Clin Plastic Surg 32 (2005) 209 – 222
Chronic Wounds
Kouros Izadi, MD, DDS*, Parham Ganchi, MD, PhD
Division of Plastic Surgery, Department of Surgery, New Jersey Medical School – UMDNJ, 90 Bergen Street,
Newark, NJ 07103, USA
The definition of a chronic wound is not clearly
outlined in the literature. Chronic wounds develop
when there is a disruption in the normal healing
process. They fail to heal within a ‘‘normal’’ period
of time when similar wounds would otherwise have
healed. Wounds that have failed to progress through
a normal sequence of repair in 4 to 8 weeks are gen-
erally presumed to be chronic. Chronic wounds can
be a challenge to the patient, the health care pro-
fessional, and the health care system. Venous leg
ulcers, pressure sores, ischemic ulcers, and diabetic
foot ulcers are examples of chronic wounds. There
are over 4 million Americans afflicted with these
types of wounds, with an annual treatment cost of
9 billion dollars. A large percentage of these wounds
occur in the growing elderly population. This be-
comes a large burden to society because of the loss
of productivity and escalating health care costs [1].
Many factors can impair wound healing. Some
of the local or intrinsic factors that impair wound
healing include foreign bodies, tissue maceration,
ischemia, and infection [2]. Medical disorders that
are known to negatively affect wound healing include
malnutrition, diabetes, and renal disease [2]. The
pathophysiology of chronic wounds is not fully
understood, and this incomplete understanding of
the process results in many treatment failures. The
ideal healing environment can be easily disrupted.
This article describes the many processes that may
inhibit or retard wound healing and some of the
* Corresponding author.
E-mail address: Kiny10032@aol.com (K. Izadi).
0094-1298/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.cps.2004.11.011
ways that the clinician may alter those processes
to optimize healing. To facilitate healing, clinicians
must be current on the physiology of wound healing
and have in their armamentarium all the accepted and
proven technologies that are available.
Impairment of wound healing
There are many factors that impair the healing
process and delay or alter the normal sequence of
wound healing. These factors are usually classified as
intrinsic and extrinsic. The intrinsic, or local factors,
that may alter wound healing include ischemia, infec-
tion, presence of necrotic tissue, and foreign bodies
in the wound. The extrinsic or external factors that
need to be considered in the evaluation of a chronic
wound are diabetes mellitus, cancer, chronic disease
(chronic renal failure), steroid use, radiation injury,
and malnutrition. It is often a combination of these
factors that plays an important role in the chronic
wound. The clinician needs to break the cycle in these
circumstances to be able to manage the chronic
wound successfully. Factors that are known to impair
wound healing must be identified and corrected [3].
Intrinsic factors
Ischemia and wound hypoxia
The transport of oxygen to the injured tissue is
one of the most important steps in wound healing
[4,5]. There are a variety of vascular and systemic
disorders that unfavorably affect the delivery of
plasticsurgery.theclinics.com
210 izadi
oxygen and nutrients to the injured tissue. These
include arterial occlusive disease and chronic venous
insufficiency, which are the most common etiologies
in this group of patients. These disorders consist of
vaso-occlusive disease, such as atherosclerosis and
thrombosis of blood vessels, loss of endothelial integ-
rity by autoimmune disorders, and disruption of
vessels by trauma [6].
Obstruction of blood flow to the wound results
in a relative decrease in the perfusion pressure of
oxygen and a hypoxic wound. The chronic hypoxia
results in a nonhealing wound and a host that is
susceptible to infection [7]. The combination of
hypoxia and infection leads to a vicious cycle that
is hard to break. Wounds with oxygen tensions of
35 mm Hg or less in the adjacent skin of the
extremities do not heal. Low tissue oxygen levels
have been demonstrated in nonhealing wounds [8]. In
settings when wound hypoxia can be verified,
hyperbaric oxygen is an effective way to improve
oxygen delivery [9]. Supplemental oxygen may also
improve wound healing. This can affect replication of
fibroblasts and collagen synthesis. Advances in
vascular surgery allow for bypass of occluded blood
vessels and improvement in oxygen delivery, allow-
ing wounds to heal.
Venous ulcers are another source of chronic,
nonhealing wounds that are difficult to treat. The
exact mechanism is not well understood. Chronic
venous insufficiency is caused by abnormalities of
the venous walls and valves that lead to obstruction
or reflux of blood flow in the veins [10,11]. Impair-
ment of oxygen delivery to tissues from capillaries is
thought to be the underlying mechanism leading to
venous ulcers. Accumulation of proteinaceous exu-
dates and subsequent fibrosis of this fluid around the
capillaries and within the interstitium creates a barrier
to the diffusion of oxygen and nutrients to the tissues.
Lysosomal enzymes and proinflammatory mediators
are released, exacerbating the problem and causing
tissue breakdown [5,12].
Anemia alone is not thought to affect wound
healing [13], although patients with anemia usually
suffer from other systemic and local conditions that
may affect wound healing. Proper evaluation and
work-up of the patient with a chronic wound may
reveal hematologic abnormalities that must be cor-
rected for successful comprehensive management of
the patient. In summary, reversible vascular disorders
must be diagnosed and managed with appropriate
surgical or interventional care. Vasculitis is usually
treated medically. With the appropriate surgical and
medical interventions, blood flow and oxygen deliv-
ery to the wound should be optimized.
& ganchi
Infection
Open wounds have lost their protective skin bar-
rier and are invariably colonized with microbes.
Contamination is defined as the presence of non-
replicating organisms within a wound [14]. Coloni-
zation is defined as the presence of replicating
organisms in the wound without host tissue damage
[14]. Wound infection is defined as the presence of
replicating organisms in a wound with local tissue
damage [14]. Biofilm is a slimy layer of bacteria
encased in a hydrated matrix of polysaccharides and
proteins that attach to necrotic tissue and surgical
implants [15,16]. Biofilm is a structurally complex,
dynamic system that provides bacteria a protected
mode of growth that allows cells to survive and thrive
in chronic wounds [17]. Antibiotic resistance of
bacteria in the biofilm contributes to the chronicity
of infections [18].
In contrast to acutely injured contaminated
wounds, all chronic wounds contain a tissue level of
microbial flora [19,20]. Infection can alter the healing
process by prolonging the inflammatory phase of
wound healing. The mechanism by which this occurs
is believed to be due to the effect of bacterial en-
zymes. The enzymatic action of bacterial byproducts
is believed to degrade fibrin and growth factors that
are essential for healing [21 – 23]. The decrease in
host defenses and relative lack of oxygen in the
tissues results in a host that is unable to successfully
propagate an immune response to combat the infec-
tion. Wound infection is defined as a bacterial count
> 105/g of tissue for most bacteria [24 – 27]. Success-
ful closure of wounds (eg, burns and pressure sores)
and techniques such as skin grafting and flap cover-
age have been shown to be dependent on maintaining
a level below 105 organisms per gram of tissue on
biopsy [28 – 32]. Factors that may increase the like-
lihood of infection include immune suppression
(organ transplant recipients), malnutrition, hypoxia
(arterial or venous insufficiency), and the presence of
a foreign body and necrotic tissue that serves as a
nidus for infection. The risk of developing chronic
fungal or unusual bacterial infections should be kept
in mind and investigated if the initial cultures yield
negative results.
A thorough evaluation of the wound must be
made to rule out infection. The initial step involves
a thorough history, inspection of the wound, and
thorough physical evaluation. Cultures and tissue
biopsy are obtained only on select cases. Deeper
infections may not be diagnosed as easily and may
require more sophisticated methods such as CT or
MRI. Skeletal involvement may need to be ruled out
at the onset of treatment to determine the extent of
 chronic wounds
the problem. Radioisotope scanning may be useful in
these situations.
Foreign body
The presence of avascular foreign material creates
an environment where bacteria can thrive. Exposure
of orthopedic hardware, vascular grafts, or devitalized
bone in an open wound predisposes it to infection
and a protracted healing period. Generally, exposed
foreign bodies must be removed from open wounds.
It may be possible to salvage some foreign bodies,
such as orthopedic hardware, with the use of the
vacuum assisted closure (VAC) device [33,34].
Devitalized bone or necrotic tissue must be removed
to allow the host to repair the wound. It may be
difficult to remove all nonviable tissue in one
operation. Multiple debridements may be necessary
to obtain a healthy viable tissue bed ready for closure.
In a recalcitrant wound, radiographic examination
may prove beneficial in identifying foreign bodies.
Radiation
Radiation therapy can have a devastating impact
on wound healing. The effects are dependent on the
dose of radiation, the site of the wound, and con-
comitant surgery or chemotherapy. Radiation effects
on normal tissues can be divided into acute and
chronic. Acute or early radiation effects are changes
observed during or immediately after radiation
therapy. The late or chronic effects are seen weeks
to years after therapy. Although acute effects can be
severely disabling to the patient, it is the chronic
progressive late effects that permanently alter a
patient’s ability to heal (Fig. 1). The acute effects
include erythema, mucositis, and frank ulceration at
the site of injury. Fibrosis, lymphedema, osteoradio-
necrosis, and vascular changes can develop in the
Fig. 1. Radiation wound.
211
chronic stages of injury. The most important of
these detrimental effects is damage to the blood
vessels and the cells in the vicinity of the radiation
portal. Histologic examination of irradiated tissue has
shown endarteritis obliterans of the microvasculature
[35,36]. Radiation injury causes endarteritis that
inhibits wound healing by interrupting the normal
angiogenesis that takes place when tissues are injured
[37]. There is damage at the cellular level and to
oxygen delivery. This may be improved by hyper-
baric oxygen therapy. The hypoxic, hypocellular,
avascular nature of irradiated skin makes it prone to
ulceration and delayed healing. Postradiation injury
poses difficult challenges to the clinician. The high-
energy megavoltage portals used by radiation oncolo-
gists decrease the dosage delivered to the normal
adjacent tissues and minimize the untoward effects
of radiation that were more commonly seen with the
low-energy orthovoltage therapy in the past. Any
wound present in a radiation field must be biopsied to
rule out recurrent or persistent tumor.
Cancer
The patient with cancer often has abnormalities of
wound healing. There are a number of variables
that need to be considered in this setting. These in-
clude malnutrition and catabolic conditions that im-
pair the wound healing process. The administration
of chemotherapy and radiation may directly and
indirectly affect wound healing as well.
Occasionally, neoplasms can mimic or develop in
chronic wounds. A high level of suspicion is prudent.
These neoplasms include squamous cell carcinomas
and basal cell carcinomas and tend to be more
aggressive varieties [38]. Systemic disorders such
as lymphoma may initially present as a nonhealing
skin ulcer. Biopsies of these lesions are performed
to determine the presence of tumor in the wound. The
presence of a malignancy within a wound precludes
the wound from healing.
Extrinsic factors
Diabetes mellitus
Diabetes mellitus has been estimated to afflict
15 to 20 million patients in the United States, half
of whom are undiagnosed [39].The effects of uncon-
trolled diabetes on wound healing are well known to
most clinicians [40 – 44]. Patients with diabetes
mellitus make up a large percentage of patients with
chronic wounds. The diabetic foot is characterized
by sensory, motor, and autonomic neuropathy and
macrovascular disease, which can lead to ulceration,
infection, gangrene, and eventual amputation [45].
212 izadi
Diabetic ulcers usually occur due to the patient’s
inability to sense pressure because of neuropathy
[46]. The effects of neuropathy are many and include
an increase in repeated trauma and eventual skin
breakdown and ulceration. Patients with diabetes
are also at higher risk for peripheral vascular disease,
especially of the infrapopliteal system. Large-vessel
disease can be a source of ischemia in this patient
population. The combination of poor blood flow
[47,48] and altered collagen metabolism can exacer-
bate the chronic wound in patients with diabetes.
Wounds in patients with diabetes have been shown
to have reduced tensile strength [49]. A decrease in
the immunologic defense mechanism is thought to
be present in patients with diabetes. Granulocytes
have been shown to have decreased chemotaxis,
adhesion, phagocytosis, and, as a result, a defect in
bactericidal activity [50 – 52]. Epithelialization is
impaired and further aggravates the poor healing
noted in these patients.
Cardiovascular insufficiency
Patients with impaired cardiovascular function
present a challenge. The decrease in the perfusion
pressure of organs, which include skin and healing
wounds, may prolong and jeopardize the process of
repair. Because the cardiovascular disease may be life
threatening, primary therapeutic attention is directed
toward perfusion of viscera and not skin perfusion
and integrity. A concerted effort to optimize the
patient’s cardiovascular status and alleviate the
immediate risk allows the wound specialist to con-
centrate on the problem and pursue the means to
allow the patient to heal.
Steroids
Glucocorticoids have been used for many years
to treat a number dermatologic disorders, transplant
recipients, and autoimmune disorders. The effects
of steroids are dose and time dependent. Short treat-
ment protocols are not associated with significant
delays in wound healing. Systemic steroid admin-
istration has been shown to decrease the inflamma-
tory response and affect almost all phases of wound
healing [53 – 58]. The effects on wound healing may
be long lasting when steroids are administered on a
daily basis and may impair the repair process for up
to 1 year after the administration of the medication
[12]. Steroids alter the inflammatory phase of wound
healing by inhibiting macrophage activity, angio-
genesis, fibrogenesis, and wound contraction
[12,59,60]. The effects of steroids on wound healing
may be reversed with the administration of vitamin A
[7,53,61,62]. Steroids inhibit the release of lysosomal
& ganchi
enzymes that are essential in the inflammatory phase
of wound healing. Vitamin A is thought to antagonize
this effect and allow the release of lysosomal en-
zymes [12].
Chemotherapy
Antineoplastic agents are being used widely for
the management of malignant disease, autoimmune
disorders, and dermatologic conditions. These drugs
disrupt tumor growth and affect wound healing
because they target rapidly dividing cells [63]. The
effects of these medications are widespread, and
the resultant anemia, granulocytopenia, and thrombo-
cytopenia alter the balance that is essential for proper
wound healing. The inhibition of immunologic
defense mechanisms makes the host more susceptible
to infection, and a vicious cycle ensues. Each anti-
neoplastic agent has a different mechanism of action.
Administration of chemotherapeutic agents 2 weeks
after wound closure minimizes the risk of complica-
tions from these medications [61,64]. Pre-operative
administration of antineoplastic agents is believed to
be more significant in impairing wound healing.
Appropriate coordination of surgical care is manda-
tory in a patient that is undergoing chemotherapy so
that optimal timing is chosen for treatment [65].
Iatrogenic agents
Some of the agents used for wound care may have
a detrimental effect on wound healing. Alcohol con-
taining agents, antimicrobials such as Dakin’s solu-
tion, and povidone iodine are known to be toxic to
the cellular components of the wound and to alter
the balance toward a nonhealing wound [66,67]. A
complete history of wound care products is an
important component of management. Once an agent
is identified, the patient or the caregiver needs to be
educated regarding its use or misuse.
Factitious disorders (Munchausen syndrome and
Munchausen syndrome by proxy) are difficult to di-
agnose and may present a dilemma to the physician.
The diagnosis is usually one of exclusion, and, once
diagnosed, treatment should be rendered by a psy-
chiatrist familiar with these disorders.
Malnutrition
The optimal conditions for wound healing require
a thorough assessment of the nutritional status of
the patient [68]. Before initiation of any heroic efforts
to manage wounds that have been present for an
extended period of time, one must thoroughly search
for causes that may explain the presence of the
wound in the first place. To optimize the nutritional
status of a patient, a clear understanding of the
 chronic wounds
patient’s caloric requirements and a facility with nu-
tritional supplements and vitamins are a must. Protein
malnutrition is associated with suboptimal wound
healing, cell synthesis, wound remodeling, angio-
genesis and fibroblast proliferation [69,70]. Protein
and vitamin deficiency is known to impair the im-
mune system, making the host more susceptible to
infection. It has been shown that as little as 4 weeks
of malnutrition may alter the function of the in-
flammatory cells that are vital to wound healing
[71]. Patients with diabetes are often maintained on
caloric restriction, which may be insufficient energy
to promote healing.
As part of a multidisciplinary approach to manage
a patient with a chronic wound, every effort should be
made to obtain a thorough history regarding weight
loss, appetite, vomiting, diarrhea, and eating habits
[72,73]. Physical examination includes evaluation
of muscle, fat, and subcutaneous fat loss. Edema can
be seen in hypoproteinemia. Laboratory studies in-
clude serum protein and albumin and other specific
nutritional parameters [12].
Depletion of vitamin C, which is rare in the
United States, may result in disruption of collagen
formation. Vitamin C serves as a cofactor in the hy-
droxylation of proline in the production of colla-
gen, and its deficiency results in delayed wound
healing. Deficiencies in zinc, iron, copper, and mag-
nesium also affect wound healing. Wound patients
should receive multivitamins and appropriate nutri-
tional support.
Tobacco
Cigarette smoking has long been known to impair
wound healing. Tobacco is a potent vasoconstrictor,
decreasing oxygen delivery to healing wounds [74].
Nicotine acts via the sympathetic nervous system
to cause systemic vasoconstriction. Tobacco smoke
contains carbon monoxide that binds to hemoglobin
and reduces the oxygen-carrying capacity of hemo-
globin [75]. Hydrogen cyanide is one of the compo-
nents of cigarette smoke and is known to interfere
with cellular respiration. Nicotine is known to be
detrimental to flaps [76] and to dramatically increase
the failure rate of microvascular surgery [77,78]. The
healing potential for patients who smoke has been
found to be equal to that of nonsmokers when ces-
sation of smoking is encouraged as little as 2 weeks
before surgery.
Psychologic factors
The burden and disability experienced by patients
who have chronic wounds alters their way of life.
Motivating such a patient to follow a wound care
213
protocol can pose a challenge for the clinician. The
patient needs to be optimized not only medically
and surgically but also socially. There must be a
complete review of the patient’s support system to
identify any difficulties that may be encountered
during the course of treatment. A social worker
should assess the social environment and help
facilitate patient compliance with the treatment
protocol. The ability of the patient and his family/
caregiver to comply with the treatment protocol is
one of the most important factors in determining the
overall success of treatment.
Chronic disease
Advances in medicine have allowed a compre-
hensive approach to the management of patients with
debilitating, chronic diseases. The wound manage-
ment team plays a critical role in this era of compre-
hensive care. As the aging population increases, there
will be an increase in the number of patients that
will develop chronic wounds. The pathophysiology
of chronic wounds in this patient population is
multifactorial. Patients with chronic diseases such
as cardiac, renal, and hepatic pathology develop a
multitude of physiologic abnormalities that make
them susceptible to developing chronic wounds. The
constant chronic nature of these pathologic systemic
conditions also negatively alters the patient’s social
and environmental status.
Evaluation and management
Psychosocial aspects
One of the most important issues in managing
patients with chronic wounds is the integration of
social and physical ailments. There are a variety
of social and psychologic issues that need to be
addressed in this patient population. The chronically
ill patient is prone to suffering from depression and
a lack of motivation. The combination of chronic
disease and a wound that fails to heal further under-
mines the motivation of the patient to provide self-
care and remain compliant with the physician’s
treatment plan. A thorough evaluation of the patient’s
social and medical status can have a significant
impact on the success of the wound care protocol.
Further optimization of the patient’s current social
and psychological status is beneficial as therapy
progresses. A clear goal must be set and explained
to the patient and the caregiver from the beginning
of treatment so that there are no misconceptions
or misunderstandings regarding the plan. In cases of
214 izadi
recalcitrant wounds, the possibility of failure must
be discussed so that the patient is not disappointed
after a long and labor-intensive effort.
The management of extrinsic factors in patients
with chronic wounds is of utmost importance. There
are some extrinsic factors that can be controlled by
the physician, such as strict glucose control for the
diabetic patient, tapering of steroid use in a patient
who suffers from autoimmune disorders, and opti-
mizing the nutritional status of a patient who is
malnourished. Close cooperation with the patient’s
medical doctor can be valuable in these cases.
Intrinsic factors: wound bed preparation
Debridement
The initial management of a patient with a chronic
wound involves a close and thorough examination of
the wound to outline a surgical strategy and to deter-
mine if the wound is ready for closure. Thorough
debridement of all necrotic tissue is the initial step
in generating an environment that allows healing to
Fig. 2. (A) Sacral decubitus ulcer with necrotic tissue. (B) Methylene blue applied to the wound. (C) Appearance of the wound
after debridement with Versajet.
& ganchi
occur [79]. The process of debridement reduces the
bacterial load and their byproducts allowing the
wound to enter a more favorable phase of healing
[80]. The presence of necrotic, nonviable tissue in-
hibits wound healing and renders the wound suscep-
tible to infection, which further retards wound
healing. The removal of all necrotic tissue and ex-
posure of the whole wound allows one to more
predictably examine and plan future coverage of
the wound. We prefer to perform all debridements
in the operating room where complete access, proper
instrumentation and lighting, and patient comfort
may be optimally delivered. Electrocautery is also
available in the operating room, allowing for meticu-
lous hemostasis. It is difficult to adequately debride a
wound at the bedside. The exceptions are diabetic
plantar ulcers, which can be painlessly debrided of
the typical keratinacious debris at the bedside. There
are a variety of ways to remove necrotic tissue. Many
have proven useful when used properly.
Scalpel or scissors are usually used to sharply
debride necrotic skin and subcutaneous tissue. In
 chronic wounds
cases where more refined, controlled removal of
necrotic tissue is important, such as around vital
structures, we have found the high-pressure parallel
water jet system to be useful. This is a high-pressure
water jet/vacuum evacuator (Versajet; Smith &
Nephew, Tampa, FL) with an adjustable control that
allows precise, controlled, thin-layer excision of
nonviable tissue (Fig. 2). This system is useful in
situations where nearby structures must be protected
or in wounds where minimal healthy tissue remains
and must be preserved. This tissue may allow for
coverage of the wound with a skin graft where a flap
may have otherwise been necessary. The water jet
serves to irrigate the wound and remove necrotic
debris and bacteria.
High-pressure pulse lavage has been shown to
decrease bacterial counts and remove some necrotic
material from the wound, improving the wound en-
vironment. Treatment of infection is an important
adjunct in the management of chronic wounds.
Wound dressings
After the eradication of necrotic tissue and con-
trol of infection in a wound, the appropriate dressing
must be chosen. A moist environment has been found
to provide the best condition for wound healing.
Wound desiccation is known to be detrimental to
wound healing [81,82]. Most clinicians use wet-to-
dry dressings to manage chronic wounds. The
advantage of this dressing is repeated debridements
after each dressing change. However, healthy tissues
are sacrificed when these dressings are allowed to
dry. For clean wounds, moist-to-moist dressings pro-
vide a more ideal environment that prevents desic-
cation and promotes healing. Ideally, a wound is
debrided early in its management and is treated with
moist dressings to optimize healing. There are many
dressings available to the clinician. An understanding
of the basic requirements of wound healing allows
the clinician to chose the dressing that best suits
his patient’s needs.
Compression therapy is usually chosen for pa-
tients who have chronic venous insufficiency or
impairment of healing secondary to edema. Com-
pression dressings reduce fluid extravasation into
the extracellular space, allowing for better diffusion
of oxygen and nutrients to the wound [83].
The introduction of the vacuum assisted closure
(VAC) (KCI, San Antonio, TX) device has revolu-
tionized the management of chronic wounds [84].
The VAC dressing is a sponge and suction drainage
system that is applied to the wound and covered with
215
an airtight adhesive plastic dressing. Suction is con-
tinuously applied to the affected wound, and the
dressing is changed every 2 to 5 days. The VAC
dressing needs to be changed more frequently in the
pediatric population due to the more rapid rate of
granulation tissue formation that can grow into the
sponge dressing. The VAC dressing allows for less
frequent dressing changes, reduces edema in the
wound, and augments formation of fine granulation
tissue receptive to flap or skin graft closure. It main-
tains a moist environment that is optimal for wound
healing. Studies have shown that this method allows
granulation tissue formation even in extreme cases
such as overexposed bone and orthopedic hardware
[85 – 88] (Fig. 3). The bacterial load in wounds that
are managed with the VAC dressing is under
investigation, and contradictory evidence exists as
to whether there is an increase or decrease in the
number and type of bacteria [89,90]. The VAC dress-
ing acts as a temporary cover for open wound so that
closure can be performed in a more controlled setting.
The VAC can be thought of as a semi-occlusive
dressing that is continuously drained via the suction
system. Complications associated with the VAC
dressing are uncommon in experienced hands, but
toxic shock syndrome, hematoma, bleeding, and pain
have been reported in the literature [91,92].
Edema control
Persistent edema is detrimental to wound healing.
There are a variety of dressings that can be applied
to aid in the control and relief of edema. Compres-
sion stockings, Unna’s paste boots, elastic wrapping,
multilayer compression wraps, and pneumatic com-
pression devises are useful modalities to treat chronic
venous insufficiency and edema [10]. Compression
has been shown to increase healing rates in venous
leg ulcers [93]. Elevation of the extremity is a simple
and cost-effective method to decrease edema. The
VAC dressing has been shown to decrease edema,
likely by removing extracellular fluid. Proper educa-
tion of the patient is mandatory when this type of
therapy is prescribed. Patient cooperation is an im-
portant factor in determining the efficacy of these
treatment modalities.
Pharmacology
The pharmacologic aspects of wound manage-
ment include replacement of nutrients and blood
products, institution of antibiotics to treat clinically
216 izadi & ganchi

Fig. 3. (A) A 65-year-old man with circumferential wound of the lower extremity underwent bypass surgery. (B) Debridement
of the wound. (C) VAC treatment completed over a 2-month period. (D) Healed wound after application of skin graft.

significant infections, management of the patient’s
underlying medical condition, and topical agents to
treat the wound. The replacement of nutrients,
vitamins, and trace elements assures adequate sub-
strate to allow wound healing to occur unhindered.
Optimizing the nutritional status of the patient is not
a static protocol and needs to be assessed frequently
to assure a benefit. The advice and assessment of a
nutritionist can be beneficial. Replacement of blood
products should be done cautiously. There are risks
with transfusion therapy, and only in select cases
where a clear benefit exists should this be considered.
The decision to transfuse a patient is controversial
and needs to be individualized. Surgical procedures
should be planned and executed meticulously to
minimize blood loss, which can compound under-
lying anemia. Treatment with erythropoietin and iron
can help reverse anemia.
All open wounds are contaminated, and attempts
should be made to remove all nonviable tissue and
 chronic wounds
reduce the bacterial load. Indiscriminate use of
topical agents is not recommended because adjacent
healthy tissues may be damaged by these medica-
tions. Acetic acid, Povidone-iodine solutions, hydro-
gen peroxide, and Dakin’s solution are known to
cause damage to healthy granulation tissue.
One of the interesting pharmacologic modalities
being promoted for the management of chronic
wounds is anabolic steroids. Persistent weight loss
is seen in some patients despite satisfactory medical
and nutritional management. These patients may be
candidates for anabolic steroid therapy to reverse
their hormonal discrepancy. Anabolic agents such as
oxandrolone have been used with success to halt this
catabolic process and are worth considering for select
patients [88].
Pentoxifylline has been used for many years for
the treatment of intermittent claudication and to
improve blood flow to ischemic wounds [94]. The
mechanism of action of this medication is not clearly
understood. It is hypothesized to increase fibrinolysis,
reduce leukocyte adhesiveness, and increase red
blood cell deformability [95].
Hyperbaric oxygen therapy
Hyperbaric oxygen (HBO) chambers were de-
veloped for the treatment of diving decompression
sickness. The use of HBO has expanded to treat a
variety of conditions and ailments, including chronic
wounds. Hyperbaric oxygen may be of benefit to
tissues that are hypoxic and problematic wounds
[96]. The definitive indications for the treatment
of wounds with hyperbaric oxygen are controversial.
It is well known that optimal delivery of oxygen to
the wound is pivotal in creating an environment
conducive to healing. Optimizing oxygen delivery to
ischemic wounds should be addressed in a compre-
hensive manner, including appropriate investigations
to diagnose arterial disease that may be amenable to
surgical intervention. In patients with hypoxia that
cannot be corrected surgically, one may take advan-
tage of intermittent HBO to increase the oxygen
tension in the wound [91,97,98]. HBO in patients
with limited arterial delivery is beneficial but does
not supplant revascularization. Oxygen delivery in
these cases is most significantly improved by bypass
surgery or by the introduction of a well-vascularized
free tissue transfer [99]. Cost and access to hyperbaric
chambers makes routine use difficult for the majority
of patients.
In a systematic review, Chang et al [100] suggest
that HBO therapy may be beneficial in chronic non-
217
healing diabetic wounds, compromised skin grafts,
osteoradionecrosis, soft tissue radionecrosis, and gas
gangrene compared with standard wound care alone.
However, the HBO literature has not provided de-
finitive proof of its efficacy and cost effectiveness.
Coverage
Wound dressings
A plethora of wound dressings exist to address
almost all conceivable wound types. Many wounds
proceed to full healing with proper dressings in addi-
tion to patient optimization and wound preparation.
Skin grafts
Less complicated, well-vascularized wounds can
be covered with skin grafts. Most wounds can be
covered with split thickness skin grafts. There are
instances when there are advantages to performing a
full-thickness skin graft, such as wounds of the face
where local flaps are not applicable and over hand
and joint surfaces. Full-thickness skin grafts tend to
retain more of the characteristics of normal skin and
thus may allow a more cosmetic and functional graft
for reconstruction. The availability of split thick-
ness grafts and the ability to mesh the graft allows
for coverage of larger areas as compared with full-
thickness skin grafts. Full-thickness skin grafts are
preferred in children where growth occurs as the
child matures. Although all skin grafts require a
well-vascularized bed, split-thickness skin grafts
are able to tolerate suboptimal conditions better than
full-thickness grafts. Furthermore, the supply of
full-thickness skin grafts is somewhat limited, and
closure of the donor site can be problematic.
Skin substitutes
A variety of biologically active modalities are
available to cover open wounds. Transcyte (Smith &
Nephew, Largo, FL) stabilizes wounds and cuts
down on fluid and protein loss [101,102]. Integra
(Integra neurosciences, Plainsboro, NJ) provides a
neodermis in preparation for STSG. This approach
minimizes contracture in burn injuries. Apligraf
(Novartis, Basel, Switzerland) and Dermagraft
(Smith & Nephew) are skin substitutes that consists
of artificial dermis seeded with live fibroblasts
[103,104]. This has been shown to facilitate healing
218 izadi
of diabetic foot and venous leg ulcers. Regranex
(Ortho McNeil, Ethicon Inc., Somerville, NJ) is a gel
containing recombinant PDGF and has been shown
to be effective in treating diabetic ulcers [105,106].
Local flaps
Local flaps have several advantages in more
complicated wounds. There is better color and quality
match as compared with free flaps and skin grafts.
The donor site is usually repaired linearly or covered
with a skin graft as needed. The appearance of the
scar can be improved by placing the incisions in the
natural skin folds or by hiding them in inconspicuous
locations. The clinician needs to be experienced in
performing these procedures to obtain optimal func-
tional and cosmetic results. The quality and quantity
of adjacent tissue also needs to be evaluated before
committing to local flap coverage. This holds true
especially in cases where infection and radiation have
Fig. 4. (A) Infected open tibia/fibular fracture. (B) Wound after debridement and VAC dressing. (C) coverage with local
sural flap.
& ganchi
damaged the surrounding tissues making them un-
usable for this purpose. Fig. 4 shows an example of
local flap coverage.
Distant flaps
Complex wounds may be covered with free flaps
when simpler options (eg, local flaps and skin grafts)
are not possible or available. Microvascular recon-
struction can be technically challenging and can
require prolonged operative time. Patient selection is
important in optimizing outcome. The patient needs
to be in optimal medical condition to be able to
tolerate a long procedure with many inherent risks.
Advancements made in recent years offer a wide
variety of options for reconstruction that were other-
wise not possible in the past. Flaps are chosen on the
basis of the anatomy to be reconstructed and the
quality and quantity of tissue that is needed. Wounds
with significant tissue loss and lack of local donor
sites are candidates for distant tissue transfer. The
 chronic wounds
patient and family need to be well informed regarding
all the risks of the procedure.
[3]
Prevention of recurrence [4]
Risk of recurrence must be thoroughly assessed [5]
before committing a patient to a long and lengthy
surgical treatment plan. The possibility of recurrence
is always on the mind of the reconstructive surgeon [6]
and needs to be emphasized to the patient. Patients
[7]
should be instructed to avoid trauma and to comply
with their medical regimen to prevent recurrence.
Compliance with treatment is important in pre-
venting recurrence.
[8]
Nonsurgical treatment
[9]
Patients who are unstable, those with multiple
medical problems and those with intractable chronic [10]
or terminal diseases are poor candidates for surgical
therapy. The goals for managing these patients are
generally to eliminate infection, alleviate pain, and
optimize a wound care regimen. The patient should [11]
be made comfortable, and frequent examination is
mandatory to assure infection is not present.
[12]
[13]
Summary
[14]
The management of chronic wounds can be a
challenging endeavor especially in this era of
managed care and reduced reimbursements for [15]
physicians. A thorough understanding of the problem
involves a well-trained, multidisciplinary group of
[16]
physicians, nurses, therapists and social workers that
work well together. The search for an answer to the
problem begins with a thorough history and physical [17]
examination to arrive at a diagnosis. This leads to a
comprehensive wound care plan that includes local [18]
wound care, surgical closure when appropriate, and
consultation of appropriate services on a case-by-case
basis to assure an optimal outcome. [19]
[20]
References
[1] Rudolph R, Hurowitz D, Putnam J. The economics [21]
of chronic wounds. In: Rudolph R, Noe JM, editors.
Chronic problem wounds. Boston7 Little Brown &
Co.; 1983. p. 173. [22]
[2] Harding KG, Morris HL, Patel GK. Science, medi-
219
cine and the future: healing chronic wounds. BMJ
2002;324:160 – 3.
Stadelmann WK, Digenis AG, Tobin GR. Impedi-
ments to wound healing. Am J Surg 1998;176(Suppl):
39S – 47S.
Hunt TK, Zederfeldt B, Goldstick TK. Oxygen and
healing. Am J Surg 1969;118:521 – 5.
Stadelmann WK, Digenis AG, Tobin GR. Im-
pediments to wound healing. Am J Surg 1998;
176(Suppl 2A):39S – 47S.
Ramasastry SS. Chronic problem wounds. Clin Plast
Surg 1998;25:367 – 96.
Hunt TK, Hussain Z. Wound microenvironment.
In: Cohen IK, Diegelmann RF, Linblad WJ,
editors. Wound healing biochemical & clinical as-
pects. Philadelphia7 W.B. Saunders Company;
1992. p. 274 – 81.
Gordillo GM, Sen CK. Revisiting the essential role
of oxygen in wound healing. Am J Surg 2003;186:
259 – 63.
Niinikoski JH. Clinical hyperbaric oxygen therapy,
wound perfusion, and transcutaneous oximetry.
World J Surg 2004;28:307 – 11.
Berliner E, Ozbilgin B, Zarin DA. A systematic
review of pneumatic compression for treatment
of chronic venous insufficiency and venous ulcers.
J Vasc Surg 2003;37:539 – 44.
Nicolaides AN. Investgation of chrionic venbous in-
sufficiency: a consensus statement (France, March
5 – 9, 1997). Circulation 2000;102:E126 – 63.
Burns JL, Mancoll JS, Phillips L. Impairments to
wound healing. Clin Plast Surg 2003;30:47 – 56.
Hueghan C, Grislis G, Hunt TK. The effect of ane-
mia in wound healing. Ann Surg 1974;179:163 – 7.
Dow G, Brown A, Sibbald RG. Infection in chronic
wounds: controversies in diagnosis and treatment.
Ostomy Wound Manage 1999;45:23 – 40.
Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial
biofilms: from the natural environment to infectious
diseases. Nat Rev Microbiol 2004;2:95 – 108.
Parsek MR, Singh PK. Bacterial biofilms: an
emerging link to disease pathogenesis. Annu Rev
Microbiol 2003;57:677 – 701.
Stewart PS, Costerton JW. Antibiotic resistance of
bacteria in biofilms. Lancet 2001;358:135 – 8.
Costerton JW, Stewart PS, Greenberg EP. Bacterial
biofilms: a common cause of persistent infections.
Science 1999;284:1318 – 22.
Heggers JP. Defining infection in chronic wounds:
does it matter? J Wound Care 1998;7:389 – 92.
Robson MC. Management of the contaminated
wound aids in diagnosis and treatment. In: Prudue
G, editor. Symposium on basic science in plastic
surgery. St. Louis7 C.V. Mosby; 1976. p. 75.
Robson MC, Stenberg BD, Heggers JD. Wound
healing alterations caused by bacteria. Clin Plast
Surg 1990;3:485 – 92.
Ladwig GP, Robson M, Liu R, et al. Ratios of
activated matrix metalloprotinases-9 to tissue inhibi-
220 izadi
tor of matrix metalloprotineases-1 in wound fluids are
inversely correlated with healing of pressure sores.
Wound Repair Regen 2002;10:26 – 37.
[23] Bucknall TE. The effect of local infection upon
wound healing: an experimental study. Br J Surg
1980;67:851 – 5.
[24] Robson MC. Infection in the surgical patient: an
imbalance in the normal equilibrium. Clin Plast
Surg 1979;6:493 – 503.
[25] Robson MC, Krizek TK, Heggers JP. Biology of
surgical infection. In: Ravitch MM, editor. Current
problems in surgery. Chicago7 Yearbook Medical
Publishers; 1973. p. 1 – 62.
[26] Krizek TK, Robson MC, Kho E. Bacterial growth
and skin graft survival. Surg Forum 1967;18:518 – 9.
[27] Robson MC, Heggers JP. Bacterial quantification
of open wounds. Mil Med 1969;134:19 – 24.
[28] Edwards R, Harding KG. Bacteria and wound
healing. Curr Opin Infect Dis 2004;17:91 – 6.
[29] Krizek TJ, Robson MC, Kho E. Bacterial growth
and skin graft survival. Surg Forum 1967;18:518.
[30] Murphy RC, Robson MC, Heggers JP, et al. The
effect of microbial contamination on musculocuta-
neous and random flaps. J Surg Res 1986;41:75 – 80.
[31] Robson MC. Wound infection: a failure of healing
caused by an imbalance of bacteria. Surg Clin
North Am 1997;77:637 – 50.
[32] Heggers J. Assessing and controlling wound infec-
tion. Clin Plast Surg 2003;30:25 – 35.
[33] Yuan-Innes MJ, Temple CL, Lacey MS. Vacuum-
assisted closure: a new approach to spinal wounds
with exposed hardware. Spine 2001;26:E30 – 3.
[34] Kercher KW, Sling RF, Mathews BD, et al. Success-
ful salvage of infected PTFE mesh after ventral
hernia repair. Ostomy Wound Manage 2002;48:40 – 2,
44 – 5.
[35] Reinisch JF, Puckett CL. Management of radiation
wounds. Surg Clin North Am 1984;64:795 – 802.
[36] Rudolph R, Utley J, Woodard N, et al. The ultrastruc-
ture of chronic radiation damage in rat skin. Surg
Gynecol Obstet 1981;151:171.
[37] Granick M, Solomon M, Larson D. Management
of chronic radiation wounds. Clin Plast Surg 1993;
20 – 9.
[38] Dumurgier C, Pujol G, Chevalley J, et al. Pressure
sore carcinoma: a late but fulminant complication
of pressure sores in spinal cord injury patients;
case reports. Paraplegia 1991;29:390 – 5.
[39] Cowie CC, Eberhardt MS. Diabetes 1996: vital sta-
tistics. Alexandria (VA)7 American Diabetes Associ-
ation; 1996.
[40] Greenhalgh DG. Wound healing and diabetes melli-
tus. Clin Plast Surg 2003;30:37 – 45.
[41] Arquilla ER, Weringer EJ, Nakajo MD. Wound
healing: a model for the study of diabetic micro-
angiopathy. Diabetes 1976;25(Suppl):811 – 9.
[42] Goodson WH, Hunt TK. Studies of wound healing
in experimental diabetes mellitus. J Surg Res 1977;
22:214 – 27.
& ganchi
[43] Goodson WH, Hunt TK. Wound healing and the dia-
betic patient. Surg Gynecol Obstet 1979;149:600 – 8.
[44] Prakash A, Pandit PN, Sharma LK. Studies in wound
healing in experimental diabetes. Int Surg 1974;59:
25 – 8.
[45] Cianci P. Advances in the treatment of the diabetic
foot: is there a role for adjunctive hyperbaric oxygen
therapy? Wound Repair Regen 2004;12:2 – 10.
[46] Singer AJ, Clark RA. Cutaneous wound healing.
N Engl J Med 1999;341:738 – 46.
[47] Laing P. The development and complications of
diabetic foot ulcers. Am J Surg 1998;176(Suppl):
11S – 9S.
[48] Morain WD, Colen LB. Wound healing in diabetes
mellitus. Clin Plas Surg 1990;17:493 – 501.
[49] Mast BA. The skin. In: Diegelmann RF, Lindbland J,
editors. Wound healing biochemical and clinical as-
pects. Philadelphia7 W.B. Saunders; 1992. p. 341 – 55.
[50] Nolan CM, Beaty HN, Bagdade JD. Further charac-
terization of the impaired bactericidal function of
granulocytes in patients with poorly controlled dia-
betes. Diabetes 1978;27:889 – 94.
[51] Fahey III TJ, Sadaty A, Jones Jr WG, et al. Diabetes
impairs the late inflammatory response to wound
healing. J Surg Res 1991;50:308 – 13.
[52] Loots MA. Differences in cellular infiltrate and
extracellular matrix of chronic diabetic and venous
ulcers versus acute wounds. J Inves Dermatol
1998;111:850 – 7.
[53] Ehrlich HP, Hunt TK. Effects of cortisone and vita-
min A on wound healing. Ann Surg 1968;167:324.
[54] Sandberg N. Time relationship between adminis-
tration of cortisone and wound healing in rats. Acta
Chir Scand 1964;127:446 – 50.
[55] Reed BR, Clark RA. Cutaneous tissue repair:
practical implications of current knowledge II.
Am Acad Dermatol 1985;13:919 – 41.
[56] Wahl SM. Glucocorticoids and wound healing. In:
Schleimer RP, Claman HN, Oronsky AL, editors.
Anti inflammatory steroid action: basic and clinical as-
pects. San Diego7 Academic Press; 1989. p. 280 – 302.
[57] Beer HD, Fassler R, Werner S. Glucocorticoid regu-
lated gene expression during cutaneous wound repair.
Vitam Hormon 2000;59:217 – 39.
[58] Schacke H, Docke WD, Asadullah K. Mecha-
nisms involved in the side effects of glucocorticoids.
Pharmacol Ther 2002;96:23 – 43.
[59] Stephens FO, Dunphy JE, Hunt TK. Effects of
delayed administration of corticosteroids on wound
contraction. Ann Surg 1971;173:214 – 8.
[60] Hunt TK. Disorders of wound healing. World J Surg
1980;4:271 – 7.
[61] Hunt TK. Vitamin A and wound healing. J Am
Acad Dermatol 1986;15:817 – 21.
[62] Anstead GM. Steroids, retinoids, and wound healing.
Adv Wound Care 1998;11:277 – 85.
[63] Ferguson MK. The effect of antineoplastic agents
on wound healing. Surg Gynecol Obstet 1982;154:
421 – 9.
 chronic wounds
[64] Falcone RE, Nappi JF. Chemotherapy and wound
healing. Surg Clin North Am 1984;64:779 – 94.
[65] Lawrence WT, Talbot TL, Horton JA. Preoperative
or postoperative doxorubicin hydrochloride (Adria-
mycin): which is better for wound healing? Surgery
1986;100:9 – 13.
[66] Gilmore OJ, Reid C, Strokon A. A study of the ef-
fect of povidone-iodine on wound healing. Postgrad
Med J 1977;53:122 – 5.
[67] Kashyap A, Beezhold D, Wiseman J, et al. Effect
of povidone iodine dermatologic ointment on wound
healing. Am Surg 1995;61:486 – 91.
[68] Flanigan KH. Nutritional aspects of wound healing.
Adv Wound Care 1997;10:48 – 52.
[69] Powanda MC, Moyer ED. Plasma proteins and wound
healing. Surg Gynecol Obstet 1981;153:749 – 55.
[70] Pollack SV. Wound healing: a review. III. Nutri-
tional factors affecting wound healing. J Dermatol
Surg Oncol 1979;5:615 – 9.
[71] Robson MC, Burns BF, Phillips LG. Wound repair:
principles and applications. In: Ruberg RL, Smith
DJ, editors. Plastic surgery: a core curriculum.
St. Louis7 Mosby; 1994. p. 3 – 30.
[72] Thomas DR. Specific nutritional factors in wound
healing. Adv Wound Care 1997;10:40 – 3.
[73] Breslow RA, Hallfrisch J, Guy DJ, et al. The
importance of dietary protein in healing pressure
ulcers. J Am Geriatr Soc 1993;41:357 – 62.
[74] Jensen JA, Goodson WH, Hopf WH, et al. Cigarette
smoking decreases tissue oxygen. Arch Surg 1991;
126:1131 – 4.
[75] Forrest CR, Pang CY, Lindsay WK. Dose and time
effects of nicotine treatment on the capillary blood
flow and viability of random pattern skin flaps in
the rat. Br J Plas Surg 1987;40:295 – 9.
[76] Rees TD, Liverett DM, Guy GL. The effect of
cigarette smoking on skin flap survival in the face
lift patient. Plas Recon Surg 1984;73:911 – 5.
[77] Chang LD, Buncke G, Slezak S, et al. Cigarette
smoking, plastic surgery, and microsurgery. J Reconstr
Microsurg 1996;12:467 – 74.
[78] Reus III WF, Colen LB, Straker DJ. Tobacco smok-
ing and complications in elective microsurgery.
Plas Reconstr Surg 1992;89:490.
[79] Brem H, Sheehan P, Boulton AJ. Protocol for treat-
ment of diabetic foot ulcers. Am J Surg 2004;187:
1S – 10S.
[80] Steed DL, Donohoe D, Webster MW, et al. Effects
of extensive debridement and treatment of the heal-
ing of diabetic foot ulcers. J Am Coll Surg 1996;
183:61 – 4.
[81] Hinman CD, Mailbock H, Winters GD. Effects of
air exposure and occlusion in experimental human
skin wounds. Nature 1963;200:377 – 8.
[82] Rovee ET, Kurowsky CA, Labun J, et al. Effect
of local wound environment on epidermal healing. In:
Malibach HI, Rovee DT, editors. Epidermal wound
healing. Chicago7 Yearbook Medical Publishers;
1972. p. 159 – 81.
221
[83] Valencia IC, Falabella A, Kirsner RS, et al. Chronic
venous insufficiency and venous leg ulceration.
J Am Acad Dermatol 2001;44:401 – 21.
[84] Argenta LC, Morykwas MJ. Vacuum-assisted clo-
sure: a new method for wound control and treat-
ment: clinical experience. Ann Plast Surg 1997;38:
563 – 76.
[85] Loos B, Kopp J, Bach A, et al. [Salvage of exposed
alloplastic materials in irradiated wounds: a case
report]. Zentralbl Chir 2004;129(Suppl 1):S133 – 6.
[86] Bihariesingh VJ, Stolarczyk EM, Karim RB, et al.
Plastic solutions for orthopaedic problems. Arch
Orthop Trauma Surg 2004;124:73 – 6.
[87] Yuan-Innes MJ, Temple CL, Lacey MS. Vacuum-
assisted wound closure: a new approach to spi-
nal wounds with exposed hardware. Spine 2001;26:
E30 – 3.
[88] Collins N. Anabolic agents and wound healing.
Adv Skin Wound Care 2001;14:154 – 5.
[89] Weed T, Ratliff C, Drake DB. Quantifying bacterial
bioburden during negative pressure wound therapy:
does the wound VAC enhance bacterial clearance?
Ann Plast Surg 2004;52:276 – 9.
[90] Moues CM, Vos MC, Van Den Bemd GJ, et al.
Bacterial load in relation to vacuum assisted clo-
sure wound therapy: a prospective randomized clini-
cal trial. Wound Repair Regen 2004;12:11 – 7.
[91] Steenvoorde P, Van Engeleand A, Oskam J. Vacuum
assisted closure therapy and oral anticoagulation
therapy. Plas Reconstr Surg 2004;113:2220 – 1.
[92] Gwan-Nulla DN, Casal RS. Toxic shock syndrome
associated with the use of the vacuum assisted clo-
sure device. Ann Plast Surg 2001;47:552 – 4.
[93] Fletcher A, Cullum N, Sheldon TA. A systematic
review of compression treatment for venous leg
ulcers. BMJ 1997;315:576 – 80.
[94] Colgan MP, Dormandy JA, Jones PW, et al. Oxpen-
tifylline treatment of venous ulcers of the leg. BMJ
1990;300:972 – 5.
[95] Samlaska CP, Winfield E. Pentoxifylline. J Am
Acad Dermatol 1994;30:603 – 21.
[96] Zamboni WA, Browder LK, Martinez J. Hyperbaric
oxygen and wound healing. Clin Plast Surg 2003;
30:67 – 75.
[97] Perins DJD. The effects of hyperbaric oxygen on
skin flaps. In: Grabb WC, Myers MB, editors.
Skin flaps. Boston7 Little Brown; 1975. p. 53 – 63.
[98] Perins DJD. Hyperbaric oxygen and skin coverage.
HBO Rev 1983;4:179.
[99] Mathes J, Feng L-J, Hunt TK. Coverage of the
infected wound. Ann Surg 1983;198:420 – 9.
[100] Wang C, Schwaitzberg S, Berliner E, et al. Hyper-
baric oxygen for treating wounds: a systematic re-
view of the literature. Arch Surg 2003;138:272 – 9.
[101] Kumar RJ, Kimble RM, Boots R, et al. Treatment
of partial-thickness burns: a prospective, random-
ized trial using Transcyte. ANZ J Surg 2004;74:
622 – 6.
[102] Pape SA, Byrne PO. Safety and efficacy of TransCyte
222 izadi
for the treatment of partial-thickness burns. J Burn
Care Rehabil 2000;21:390.
[103] Wisser D, Rennekampff HO, Schaller HE. Skin
assessment of burn wounds covered with a collagen
based dermal substitute in a 2 year-follow-up. Burns
2004;30:399 – 401.
[104] Navsaria HA, Ojeh NO, Moiemen N, et al. Reepi-
thelialization of a full-thickness burn from stem
cells of hair follicles micrografted into a tissue-
& ganchi
engineered dermal template (Integra). Plast Reconstr
Surg 2004;113:978 – 81.
[105] Goldman R. Growth factors and chronic wound
healing: past, present, and future. Adv Skin Wound
Care 2004;17:24 – 35.
[106] Nagai MK, Embil JM. Becaplermin: recombinant
platelet derived growth factor, a new treatment for
healing diabetic foot ulcers. Expert Opin Biol Ther
2002;2:211 – 8.