Management of the

C h ron i c B u r n Wo u n d
Stephen Tyler Elkins-Williams, MDa, William A. Marston, MDb,
Charles Scott Hultman, MD, MBAa,*

KEYWORDS
 Chronic wound  Hyperbaric oxygen therapy  Marjolin ulcer  Topical growth factor

KEY POINTS
 There exists little evidence to promote or refute the use of hyperbaric oxygen therapy (HBOT) in
acute burn wounds.
 Diabetic foot burns could be separately considered, given the body of evidence in chronic diabetic
foot wounds. Further research is necessary to prove the efficacy of HBOT in this setting.
 Marjolin ulcers are malignant degeneration of chronic wounds and occur most commonly in unex-
cised full-thickness burns.
 Average time from the initial injury to development of a Marjolin ulcer is 30 years. Cancers from Mar-
jolin ulcers tend to be more aggressive than common skin cancers.
 There are many cytokine growth factors available for use on burn wounds. Some promising studies
have been performed; additional research will help determine optimum patient selection and treat-
ment regimens.

INTRODUCTION have been used to facilitate wound healing? Have

Perhaps one of the most challenging problems in
burn care is obtaining stable, definitive closure of
the chronic wound that has failed to heal, using
conventional techniques. Although most of the
burn literature focuses on management of acute
wounds, including timing, depth, and type of exci-
sion, as well as method of skin grafting, obtaining
permanent closure of chronic wounds can be
elusive. This article reviews specific consider-
ations in the workup and management of chronic
burn wounds, realizing that resurfacing is not com-
plete until the burn surgeon obtains complete
closure of the integument.
Critical to restoring integrity of the skin is obtain-
ing a detailed history about the wound, which
helps build a differential diagnosis as to why
the wound has failed to close, either secondarily
physical therapy and occupational therapy
been involved in executing a plan? Are there
environmental or patient-related issues that
have prevented the wound from closing? This
history, combined with serial physical examination
of the wound, will help build a list of possible
causes:
 Mechanical: location over tendon or extensor
joint
 Metabolic: diabetes, hypothyroidism, autoim-
mune disorders
 Infectious: acute or chronic
 Vascular: inflow (arterial) and outflow
(venous), especially in extremities
 Lymphatic: destruction of regional network
causing lymphedema
 Radiation: progressive microvascular fibrosis
 Neoplastic: possible Marjolin ulcer or cuta-
plasticsurgery.theclinics.com

or through surgical intervention. How and

when did the burn occur? What previous attempts neous metastasis

a
Division of Plastic and Reconstructive Surgery, Department of Surgery, University of North Carolina Medical
Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; b Division of Vascular Surgery,
Department of Surgery, University of North Carolina Medical Center, University of North Carolina at Chapel
Hill, Chapel Hill, NC 27599, USA
* Corresponding author.
E-mail address: Scott_Hultman@med.unc.edu

Clin Plastic Surg 44 (2017) 679–687

http://dx.doi.org/10.1016/j.cps.2017.02.024
0094-1298/17/Ó 2017 Elsevier Inc. All rights reserved.
680 Elkins-Williams et al
 Personal: smoking, not compliant with splint-
ing or garments, poor wound hygiene
 Social: limited resources and poor access to
care (transportation, wound care supplies,
caregiver)
 Psychiatric: substance abuse, Munchausen
syndrome
This article reviews 3 issues pertinent to man-
agement of the chronic burn wound: (1) use of hy-
perbaric oxygen to facilitate wound closure, (2)
application of topical growth factors, (3) and diag-
nosis and treatment of Marjolin ulcers.
HYPERBARIC OXYGEN THERAPY
Introduction
The Undersea and Hyperbaric Medical Society de-
fines hyperbaric oxygen therapy (HBOT) as “an
intervention in which an individual breathes near
100% oxygen intermittently while inside a hyper-
baric chamber that is pressurized to greater than
sea level pressure.”1 In clinical practice, this pres-
sure typically exceeds 1.4 atm.1
The concept of using hyperbaric pressure to
treat patients dates back to 1662; a British cler-
gyman named Henshaw thought that hyperbaric
pressures could speed healing in acute medical
conditions. He created a sealed chamber that he
named the Domicilium, using organ bellows to
control changes in pressure. Henshaw could not
use isolated elemental oxygen in his treatments,
however, as it would not be discovered until
more than a hundred years later.2
Over the course of the late nineteenth and early
twentieth centuries, progress was made with the
use of oxygen for treatment of decompression sick-
ness, first in normobaric settings and later with the
additional of hyperbaric pressures. But it was not
until 1955 that Churchill-Davidson and colleagues3
published “High-Pressure Oxygen and Radio-
therapy,” using HBOT to potentiate the effects of ra-
diation therapy in patients with cancer, in The Lancet.
Thus began the era of modern HBOT in medicine.
Current Uses
The use of HBOT quickly expanded to a be used in
a wide variety of medical conditions, most of which
initially lacked evidence or standard protocols.
The Undersea and Hyperbaric Medical Society
was founded in 1967 and maintains a current list
of accepted medical indications for HBOT use,
one of which is acute thermal burn injury (Box 1).4
Hyperbaric Oxygen and Burns
The theory behind use of HBOT in burn injuries is
sound. Animal models have demonstrated that
Box 1
2014 Undersea and Hyperbaric Medical
Society’s indications for hyperbaric oxygen
therapy
 Air or gas embolism
 Carbon monoxide poisoning
 Clostridial myositis and myonecrosis (gas
gangrene)
 Crush injury, compartment syndrome, and
other acute traumatic ischemias
 Decompression sickness
 Arterial insufficiencies
 Severe anemia
 Intracranial abscess
 Necrotizing soft tissue infections
 Osteomyelitis (refractory)
 Delayed radiation injury (soft tissue and bony
necrosis)
 Compromised grafts and flaps
 Acute thermal burn injury
 Idiopathic sudden sensorineural hearing loss
HBOT can increase the partial pressure of oxygen
in end organ tissues. This elevation is achieved by
increasing the PaO2 of the blood to 10 to 15 times
normal, which creates a steep gradient down
which oxygen may diffuse into hypoxic tissues.5
Theoretically, increasing oxygen tension in burn
patients could decrease leukocyte activation,
reduce so-called secondary injury, and even
reduce tissue edema through an oxygen osmotic
effect.
Evidence in Burns
Despite this, very little quality research has been
done on the effectiveness of HBOT on patients
with burn injuries. In the 2004 Cochrane review,
Villanueva and colleagues6 found only 2 quality
randomized controlled trials (RCTs) evaluating
the effectiveness of HBOT in patients with acute
thermal injuries.6
1. Hart and colleagues,7 1974: 16 patients, 10%
to 50% total body surface area (TBSA) burns,
randomized to routine burn management and
HBOT or routine burn management with sham
HBOT
a. Intervention: 100% oxygen at 2 atmosphere
absolute (ATA) for 90 minutes every 8 hours
for 24 hours, then every 12 hours until healed
b. Mean healing times shorter in the interven-
tion group (19.7 days vs 43.8 days, P<.001).

c. Method criticisms: did not describe alloca-
tion concealment methods; no definition of
healing given, and no description of the
wound size and depth at presentation given
d. Questionable applicability: skin grafts in less
than half of the patients enrolled, calls into
question relevance in the early excision
and grafting era
2. Brannen and colleagues,8 1997: 125 patients
randomized to routine burn management or
routine burn management plus HBOT
a. Intervention: 100% oxygen at 2 ATA for
90 minutes twice a day for a minimum of
10 treatments, maximum of one treatment
per percent TBSA
b. Primary outcome: length of stay
c. Secondary end points: mortality, acute fluid
requirements, number of operations
required
d. No statistically significant difference in any
of these outcomes
There have been several nonrandomized
comparative studies performed over the years
that have suggested improvements with HBOT in
survival, hospital length of stay, and speed of ree-
pithelization.5 However, multiple investigators
have concluded that there is currently insufficient
evidence to either support or refute the use of
HBOT in the setting of acute thermal burns.5,6
Any future studies seeking to clinically investi-
gate HBOT in acute burn patients will need to
seek to understand the degree, type, and size of
burn that will see the most benefit. Additionally,
the optimal frequency, duration per session, and
overall length of therapy need to be explored.
Diabetic Foot Burns
The data for use of HBOT in chronic wounds are
more established. A recent Cochrane review of
the literature determined that HBOT improved
healing for diabetes-related foot ulcers and likely
reduced the rate of major amputation in this
same population.9 The evidence was not as strong
for venous stasis ulcers, but there was evidence
that HBOT may help to reduce the size of these
wounds.
Given the success of HBOT in diabetic foot
wounds, there has been a recent investigation by
Jones and colleagues10 into developing a protocol
for management of foot burns in diabetic patients.
Their protocol for determining which patients
could benefit from HBOT is summarized (Fig. 1):
The patients who are then determined to benefit
from HBOT undergo 14 treatments; if the transcu-
taneous partial pressure of tissue oxygen mea-
surements is improving, patients receive 6
Management of the Chronic Burn Wound 681
additional treatments. Those patients who are to
be skin grafted are treated both preoperatively
and postoperatively. Unfortunately, this protocol
has only ever been compared against a group of
historic controls from the 1970s and 1980s. There
are no data currently available that compares
HBOT with standard treatment in patients with dia-
betic foot burns.
Challenges
There are practical challenges of administration of
HBOT in burn patients that must be considered.
The most severely injured acute burn patients,
those who would stand the most to gain from the
potential benefits of HBOT, are typically intubated
and critically ill. The risks of leaving the burn
intensive-care-unit setting and being transported
to an HBOT chamber 2 to 3 times daily are not triv-
ial. Additionally, these types of patients would
require the use of multi-place HBOT chambers to
accommodate nursing and support staff. Multi-
place chambers are not likely to be as available
as the cheaper and smaller mono-place chambers
more commonly in use.
Summary/Recommendations
The theory behind application of HBOT in burn
wounds seems sound, and some early trials have
shown promise. However, to date there is inade-
quate evidence to make judgment on its efficacy.
There are some practical challenges in administra-
tion of HBOT in acute burn patients. Future study,
likely across multiple centers, will be necessary to
determine the optimum patient selection and
treatment protocol for HBOT use.
TOPICAL GROWTH FACTORS
Introduction
Cytokine growth factors have been found to pro-
mote wound healing in a variety of ways:
 Encourage chemotaxis of inflammatory cells
 Stimulate endothelial cells
 Affect the migration of various cells
 Stimulate angiogenesis
 Inhibit apoptosis
 Mediate the synthesis of other cytokines.11
Mechanism of Action
In order for wounds to heal, they undergo a stan-
dard progression through various stages of wound
healing (Fig. 2):
At each stage, different humoral factors and
cells interact in specific ways. Changing these in-
teractions, or the timing of the interactions, can
alter wound healing and lead to hypertrophic scars
682 Elkins-Williams et al

Fig. 1. Algorithm for use of HBOT in diabetic foot burns. DM, diabetes mellitus; HbA1c, hemoglobin A1c. (Data
from Jones LM, Rubadue C, Brown NV, et al. Evaluation of TCOM/HBOT practice guideline for the treatment
of foot burns occurring in diabetic patients. Burns 2015;41(3):536–41.)

or nonhealing wounds. The key to successfully us-
ing cytokine growth factors in burn wounds is to
choose the proper growth factors that can speed
wound healing without causing adverse effects.
Types of Growth Factor
There have been a wide variety of types of cyto-
kine growth factors that have been investigated
for burn wounds. These growth factors include
platelet-derived growth factor (PDGF), fibroblast
growth factors (FGFs), epidermal growth factors
(EGFs), transforming growth factor (TGF) alpha,
vascular endothelial growth factor, insulinlike
growth factor I, nerve growth factor, TGF beta,
granulocyte-macrophage colony-stimulating fac-
tor (GM-CSF), and amnion-derived cellular cyto-
kine solution.12 Although the heterogeneity of the
types of available growth factors gives clinicians
and investigators a diverse toolbox, the diversity
can also make it difficult to compare and pool
studies.
Types of Burn Wounds
Further complicating matters are the different
types of wounds with which one might wish to
use a cytokine growth factor. They could be
applied to partial-thickness burns, full-thickness
burns, the interstices of meshed skin grafts, or
even skin graft donor sites. Ching and col-
leagues12 performed a very thorough review of
available studies, in both animal and human
models, investigating the use of the full spectrum
of cytokine growth factors. Although their use in
partial-thickness burns comprised most of the
data, studies have been performed in full-
thickness burns as well as over skin grafts and

Fig. 2. Phases of wound healing.
even to donor sites. There is encouraging evi-
dence for all types of cytokine growth factors in
speeding wound healing. They do note, however,
further study to generate high-quality human
data is warranted.
Current Evidence
There have been several recent high-quality RCTs
demonstrating the effectiveness of EGF and PDGF
in simulated partial-thickness burns in animal
models.13,14 In addition, as Zhang and col-
leagues15 demonstrated, at least 13 RCTs
have been performed in human subjects. All of
these studies were performed in Asia (China and
Japan), and many of them were never published
in English. Although the investigators expressed
concern over various methodological flaws in the
studies, they did note a consistent positive
improvement in speed and quality of wound heal-
ing seen with FGF, EGF, and GM-CSF in partial-
thickness burns.
These particular cytokines are likely suited to
partial-thickness burns. By definition, the depth
of a partial-thickness burn is limited to the papillary
dermis (grade IIa) or reticular dermis (grade IIb).
FGF and EGF are mitogens for endothelial cells
and dermal fibroblasts, whereas GM-CSF works
Management of the Chronic Burn Wound 683
directly on the keratinocyte and endothelial cell.
Because deeper structures, such as subcutane-
ous fat, muscle, and blood vessels, are spared,
growth factors targeting these additional tissue
types are likely unnecessary.16
Future Challenges
There is certainly a theoretic concern for cytokine
growth factors to stimulate oncogenesis. The
mechanisms by which growth factors promote tis-
sue repair are also those implicated in malignant
degeneration. Fortunately, tumor development
has not yet been seen in clinical or experimental
studies.16 Given our knowledge of the latency
time for Marjolin ulcers, however, the typical
follow-up time seen in human studies of GFs is
inadequate to detect future chronic malignant
changes as an adverse effect.
Summary
Overall, the use of cytokine growth factors, partic-
ularly FGF, EGF, and GM-CSF, has shown prom-
ise in speeding the healing of partial-thickness
burns. Additional large trials attempting to deter-
mine the optimum dosage regimen and delivery
method of GFs will be useful in the future to maxi-
mize patient benefit.
684 Elkins-Williams et al
MARJOLIN ULCERS
Introduction
Jean-Nicolas Marjolin was born in 1780. At a
young age, he rose to become the Chair of Surgi-
cal Pathology at the University of Paris by 1819. He
was a contemporary of Dupuytren, who served
concurrently as the Chair of Operative Medicine.
In 1828, Marjolin published an article describing
“cancer-like ulcers.”17 Later, in 1850, Dr Robert
Smith described neoplastic changes in a chronic
ulcerating scar tissue and labeled this “Warty ul-
cers of Marjolin.”17 De Costa again described ma-
lignant degeneration of burn scars in 1903 as
Marjolin ulcers, and the name stuck.17 Today, the
term generally refers to any long-term malignant
changes in chronic scars.
Pathophysiology and Epidemiology
It is thought that any chronic inflammatory condi-
tion, not just burn scars, can lead to Marjolin ul-
cers. Other inciting conditions are seen in Box 2:
Incidence is difficult to determine, but numbers
cited in the literature range from 0.77% to 2.0%
of deep burns that have been allowed to heal by
secondary intention.11 By far the primary histolog-
ic type of Marjolin ulcer is squamous cell carci-
noma (SCC), with Marjolin ulcer accounting for
up to 2% of diagnosed SCCs. The second most
common histologic type is basal cell carcinoma
(BCC) of the skin; Marjolin ulcers contribute to
0.03% of these overall. Rare cases of melanoma,
sarcoma, squamo-BCC, dermatofibrosarcoma
protuberans, and mesenchymal tumors have
been reported as well.11
The exact pathogenesis of Marjolin ulcers is un-
known, though several mechanisms have been
proposed. Lymphatic obliteration is thought to
diminish the body’s ability to detect cellular muta-
tions, allowing atypia to persist longer and
Box 2
Other conditions potentially leading to
Marjolin ulcer
Vaccinations
Snake bites
Osteomyelitis
Pressure sores
Spinal Cord Injury
Pilonidal abscess
Dermatitis artefacta
Venous stasis ulcers
transform into carcinoma. Additional potential
causes include
 Chronic irritation
 The avascular nature of the scar
 Release of toxins from damaged tissues
 Immunologic factors
 Repeated trauma
Another theory, the 2-hit hypothesis, states that
the burn causes some baseline mutations in the
cell. These mutations leave them more susceptible
to future DNA damage (for instance, from UV radi-
ation) leading to malignant changes.11,17
Marjolin ulcers can develop in any anatomic
location, though the most common site is the
lower extremities, followed by the upper extrem-
ities.18 They are more common in men, though
this may be a result of the increased incidence of
burns in men as well. All age groups can acquire
Marjolin ulcers; the latency period inversely relates
to patients’ age at time of injury. That is, children
typically have a very long latency time, whereas
the elderly have a much shorter latency interval.11
There are 2 type of Marjolin ulcers:
 Acute: much rarer; malignant degenerations
within 1 year
 Chronic: more common; any Marjolin ulcer
taking place more than 12 months after injury
The latency period for chronic ulcers can vary
widely (ranging from 11–75 years), but the average
is thought to be 30 years.19 When considering
classifying a new diagnosis of malignancy as a
Marjolin ulcer, it is useful to keep in mind the
criteria proposed by Giblin and colleagues20 as
seen in Box 3.
Clinical Presentation
Any nonhealing or ulcerative wound that appears in
a chronic scar should raise suspicion for a Marjolin
Box 3
Establishing relation of cancer to burn scar
1. Incontrovertible evidence of the burn (by
wound or scar)
2. Cancer origin within the boundaries of the
burn scar
3. Absence of precursory or similar neoplasm
on the site before the burn
4. Histologic type of cancer compatible with
the type of tissue that was burned (ie, SCC,
BCC, and so forth, in burned skin)
5. Appropriate interval of time between burn
injury and development of cancer
 Management of the Chronic Burn Wound 685

ulcer. The clinical appearance is most commonly a In developed nations, early excision and grafting
flat, ulcerative lesion with elevated margins and is standard. The patients most at risk for develop-
surrounding induration. They can also appear as ment of Marjolin ulcers are those with poor access
an exophytic lesion resembling granulation tis- to health care. In a recent large series from
sue.11,17,19 There should be a low threshold to Bangladesh, Das and colleagues21 included 140
obtain a biopsy in the appropriate clinical scenario. patients with burn scar ulcers over a 10-year
period, of which 46 (33%) were found to have ma-
Workup and Treatment lignant changes. Of the patients with malignancy,
Once a biopsy confirms the diagnosis, patients 77% had a primary-level education or less. Appro-
should be worked up with staging in accordance priate treatment of deep burns with excision and
with usual oncologic principles. grafting at the time of injury minimizes the future
risk of malignant transformation of resultant scars
 There is no TMN staging specific to Marjolin to Marjolin ulcers.
ulcers.
 The staging system for the histologic type of Case Report
tumor should be used.
 Marjolin ulcers tend to be more aggressive The authors present a 75-year-old woman who
than common skin cancers. had sustained a more than 50% TBSA burn
 Metastasis rate of 27.5%14 from a house fire when she was 4 years old.
 A thorough lymph node examination should Over the course of 11 months, she developed a
be performed. nonhealing ulcer in the right upper quadrant of
 Consider imaging to look for distant her abdominal wall, managed initially by a wound
metastases. care center, with topical growth factors and bio-
 Chest radiography logical dressings. Punch biopsy was eventually
 Brain computed tomography obtained, revealing a diagnosis of SCC, arising
 Abdominal ultrasound or cross-sectional from her burn scar. Physical examination by the
imaging senior author was positive for an ulcerative,
5  8-cm skin lesion (Fig. 3), which was fixed to
Surgery remains the primary treatment of Marjo- the underlying fascia but negative for axillary or
lin ulcers. A wide excision of the primary lesion
should be performed. Most investigators advocate
for at least 2-cm margins,11,17,19 with a split-
thickness skin graft or flap coverage of the wound.
Occasionally, amputation is needed. Most agree
that a prophylactic lymph node dissection is not
indicated. Clinically positive nodes warrant biopsy
and/or lymph node dissection. Some investigators
advocate for a sentinel node biopsy to be per-
formed if nodes are clinically negative. There is
no standard agreed on protocol for the addition
of adjuvant therapies after adequate surgical exci-
sion. Those described include radiotherapy;
chemotherapy with agents, such as topical 5-fluo-
rouracil, methotrexate, and L-phenylalanine
mustard; and intra-arterial limb isolation perfusion
therapy.17 Poor prognosis when compared with
other types of skin cancer is to be expected.

Prevention
Prevention is perhaps the best strategy in treat-
ment of Marjolin ulcers. Allowing burn wounds to
go unexcised and heal by secondary intention pla-
ces patients at much high risk for development of
Marjolin ulcers in the future. Patients with resultant
fragile burn scars should have these re-excised, or
at the minimum closely monitored, to ensure that Fig. 3. A 75-year-old woman with a Marjolin ulcer in
they do not undergo malignant transformation. right upper abdominal wall.
686 Elkins-Williams et al
Fig. 4. Status post resection and skin graft, with 85%
take, secondary to zoster infection in dermatome.
Fig. 5. Three years following wide local excision, no
evidence of recurrent disease.
inguinal adenopathy. Computed tomography
scan demonstrated extension to, but not through,
the anterior rectus abdominis fascia, with no evi-
dence of nodal involvement. At the time of surgi-
cal resection, 1 month later, the lesion had grown
to 7  9 cm and was excised with a 2- to 3-cm
margin, leaving a 13  14-cm defect that was
skin grafted. Sentinel lymph node biopsy was
also performed with lymphoscintigraphy and lym-
phazurin blue dye, localizing the basin to the right
groin, where 2 sentinel lymph nodes were
removed. Frozen-section biopsies were obtained
from all 4 quadrants, as well as the deep margin,
all of which were negative for tumor, as were the
lymph nodes from the right groin. Her postopera-
tive course was complicated by a herpes zoster
wound infection, which resulted in an initial 85%
take of her skin graft (Fig. 4). Three years later,
she remains free of disease (Fig. 5). Tumor sur-
veillance is performed by semiannual physical
examination.
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