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 simply stating that there are three phases: inflammation, proliferation, 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 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 involves much more than simply stating
there are three phases: inflammation, proliferation, 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 interactions 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 problems. This article will provide the reader with a
wide overview of wound healing and woundhealing problems and solutions.
WOUND HEALING
Wound healing has traditionally been divided
into three distinct phases: inflammation, proliferation, 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 cascade (both the intrinsic and extrinsic pathways),
initiating the inflammatory phase. After injury occurs, the cell membranes release the potent vasoconstrictors thromboxane A2 and prostaglandin
2-␣. The clot that forms is made of collagen, platelets, 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 endothelial cells.6 It also serves to concentrate the cytokines 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-
www.plasreconsurg.org
1e-S
Plastic and Reconstructive Surgery • June Supplement 2006
Table 1. Summary of Inflammatory Cytokines*
Cytokine
Cell of Origin
Function
EGF
Platelets, macrophages
FGF
Macrophages, mast cells, T lymphocytes,
endothelial cells
Lymphocytes, fibroblasts
IFNs (␣, ␤, and ␥)
ILs (1, 2, 6, and 8)
Macrophages, mast cells, keratinocytes,
lymphocytes
KGF
Fibroblasts
PDGF
Platelets, macrophages, endothelial cells
TGF-␣
Macrophages, T lymphocytes, keratinocytes
TGF-␤
Platelets, T lymphocytes, macrophages,
endothelial cells, keratinocytes
Destroyed wound cells
Macrophages, mast cells, T lymphocytes
Thromboxane A2
TNF
Mitogenic for keratinocytes and fibroblasts,
stimulates keratinocyte migration
Chemotactic and mitogenic for fibroblasts and
keratinocytes, stimulates angiogenesis
Activate macrophages, inhibit fibroblast
proliferation
IL-1: induces fever and adrenocorticotrophic
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 acutephase reactants by the liver
IL-8: enhances neutrophil adherence, chemotaxis,
and granule release
Stimulates keratinocyte migration, differentiation,
and proliferation
Cell chemotaxis, mitogenic for fibroblasts,
stimulates angiogenesis, stimulates wound
contraction
Mitogenic for keratinocytes and fibroblasts,
stimulates keratinocyte migration
Cell chemotaxis stimulates angiogenesis and
fibroplasia
Potent vasoconstrictor
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 inflammatory cells is critical, especially for the macrophage.
An activated macrophage is important for the
transition into the proliferative phase. An activated macrophage will mediate angiogenesis, fibroplasia, 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 cytokines are secreted by the macrophage, including
collagenases, which débride the wound; ILs and
TNF, which stimulate fibroblasts (produce collagen) and promote angiogenesis; and TGF,
which stimulates keratinocytes.
2e-S
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 destroyed, then epithelial cells located on the skin
edge begin proliferating and sending out projections to re-establish a protective barrier.4,11 Angiogenesis, stimulated by TNF-␣, is marked by endothelial cell migration and capillary formation. The
migration of capillaries into the wound bed is
critical for proper wound healing. The granulation phase and tissue deposition require nutrients
supplied by the capillaries, and failure of this to
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 reestablish a protective barrier against fluid losses
and further bacterial invasion. The stimulus for
epithelial proliferation and chemotaxis is epidermal growth factor (EGF) and TGF-␣ produced by
activated platelets and macrophages (fibroblasts
do not appear to synthesize TGF-␣).4,11 Epithelization begins shortly after wounding and is first stimulated by inflammatory cytokines. IL-1 and TNF-␣
upregulate keratinocyte growth factor (KGF) gene
expression in fibroblasts. In turn, fibroblasts synthesize 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 humans, 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 fibroblasts and are derived from platelets and macrophages. PDGF expression by fibroblasts is amplified by autocrine and paracrine signaling.
Fibroblasts already located in the wound site
(termed “wound fibroblasts”) will begin synthesizing collagen and transform into myofibroblasts for
wound contraction (induced by macrophage-secreted TGF-␤1); they have less proliferation compared with the fibroblasts coming in from the
wound periphery.15–17 In response to PDGF, fibroblasts begin synthesizing a provisional matrix composed 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 wound’s 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 production 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 biochemically different from collagen from uninjured skin. Granulation tissue collagen has a
greater hydroxylation and glycosylation of lysine
residues, and this increase of glycosylation correlates 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 uninjured 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
3e-S
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 function can potentially influence wound healing. This
section will briefly highlight the effect several factors have on wound healing.
Local Factors
Several local factors can greatly influence
wound healing. Ischemic tissues, wounds with foreign 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 currency, 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 protein 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 endothelium to localized hypoxia in the early phase
of wound healing is to precipitate vasodilation,
stimulate fibrin deposition, and increase proinflammatory activity, capillary leak, and neovascu-
Fig. 1. Local factors affecting wound healing.
4e-S
larization. The endothelial cell response to sustained hypoxia is a TNF-␣ induction of apoptosis.
Sustained hypoxia will result in endothelial cell
apoptosis.25
Wound neutrophil activity has been demonstrated to be impaired at lower oxygen tensions
identified in wounds. Low temperature, low pH,
and elevated glucose concentrations also limit leukocyte function.26 Fibroblasts exposed to longer
periods of hypoxia may not participate in the formation of the extracellular matrix, thus delaying
healing.27
Infection
Local wound infection and foreign bodies affect healing by prolonging the inflammatory
phase. If the bacterial count in the wound exceeds
105 organisms per gram of tissue, or if any betahemolytic Streptococcus is present, the wound will
not heal by any means, including flap closure, skin
graft placement, or primary sutures.28 The bacteria 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 destruction of surrounding, previously normal tissue.
Wound contamination in association with tissue
hypoxia potentially suppresses macrophage-regulated 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 prolong the inflammatory phase. Wounds with foreign bodies cannot contract, repopulate the area
with capillaries, or completely epithelize (depending 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 associated with ischemic tissue injury can potentially
further compromise perfusion. The inflammatory
response to wounding may be prolonged as a result, 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 produce most of the nitric oxide associated with ischemia-reperfusion injury.32 Mast cells are resident
Volume 117, Number 7S • Wound Healing
tissue inflammatory cells that, when stimulated,
release numerous cytokines and histamines responsible for an intense inflammatory reaction
and edema.
Raised tissue pressure, either externally (pressure) or internally (compartment syndrome), induces increased capillary closure through its effect
on critical closing pressures. Compromised cellular function due to prolonged, severe hypoxia may
rapidly progress to cell death, with necrosis of skin,
adipose tissue, and muscle, thus precipitating ulceration and further contributing locally to impaired healing. In critical illness, additional risk
factors, including depletion of soft-tissue adipose
and protein components, tissue edema due to lowered plasma oncotic pressures, leaky endothelium, and potentially compromised peripheral
perfusion, may further compromise tissue perfusion 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 patents in an attempt to predict wound complications
in abdominal and breast reconstructive surgery.33–35
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 profound effects on the ability of a patient to mount
a response to injury and infection. Poor nutrition,
specific organ compromise, ectopic hormone production, and immune and hematological effects,
together with aggressive therapies, including potent antimetabolic, cytotoxic, and steroidal agents
and radiation, are all associated with compromised 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 associated 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. Although 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 process are now known. Sorbitol, a toxic byproduct of
glucose metabolism, accumulates in tissues and is
implicated in many of the renal, ocular, and vascular complications associated with diabetes.44 Increased dermal vascular permeability results in
pericapillary albumin deposition, which impairs
the diffusion of oxygen and nutrients.43 Hyperglycemia-associated nonenzymatic glycosylation inhibits the function of structural and enzymatic
proteins. In addition, glycosylated collagen is resistant to enzymatic degradation and less soluble
than the normal protein product.44
Experimental studies of diabetic animal models and wound healing show decreased granulation, decreased collagen in granulation tissue, and
defects in collagen maturation.45 Human studies
of healing in diabetic patients parallel these findings, showing slow wound maturation and decreased numbers of dermal fibroblasts. Growth
factor abnormalities have also been shown in recent studies.
Hypothyroidism
Experimental data and anecdotal series show
that hypothyroidism causes delayed wound
healing.46,47 Rats pharmacologically rendered hypothyroid have decreased collagen production, as
measured by extractable soluble hydroxyproline
levels.48 Hypothyroidism also significantly decreases wound tensile strength in rats.49 Irradiation 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, neuropsychiatric 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
5e-S
Plastic and Reconstructive Surgery • June Supplement 2006
It also is widely accepted that elderly patients heals
more slowly than younger patients.53,54 This information should be balanced with the fact that older
patients generally have more comorbidities than
younger patients. Coronary artery disease, peripheral vascular disease, diabetes, and pulmonary
compromise are more common with advanced
age and may affect the healing process independent of age. Experimental studies show that the
inflammatory and proliferative phases are less efficient in older animals, particularly compared
with very young subjects.54 A longitudinal study of
hamster fibroblast cultures over the span of the
animal’s life showed progressively decreasing proliferative 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, although the deposition of dermal collagen is equivalent between young and older, healthy volunteers. 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 fundamentally different from normal postnatal healing. “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 identical 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/collagen/protein complex acting in fetal wound
healing to check scar formation, and concluded
that healing in fetuses involved a much more efficient 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-
6e-S
sue” collagen. Not only are the amounts of collagen deposited in fetal and in adult wounds markedly 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 mesenchymal 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 gestation.
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
adult’s in that it lacks collagen and instead contains predominantly hyaluronic acid.25,62 The fetal
wound contains a persistent abundance of hyaluronic 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 pathologic, postnatal processes.
Whitby and Ferguson61 conclude that it may be
possible to manipulate the adult wound to produce more fetal-like, scarless wound healing by
therapeutically altering the levels of growth substances 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 responsible 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 categorized as local (from small vessel occlusion-emboli
or external compression) or general (from decreases in circulatory volumes, cardiac insufficiency, inotropic infusions, or large vessel disruption). Inadequate tissue perfusion (the definition
of shock) results in tissue hypoxia.
release of anaerobic metabolites and reactive oxygen species creating additional oxidative stresses.
Fat emboli and disseminated intravascular coagulation following severe trauma can cause respiratory complications and occlusion of both larger
and smaller cutaneous vessels, as well as general
and focal tissue hypoxia and multiple-organ dysfunction syndrome.81,82
Hypothermia and Pain
Hypothermia also has a profound effect on
cutaneous perfusion by inducing peripheral vasoconstriction; therefore, the thermal insulation of
wounds is important. Painful stimuli cause a diffuse adrenergic discharge, leading to cutaneous
vasoconstriction; thus, adequate pain control can
improve cutaneous perfusion and potentially improve healing.42
Sepsis
The sepsis-associated mortality rate in an intensive care setting remains high. The endotoxinrelated excessive secretion of proinflammatory
mediators is believed to be important in the development of whole-body inflammation and septic
shock. Systemic inflammation in sepsis appears to
have a biphasic pattern, which includes a hypoinflammatory state associated with immunodeficiency characterized by monocyte deactivation
and immunoparalysis.83 A compromised leukocytic activity and deranged inflammatory response
will have inhibitory effects on wound healing.84
Septicemia can have profound effects on coagulation. Activation of the clotting cascade, via plasma- 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 microcirculatory thrombosis, with potentially widespread effects 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 responses in sepsis affect plasma viscosity and erythrocyte rheologic characteristics.86 This may have
important implications in tissue perfusion, particularly in situations where the capillary blood velocities 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.
Major Trauma and Burns
Severe trauma and tissue loss can result in
hypovolemic shock as a consequence of circulatory volume loss or compromised cardiac function. The systemic inflammatory response syndrome that occurs in major trauma states is
characterized by elevation of circulating cytokines
and inflammatory mediators, including TNF-␣, resulting in activation and consumption of clotting
factors and platelets potentially leading to clotting
anomalies, disseminated intravascular coagulation, and subsequent delays in wound healing.77
The infusion of large volumes of packed red blood
cells also will affect coagulation, largely by dilutional effects, as will cold intravenous fluid
replacement.78 The development of a posttraumatic immunoparalysis has implications in developing sepsis and subsequent delays in wound healing. 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 particular, elicit a major and often prolonged local
inflammatory response associated with local tissue
ischemia, thrombosis, and an intense vasoconstriction resistant to the effects of nitric oxide.79 There
is evidence that peripheral vasoconstriction persists for up to 60 hours after hypovolemia, despite
adequate resuscitation and a normal mean arterial
pressure. Mild or moderate anemia does not appear to deleteriously affect healing in a well-perfused wound, with collagen deposition being proportional to wound tissue oxygenation and
perfusion.80 The reperfusion of injured tissue itself can be deleterious to wound healing, with the
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 indirectly as a result of dysfunctional bowel secondary
to severe metabolic anomaly, trauma, or denervation causing a paralytic ileus. Bacterial translocation of gut bacteria and toxins to the portal cir-
7e-S
Plastic and Reconstructive Surgery • June Supplement 2006
culation can occur, causing sepsis and increased
oxidative stress.
Hepatic Failure
Decreased clotting factors, low plasma proteins, decreased bactericidal activity, and failure of
glucose regulation can all contribute to soft-tissue
wound failure.
Renal Failure
Acute or chronic renal impairment may require dialysis treatment. Raised levels of uremic
toxins and metabolic acidosis will affect wound
healing by influencing both the innate and adaptive immune systems. Hemodialysis and peritoneal
dialysis are associated with increased susceptibility
to infections. Downregulation of circulating neutrophils due to their repeated activation triggering
by dialysis membranes has been demonstrated.
Circulating reactive oxygen species are also increased 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. Tissue hypoxia secondary to hypoxemia will have profound effects on healing at all levels.
Nutrition
Septic, surgical, and trauma patients in hypermetabolic states associated with the release of endogenous cytokines from activated leukocytes experience excessive protein loss in an effort to
maintain normoglycemia; these patients require
additional caloric input to counter a negative nitrogen balance. Such patients consume body
stores of fat and protein, particularly skeletal muscle, more rapidly than patients with normal metabolism. This, together with depletion of micronutrients and immunonutrients, has implications
in immune system function and healing.88 Elevated steroid levels because of stress are intimately
involved in muscle catabolism. Insulin administration 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 because 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 actions of lymphocytes, macrophages, and, in particular, neutrophils, and may be of particular benefit 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 function and wound healing. Many trace metals, including 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, selenium, several other metals, and several vitamins,
including A, B, C, and E, have been implicated in
immune dysfunction.95 Vitamin C is the main vitamin 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 important in the synthesis of nitric oxide, and deficiency 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 ascorbic 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, especially 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 reviewed 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 vasoconstrictive substance that decreases proliferation
of erythrocytes, macrophages, and fibroblasts. Hydrogen cyanide is inhibitory to oxidative metabolism enzymes. Carbon monoxide decreases the
Volume 117, Number 7S • Wound Healing
oxygen-carrying capacity of hemoglobin by competitively inhibiting oxygen binding.98 In one
study using human volunteers, subcutaneous partial pressure of oxygen decreased significantly after 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 deposition and prostacyclin formation, all of which negatively affect wound healing.100 Vasoconstriction
associated with smoking is not a transient phenomenon. 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 globally 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 inflammatory infiltrate is the most obvious effect of
steroids.103 The macrophage response to chemotactic factors is inhibited. Effective phagocytosis by
polymorphonuclear neutrophils and macrophages also is decreased as a result of the stabilizing 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 experimentally. Glucocorticoids also inhibit epithelial regeneration. The application of hydrocortisone 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 response and promotes epithelialization and the
synthesis of collagen and ground substances. Vitamin 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 supplementation 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 longterm consequences for radiated tissue. In patients
with acute radiation injury, the skin becomes erythematous and edematous. Histologically, dilation
of fine blood vessels, endothelial edema, and lymphatic obliteration are seen. As the acute response
abates, thrombosis and fibrinoid necrosis of capillaries occur.109 In this setting, although perfusion of
radiation-damaged skin is seen with fluorescein
injection,107 effective tissue oxygenation is inadequate. Blood vessel appearance is varied, either
thick-walled, telangiectatic, or thrombosed. The
deposition of dense, hyalinized collagen characterizes radiated dermis. The endpoint of chronic radiation damage is the nonhealing ulcer. Obvious necrotic tissue is seen, and there is loss of epithelial
coverage.110 Electron microscopy of human radiation ulcers reveals varying degrees of vascular injury
and few myofibroblasts.110
The mechanisms of radiation damage and inhibited wound healing are currently being studied. Experimentally, healing immediately after irradiation 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 delayed up to 2 weeks.109 Clinically, few surgical procedures 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 proliferate 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 reactions have poor survival rates relative to those from
patients who have a less severe injury.100 Thus,
fibroblast defects have emerged as a central problem in the inhibited healing of chronic radiation
injury.
Cellular mechanisms of phagocytosis and bacteriocidal metabolic functions in polymorphonuclear neutrophils harvested from tissue with
chronic radiation damage also are impaired. The
effect increases as time passes after therapy, which
9e-S
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 debated. In retrospective studies, patients undergoing surgery after failing primary radiotherapy for
early-stage tumors do not show an increase in severity of complications or length of hospital
stay.115,116 One prospective trial comparing antibiotic 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 aggressive radiation regimens, concern regarding increased 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 “organ preservation” protocols, in an attempt to cure
patients with cancer without disfiguring or functionally 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 chemotherapy increases the risk of serious postoperative complications.122 This risk appears to decrease if surgery is delayed for more than 1 year.123
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 common 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 congenital form can be autosomal dominant, recessive, or X-linked recessive. Acquired cutis laxa can
result from drug ingestions, some solid and hematogenous neoplasms, and inflammatory skin
conditions.124
Ehlers-Danlos Syndrome
There are 10 identifiable phenotypes/clinical
subtypes of Ehlers-Danlos syndrome. The different types have autosomal dominant and recessive
inheritance. Individuals with the syndrome demonstrate connective tissue abnormalities as a result
of defects in the inherent strength, elasticity, integrity, 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 accurate diagnosis of the Ehlers-Danlos syndrome
and allow a clearer distinction of disorders that
Table 3. Syndromes Associated with Abnormal Wound Healing
Syndrome
Cutis laxa
Brief Description
Wound Result
Defective elastin fibers; can
Thick, stretchy skin; easy bruising; hernias are
be acquired or congenital
common
Ehlers-Danlos
Deficit in collagen metabolism; has autosomal Total failure of the mechanical
dominance and recessive inheritance
properties of the skin; poor wound healing,
leading to wide, thin scars (classically described
as “cigarette paper scars”); skin tears easily
Homocystinuria
Cystathionine synthetase deficiency
Advanced arteriosclerosis; associated arterial and
venous thrombosis; platelet malfunction
Osteogenesis imperfecta Defective gene for type I collagen
Wide scars
10e-S
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)
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
*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 include 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 woundhealing problems because of poor wound perfusion secondary to thrombosis. These patients have
defects in methylation and/or transsulfuration enzymes that cause the accumulation of homocysteine. Homocysteine is formed from ingested methionine. Homocysteine has cytotoxic effects on
vascular endothelium and causes intimal thicken-
ing, lipid-laden macrophages, and smooth cell
proliferation. Homocysteine initiates the coagulation pathway by enhancing factor V activity, increasing factor Xa-catalyzed prothrombin activation, 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 disorder of connective tissue affecting bone and soft
tissues. The general clinical features of this disorder include bone fragility, neonatal dwarfism, deformities 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-
11e-S
Plastic and Reconstructive Surgery • June Supplement 2006
Table 5. Bioengineered Skin Replacements*
Composition
Cultured keratinocytes autografts
Treated cadaver skin allograft
Bovine collagen/glycosaminoglycan/Silastic
Neonatal fibroblasts/polyglactin mesh allograft
Neonatal fibroblasts/keratinocytes collagen allografts
Structure
Living
Trade Name
Epidermal
Dermal
Dermal
Dermal
Composite
Yes
No
No
Yes
Yes
Epicel
AlloDerm
Integra
Dermagraft
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 migration 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 wellknown proverb; Bennet and Schultz134 introduced
the acronym TIME to highlight the four key clinical scenarios the clinician should check through
when a patient’s wound healing stalls: tissue nonviable or deficient, infection or inflammation,
moisture imbalance, and edge of wound nonadvancing or nonmigrating.135 Adjuncts to wound
healing attempt to address and correct these obstacles to wound healing. They include bioengineered skin, electrostimulation, growth factors,
hydrotherapy, hyperbaric oxygen, lasers, lightemitting 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 prohealing 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 healing, but it has been studied extensively with the Apligraf product. The cells contained in the Apligraf
grow and proliferate, producing growth factors, collagens, and extracellular matrix proteins, which
stimulate reepithelialization, formation of granulation tissue, angiogenesis, and neutrophil and monocyte chemotaxis. Extensive clinical experience suggests 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
12e-S
placed in chronic wounds, outgrowth of previously
dormant keratinocytes at the wound edge is observed, 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 communication between the tissue-engineered product and
the cells in the wound and other cells attracted to
the wound site through the release of wound-healing–related 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
Growth Factors
TGF-␣
Amphiregulin
IL-1, IL-3, IL-6, IL-8
TNF-␣
Granulocyte-macrophage CSF
PDGF
Basic FGF
TGF-␤
Nerve growth factor
Extracellular
Matrix Molecules
Collagen, types IV and VII
Laminin
Kalinin
Fibronectin
Thrombospondin
Glycosaminoglycans
Plasminogen activator
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.
Volume 117, Number 7S • Wound Healing
Electrostimulation is believed to restart or accelerate the wound-healing process by imitating
the natural electrical current that occurs in skin
when it is injured.142–145 This current of injury was
found to vary in specific ways during the regeneration process, with current ceasing to flow as
healing is completed or arrested.146 Electrical current applied to wounded tissue increases the migration of cells vital to the wound-healing process
(i.e., neutrophils, macrophages,147–149 and
fibroblasts).146,150,151 Investigators have found that
electrostimulation resulted in a 109 percent increase in collagen,150 a 40 percent increase in tensile 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 healing in chronic wounds. There are four primary
types of stimulation use: direct current, low-frequency pulsed current, high-voltage pulsed
current, and pulsed electromagnetic fields (Table 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
Growth Factors
Currently there are four commercially prepared growth factor products available (Table
9).136,172–178
Hydrotherapy
Whirlpool treatments are one of the oldest
adjunctive therapies still in use. Whirlpool therapy
supports wound healing by débriding 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 replacing the whirlpool are pulsed lavage and the VersaJet (Smith & Nephew, Inc., Largo, Fla.). Pulsed
lavage delivers an irrigating solution under pressure (4 to 15 psi). Haynes et al.183 demonstrated
that the rate of granulation tissue formation was
greater in patients receiving pulse lavage compared with those receiving whirlpool therapy. The
VersaJet Hydrosurgery System is a water jet–powered surgical tool designed to efficiently débride
a wound by removing damaged disuse and con-
Table 7. Electrostimulation Modalities in Clinical Practice
Description
Direct current
A negative or positive electrode is placed in the wound with
the other one distant to the wound. A current of 0.03 to
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
than 25 years to treat muscular pain as transcutaneous
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
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 (15–40 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
energy at a pulse rate of 80 to 600 pulses per second and
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
Clinical Trials
Ischemic ulcers,133 venous ulcers,156 nonunion bone
healing157,158
Pressure ulcers159–161 (especially in spinal cord injury
patients)
Pressure ulcers,162–165 mixed-chronic ulcers159,
166
Nonunion bone healing,70,126,167,168 pressure ulcers,169
venous ulcers170,171
13e-S
Plastic and Reconstructive Surgery • June Supplement 2006
Table 8. Effect of Polarity on Wound Healing
Positive Current
Promotes epithelial growth
and organization
Acts as a vasoconstrictor and induces clumping
Denatures protein
Aids in preventing postischemic
lipid peroxidation
Decreases mast cells in
Attracts macrophages
Negative Current
Both
Decreases edema around the electrode
Lyses or liquefies necrotic tissue
Stimulates growth of granulation tissue
Increases blood flow
Causes fibroblasts to proliferate
and make collagen
Induces epidermal cell migration
Attracts neutrophils
Stimulates neurite growth directionally
Stimulates neovasculature
Has a bacteriostatic effect
Stimulates receptor sites for
certain growth factors
taminants precisely, without the collateral trauma
associated with traditional surgical modalities
(heat and aggressive sharp débridement).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 therapies, and the American Medical Association condemned his treatments in 1942 for a lack of scientific 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 demonstrated 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 statistically significant outcome differences with respect
to mortality rates and length of hospitalization. Two
studies found that the mean number of débride-
14e-S
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 addition 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, hyperbaric 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 0.1°C to 0.5°C.195 Lowenergy 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 physiological 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, stimulation of photoreceptors in the mitochondria respiratory 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
Volume 117, Number 7S • Wound Healing
Table 9. Commercially Available Growth Factor Products
Name
Growth Factor
Type
Indication
Comments
Procuren
(Curative Health
Services)
PDGF
Diabetic foot
ulcers
Regranex
(Ortho-McNeil
Pharmaceutical)
PDGF-BB
fraction
Diabetic foot
ulcers
Leukine
(Immunex Corp.)
GM-CSF
Treatment for
patients with
AML and bone
marrow rescue
Repifermin
(Human Genome
Sciences)
KGF-2
Treatment for
cancer
therapy-induced
mucositis,
venous ulcers,
skin grafts
wounds.202 Lasers affect wound healing at many different levels. The helium-neon laser light at 633 nm
was optimal for wound healing195 using 1 mW exposures and greater to provide 4 J/cm2 energy density. Later studies of in vitro skin fibroblast stimulation 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.203–205 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 cytochrome aa3, cytochrome oxidase, and other mitochondrial chromophores. Fibroblasts irradiated at
660 nm with 2.16 J/cm2 increased fibroblast growth
factor synthesis and fibroblast proliferation.205 Concurrent DNA synthesis measurements confirmed
this.206,207 Karu208 demonstrated increased DNA synthesis by irradiation at 680 nm, increased protein
synthesis at 750 nm, and increased cell proliferation
The first product to be commercially available.
Patient’s blood is used to collect platelets. Because
blood is used, other growth factors may be part
of the preparation.
The first recombinant human growth factor to be
used in clinical practice
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 débridement 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
Macrophages and inflammation play an important
role in the first phase of wound healing; this
material has been tried in some chronic wounds
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.
Shown to significantly increase healing and
epithelialization over the wound bed177
The initial trial in venous ulcers178 has shown very
promising results, and it is currently in phase 2
clinical development.
at 890 nm, which was 10 times more effective than
other near-infrared wavelengths, requiring only 1
J/cm2. Laser stimulation of collagen synthesis, measured 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 produced 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 –208,211–214
Laser biostimulation has a variety of effects at
different wavelengths, and it would appear that
optimal treatment of a wound would require several applications at different wavelengths.
Light-Emitting Diodes
The National Aeronautics and Space Administration 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 human 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-emitting diodes alone or in combination with hyperbaric 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 submariners. 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 control healing (7 days compared with approximately
14 days). This is significant because wound healing
is slow aboard submarines due to the higher carbon dioxide and lower oxygen levels.201 Lightemitting diode therapy is also being investigated as
therapy for neural cancers,215,216 leukemia, lymphomas, and Barrett’s esophagus.201
Negative Pressure Therapy
Negative pressure therapy (or vacuum-assisted
closure), developed at the Bowman Gray School of
Medicine, uses a subatmospheric pressure dressing 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 therapy decreases the wound bacterial count to less
than 105 organisms per gram of tissue.52 The negative pressure dressing is convenient to use; it requires 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 necrotic tissue, (2) osteomyelitis is untreated, (3)
body cavity or organ fistulas are present, (4) malignancy is present in the wound, or (5) treatment
would place the foam dressing directly over exposed arteries and veins. Negative pressure therapy should be used cautiously when there is active
bleeding in the wound, when hemostasis is difficult after débridement, 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 converted 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 improve 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 bubbles, and streaming is a unidirectional, steady mechanical force. These effects cause changes in the
cell membrane permeability and enhance diffusion of cellular metabolites.37
Ultrasound’s effect on wound healing in the laboratory include cellular recruitment, collagen synthesis, increased collagen tensile strength, angiogenesis, wound contraction, fibroblast and macrophage
stimulation, fibrinolysis, reduction of the inflammatory healing phase, and promotion of the proliferTable 10. Common Low-Energy Lasers
Laser System
Argon (Ar)
Carbon dioxide (CO2)
Dye
Gallium-arsenide (GaAs)
or infrared (IR)
Gallium-aluminum-arsenide (GaAlAs)
Helium-neon (HeNe)
Neodymium:yttrium-aluminium-garnet
(Nd:YAG)
Ruby
Wavelength (nm)
488–514
10,600
Variable
904
830
632.8
1064
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. Ultrasound treatment of pressure ulcers showed a similar division; some showed improvement223 and
others224,225 did not.
KELOIDS AND HYPERTROPHIC SCARS
Hypertrophic scars are raised scars that remain confined to the limits of the incision (Fig. 2).
Keloids are scars that have overgrown their boundaries (Fig. 3).
Differences between Keloids and Hypertrophic
Scars
Histologic Differences
Light microscopy reveals large collagen bundles in keloidal scars but not in hypertrophic
scars.226,227 Keloidal scars may have few macrophages, but they have abundant eosinophils, mast
cells, plasma cells, and lymphocytes226 and are associated with a mucopolysaccharide ground substance; hypertrophic scars have only scant
amounts.226 No morphologic differences in keloidal and hypertrophic scar fibroblasts have been
found, but their biological behavior is different.
Hypertrophic scars have nodules containing cells
and collagen within the middle to deep part of the
scar.228 Within these nodules are ␣-smooth muscle
actin–staining myofibroblasts, which are absent
from normal dermis, normal scars, and 88 percent
of keloidal scars.
Differences Observed with Electron
Microscopy
Ehrlich et al.228 found an amorphous substance around keloidal fibroblasts that separated
them from the collagen bundles. This substance
was not seen in hypertrophic scars. Kischer and
Fig. 2. Hypertrophic scar.
Fig. 3. Ear keloid.
Hendrix229 found that collagen bundles were
“crisp” in hypertrophic scars and more “glazed” in
keloidal scars. In addition, differences were found
in the degree of microvascular injury seen in the
keloidal scars.
Differences in Metabolic Activity
Ueda et al.230 found that keloidal scars had
higher levels of adenosine triphosphate and fibroblasts up to 10 years after formation, compared
with hypertrophic scars. Nakaoka et al.231 found a
higher density of fibroblasts in both keloidal scars
and hypertrophic scars, but keloidal scars had a
higher expression of proliferating cell nuclear antigen, which the authors believed may help explain the tendency of keloidal scars to grow beyond 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 physical growth and most often form between the ages
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 incidence 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 Although the three most common causes in Oluwasanmi’s field survey235 were unspecified trauma,
vaccinations, and tattoos, the most common predisposing factor in a hospital review was earlobe
piercing. In a predominantly black and Hispanic
population, Cosman and Wolff236 noted the incidence 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 strategies that appear to have some benefit in the treatment and management of keloids.
Trauma
Trauma seems to be the most common antecedent factor to developing a keloid.216 Random
(e.g., laceration, burn, vaccination, bug bite) and
planned (e.g., surgery, tattoos, ear piercing) traumatic 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 collagen. 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, female genitalia, corneum, intraoral region, and plantar region have also been reported.238
Abnormal Fibroblast Activity
Fibroblasts from hypertrophic scars and keloidal 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 fibronectin synthesis242 by fibroblasts. IFN-␣ and
IFN-␥ have been shown to reduce both collagen
synthesis from fibroblasts and fibroblast proliferation.
Decreased Apoptosis
Programmed cell death, or apoptosis, is believed to play a role in wound healing and possibly
keloidal scar formation.249 Lower rates of apoptosis 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 healing, leading to migration of inflammatory cells,
formation of granulation tissue, and collagen synthesis. 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 fibroblasts have increased levels of plasminogen activator 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 examine the levels of immunoglobulins within keloidal 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 occluded 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 fibroblasts in response to hypoxia. Gira et al.254
found that VEGF production was abundant in keloids 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 keloidal 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 keloidal scars is dependent on random damage to pilosebaceous structures.257
Keloids can be considered a mesenchymal
neoplasm. Keloid fibroblasts have been shown to
contain the oncogene gli-1 and express the protein Gli-1.258 Immunohistochemistry staining for
gli-1 showed a strong presence in the cytoplasm,
similar to basal cell carcinoma, which also expresses 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 biochemical 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.
Surgical incision, trauma, burns, inflammation, infection, and puncture wounds are the most common
inciting events.216 Symptoms associated with keloid
formation include pain, pruritus, hyperpigmentation, disfigurement, and decreased self-esteem
(which appears most commonly in the teenage population). Pruritus is experienced transiently in normal healing wounds, but persistent pruritus is associated 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 recurrence. Keloid recurrence rates range from 0 to
100 percent. The literature is replete with retrospective, 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 study’s new and improved keloid treatment strategy. Finally, many
studies include both hypertrophic scars and keloids in the subject population. A summary of the
most common treatment strategies is provided below.
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
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
*Adapted in part from Aston, S. J., Beasley, R. W., and Thorne, C. H. M. (Eds.), Grabb and Smith’s Plastic Surgery, 5th Ed. Philadelphia:
Lippincott-Raven, 1997. Chap. 1.
19e-S
Plastic and Reconstructive Surgery • June Supplement 2006
Excision Alone
Excision alone has not been successful in eliminating keloids. Recurrence rates range from 45 to
93 percent.234,260 Excision is the most obvious treatment, but it has met with little success when it is
performed alone. Apfelberg et al.261 proposed using 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 reported in his series, which had a 40 percent recurrence rate. Weimar and Ceilley262 incorporated
the autograft technique for use with adjunctive
measures, pressure therapy, and steroid injections, but results were not provided. Adams126 described a suprakeloid flap with postoperative radiation therapy for the successful treatment of an
earlobe keloid.
Core excision of a dumbbell keloid located on
the earlobe with anterior and posterior components has excellent cure rates when it is used along
with steroids. Core excision results in a full-thickness 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 definitive 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 reducing pruritus, erythema, and the height of keloids, 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. Prospective, 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 perioperatively, 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 proliferation. Triamcinolone acetonide seems to be the
steroid of choice. Studies vary significantly regarding 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. Alternatively, some physicians use it preoperatively, intraoperatively, postoperatively, or in some combination 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, epidermal atrophy, telangiectasias, and skin necrosis.
Occasionally, these changes may be only temporary. Systemic side effects and Cushing’s syndrome
are rare and are associated with improper steroid
use.
One of the first studies to report results of triamcinolone acetonide injection found that 88 percent of keloids (n ⫽ 22) injected with steroids regressed 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. Complications included atrophy, depigmentation, and
recurrence. Currently, most practitioners do not administer such high doses. Monthly doses of approximately 12 mg are recommended.270 This modality
continues to be a mainstay of treatment. Perioperative 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 keloids 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 treatment 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, radiation is no longer used to treat acne. Although
adequate data are lacking, it is estimated that the
risk of developing skin cancer from radiation exposures 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 effective 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 pressure 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 circulation. Pressure earrings have been developed
for postoperative use on keloids involving the earlobe. Intralesional verapamil combined with 6
months of pressure therapy used after keloid excision 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” (keloids) with compressive therapy using magnetic
disks after surgical excision. With a mean follow-up of 18.1 months, they had only one recurrence 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 needle 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, requiring fewer treatments. Twelve lesions were frozen 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 percent reduction in lesion volume, with significantly
improved subjective (pain, itching) and objective
(hardness, color) ratings. Pretreatment and posttreatment histologic analysis demonstrated improved scar organization after needle cryosurgery.
Interferon
Interferons interfere with fibroblasts’ ability to
synthesize collagen. Specifically, IFN-␣-2b normalizes 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 acetaminophen. In a retrospective study, Berman and
Flores307 found that the recurrence rate with postexcisional use of IFN-␣-2b (18.7 percent) was superior to that for excision alone (51.1 percent)
and for postexcisional steroid (triamcinolone) injections (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
patients treated with IFN were reinjected 1 week
later with 5 million U. Follow-up was only 7 months
on average, but the differences were statistically
significant. Conejo-Mir et al.278 achieved a 3-year 0
percent recurrence rate with the combination of
carbon dioxide laser excision and IFN-␣-2b injections for earlobe keloids. IFN-␣-2b seems to be
effective in decreasing the keloid recurrence rate.
In a recent, smaller prospective study,37 of 13 keloids treated with postoperative intralesional IFN␣-2b, seven recurred (54 percent). In contrast, 26
keloids treated with triamcinolone (control
group) had a 15 percent recurrence rate.
IFN-␥ is believed to work in manner similar to
IFN-␣-2b. There have been several anecdotal reports regarding the benefits of IFN-␥ in treating
keloids. More recently, a pilot study examined the
treatment of keloids with this modality.279 In a
placebo-controlled, randomized, double-blind
study, patients with two keloids had one keloid
randomized to excision and postoperative placebo injections and the other to IFN-␥ injections.
In the experimental group, patients were given a
series of 10 injections of 10 ␮g of IFN-␥. Only seven
patients were enrolled in the study, three of whom
dropped out at the 1-year follow-up examination.
Experimental and control groups had uniformly
poor results, with an approximate 75 percent recurrence rate. Because of the small sample size,
conclusions could not be drawn.
Imiquimod is a relatively new agent, an immune response modifier that indirectly acts to
stimulate innate and cell-mediated immune pathways, thereby enhancing the body’s natural ability
to heal.280 Along with inducing and activating natural killer cells, macrophages, and Langerhans
cells, imiquimod also induces the local synthesis
and release of cytokines, including IFN-␣, IFN- ␥,
TNF-␣, and IL-1, IL-6, IL-8, and IL-12, when topically applied.281 A variety of case reports and clinical studies have documented recent successes associated with the use of imiquimod and its
antiviral, antitumor, and immunoregulatory properties, especially in conditions in which interferons have also been used successfully in treatment.
Berman and Kaufman282 examined the effects of
topical application of imiquimod 5% cream after
surgical excision of 13 keloids from 12 patients.
Imiquimod 5% cream was applied nightly directly
to the suture line and to the surrounding area
beginning on the day of the surgery and continuing for a total of 8 weeks. At 24 weeks, no recurrence of keloidal growth was noted among the 11
keloids of the 10 patients who completed the
22e-S
study, a recurrence rate lower than those previously reported in the literature for surgery alone.
Silicone Gel Sheets
The mechanism of action of silicone gel sheeting, also known as hydrocolloid dressing, is not
fully known. Scar hydration is facilitated by the
presence of this occlusive dressing. Hydrocolloid
dressings have been deemed safe for treating
wounds in the initial stages of healing.283 Silicone
gel probably acts as an impermeable membrane
that keeps the skin hydrated.37 In vitro experiments have shown that silicone is inert and does
not affect fibroblast function or survival; however,
enhanced keratinocyte hydration alters growth
factor secretion, which in turn affects fibroblast
function and collagen production.284 The clinical
effects of silicone gel do not appear to be mediated by changes in pressure, temperature, or tissue
oxygenation.37 In an animal study, no detrimental
effect was found when silicone gel sheets were
compared with Nu-Gauze dressings in the immediate postoperative period. Histologic examination of the wounds revealed no evidence of silicone leakage into the tissues. Prevention or
improvement of keloids was not addressed in the
study. In human trials, topical silicone gel was used
to treat 22 keloids in 18 patients, with an 86 percent significant objective response rate.285 Silicone
gel sheets may reduce recurrence rates after excision. It is a benign intervention that does not
increase the rate of recurrence, and it may be
useful as an adjunctive measure.
A brief summary of keloid treatments is shown
in the Table 12.286 –299 The reader should be aware
that most of the studies include a mixture of patients with keloidal scars and hypertrophic scars,
and they are rarely discussed separately.
Practical Guidance
Prevention is the best keloid therapy.
Proposals259 for prevention include avoiding
nonessential cosmetic surgery in keloid-forming
patients, closing wounds with minimal tension,
using cuticular, monofilament, synthetic permanent sutures in an effort to decrease tissue reaction, avoiding Z-plasties or any wound-lengthening techniques, and avoiding, as often as
possible, making incisions that cross joints and
follow skin creases.259
Despite a broad range of therapeutic possibilities, there is no universally effective treatment for
keloids. A few treatment options, such as corticosteroid injections and perhaps compression, are
Volume 117, Number 7S • Wound Healing
Table 12. Comparison of Treatment Modalities and Results*
Treatment
No. of Patients
Results
5-FU ⫹ steroids (intralesional)286
10
5-FU286
10
Bleomycin287
Cryosurgery ⫹ steroid
(intralesional)288
Cryotherapy289
IFN-␥ (monotherapy)307
IFN-2␣-2b (monotherapy)291
13
58
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.
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.
Compete flattening, 42.8%
Complete regression, 70.6%; improvement, 13.7%; recurrence, 15.5%
93 (38 HS, 55 KS)
10
22
IFN-2␣-2b ⫹ surgery308
124
IFN-2␣-2b ⫹ surgery278
Imiquimod282
30
13 keloids in 12
patients
82
Laser265 (77 with Argon, 5
with CO2)
Pulsed dye laser267
Pulsed dye laser292
Radiation (postsurgical)293
Radiation (postsurgical)272
Radiation (postsurgical)294
16
10
393
24
147 KS
Silicone295
94 (80 HS, 14 KS)
Silicone296
Steroids (intralesional) after
excision309
Steroids (intralesional)286
46
58 (21 HS, 37 KS)
Surgery ⫹ silicone ⫹ verpamil298
Surgery ⫹ silicone298
Verapamil (intralesional) ⫹
excision238
10
22
22
22
61.3% had excellent or good results, 29% had poor response, 9.7% had no response
All 10 scars flattened, five out of 10 flattened greater than 50% of original height
Only three out of 22 patients (14%) showed a reduction in size; nine patients withdrew
from study (seven because of pain)
Recurrence was 18% after surgery and postoperative IFN treatment compared with 51%
of patients treated with surgery ⫹ triamcinolone
33% recurrence rate after IFN ⫹ laser excision; 19% recurrence rate after IFN ⫹ surgery
5% cream was applied to surgical scar after keloid was excised. At 24 weeks, there was no
recurrence in 11 keloids of the 10 patients who completed the study.
55% excellent or good improvement (softening, flattening, lack of
progression/recurrence), 11% poor
Effective in reducing pruritus and erythema and flattening scar in 57-83%
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.
Cosmetic results excellent in 92%, favorable in 6%; only a 2.4% recurrence
Irradiation given after keloid excised; 54% recurrence at 24 months
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)
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.
Excellent, 13%; good, 47.8%; fair, 26; poor, 13%
No recurrence, 93.1%; partial recurrence, 5.2%; full recurrence, 1.7%
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.
Complete result, 54%; partial result, 36%; absence of results, 9%
Complete result, 0; partial result, 18%; absence of results, 82%
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.
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.
used as monotherapy. Polytherapy or a “shotgun
approach” is used most often, and specific treatments 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 therapy in wound healing, and it is recommended to
the reader who wants more detailed information.
Inserting the desired genome can be accomplished through several different vehicles: biologic (viral) techniques, chemical methods via cationic liposomes, and physical insertion.
Viral Techniques
Many different viruses have been tried in gene
therapy. There are four popular virus types: retroviruses, 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 deleting 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 under the control of a more powerful promoter sequence, such as the cytomegalovirus promoter.
Two complications of retroviral vectors limit their
use. One is the theoretical risk of inducing neoplastic transformation in the target cell—an event
termed insertional mutagenesis—which could occur should the viral genome integrate in proximity
to a cellular proto-oncogene, driving its production, or by disrupting a tumor suppressor gene.
The other complication is the risk of generating a
replication-competent virus, as evidenced by reports of several outbreaks of wild-type virus from
recombinant virus–producing cell lines.302
Cationic Liposomes
Cationic liposomes are lipid bilayer spheres
that are rendered cationic (positively charged)
and associate in a noncovalent fashion with negatively charged DNA to form liposome-DNA complexes. 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 involves 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 application, lack of toxicity, and ability to carry large
amounts of DNA. Although currently used in 13
percent of all gene therapy clinical trials, lipofection 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 delivering the plasmid DNA directly into the cell301:
direct injection using a hypodermic needle, microseeding, particle-mediated transfer (using a
gene gun), and electroporation.
Direct Injection Using a Hypodermic Needle
Direct injection involves injecting naked plasmid 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 liposomeDNA 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 delivered 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 single injection, possibly because the DNA is delivered by smaller, finer solid microneedles.
Particle-Mediated Transfer (Gene Gun)
Particle-mediated gene transfer involves bombarding cells and tissues with particles or microparticles 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-pressure helium) that drives the particles into the target cell, where the DNA dissociates from the particles 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 include a relatively low level of transfection, estimated in monolayer culture as being 3 to 15 percent. 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 containing 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
[email protected]
REFERENCES
1. Serhan, C., and Chiang, N. Novel endogenous small molecules as the checkpoint controllers in inflammation and
resolution entrée for resolemics. Rheum. Dis. Clin. North Am.
30: 69, 2004.
2. Schilling, J. Wound healing. Surg. Clin. North Am. 56: 859,
1976.
3. Henry, G., and Garner, W. Inflammatory mediators in
wound healing. Surg. Clin. North Am. 83: 483, 2003.
4. Lawrence, W., and Diegelmann, R. Growth factors in wound
healing. Clin. Dermatol. 12: 157, 1994.
5. Witte, M., and Barbul, A. General principles of wound healing. Surg. Clin. North Am. 77: 509, 1997.
6. Kurkinen, M., Vaheri, A., Roberts, P., et al. Sequential appearance of fibronectin and collagen in experimental granulation tissue. Lab. Invest. 43: 47, 1980.
7. Martin, P. Wound healing-aiming for perfect skin regeneration. Science 276: 75, 1997.
8. Pohlman, T., Stanness, K., Beatty, P., et al. An endothelial
cell surface factor(s) induced in vitro by lipopolysaccharide,
interleukin 1 and tumor necrosis factor-alpha increases
neutrophil adherence by a CDw18-dependent mechanism.
J. Immunol. 136: 4548, 1986.
9. Bevilacqua, M., Pober, J., Wheeler, M., et al. Interleukin 1
acts on cultured human vascular endothelium to increase
the adhesion of polymorphonuclear leukocytes, monocytes,
and related leukocyte cell lines. J. Clin. Invest. 76: 2003,
1985.
10. Witte, M., and Barbul, A. Role of nitric oxide in wound
repair. Am. J. Surg. 183: 406, 2002.
11. Grotendorst, G., Soma, Y., Takehara, K., et al. EGF and
TGF-alpha are potent chemoattractants for endothelial
cells and EGF-like peptides are present at sites of tissue
regeneration. J. Cell Physiol. 139: 617, 1989.
12. Smola, H., Thiekotter, G., and Fusenig, N. Mutual induction of growth factor gene expression in by epidermaldermal cell interaction. J. Cell Biol. 122: 417, 1993.
13. Xia, Y., Zhao, Y., Marcus, J., et al. Effects of keratinocyte
growth factor-2 (KGF-2) on wound healing in an ischemiaimpaired rabbit ear model and on scar formation. J. Pathol.
188: 431, 1999.
14. Jimenez, P., and Rampy, M. Keratinocyte growth factor-2
accelerates wound healing in incisional wounds. J. Surg. Res.
81: 238, 1999.
15. Regan, M., Kirk, S., Wasserkrug, H., et al. The wound environment as a regulator of fibroblast phenotype. J. Surg.
Res. 50: 442, 1991.
16. Ehrlich, H., and Krummel, T. Regulation of wound healing
from a connective tissue perspective. Wound Repair Regen. 4:
203, 1996.
17. Desmouliere, A., Geinoz, A., Gabbiani, F., et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122: 103,
1993.
Pierce, G., Mustoe, T., Altrock, B., et al. Role of plateletderived growth factor in wound healing. J. Cell Biochem. 45:
319, 1991.
Diegelmann, R. Analysis of collagen synthesis. Methods Mol.
Med. 78: 349, 2003.
Madden, J. S., and H. C. The rate of collagen synthesis and
deposition in dehisced and resutured wounds. Surg. Gynecol.
Obstet. 130: 487, 1970.
Forrest, L. Current concepts in soft connective tissue wound
healing. Br. J. Surg. 70: 133, 1983.
Sabiston, D. Textbook of Surgery: The Biological Basis of Modern
Surgical Practice, 15th Ed. St. Louis, Mo.: Saunders, 1997. P.
209.
Hurtado, A. J., and Crowther, D. S. Methyl methacrylate
stent for prevention of postexcisional recurrent ear keloid.
J. Prosthet. Dent. 54: 245, 1985.
Kivisaari, J., Vihersaari, T., Renvall, S., et al. Energy metabolism of experimental wounds at various oxygen environments. Ann. Surg. 181: 823, 1975.
Longaker, M. T., Adzick, N. S., Hall, J., et al. Studies in fetal
wound healing: VII. Fetal wound healing may be modulated
by hyaluronic acid stimulating activity in amniotic fluid.
J. Pediatr. Surg. 25: 430, 1990.
Allen, D. B., Maguire, J. J., Mahdavian, M., et al. Wound
hypoxia and acidosis limit neutrophil bacterial killing
mechanisms. Arch. Surg. 132: 991, 1997.
Steinbrech, D. S., Longaker, M. T., Mehrara, B., et al. Fibroblast response to hypoxia: The relationship between angiogenesis and matrix regulation. J. Surg. Res. 84: 127, 1999.
Robson, M. C. Wound infection: A failure of wound healing
caused by an imbalance of bacteria. Surg. Clin. North Am. 77:
637, 1997.
Bankey, P., Fiegel, V., Singh, R., et al. Hypoxia and endotoxin induce macrophage-mediated suppression of fibroblast proliferation. J. Trauma 29: 972, 1989.
Steed, D. L. Debridement. Am. J. Surg 187: 71S, 2004.
Simman, R., Alani, H., and Williams, F. Effect of mitomycin
C on keloid fibroblasts: An in vitro study. Ann. Plast. Surg.
50: 71, 2003.
Messina, A., Knight, K. R., Dowsing, B., et al. Localization
of inducible nitric oxide synthase to mast cells during ischemia/reperfusion injury of skeletal muscle. Lab. Invest. 80:
423, 2000.
Riou, J. P., Cohen, J. R., and Johnson, H., Jr. Factors influencing wound dehiscence. Am. J. Surg. 163: 324, 1992.
Lingen, M. Role of leukocytes and endothelial cells in the
development of angiogenesis in inflammation and wound
healing. Arch. Pathol. Lab. Med. 125: 67, 2001.
Chang, C. H., Song, J. Y., Park, J., et al. The efficacy of
magnetic disks for the treatment of earlobe hypertrophic
scar. Ann. Plast. Surg. 54: 566, 2005.
Farrar, M., and Schreiber, R. The molecular cell biology of
interferon-gamma and its receptor. Annu. Rev. Immunol. 11:
571, 1993.
Al-Attar, A., Mess, S., Thomassen, J., et al. Keloid pathogenesis and treatment. Plast. Reconstr. Surg. 117: 286, 2006.
Ashcroft, G. S., Greenwell-Wild, T., Horan, M., et al. Topical
estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am.
J. Pathol. 155: 1137, 1999.
Dalgleish, A. G., and O’Byrne, K. J. Chronic immune activation and inflammation in the pathogenesis of AIDS and
cancer. Adv. Cancer Res. 84: 231, 2002.
25e-S
Plastic and Reconstructive Surgery • June Supplement 2006
40. Salm, R., Wullich, B., Kiefer, G., et al. Effects of a three-drug
antineoplastic protocol of wound healing in rats: A biomechanical and histologic study on gastrointestinal anastomoses and laparotomy wounds. J. Surg. Oncol. 47: 5, 1991.
41. Bujko, K., Suit, H. D., Springfield, D., et al. Wound healing
after preoperative radiation for sarcoma of soft tissues. Surg.
Gynecol. Obstet. 176: 124, 1993.
42. Williams, D. T., and Harding, K. Healing responses of skin
and muscle in critical illness. Crit. Care Med. 31: S547, 2003.
43. Bucalo, B., Eaglstein, W. H., and Falanga, V. Inhibition of
cell proliferation by chronic wound fluid. Wound Repair
Regen. 1: 181, 1993.
44. He, Z., and King, G. L. Microvascular complications of
diabetes. Endocrinol. Metab. Clin. North Am. 33: 215, 2004.
45. Chow, L. W., Loo, W. T., Yuen, K., et al. The study of
cytokine dynamics at the operation site after mastectomy.
Wound Repair Regen. 11: 326, 2003.
46. Alexander, G., and Ebrahim, M. K. Spontaneous bleeding
following steroid injection and silicone-gel sheeting in a
keloid scar. Br. J. Plast. Surg. 55: 172, 2002.
47. Talmi, Y. P., Finkelstein, Y., and Zohar, Y. Pharyngeal fistulas
in postoperative hypothyroid patients. Ann. Otol. Rhinol.
Laryngol. 98: 267, 1989.
48. Kowalewski, K., and Yong, S. Hydroxyproline in healing
dermal wounds of normal and hypothyroid rats. Acta Endocrinol. (Copenh.) 54: 1, 1967.
49. Lennox, J., and Johnston, I. D. The effect of thyroid status
on nitrogen balance and the rate of wound healing after
injury in rats. Br. J. Surg. 60: 309, 1973.
50. Pech, A., Cannoni, M., Dessi, P., et al. Postoperative monitoring and treatment. Acta Otorhinolaryngol. Belg. 41: 893,
1987.
51. Ladenson, P. W., Levin, A. A., Ridgway, E., et al. Complications of surgery in hypothyroid patients. Am. J. Med. 77:
261, 1984.
52. Morykwas, M. J., Argenta, L. C., Shelton-Brown, E. et al.
Vacuum-assisted closure: A new method for wound control
and treatment: Animal studies and basic foundation. Ann.
Plast. Surg. 38: 553, 1997.
53. Phillips, T. J., Gerstein, A. D., and Lordan, V. A randomized
controlled trial of hydrocolloid dressing in the treatment of
hypertrophic scars and keloids. Dermatol. Surg. 22: 775, 1996.
54. Van de Kerkhof, P. C., Van Bergen, B., Spruijt, K., et al.
Age-related changes in wound healing. Clin. Exp. Dermatol.
19: 369, 1994.
55. Bruce, S. A., and Deamond, S. F. Longitudinal study of in
vivo wound repair and in vitro cellular senescence of dermal
fibroblasts. Exp. Gerontol. 26: 17, 1991.
56. Eichholtz, T., Jalink, K., Fahrenfort, I., et al. The bioactive
phospholipid lysophosphatidic acid is released from activated platelets. Biochem. J. 291: 677, 1993.
57. Freedland, M., Karmiol, S., Rodriguez, J., et al. Fibroblast
responses to cytokines are maintained during aging. Ann.
Plast. Surg. 35: 290, 1995.
58. Mast, B. A., Diegelmann, R. F., Krummel, T., et al. Scarless
wound healing in the mammalian fetus. Surg. Gynecol. Obstet.
174: 441, 1992.
59. Siebert, J. W., Burd, A. R., McCarthy, J., et al. Fetal wound
healing: A biochemical study of scarless healing. Plast. Reconstr. Surg. 85: 495, 1990.
60. Rowsell, A. Fetal wound healing: A biochemical study of
scarless healing (Discussion). Plast. Reconstr. Surg. 85: 503,
1990.
61. Whitby, D. J., and Ferguson, M. W. Immunohistochemical
localization of growth factors in fetal wound healing. Dev.
Biol. 147: 207, 1991.
26e-S
62. Longaker, M. T., Harrison, M. R., Crombleholme, T., et al.
Studies in fetal wound healing: I. A factor in fetal serum that
stimulates deposition of hyaluronic acid. J. Pediatr. Surg. 24:
789, 1989.
63. Longaker, M. T., Whitby, D. J., Adzick, N., et al. Studies in
fetal wound healing: VI. Second and early third trimester
fetal wounds demonstrate rapid collagen deposition without scar formation. J. Pediatr. Surg. 25: 63, 1990.
64. Lorenz, H. P., Longaker, M. T., Perkocha, L., et al. Scarless
wound repair: A human fetal skin model. Development 114:
253, 1992.
65. Bleacher, J. C., Adolph, V. R., Dillon, P., et al. Fetal tissue
repair and wound healing. Dermatol. Clin. 11: 677, 1993.
66. Sullivan, K. M., Lorenz, H. P., Meuli, M., et al. A model of
scarless human fetal wound repair is deficient in transforming growth factor beta. J. Pediatr. Surg. 30: 198, 1995.
67. Ellis, I. R., and Schor, S. L. Differential effects of TGF-beta1
on hyaluronan synthesis by fetal and adult skin fibroblasts:
Implications for cell migration and wound healing. Exp. Cell
Res. 228: 326, 1996.
68. Cass, D. L., Meuli, M., and Adzick, N. S. Scar wars: Implications of fetal wound healing for the pediatric burn patient. Pediatr. Surg. Int. 12: 484, 1997.
69. Liechty, K. W., Crombleholme, T. M., Cass, D., et al. Diminished interleukin-8 (IL-8) production in the fetal
wound healing response. J. Surg. Res. 77: 80, 1998.
70. Stelnicki, E. J., Longaker, M. T., Holmes, D., et al. Bone
morphogenetic protein-2 induces scar formation and skin
maturation in the second trimester fetus. Plast. Reconstr.
Surg. 101: 12, 1998.
71. Scheid, A., Wenger, R. H., Schaffer, L., et al. Physiologically
low oxygen concentrations in fetal skin regulate hypoxiainducible factor 1 and transforming growth factor-beta3.
FASEB J. 16: 411, 2002.
72. Beanes, S. R., Dang, C., Soo, C., et al. Down-regulation of
decorin, a transforming growth factor-beta modulator, is
associated with scarless fetal wound healing. J. Pediatr. Surg.
36: 1666, 2001.
73. Lee, N. J., Wang, S. J., Durairaj, K., et al. Increased expression of transforming growth factor-beta1, acidic fibroblast
growth factor, and basic fibroblast growth factor in fetal
versus adult fibroblast cell lines. Laryngoscope 110: 616, 2000.
74. Liechty, K. W., Adzick, N. S., and Crombleholme, T. M.
Diminished interleukin 6 (IL-6) production during scarless
human fetal wound repair. Cytokine 12: 671, 2000.
75. Whitby, D. J., Longaker, M. T., Harrison, M., et al. Rapid
epithelialisation of fetal wounds is associated with the early
deposition of tenascin. J. Cell Sci. 99 (Pt. 3): 583, 1991.
76. Luomanen, M., and Virtanen, I. Distribution of tenascin in
healing incision, excision and laser wounds. J. Oral Pathol.
Med. 22: 41, 1993.
77. McGee, G., Davidson, J., Buckley, A., et al. Recombinant
basic fibroblast growth factor accelerates wound repair.
J. Surg. Res. 45: 145, 1988.
78. Rudolph, R., and Boyd, C. R. Massive transfusion: Complications and their management. South. Med. J. 83: 1065, 1990.
79. Lindblom, L., Cassuto, J., Yregard, L., et al. Role of nitric
oxide in the control of burn perfusion. Burns 26: 19, 2000.
80. Jonsson, K., Jensen, J. A., Goodson, W. H. III, et al. Tissue
oxygenation, anemia, and perfusion in relation to wound
healing in surgical patients. Ann. Surg. 214: 605, 1991.
81. Mellor, A, and Soni, N. Fat embolism. Anaesthesia 56: 145,
2001.
82. Gando, S., Nanzaki, S., and Kemmotsu, O. Disseminated
intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after
Volume 117, Number 7S • Wound Healing
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
trauma: Application of clinical decision analysis. Ann. Surg.
229: 121, 1999.
Kox, W. J., Volk, T., Kox, S., et al. Immunomodulatory
therapies in sepsis. Intensive Care Med. 26 (Suppl. 1): S124,
2000.
Rico, R. M., Ripamonti, R., Burns, A., et al. The effect of
sepsis on wound healing. J. Surg. Res. 102: 193, 2002.
Hardaway, R. M. A review of septic shock. Am. Surg. 66: 22,
2000.
Castro, V. J., Astiz, M. E., and Rackow, E. C. Effect of crystalloid and colloid solutions on blood rheology in sepsis.
Shock 8: 104, 1997.
Cohen, G., Haag-Weber, M., and Horl, W. H. Immune
dysfunction in uremia. Kidney Int. Suppl. 62: S79, 1997.
Tredget, E. B., Demare, J., Chandran, G., et al. Transforming growth factor-beta and its effect on reepithelialization
of partial-thickness ear wounds in transgenic mice. Wound
Repair Regen. 13: 61, 2005.
Gore, D. C., Wolf, S. E., Herndon, D., et al. Relative influence of glucose and insulin on peripheral amino acid metabolism in severely burned patients. J.P.E.N. J. Parenter.
Enteral Nutr. 26: 271, 2002.
Wang, J., Stuehr, D., Ikeda-Saito, M., et al. Heme coordination and structure of the catalytic site in nitric oxide
synthase. J. Biol. Chem. 268: 22255, 1993.
Ruberg, R. L. Role of nutrition in wound healing. Surg. Clin.
North Am. 64: 705, 1984.
Haydock, D. A., and Hill, G. L. Impaired wound healing in
surgical patients with varying degrees of malnutrition.
J.P.E.N. J. Parenter. Enteral Nutr. 10: 550, 1986.
Fullana, F., Grande, L., Fernadez-Llamazares, J., et al. Skin
prolylhydroxylase activity and wound healing. Eur. Surg. Res.
25: 370, 1993.
Liszewski, R. F. The effect of zinc on wound healing: A
collective review. J. Am. Osteopath. Assoc. 81: 104, 1981.
Mora, R. J. Malnutrition: Organic and functional consequences. World J. Surg. 23: 530, 1999.
Mosely, L. H., and Finseth, F. Cigarette smoking: Impairment of digital blood flow and wound healing in the hand.
Hand 9: 97, 1977.
Goldminz, D., and Bennett, R. G. Cigarette smoking and
flap and full-thickness graft necrosis. Arch. Dermatol. 127:
1012, 1991.
Silverstein, P. Smoking and wound healing. Am. J. Med. 93:
22S, 1992.
Jensen, J. A., Goodson, W. H., Hopf, H., et al. Cigarette
smoking decreases tissue oxygen. Arch. Surg. 126: 1131,
1991.
Smith, J. B., and Fenske, N. A. Cutaneous manifestations
and consequences of smoking. J. Am. Acad. Dermatol. 34:
717, 1996.
Siana, J. E., Rex, S., and Gottrup, F. The effect of cigarette
smoking on wound healing. Scand. J. Plast. Reconstr. Surg.
Hand Surg. 23: 207, 1989.
Petratos, P. B., Felsen, D., Trierweiler, G., et al. Transforming growth factor-beta2 (TGF-beta2) reverses the inhibitory
effects of fibrin sealant on cutaneous wound repair in the
pig. Wound Repair Regen. 10: 252, 2002.
Constant, J. S., Feng, J. J., Zabel, D., et al. Lactate elicits
vascular endothelial growth factor from macrophages: A
possible alternative to hypoxia. Wound Repair Regen. 8: 353,
2000.
Drake, D. B., and Oishi, S. N. Wound healing considerations
in chemotherapy and radiation therapy. Clin. Plast. Surg. 22:
31, 1995.
105. Brauchle, M., Fassler, R., and Werner, S. Suppression of
keratinocyte growth factor expression by glucocorticoids in
vitro and during wound healing. J. Invest. Dermatol. 105: 579,
1995.
106. Beck, E., Duckert, F., and Ernst, M. The influence of fibrin
stabilizing factor on the growth of fibroblasts in vitro and
wound healing. Thromb. Diathes. Haemorr. 6: 485, 1961.
107. Anstead, G. M. Steroids, retinoids, and wound healing. Adv.
Wound Care 11: 277, 1998.
108. Petry, J. J. Surgically significant nutritional supplements.
Plast. Reconstr. Surg. 97: 233, 1996.
109. Bernstein, H. Treatment of keloids by steroids with biochemical tests for diagnosis and prognosis. Angiology 15:
253, 1964.
110. Rudolph, R., Arganese, T., and Woodward, M. The ultrastructure and etiology of chronic radiotherapy damage in
human skin. Ann. Plast. Surg. 9: 282, 1982.
111. Wang, Q., Dickson, G. R., Abram, W., et al. Electron irradiation slows down wound repair in rat skin: A morphological investigation. Br. J. Dermatol. 130: 551, 1994.
112. Yanase, A., Ueda, M., Kaneda, T., et al. Irradiation effects
on wound contraction using a connective tissue model.
Ann. Plast. Surg. 30: 435, 1993.
113. Nall, A. V., Brownlee, R. E., Colvin, C., et al. Transforming
growth factor beta 1 improves wound healing and random
flap survival in normal and irradiated rats. Arch. Otolaryngol.
Head Neck Surg. 122: 171, 1996.
114. Gabka, C. J., Benhaim, P., Mathes, S., et al. An experimental
model to determine the effect of irradiated tissue on neutrophil function. Plast. Reconstr. Surg. 96: 1676, 1995.
115. Marcial, V. A., Gelber, R., Kramer, S., et al. Does preoperative irradiation increase the rate of surgical complications
in carcinoma of the head and neck? A Radiation Therapy
Oncology Group Report. Cancer 49: 1297, 1982.
116. Marcial, V. A., Hanley, J. A., Ydrach, A., et al. Tolerance of
surgery after radical radiotherapy of carcinoma of the oropharynx. Cancer 46: 1910, 1980.
117. Johnson, J. T., Schuller, D. E., Silver, F., et al. Antibiotic
prophylaxis in high-risk head and neck surgery: One-day vs.
five-day therapy. Otolaryngol. Head Neck Surg. 95: 554, 1986.
118. Ariyan, S., Kraft, R. L., and Goldberg, N. H. An experimental model to determine the effects of adjuvant therapy on
the incidence of postoperative wound infection: II. Evaluating preoperative chemotherapy. Plast. Reconstr. Surg. 65:
338, 1980.
119. Girod, D. A., McCulloch, T. M., Tsue, T., et al. Risk factors
for complications in clean-contaminated head and neck
surgical procedures. Head Neck 17: 7, 1995.
120. Metson, R., Freehling, D. J., and Wang, C. C. Surgical complications following twice-a-day versus once-a-day radiation
therapy. Laryngoscope 98: 30, 1988.
121. de Waard, J. W., de Man, B. M., Wobbes, T., et al. Inhibition
of fibroblast collagen synthesis and proliferation by levamisole and 5-fluorouracil. Eur. J. Cancer 34: 162, 1998.
122. Panje, W. R., and Morris, M. R. [Plastic reconstructions in
the neck area: Superficial soft tissues of the neck: scar
revisions]. Laryngorhinootologie 79: OP43, 2000.
123. Sassler, A. M., Esclamado, R. M., and Wolf, G. T. Surgery
after organ preservation therapy: Analysis of wound complications. Arch. Otolaryngol. Head Neck Surg. 121: 162, 1995.
124. Banks, N. D., Redett, R. J., Mofid, M., et al. Cutis laxa:
Clinical experience and outcomes. Plast. Reconstr. Surg. 111:
2434, 2003.
125. Beighton, P., De Paepe, A., Steinmann, B., et al. EhlersDanlos syndromes: Revised nosology, Villefranche, 1997.
27e-S
Plastic and Reconstructive Surgery • June Supplement 2006
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am. J. Med. Genet. 77: 31, 1998.
Adams, W. J. The role of plastic surgery in congenital cutis
laxa: a 10-year follow-up (Discussion). Plast. Reconstr. Surg.
104: 1179, 1999.
Pandeya, N. K. Operating on patients with Ehlers-Danlos
syndrome. Plast. Reconstr. Surg. 105: 1904, 2000.
Rees, M. M., and Rodgers, G. M. Homocysteinemia: Association of a metabolic disorder with vascular disease and
thrombosis. Thromb. Res. 71: 337, 1993.
Tofler, G. H., D’Agostino, R. B., Jacques, P., et al. Association between increased homocysteine levels and impaired
fibrinolytic potential: Potential mechanism for cardiovascular risk. Thromb. Haemost. 88: 799, 2002.
D’Angelo, A., Mazzola, G., Crippa, L., et al. Hyperhomocysteinemia and venous thromboembolic disease. Haematologica 82: 211, 1997.
Bostom, A. G., and Selhub, J. Homocysteine and arteriosclerosis: Subclinical and clinical disease associations. Circulation 99: 2361, 1999.
Baitner, A. C., Maurer, S. G., Gruen, M., et al. The genetic
basis of the osteochondrodysplasias. J. Pediatr. Orthop. 20:
594, 2000.
Hess, C. L., Howard, M. A., and Attinger, C. E. A review of
mechanical adjuncts in wound healing: Hydrotherapy, ultrasound, negative pressure therapy, hyperbaric oxygen,
and electrostimulation. Ann. Plast. Surg. 51: 210, 2003.
Bennet, N., and Schultz, G. Growth factors and wound
healing: Biochemical properties of growth factors and their
receptors. Am. J. Surg. 165: 728, 1993.
Ayello, E. A., Dowsett, C., Schultz, G., et al. TIME heals all
wounds. Nursing 34: 36, 2004.
Limova, M. New therapeutic options for chronic wounds.
Dermatol. Clin. 20: 357, 2002.
Jimenez, P. A., and Jimenez, S. E. Tissue and cellular approaches to wound repair. Am. J. Surg. 187:56S, 2004.
Sabolinski, M. L., Alvarez, O., Auletta, M., et al. Cultured
skin as a “smart material” for healing wounds: Experience
in venous ulcers. Biomaterials 17: 311, 1996.
Muhart, M., McFalls, S., Kirsner, R., et al. Behavior of tissueengineered skin: A comparison of a living skin equivalent,
autograft, and occlusive dressing in human donor sites.
Arch. Dermatol. 135: 913, 1999.
Falanga, V., and Sabolinski, M. A bilayered living skin construct (Apligraf) accelerates complete closure of hard-toheal venous ulcers. Wound Repair Regen. 7: 201, 1999.
Falanga, V., Margolis, D., Alvarez, O., et al. Rapid healing
of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group. Arch. Dermatol. 134: 293, 1998.
Barker, A. T., Jaffe, L. F., and Vanable, J. W., Jr. The glabrous
epidermis of cavies contains a powerful battery. Am.
J. Physiol. 242: R358, 1982.
Foulds, I. S., and Barker, A T. Human skin battery potentials
and their possible role in wound healing. Br. J. Dermatol. 109:
515, 1983.
Barker, A. T. Measurement of direct currents in biological
fluids. Med. Biol. Eng. Comput. 19: 507, 1981.
Cunliffe-Barnes, T. Healing rate of human skin determined
by measurement of electric potential of experimental abrasions: Study of treatment with petrolatum and with petrolatum containing yeast and liver extracts. Am. J. Surg. 69: 82,
1945.
Cruz, N. I., Bayron, F. E., and Suarez, A. J. Accelerated
healing of full-thickness burns by the use of high-voltage
28e-S
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
pulsed galvanic stimulation in the pig. Ann. Plast. Surg. 23:
49, 1989.
Eberhardt, A., Szczypiorski, P., and Korytowski, G. Effect of
transcutaneous electrostimulation on the cell composition
of skin exudate. Acta Physiol. Pol. 37: 41, 1986.
Fukushima, K., Senda, N., Iuri, H., et al. Studies of galvanotaxis of leukocytes. Med. J. Osaka Univ. 4: 195, 1953.
Orida, N., and Feldman, J. D. Directional protrusive pseudopodial activity and motility in macrophages induced by
extracellular electric fields. Cell Motil. 2: 243, 1982.
Alvarez, O. M., Mertz, P. M., Smerbeck, R., et al. The healing
of superficial skin wounds is stimulated by external electrical current. J. Invest. Dermatol. 81: 144, 1983.
Bourguignon, G. J., and Bourguignon, L. Y. Electric stimulation of protein and DNA synthesis in human fibroblasts.
FASEB J. 1: 398, 1987.
Smith, J., Romansky, N., Vomero, J., et al. The effect of
electrical stimulation on wound healing in diabetic mice.
J. Am. Podiatr. Assoc. 74: 71, 1984.
Brown, M., McDonnell, M. K., and Menton, D. N. Electrical
stimulation effects on cutaneous wound healing in rabbits:
A follow-up study. Phys. Ther. 68: 955, 1988.
Hecker, B., Carron, H., and Schwartz, D. P. Pulsed galvanic
stimulation: Effects of current frequency and polarity on
blood flow in healthy subjects. Arch. Phys. Med. Rehabil. 66:
369, 1985.
Kaada, B. Vasodilation induced by transcutaneous nerve
stimulation in peripheral ischemia (Raynaud’s phenomenon and diabetic polyneuropathy). Eur. Heart J. 3: 303,
1982.
Katelaris, P. M., Fletcher, J. P., Little, J., et al. Electrical
stimulation in the treatment of chronic venous ulceration.
Aust. N. Z. J. Surg. 57: 605, 1987.
Connolly, J. F. Selection, evaluation and indications for
electrical stimulation of ununited fractures. Clin. Orthop.
Relat. Res. : 39, 1981.
Zichner, L. Repair of nonunions by electrically pulsed current stimulation. Clin. Orthop. Relat. Res. : 115, 1981.
Feedar, J. A., Kloth, L. C., and Gentzkow, G. D. Chronic
dermal ulcer healing enhanced with monophasic pulsed
electrical stimulation. Phys. Ther. 71: 639, 1991.
Griffin, J. W., Tooms, R. E., Mendius, R., et al. Efficacy of
high voltage pulsed current for healing of pressure ulcers
in patients with spinal cord injury. Phys. Ther. 71: 433, 1991.
Baker, L. L., Chambers, R., DeMuth, S., et al. Effects of
electrical stimulation on wound healing in patients with
diabetic ulcers. Diabetes Care 20: 405, 1997.
Kloth, L. C. 5 questions-and answers-about negative pressure wound therapy. Adv. Skin Wound Care 15: 226, 2002.
Wood, J. M., Evans, P. E., III, Schallreuter, K., et al. A
multicenter study on the use of pulsed low-intensity direct
current for healing chronic stage II and stage III decubitus
ulcers. Arch. Dermatol. 129: 999, 1993.
Gentzkow, G. D., and Miller, K. H. Electrical stimulation for
dermal wound healing. Clin. Podiatr. Med. Surg. 8: 827, 1991.
Feedar, J. A., and Kloth, L. C. Acceleration of wound healing with high voltage pulsating direct current (Abstract).
Phys. Ther. 65: 741, 1985.
Gogia, P. P., Marquez, R. R., and Minerbo, G. M. Effects of
high voltage galvanic stimulation on wound healing. Ostomy
Wound Manage. 38: 29, 1992.
Bassett, C. A., Mitchell, S. N., and Gaston, S. R. Treatment
of ununited tibial diaphyseal fractures with pulsing electromagnetic fields. J. Bone Joint Surg. (Am.) 63: 511, 1981.
Volume 117, Number 7S • Wound Healing
168. de Haasc, W. G., Watson, J., and Morrison, D. M. Noninvasive treatment of ununited fractures of the tibia using
electrical stimulation. J. Bone Joint Surg. (Br.) 62: 465, 1980.
169. Salzberg, C. A., Cooper-Vastola, S. A., Perez, F., et al. The
effects of non-thermal pulsed electromagnetic energy on
wound healing of pressure ulcers in spinal cord-injured
patients: A randomized, double-blind study. Ostomy Wound
Manage. 41: 42, 1995.
170. Itoh, M., Montemayor, J. S., Jr., Matsumoto, E., et al. Accelerated wound healing of pressure ulcers by pulsed high
peak power electromagnetic energy (Diapulse). Decubitus 4:
24, 1991.
171. Stiller, M. J., Pak, G. H., Shupack, J., et al. A portable pulsed
electromagnetic field (PEMF) device to enhance healing of
recalcitrant venous ulcers: A double-blind, placebo-controlled clinical trial. Br. J. Dermatol. 127: 147, 1992.
172. Ladin, D. Becaplermin gel (PDGF-BB) as topical wound
therapy. Plastic Surgery Educational Foundation DATA
Committee. Plast. Reconstr. Surg. 105: 1230, 2000.
173. Kallianinen, L. K., Hirshberg, J., Marchant, B., et al. Role of
platelet-derived growth factor as an adjunct to surgery in the
management of pressure ulcers. Plast. Reconstr. Surg. 106:
1243, 2000.
174. Staeva-Vieira, T., and Freedman, L. 125-Dihydroxyvitamin
D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4⫹ T cells. J. Immunol. 168:
1181, 2002.
175. Da Costa, R. M., Ribeiro Jesus, F. M., Aniceto, C., et al.
Randomized, double-blind, placebo-controlled, dose- ranging study of granulocyte-macrophage colony stimulating
factor in patients with chronic venous leg ulcers. Wound
Repair Regen. 7: 17, 1999.
176. Groves, R. W., and Schmidt-Lucke, J. A. Recombinant human GM-CSF in the treatment of poorly healing wounds.
Adv. Skin Wound Care 13: 107, 2000.
177. Soler, P. M., Wright, T. E., Smith, P., et al. In vivo characterization of keratinocyte growth factor-2 as a potential
wound healing agent. Wound Repair Regen. 7: 172, 1999.
178. Robson, M. C., Phillips, T. J., Falanga, V., et al. Randomized
trial of topically applied repifermin (recombinant human
keratinocyte growth factor-2) to accelerate wound healing
in venous ulcers. Wound Repair Regen. 9: 347, 2001.
179. Meldrum, R. Survey of Staphylococcus aureus contamination
in a hospital’s spa and hydrotherapy pools. Commun. Dis.
Public Health 4: 205, 2001.
180. Sehulster, L., and Chinn, R. Y. Guidelines for environmental infection control in health-care facilities: Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). M.M.W.R. Recomm.
Rep. 52: 1, 2003.
181. Simor, A. E., Lee, M., Vearncombe, M., et al. An outbreak
due to multiresistant Acinetobacter baumannii in a burn unit:
Risk factors for acquisition and management. Infect. Control
Hosp. Epidemiol. 23: 261, 2002.
182. Berrouane, Y. F., McNutt, L. A., Buschelman, B., et al.
Outbreak of severe Pseudomonas aeruginosa infections
caused by a contaminated drain in a whirlpool bathtub.
Clin. Infect. Dis. 31: 1331, 2000.
183. Haynes, L. J., Brown, M. H., Handley, B., et al. Comparison
of Pulsavac and sterile whirlpool regarding the promotion
of tissue granulation. Phys. Ther. 74: S4, 1994.
184. Klein, M. B., Hunter, S., Heimbach, D., et al. The Versajet
water dissector: A new tool for tangential excision. J. Burn
Care Rehabil. 26: 483, 2005.
185. Bill, T. J., Hoard, M. A., and Gampper, T. J. Applications of
hyperbaric oxygen in otolaryngology head and neck sur-
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
gery: Facial cutaneous flaps. Otolaryngol. Clin. North Am. 34:
753, 2001.
Nichter, L. S., Morwood, D. T., Williams, G., et al. Expanding the limits of composite grafting: A case report of successful nose replantation assisted by hyperbaric oxygen
therapy. Plast. Reconstr. Surg. 87: 337, 1991.
Hart, G. B., and Mainous, E. G. The treatment of radiation
necrosis with hyperbaric oxygen (OHP). Cancer 37: 2580,
1976.
Mounsey, R. A., Brown, D. H., O’Dwyer, T., et al. Role of
hyperbaric oxygen therapy in the management of mandibular osteoradionecrosis. Laryngoscope 103: 605, 1993.
Bowersox, J. C., Strauss, M. B., and Hart, G. B. Clinical
experience with hyperbaric oxygen therapy in the salvage of
ischemic skin flaps and grafts. J. Hyperb. Med. 1: 141, 1986.
Perrins, D. J. Influence of hyperbaric oxygen on the survival
of split skin grafts. Lancet 1: 868, 1967.
Shupak, A., Shoshani, O., Goldenberg, I., et al. Necrotizing
fasciitis: An indication for hyperbaric oxygenation therapy?
Surgery 118: 873, 1995.
Brown, D. R., Davis, N. L., Lepawsky, M., et al. A multicenter
review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy.
Am. J. Surg. 167: 485, 1994.
Kuncir, E. J., Tillou, A., St. Hill, C., et al. Necrotizing softtissue infections. Emerg. Med. Clin. North Am. 21: 1075, 2003.
Boykin, J. V., Jr. The nitric oxide connection: Hyperbaric
oxygen therapy, becaplermin, and diabetic ulcer management. Adv. Skin Wound Care 13: 169, 2000.
Basford, J. R. Low-energy laser therapy: Controversies and
new research findings. Lasers Surg. Med. 9: 1, 1989.
Karu, T. Laser biostimulation: A photobiological phenomenon. J. Photochem. Photobiol. B. 3: 638, 1989.
Beauvoit, B., Kitai, T., and Chance, B. Contribution of the
mitochondrial compartment to the optical properties of the
rat liver: A theoretical and practical approach. Biophys. J. 67:
2501, 1994.
Beauvoit, B., Evans, S. M., Jenkins, T., et al. Correlation
between the light scattering and the mitochondrial content
of normal tissues and transplantable rodent tumors. Anal.
Biochem. 226: 167, 1995.
Kleinkort, J. Low-level laser therapy. Rehab. Manag. 18: 51,
2005.
Karu, T., Pyatibrat, L., and Kalendo, G. Irradiation with
He-Ne laser increases ATP level in cells cultivated in vitro.
J. Photochem. Photobiol. B. 27: 219, 1995.
Whelan, H, Buchmann, E. V., Whelan, N. T., et al. NASA
light-emitting diode medical applications from deep space
to deep sea. Space Tech. Appl. Intl. Forum 552: 35, 2001.
Conlan, M. J., Rapley, J. W., and Cobb, C. M. Biostimulation
of wound healing by low-energy laser irradiation: A review.
J. Clin. Periodontol. 23: 492, 1996.
Lubart, R., Wollman, Y., Friedmann, H., et al. Effects of
visible and near-infrared lasers on cell cultures. J. Photochem.
Photobiol. B 12: 305, 1992.
Lubart, R., Friedmann, H., Sinyakov, M., et al. Changes in
calcium transport in mammalian sperm mitochondria and
plasma membranes caused by 780 nm irradiation. Lasers
Surg. Med. 21: 493, 1997.
Yu, W., Naim, J. O., and Lanzafame, R. J. The effect of laser
irradiation on the release of bFGF from 3T3 fibroblasts.
Photochem. Photobiol. 59: 167, 1994.
Mester, E., Mester, A. F., and Mester, A. The biomedical
effects of laser application. Lasers Surg. Med. 5: 31, 1985.
Abergel, R. P., Lyons, R. F., Castel, J., et al. Biostimulation
of wound healing by lasers: Experimental approaches in
29e-S
Plastic and Reconstructive Surgery • June Supplement 2006
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
animal models and in fibroblast cultures. J. Dermatol. Surg.
Oncol. 13: 127, 1987.
Karu, T. Photobiology of low-power laser effects. Health
Phys. 56: 691, 1989.
Whelan, H. T., Houle, J. M., Donohoe, D. L., et al. Medical
applications of space light-emitting diode technology—
space station and beyond. Space Tech. Appl. Intl. Forum 458:
3, 1999.
McCaughan, J. S., Jr., Bethel, B. H., Johnston, T., et al. Effect
of low-dose argon irradiation on rate of wound closure.
Lasers Surg. Med. 5: 607, 1985.
Lyons, R. F., Abergel, R. P., White, R., et al. Biostimulation
of wound healing in vivo by a helium-neon laser. Ann. Plast.
Surg. 18: 47, 1987.
Kana, J. S., Hutschenreiter, G., Haina, D., et al. Effect of
low-power density laser radiation on healing of open skin
wounds in rats. Arch. Surg. 116: 293, 1981.
Falanga, V., Fujitani, R. M., Diaz, C., et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline:
Efficacy in a randomized, placebo-controlled trial. Wound
Repair Regen. 7: 208, 1999.
Braverman, B., McCarthy, R. J., Ivankovich, A., et al. Effect
of helium-neon and infrared laser irradiation on wound
healing in rabbits. Lasers Surg. Med. 9: 50, 1989.
Nakane, M., Schmidt, H., Pollock, J., et al. Cloned human
brain nitric oxide synthase is highly expressed in skeletal
muscle. FEBS Lett. 316: 175, 1993.
Whelan, H. T., Schmidt, M. H., Segura, A., et al. The role
of photodynamic therapy in posterior fossa brain tumors: A
preclinical study in a canine glioma model. J. Neurosurg. 79:
562, 1993.
Callam, M. J., Harper, D. R., Dale, J., et al. A controlled trial
of weekly ultrasound therapy in chronic leg ulceration.
Lancet 2: 204, 1987.
Argenta, L. C., and Morykwas, M. J. Vacuum-assisted closure: A new method for wound control and treatment:
Clinical experience. Ann. Plast. Surg. 38: 563, 1997.
Webster, D. F., Harvey, W., Dyson, M., et al. The role of
ultrasound-induced cavitation in the “in vitro” stimulation
of collagen synthesis in human fibroblasts. Ultrasonics 18: 33,
1980.
Wiles, P. G., Boothby, M., Griffiths, M., et al. Pulsed ultrasound therapy and skin blood-flow. Lancet 2: 572, 1987.
Dyson, M., Franks, C., and Suckling, J. Stimulation of healing of varicose ulcers by ultrasound. Ultrasonics 14: 232,
1976.
Mirastschijski, U., Konrad, D., Lundberg, E., et al. Effects of
a topical enamel matrix derivative on skin wound healing.
Wound Repair Regen. 12: 100, 2004.
Selkowitz, D. M., Cameron, M. H., Mainzer, A., et al. Efficacy
of pulsed low-intensity ultrasound in wound healing: A single-case design. Ostomy Wound Manage. 48: 40, 2002.
McDiarmid, T., Burns, P. N., Lewith, G., et al. Ultrasound
in the treatment of pressure sores. Physiotherapy 71: 66, 1985.
Nussbaum, E. L., Biemann, I., and Mustard, B. Comparison
of ultrasound/ultraviolet-C and laser for treatment of pressure ulcers in patients with spinal cord injury. Phys. Ther. 74:
812, 1994.
Blackburn, W. R., and Cosman, B. Histologic basis of keloid
and hypertrophic scar differentiation: Clinicopathologic
correlation. Arch. Pathol. 82: 65, 1966.
Boyadjiev, C., Popchristova, E., and Mazgalova, J. Histomorphologic changes in keloids treated with Kenacort.
J. Trauma 38: 299, 1995.
30e-S
228. Ehrlich, H. P., Desmouliere, A., Diegelmann, R., et al. Morphological and immunochemical differences between keloid and hypertrophic scar. Am. J. Pathol. 145: 105, 1994.
229. Kischer, C. W., and Hendrix, M. J. Fibronectin (FN) in
hypertrophic scars and keloids. Cell Tissue Res. 231: 29, 1983.
230. Ueda, K., Furuya, E., Yasuda, Y., et al. Keloids have continuous high metabolic activity. Plast. Reconstr. Surg. 104: 694,
1999.
231. Nakaoka, H., Miyauchi, S., and Miki, Y. Proliferating activity
of dermal fibroblasts in keloids and hypertrophic scars. Acta
Dermatol. Venereol. 75: 102, 1995.
232. Janssen de Limpens, A. M., and Cormane, R. H. Keloids and
hypertrophic scars: Immunological aspects. Aesthetic Plast.
Surg. 6: 149, 1982.
233. Fitzpatrick, F., and Soberman, R. Regulated formation of
eicosanoids. J. Clin. Invest. 107: 1347, 2001.
234. Niessen, F. B., Spauwen, P. H., Schalkwijk, J., et al. On the
nature of hypertrophic scars and keloids: A review. Plast.
Reconstr. Surg. 104: 1435, 1999.
235. Oluwasanmi, J. O. Keloids in the African. Clin. Plast. Surg.
1: 179, 1974.
236. Cosman, B., and Wolff, M. Correlation of keloid recurrence
with completeness of local excision: A negative report. Plast.
Reconstr. Surg. 50: 163, 1972.
237. Porter, R. A., Brown, R. A., Eastwood, M., et al. Ultrastructural changes during contraction of collagen lattices by
ocular fibroblasts. Wound Repair Regen. 6: 157, 1998.
238. Copcu, E., Sivrioglu, N., and Oztan, Y. Combination of
surgery and intralesional verapamil injection in the treatment of the keloid. J. Burn Care Rehabil. 25: 1, 2004.
239. Younai, S., Nichter, L. S., Wellisz, T., et al. Modulation of
collagen synthesis by transforming growth factor-beta in
keloid and hypertrophic scar fibroblasts. Ann. Plast. Surg.
33: 148, 1994.
240. Abergel, R. P., Pizzurro, D., Meeker, C., et al. Biochemical
composition of the connective tissue in keloids and analysis
of collagen metabolism in keloid fibroblast cultures. J. Invest. Dermatol. 84: 384, 1985.
241. Russell, S. B., Trupin, J. S., Myers, J., et al. Differential
glucocorticoid regulation of collagen mRNAs in human
dermal fibroblasts: Keloid-derived and fetal fibroblasts are
refractory to down-regulation. J. Biol. Chem. 264: 13730,
1989.
242. Babu, M., Diegelmann, R., and Oliver, N. Fibronectin is
overproduced by keloid fibroblasts during abnormal wound
healing. Mol. Cell Biol. 9: 1642, 1989.
243. McCoy, B. J., and Cohen, I. K. Effects of various sera on
growth kinetics and collagen synthesis by keloid and normal
dermal fibroblasts. Plast. Reconstr. Surg. 67: 505, 1981.
244. Bettinger, D. A., Yager, D. R., Diegelmann, R., et al. The
effect of TGF-beta on keloid fibroblast proliferation and
collagen synthesis. Plast. Reconstr. Surg. 98: 827, 1996.
245. Uitto, J., Perejda, A. J., Abergel, R., et al. Altered steady-state
ratio of type I/III procollagen mRNAs correlates with selectively increased type I procollagen biosynthesis in cultured keloid fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 82: 5935,
1985.
246. Calderon, M., Lawrence, W. T., and Banes, A. J. Increased
proliferation in keloid fibroblasts wounded in vitro. J. Surg.
Res. 61: 343, 1996.
247. Lee, T. Y., Chin, G. S., Kim, W., et al. Expression of transforming growth factor beta 1, 2, and 3 proteins in keloids.
Ann. Plast. Surg. 43: 179, 1999.
248. Peltonen, J., Hsiao, L. L., Jaakkola, S., et al. Activation of
collagen gene expression in keloids: Co-localization of type
Volume 117, Number 7S • Wound Healing
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
I and VI collagen and transforming growth factor-beta 1
mRNA. J. Invest. Dermatol. 97: 240, 1991.
Jude, E. B., Tentolouris, N., Appleton, I., et al. Role of
neuropathy and plasma nitric oxide in recurrent neuropathic and neuroischemic diabetic foot ulcers. Wound Repair Regen. 9: 353, 2001.
Ladin, D. A., Hou, Z., Patel, D., et al. p53 and apoptosis
alterations in keloids and keloid fibroblasts. Wound Repair
Regen. 6: 28, 1998.
Sayah, D. N., Soo, C., Shaw, W., et al. Downregulation of
apoptosis-related genes in keloid tissues. J. Surg. Res. 87: 209,
1999.
Tuan, T. L., Zhu, J. Y., Sun, B., et al. Elevated levels of
plasminogen activator inhibitor-1 may account for the altered fibrinolysis by keloid fibroblasts. J. Invest. Dermatol.
106: 1007, 1996.
Kischer, C. W., Thies, A. C., and Chvapil, M. Perivascular
myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Hum. Pathol. 13: 819, 1982.
Gira, A. K., Brown, L. F., Washington, C., et al. Keloids
demonstrate high-level epidermal expression of vascular
endothelial growth factor. J. Am. Acad. Dermatol. 50: 850,
2004.
Steinbrech, D. S., Mehrara, B. J., Chau, D., et al. Hypoxia
upregulates VEGF production in keloid fibroblasts. Ann.
Plast. Surg. 42: 514, 1999.
Yagi, K. I., Dafalla, A. A., and Osman, A. A. Does an immune
reaction to sebum in wounds cause keloid scars? Beneficial
effect of desensitisation. Br. J. Plast. Surg. 32: 223, 1979.
Fong, E. P., Chye, L. T., and Tan, W. T. Keloids: Time to
dispel the myths? Plast. Reconstr. Surg. 104: 1199, 1999.
Tzeng, E., Kim, Y., Pitt, B., et al. Adenoviral transfer of the
inducible nitric oxide synthase gene blocks endothelial cell
apoptosis. Surgery 122: 255, 1997.
Poochareon, V. N., and Berman, B. New therapies for the
management of keloids. J. Craniofac. Surg. 14: 654, 2003.
Lawrence, W. T. In search of the optimal treatment of
keloids: Report of a series and a review of the literature.
Ann. Plast. Surg. 27: 164, 1991.
Apfelberg, D. B., Maser, M. R., and Lash, H. The use of
epidermis over a keloid as an autograft after resection of the
keloid. J. Dermatol. Surg. 2: 409, 1976.
Weimar, V. M., and Ceilley, R. I. Treatment of keloids on
earlobes. J. Dermatol. Surg. Oncol. 5: 522, 1979.
Salasche, S. J., and Grabski, W. J. Keloids of the earlobes: a
surgical technique. J. Dermatol. Surg. Oncol. 9: 552, 1983.
Norris, J. E. The effect of carbon dioxide laser surgery on
the recurrence of keloids. Plast. Reconstr. Surg. 87: 44, 1991.
Henderson, D. L., Cromwell, T. A., and Mes, L. G.. Argon
and carbon dioxide laser treatment of hypertrophic and
keloid scars. Lasers Surg. Med. 3: 271, 1984.
Apfelberg, D. B., Maser, M. R., White, D., et al. Failure of
carbon dioxide laser excision of keloids. Lasers Surg. Med. 9:
382, 1989.
Alster, T. S., and Williams, C. M. Treatment of keloid sternotomy scars with 585 nm flashlamp-pumped pulsed-dye
laser. Lancet 345: 1198, 1995.
Alster, T. S., and Handrick, C. Laser treatment of hypertrophic scars, keloids, and striae. Semin. Cutan. Med. Surg.
19: 287, 2000.
Messadi, D. V., Le, A., Berg, S., et al. Expression of apoptosisassociated genes by human dermal scar fibroblasts. Wound
Repair Regen. 7: 511, 1999.
Sclafani, A. P., Gordon, L., Chadha, M., et al. Prevention of
earlobe keloid recurrence with postoperative corticosteroid
injections versus radiation therapy: A randomized, prospec-
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
tive study and review of the literature. Dermatol. Surg. 22:
569, 1996.
Ketchum, L. D., Smith, J., Robinson, D., et al. The treatment
of hypertrophic scar, keloid and scar contracture by triamcinolone acetonide. Plast. Reconstr. Surg. 38: 209, 1966.
Norris, J. E. Superficial x-ray therapy in keloid management:
A retrospective study of 24 cases and literature review. Plast.
Reconstr. Surg. 95: 1051, 1995.
Botwood, N., Lewanski, C., and Lowdell, C. The risks of
treating keloids with radiotherapy. Br. J. Radiol. 72: 1222,
1999.
Niessen, F. B., Spauwen, P. H., Robinson, P., et al. The use
of silicone occlusive sheeting (Sil-K) and silicone occlusive
gel (Epiderm) in the prevention of hypertrophic scar formation. Plast. Reconstr. Surg. 102: 1962, 1998.
Sherris, D. A., Larrabee, W. F., Jr., and Murakami, C. S.
Management of scar contractures, hypertrophic scars, and
keloids. Otolaryngol. Clin. North Am. 28: 1057, 1995.
Lawrence, W. T. Treatment of earlobe keloids with surgery
plus adjuvant intralesional verapamil and pressure earrings.
Ann. Plast. Surg. 37: 167, 1996.
Zouboulis, C. C., Rosenberger, A. D., Forster, T., et al.
Modification of a device and its application for intralesional
cryosurgery of old recalcitrant keloids. Arch. Dermatol. 140:
1293, 2004.
Conejo-Mir, J. S., Corbi, R., and Linares, M. Carbon dioxide
laser ablation associated with interferon alfa-2b injections
reduces the recurrence of keloids. J. Am. Acad. Dermatol. 39:
1039, 1998.
Broker, B. J., Rosen, D., Amsberry, J., et al. Keloid excision
and recurrence prophylaxis via intradermal interferongamma injections: A pilot study. Laryngoscope 106: 1497,
1996.
Sauder, D. N. Mechanism of action and emerging role of
immune response modifier therapy in dermatologic conditions J. Cutan. Med. Surg, 8 (Suppl. 3): 3, 2004.
Miller, R. L., Gerster, J. F., Owens, M., et al. Imiquimod
applied topically: A novel immune response modifier and
new class of drug. Int. J. Immunopharmacol. 21: 1, 1999.
Berman, B., and Kaufman, J. Pilot study of the effect of
postoperative imiquimod 5% cream on the recurrence rate
of excised keloids. J. Am. Acad. Dermatol. 47: S209, 2002.
Clugston, P. A., Vistnes, M. D., Perry, L., et al. Evaluation of
silicone-gel sheeting on early wound healing of linear incisions. Ann. Plast. Surg. 34: 12, 1995.
Chang, C. C., Kuo, Y. F., Chiu, H., et al. Hydration, not
silicone, modulates the effects of keratinocytes on fibroblasts. J. Surg. Res. 59: 705, 1995.
Mercer, N. S. Silicone gel in the treatment of keloid scars.
Br. J. Plast. Surg. 42: 83, 1989.
Manuskiatti, W., and Fitzpatrick, R. E. Treatment response
of keloidal and hypertrophic sternotomy scars: Comparison
among intralesional corticosteroid, 5-fluorouracil, and
585-nm flashlamp-pumped pulsed-dye laser treatments.
Arch. Dermatol. 138: 1149, 2002.
Espana, A., Solano, T., and Quintanilla, E. Bleomycin in the
treatment of keloids and hypertrophic scars by multiple
needle punctures. Dermatol. Surg. 27: 23, 2001.
Hirshowitz, B., Lerner, D., and Moscona, A. R. Treatment
of keloid scars by combined cryosurgery and intralesional
corticosteroids. Aesthetic Plast. Surg. 6: 153, 1982.
Zouboulis, C. C., Blume, U., Buttner, P., et al. Outcomes
of cryosurgery in keloids and hypertrophic scars: A prospective consecutive trial of case series. Arch. Dermatol.
129: 1146, 1993.
31e-S
Plastic and Reconstructive Surgery • June Supplement 2006
290. Granstein, R. D., Rook, A., Flotte, T., et al. A controlled trial
of intralesional recombinant interferon-gamma in the treatment of keloidal scarring: Clinical and histologic findings.
Arch. Dermatol. 126: 1295, 1990.
291. al-Khawajah, M. M. Failure of interferon-alpha 2b in the
treatment of mature keloids. Int J. Dermatol. 35: 515, 1996.
292. Manuskiatti, W., Fitzpatrick, R. E., and Goldman, M. P.
Energy density and numbers of treatment affect response of
keloidal and hypertrophic sternotomy scars to the 585-nm
flashlamp-pumped pulsed-dye laser. J. Am. Acad. Dermatol.
45: 557, 2001.
293. Borok, T. L., Bray, M., Sinclair, I., et al. Role of ionizing
irradiation for 393 keloids. Int J. Radiat. Oncol. Biol. Phys. 15:
865, 1988.
294. Ogawa, R., Mitsuhashi, K., Hyakusoku, H., et al. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: Retrospective study of 147 cases followed
for more than 18 months. Plast. Reconstr. Surg. 111: 547,
2003.
295. Dockery, G. L., and Nilson, R. Z. Treatment of hypertrophic
and keloid scars with Silastic gel sheeting. J. Foot Ankle Surg.
33: 110, 1994.
296. Ohmori, S. Effectiveness of Silastic sheet coverage in the
treatment of scar keloid (hypertrophic scar). Aesthetic Plast.
Surg. 12: 95, 1988.
297. Ridgway, P. F., Ziprin, P., Peck, D., et al. Hypoxia increases
reepithelialization via an alphavbeta6-dependent pathway.
Wound Repair Regen. 13: 158, 2005.
298. D’Andrea, F., Brongo, S., Ferraro, G., et al. Prevention and
treatment of keloids with intralesional verapamil. Dermatology 204: 60, 2002.
299. Shaffer, J. J., Taylor, S. C., and Cook-Bolden, F. Keloidal
scars: A review with a critical look at therapeutic options.
J. Am. Acad. Dermatol. 46: S63, 2002.
32e-S
300. Mustoe, T. A., Cooter, R. D., Gold, M., et al. International
clinical recommendations on scar management. Plast. Reconstr. Surg. 110: 560, 2002.
301. Petrie, N. C., Yao, F., and Eriksson, E. Gene therapy in
wound healing. Surg. Clin. North Am. 83: 597, 2003.
302. Mulligan, R. C. The basic science of gene therapy. Science
260: 926, 1993.
303. Meuli, M., Liu, Y., Liggitt, D., et al. Efficient gene expression
in skin wound sites following local plasmid injection.
J. Invest. Dermatol. 116: 131, 2001.
304. Andree, C., Swain, W. F., Page, C., et al. In vivo transfer and
expression of a human epidermal growth factor gene accelerates wound repair. Proc. Natl. Acad. Sci. U.S.A. 91:
12188, 1994.
305. Eming, S. A., Whitsitt, J. S., He, L., et al. Particle-mediated
gene transfer of PDGF isoforms promotes wound repair.
J. Invest. Dermatol. 112: 297, 1999.
306. Benn, S. I., Whitsitt, J. S., Broadley, K., et al. Particle-mediated gene transfer with transforming growth factor-beta1
cDNAs enhances wound repair in rat skin. J. Clin. Invest. 98:
2894, 1996.
307. Larrabee, W. F., Jr., East, C. A., Jaffe, H. S., Stephenson, C.,
and Peterson, K. E. Intralesional interferon gamma treatment for keloids and hypertrophic scars. Arch. Otolaryngol.
Head Neck Surg. 116: 1159, 1990.
308. Berman, B., and Flores, F. Recurrence rates of excised
keloids treated with postoperative triamcinolone acetonide
injections or interferon alfa-2b injections. J. Am. Acad. Dermatol. 37 (5 Pt. 1): 755, 1997.
309. Chowdri, N. A., Masarat, M., Mattoo, A., and Darzi, M. A.
Keloids and hypertrophic scars: Results with intraoperative
and serial postoperative corticosteroid injection therapy.
Aust. N. Z. J. Surg. 69: 655, 1999.