial improvement in both convenience and
comfort has been gained compared with saline gauze
dressings. A new class of engineered skin replacements
288 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
that show great promise in chronic wound care has been
developed and is changing chronic wound care. The
optimal open wound dressing maintains a moist, clean
environment that prevents pressure and mechanical
trauma, reduces edema, stimulates repair, and is inex-
pensive. Less frequent dressing changes and prevention
of skin irritation are also beneficial.
Different classifications of wound dressings are used
depending on their function in the wound (debride-
ment, antibacterial, occlusive, absorbent, adherence),
type of material used to produce the dressing (e.g.,
hydrocolloid, alginate, collagen) and the physical form
of the dressing (ointment, film, foam, gel).48 The latter
classifications were used in Table 15.5 to give an over-
view of currently available wound dressings.
The films are gas-permeable, maintain a moist envi-
ronment, and are useful for partial-thickness dermal
wounds such as skin graft donor sites. For highly exu-
dative wounds, the absorptive dressings are useful to
create a moist environment without excess fluid and
proteinaceous material accumulation. Hydrocolloid
dressings are useful for locations where adhesion is nec-
essary, such as the extremities and over bone promi-
nences. They are relatively thick and can stay in place
for 2–3 days. As their absorptive capacity is reached,
they lose adhesiveness, and gentle atraumatic removal
is facilitated. Hydrogels are similar to hydrocolloid
dressings except that they have little adhesiveness and
are especially useful for dressing tendons, ligaments or
facial wounds. Alginates can absorb 15–20 times their
weight of fluid, making them suitable for highly exuding
wounds. However, they should not be used on wounds
with little or no exudate as they will adhere to the
healing wound surface, causing pain and damaging
healthy tissue on removal.188
Subatmospheric pressure
A subatmospheric dressing device (VAC, KCI, Texas,
US) is available for vacuum-assisted closure. The
apparatus consists of a sponge to fill the wound cavity,
a vacuum pump, and a transparent film. It can be used
in both inpatient and outpatient settings. Vacuum-
assisted closure is useful for decreasing the size of large
wounds on the extremities and trunk in preparation for
reconstruction. The device can aid the healing of pres-
sure sores, skin graft donor sites, and venous stasis
ulcers.189,190 An international expert working group
has defined recommendations for the use of vacuum-
assisted closure treatment for diabetic foot ulcers,
complex leg ulcers, pressure ulcers, dehiscent sternal
wounds, open abdominal wounds, and traumatic
wounds.191 Treatment by vacuum-assisted closure has
induced granulation tissue formation over exposed
bone and tendon. The beneficial mechanism is hypoth-
esized to be due to its reduction of surrounding tissue
edema, decrease of bacterial wound colonization, and
increase in local blood supply, granulation, and wound
cell proliferation. Presumably mechanical transduction,
the conversion of mechanical stimuli to biochemical
signals, is responsible for the effects seen with vacuum-
assisted wound closure.192 Mechanical forces deform
tissues; this leads to cellular deformation, which is
followed by stimulation of growth factor pathways,
resulting in increased mitosis and production of new
tissue.193
Recently, the traditional negative-pressure therapy
combined with intermittent liquid instillation was intro-
duced for the treatment of problematic acute wounds.
Typical instillation solutions include normal saline, anti-
biotics, antifungals, antiseptics, and local anesthetics to
reduce microbial infection or pain, respectively.194
Compression therapy
Edema in the lower extremity – whether it is due to
venous insufficiency, lymphedema, cardiovascular
disease, or metabolic derangement – must be aggres-
sively treated if a wound is present. Elevation and com-
pression therapy must be applied. Four-layer dressing
wraps of the lower extremity consisting of gauze, cast
padding, Coban, and elastic wraps are commonly used.
After a venous stasis wound has healed, 30–40-mmHg
pressure stockings must be worn continuously to
prevent recurrence, which can be as low as 17% during
the next 3 years.195,196 Caution should be exercised in
patients with peripheral neuropathy and arteriosclero-
sis. Lymph edema associated with chronic leg ulcers
that are refractory to conventional compression therapy
can be reduced with intermittent pneumatic compres-
sion as an adjunct treatment. Through an electrically
inflatable boot, compression within a range of 20–
120 mmHg at preset intervals is provided, improving
venous and lymphatic flow.196
Table 15.5  Classes of wound dressings and engineered skin replacements*
Class Composition Characteristics and function Commercial examples

Gauze Woven cotton fibers Permeable with desiccation; debridement; Curity, Mepilex, Mepitel
painful removal
Tulles Open-weave cloth soaked in soft Low adherent, suitable for flat, shallow wounds Adaptic, Grassolind, Jelonet,
paraffin or chlorhexidine, with low exudates Tullegras, Urgotul
textiles, or multilayered or
perforated plastic films
Film Plastic (polyurethane); Allows water vapor permeation; adhesive; OpSite, Tegaderm
semipermeable impermeable for liquids and bacteria
Foam Hydrophilic (wound side) and Highly absorbent; for necrotic and exudative Lyofoam, Allevyn, Tielle
hydrophobic (outer side) wounds
polyurethane or silicone
foams; semipermeable
Hydrogel Water (96%) and polymer Aqueous environment; requires secondary Aquaform, Intrasite, Purilon,
(polyethylene oxide) dressing; no adherence; not recommended Vigilon, Aquasorb
if infection is present; semipermeable
Hydrocolloid Hydrophilic colloidal particles and Absorbs fluid; necrotic tissue autolysis; little Comfeel, DuoDERM, IntraSite,
adhesive adherence; occlusive Tegasorb
Absorptive powder, Starch copolymers, hydrocolloid Absorbs exudate; used as a filler; good for Aquacel, Geliperm, GranuGel
paste and fiber particles deep wounds paste, DuoDERM granules
Alginate Calcium and sodium salts of Absorbs exudate and forms a hydrophilic gel Algisite, Algosteril, Kaltostat
alginic acid found in brown after ion exchange with wound fluid; not SeaSorb, Sorbsan,
seaweed suited for dry wounds Suprasorb
Antimicrobial 1. Silver (in ionic or nanocrystalline Suited for colonized or infected wounds: 1. Acticoat, Actisorb, Silver 200,
dressings form) 1. Absorptive: cadexomer iodine (caution: thyroid Aquacel Ag
2. Iodine diseases) 2. Iodosorb
(a) as povidone-iodine 2. Control of odor caused by anaerobic bacteria, 3. Metrotop Gel
(b) as cadexomer iodine used for fungating malignant wounds 4. Octinidine/Lavanid Gel
3. Metronidazole gel 3. Used for burns
4. Octinidine gel
Silicone Silicone sheets Sheet induces a localized electromagnetic Sil-K, Mepitel, Mepilex
field and increased skin temperature;
decreases scar formation?
Subatmospheric Vacuum pump, sponge, plastic Sponge conforms to wound and vacuum VAC device
pressure film removes edema fluid and bacteria;
stimulation of granulation, vascularization,
and wound cell proliferation
Dermal collagen Fine-mesh fabric (silicone, nylon) Nonadherent; semipermeable Biobrane
replacement with dermal porcine collagens
Dermal matrix Acellular matrix Permeable; increased stimulation of repair? AlloDerm (human, dermis), SIS
replacement (porcine, small-bowel
submucosa), Integra
(bovine collagen, shark
cartilage, and silicone
sheet)
Dermal living Absorbable matrix populated with Permeable; increased stimulation of repair? Dermagraft (bioabsorbable
replacement allogenic human fibroblasts scaffold), TransCyte (nylon
mesh coated with porcine
collagen)
Epidermal living Autologous keratinocytes on Permeable; increased stimulation of repair? Epicel
replacement murine feeder cells
Skin living Bovine collagen matrix populated Impermeable; increased stimulation of repair? Apligraf, OrCel
replacement with neonatal human
fibroblasts with an outer layer
of human keratinocytes
*Multiple brands within each class are available, and a partial list is given. No particular brands are recommended.
(Modified from Lorenz et al.7 and Enoch et al.196)
290 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
Pharmacologic treatment
Collagenases, e.g., streptodornase, streptokinase (Vari­
dase), are useful for the treatment of wounds requiring
fine debridement of necrotic tissue that is not amenable
to surgical debridement. This could be a thin, superficial
layer of adherent exudate or small amounts of necrotic
tissue remaining after a bedside wound debridement.
Theoretically, collagenase would be detrimental to a
clean wound in the proliferative phase when ECM syn-
thesis and deposition favor accumulation rather than
degradation.
Because of highly sensitizing potential and induction
of bacterial resistance, antibiotic wound dressings and
ointments have largely been abandoned. Instead, anti-
microbial products have become standard therapy for
contaminated or infected wounds. In burns, silver sul-
fadiazine cream has largely been replaced by octinidine
gel due to better dressing removal and burn wound
assessment qualities of the gel.
Engineered skin replacements
With the biotechnology revolution, several dermal and
skin replacements are now available through tissue-
engineering technology (Table 15.5). These products
have the additional potential benefit of accelerating or
augmenting repair because of their biocomponents.
Growth factors are present in products with acellular
dermal matrices. Some products contain living fibro­
blast and keratinocyte layers that secrete matrix com­
ponents, proteases, and active growth factors. These
products are typically placed on open wounds similarly
to autologous skin grafts under sterile conditions with
bolster support.197 Their major advantages are the lack
of a donor site wound and scar and placement in an
office setting. Disadvantages are limited shelf-life and
high cost, especially if they are applied repeatedly to
the same wound, yet models predict that they can be
less expensive than nonsurgical therapy.198 The bilay-
ered human keratinocyte–fibroblast construct on a
bovine collagen matrix, Apligraf ™, has been shown to
improve healing of venous stasis, diabetic, and arterial-
insufficiency wounds.199 However, these studies com­
pare its use against local wound care. No comparison
has been made against autogenous skin graft treat-
ment. In vitro, reduced keratinocyte migration on a
de-epidermized substratum compared to adult split
thickness skin.200 Presumably, artificial skin products
accelerate wound healing by growth factor delivery and
paracrine stimulation of endogenous wound margin
keratinocytes.201
Although the unique biology of engineered skin
replacement dressings can aid in the treatment of
impaired wounds, their efficacy compared with autog-
enous skin grafts has not been determined. For many
biological products, no randomized controlled trials
exist and current evidence is based on nonrandomized
studies, reviews, and case reports. Products of human
origin expose the patient to the danger of disease trans-
mission and bovine, porcine, or human constituents can
cause immunological side-effects or have religious and
ethical implications.
Cultured epidermal autografts (Epicel) are used for
second- and third-degree burns and require a culture
time of 2–3 weeks until application to the wound. The
patient’s keratinocytes are harvested and cultured on
irradiated murine feeder keratinocytes. Apart from a
long culture time, these products are difficult to handle
and lead to blistering, resulting in contractures and
scarring.202
Excessive scar treatment
Scar classification
Before antiscarring therapy is instituted, an accurate
description and classification of the scar type are useful.
This assists with assessment of the outcome after late
follow-up. A clinically based scar classification scheme
has been proposed by the International Advisory Panel
on Scar Management, which is composed of plastic sur-
geons, burn surgeons, and dermatologists (Table 15.6).203
Consistent and accurate diagnosis of scar types is essen-
tial for optimal management and useful literature
interpretation.
Therapies
Many treatment modalities have been developed for the
prevention and management of hypertrophic scarring
and keloids. Many of the techniques have well-
documented and time-proven clinical use, but few have
been supported by randomized, prospective studies.

Table 15.6  Clinical classification of scars203
Scar type Characteristics
Mature scar A light-colored, flat scar
Immature scar A red, sometimes itchy or painful, and slightly
elevated scar in the process of
remodeling. Many of these will mature
normally over time, become flat, and
assume a pigmentation that is similar to
the surrounding skin, although they can be
paler or slightly darker
Linear A red, raised, sometimes itchy scar confined
hypertrophic to the border of the original surgical
(e.g., surgical incision. This usually occurs within weeks
or traumatic) of surgery. These scars may increase in
scar size rapidly for 3–6 months and then, after
a static phase, begin to regress. They
generally mature to have an elevated,
slightly rope-like appearance with
increased width, which is variable. The full
maturation process may take up to 2 years
Widespread A widespread red, raised, sometimes itchy
hypertrophic scar confined to the border of the burn
(e.g., burn) injury
scar
Minor keloid A focally raised, itchy scar extending over
normal tissue. This may develop up to
1 year after injury and does not regress on
its own. Simple surgical excision is often
followed by recurrence. There may be a
genetic abnormality involved in keloid
scarring. Typical sites include earlobes
Major keloid A large, raised (>0.5 cm) scar, possibly
painful or pruritic and extending over
normal tissue. This often results after minor
trauma and can continue to spread for
years
This inherent problem makes choosing the best treat-
ment modality difficult on the basis of objective scien-
tific evidence. Therefore, most modalities are applied on
the basis of the treating physician’s personal biases and
experiences. Scar therapies, with their respective advan-
tages and disadvantages, are listed in Table 15.7.
Prevention
The first step toward treatment of excessive scarring is
early recognition and institution of therapy after surgery
or trauma. Meticulous tissue handling, suturing, and
wound management with efforts to prevent infection
Clinical wound management 291
are mandatory.203 Sun protection to reduce scar hyper-
pigmentation is essential. Patients who are at increased
risk of excessive scarring benefit from preventive tech-
niques, which include silicone gel sheeting or ointments,
hypoallergenic microporous tape, and concurrent intral-
esional steroid injection.203
Silicone gel sheeting is widely used for hypertrophic
scar and keloid treatment. Silicone gel sheeting has a
20-plus-year history with several randomized, control-
led trials that support its safe and effective use.204,205 It
is painless and thus useful for children. Proposed mech-
anisms of action for scar reduction include improved
hydration and occlusion,206 increased temperature ele-
vation of 1°C (or less) that can affect collagenase kinet-
ics, and change in the adhesion molecule expression of
the lymphocytic infiltrate.207 When treatment with sili-
cone gel sheeting is not feasible (e.g., scar location on
the face, scalp, or neck), silicone oil-based creams are an
alternative.208 For example, silicone-based creams are
frequently used on cleft lip repair scars, hypertrophic
scars after burns, or hand injury without allergic or
other untoward reaction to date.
Microporous hypoallergenic tape can relieve tension
across wounds and minimize the excessive scar risk
from shearing. Although there are no prospective, con-
trolled studies to support its use, tape is routinely used
and recommended by many authors.203 The tape is
applied for a few weeks after surgery. In patients who
are at extremely high risk, such as after excision of
keloid or hypertrophic scar, concurrent intralesional
steroid injections can be given prophylactically, fol-
lowed by monthly injections as necessary. Success rates,
measured by no recurrence, are reported up to 92% for
keloids and 95% for hypertrophic scars at a mean
follow-up of 30.5 months.209
Treatment algorithm
Immature hypertrophic scars (red)
Once excessive scarring is identified, the International
Advisory Panel on Scar Management consensus initial
management is silicone gel sheeting, steroid injection,
and localized pressure therapy (Fig. 15.8).203 It can be
difficult to predict whether immature hypertrophic
scars (red, slightly raised) will regress or progress. When
erythema persists for more than 1 month, the risk of
292 • 15 • Skin wound healing: Repair biology, wound, and scar treatment

Table 15.7  Scar prevention and reduction therapies203

Therapy Advantages Disadvantages

Surgical excision
Surgical lengthening (Z-plasty, W-plasty)
Steroid intralesional injection
Silicone gel sheeting
Pressure therapy
Radiation after surgery
Laser
Cryotherapy
Microporous tape
Popular treatments (vitamin E, onion
extracts, and other plant creams)
Physical therapy treatments: ultrasound,
pulsed electrical stimulation,
hydrotherapy, massage
Recombinant human TGF-β3 (avotermin),
rh Il-10 (ilodecakin), TGF-β1 inhibitors
Anti-inflammatory/proliferative medication
injections (5-fluorouracil, interferons,
retinoids, histamine antagonists)
Calcium channel blockers (verapamil)
Experimental therapies (bleomycin,
imiquimod, cyclosporine)
Medical needling
Excess scar removed
Increased mobility and range of motion
Cost, ease
Cost, ease of use, noninvasive
Noninvasive, some proven efficacy
Some proven efficacy
Pulsed-dye 585- or 595-nm laser best for
decreasing red color; carbon dioxide,
Nd : YAG, pulsed Erb : YAG lasers with
some efficacy; selective photothermolysis
by erbium-doped fiber lasers (1550 nm)
Some proven efficacy in keloid reduction
Ease, low cost
Ease, low cost
Patient participation; increased joint range of
motion; can decrease scar pain, pruritus
Clinical-phase trials
Fluorouracil: repeated application necessary,
no systemic effects
Retinoids: still experimental, reduce scar
tissue and sebum production
Clinical trials ongoing, good efficacy
Experimental, some efficacy
Clinical phase trials using the Medical
Roll-CIT, low cost, ease
High recurrence without adjuvant therapy, cost
Some excess scar persists, occasionally worse
cosmesis
Multiple treatments; telangiectasia,
hypopigmentation
Difficult application on head, neck, across joints
Cumbersome garment, cost high if custom-
made, constant use for months to years
Risk of carcinogenesis, cost
Costs, multiple treatments
Dye laser: reduced efficacy in darker-skinned
patients and thick (>1 cm) hypertrophic scars
50% recurrence rate with carbon dioxide laser
Hypopigmentation, pain, skin atrophy
No proven benefit, except uncontrolled reports
No proven benefit
No quantitative proven efficacy, cost
Experimental, high costs, lack of efficacy
Fluorouracil: single administration with recurrence
Interferon: high recurrence rate, adverse
systemic effects
Retinoids: adverse effects with photosensitivity
and skin irritation
Still experimental
No proven benefit, systemic side-effects?
Pretreatment with retinoids, general anesthesia
needed for treatment of larger surfaces, short
follow-up, recurrence

progression to linear hypertrophic scar increases, and
appropriate therapy should be started.
Linear hypertrophic scars (red, slightly raised)
Treatment options include the application of pressure
garments or topical silicone sheets, 585-nm pulsed-dye
laser therapy, and re-excision. The last option is most
useful in cases of excess scar due to wound infection or
dehiscence. If the original wound was closed following
the basic tenets described and healed otherwise unevent-
fully, re-excision with primary closure is not likely to
result in an improved scar. Recurrence of hypertrophic
scar is high in these circumstances, and therefore most
plastic surgeons do not treat hypertrophic scar with exci-
sion and primary closure unless they plan adjuvant
therapy. Silicone gel has proven benefit from rand-
omized, controlled trials and is a recommended first-line
 Clinical wound management 293

Scar

Classification

Immature hypertrophic Linear hypertrophic Minor keloid Major keloid Widespread burn
(red, slightly raised) (red/raised, itchy) (red, raised) -high risk- hypertrophic scar
(dark/raised) (red, raised)

If patient concerned or Silicone gel sheeting (2 months)

high risk for excessive
scar: tape or silicone
Initial gel sheeting/ointment Steroid injections 2.5–20 mg/mL (face); 20–40 mg/mL (body); Burn
management repeat monthly as needed specialty
Progress to treatment as unit
for hypertrophic scar
if erythema persists Localized pressure therapy if possible
more than 1 month Duration 3–12 months

Pressure
therapy Specific wavelength laser therapy Pressure
garments and/or
silicone gel
Secondary Surgery with adjunctive silicone gel sheeting sheeting
management (duration 2 months) (6–12 months)

Unit specializing in scar therapy

Combination/monotherapy—
Primarily: Steroids, silicones, pressure therapy, surgery/grafting
Occasionally: Cryotherapy, radiotherapy, laser, other therapies

Fig. 15.8  Scar management algorithm. (Reproduced from Mustoe TA, Cooter RD, Gold MH, et al. International clinical recommendations on scar management.
Plast Reconstr Surg 2002; 110: 560–571, with permission.)

therapy.203 Concurrent steroid injections are helpful for

pruritic or resistant scars. Pressure therapy can be added
when feasible. Pulsed-dye laser (585 and 595 nm) treat-
ment of hypertrophic scars is another alternative. Light
energy from the pulsed-dye laser is absorbed by intra-
vasal hemoglobin leading to coagulation, vessel obstruc-
tion, and tissue hypoxia with necrosis. As a consequence,
new collagen synthesis, collagen fiber realignment, and
remodeling are the molecular bases for the effects seen
after pulsed-dye laser treatment.210
Widespread burn hypertrophic scars (red, raised)
Extensive surface-area burn hypertrophic scars may
best be treated at burn centers when feasible.
Multimodality therapies are generally used; these
include silicone gel sheeting, custom-fitted pressure
garments, and physical therapy alone or with massage,
electrical stimulation, or ultrasound. Steroid injection of
especially difficult areas is sometimes necessary. Laser
treatment can be useful.211 Surgical treatment with
294 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
Z-plasty, excision and grafting, and flap reconstruction
is frequently required.203
Minor keloids (red, raised)
No uniformly successful treatment for keloid scar exists.
Excision and primary closure invariably result in recur-
rence. Therefore, additional therapy is necessary, and its
efficacy depends on the timing of the patient’s presenta-
tion. Steroid injection directly into the keloid has the
most benefit early in the keloid course.212 Steroid has
been shown to decrease collagen gene expression.213
Mixed with 2% plain lidocaine in a 50 : 50 ratio, triamci-
nolone acetonide 10 mg/mL is commonly used initially;
if no response occurs, 40 mg/mL concentration is
attempted. Silicone gel sheeting should be used concur-
rently. Patients presenting with mature keloid lesions of
months to years in duration that are slowly changing
respond poorly to steroid injection and silicone sheet-
ing. Surgical excision with adjuvant therapy including
intralesional steroids, silicone sheeting, and pressure
therapy is a reasonable treatment alternative.210 Careful
follow-up is necessary to prevent recurrence. A short
course of low-dose radiation therapy to the keloid exci-
sion site immediately after excision has been shown to
reduce the rate of recurrence.214
Major keloids (dark, raised)
Major keloids are difficult to treat effectively, and many
are resistant to any treatment. Surgical therapy with all
adjunctive therapies described before may still fail and
result in recurrence. Radiation therapy is generally used
in this group, provided the patient is not young and
accepts the possible risk of late cancer formation. Before
surgery is performed with postoperative adjuvant
therapy, patients should be counseled about the high
rate of recurrence with the risk that the next keloid will
be larger and more difficult to control. As recommended
by the International Advisory Panel on Scar
Management, these patients may best be treated by
clinicians with a special interest in keloid treatment.203
Impact of scar on plastic surgery
Besides hypertrophic scarring and keloid formation in
the skin, scar affects every aspect of plastic surgery.
Scar and fibrosis are the outcome after tissue repair and,
when excessive, lead to clinical disease. For example,
fibrosis of joint capsules leads to contracture, which can
be debilitating. Anastomotic fibrosis of free jejunal flaps
to the esophagus or pharynx leads to lumen obstruction.
Breast implant capsules are the normal fibrotic response
to injury, which can be excessive and develop into cap-
sular contracture. Nerve repair sites with excess fibrosis
commonly develop neuromas and functional repair
failure. Scarring at tendon repair sites restricts motion.
Dupuytren disease is a fibroproliferative disorder that
involves the palmar fascia and the deep dermis. Each
of these excessive scarring conditions leads to morbid-
ity of the patient, which can require further surgical
treatment.
Emerging scar therapies
A great deal of research is focused on the development
of treatment strategies to reduce or prevent scarring.
Prompted by fetal wound-healing observations, inves-
tigators initially analyzed the antiscarring effect of anti-
TGF-β strategies. Treatment with neutralizing antibody
to TGF-β decreased the inflammatory response and
reduced scar formation in experimental postnatal rodent
wounds.215 More evidence that TGF-β-related strategies
may be successful is provided by a study showing that
exogenous addition to wounds of fibromodulin, a TGF-β
modulator, reduces scar.89 Clearly, more studies are
needed, and because of the redundancy of action among
growth factors, TGF-β is likely not to be the only growth
factor targeted to reduce human scar and fibrosis.
Newer treatment modalities, such as intralesional
injection of bleomycin, 5-fluorouracil, and, imiquimod
may be useful in the future. These act by decreasing
inflammation and collagen synthesis; however, their
mechanisms of action remain under investigation.
Interferon therapy was left because of adverse side-
effects and high recurrence rates.210,216 Other novel strat-
egies include the application of antifibrotic human
recombinant growth factors and cytokines (e.g., rh
IL-10), anti-inflammatory substances, protease inhibi-
tors, and molecules that interfere with profibrotic
cytokine function (e.g., TGF-β) and collagen synthesis
at the wound site.217
Clinical trials are currently performed using two dif-
ferent novel techniques for scar reduction. Selective
photothermolysis is induced by erbium-doped fiber

lasers operating at a wavelength of 1550 nm, targeting
water as a chromophore. This creates dermal microle-
sions with controlled width, depth, and densities fol-
lowed by neocollagenesis.218 These lasers are used for
the treatment of hyperpigmentation and acne scars as
well as surgical and traumatic scars. Percutaneous col-
lagen induction therapy is currently used in our depart-
ment for reduction of hypertrophic scars, striae distensae,
wrinkles, and skin laxity. After pretreatment with
vitamin A and C cream, patients are treated under
anesthesia. Needles of the Medical Roll-CIT create
dermal microwounds and separate collagen structures
connecting the scar with the upper dermis. Through the
following inflammatory reaction, collagen remodeling
is induced with consequent scar flattening.219
Future perspectives
Growth factor and
protease-scavenging therapy
The best-studied growth factors with the most promise
to improve healing are PDGF, TGF-β, and members of
the FGF family (Table 15.1). However, before wide-
spread use, several obstacles must be overcome, includ-
ing efficacious application, vehicle development, and
cost. For example, nonhealing human wound fluid and
tissue have increased protease activity, which probably
degrades rapidly exogenously applied peptide growth
factors.118,220 Products targeting excessive activity could
be protease-scavenging matrices (e.g., Promogran),196
selective inhibitors,221 or specific antibodies.
Experimental and clinical trials have reported some
efficacy of growth factors for treatment of chronic or
burn wounds. VEGF gene transfer was effective in
ischemic leg ulcers with formation of collateral vessels.222
Topical recombinant bovine FGF, human KGF (repifer-
min), and GM-CSF increased healing of chronic pres-
sure and venous leg ulcers, respectively. Topical
recombinant human EGF had a positive effect on healing
of second-degree burn wounds whereas topical recom-
binant human PDGF-BB (becaplermin), TGF-β2 and
granulocyte colony-stimulating factor were effective on
diabetic foot ulcers. However, for chronic wound
therapy, so far only PDGF-BB has been licensed for com-
mercial use in the US and Europe.196,223
Future perspectives 295
Gene therapy
Gene therapy to enhance wound repair through intro-
duction of a growth factor gene, or other therapeutic
gene, into repair cells is actively undergoing investiga-
tion. With this approach, the gene must be delivered to
the target cell and its expression sustained at a thera-
peutic level; the level and timing of its expression must
be reversibly controlled so that it can be stopped when
it is no longer needed.224 Several delivery vehicles are
being developed, each with unique advantages and dis-
advantages. Replication-deficient adenovirus, herpes
simplex virus type 1, and retrovirus vectors have been
successfully used to transfect epidermal and dermal
cells and tissues.224,225 Other delivery approaches elimi-
nate the virus and its possible risk of untoward side-
effects due to antigenicity, potential recombination with
wild-type viruses, and cellular damage from persistent
viral exposure. Nonviral methods are categorized into
chemical and physical methods of gene transfer.
Liposome-mediated gene transfer is a chemical method
in which the gene is bound to a synthetic liposome
vesicle and carried into the target cell by endocytosis.
FGF,226 IGF-1,224 KGF,227 and VEGF228 genes have been
successfully transferred into experimental wounds.
Particle-mediated gene transfer (gene gun) directly
injects DNA into the cells and has been used for TGF-
β1,229 EGF,230 and PDGF231 gene transfer in experimental
wounds. Gene therapy is likely to become an increas-
ingly important tool for the treatment of nonhealing
wounds as its methods advance. In a phase I clinical
trial the safety, feasibility, and biologic plausibility of
adenovirus-mediated rhPDGF-BB gene therapy to treat
venous leg ulcer disease were demonstrated.232
Extreme redundancy exists in the function of growth
factors at the wound site. In addition, multiple simulta-
neous processes are occurring during repair. Thus, it is
likely that multiple growth factors may need to be
added on impaired and even otherwise normal wounds
to effect a clinically significant improvement in repair
quality and rate. Different growth factor combinations
may be needed to treat impaired wounds due to
different underlying diseases, such as diabetes versus
arterial insufficiency. To complicate matters further,
neutralization of certain growth factors may be neces-
sary as well as augmentation of other factors in the
same wound.
296 • 15 • Skin wound healing: Repair biology, wound, and scar treatment
Stem cell therapy
Multipotent adult stem cells have come into focus as
cellular replacement and growth factor delivery source
for skin tissue defects and nonhealing wounds because
of abundance and easy accessibility in each patient.
Furthermore, autologous grafting avoids the risk of
rejection and ethical or moral considerations concerning
allogenic or embryonic material. Two major types of
adult stem cells are available: epidermal and mesenchy-
mal stem cells (MSCs). Epidermal stem cells are located
to the basal layer and hair follicles, and contribute to
re-epithelialization after wounding.233 Takahashi et al.
reported another promising access to epidermal cells
by reprogramming dermal fibroblasts into pluripotent
epidermal stem cells.234
MSCs are found in various mesoderm-derived
tissues. MSCs have the potential either to transdiffer-
entiate into tissues of mesodermal origin, e.g., skeletal
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derived MSC.236 Because of easier accessibility and
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(adMSC) for soft-tissue replacement and coverage
of nonhealing wounds are currently ongoing in our
department.
Our understanding of the biomolecular regulation of
repair and handling of autologous cells and tissues is
rapidly expanding while modern biotechnology keeps
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whether it is worthwhile continuing these futuristic
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