Clin Plastic Surg 30 (2003) 1 – 12
Acute wound healing
An overview
JoAn L. Monaco, MS, MD, W. Thomas Lawrence, MPH, MD, FACS*
Section of Plastic Surgery, Sutherland Institute, University of Kansas Medical Center, 3901 Rainbow Boulevard,
Kansas City, KS 66160, USA
The past 2 decades have produced more advances
in wound care than have the previous 2000 years as
a result of rapid expansion in the knowledge of the
healing process at the molecular level. The coordi-
nated interplay of technology and expanding scien-
tific knowledge has provided wound-care methods
that have greatly improved the ability to heal
wounds with few complications. These advances
serve as a prelude to the impetus that is likely to
come in the future.
Two broad categories exist for the classification of
wounds: chronic and acute. Acute wounds undergo a
complex interactive process involving a variety of
cell types that leads to a healed wound. Conversely,
chronic wounds have proceeded through portions of
the repair process without establishing a functional
anatomic result [1]. The present discussion focuses
on the healing of acute wounds.
Although the wound-healing process varies among
different tissue types, there are more similarities than
differences between them. In this discussion, skin is
considered as a representative tissue type. There are
also different types of acute skin wounds, including
incisional wounds, partial thickness injuries, and
wounds involving significant tissue loss. Different
types of wounds involve different phases of the healing
process to varying degrees, although the phases them-
selves remain the same.
* Corresponding author.
E-mail address: tlawrence@kumc.edu (W.T. Lawrence).
0094-1298/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S 0 0 9 4 - 1 2 9 8 ( 0 2 ) 0 0 0 7 0 - 6
Phases of wound healing
Healing of an acute wound follows a predictable
chain of events. This chain of events occurs in a
carefully regulated fashion that is reproducible from
wound to wound. The phases of wound healing are
overlapping, but are described in a linear fashion for
the purpose of clarity. The five phases that characterize
wound healing include (1) hemostasis, (2) inflam-
mation, (3) cellular migration and proliferation, (4)
protein synthesis and wound contraction, and (5)
remodeling (Fig. 1).
Hemostasis
All significant trauma creates a vascular injury and
thereby initiates the molecular and cellular responses
that establish hemostasis. The healing process cannot
proceed until hemostasis is accomplished. Primary
contributors to hemostasis include vasoconstriction,
platelet aggregation, and fibrin deposition resulting
from the coagulation cascades. The end product of the
hemostatic process is clot formation. Clots are pri-
marily composed of fibrin mesh and aggregated plate-
lets along with embedded blood cells [2]. The
importance of clot formation is profound. This process
prevents further fluid and electrolyte loss from the
wound site and limits contamination from the outside
environment. Fibrin is also the mesh material in the
provisional wound matrix onto which fibroblasts and
other cells migrate as the healing process proceeds.
Vasoconstriction
Vasoconstriction is initiated by the release of vaso-
active amines, which occurs when the dermis is
2 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12

Fig. 1. The acute wound-healing cascade. The progression of acute wound healing from hemostasis to the final phases of
remodeling is dependent on a complex interplay of varied acute wound-healing events. Cytokines play a central role in wound
healing and serve as a central signal for various cell types and healing events.

penetrated. Epinephrine is released into the peripheral
circulation, whereas stimulation of the sympathetic
nervous system results in local norepinephrine release.
Injured cells secrete prostaglandins, such as thrombox-
ane, that contribute further to vasoconstriction.
Platelet aggregation
Platelet aggregation is stimulated by exposure to
tissue factors released by damaged cells. Platelets
adhere to the vascular subendothelium and to each
other in a process involving fibrinogen and von
Willebrand factor [3]. Laminin, thrombospondin, and
vitronectin may also be involved. As platelets aggre-
gate and adhere, they release the contents of alpha
granules, dense bodies, and lysosomes within their
cytoplasm [4].
Alpha granules contain a variety of immunomodu-
latory and proteinaceous factors that are involved in
both the early and late phases of healing. Specifically,
these factors include albumin, fibrinogen, fibronectin
[5], IgG, and coagulation factors V and VIII, as well as
platelet-derived growth factor (PDGF), transforming
growth factors a and b (TGF-a and TGF-b), fibroblast
growth factor-2 (FGF-2), and platelet-derived epi-
dermal growth factors (EGFs), and endothelial cell
growth factors [6]. Of these factors, PDGF, TGF-b,
and FGF-2 are the most important.
Dense bodies contain necessary fuel-providing
compounds that contribute to the healing process.
These compounds include calcium, serotonin, ADP,
and ATP. Some of these compounds are also involved
in initiation of the coagulation cascades.
Fibrin and the coagulation cascades
The coagulation cascades are composed of intrinsic
and extrinsic components that are individually trig-
gered. The intrinsic cascade is not required for normal
healing, whereas the extrinsic cascade is essential [7].
The intrinsic coagulation cascade is initiated by activa-
tion of factor XII, which occurs when blood is exposed
to foreign surfaces. The more critical extrinsic coagu-
lation cascade is initiated by exposure to a ‘‘tissue
factor’’ that binds factor VII or factor VIIa. Tissue
factor is found on extravascular cell surfaces and, in
particular, on adventitial fibroblasts. The actions of the
intrinsic and extrinsic pathways result in the produc-
 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
tion of thrombin, which catalyzes the conversion of
fibrinogen to fibrin.
Thrombin itself stimulates increased vascular per-
meability in addition to facilitating the extravascular
migration of inflammatory cells [8]. Fibrin forms the
meshwork that stabilizes the platelet plug. It also
becomes a key component of the provisional matrix
that develops in the wound soon after injury. Fibrin
becomes coated with vitronectin derived from serum
and aggregating platelets. This action facilitates the
binding of fibronectins, which are produced by fibro-
blasts and epithelial cells [5]. Fibronectins are the
second key component of the early provisional wound
matrix. The fibronectin molecule has nearly a dozen
binding sites for cellular attachment [9]. These attach-
ment sites are essential for cellular migration along the
matrix. The fibrin – fibronectin matrix also traps cir-
culating cytokines for use in the ensuing stages of
healing [10].
Inadequate fibrin formation is associated with
impaired wound healing. This is observed in factor
XIII (fibrin-stabilizing factor) deficiency, which is
thought to impair cellular adhesion and chemotaxis
[11]. Any process that removes fibrin from the wound
will disrupt the formation of extracellular matrix and
also, consequently, will delay wound healing [12,13].
Inflammation
Inflammation is characterized by the erythema,
edema, heat, and pain as first described by Hunter in
1794. At the tissue level, increased vascular perme-
ability and the sequential migration of leukocytes into
the extravascular space characterize inflammation [1].
One of the primary functions of inflammation is to
bring inflammatory cells to the injured area [14].
These cells then destroy bacteria and eliminate debris
from dying cells and damaged matrix so that the
repair processes can proceed [15].
Although inflammation is often thought of as the
second phase of wound healing, signs of inflam-
mation, including erythema and heat, develop soon
after injury as a result of vasodilatation. Vasodilata-
tion follows the initial vasoconstriction that reverses
10 to 15 minutes after injury. Simultaneously, the
endothelial cells lining the capillaries in the vicinity
of the wound develop gaps between them, which
permit the leakage of plasma from the intravascular
space to the extravascular compartment [16]. The
migration of fluid into the injured area generates
edema, which contributes to the sensation of pain
that characterizes inflammation.
The transition from vasoconstriction to vasodila-
tion is mediated by a variety of factors. Endothelial
3
products and mast cell-derived factors such as leuko-
trienes, prostaglandins, and, in particular, histamine
contribute to vasodilation [17,18]. Kinins, released by
protein-binding molecules in the plasma via activa-
tion of kallikrein, also contribute to this process.
Capillary leak is primarily mediated by the release
of histamine, kinins, and prostaglandins. There is an
additional influence from thrombin and the com-
plement system. Complement factors C3a and C5a
are significant contributors to capillary leak and
also act as chemoattractants for neutrophils and
monocytes [19]. Their chemotactic function is depen-
dent on the release of TGF-b and formyl-methionyl
peptides [20].
Leukocyte migration into the wounded area is
stimulated by collagen, elastin breakdown products,
complement factors, and immunomodulatory factors
including TGF-b, tumor necrosis factor-a (TNF-a),
interleukin-1 (IL-1), PDGF, leukotriene B4, and plate-
let factor IV. Leukocytes adhere to endothelial cells
lining the capillaries in the wounded area through an
interaction of intracellular adhesion molecules on the
endothelial cell membranes and integrins expressed on
the cell surface of the leukocytes. This process is
known as margination. Platelet factor IV and platelet-
activating factor then increase the expression of CD11/
CD18, an integrin on the neutrophil surface that
facilitates transmigration of leukocytes through the
endothelium [21] in a process known as diapedesis.
Migrating monocytes transform into macrophages
as they migrate into the extravascular space in a
process that is stimulated by chemotactic factors such
as fibronectin, elastin derived from damaged matrix,
complement components, enzymatically active
thrombin, TGF-b, and serum factors [11]. All leuko-
cytes require activation before they can perform their
vital functions in the wound environment [22]. IL-2
and INF-s derived from T lymphocytes are involved
in macrophage activation [23].
After activation, macrophages and neutrophils
initiate cellular wound debridement by phagocytosing
bacteria and foreign material [24]. Both cell types
have surface receptors that allow them to recognize,
bind, and engulf foreign material [25]. Macrophage
binding receptors include the immunoglobulin-type
adhesion molecule CD14 that binds lipopolysaccha-
ride [26] and the CD11b-CD18 ab integrin. After
binding, bacteria and debris are engulfed and digested
by oxygen radicals and hydrolytic enzymes within
the inflammatory cells. In addition to phagocytosing
debris, macrophages also contribute to its breakdown
extracellularly by releasing matrix metalloproteinases
(MMPs) such as collagenase and elastase into the
wounded area [27].
4 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
In addition to contributing to phagocytosis, mac-
rophages are also a primary source of cytokines that
mediate later aspects of the healing process. Some
macrophages primarily phagocytose foreign materials
and produce MMPs, whereas others primarily pro-
duce cytokines. Unlike polymorphonuclear leuko-
cytes, the removal of macrophages from the healing
milieu will significantly alter and impede the healing
process [14]. The presence or absence of polymor-
phonuclear leukocytes will only alter the rate of
wound infection [28]. The added function of cytokine
production differentiates the activities of the two cell
types and makes macrophages more essential.
The role of the macrophage is complex in that
this multipurpose cell is involved in many aspects of
healing through the cytokines and immunomodula-
tory factors it produces (Fig. 2). Macrophage-pro-
duced cytokines are involved in angiogenesis,
fibroblast migration and proliferation, collagen pro-
duction [29], and possibly wound contraction. TGF-
b, IL-1, insulin-like growth factor-1 (IGF-1), FGF-2,
and PDGF are several of the more critical macro-
phage-derived cytokines. TGF-b regulates its own
production by macrophages in an autocrine manner
[30]. It also stimulates macrophages to secrete
PDGF, FGF-2, TNF-a, and IL-1 [20] through bind-
Fig. 2. Cell interactions. Acute wound healing is dependent on a complex interplay of various inflammatory markers and cell
types. Macrophages are crucial to the various phases of acute wound healing and serve as a central stimulator for several different
cell types involved in wound healing.
ing of the epidermal growth factor receptor. Further-
more, macrophages also release nitric oxide, which
may serve an antimicrobial function as well as other
functions during the healing process [28]. The
inhibition of nitric oxide release has been found to
impair wound healing in an in vivo mouse model
[31]. The complete role of nitric oxide in wound
healing has yet to be fully delineated.
T lymphocytes play a crucial role in the wound-
healing process as well, and the removal of circulat-
ing T lymphocytes inhibits the healing cascade [32].
Seventy to eighty percent of normal peripheral blood
lymphocytes are mature T lymphocytes. B lympho-
cytes contribute the remaining 10% to 15% and have
not been found to play any role in wound healing
[33]. Typically, both CD4-positive and CD8-positive
T lymphocytes are present in maximal concentrations
5 to 7 days after injury under the influence of IL-2
and various other immunomodulatory factors [34,35].
T lymphocytes—especially CD4-positive T lympho-
cytes—are important sources of cytokines including
IL-1, IL-2, TNF-a, fibroblast activating factor, EGF,
and TGF-b [36 – 38]. Among other functions, these
factors regulate the process of T-cell proliferation and
differentiation in an autocrine fashion. T cells are also
the primary effectors of cell-mediated immunity and
 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
subsets of T cells mature into cytotoxic cells capable
of lysing virus-infected and foreign cells [22].
Other inflammatory cell types include eosinophils
and basophils. These leukocytes are nonspecific
amplifiers and effectors of specific immune re-
sponses [39]. Both eosinophils and basophils in
unchecked accumulation can lead to host tissue
damage, as seen in eosinophil-mediated systemic
necrotizing vasculitis [33]. These cell types reach
their highest concentrations in wounds 24 to 48 hours
after injury, and are capable of producing TGF-a
[32]. Their complete role in inflammation remains to
be delineated.
As the healing process proceeds, inflammatory
cells trapped within clots are sloughed [40]. Neutro-
phils remaining within the wound become senescent
and undergo apoptosis [41]. Apoptosis is character-
ized by the activation of endogenous calcium-
dependent endonucleases. The activation of these
endonucleases results in cleavage of chromatin into
oligonucleosome DNA fragments [42], and is indic-
ative of irreversible cell death. The stimuli that lead to
inflammatory cell apoptosis during tissue repair and
scar formation have yet to be determined. Neutrophils
are the first of the inflammatory cells to become
apoptotic. They are then phagocytosed by macro-
phages [24]. Macrophages and lymphocytes remain
in the wound for approximately 7 days and then
gradually diminish in number unless a noxious stimu-
lant of further inflammation persists. Inflammatory
cell apoptosis influences antigen presentation and,
probably more importantly, contributes to modulation
of cytokine concentrations [16].
Cytokines
The wound-healing process is, in large part,
regulated by the ordered production of cytokines that
control gene activation responsible for cellular migra-
tion and proliferation and synthetic activities. As
mentioned, platelets and macrophages are key cyto-
kine sources, although many other cells produce
them. Control of the release of cytokines is, in part,
regulated by other cytokines and, in part, regulated
by characteristics of the tissue milieu [43,44]. An
often underreported signal for cytokine release is
tissue hypoxia. Hypoxia has been shown to stimulate
the release of TNF-a, TGF-b, vascular endothelial
growth factor (VEGF), and IL-8 (IL-8) from fibro-
blasts, endothelial cells, and macrophages [2,36,
37,45].
‘‘Cytokine networks’’ exist where multiple cell
types involved in the healing process have receptors
for the same cytokine. This permits stimulation of
5
multiple different activities by single cytokines [46].
This redundancy is most likely important in that
different factors may play greater or lesser roles at
different time points or at different sites.
Many cytokines can also stimulate several differ-
ent cellular functions in a single cell, which are often
dependent on the concentration of the cytokine. This
further allows individual cytokines to have varying
effects at different points during the healing process.
TGF-b, for example, is a macrophage chemoattractant
when circulating in the fentomolar range, but cannot
stimulate collagen synthesis by fibroblasts until found
in the nanomolar range [16]. In addition, PDGF
facilitates chemotaxis for fibroblasts, but only at a
100-fold greater concentration gradient than is neces-
sary to stimulate fibroblast proliferation [47,48].
Cellular activity is also regulated by the balance of
cytokines and cytokine isoforms with conflicting
activities. Cytokines such as PDGF, TGF-b, and
FGF-2 accelerate collagen synthesis scar formation
[49]. Other cytokines slow collagen synthesis, includ-
ing the b3 isoform of TGF-b and INF-a and INF-a2b
[41]. Cellular activity is, therefore, modulated by the
balance of cytokines with competing functions. Loss
of network balance has been implicated in chronic
wound healing pathways [2].
Cellular migration and proliferation
The cellular milieu in wounds changes dramat-
ically in the first week post acute injury. The initial
fibrin – fibronectin matrix is heavily populated by
inflammatory cells, whereas fibroblasts and endothe-
lial cells will predominate as healing progresses. Re-
establishment of the epithelial surface is also initiated
within the first several days after injury, as is revas-
cularization of the damaged area. Cytokine networks
continue to be a part of the process as cytokine
release contributes to fibroplasia, epithelialization,
and angiogenesis [44]. Although much is known
about the signals that stimulate the predominant
activities during this phase of healing, less is known
about the signals that bring these activities to a
controlled end. Negative feedback mechanisms that
deactivate cells after they have completed their work
are also essential for normal healing.
Additional fibroblasts are required in the healing
wound, in that native cells are lost or damaged in any
injury. Repopulation of the wounded area with fibro-
blasts occurs as a result of fibroblast migration from
adjacent tissues and proliferation of cells in the wound.
In addition, undifferentiated cells in the vicinity of the
wound may transform into fibroblasts under the influ-
ence of cytokines in the wound milieu [50].
6 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
Factors that stimulate fibroblast migration include
PDGF [48], TGF-b [50], EGF [51], and fibronectin
[18]. Upregulation of cell membrane integrin recep-
tors that bind fibronectin and fibrin in the provisional
wound matrix is required for fibroblasts to migrate
[52,53], and PDGF [54,55] and TGF-b [50] both
contribute to the migratory process in this manner.
Integrin expression is, therefore, vital to the migra-
tion of fibroblasts and other cell types. There are over
20 different integrin molecules, and most have a and b
subunits [21]. Different cells express different integ-
rins, and individual cells can often express more than
one integrin, often under the influence of varied
cytokines. Cellular migration requires cell mem-
brane-bound integrins to be bound to fibronectin in
the extracellular matrix [56]. A migrating cell then
develops lamellopodia that extend outward until
another binding site is detected in the matrix [57].
By releasing the primary binding site and pulling itself
toward the second site, the cell migrates, using the new
site as an anchor [17]. Fibronectin fragments stimulate
this migratory process [18]. The orientation of fibers in
the matrix also influences cellular migration, in that
cells tend to migrate along fibers and not across them.
The ability of fibroblasts to migrate may be
impeded by residual debris in the wound envi-
ronment. To facilitate migration through such debris,
fibroblasts secrete several proteolytic enzymes
including MMP-1, gelatinase (MMP-2), and strome-
lysin (MMP-3) [58,59]. TGF-b stimulates fibroblasts
to secrete these enzymes [30,60,61].
The proliferation of residual fibroblasts in the
wounded area, as well as fibroblasts that have migrated
to it, is regulated by a variety of cytokines. PDGF and
TGF-b are two of the most important cytokines
involved in this process. PDGF often works in concert
with IGF to facilitate fibroblast proliferation [48].
PDGF primarily stimulates cells to progress through
the early G0 and G1 phases of the cell cycle [47]. IGF,
which is derived primarily from hepatocytes and
fibroblasts [37], then facilitates progression through
the subsequent S1, G2, and M phases of the cell cycle.
Angiogenesis
The angiogenic process becomes active from day 2
after wounding [39]. Factors in the wound milieu that
contribute to angiogenesis include high lactate levels,
acidic pH, and, in particular, decreased oxygen tension
[35]. The severe degree of hypoxia in granulation
tissue most likely results from both disruption of the
native vasculature and increased oxygen consumption
by cells in the wound environment [40]. Proliferating
cells are known to consume oxygen three to five times
faster than do cells in resting phases of the cell cycle.
During angiogenesis, endothelial sprouts derive
from intact capillaries at the wound periphery [62].
The sprouts grow through cellular migration and
proliferation. The endothelial cells develop a cur-
vature and begin to produce a lumen as the chain of
endothelial cells elongates. Eventually, the endothe-
lial sprout comes into contact with a sprout derived
from a different capillary, and they interconnect
generating a new capillary.
Endothelial migration during angiogenesis in-
volves binding integrin domains within the provi-
sional fibrin – fibronectin matrix in a similar manner
to fibroblasts. Upregulation of ab3 integrins is spe-
cifically associated with angiogenesis. Endothelial
cell migration is also facilitated by the cell’s ability
to produce MMPs that break down collagen and
plasminogen activator, which facilitates movement
through the matrix.
As mentioned, the angiogenic process is regulated
by a variety of cytokines. The two most important
cytokines that contribute to angiogenesis are FGF-2
[63]—which has also been known as basic fibroblast
growth factor—and VEGF [64]. Heparin is a neces-
sary cofactor for FGF-2 [65]. Cytokine concentra-
tions diminish as the wounded area becomes
revascularized, and this flux in angiogenic cytokines
may facilitate maturation of the vascular system.
Epithelialization
Following acute injury, reconstruction of injured
epithelium is crucial for re-establishment of the barrier
functions of the skin. Reconstruction of injured epi-
thelium begins almost immediately after wounding.
Incisional skin injuries, with a minimal epithelial gap,
are typically re-epithelialized within 24 to 48 hours
after initial injury [2,66], although larger wounds can
take much longer to regenerate a neoepithelium.
During the first 24 hours after injury, basal cells
present at the wound edge elongate and begin to
migrate across the denuded wound surface. If the
initial injury does not destroy epithelial appendages
such as hair follicles and sweat glands, these struc-
tures also contribute migratory epithelial cells to the
healing process. These cells migrate across the
wounded area essentially as a monolayer. Approx-
imately 24 hours after the initiation of cellular migra-
tion, basal cells at the wound edge and in the
appendages, if present, begin to proliferate, contrib-
uting additional cells to the healing monolayer. The
migration of epithelial cells continues until overlap is
achieved with other epithelial cells migrating from
different directions. At that point, ‘‘contact inhibi-
tion’’ results in cessation of cellular migration. The
processes of cellular migration and proliferation
 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
occur under the control of various cytokines includ-
ing EGF [66,67], TGF-a, platelet-derived EGF, and
keratinocyte growth factor (KGF, also known as
FGF-7) [68]. Some derive from inflammatory cells
and others derive from the epithelial cells themselves.
Cellular migration may also require the secretion of
MMPs to penetrate eschar or scab [69].
Epithelial cell migration requires the development
of actin filaments within the cytoplasm of migratory
cells and the disappearance of desmosomes and
hemidesmosomes that link them to one another and
to the basement membrane, respectively. At least
some of these processes are dependent on changes
in integrins expressed on the cell membranes [70]. It
is thought that decreased calcium or increased mag-
nesium concentrations stimulate the downregulation
of the critical integrins, although the precise signal is
not yet known [56].
If the epidermal basement membrane is intact,
cells simply migrate over it. In wounds in which it
has been destroyed, the cells initially begin to mi-
grate over the fibrin – fibronectin provisional matrix
[12,13]. As they migrate across the matrix, however,
epithelial cells regenerate a new basement membrane.
Re-establishment of a basement membrane under the
migrating cells involves the secretion of tenasin,
vitronectin, and type I and V collagens [71].
When contact inhibition is achieved, hemides-
mosomes re-form between the cells and basement
membrane, and tenasin and vitronectin secretion
diminishes. The cells become more basaloid [72],
and further cellular proliferation generates a multi-
laminated neoepidermis covered by keratin. The neo-
epidermis is similar to the native epidermis, although
it is slightly thinner, the basement membrane is
flatter, and rete pegs that normally penetrate the
dermis are absent.
Protein synthesis and wound contraction
Synthesis and deposition of proteins and wound
contraction are the wound-healing events that begin
to predominate 4 to 5 days after wounding. The
quality and quantity of matrix deposited during this
phase of healing significantly influence the strength
of a scar [73]. Collagen constitutes more than 50% of
the protein in scar tissue, and its production is
essential to the healing process [74]. Fibroblasts are
responsible for the synthesis of collagen and other
proteins regenerated during the repair process. Col-
lagen synthesis is stimulated by TGF-b, PDGF, and
EGF [75]. Collagen synthesis is also affected by
characteristics of the patient and the wound including
age, tension, pressure, and stress [76]. Collagen
7
synthesis continues at a maximal rate for 2 to 4 weeks
and subsequently begins to slow.
Healing aberrations are often the result of aberra-
tions in collagen deposition, although the underlying
causes may vary. In diabetes, impaired activation of
inflammatory cells coupled with deficiencies in other
aspects of the healing process result in limited col-
lagen deposition and impaired healing [77]. Con-
versely, keloid formation results from excessive
collagen synthesis for which a preventative measure
has yet to be found [78].
As mentioned, the initial wound matrix is com-
posed primarily of fibrin and fibronectin. As protein
synthesis accelerates, the nature of the wound matrix
changes. Collagen and other proteins such as proteo-
glycans gradually replace fibrin as primary matrix
constituents. Proteoglycans are a key component of
mature matrix and are actively synthesized during
this phase of healing. Additional proteins such as
thrombospondin I and SPARC (secreted protein
acidic rich in cysteine)—which support cellular
recruitment and stimulate wound remodeling—are
also produced and are found in the mature wound
matrix as well [79].
Collagen makes up 25% of protein in the body
and more than 50% of protein in scar tissue [74].
The concentration of collagen subtypes varies among
tissues. Type I collagen predominates and makes up
80% to 90% of the collagen seen in intact dermis.
The remaining 10% to 20% is type III collagen. In
contrast, granulation tissue that forms soon after
injury contains 30% type III collagen. Accelerated
type III collagen synthesis is correlated with fibro-
nectin secretion after injury [75]. Type II collagen is
seen almost exclusively in cartilage, whereas type IV
collagen is found in basement membranes. Type V
collagen is found in blood vessels, whereas type VII
collagen forms the anchoring fibrils of epidermal
basement membrane [80].
Type I collagen consists of a triple helix involving
three polypeptide chains that are synthesized sepa-
rately within the fibroblast. The polypeptide chains
consist of a repeating glycine-X-Y pattern, in which
the X position is often proline and the Y position is
often hydroxyproline. The interaction of chains ini-
tiates the formation of the triple helix, which is
secreted as ‘‘procollagen’’ into the extracellular envi-
ronment [81].
Collagen undergoes eight posttranslational steps
intracellularly prior to its extracellular secretion in
the form of procollagen [29]. A critical step involves
hydroxylation of proline and lysine moieties within
the polypeptide chains. Hydroxylation of proline and
lysine requires specific enzymes and the cofactors
8 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
oxygen, vitamin C, ferrous iron, and a ketoglutarate.
Hydroxyproline is an important marker of the quan-
tity of collagen within tissues in that it is almost
exclusively found in collagen. Hydroxylysine is an
essential element for cross-link formation both within
and between collagen molecules [81]. Deficiencies in
vitamin C (scurvy) or suppression of enzymatic
activity by corticosteroids can lead to underhydroxy-
lated collagen that is incapable of generating strong
cross-links.
Procollagen-C proteinases and procollagen-N pro-
teinases cleave the propeptide ends of the procollagen
molecules after they have been secreted into the
extracellular space. This decreases the solubility of
the molecules and initiates the formation of fibrils.
During fibril formation, collagen molecules are ini-
tially linked together by electrostatic bonds. Sub-
sequent to this, free amino groups on lysine and
hydroxylysine residues within the collagen molecules
are transformed to aldehyde residues by the enzyme
lysyl oxidase. The aldehyde residues interact with
nontransformed lysine or hydroxlysine residues on
adjacent molecules, resulting in the formation of
stable covalent cross-links between the molecules
[35]. These cross-links stabilize the conjoined col-
lagen molecules as fibrils and fibers.
As mentioned, proteoglycans are also normal der-
mal matrix proteins that are synthesized by fibroblasts
after injury. Their concentration in injured tissue
gradually increases with time in a manner paralleling
collagen. Proteoglycans consist of a protein core
covalently linked to one or more glycosaminoglycans
[82]. Proteoglycans bind proteins and alter their ori-
entation in a manner that influences their activity.
Dermatan sulfate is a proteoglycan that orients col-
lagen molecules in a manner that facilitates fibril
formation. Hyaluronan, another proteoglycan, contrib-
utes to skin’s viscoelastic properties and acts as a
potent modulator of cellular migration [82].
Elastin is another component of wound matrix that
provides elasticity to normal skin. It is not synthesized
in response to injury and is subsequently not found in
scar. This lack of elastin in scar tissue contributes to the
increased stiffness and decreased elasticity of scar as
compared with normal dermis.
Wound contraction begins 4 to 5 days after initial
injury and actively continues for approximately
2 weeks. The process continues for a longer period
of time in wounds that remain open at the end of the
2-week interval. In an open wound, the results of
wound contraction are evident because wound edges
draw closer to each other. In an incisional wound,
wound contraction simply results in scar shortening
and is less apparent. The rate of contraction varies
between anatomic locations, but averages approxi-
mately 0.6 to 0.7 mm per day. The rate of contraction
can often be predicted by the degree of skin laxity at
the wound site. A wound on the scalp or pretibial area
will contract significantly more slowly than a buttock
wound. Wound shape also affects the rate of contrac-
tion, with square wounds contracting more quickly
than circular wounds. Circular stomas are therefore
less likely to have compromised patency secondary
to contraction.
Wound contraction is characterized by a predom-
inance of myofibroblasts at the wound periphery.
Myofibroblasts are modified fibroblasts that were
initially described by Gabbiani et al in 1971 [83].
The defining characteristics of myofibroblasts include
actin-rich microfilaments in the cytoplasm, a multi-
lobulated nucleus, and abundant rough endoplasmic
reticulum that can only be discerned by electron
microscopy. The time frame in which myofibroblasts
are present within the wound does not correspond
perfectly to the course of wound contraction, although
it is fairly close. Myofibroblasts appear 4 to 6 days
after initial injury and are commonly seen in the
wound during the ensuing 2 to 3 weeks. Their dis-
appearance is suspected to be via apoptosis. Although
Gabbiani et al [83] postulated that these cells were the
‘‘motor’’ that contracted a wound, more recent work
with collagen lattices has suggested that fibroblasts in
the central portion of the wound may be more critical
to the contraction process [42]. It is clear, however,
that the process of wound contraction is cell mediated
and does not require collagen synthesis. TGF-b and
possibly other cytokines are involved in the wound
contraction process [84].
Wound contraction is sometimes not a desirable
healing event. Wound contraction across joints can
produce contractures that significantly limit function.
In cases in which contraction inhibition is preferred,
skin grafting, especially with thicker grafts, is used to
limit contraction. Splints can also limit undesirable
contraction in certain anatomic locations if utilized
for prolonged periods.
Remodeling
Scar remodeling begins to predominate as the
primary wound-healing activity approximately
21 days after injury. The rate of collagen synthesis
diminishes and reaches coincidence with the rate of
collagen breakdown. The downregulation of collagen
synthesis is mediated by g-interferon [85], TNF-a
[86], and collagen matrix itself [29].
Matrix metalloproteinases (MMPs) are intimately
involved with the breakdown of collagen molecules
 J.L. Monaco, W.T. Lawrence / Clin Plastic Surg 30 (2003) 1–12
that occurs actively during the remodeling process.
The MMPs have been alluded to previously and are
involved in many aspects of the healing process.
MMPs represent a family of at least 25 enzymes that
break down different extracellular matrices [58 – 60].
They are produced by a variety of cell types, and
different cells generally synthesize different enzymes.
The MMP activity within tissues is modulated by
tissue inhibitors of metalloproteinases (TIMPs) [87].
Four isoforms of TIMPs have been described [87].
The balance of MMPs and TIMPs within tissues is
critical to enzyme activity and is regulated by cyto-
kines including TGF-b, PDGF, and IL-1 [43,61,88].
All of the functions provided by MMPs during
wound healing have not been clearly delineated.
Elevated concentrations of MMPs are seen in chronic
ulcers [77], yet deletion of MMP-3 in mice causes
failure of wound contraction with a significant delay
in healing [73], thereby implicating a complex regu-
latory pathway.
The nature of the wound matrix changes with scar
remodeling. Immature scar contains a disorganized
array of fine collagen fibers, which is gradually
replaced by thicker fibers arranged in an orientation
paralleling skin stresses. In addition, the number of
cross-links both within and between molecules gradu-
ally increases. As the nature of the collagen matrix
changes, it becomes less cellular through apoptosis of
cells involved in the healing process. As mentioned,
the ratio of type I to type III collagen changes, and the
quantity of water and proteoglycans diminish. Nor-
mal skin shows a basketlike weave pattern that is
never completely reproduced with scar remodeling.
Although seemingly not as complex as other
aspects of the healing process, remodeling is essential
to the formation of a strong wound. The remodeling
process is associated with a substantial increase in
wound-breaking strength. Wound strength 1 week
after injury is 3% of normal dermis. After 3 weeks,
when the remodeling phase begins to predominate, the
wound will have only approximately 20% the strength
of normal dermis. At 3 months, however, the wound
will have 80% the strength of normal dermis, with the
significant increase in strength resulting from the
contribution of remodeling. Remodeling will continue
for up to 12 months after a wound is created, although
scars never regain the strength of normal dermis.
Summary
The ability to heal an injury is a biologic necessity
for all organisms, with mammals lagging in pro-
ficiency when compared with lower life forms that
9
have the ability to regenerate differentiated structures.
Technology and increased scientific knowledge have
established a coordinated interplay that has improved
the ability to manage wounds in a logical manner, and,
on occasion, to accelerate the healing process. Insight
into the complex chain of events leading to the
formation of scar is a necessity for every individual
who attempts wound management.
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