CME

Wound Healing: An Overview

George Broughton II,
M.D., Ph.D., COL., M.C.,
U.S.A.
Jeffrey E. Janis, M.D.
Christopher E. Attinger,
M.D.
Dallas, Texas; and Washington, D.C.
Learning Objectives: After studying this article, the participant should be able
to: 1. Describe the actions of inflammatory mediators, growth factors, and nitric
oxide involved in wound healing. 2. Describe the different cellular elements and
their function in wound healing. 3. Discuss the three phases of wound healing
and the relationships between mediators and cells for each. 4. Discuss the
similarities and differences between keloids and hypertrophic scar and the
treatment options for each. 5. Discuss the systemic and external factors involved
in wound healing. 6. Discuss future wound-healing opportunities.
Summary: Understanding wound healing today involves much more than sim-
ply stating that there are three phases: inflammation, proliferation, and mat-
uration. Wound healing is a complex series of reactions and interactions among
cells and mediators. Each year, new mediators are discovered and our un-
derstanding of inflammatory mediators and cellular interactions grows. This
article will attempt to provide a concise overview on wound healing and wound
management. (Plast. Reconstr. Surg. 117: 1e-S, 2006.)

U
nderstanding wound healing today in-
volves much more than simply stating
there are three phases: inflammation, pro-
liferation, and maturation. Wound healing is a
complex series of reactions and interactions
among cells and mediators. Each year, new
mediators are discovered and our understanding
of inflammatory mediators and cellular interac-
tions grows. Many intrinsic and extrinsic factors
affect wound healing, and an enormous industry
provides the clinician with a huge and complex
armamentarium to battle wound-healing prob-
lems. This article will provide the reader with a
wide overview of wound healing and wound-
healing problems and solutions.
WOUND HEALING
Wound healing has traditionally been divided
into three distinct phases: inflammation, prolifer-
ation, and remodeling.1,2 A detailed review of the
basic science of wound healing can be found in
From the Department of Plastic Surgery, Nancy L & Perry
Bass Advanced Wound Healing Laboratory, University of
Texas Southwestern Medical Center; and the Georgetown
Limb Center, Georgetown University Medical Center.
Received for publication February 1, 2006; revised March
18, 2006.
The opinions or assertions contained herein are the private
views of the author (G.B.) and are not to be construed as
official or as reflecting the views of the Department of the Army
or the Department of Defense.
Copyright 2006 by the American Society of Plastic Surgeons
DOI: 10.1097/01.prs.0000222562.60260.f9
this Supplement. This discussion will serve as a
broad overview of clinical wound healing. Table 1
summarizes the inflammatory mediators by source
and function.3,4
Hemostasis and Inflammation (from
Immediately upon Injury through
Days 4 to 6)
The inflammatory phase is characterized by
hemostasis and inflammation. Collagen exposed
during wound formation activates the clotting cas-
cade (both the intrinsic and extrinsic pathways),
initiating the inflammatory phase. After injury oc-
curs, the cell membranes release the potent vaso-
constrictors thromboxane A2 and prostaglandin
2-. The clot that forms is made of collagen, plate-
lets, thrombin, and fibronectin, and these factors
release cytokines and growth factors (Table 2) that
initiate the inflammatory response.5 The fibrin
clot serves as scaffolding for arriving cells, such as
neutrophils, monocytes, fibroblasts, and endothe-
lial cells.6 It also serves to concentrate the cyto-
kines and growth factors.7
Chemotaxis and Activation
Immediately after the clot is formed, a cellular
distress signal is sent out and neutrophils are the
first responders. As the inflammatory mediators
accumulate, and prostaglandins are elaborated,
the nearby blood vessels vasodilate to allow for the
increase cellular traffic as neutrophils are drawn
into the injured area by interleukin (IL)-1, tumor
necrosis factor (TNF)-, transforming growth fac-

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 Plastic and Reconstructive Surgery June Supplement 2006

Table 1. Summary of Inflammatory Cytokines*

Cytokine Cell of Origin Function
EGF Platelets, macrophages Mitogenic for keratinocytes and fibroblasts,
stimulates keratinocyte migration
FGF Macrophages, mast cells, T lymphocytes, Chemotactic and mitogenic for fibroblasts and
endothelial cells keratinocytes, stimulates angiogenesis
IFNs (, , and ) Lymphocytes, fibroblasts Activate macrophages, inhibit fibroblast
proliferation
ILs (1, 2, 6, and 8) Macrophages, mast cells, keratinocytes, IL-1: induces fever and adrenocorticotrophic
lymphocytes hormone release; enhances TNF- and IFN-,
activates granulocytes and endothelial cells; and
stimulates hematopoiesis
IL-2: activates macrophages, T cells, natural killer
cells, and lymphokine-activated killer cells;
stimulates differentiation of activated B cells;
stimulates proliferation of activated B and T
cells; and induces fever
IL-6: induces fever and enhances release of acute-
phase reactants by the liver
IL-8: enhances neutrophil adherence, chemotaxis,
and granule release
KGF Fibroblasts Stimulates keratinocyte migration, differentiation,
and proliferation
PDGF Platelets, macrophages, endothelial cells Cell chemotaxis, mitogenic for fibroblasts,
stimulates angiogenesis, stimulates wound
contraction
TGF- Macrophages, T lymphocytes, keratinocytes Mitogenic for keratinocytes and fibroblasts,
stimulates keratinocyte migration
TGF- Platelets, T lymphocytes, macrophages, Cell chemotaxis stimulates angiogenesis and
endothelial cells, keratinocytes fibroplasia
Thromboxane A2 Destroyed wound cells Potent vasoconstrictor
TNF Macrophages, mast cells, T lymphocytes Activates macrophages, mitogenic for fibroblasts,
stimulates angiogenesis
EGF, epidermal growth factor; FGF, fibroblast growth factor; IFN, interferon; IL, interleukin; KGF, keratinocyte growth factor; PDGF,
platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor.
*From Henry, G., and Garner, W. Inflammatory mediators in wound healing. Surg. Clin. North Am. 83: 483, 2003; and Lawrence, W., and
Diegelmann, R. Growth factors in wound healing. Clin. Dermatol. 12: 157, 1994.

tor (TGF)-, platelet factor-4 (PF4), and bacterial
products.8,9 Monocytes in the nearby tissue and
in the blood will be attracted to the area and
transform into macrophages, usually around 48 to
96 hours after injury. Activation of the inflamma-
tory cells is critical, especially for the macrophage.
An activated macrophage is important for the
transition into the proliferative phase. An acti-
vated macrophage will mediate angiogenesis, fi-
broplasia, and synthesize nitric oxide.10
Neutrophils will enter into the wound site
and begin clearing it of invading bacteria and
cellular debris. The neutrophil releases caustic
proteolytic enzymes that will digest bacteria and
nonviable tissue. The next cells present in the
wound are the leukocytes and the macrophages
(monocytes). The macrophage is essential for
wound healing. Numerous enzymes and cyto-
kines are secreted by the macrophage, including
collagenases, which debride the wound; ILs and
TNF, which stimulate fibroblasts (produce col-
lagen) and promote angiogenesis; and TGF,
which stimulates keratinocytes.
Proliferative Phase (Epithelization,
Angiogenesis, and Provisional Matrix
Formation; Day 4 through 14)
Epithelialization, angiogenesis, granulation
tissue formation, and collagen deposition are the
principal steps in this building portion of wound
healing. Epithelialization occurs early in wound
repair. If the basement membrane remains intact,
the epithelial cells migrate upward in the normal
pattern. The epithelial progenitor cells remain
intact below the wound (in skin appendages), and
the normal layers of epidermis are restored in 2 to
3 days. If the basement membrane has been de-
stroyed, then epithelial cells located on the skin
edge begin proliferating and sending out projec-
tions to re-establish a protective barrier.4,11 Angio-
genesis, stimulated by TNF-, is marked by endo-
thelial cell migration and capillary formation. The
migration of capillaries into the wound bed is
critical for proper wound healing. The granula-
tion phase and tissue deposition require nutrients
supplied by the capillaries, and failure of this to

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Volume 117, Number 7S Wound Healing

occur results in a chronically unhealed wound.
Epithelial cells located on the skin edge begin
proliferating and sending out projections to re-
establish a protective barrier against fluid losses
and further bacterial invasion. The stimulus for
epithelial proliferation and chemotaxis is epider-
mal growth factor (EGF) and TGF- produced by
activated platelets and macrophages (fibroblasts
do not appear to synthesize TGF-).4,11 Epitheliza-
tion begins shortly after wounding and is first stim-
ulated by inflammatory cytokines. IL-1 and TNF-
upregulate keratinocyte growth factor (KGF) gene
expression in fibroblasts. In turn, fibroblasts syn-
thesize and secrete KGF-1, KGF-2, and IL-6, which
simulate neighboring keratinocytes to migrate in
the wound area, proliferate, and differentiate in
the epidermis.12,13 It has been shown that, for hu-
mans, KGF-2 is most important for directing this
process.14
The final part of the proliferative phase is
granulation tissue formation. Fibroblasts migrate
into the wound site from the surrounding tissue,
become activated, and begin synthesizing collagen
and proliferate. Platelet-derived growth factor
(PDGF) and EGF are the main signals to fibro-
blasts and are derived from platelets and macro-
phages. PDGF expression by fibroblasts is ampli-
fied by autocrine and paracrine signaling.
Fibroblasts already located in the wound site
(termed wound fibroblasts) will begin synthesiz-
ing collagen and transform into myofibroblasts for
wound contraction (induced by macrophage-se-
creted TGF-1); they have less proliferation com-
pared with the fibroblasts coming in from the
wound periphery.1517 In response to PDGF, fibro-
blasts begin synthesizing a provisional matrix com-
posed of collagen type III, glycosaminoglycans,
and fibronectin.18
Maturation and Remodeling (Day 8 through
Year 1)
Clinically, the maturation and remodeling
phase is perhaps the most important. The main
feature of this phase is the deposition of collagen
in an organized and well-mannered network. If
patients have matrix deposition problems (from
diet or disease), then the wounds strength will be
greatly compromised; if there is excessive collagen
synthesis, then a hypertrophic scar or keloid can
result.
Net collagen synthesis will continue for at least
4 to 5 weeks after wounding. The increased rate of
collagen synthesis during wound healing is not
only from an increase in the number of fibroblasts
but also from a net increase in the collagen pro-
duction per cell.19,20 The collagen that is initially
laid down is thinner than collagen in uninjured
skin and is orientated parallel to the skin. Over
time, the initial collagen threads are reabsorbed
and deposited thicker and organized along the
stress lines. These changes are also accompanied
by a wound with an increased tensile strength,
indicating a positive correlation between collagen
fiber thickness/orientation and tensile strength.5
The collagen found in granulation tissue is bio-
chemically different from collagen from unin-
jured skin. Granulation tissue collagen has a
greater hydroxylation and glycosylation of lysine
residues, and this increase of glycosylation corre-
lates with the thinner fiber size.21 The collagen in
the scar (even after a year of maturing) will never
become as organized the collagen found in unin-
jured skin. Wound strength also never returns to
100 percent. At 1 week, the wound has only 3
percent of its final strength; at 3 weeks, 30 percent;
and at 3 months (and beyond), approximately 80
percent.22

Table 2. Mediators Found in a Blood Clot

Mediator
Fibrin, plasma fibronectin
Factor XIII (fibrin-stabilizing factor)
Circulatory growth factors
Complement
Cytokines, growth factors
Fibronectin
Platelet-activating factor
Thromboxane A2 (via platelet COX-1)
Serotonin
Platelet factor IV
Action
Coagulation, chemoattraction, adhesion, scaffolding for cell
migration
Induces chemoattraction and adhesion
Regulation of chemoattraction, mitogenesis, fibroplasia
Antimicrobial activity, chemoattraction
Regulation of chemoattraction, mitogenesis, fibroplasia
Early matrix, ligand for platelet aggregation
Platelet aggregation
Vasoconstriction, platelet aggregation, chemotaxis
Induces vascular permeability, chemoattractant for neutrophils
Chemotactic for fibroblasts and monocytes, neutralizes activity of
heparin, inhibits collagenase

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 Plastic and Reconstructive Surgery June Supplement 2006
FACTORS IN WOUND HEALING
The complexity of wound healing makes it
vulnerable to interruption at many levels. Factors
that affect physiologic responses and cellular func-
tion can potentially influence wound healing. This
section will briefly highlight the effect several fac-
tors have on wound healing.
Local Factors
Several local factors can greatly influence
wound healing. Ischemic tissues, wounds with for-
eign bodies, infection, contamination, and so on,
will all affect wound healing. The Venn diagram
(Fig. 1) highlights these obstacles.
Ischemia
Healing is an energy-dependent process and
requires an adequate supply of the energy cur-
rency, adenosine triphosphate (ATP). The initial
anaerobic conditions following injury stimulate
cells to adopt anaerobic production of ATP via
glycolysis.23 The proliferative phase of healing is
characterized by increased metabolism and pro-
tein synthesis requiring much larger quantities of
ATP via oxidative phosphorylation. This demands
a rich blood supply to provide glucose and oxygen.
Hypoxia (or decreased glucose) has the potential
to slow or halt the healing process.24
The physiologic response of the vascular en-
dothelium to localized hypoxia in the early phase
of wound healing is to precipitate vasodilation,
stimulate fibrin deposition, and increase proin-
flammatory activity, capillary leak, and neovascu-
Fig. 1. Local factors affecting wound healing.
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larization. The endothelial cell response to sus-
tained hypoxia is a TNF- induction of apoptosis.
Sustained hypoxia will result in endothelial cell
apoptosis.25
Wound neutrophil activity has been demon-
strated to be impaired at lower oxygen tensions
identified in wounds. Low temperature, low pH,
and elevated glucose concentrations also limit leu-
kocyte function.26 Fibroblasts exposed to longer
periods of hypoxia may not participate in the for-
mation of the extracellular matrix, thus delaying
healing.27
Infection
Local wound infection and foreign bodies af-
fect healing by prolonging the inflammatory
phase. If the bacterial count in the wound exceeds
105 organisms per gram of tissue, or if any beta-
hemolytic Streptococcus is present, the wound will
not heal by any means, including flap closure, skin
graft placement, or primary sutures.28 The bacte-
ria prolong the inflammatory phase and interfere
with epithelialization, contraction, and collagen
deposition. The endotoxins themselves stimulate
phagocytosis and the release of collagenase, which
contributes to collagen degradation and destruc-
tion of surrounding, previously normal tissue.
Wound contamination in association with tissue
hypoxia potentially suppresses macrophage-regu-
lated fibroblast proliferation.29
Foreign Bodies
Foreign bodies (which also include nonviable
tissue) are a physical obstacle to wound healing
and an asylum for bacteria. Foreign bodies pro-
long the inflammatory phase. Wounds with for-
eign bodies cannot contract, repopulate the area
with capillaries, or completely epithelize (depend-
ing on the size and location of the foreign body).
Wounds with necrotic tissue will not heal until all
the necrotic tissue is removed.30
Edema/Elevated Tissue Pressure
The edema and locally raised pressures asso-
ciated with ischemic tissue injury can potentially
further compromise perfusion. The inflammatory
response to wounding may be prolonged as a re-
sult, thus delaying the healing process. This is
dramatically demonstrated in the development of
compartment syndrome in limb skeletal muscles
following ischemia and reperfusion.31 Mast cells in
skeletal muscle have been demonstrated to pro-
duce most of the nitric oxide associated with isch-
emia-reperfusion injury.32 Mast cells are resident
Volume 117, Number 7S Wound Healing
tissue inflammatory cells that, when stimulated,
release numerous cytokines and histamines re-
sponsible for an intense inflammatory reaction
and edema.
Raised tissue pressure, either externally (pres-
sure) or internally (compartment syndrome), in-
duces increased capillary closure through its effect
on critical closing pressures. Compromised cellu-
lar function due to prolonged, severe hypoxia may
rapidly progress to cell death, with necrosis of skin,
adipose tissue, and muscle, thus precipitating ul-
ceration and further contributing locally to im-
paired healing. In critical illness, additional risk
factors, including depletion of soft-tissue adipose
and protein components, tissue edema due to low-
ered plasma oncotic pressures, leaky endothe-
lium, and potentially compromised peripheral
perfusion, may further compromise tissue perfu-
sion by raising interstitial pressures.31
SYSTEMIC OBSTACLES
A patient may already have characteristics that
predispose him or her to soft-tissue wound-healing
dysfunction. This has been studied in surgical pat-
ents in an attempt to predict wound complications
in abdominal and breast reconstructive surgery.3335
These characteristics include obesity, cardiovascular
disease affecting tissue perfusion, respiratory disease
affecting adequate blood oxygenation, metabolic
disease, endocrine disease, and renal and hepatic
failure. Diabetes mellitus affects soft-tissue healing
via metabolic, vascular, and neuropathic pathways,
as typified in diabetic foot disease.36 Increasing age
is associated with delayed healing, but it is difficult to
separate the effects of age alone from those diseases
commonly associated with age.37 Supplementation
using topical estrogen has been demonstrated to
improve healing in elderly women.38
Malignancy and its treatments can have pro-
found effects on the ability of a patient to mount
a response to injury and infection. Poor nutrition,
specific organ compromise, ectopic hormone pro-
duction, and immune and hematological effects,
together with aggressive therapies, including po-
tent antimetabolic, cytotoxic, and steroidal agents
and radiation, are all associated with compro-
mised immunity, increased susceptibility to sepsis,
and failure of tissue repair.39 41
The stresses associated with critical illness may
further significantly affect healing. Critical illness
places higher demands on tissue oxygen supply
because of the stresses of acute illness and the
requirements of increased cellular activity associ-
ated with wound healing.42
Diabetes Mellitus
Increased serum glucose has a major effect on
wound healing. This is most likely a multifactorial
process due to hyperglycemia-related deleterious
effects on molecular and cellular physiology. Al-
though traditional teaching is that the etiology of
diabetic complications is microvascular occlusive
disease, recent research does not support this.43
Several defects that may influence the healing pro-
cess are now known. Sorbitol, a toxic byproduct of
glucose metabolism, accumulates in tissues and is
implicated in many of the renal, ocular, and vas-
cular complications associated with diabetes.44 In-
creased dermal vascular permeability results in
pericapillary albumin deposition, which impairs
the diffusion of oxygen and nutrients.43 Hypergly-
cemia-associated nonenzymatic glycosylation in-
hibits the function of structural and enzymatic
proteins. In addition, glycosylated collagen is re-
sistant to enzymatic degradation and less soluble
than the normal protein product.44
Experimental studies of diabetic animal mod-
els and wound healing show decreased granula-
tion, decreased collagen in granulation tissue, and
defects in collagen maturation.45 Human studies
of healing in diabetic patients parallel these find-
ings, showing slow wound maturation and de-
creased numbers of dermal fibroblasts. Growth
factor abnormalities have also been shown in re-
cent studies.
Hypothyroidism
Experimental data and anecdotal series show
that hypothyroidism causes delayed wound
healing.46,47 Rats pharmacologically rendered hy-
pothyroid have decreased collagen production, as
measured by extractable soluble hydroxyproline
levels.48 Hypothyroidism also significantly de-
creases wound tensile strength in rats.49 Irradia-
tion of hypothyroid pigs resulted in poor
healing.50 These studies indicate the deleterious
effect of inadequate thyroid hormone levels on
fibroblast function and subsequent wound
strength. Compounding these local effects are the
systemic complications (i.e., higher risk of heart
failure, risk of intraoperative hypotension, neuro-
psychiatric disturbances, and lack of postoperative
fever) for which the postoperative hypothyroid
patient is at risk.51
Age
It is well accepted that aging patients have
higher rates of complications and mortality than
do younger persons undergoing major surgery.52
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 Plastic and Reconstructive Surgery June Supplement 2006
It also is widely accepted that elderly patients heals
more slowly than younger patients.53,54 This infor-
mation should be balanced with the fact that older
patients generally have more comorbidities than
younger patients. Coronary artery disease, periph-
eral vascular disease, diabetes, and pulmonary
compromise are more common with advanced
age and may affect the healing process indepen-
dent of age. Experimental studies show that the
inflammatory and proliferative phases are less ef-
ficient in older animals, particularly compared
with very young subjects.54 A longitudinal study of
hamster fibroblast cultures over the span of the
animals life showed progressively decreasing pro-
liferative capacity over time.55 Studies of healthy
human volunteers do not completely support
these findings. Skin graft donor sites have slower
reepithelialization rates in older persons, al-
though the deposition of dermal collagen is equiv-
alent between young and older, healthy volun-
teers. The fact that proteins other than collagen
are less abundant in older subjects wounds may
indicate age-related differences in the production
of the extracellular matrix.56 Studies suggest that
the defect in age-related wound healing is related
to abnormal initiation of healing as a result of
insufficient presence of growth factors.57
Fetal Wound Healing
Tissue repair in the mammalian fetus is fun-
damentally different from normal postnatal heal-
ing. In adult humans, injured tissue is repaired by
collagen deposition, collagen remodeling, and
eventual scar formation. [In contrast], fetal
wound healing seems to be more of a regenerative
process with minimal or no scar formation.58
Siebert et al.59 examined healing fetal wounds
histologically and biochemically and found that
they contained a small amount of collagen iden-
tical to that found in the exudate from wounds in
adults (i.e., type III collagen but no type I). The
fetal wound matrix was also rich in hyaluronic
acid, which has been associated experimentally
with decreased scarring postnatally. The authors
proposed a mechanism of a hyaluronic acid/col-
lagen/protein complex acting in fetal wound
healing to check scar formation, and concluded
that healing in fetuses involved a much more ef-
ficient process of matrix reorganization than that
which takes place after birth. True regeneration
apparently does not play a role in fetal healing,
based on the few appendage elements seen.
Rowsell60 suggests that the collagen present in
fetal wounds is structural rather than scar tis-
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sue collagen. Not only are the amounts of colla-
gen deposited in fetal and in adult wounds mark-
edly different but the deposited collagen is also
handled differently. The fetal pattern of wound
healing is characterized, at least in the early fetus,
by the deposition of glycosaminoglycans at the
wound site into which rapidly proliferating mes-
enchymal cells of all types migrate, differentiate,
and mature.61 The transition from fetal to adult
patterns of wound healing for different tissues
probably occurs at different times during gesta-
tion.
In their review of scarless wound healing in the
mammalian fetus, Mast and coworkers58 state that
a striking difference between postnatal and fetal
repair is the absence of acute inflammation in fetal
wounds, and offer several hypotheses to explain
this phenomenon. Epithelialization occurs at a
much faster rate in fetal wounds, but adult-like
angiogenesis is absent. More importantly, the fetal
wound matrix is markedly different from the
adults in that it lacks collagen and instead con-
tains predominantly hyaluronic acid.25,62 The fetal
wound contains a persistent abundance of hyal-
uronic acid, while collagen deposition is rapid,
nonexcessive, and highly organized,63 so that the
normal dermal structure is restored and scarring
does not occur. The authors speculate about the
applications of scarless fetal healing, namely, for
intrauterine repair and in the treatment of patho-
logic, postnatal processes.
Whitby and Ferguson61 conclude that it may be
possible to manipulate the adult wound to pro-
duce more fetal-like, scarless wound healing by
therapeutically altering the levels of growth sub-
stances and their inhibitors. This hope is shared by
other groups,64 69 though it has not yet emerged
in the clinical setting. Bone morphogenetic
protein-2,70 hypoxia-inducible factor 1,71 decorin
(a TGF- modulator),72 - and -fibroblast growth
factor,73,74 IL-6,74 and IL-869 are also under study.
Tenascin (cytotactin) is a large, extracellular
matrix glycoprotein synthesized by fibroblasts that
is present during embryogenesis but only sparsely
distributed in the connective tissue papillae of
adults. Tenascin is present earlier in fetal wounds,
compared with adult wounds, and may be respon-
sible for initiating cell migration and the rapid
epithelialization of fetal wounds.75 Some
investigators75,76 believe that tenascin could be a
modulator of cell growth and movement and that
it may influence the deposition and organization
of other extracellular matrix glycoproteins during
tissue repair.
Volume 117, Number 7S Wound Healing
Tissue Perfusion
Disruption of tissue perfusion can be catego-
rized as local (from small vessel occlusion-emboli
or external compression) or general (from de-
creases in circulatory volumes, cardiac insuffi-
ciency, inotropic infusions, or large vessel disrup-
tion). Inadequate tissue perfusion (the definition
of shock) results in tissue hypoxia.
Hypothermia and Pain
Hypothermia also has a profound effect on
cutaneous perfusion by inducing peripheral vaso-
constriction; therefore, the thermal insulation of
wounds is important. Painful stimuli cause a dif-
fuse adrenergic discharge, leading to cutaneous
vasoconstriction; thus, adequate pain control can
improve cutaneous perfusion and potentially im-
prove healing.42
Major Trauma and Burns
Severe trauma and tissue loss can result in
hypovolemic shock as a consequence of circula-
tory volume loss or compromised cardiac func-
tion. The systemic inflammatory response syn-
drome that occurs in major trauma states is
characterized by elevation of circulating cytokines
and inflammatory mediators, including TNF-, re-
sulting in activation and consumption of clotting
factors and platelets potentially leading to clotting
anomalies, disseminated intravascular coagula-
tion, and subsequent delays in wound healing.77
The infusion of large volumes of packed red blood
cells also will affect coagulation, largely by dilu-
tional effects, as will cold intravenous fluid
replacement.78 The development of a posttrau-
matic immunoparalysis has implications in devel-
oping sepsis and subsequent delays in wound heal-
ing. Maintenance of a normovolemic state and
body temperature together with good analgesia
will facilitate adequate peripheral perfusion to
soft-tissue injuries. Deep soft-tissue burns, in par-
ticular, elicit a major and often prolonged local
inflammatory response associated with local tissue
ischemia, thrombosis, and an intense vasoconstric-
tion resistant to the effects of nitric oxide.79 There
is evidence that peripheral vasoconstriction per-
sists for up to 60 hours after hypovolemia, despite
adequate resuscitation and a normal mean arterial
pressure. Mild or moderate anemia does not ap-
pear to deleteriously affect healing in a well-per-
fused wound, with collagen deposition being pro-
portional to wound tissue oxygenation and
perfusion.80 The reperfusion of injured tissue it-
self can be deleterious to wound healing, with the
release of anaerobic metabolites and reactive ox-
ygen species creating additional oxidative stresses.
Fat emboli and disseminated intravascular coag-
ulation following severe trauma can cause respi-
ratory complications and occlusion of both larger
and smaller cutaneous vessels, as well as general
and focal tissue hypoxia and multiple-organ dys-
function syndrome.81,82
Sepsis
The sepsis-associated mortality rate in an in-
tensive care setting remains high. The endotoxin-
related excessive secretion of proinflammatory
mediators is believed to be important in the de-
velopment of whole-body inflammation and septic
shock. Systemic inflammation in sepsis appears to
have a biphasic pattern, which includes a hypoin-
flammatory state associated with immunodefi-
ciency characterized by monocyte deactivation
and immunoparalysis.83 A compromised leuko-
cytic activity and deranged inflammatory response
will have inhibitory effects on wound healing.84
Septicemia can have profound effects on coagu-
lation. Activation of the clotting cascade, via plas-
ma- and endothelial-related inflammatory
changes, can lead to disseminated intravascular
coagulation with a profound decrease in platelets
and loss of a functional, organized clotting system.
Disseminated intravascular coagulation in sepsis,
as in major trauma, is associated with microcircu-
latory thrombosis, with potentially widespread ef-
fects on tissue perfusion in the soft tissues and
major organs leading to multiple-organ failure.85
These factors will compromise hemostasis and,
therefore, healing. The systemic inflammatory re-
sponses in sepsis affect plasma viscosity and eryth-
rocyte rheologic characteristics.86 This may have
important implications in tissue perfusion, partic-
ularly in situations where the capillary blood ve-
locities are reduced. Hypothermia, potentially
made worse by the infusion of cold intravenous
fluid and fresh-frozen plasma (or an equivalent),
will compromise clotting and healing.
Specific Organ Failure
Gut Failure
A critically ill patient may have impaired gut
absorption, either directly as a result of abdominal
catastrophe or gastrointestinal surgery or indi-
rectly as a result of dysfunctional bowel secondary
to severe metabolic anomaly, trauma, or denerva-
tion causing a paralytic ileus. Bacterial transloca-
tion of gut bacteria and toxins to the portal cir-
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 Plastic and Reconstructive Surgery June Supplement 2006
culation can occur, causing sepsis and increased
oxidative stress.
Hepatic Failure
Decreased clotting factors, low plasma pro-
teins, decreased bactericidal activity, and failure of
glucose regulation can all contribute to soft-tissue
wound failure.
Renal Failure
Acute or chronic renal impairment may re-
quire dialysis treatment. Raised levels of uremic
toxins and metabolic acidosis will affect wound
healing by influencing both the innate and adap-
tive immune systems. Hemodialysis and peritoneal
dialysis are associated with increased susceptibility
to infections. Downregulation of circulating neu-
trophils due to their repeated activation triggering
by dialysis membranes has been demonstrated.
Circulating reactive oxygen species are also in-
creased as a result of dialysis membrane activation.
Deficient responses of both B and T lymphocytes
also are associated with renal dialysis.87
Respiratory Failure
Adequate gaseous exchange is essential for all
biological systems, including wound healing. Tis-
sue hypoxia secondary to hypoxemia will have pro-
found effects on healing at all levels.
Nutrition
Septic, surgical, and trauma patients in hyper-
metabolic states associated with the release of en-
dogenous cytokines from activated leukocytes ex-
perience excessive protein loss in an effort to
maintain normoglycemia; these patients require
additional caloric input to counter a negative ni-
trogen balance. Such patients consume body
stores of fat and protein, particularly skeletal mus-
cle, more rapidly than patients with normal me-
tabolism. This, together with depletion of micro-
nutrients and immunonutrients, has implications
in immune system function and healing.88 Ele-
vated steroid levels because of stress are intimately
involved in muscle catabolism. Insulin adminis-
tration may help modulate muscle protein losses
in patients with severe burns.89 Growth hormone
stimulates wound healing, but its effects in critical
illness need further study.90
Glucose is the main fuel for wound repair.
Protein malnutrition and particularly deficiencies
in the amino acids arginine and methionine are
associated with compromised wound healing be-
cause of prolonged inflammation and disruption
of matrix deposition, cellular proliferation, and
angiogenesis.91,92 Malnutrition is associated with
decreased deposition of collagen in skin wounds.93
8e-S
Glutamine has been reported to enhance the ac-
tions of lymphocytes, macrophages, and, in par-
ticular, neutrophils, and may be of particular ben-
efit in severe infection and trauma.90 Glycine has
inhibitory effects on leukocytes and may have an
important role in reducing inflammation-related
tissue injury.9 Micronutrients such as vitamins and
minerals are critically important in immune func-
tion and wound healing. Many trace metals, in-
cluding manganese, magnesium, copper, calcium,
and iron, are cofactors in collagen production,
and deficiencies influence collagen synthesis.91
Zinc influences reepithelialization and collagen
deposition.94 Zinc has also been demonstrated to
greatly influence B and T lymphocyte activity, but
many other nutrients, including copper, sele-
nium, several other metals, and several vitamins,
including A, B, C, and E, have been implicated in
immune dysfunction.95 Vitamin C is the main vi-
tamin associated with poor healing, because of its
influence on collagen modification.91 L-Arginine
is required in a variety of metabolic functions,
wound healing, and endothelial function. It is im-
portant in the synthesis of nitric oxide, and defi-
ciency is linked to immune dysfunction and failure
of wound repair. Maintenance of plasma oncotic
pressure is dependent on adequate production of
plasma proteins and is important in maintaining
body water distribution and preventing soft-tissue
edema. Vitamins and minerals, particularly ascor-
bic acid, zinc, and selenium, are essential for
wound repair. Copper recently has been linked to
the production of vascular endothelial growth
factor.12
Smoking
Clinicians have long suspected that smoking
has a poisonous effect on healing wounds, espe-
cially postsurgical flaps and grafts. In 1977, Mosely
and Finseth96 demonstrated the detrimental effect
of smoking on healing hand wounds. Many studies
have since confirmed that smoking is harmful to
a healing wound. Goldminz and Bennett97 re-
viewed 916 flaps and full-thickness grafts and
found that 1-pack-per-day smokers had three
times the frequency of necrosis as nonsmokers
and that 2-pack-per-day smokers had necrosis six
times more frequently than nonsmokers did.97
The mechanism of these harmful effects is likely
multifactorial. Nicotine is an addictive and vaso-
constrictive substance that decreases proliferation
of erythrocytes, macrophages, and fibroblasts. Hy-
drogen cyanide is inhibitory to oxidative metab-
olism enzymes. Carbon monoxide decreases the
Volume 117, Number 7S Wound Healing
oxygen-carrying capacity of hemoglobin by com-
petitively inhibiting oxygen binding.98 In one
study using human volunteers, subcutaneous par-
tial pressure of oxygen decreased significantly af-
ter 10 minutes of cigarette smoking. The effect
lasted for almost 1 hour.99 Taken together, this
triad has obvious implications for reduction of the
cellular response and efficiency of the healing
process.
Smoking also increases platelet aggregation
and blood viscosity and decreases collagen depo-
sition and prostacyclin formation, all of which neg-
atively affect wound healing.100 Vasoconstriction
associated with smoking is not a transient phe-
nomenon. Smoking a single cigarette may cause
cutaneous vasoconstriction for up to 90 minutes;
hence, a pack-a-day smoker sustains tissue hypoxia
for most of each day.
Smoking also affects the cosmetic appearance
of wounds,101 which has serious ramifications for
the smoker who desires facial cosmetic surgery.
Corticosteroids
Anti-inflammatory steroid medications glo-
bally inhibit cell growth and production.102 They
are also well known to have widespread negative
effects on the wound-healing process. This is seen
clinically and experimentally. A decreased inflam-
matory infiltrate is the most obvious effect of
steroids.103 The macrophage response to chemo-
tactic factors is inhibited. Effective phagocytosis by
polymorphonuclear neutrophils and macro-
phages also is decreased as a result of the stabi-
lizing effect of steroids on lysosomes.104 Because of
the lack of an appropriate initial inflammatory
response, these cells do not produce the typical
growth factor profile.105 This has been shown ex-
perimentally. Glucocorticoids also inhibit epithe-
lial regeneration. The application of hydrocorti-
sone to epidermal cultures decreases cell
proliferation.
Steroids have a direct inhibitory effect on the
fibroblast genome, which has been shown in cell
culture.105,102 Corticosteroid-treated rat fibroblasts
have minimal endoplasmic reticulum, indicating a
low-secretory state.106 Without the appropriate
deposition and maturation of collagen, there is
less wound strength and wound dehiscence is
likely. Vitamin A restores the inflammatory re-
sponse and promotes epithelialization and the
synthesis of collagen and ground substances. Vi-
tamin A does not reverse the detrimental effects of
glucocorticoids on wound contraction and
infection.107 The recommended dose of vitamin A
is 25,000 IU by mouth daily preoperatively108 and
for 3 days postoperatively. Vitamin A supplemen-
tation should not be given to pregnant women.
Ionizing Radiation and Chemotherapy
Ionizing radiation either directly damages the
genome or injures the DNA through the production
of free radicals.104 This effect has short- and long-
term consequences for radiated tissue. In patients
with acute radiation injury, the skin becomes ery-
thematous and edematous. Histologically, dilation
of fine blood vessels, endothelial edema, and lym-
phatic obliteration are seen. As the acute response
abates, thrombosis and fibrinoid necrosis of capil-
laries occur.109 In this setting, although perfusion of
radiation-damaged skin is seen with fluorescein
injection,107 effective tissue oxygenation is inade-
quate. Blood vessel appearance is varied, either
thick-walled, telangiectatic, or thrombosed. The
deposition of dense, hyalinized collagen character-
izes radiated dermis. The endpoint of chronic radi-
ation damage is the nonhealing ulcer. Obvious ne-
crotic tissue is seen, and there is loss of epithelial
coverage.110 Electron microscopy of human radia-
tion ulcers reveals varying degrees of vascular injury
and few myofibroblasts.110
The mechanisms of radiation damage and in-
hibited wound healing are currently being stud-
ied. Experimentally, healing immediately after ir-
radiation is hampered by slowed fibroblast
proliferation, migration, and contraction.111,112
Impairment of the acute inflammatory response
and granulation formation also occurs.109,111 The
production of mRNA coding for collagen is de-
layed up to 2 weeks.109 Clinically, few surgical pro-
cedures are performed on patients with acutely
radiated tissues. The greater concern lies with the
patient who has chronic radiation damage.
Fibroblast cultures from radiation ulcers pro-
liferate at a slower rate compared with cultures of
cells from nearby unirradiated tissue.110,113 Effects
vary between patients. Each person has a differing
sensitivity to radiation injury. Human fibroblasts
cultured from patients with severe radiation reac-
tions have poor survival rates relative to those from
patients who have a less severe injury.100 Thus,
fibroblast defects have emerged as a central prob-
lem in the inhibited healing of chronic radiation
injury.
Cellular mechanisms of phagocytosis and bac-
teriocidal metabolic functions in polymorphonu-
clear neutrophils harvested from tissue with
chronic radiation damage also are impaired. The
effect increases as time passes after therapy, which
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 Plastic and Reconstructive Surgery June Supplement 2006
cannot be a result of a direct effect of radiation on
the neutrophils because their life span is too short.
The local wound environment is the spotlight of
the problem. Irradiated tissue may not prime the
neutrophils with the appropriate cytokines and
growth factors needed for activation,114 which has
a major effect on the incidence of postoperative
infection in previously irradiated patients.
The association between radiation damage
and postoperative complications has been de-
bated. In retrospective studies, patients undergo-
ing surgery after failing primary radiotherapy for
early-stage tumors do not show an increase in se-
verity of complications or length of hospital
stay.115,116 One prospective trial comparing antibi-
otic regimens did not show any increase in wound
infection rate in radiated patients,117 although
other investigators have shown increased rates of
postoperative infections118 and major wound
complications.119 With the advent of more aggres-
sive radiation regimens, concern regarding in-
creased operative complications has surfaced.
Twice-a-day hyperfractionation protocols versus
once-a-day radiation do not seem to increase the
surgical morbidity.120
Chemotherapy now is included in many or-
gan preservation protocols, in an attempt to cure
patients with cancer without disfiguring or func-
tionally devastating surgery. If chemotherapy is
given perioperatively, the resultant bone marrow
suppression inhibits the formation of an adequate
inflammatory response needed for the initiation
of the healing process. Experimental studies show
the inhibition of fibroblast collagen production121
and a decreased ability to fight off wound
infection118 with the application of antineoplastic
agents. These effects appear to be transient, as
opposed to the progressive nature of radiation
damage. The combination of radiation and che-
motherapy increases the risk of serious postoper-
ative complications.122 This risk appears to de-
crease if surgery is delayed for more than 1 year.123
Table 3. Syndromes Associated with Abnormal Wound Healing
Syndrome Brief Description
Cutis laxa Defective elastin fibers; can
be acquired or congenital
Ehlers-Danlos Deficit in collagen metabolism; has autosomal Total failure of the mechanical
dominance and recessive inheritance
Homocystinuria Cystathionine synthetase deficiency
Osteogenesis imperfecta Defective gene for type I collagen
10e-S
Surgery for patients with previous radiotherapy
should be approached cautiously.
SYNDROMES ASSOCIATED WITH
ABNORMAL WOUND HEALING
There are several genetic syndromes that can
adversely affect wound healing. The more com-
mon of the rare syndromes are discussed below
(Table 3).
Cutis Laxa
There are two broad classifications of cutis
laxa: congenital and acquired (Table 4). The con-
genital form can be autosomal dominant, reces-
sive, or X-linked recessive. Acquired cutis laxa can
result from drug ingestions, some solid and he-
matogenous neoplasms, and inflammatory skin
conditions.124
Ehlers-Danlos Syndrome
There are 10 identifiable phenotypes/clinical
subtypes of Ehlers-Danlos syndrome. The differ-
ent types have autosomal dominant and recessive
inheritance. Individuals with the syndrome dem-
onstrate connective tissue abnormalities as a result
of defects in the inherent strength, elasticity, in-
tegrity, and healing properties of the tissues. All of
the subtypes share varying degrees of the four
major clinical features: skin hyperextensibility,
joint hypermobility, tissue fragility, and poor
wound healing. As many as 50 percent of patients
with the syndrome do not have a type or form that
can be classified easily on the clinical basis alone,
which complicates the diagnostic process for the
clinician because specific molecular diagnosis or
confirmation (if available) may not be possible
until a clinical subtype has been defined. Beighton
et al.125 revised the nosology to facilitate an ac-
curate diagnosis of the Ehlers-Danlos syndrome
and allow a clearer distinction of disorders that
Wound Result
Thick, stretchy skin; easy bruising; hernias are
common
properties of the skin; poor wound healing,
leading to wide, thin scars (classically described
as cigarette paper scars); skin tears easily
Advanced arteriosclerosis; associated arterial and
venous thrombosis; platelet malfunction
Wide scars
Volume 117, Number 7S Wound Healing
Table 4. Cutis Laxa*
Classification of Cutis Laxa
Congenital
Autosomal dominant
Autosomal recessive
Type I
Type II (congenital cutis laxa with ligamentous
laxity and delayed development)
Type III (de Barsy syndrome)
X-linked recessive (defect in lysyl oxidase activity)
Acquired
Drug ingestion
Paraneoplastic
Postinflammatory (Sweet syndrome, bowel bypass
syndrome, postinflammatory elastolysis and
cutis laxa, Marshall syndrome)
*Banks, N. D., Redett, R. J., Mofid, M., et al. Cutis laxa: Clinical experience and outcomes. Plast. Reconstr. Surg. 111: 2434, 2003.
overlap with the syndrome. The new classification
scheme includes the following:
Classic type (formerly types I and II)
Hypermobility type (formerly type III)
Vascular type (formerly type IV)
Kyphoscoliosis type (formerly type VI)
Arthrochalasia type (formerly type VIIB)
Dermatosparaxis type (formerly type VIIC)
This new classification scheme does not in-
clude types V, VIII, IX, and X, all of which have
only been described in one family. Most current
literature still refers to Ehlers-Danlos syndrome
patients as types I, II, or III (the most common).
Elective surgery is considered contraindicated in
patients with Ehlers-Danlos syndrome,126 although
some would disagree.127
Homocystinuria
Patients with homocystinuria have wound-
healing problems because of poor wound perfu-
sion secondary to thrombosis. These patients have
defects in methylation and/or transsulfuration en-
zymes that cause the accumulation of homocys-
teine. Homocysteine is formed from ingested me-
thionine. Homocysteine has cytotoxic effects on
vascular endothelium and causes intimal thicken-
Clinical Features
Hyperextensible skin, hernias, benign course
Multisystem involvement
Emphysema, cardiovascular abnormalities, diverticula,
hernias
Retarded growth, skeletal dysplasia, facial
dysmorphism
Mental retardation, corneal clouding, joint
hypermobility, growth retardation, facial
dysmorphism, skeletal dysplasia
Hyperextensible skin
Generalized skin involvement associated with
ingestion of penicillamine, penicillin, isoniazid,
melphalan, and phenacetin
Skin manifestation of paraneoplastic syndromes
associated with solid or hematogenous neoplasias
(chronic neutrophilic leukemia, chronic
myelogenous leukemia)
Hyperextensible skin lesions with inflammatory
infiltrates; Sweet syndrome is a hypersensitivity
reaction to bacterial antigens that leads to a
localized increase in granulocytes. Neutrophils
release elastase and destroys elastic fibers and may
eventually lead to hypoelastosis of skin. If cutis laxa
develops as a consequence of Sweet syndrome, the
condition is called Marshall Syndrome
ing, lipid-laden macrophages, and smooth cell
proliferation. Homocysteine initiates the coagu-
lation pathway by enhancing factor V activity, in-
creasing factor Xa-catalyzed prothrombin activa-
tion, suppressing protein C activation, and
inducing endothelial cell tissue activity. Reduced
antithrombin III activity has been seen in some
patients, but this association has not been
established.128 130 Patients with homocystinuria
are also at very high risk for coronary vascular
disease.131
Osteogenesis Imperfecta
Osteogenesis imperfecta is a heritable disor-
der of connective tissue affecting bone and soft
tissues. The general clinical features of this disor-
der include bone fragility, neonatal dwarfism, de-
formities of the long bones, scoliosis, ligamentous
laxity, blue sclerae, defective dentinogenesis, and
deafness. There are four major forms, but all have
mutations in the genes that encode type I
collagen.132
ADJUNCTS TO WOUND HEALING
Failures of wounds to heal are generally the
result of wound hypoxia, infection, edema, and
metabolic abnormalities. Wounds require a min-
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 Plastic and Reconstructive Surgery June Supplement 2006

Table 5. Bioengineered Skin Replacements*

Composition Structure Living Trade Name
Cultured keratinocytes autografts Epidermal Yes Epicel
Treated cadaver skin allograft Dermal No AlloDerm
Bovine collagen/glycosaminoglycan/Silastic Dermal No Integra
Neonatal fibroblasts/polyglactin mesh allograft Dermal Yes Dermagraft
Neonatal fibroblasts/keratinocytes collagen allografts Composite Yes Apligraf, OrCel
*From Limova, M. New therapeutic options for chronic wounds. Dermatol. Clin. 20: 357, 2002.
OrCel is a product made by Ortec International that is very similar to Apligraf. It was formerly known as Composite Cultured Skin.

imum oxygen tension of 30 mmHg for normal cell
division. Oxygen also increases fibroblast migra-
tion and replication, normal collagen production,
and leukocyte killing.133 Infection keeps the
wound in the inflammatory phase.28 Wound
edema acts as a barrier to oxygen and nutrients by
increasing the distance that they must diffuse
across.133 Metabolic derangements affect wound
healing in a variety of ways, depending on the
abnormality. Time heals all wounds is a well-
known proverb; Bennet and Schultz134 introduced
the acronym TIME to highlight the four key clin-
ical scenarios the clinician should check through
when a patients wound healing stalls: tissue non-
viable or deficient, infection or inflammation,
moisture imbalance, and edge of wound nonad-
vancing or nonmigrating.135 Adjuncts to wound
healing attempt to address and correct these ob-
stacles to wound healing. They include bioengi-
neered skin, electrostimulation, growth factors,
hydrotherapy, hyperbaric oxygen, lasers, light-
emitting diodes, negative pressure therapy, and
ultrasound.
Bioengineered Skin
Living bioengineered skin equivalents are
food on the hoof for the wound, providing a
living supply of growth factors and cytokines and
a collagen matrix to build upon. A summary of the
bioengineered skin replacements and the pro-
healing factors found in living products are shown
Tables 5 and 6.136,137
The mechanism of action is not fully understood
on how these skin equivalents initiates wound heal-
ing, but it has been studied extensively with the Apli-
graf product. The cells contained in the Apligraf
grow and proliferate, producing growth factors, col-
lagens, and extracellular matrix proteins, which
stimulate reepithelialization, formation of granula-
tion tissue, angiogenesis, and neutrophil and mono-
cyte chemotaxis. Extensive clinical experience sug-
gests that Apligraf acts as a potent cellular remedy
that can provide a different and adaptable response
in acute and chronic wounds.137 After Apligraf is
placed in chronic wounds, outgrowth of previously
dormant keratinocytes at the wound edge is ob-
served, suggesting that Apligraf releases factors that
activate keratinocytes and stimulate migration and
reepithelialization.138 140
It is believed that Apligraf stimulates wound
healing in two phases.137 During the initial phase,
the release of growth factors from Apligraf cells
results in healing from the skin edge. Apligraf
covers the wound, provides a barrier, and interacts
with the wound bed to stimulate wound healing.141
In the second phase, there is cellular communi-
cation between the tissue-engineered product and
the cells in the wound and other cells attracted to
the wound site through the release of wound-heal-
ingrelated growth factors and cytokines.
Electrostimulation
Electrical current in skin was first described as
far back as 1860 by DuBois-Reymond. In 1945, it
was observed that wounds had a positive potential
compared with the surrounding skin. In 1982,
Barker described the skin battery. He found that
the skin surface was always negatively charged
(compared with the deeper skin layers), and he
measured transcutaneous voltages up to 40
mV.142,143
Table 6. Pro-Wound Healing Factors Found in Living
Bioengineered Skin Equivalents*
Cytokines and Extracellular
Growth Factors Matrix Molecules
TGF- Collagen, types IV and VII
Amphiregulin Laminin
IL-1, IL-3, IL-6, IL-8 Kalinin
TNF- Fibronectin
Granulocyte-macrophage CSF Thrombospondin
PDGF Glycosaminoglycans
Basic FGF Plasminogen activator
TGF-
Nerve growth factor
CSF, colony-stimulating factor; FGF, fibroblast growth factor.
*From Limova, M. New therapeutic options for chronic wounds.
Dermatol. Clin. 20: 357, 2002; and Jimenez, P. A., and Jimenez, S. E.
Tissue and cellular approaches to wound repair. Am. J. Surg. 187: 56S,
2004.

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Volume 117, Number 7S Wound Healing

Electrostimulation is believed to restart or ac- Growth Factors

celerate the wound-healing process by imitating
the natural electrical current that occurs in skin
when it is injured.142145 This current of injury was
found to vary in specific ways during the regen-
eration process, with current ceasing to flow as
healing is completed or arrested.146 Electrical cur-
rent applied to wounded tissue increases the mi-
gration of cells vital to the wound-healing process
(i.e., neutrophils, macrophages,147149 and
fibroblasts).146,150,151 Investigators have found that
electrostimulation resulted in a 109 percent in-
crease in collagen,150 a 40 percent increase in ten-
sile strength,152 and a 36 percent increase in tensile
strength.153 Electrostimulation may also play a role
in wound healing through improved blood
flow.154,155
These findings have sparked investigators to
use electrostimulation to promote wound heal-
ing in chronic wounds. There are four primary
types of stimulation use: direct current, low-fre-
quency pulsed current, high-voltage pulsed
current, and pulsed electromagnetic fields (Ta-
ble 7).70,126,133,156 171
Current polarity has been found to have some
unique actions on wound healing. These effects
are summarized in Table 8.133
Currently there are four commercially pre-
pared growth factor products available (Table
9).136,172178
Hydrotherapy
Whirlpool treatments are one of the oldest
adjunctive therapies still in use. Whirlpool therapy
supports wound healing by debriding the wound,
warming the injured extremity, and providing
buoyancy and gentle limb resistance for physical
therapy.133 Whirlpool treatments have fallen in
disfavor because of nosocomial contamination
and transmission of virulent infections.179 182
Whirlpool treatments for open wounds require
strict adherence to guidelines to minimize this
risk.180 New forms of hydrotherapy that are replac-
ing the whirlpool are pulsed lavage and the Ver-
saJet (Smith & Nephew, Inc., Largo, Fla.). Pulsed
lavage delivers an irrigating solution under pres-
sure (4 to 15 psi). Haynes et al.183 demonstrated
that the rate of granulation tissue formation was
greater in patients receiving pulse lavage com-
pared with those receiving whirlpool therapy. The
VersaJet Hydrosurgery System is a water jetpow-
ered surgical tool designed to efficiently debride
a wound by removing damaged disuse and con-

Table 7. Electrostimulation Modalities in Clinical Practice

Description Clinical Trials
Direct current
A negative or positive electrode is placed in the wound with Ischemic ulcers,133 venous ulcers,156 nonunion bone
the other one distant to the wound. A current of 0.03 to healing157,158
1 mA is passed across the wound for 1 to 3 hours, until
the wound is healed. As healing plateaus, the polarity is
reversed. This mode is rarely used today, because there
are more efficient forms of electrostimulation.
Low-frequency pulsed current (tetanizing current)
Physical therapists have been using this modality for more Pressure ulcers159161 (especially in spinal cord injury
than 25 years to treat muscular pain as transcutaneous patients)
electrical nerve stimulation. A current of 50 mA, with a
frequency of 2 to 100 Hz, is delivered in pulses of 45 to
500 sec and causes contraction of surrounding muscle,
resulting in increased blood flow.133
High-voltage pulsed current
The negative electrode is placed in the wound and the Pressure ulcers,162165 mixed-chronic ulcers159, 166

positive electrode is placed on the wound edge. A

current of 100 to 150 V (usually 200 V), with short
pulse duration and a low current (1540 mA), is applied.
Once the healing rate plateaus, the polarity is reversed.133
Pulsed electromagnetic field
A pulsed electromagnetic field delivers 27.12 MHz of Nonunion bone healing,70,126,167,168 pressure ulcers,169
energy at a pulse rate of 80 to 600 pulses per second and venous ulcers170,171
a per-pulse power range of 293 to 975 peak Watts. The
therapy is given twice a day for 30 minutes per session
until the wound is healed.133

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 Plastic and Reconstructive Surgery June Supplement 2006

Table 8. Effect of Polarity on Wound Healing

Positive Current Negative Current Both
Promotes epithelial growth Decreases edema around the electrode Stimulates neovasculature
and organization Lyses or liquefies necrotic tissue Has a bacteriostatic effect
Acts as a vasoconstrictor and induces clumping Stimulates growth of granulation tissue Stimulates receptor sites for
Denatures protein Increases blood flow certain growth factors
Aids in preventing postischemic Causes fibroblasts to proliferate
lipid peroxidation and make collagen
Decreases mast cells in Induces epidermal cell migration
Attracts macrophages Attracts neutrophils
Stimulates neurite growth directionally

taminants precisely, without the collateral trauma
associated with traditional surgical modalities
(heat and aggressive sharp debridement).184
Hyperbaric Oxygen
Oxygen therapy has its roots dating back to
1662, with the construction of a pressurized room,
or domicillium, by an English physician named
Henshaw. The room was pressurized by bellows
that raised the air pressure a few pounds per
square inch above ambient pressure. This,
claimed Henshaw, was good for most afflictions of
the lungs and bowels. Junod treated pulmonary
diseases in 1834 by placing patients in a chamber
with 2 to 4 atmospheres of pressure. Dr. Orval
Cunningham constructed the largest hyperbaric
chamber in 1928; it was five stories high, 64 feet in
diameter, and had multiple floors, each holding
12 beds. Cunningham never recorded his thera-
pies, and the American Medical Association con-
demned his treatments in 1942 for a lack of sci-
entific proof.185
Atmospheric pressure at sea level is 1 ATA. At
1 ATA, the oxygen dissolved in blood is 1.5 ml/dl;
at 3 ATA, dissolved oxygen in blood is 6 ml/dl.
Normal subcutaneous tissue oxygen tension is 30
to 50 mmHg. Dividing cells in a wound require an
oxygen tension of at least 30 mmHg. Tissues in
wounds that are not healing have partial pressure
of oxygen values of 5 to 20 mmHg. A dive of 2.4
ATA will result in a wound partial pressure of
oxygen of 800 to 1100 mmHg.133
Many reports in the literature have demon-
strated benefit from hyperbaric oxygen treatment
for a variety of conditions, including amputations,186
osteoradionecrosis,187,188 surgical flaps, and skin
grafts.185,189,190 The success of hyperbaric oxygen
treatment for necrotizing soft-tissue infections has
been controversial. Studies have failed to show sta-
tistically significant outcome differences with respect
to mortality rates and length of hospitalization. Two
studies found that the mean number of debride-
ments was higher in patients treated with hyperbaric
oxygen.191,192 There is, however, a bias for treated
patients to be younger and have positive clostridial
wound cultures and more severe infection.193 In ad-
dition to simply providing more oxygen to the
wound site, hyperbaric oxygen therapy also increases
expression of nitric oxide, which is crucial for wound
healing.194 In an ischemic rabbit ear model, hyper-
baric oxygen therapy in combination with PDGF or
TGF-1 had a synergistic effect that totally reversed
the healing deficits caused by ischemia.13
Lasers
Light amplification by stimulated emission of
radiation (or laser) management of open wounds
has been used for more than 35 years in Europe and
Russia. Only in the past 10 years has laser therapy for
wounds been used in the United States. Lasers for
wound management are low-energy lasers capable of
raising tissue temperature 0.1C to 0.5C.195 Low-
energy laser treatment is called biostimulation.196
Low-energy lasers appear to function according to
the Arndt-Schulz law, which states that less is more.
In other words, weak biostimulation excites physio-
logical activity, moderate favors physiologic effect,
strong impedes physiological processes, and very
strong stimuli arrests physiological stimulation and is
destructive. Low-energy stimulation of tissue results
in increased cellular activity in wounded skin.197,198
The mechanism for enhanced physiologic activity is
not fully understood. It is believed to be caused by
the stimulation of ascorbic acid uptake by cells, stim-
ulation of photoreceptors in the mitochondria re-
spiratory chain, changes in cellular ATP or cyclic
AMP levels, and cell membrane stabilization.199 201
The common types of low-energy lasers are
shown in Table 10. The two most common lasers
used clinically are the helium-neon laser and the
gallium-arsenide (or infrared) lasers.
Lasers have been shown to increase the healing
(especially when combined with hyperbaric oxygen
treatments) of ischemic, hypoxic, and infected

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Table 9. Commercially Available Growth Factor Products

Growth Factor
Name Type Indication Comments
Procuren PDGF Diabetic foot The first product to be commercially available.
(Curative Health ulcers Patients blood is used to collect platelets. Because
Services) blood is used, other growth factors may be part
of the preparation.
Regranex PDGF-BB Diabetic foot The first recombinant human growth factor to be
(Ortho-McNeil fraction ulcers used in clinical practice
Pharmaceutical) Shown to substantially increase wound healing in
diabetic foot ulcers when compared with
standard care alone. However, the treatment
needs to be carried out with aggressive standard
wound care, including debridement of necrotic
or hyperkeratotic tissue and off-loading of the
area of the ulceration.172
It appears that Regranex can be useful in a variety
of other types of wounds, such as pressure
ulcers, and currently trials for venous
insufficiency ulcers are underway.173
There have also been select instances of case
reports utilizing Regranex in other chronic and
acute wounds, such as pyoderma
gangrenosum,174 ulcers of vasculitis, and acute
surgical defects.136
Leukine GM-CSF Treatment for Macrophages and inflammation play an important
(Immunex Corp.) patients with role in the first phase of wound healing; this
AML and bone material has been tried in some chronic wounds
marrow rescue as an injectable material around the area of the
ulcers and topically as an aqueous solution.175,176
Results have been promising, but it is not
currently approved for use in chronic wounds.
Repifermin KGF-2 Treatment for Shown to significantly increase healing and
(Human Genome cancer epithelialization over the wound bed177
Sciences) therapy-induced The initial trial in venous ulcers178 has shown very
mucositis, promising results, and it is currently in phase 2
venous ulcers, clinical development.
skin grafts

wounds.202 Lasers affect wound healing at many dif-
ferent levels. The helium-neon laser light at 633 nm
was optimal for wound healing195 using 1 mW ex-
posures and greater to provide 4 J/cm2 energy den-
sity. Later studies of in vitro skin fibroblast stimula-
tion demonstrated that consecutive exposures to 660
nm and 780 nm of laser light at 24-hour intervals
increased collagen production fourfold compared
with untreated cultures.203205 Beauvoit et al.197,198
demonstrated that mitochondria provide 50 percent
of the tissue absorption coefficient and 100 percent
of the light scattering at 780 nm because of cyto-
chrome aa3, cytochrome oxidase, and other mito-
chondrial chromophores. Fibroblasts irradiated at
660 nm with 2.16 J/cm2 increased fibroblast growth
factor synthesis and fibroblast proliferation.205 Con-
current DNA synthesis measurements confirmed
this.206,207 Karu208 demonstrated increased DNA syn-
thesis by irradiation at 680 nm, increased protein
synthesis at 750 nm, and increased cell proliferation
at 890 nm, which was 10 times more effective than
other near-infrared wavelengths, requiring only 1
J/cm2. Laser stimulation of collagen synthesis, mea-
sured by incorporation of radioactive amino acids,
was demonstrated at 693 nm, with similar results.
Growth factor production and collagen synthesis may
be improved at wavelengths of 660 to 680 nm, and
stimulation of new small blood vessel growth was pro-
duced at a wavelength of 880 nm.209 Studies in human
wounds have shown that low-energy lasers promote
greater amounts of epithelialization for wound
closure210 and better tissue healing.206 208,211214
Laser biostimulation has a variety of effects at
different wavelengths, and it would appear that
optimal treatment of a wound would require sev-
eral applications at different wavelengths.
Light-Emitting Diodes
The National Aeronautics and Space Admin-
istration has developed a light-emitting diode that

15e-S
 Plastic and Reconstructive Surgery June Supplement 2006
can be made to produce multiple wavelengths and
be arranged in large, flat arrays to treat large
wounds. The treatment area for a laser is limited-
large areas must be treated in a grid-like pattern.
The agency developed the light-emitting diode in
response to their research on wound healing in a
weightless environment. Studies on cells exposed
to microgravity and hypergravity indicate that hu-
man cells need gravity to stimulate growth. As the
gravitational force increases or decreases, the cell
function responds in a linear fashion. This poses
significant health risks for astronauts in long-term
space flight.201,209 Work done on shuttle missions
and on the space station has shown significant
improvements of wound healing using light-emit-
ting diodes alone or in combination with hyper-
baric oxygen treatment. Light-emitting diode
therapy is done at wavelengths of 680, 730, and 880
nm simultaneously.209 The array was tested by the
U.S. Special Operations Command on submari-
ners. Reports indicated a 50 percent faster healing
of lacerations in crew members treated with a
light-emitting diode array with three wavelengths
combined in a single unit (670, 720, and 880 nm)
compared those who underwent untreated con-
trol healing (7 days compared with approximately
14 days). This is significant because wound healing
is slow aboard submarines due to the higher car-
bon dioxide and lower oxygen levels.201 Light-
emitting diode therapy is also being investigated as
therapy for neural cancers,215,216 leukemia, lym-
phomas, and Barretts esophagus.201
Negative Pressure Therapy
Negative pressure therapy (or vacuum-assisted
closure), developed at the Bowman Gray School of
Medicine, uses a subatmospheric pressure dress-
ing to convert an open wound into a controlled
closed wound.52,217,218 The negative pressure exerts
many effects on both gross and microscopic levels.
The negative pressure removes interstitial fluid
and edema to improve tissue oxygenation. It also
removes inflammatory mediators that suppress
the normal progression of wound healing.43,218
Granulation tissue forms more rapidly (103.4
35.5 percent) than in controls, and 5 days of ther-
apy decreases the wound bacterial count to less
than 105 organisms per gram of tissue.52 The neg-
ative pressure dressing is convenient to use; it re-
quires changing every 48 to 72 hours and has few
complications. The dressing is used in a variety of
wound types, involving soft-tissue loss, exposed
bone and hardware, and weeping wounds, and as
a skin graft bolster. Negative pressure therapy is
16e-S
contraindicated when (1) wounds contain ne-
crotic tissue, (2) osteomyelitis is untreated, (3)
body cavity or organ fistulas are present, (4) ma-
lignancy is present in the wound, or (5) treatment
would place the foam dressing directly over ex-
posed arteries and veins. Negative pressure ther-
apy should be used cautiously when there is active
bleeding in the wound, when hemostasis is diffi-
cult after debridement, and when anticoagulant
therapy is used.162 The vacuum dressing is a great
temporizer and gives the patient and surgeon time
to transform a hostile wound into a manageable
one.
Ultrasound
The therapeutic effects of ultrasound therapy
are from its thermal and nonthermal properties.
Ultrasound results when electrical energy is con-
verted to sound waves at frequencies greater than
20,000 Hz. Sound waves are transmitted to the
tissue through a hydrated medium sandwiched
between the tissue and the transducer. The depth
of penetration depends on the frequency; the
lower the frequency, the deeper the penetration.
Ultrasound therapy has traditionally been used to
relieve muscular spasm for musculoskeletal pain,
but the thermal component (a setting of 1 to 1.5
W/cm2) of ultrasound has also been used to im-
prove scar outcome. The nonthermal component
of ultrasound (at a setting of 0.3 to 1 W/cm2)
produces two effects: cavitation and streaming.133
Cavitation is defined as the formation of gas bub-
bles, and streaming is a unidirectional, steady me-
chanical force. These effects cause changes in the
cell membrane permeability and enhance diffu-
sion of cellular metabolites.37
Ultrasounds effect on wound healing in the lab-
oratory include cellular recruitment, collagen syn-
thesis, increased collagen tensile strength, angiogen-
esis, wound contraction, fibroblast and macrophage
stimulation, fibrinolysis, reduction of the inflamma-
tory healing phase, and promotion of the prolifer-
Table 10. Common Low-Energy Lasers
Laser System Wavelength (nm)
Argon (Ar) 488514
Carbon dioxide (CO2) 10,600
Dye Variable
Gallium-arsenide (GaAs)
or infrared (IR) 904
Gallium-aluminum-arsenide (GaAlAs) 830
Helium-neon (HeNe) 632.8
Neodymium:yttrium-aluminium-garnet
(Nd:YAG) 1064
Ruby 694
Volume 117, Number 7S Wound Healing

ative healing phase.133,219,220 Clinically, the results are

not as comparable. Ultrasound is used most often to
treat venous stasis ulcers and pressure sores.
Some217,221 have shown a demonstrable reduction in
wound size compared with placebo. Mirastschijski et
al.222 were unable to show any improvement in
wound healing with ultrasound versus placebo. Ul-
trasound treatment of pressure ulcers showed a sim-
ilar division; some showed improvement223 and
others224,225 did not.

KELOIDS AND HYPERTROPHIC SCARS

Hypertrophic scars are raised scars that re-
main confined to the limits of the incision (Fig. 2).
Keloids are scars that have overgrown their bound-
aries (Fig. 3).

Differences between Keloids and Hypertrophic

Scars
Histologic Differences
Light microscopy reveals large collagen bun-
dles in keloidal scars but not in hypertrophic
scars.226,227 Keloidal scars may have few macro-
phages, but they have abundant eosinophils, mast
cells, plasma cells, and lymphocytes226 and are as-
sociated with a mucopolysaccharide ground sub- Fig. 3. Ear keloid.
stance; hypertrophic scars have only scant
amounts.226 No morphologic differences in keloi-
dal and hypertrophic scar fibroblasts have been Hendrix229 found that collagen bundles were
found, but their biological behavior is different. crisp in hypertrophic scars and more glazed in
Hypertrophic scars have nodules containing cells keloidal scars. In addition, differences were found
and collagen within the middle to deep part of the in the degree of microvascular injury seen in the
scar.228 Within these nodules are -smooth muscle keloidal scars.
actinstaining myofibroblasts, which are absent Differences in Metabolic Activity
from normal dermis, normal scars, and 88 percent Ueda et al.230 found that keloidal scars had
of keloidal scars. higher levels of adenosine triphosphate and fibro-
blasts up to 10 years after formation, compared
Differences Observed with Electron
with hypertrophic scars. Nakaoka et al.231 found a
Microscopy
higher density of fibroblasts in both keloidal scars
Ehrlich et al.228 found an amorphous sub-
and hypertrophic scars, but keloidal scars had a
stance around keloidal fibroblasts that separated
higher expression of proliferating cell nuclear an-
them from the collagen bundles. This substance
tigen, which the authors believed may help ex-
was not seen in hypertrophic scars. Kischer and
plain the tendency of keloidal scars to grow be-
yond the boundary of the original wound.
Other Differences
Antinuclear antibodies against fibroblasts and
epithelial and endothelial cells have been found
in patients with keloidal scars but not in those with
hypertrophic scars.232

Epidemiology
Keloids tend to occur during periods of phys-
ical growth and most often form between the ages
Fig. 2. Hypertrophic scar. of 10 and 30 years.233 A keloid rarely forms in an

17e-S
 Plastic and Reconstructive Surgery June Supplement 2006
elderly person. Keloids occur in persons of all
races; darkly pigmented skin is affected 15 times
more often than is lighter skin.216,234 No reports
exist of the occurrence of a keloid in an albino
person. In a rural African population, the inci-
dence was noted to be approximately equal in
males and females (5.4 and 6.2 percent,
respectively).235 The teenage population has a
higher incidence, with keloids occurring in 12.2
percent of boys and 14.4 percent of girls.235 Al-
though the three most common causes in Olu-
wasanmis field survey235 were unspecified trauma,
vaccinations, and tattoos, the most common pre-
disposing factor in a hospital review was earlobe
piercing. In a predominantly black and Hispanic
population, Cosman and Wolff236 noted the inci-
dence of keloid formation to be between 4.5 and
16 percent in a review of three large series. Data
regarding the incidence of recurrence based on
ethnicity or degree of skin pigmentation are
nonexistent.237
Pathogenesis
The etiology of keloid formation is not entirely
clear. Porter et al.237 compiled a list of possible
causes derived from numerous treatment strate-
gies that appear to have some benefit in the treat-
ment and management of keloids.
Trauma
Trauma seems to be the most common ante-
cedent factor to developing a keloid.216 Random
(e.g., laceration, burn, vaccination, bug bite) and
planned (e.g., surgery, tattoos, ear piercing) trau-
matic events were reported to cause the formation of
a keloid. Keloids may develop within 1 year of the
traumatic event, but occasionally they can form
many years later. After a traumatic injury, a keloid
forms because fibroblasts haphazardly lay down col-
lagen. Keloids can be seen on all parts of the body,
but the sternum and supradeltoid regions are the
most often affected. Keloids of the ears, penis, fe-
male genitalia, corneum, intraoral region, and plan-
tar region have also been reported.238
Abnormal Fibroblast Activity
Fibroblasts from hypertrophic scars and keloi-
dal scars have different properties. Hypertrophic
scar fibroblasts have a moderate increase in their
basal level of collagen production, but they still
respond normally to growth factors.239 In contrast,
fibroblasts from keloidal scars produce high levels
of collagen,240 elastin,241 fibronectin,229,242 and
proteoglycan243 and show abnormal responses to
stimulation.244 Collagen type I is predominantly
produced by keloidal fibroblasts.245 These fibro-
18e-S
blasts have been show to have a greater capacity to
proliferate.246
Increased Levels of Growth Factor and
Other Cytokines
TGF- has three subtypes: 1, 2, and 3.247 Levels
of types 1 and 2, which stimulate fibroblasts, are
increased in keloidal scars, whereas levels of type
3 TGF- are not increased. TGF- type 1 has been
associated with increased collagen239,248 and fi-
bronectin synthesis242 by fibroblasts. IFN- and
IFN- have been shown to reduce both collagen
synthesis from fibroblasts and fibroblast prolifer-
ation.
Decreased Apoptosis
Programmed cell death, or apoptosis, is be-
lieved to play a role in wound healing and possibly
keloidal scar formation.249 Lower rates of apopto-
sis have been observed in keloidal fibroblasts.250 It
has been suggested that keloidal fibroblasts resist
physiological cell death, continuing to proliferate
and produce collagen.251
Increased Levels of Plasminogen Activator
Inhibitor-1
Fibrin plays an important part in wound heal-
ing, leading to migration of inflammatory cells,
formation of granulation tissue, and collagen syn-
thesis. Regulation of fibrin is important in wound
healing; it is degraded by plasmin, which in turn
is regulated by a number of activators (urokinase
and plasminogen activator) and inhibitors (tissue
plasminogen activator inhibitor 1). Keloidal fibro-
blasts have increased levels of plasminogen acti-
vator inhibitor-1 and low levels of urokinase.252
This may lead to reduced collagen removal and
contribute to scar formation.252
Abnormal Immune Reactions
Theories that keloidal scars are generated by
specific immune reactions led researchers to ex-
amine the levels of immunoglobulins within ke-
loidal scars. The overall results are conflicting. It
has been suggested that antigenic substances may
be present in keloidal scars.
Hypoxia as an Etiologic Factor
Tissue hypoxia has been implicated in keloidal
scar formation. Histologic examination shows oc-
cluded microvessels with plump endothelial cells
lining the vessel wall.253 The mechanism by which
hypoxia may lead to keloidal scar formation is
unclear. Vascular endothelial growth factor
(VEGF) has been shown to be released from fi-
broblasts in response to hypoxia. Gira et al.254
found that VEGF production was abundant in ke-
loids and that the source of the VEGF was the
overlying epidermis. Steinbrech et al.,255 however,
Volume 117, Number 7S Wound Healing
found no difference in VEGF levels between ke-
loidal fibroblasts and normal dermal fibroblasts.
Other Theories Regarding Etiology
There is a theory that keloidal scars are caused
by an immune reaction to sebum.256 This theory is
supported by the following observations: keloidal
scars are more common in adolescence; they
rarely occur on the palms and soles; spontaneous
keloidal scars occur in skin areas with sebaceous
activity; and one scar may be keloidal, whereas an
adjacent scar may be normal. Researchers positing
this theory suggest that the development of keloi-
dal scars is dependent on random damage to pi-
losebaceous structures.257
Keloids can be considered a mesenchymal
neoplasm. Keloid fibroblasts have been shown to
contain the oncogene gli-1 and express the pro-
tein Gli-1.258 Immunohistochemistry staining for
gli-1 showed a strong presence in the cytoplasm,
similar to basal cell carcinoma, which also ex-
presses the gli-1 oncogene. This oncogene is not
expressed in fibroblasts from normal tissue and
nonhypertrophic scars. Rapamycin (sirolimus)
and tacrolimus (FK506) have been shown to be
beneficial for keloid regression, and both drugs
bind the cellular receptor (FKBP12), which is a
cis-trans- prolyl isomerase-the same target of the
Gli-1 protein. Table 11 summarizes the biochem-
ical alterations seen in keloids and hypertrophic
scars.
Clinical Presentation
Hypertrophic scars may regress with time and
occur earlier after injury (usually within 4 weeks).
Most keloids form within 1 year of wounding, but
some may begin to grow years after the initial injury.
Table 11. Biochemical Alternations Seen in Excessive Scar Formation*
Biochemical Alternation
Prolyl hydroxylase
Total collagen
Collagen type I
Plasminogen activator inhibitor-1
Chondroitin-4-sulfate
Glycosaminoglycans
Fibronectin
Elastin
Hyaluronic acid
Apoptosis
TGF-
VEGF
gli-1 oncogene
*Adapted in part from Aston, S. J., Beasley, R. W., and Thorne, C. H. M. (Eds.), Grabb and Smiths Plastic Surgery, 5th Ed. Philadelphia:
Lippincott-Raven, 1997. Chap. 1.
Surgical incision, trauma, burns, inflammation, in-
fection, and puncture wounds are the most common
inciting events.216 Symptoms associated with keloid
formation include pain, pruritus, hyperpigmenta-
tion, disfigurement, and decreased self-esteem
(which appears most commonly in the teenage pop-
ulation). Pruritus is experienced transiently in nor-
mal healing wounds, but persistent pruritus is asso-
ciated with keloid formation.259 Lesions can be
located in various places but predominate on the
head, neck, and earlobe in those patients who
present for treatment.235 Areas of the head and neck
that are spared include the eyelids and the mucous
membranes.259
Treatment Options
The availability of so many treatment options
speaks to the fact that none of them has proved to
be completely effective. The primary problem with
treatment of keloidal scars is the high rate of re-
currence. Keloid recurrence rates range from 0 to
100 percent. The literature is replete with retro-
spective, uncontrolled studies with small sample
sizes. The few randomized prospective studies that
do exist also have small sample sizes, so statistical
significance may be lacking. Beyond the basic
problems of study design, these studies are not
uniform with regard to outcome measures and
duration of follow-up. To add further confusion,
there is little standardization of analysis that takes
into account previous treatments that subjects
have had before the current studys new and im-
proved keloid treatment strategy. Finally, many
studies include both hypertrophic scars and ke-
loids in the subject population. A summary of the
most common treatment strategies is provided be-
low.
Observation
Activity: keloid hypertrophic scar normal
Synthesis: keloid hypertrophic scar normal
Cross-linking: normal keloid
Content: keloid normal
Levels: keloid normal
Content: keloid hypertrophic scar normal
Content: hypertrophic scar normal
Synthesis: keloid normal
Receptor expression: keloid normal
Synthesis: keloid normal
Degradation: normal hypertrophic scar
Normal keloid
Types 1 and 2: keloid normal
Type 3: keloid normal
Content: keloid (keratinocytes) normal
Present in keloid, absent in normal
19e-S
 Plastic and Reconstructive Surgery June Supplement 2006
Excision Alone
Excision alone has not been successful in elim-
inating keloids. Recurrence rates range from 45 to
93 percent.234,260 Excision is the most obvious treat-
ment, but it has met with little success when it is
performed alone. Apfelberg et al.261 proposed us-
ing the keloid epidermis as an autograft for wound
closure after keloid excision. Using the keloidal
skin avoids donor-site morbidity, decreases the
amount of tension on the closure, and lessens the
cosmetic deformity. Only five patients were re-
ported in his series, which had a 40 percent re-
currence rate. Weimar and Ceilley262 incorporated
the autograft technique for use with adjunctive
measures, pressure therapy, and steroid injec-
tions, but results were not provided. Adams126 de-
scribed a suprakeloid flap with postoperative ra-
diation therapy for the successful treatment of an
earlobe keloid.
Core excision of a dumbbell keloid located on
the earlobe with anterior and posterior compo-
nents has excellent cure rates when it is used along
with steroids. Core excision results in a full-thick-
ness defect; the anterior wound is closed primarily
and the posterior wound is allowed to granulate
close. Six patients were treated successfully in this
manner without recurrence at more than 1 year.263
Excision alone is not recommended as defin-
itive therapy. Adjuvant therapy has become the
standard of care to improve outcomes.
Laser Excision
Different forms of laser therapy for keloids
have been evaluated over the years. Lasers, which
cause a range of nonspecific to specific thermal
tissue reactions, are believed to wound in such a
way so as to minimize scar contraction compared
with scalpel wounds. Both carbon dioxide and
argon lasers showed early promise in excision,
creating a dry and bloodless surgical environment
with limited damage in surrounding tissue. These
lasers are not frequently used at present, however,
because long-term studies revealed recurrence
rates of up to 92 percent when they were used as
a single modality.233,234,264 266
The most promising form of laser therapy
seems to be the 585-nm flashlamp-pumped
pulsed-dye laser, which has been effective in re-
ducing pruritus, erythema, and the height of ke-
loids, with improvement in 57 to 83 percent of
cases.264 268
Laser excision yields the best results when
combined with adjunctive therapy. It is unclear if
there is truly any variation in results of laser versus
20e-S
scalpel excision performed in isolation. Prospec-
tive, randomized, controlled trials would benefit
the understanding of whether lasers provide more
benefit than scalpel excision.
Steroids
Intralesional steroids often are used for initial
treatment of the keloid. More commonly, they are
the adjunctive treatment of choice periopera-
tively, because they are readily available and easily
used. Steroids suppress the inflammatory phase of
wound healing, decrease collagen production by
the fibroblast, and decrease fibroblast prolifera-
tion. Triamcinolone acetonide seems to be the
steroid of choice. Studies vary significantly regard-
ing the strength of the steroid preparation used
and at what point in the treatment regimen it is
administered. Of the range of dose strengths, 40
mg/ml is the most common strength used to treat
keloids. With regard to timing of administration,
it is occasionally used preoperatively at one or
several sessions269,270; this is followed by excision
and further postoperative treatment. Alterna-
tively, some physicians use it preoperatively, intra-
operatively, postoperatively, or in some combina-
tion of the three. No one regimen proved to be
more beneficial. Adverse reactions with the use of
intralesional steroids include localized problems,
such as depigmentation, hypopigmentation, epi-
dermal atrophy, telangiectasias, and skin necrosis.
Occasionally, these changes may be only tempo-
rary. Systemic side effects and Cushings syndrome
are rare and are associated with improper steroid
use.
One of the first studies to report results of tri-
amcinolone acetonide injection found that 88 per-
cent of keloids (n 22) injected with steroids re-
gressed to varying degrees and that pruritus
disappeared within 3 to 5 days of injections.271 The
best responses were noted when the injection was
performed at times of excision and with follow-up
visits. High doses, up to 120 mg, were injected. Com-
plications included atrophy, depigmentation, and
recurrence. Currently, most practitioners do not ad-
minister such high doses. Monthly doses of approx-
imately 12 mg are recommended.270 This modality
continues to be a mainstay of treatment. Perioper-
ative steroids generally are considered the standard
of care, because most controlled studies use this as
the control arm.233,270
Radiation Therapy
Radiation therapy has been used to treat ke-
loids since 1906234 and has been successful in erad-
Volume 117, Number 7S Wound Healing
icating this benign lesion. When used alone, it was
noted to have a wide range of cure rates, from 15
to 94 percent.260 When the lesions are first excised
and subsequently radiated, however, the response
rates increase to 33 to 100 percent.260 The results
of studies performed in the recent past (1974 to
1990) have shown that the response rates are even
better, from 64 to 98 percent.260 Success seems to
depend on the number of rads delivered to the
surgical site and institution of the radiation treat-
ment in the immediate postoperative period.
In a retrospective study of 24 patients treated
with postexcisional superficial radiation therapy,
patients had a dosage of 800 to 1200 rads divided
into one to three doses delivered to the bed of the
wound.272 A recurrence rate of 53 percent was
reported, one of the highest in the literature for
this modality.
Controversy abounds regarding the safety of
delivering radiation to a benign tumor.273 There
are anecdotal reports regarding the development
of malignancy after treatment of a keloid with
radiation.273 Patients treated with radiation for
acne in the past have an increased incidence of
skin cancer, which may develop up to 30 to 40
years after the radiation exposure. Currently, ra-
diation is no longer used to treat acne. Although
adequate data are lacking, it is estimated that the
risk of developing skin cancer from radiation ex-
posures of less than 1000 Gy is low.237 Although the
dose administered for the treatment of keloids is
low, long-term follow-up is needed to determine
the actual risk for development of malignancy;
however, this modality seems to be a highly effec-
tive adjunctive measure for eradicating the keloid.
Pressure Therapy
Pressure therapy is effective in the treatment
of hypertrophic scars and keloids, especially after
burn injury. This therapeutic strategy is used in
combination with other treatment modalities
(e.g., silicone gels or sheets to enhance the pres-
sure treatment). Maximum benefit is achieved by
wearing the pressure appliance for 18 to 24 hours
per day for at least 4 to 6 months.233,274,275 Good
response rates were seen in 90 to 100 percent of
patients treated with keloid excision followed by
pressure therapy, especially when the keloid was
located on the earlobe.233,274,275 The amount of
pressure delivered should be between 24 and 30
mmHg, to avoid decreased peripheral blood cir-
culation. Pressure earrings have been developed
for postoperative use on keloids involving the ear-
lobe. Intralesional verapamil combined with 6
months of pressure therapy used after keloid ex-
cision resulted in a 55 percent cure rate.276
Magnetic Disks
Chang et al.35 treated 47 patients (91 auricles)
with hypertrophic scarring of the earlobe (ke-
loids) with compressive therapy using magnetic
disks after surgical excision. With a mean fol-
low-up of 18.1 months, they had only one recur-
rence 13 months after surgery. This was treated
with additional disk compression for 3 months.
Thirty-one of the 47 patients complained of pain
with the disk therapy. The pain was treated by
reducing the compression intensity, by attaching
a silicone gel sheet to the magnetic disk, or by
reducing the amount of time patients had to wear
the disk. The authors offer no explanation for why
the magnetic disks work, except that they are a
form of compression therapy.
Cryosurgery
Serial cryotherapy treatments using spray or
contact methods have traditionally been useful for
managing hypertrophic scars and keloids.
Zouboulis et al.277 introduced an intralesional nee-
dle cryosurgery device for both hypertrophic scars
and keloids The authors advocate this method as
more effective for treating deeper parts of scars
and keloids than spray or contact methods, re-
quiring fewer treatments. Twelve lesions were fro-
zen with a cryoneedle inserted along the long axis
of the lesion; the needle was connected to a liquid
nitrogen source. They found an average 51 per-
cent reduction in lesion volume, with significantly
improved subjective (pain, itching) and objective
(hardness, color) ratings. Pretreatment and post-
treatment histologic analysis demonstrated im-
proved scar organization after needle cryosurgery.
Interferon
Interferons interfere with fibroblasts ability to
synthesize collagen. Specifically, IFN--2b normal-
izes the collagen and glycosaminoglycan of the
keloid.233 Complications with IFN--2b injection
include flu-like symptoms, headache, fever, and
myalgias. These symptoms may be tolerable with
the prophylactic administration of acetamino-
phen. In a retrospective study, Berman and
Flores307 found that the recurrence rate with pos-
texcisional use of IFN--2b (18.7 percent) was su-
perior to that for excision alone (51.1 percent)
and for postexcisional steroid (triamcinolone) in-
jections (58.4 percent). IFN--2b was injected into
the wound at a dosage of 1 million U in 0.1 ml per
21e-S
 Plastic and Reconstructive Surgery June Supplement 2006

linear centimeter per treatment. Twelve of the 16 study, a recurrence rate lower than those previ-
patients treated with IFN were reinjected 1 week ously reported in the literature for surgery alone.
later with 5 million U. Follow-up was only 7 months
on average, but the differences were statistically Silicone Gel Sheets
significant. Conejo-Mir et al.278 achieved a 3-year 0
The mechanism of action of silicone gel sheet-
percent recurrence rate with the combination of
ing, also known as hydrocolloid dressing, is not
carbon dioxide laser excision and IFN--2b injec-
fully known. Scar hydration is facilitated by the
tions for earlobe keloids. IFN--2b seems to be
presence of this occlusive dressing. Hydrocolloid
effective in decreasing the keloid recurrence rate.
dressings have been deemed safe for treating
In a recent, smaller prospective study,37 of 13 ke-
wounds in the initial stages of healing.283 Silicone
loids treated with postoperative intralesional IFN-
gel probably acts as an impermeable membrane
-2b, seven recurred (54 percent). In contrast, 26
that keeps the skin hydrated.37 In vitro experi-
keloids treated with triamcinolone (control
ments have shown that silicone is inert and does
group) had a 15 percent recurrence rate.
not affect fibroblast function or survival; however,
IFN- is believed to work in manner similar to
enhanced keratinocyte hydration alters growth
IFN--2b. There have been several anecdotal re-
factor secretion, which in turn affects fibroblast
ports regarding the benefits of IFN- in treating
function and collagen production.284 The clinical
keloids. More recently, a pilot study examined the
effects of silicone gel do not appear to be medi-
treatment of keloids with this modality.279 In a
ated by changes in pressure, temperature, or tissue
placebo-controlled, randomized, double-blind
oxygenation.37 In an animal study, no detrimental
study, patients with two keloids had one keloid
effect was found when silicone gel sheets were
randomized to excision and postoperative pla-
compared with Nu-Gauze dressings in the imme-
cebo injections and the other to IFN- injections.
diate postoperative period. Histologic examina-
In the experimental group, patients were given a
tion of the wounds revealed no evidence of sili-
series of 10 injections of 10 g of IFN-. Only seven
cone leakage into the tissues. Prevention or
patients were enrolled in the study, three of whom
improvement of keloids was not addressed in the
dropped out at the 1-year follow-up examination.
study. In human trials, topical silicone gel was used
Experimental and control groups had uniformly
to treat 22 keloids in 18 patients, with an 86 per-
poor results, with an approximate 75 percent re-
cent significant objective response rate.285 Silicone
currence rate. Because of the small sample size,
gel sheets may reduce recurrence rates after ex-
conclusions could not be drawn.
cision. It is a benign intervention that does not
Imiquimod is a relatively new agent, an im-
increase the rate of recurrence, and it may be
mune response modifier that indirectly acts to
useful as an adjunctive measure.
stimulate innate and cell-mediated immune path-
A brief summary of keloid treatments is shown
ways, thereby enhancing the bodys natural ability
in the Table 12.286 299 The reader should be aware
to heal.280 Along with inducing and activating nat-
that most of the studies include a mixture of pa-
ural killer cells, macrophages, and Langerhans
tients with keloidal scars and hypertrophic scars,
cells, imiquimod also induces the local synthesis
and they are rarely discussed separately.
and release of cytokines, including IFN-, IFN- ,
TNF-, and IL-1, IL-6, IL-8, and IL-12, when top-
ically applied.281 A variety of case reports and clin- Practical Guidance
ical studies have documented recent successes as- Prevention is the best keloid therapy.
sociated with the use of imiquimod and its Proposals259 for prevention include avoiding
antiviral, antitumor, and immunoregulatory prop- nonessential cosmetic surgery in keloid-forming
erties, especially in conditions in which interfer- patients, closing wounds with minimal tension,
ons have also been used successfully in treatment. using cuticular, monofilament, synthetic perma-
Berman and Kaufman282 examined the effects of nent sutures in an effort to decrease tissue re-
topical application of imiquimod 5% cream after action, avoiding Z-plasties or any wound-length-
surgical excision of 13 keloids from 12 patients. ening techniques, and avoiding, as often as
Imiquimod 5% cream was applied nightly directly possible, making incisions that cross joints and
to the suture line and to the surrounding area follow skin creases.259
beginning on the day of the surgery and continu- Despite a broad range of therapeutic possibil-
ing for a total of 8 weeks. At 24 weeks, no recur- ities, there is no universally effective treatment for
rence of keloidal growth was noted among the 11 keloids. A few treatment options, such as cortico-
keloids of the 10 patients who completed the steroid injections and perhaps compression, are

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Volume 117, Number 7S Wound Healing

Table 12. Comparison of Treatment Modalities and Results*

Treatment No. of Patients Results

5-FU steroids (intralesional)286
5-FU286
Bleomycin287
Cryosurgery steroid
(intralesional)288
Cryotherapy289
IFN- (monotherapy)307
IFN-2-2b (monotherapy)291
IFN-2-2b surgery308
IFN-2-2b surgery278
Imiquimod282
Laser265 (77 with Argon, 5
with CO2)
Pulsed dye laser267
Pulsed dye laser292
Radiation (postsurgical)293
Radiation (postsurgical)272
Radiation (postsurgical)294
Silicone295
Silicone296
Steroids (intralesional) after
excision309
Steroids (intralesional)286
Surgery silicone verpamil298
Surgery silicone298
Verapamil (intralesional)
excision238
5-FU, 5-fluorouracil; HS, hypertrophic scar; KS, keloidal scar; PDL, pulsed dye laser.
*Nearly all of the above studies contain a mixture of hypertrophic and keloid scars. When differences were noted by the author, those differences
were included in the table. Otherwise, both types of scar were treated equally.
10 All subjects showed significant flattening compared with control for all treatment arms.
The most flattening was observed in the steroid treatment group, followed by steroid
5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.
10 All subjects showed significant flattening compared with control for all treatment arms.
The most flattening was observed in the steroid treatment group, followed by steroid
5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.
13 Compete flattening, 42.8%
58 Complete regression, 70.6%; improvement, 13.7%; recurrence, 15.5%
93 (38 HS, 55 KS) 61.3% had excellent or good results, 29% had poor response, 9.7% had no response
10 All 10 scars flattened, five out of 10 flattened greater than 50% of original height
22 Only three out of 22 patients (14%) showed a reduction in size; nine patients withdrew
from study (seven because of pain)
124 Recurrence was 18% after surgery and postoperative IFN treatment compared with 51%
of patients treated with surgery triamcinolone
30 33% recurrence rate after IFN laser excision; 19% recurrence rate after IFN surgery
13 keloids in 12 5% cream was applied to surgical scar after keloid was excised. At 24 weeks, there was no
patients recurrence in 11 keloids of the 10 patients who completed the study.
82 55% excellent or good improvement (softening, flattening, lack of
progression/recurrence), 11% poor
16 Effective in reducing pruritus and erythema and flattening scar in 57-83%
10 All subjects showed significant flattening compared with control for all treatment arms.
The most flattening was observed in the steroid treatment group, followed by steroid
5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.
393 Cosmetic results excellent in 92%, favorable in 6%; only a 2.4% recurrence
24 Irradiation given after keloid excised; 54% recurrence at 24 months
147 KS 32.7% total recurrence rate within 18 months; the highest (41.7%) over high tension
areas (chest wall, scapular region, upper limb) versus a 13.5% recurrence at low
tension areas (neck, earlobes, lower limb)
94 (80 HS, 14 KS) Overall, 84% were greatly improved, 11% were somewhat improved, and 5% had no
improvement. Silicone greatly improved scar in 92.5% of hypertrophic scars and
35.7% of keloidal scars. Somewhat improved were 6.25% of hypertrophic scars and
35.7% of keloids. No improvement was seen in 1.25% of hypertrophic and 28.8% of
keloidal scars.
46 Excellent, 13%; good, 47.8%; fair, 26; poor, 13%
58 (21 HS, 37 KS) No recurrence, 93.1%; partial recurrence, 5.2%; full recurrence, 1.7%
10 All subjects showed significant flattening compared with control for all treatment arms.
The most flattening was observed in the steroid treatment group, followed by steroid
5-FU, 5-FU alone, and PDL treatment. Scar texture was better with PDL treatment.
22 Complete result, 54%; partial result, 36%; absence of results, 9%
22 Complete result, 0; partial result, 18%; absence of results, 82%
22 Verapamil was injected intralesionally and into the donor site (when skin graft was used)
after excision of keloid with W-plasty. At 2-year follow-up, there were two recurrences
(9%) (recurrent keloids were smaller than the originals), and four (18%) had
hypertrophic-appearing scars; one patient developed a keloid at the skin donor site.

used as monotherapy. Polytherapy or a shotgun
approach is used most often, and specific treat-
ments are chosen on a patient-by-patient basis.237
For example, although injected triamcinolone is
considered to be efficacious as a first-line therapy,
silicone gel sheets may be more useful in children
and others who cannot tolerate the pain of other
therapies.300
FUTURE WOUND-HEALING THERAPIES
Gene therapy is the future for wound-healing
strategies. Current research is aimed at inserting
growth factor genomes into the wound. Petrie et
al.301 have written an excellent review of gene ther-
apy in wound healing, and it is recommended to
the reader who wants more detailed information.
Inserting the desired genome can be accom-
plished through several different vehicles: bio-
logic (viral) techniques, chemical methods via cat-
ionic liposomes, and physical insertion.
Viral Techniques
Many different viruses have been tried in gene
therapy. There are four popular virus types: ret-
roviruses, adenoviruses, adenoassociated viruses,
and herpes simplex virus. The principles behind

23e-S
 Plastic and Reconstructive Surgery June Supplement 2006
creating a recombinant viral vector involve delet-
ing essential parts of the viral genome to render
viral replication defunct and inserting the gene of
interest. The transgene inserted is limited by the
packaging capacity of the vector. Although the
endogenous viral promoter may be able to drive
the expression of the inserted gene, this process is
usually optimized by cloning the target gene un-
der the control of a more powerful promoter se-
quence, such as the cytomegalovirus promoter.
Two complications of retroviral vectors limit their
use. One is the theoretical risk of inducing neo-
plastic transformation in the target cellan event
termed insertional mutagenesiswhich could oc-
cur should the viral genome integrate in proximity
to a cellular proto-oncogene, driving its produc-
tion, or by disrupting a tumor suppressor gene.
The other complication is the risk of generating a
replication-competent virus, as evidenced by re-
ports of several outbreaks of wild-type virus from
recombinant virusproducing cell lines.302
Cationic Liposomes
Cationic liposomes are lipid bilayer spheres
that are rendered cationic (positively charged)
and associate in a noncovalent fashion with neg-
atively charged DNA to form liposome-DNA com-
plexes. The rationale for coating nucleic acid with
lipids is to allow highly negatively charged nucleic
acid molecules to traverse the plasma membrane
of the target cell. Lipofection is the term used to
refer to gene transfer by this mechanism. It in-
volves the addition of the complexes to the target
cells, following which the molecules adsorb to the
cell membrane and deliver the bound DNA. The
advantages of lipofection include repeated appli-
cation, lack of toxicity, and ability to carry large
amounts of DNA. Although currently used in 13
percent of all gene therapy clinical trials, lipofec-
tion is limited by a low rate of stable integration
into the target cell and a lack of specificity.301
Physical Insertion Methods
There are several methods of physically deliv-
ering the plasmid DNA directly into the cell301:
direct injection using a hypodermic needle, mi-
croseeding, particle-mediated transfer (using a
gene gun), and electroporation.
Direct Injection Using a Hypodermic Needle
Direct injection involves injecting naked plas-
mid DNA solution directly into the target tissue to
enable transgene expression. It is a desirable
mode of transfection because it is versatile and can
24e-S
be used for plasmid DNA solution and liposome-
DNA complexes. It has a lower incidence of effects
exhibited by some viral vectors, such as elicitation
of an adverse immune response and insertional
mutagenesis. This technique has the disadvantage
of low levels of transfection.303
Microseeding
Microseeding is a technique for in vivo gene
transfer. A plasmid DNA solution of choice is de-
livered directly to the target cells of the skin by a
set of oscillating solid microneedles driven by a
modified tattooing device. Because no special
preparation is required, recombinant viral vectors
can be delivered efficiently. No foreign material is
deposited, as can occur with particle-mediated
gene transfer, and microseeding has a much
higher transfection efficiency compared with sin-
gle injection, possibly because the DNA is deliv-
ered by smaller, finer solid microneedles.
Particle-Mediated Transfer (Gene Gun)
Particle-mediated gene transfer involves bom-
barding cells and tissues with particles or micro-
particles coated with DNA. The microparticles are
composed of gold or tungsten and are 1 to 5 m
in diameter. The particles are coated with the
DNA of interest and loaded into a device known
as the gene gun before being accelerated by a
force (either an electrical discharge or high-pres-
sure helium) that drives the particles into the tar-
get cell, where the DNA dissociates from the par-
ticles and is expressed. Advantages of this
technique include its broad spectrum for being
able to transfect a wide variety of target tissues in
vivo and in vitro, including skin, liver, pancreas,
kidney, muscle, and cornea, and the high loading
capacity of the microparticles, which permits the
introduction of multiple genes. Limitations in-
clude a relatively low level of transfection, esti-
mated in monolayer culture as being 3 to 15 per-
cent. EGF,304 PDGF,305 and TGF-306 are among
the growth factors that have been delivered by
particle-mediated gene transfer, and all have been
shown to accelerate the wound-healing response.
Electroporation
The principle of electroporation rests on the
ability of electrical field pulses to create pores in the
cell membrane. Cells suspended in a medium con-
taining plasmid DNA and treated with electrical field
pulses take up and express DNA from the medium.
Volume 117, Number 7S Wound Healing
SUMMARY
Successful wound management requires a
thorough understanding of wound healing and
the factors that influence it.
George Broughton, II, M.D., Ph.D.
Department of Plastic Surgery
University of Texas Southwestern Medical Center
5323 Harry Hines Boulevard
Dallas, Texas 75390-9132
george.broughton@us.army.mil
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