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J Burn Care Res. Author manuscript; available in PMC 2018 May 01.
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Published in final edited form as:

J Burn Care Res. 2017 ; 38(3): e605–e613. doi:10.1097/BCR.0000000000000538.

Burn Wound Healing and Tissue Engineering

Adam J Singer, MD1 and Steven T Boyce, PhD2
1Department of Emergency Medicine, Stony Brook University, Stony Brook, NY
2Department of Surgery, University of Cincinnati, Cincinnati, OH

8.1 Definition
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Wound healing is a complex and dynamic process that starts after injury and continues for
months to years as the scar undergoes remodelling. For the purpose of this paper wound
healing refers to the initial phase of healing that ends with wound closure or re-
epithelialization and restoration of the epidermal barrier, either by secondary spontaneous
healing, or by primary closure as with a skin graft. According to the FDA Guidance for
Industry Chronic Cutaneous Ulcer and Burn Wounds - Developing Products for Treatment,
complete wound closure is defined as skin re-epithelialization without drainage or dressing
requirements confirmed at two consecutive study visits 2 weeks apart.1

8.2 Indications for clinical care and research

Wound closure after burns is one of the most important determinants of survival and long-
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term outcomes such as function and aesthetics. Early wound closure reduces the risk of
infection and fluid losses and has been shown to reduce mortality, length of hospital stay,
and subsequent hypertrophic scarring.2–5 Thus, early closure of burns is a cornerstone of
comprehensive burn care. Despite its importance, validated methods to objectively measure
wound closure are lacking, making any comparisons of novel therapies difficult.

It is understood generally that wound healing and long-term outcomes are determined by
burn depth. While partial thickness burns can heal spontaneously with minimal scarring,
deep partial thickness and full thickness burns require more than three weeks to close and
are often associated with significant scarring and functional limitations unless excised and
grafted within the first few days of injury.6 Thus, accurate diagnosis of burn depth is
necessary in order to achieve optimal outcomes. It is also known that burn injury may
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continue to progress over the first few days leading to the conversion of superficial burns to
deep burns. Better understanding of the mechanisms leading to burn wound conversion is
likely to lead to novel therapies that limit burn wound progression leading ultimately to
better healing.

Because burns are characterized by the presence of various amounts of non-viable, necrotic
tissue, removal of the eschar and proper wound bed preparation are necessary, regardless of

Correspondence: Adam J Singer, MD, Department of Emergency Medicine, Stony Brook University, 8350 SUNY 8350, Stony Brook,
NY 11794-8350, [email protected].
 Singer and Boyce Page 2

whether wound closure is to be achieved by primary or secondary closure. For these reasons,
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research in wound healing is necessary to identify the optimal approach to wound

preparation and closure.

8.3 Priorities in wound healing research

Priorities in wound healing research were established at the State of the Science conference
of the American Burn Association (ABA) in 20067, and included: 1. Development and
validation of standardized tools to assess wound healing; 2. Defining, grading, and
understanding the pathophysiology of hypertrophic scarring and pruritus; 3. Development of
innovative treatment modalities for wound healing and scarring; and, 4. Optimization of
wound healing. Those priorities were complemented by the ABA in 2012 with metrics for
evaluation of burn wound healing, burn wound infection, wound closure, and identification
of gaps in knowledge to promote opportunities for research 8.
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To advance the current state of the science, members of the committee agreed upon the
following priorities in wound healing research over the next ten years:

• Development and validation of inexpensive, simple and reliable methods to

determine burn depth

• Better understanding of the pathophysiology of burn wound conversion and

discovery of methods to prevent or reduce burn injury progression

• Need for alternative methods to achieve eschar removal while preserving viable
tissue, and the development of tools to assist the surgeon in determining the
endpoint for eschar removal in addition to bleeding of viable tissue

• Development of novel methods for early diagnosis of burn wound infection and
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better therapies to address biofilms, such as novel topical antimicrobial or

antiseptic agents effective against multi-drug resistant organisms

• Development and validation of non-invasive and objective tools to measure

wound closure

• Development of methods to accelerate wound closure and promote durable

wound closure with less breakdown after closure

• Development of advanced skin substitutes, which contain all elements of native

skin (i.e., epidermal barrier, basement membrane, dermis, hair follicles, sweat
and sebaceous glands, nerves, vessels, pigment, immune cells) 9
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4.0 State of the Science

The current paper is not intended to be a comprehensive review article on all the topics
identified as priorities for research. Rather, this section will summarize some of the past
findings emphasizing the most recent promising developments in each respective area.

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4.1 Determination of Burn Depth

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Accurate determination of burn depth is one of the most important decisions in burn care. It
not only predicts healing but also helps determine optimal therapy. Despite its critical
importance, in most cases, clinical assessment is used for determining burn depth.
Unfortunately, even when performed by an experienced burn clinician, the accuracy of
clinical assessment is less than 75%10,11. As a result, a large number of methods have been
developed and evaluated for increasing the accuracy of burn depth determination including
radioactive isotopes, vital dyes, thermography, photometry, MRI, and ultrasound.12 Of all
methods, scanning laser Doppler imaging (LDI) is the most commonly used to help
determine burn depth.13 While some studies suggest an accuracy of up to 96–100% 2 days
earlier than clinical assessment, others have found lower accuracy and called for greater
validity and reproducibility.14 A recent systematic review of 26 studies confirmed that LDI
was more accurate and feasible to use than laser Doppler flowmetry.15 However, due to
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several limitations, such as large size, high cost and long image acquisition times, LDI has
not been widely adopted outside of research settings. Fast LDI, using a faster laser Doppler
Line Scanner (LDLS) that scans 300 cm2 in 4 s significantly reduces scanning time
increasing its feasibility, especially in children. A recent analysis of 596 burn areas from 204
patients demonstrated an accuracy of 94.2% for the new scanner compared with 94.1% for
the original LDI scanner.16 Its smaller size and mobility were additional benefits of the new
scanner. In this study, as in many other LDI studies, scans were performed between 2–5 days
after injury. However, by 5 days after injury, clinical accuracy is greatly improved. Thus,
there is still a need for reliable and simple methods that allows accurate depth determination
as early as possible after injury.

Advancements in infrared thermography have also renewed the interest in this modality for
diagnosing burn depth. A recent clinical study of 39 burns found that the overall accuracy of
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static thermography (using a hand held, commercially available camera) in predicting burn
depth was considerably higher than that of clinical assessment; 87.2% (95% CI: 71.8–95.2)
vs. 54.1% (95% CI: 37.1–70.2), as early as 48 hours after injury.17 Active dynamic
thermography, which measures the ability of tissue to conduct heat transfer relative to its
surroundings, has also been explored in animal models with promising results.18 Another
promising modality is dermoscopy, which allows visualization of the microanatomy of the
skin’s vasculature using a small, hand-held device. A study of 30 burns, which were
assessed between 4–166 h after injury, demonstrated an accuracy of 96.7% at distinguishing
between superficial and deep dermal burns.19 A study comparing infrared thermography,
spectrophotometric intra-cutaneous analysis and LDI in adult patients with burns
demonstrated that both thermography and spectrophotometry were less expensive, easier to
use and more acceptable to patients than LDI.20
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Other novel modalities that have been recently evaluated for burn depth diagnosis include
video-microscopy, optical coherence tomography (OCT), photoacoustic imaging and
hyperspectral imaging.21–25

Attempts to enhance the accuracy of burn depth estimation have also combined several
methods of assessment. For example, dual imaging with optical coherence tomography
(OCT) and pulse speckle imaging (PSI) has been evaluated in a porcine model at 1 h, 24 h,

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and 48 h after injury. The combined performance provided an overall Receiver Operating
Characteristic-Area Under the Curve of 0.87.26
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While there have been major technological advances in the area of burn depth diagnosis, an
ideal or optimal method, which is non-invasive, simple, rapid, cost effective, and accurate as
early as possible after injury remains elusive. Further research in this area is encouraged to
attain this goal. For a more in depth review of recent developments in methods to diagnose
burn depth the reader is referred to Paul et al.27

4.2 Limiting Burn Injury Progression and Conversion

Burn injury progression, or the conversion of superficial burns to deep burns, is
characteristic of many burns leading to worse outcomes. While incompletely understood, a
number of mechanisms likely play a role in its pathophysiology.28,29 Injury progression
occurs as a result of reduced dermal microcirculation, free radical generation, and the release
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of a large number of cytokines and wound modulators. Increased vascular permeability leads
to tissue edema and together with hypercoagulability and vessel thrombosis further impair
dermal perfusion. Based on these observations a large number of potential therapies have
been evaluated in an attempt to limit inflammation and oxidative stress and improve dermal
circulation thereby reducing burn injury progression and conversion. A comprehensive
review of the many therapies evaluated thus far is beyond the scope of this paper, and is
presented in greater detail in a review by Shupp et al.29 However, to date, none of these
therapies have been approved for use in limiting burn progression. This is not surprizing
since the pathophysiology of injury progression is multifactorial and may vary from patient
to patient, and burn to burn. Thus, multimodal approaches using more than one agent or
therapeutic interventions, specifically tailored to the individual patient and burn, may be
more effective than currently available unimodal approaches. However, better understanding
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of the underlying pathophysiology as well as the contributions of individual interactions

between the genetic makeup of the burned patient and environmental insult may open up
new avenues for exploration and development.

4.3 Eschar Removal

In 1970 Janzekovic reintroduced the concept of early excision and immediate grafting of
deep burns.30 Since this monumental publication, early excision of the burn eschar has
become the standard of care for deep burns31. While the critical importance of early eschar
removal and wound coverage is well accepted, the exact method and timing remain the
subjects of debate. While very effective, in its current form, tangential excision is traumatic,
requires specialized personnel and equipment and is often delayed several days until
accurate burn determination can be made, especially in mixed and indeterminate depth
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burns. Furthermore, the extent of excision is based on visual presence of bleeding of the
viable wound bed, which may not always be accurate. A histological study of excised burn
eschar suggests that not uncommonly, normal viable tissue is sacrificed while non-viable
eschar may remain32. Thus, additional methods that enhance surgical assessment of the
endpoint of excision beyond visualization of bleeding may further improve the selectivity
and specificity of this time honoured procedure. Alternative methods of eschar removal that

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are less traumatic and more selective than excision include laser debridement and rapid
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enzymatic debridement.

An observational study has suggested that topical application of methylene blue to burns
with mixed depth may help to distinguish between viable and nonviable tissue facilitating
more precise and complete wound debridement.33 A hydrosurgery system has also been
advocated for burn wound debridement, with the suggestion that enhanced preservation of
dermal tissue might reduce subsequent scarring. Thirty-one children underwent conventional
debridement, and 30 underwent hydromechanical debridement. There was a significant
difference in the amount of viable dermal preservation between the two groups (p=0.02),
with more viable tissue lost in the conventional group (median 325 μm) versus the
hydrosurgery group (median 35 μm).34 However, there was no difference in graft take and
3–6 month scarring. Thus further refinements or alternative methods are required in order to
improve upon conventional surgical excision.
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Use of laser for burn eschar debridement has also been reported, but mostly in experimental
animal models of burns35–37. A study of CO2 laser ablation in full thickness porcine burns
demonstrated that long-term scarring, based on Vancouver scar scale assessments and
histologic evaluation, was equivalent at 6 months in laser-ablated and sharply excised
burns36. While use in humans is limited,38 a pilot study in 21 children with full thickness
burns demonstrated the feasibility of laser vaporization of burn eschars in patients with
successful immediate autografting39. Since then, major refinements and advances in laser
technology have occurred that will likely further enhance this methodology for eschar
removal.

While enzymatic debridement is not new,40 a bromelain based enzymatic debridement agent
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has recently been approved by the European Medicines Agency (EMA) and is currently
undergoing an FDA regulated phase 3 clinical trial. With this agent, rapid debridement is
achieved after a single 4-hr application in most cases. A recent RCT included 182 patients
aged 4–55 years with deep partial and full thickness burns covering 5–30% of their total
body surface area (TBSA). The enzymatic agent significantly reduced the time from injury
to complete debridement (2.2 vs. 8.7 days, P<0.0001), need for surgery (24.5% vs. 70.0%,
P<0.0001), the area of burns excised (13.1% vs. 56.7%, P<0.0001) and the need for
autografting (17.9% vs. 34.1%, P=0.01) compared with standard surgical or non-surgical
treatment41. Furthermore, scar quality and quality of life scores were similar in both study
groups as were the rates of adverse events.

4.4 Management of Microbial Contamination and Wound Infection

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Loss of the stratum corneum of the epidermis provides an entry point for environmental
microorganisms which persists until the outermost layer of the skin is restored. In partial
thickness burns, this period may range from a few days to a few weeks during which
microbial organisms may proliferate, form biofilms, impede wound healing, or invade open
wounds. As discussed above, early removal of the burn eschar and frequent cleansing of the
wound will slow microbial progression. Topical application of antimicrobial agents, such as
bacitracin, nystatin and silver sulfadiazine 42,43 have been shown to promote restoration of
the stratum corneum, to initiate the long-term closure of the wound, and to support

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resolution of the inflammatory phase of healing. More recently, dressings that release
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elemental silver have been shown to be effective in reduction of wound contamination on

partial thickness burns, and to require less nursing care than administration of traditional
topical antimicrobials 44.

Current management of full-thickness wounds includes early excision, or enzymatic

debridement, both of which require a temporary coverage of open wounds with either
cadaver allograft, or an acellular skin substitute with an artificial barrier, such as silicone or
polyurethane 45–47. In full-thickness burns of large TBSA, wounds may remain open and at
risk for wound infection for months. In addition to the environmental sources of wound
organisms, the gut and the lungs also become sources of wild-type and antibiotic-resistant
organisms. Due to the ubiquitous nature of microorganisms in the hospital environment,
prophylactic administration of highly-effective topical agents, such as 5% v/v mafenide
acetate solution have been used for extended periods until autografting can be completed 48.
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However, 5% mafenide acetate solution has been shown to be cytotoxic to tissue engineered
skin substitutes 49. Tissue-engineered grafts containing cultured keratinocytes and/or
fibroblasts have been used with mixtures of antimicrobial agents that cover common types of
Gram-negative, Gram-positive and fungal organisms without toxicity to the transplanted
cells, or to the angiogenic response of the ingrowing vasculature 50,51. Although these
alternative approaches may help to control microbial overgrowth in open burn wounds, risks
of complications remain until the wounds are closed.

Among the greatest challenges of microbial management of burn wounds are multi-drug-
resistant organisms which may lead to invasive wound infection, and potentially lethal
complications, such as pneumonia, sepsis and fasciitis. Several species of bacteria, including
Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococcus
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(VRE), Carbapenem-Resistant Enterobacteriaceae spp. (CRE), Pseudomonas spp., non-

albicans Candida spp., and Aspergillus spp., have been associated with increased mortality
after burns 52,53. Most of these strains have nosocomial origins, can spread within burn units,
and be very difficult to eradicate. Although a new generation of antimicrobial agents is being
developed 52,54, it is often necessary to use agents with high chemical toxicity, such as
chlorhexidine gluconate, which may impede wound healing while controlling wound
infection.

Ultimately, wound closure with autologous epithelium restores both a source of innate
immunity, such as defensins and cathelicidins 55,56 in the epidermis, and a full complement
of immune effector cells in the dermal tissue. Together with improved nutrition to maintain
the cellular immunity 57,58, accomplishment of wound closure with autologous epidermis
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remains a definitive factor to long-term control of microbial contamination and infection of

burn wounds.

4.5 Measuring Wound Closure and Scar

Simultaneous with these novel advances, an array of non-invasive, biophysical instruments
has become available to provide absolute, objective measures of cutaneous qualities
including color, shape/surface texture, visco-elastic pliability, blood flow, surface hydration
and water vapor transpiration. With regard to wound closure, skin surface hydration

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measured by electrical capacitance has been reported after treatment of excised, full-
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thickness burns with meshed and expanded skin autograft, or engineered skin
substitutes.59,60 Because a dry epithelial surface is easily determined by an experienced
clinician, direct tracing of wounds, or scaled photography, followed by image analysis has
also been used reliably and accurately to quantify burn wound closure. 61,62 Most of the
non-invasive instruments have been validated for clinical use in the EU, but not in the US. 63
An important source of error in most assessments with instruments is the measurement of
individual points within the wound, rather than the entire wound as a heterogeneous field.
Therefore, use of a uniform sampling pattern is critical to validity of instrumental measures.
Instruments, such as the scanning LDI described above, overcome this limitation by
assessment of the entire wound field. These kinds of instruments complement traditional
ordinal scoring of scars by a trained assessor as with the Vancouver Scar Scale 64, by the
patient in the Patient-Observer Self-Assessment Score (POSAS), or by the University of
North Carolina “4P” assessment of pruritus, pain, parasthesias and pliability 65,66 scales of
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scar assessment.

4.6 Accelerating Wound Healing and Durable Wound Closure

For wounds that are judged not to require grafting, negative pressure wound therapy
(NPWT) has been reported to facilitate epithelial closure67. NPWT has also been reported to
promote engraftment of split-thickness skin grafts by improved immobilization.68 Despite
numerous anecdotal reports of the benefits of NPWT in treatment of burns, there are not yet
sufficient well-controlled, prospective, randomized clinical trials to validate any putative
benefits of NPWT in burns.

4.7 Skin Substitutes and Tissue Engineering

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In addition to the potential benefits of devices to promote, revise and assess healing wounds,
the fields of tissue engineering and regenerative medicine have begun to offer cellular
therapies for burns, other cutaneous wounds, and most of the tissues in the body. Since 2006,
advanced models of engineered skin substitutes have been described that consist of
allogeneic cells to provide temporary protection of wounds, and to promote epithelial
closure with autologous epidermal keratinocytes in the wound, or dermal-epidermal
autografts 69,70. An initial model of gene therapy with an engineered skin model secretes
elevated levels of the native antimicrobial peptide, cathelicidin, and has been cleared for
clinical trial56. Engineered skin substitutes with autologous keratinocytes are capable of
providing sufficient epidermal cell populations to cover burns up to 99% TBSA, and may be
applied as keratinocyte sheets, sprays of cell suspensions, or bi-layered compositions with
both epidermal keratinocytes and dermal fibroblasts 71. These kinds of cell therapies for skin
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wounds have been shown to provide definitive wound closure that enables survival after life-
threatening burns 70. Some of these models are applied as stratified epithelial sheets which
suppress granulation tissue and scar. Most, if not all of these cell therapies leverage the
biological capabilities of exponential cell replication to generate large cell populations to
conserve donor tissue for expansion far beyond conventional standards for meshed split-
thickness autografts. Conservation of donor skin also increases availability of sheet autograft
for early grafting of critical areas, such as the face, hands, feet and perineum.

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Despite these important advances with cell therapies, current models are based upon post-
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natal wound healing physiology which does not stimulate regeneration of native
microvasculature, sensory nerves, pigmentation, sweat glands, sebaceous glands, hair
follicles, or native dermal extracellular matrix. These structures form only during fetal
development, but are required to restore complete anatomy and physiology of the skin to an
uninjured condition. This complete restoration to the uninjured condition distinguishes
tissue engineering based on mechanisms of wound healing from regenerative medicine
based on mechanisms of embryonic and fetal development. 9 Because of the categorical
importance of true regeneration of uninjured tissues of all types, there has been explosive
growth in the fields of regenerative medicine, stem cell biology and gene therapy. Due to the
relatively rapid expansion of knowledge in the normal development and biology of human
skin, it may be predicted with confidence that discoveries of basic science knowledge will be
translated into new therapies with capabilities to minimize morbidity, and restore a more
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normal quality of life.

Concurrently with the development of advanced cell therapies, regulatory standards for
determination of safety and efficacy have also continued to advance72. Among the several
criteria for evaluation, determination of medical risk is a fundamental factor. Because most
of the novel compositions for transplantation of cells and degradable scaffolds have no
precedent, by definition, they fall by default into the highest category of regulatory risk,
which is Class 3 for devices. A high risk category places the highest burden of proof on the
developers and sponsors of the therapies, and leads to very long and costly studies to satisfy
the regulatory statutes for safety and efficacy. It may be anticipated that as precedents for
cellular therapies become established, and consensus designs emerge, that time and
resources to obtain regulatory permissions for marketing may decrease.
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5.0 Summary of Roundtable Discussion

While the group participants agreed that much progress has been made since the last State of
the Science conference, greater advancements in burn depth diagnosis, wound bed
preparation, microbial management, wound closure and the development and use of skin
substitutes are still needed greatly. Of particular importance was the perspective of the burn
survivors. According to these key stakeholders, two of the most important and unmet needs
of burn survivors are finding more effective ways to relieve burn itching, and avoiding
recurrent and problematic skin breakdown, after initial wound closure. The group
acknowledged that little was known regarding the frequency, causes, and consequences of
recurrent skin breakdown. More effective management of this lack of durability of skin
closure certainly will require better understanding of the mechanisms leading to skin
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breakdown. However, more durable methods of wound closure are clearly needed.

Recognizing that burn depth is a dynamic and progressive process as well as a major
determinant of outcome, better understanding of the mechanisms leading to the conversion
of superficial burns to deep burns is needed in order to develop novel methods to reduce
burn wound progression. This will probably require multi-pronged approaches using various
therapeutic “cocktails” that combine multiple agents targeting different pathways. In
addition, objective, simple, inexpensive, non-invasive methods that allow accurate burn

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depth diagnosis, as early as possible after injury, should also be a major research focus in the
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years to come.

The major importance of early and selective burn debridement and eschar removal,
regardless of method of wound closure, was discussed. Surgical methods of removal of the
eschar (such as tangential excision) remain the standard of care for deep partial thickness
and full thickness burns. However, this method is somewhat crude sometimes sacrificing
viable tissue while leaving non-viable tissue behind. Furthermore, the endpoint for surgical
excision is somewhat subjective and operator dependent. Thus better methods for removing
the eschar and determining the endpoint for debridement are needed. Less invasive methods
such as hydrotherapy, laser ablation, and rapid enzymatic debridement will need to continue
to be developed and evolve.

Microbial contamination of burn wounds, local infection and sepsis continue to be major
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problems leading to considerable morbidity and mortality. The emergence of numerous,

multi-drug resistant organisms has further complicated matters. The development of
methods that allow early detection of wound contamination and infection, before the patient
becomes septic, were also noted to be an important area for future research. The
development of novel topical and systemic antimicrobial agents effective against the
emerging multi-drug resistant “superbugs” will require greater cooperation and collaboration
between industry and academia. Furthermore, the central role of biofilm formation was
recognized and will need to be addressed if effective yet nontoxic therapies are to be
developed successfully.

Wound closure continues to be one of the most important outcomes of burn care. Wound
closure not only reduces evaporative water losses and protects the patients from
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contamination and infection, but it is also associated with subsequent scarring. While a
number of objective methods of measuring wound closure have been proposed, clinical
assessment remains the most commonly used method to verify closure. More objective
methods that are simple, inexpensive, and non-invasive are clearly needed. Additional
development of methods aimed at accelerating closure of the burn and donor sites is also
needed.

With regard to skin substitutes, the group acknowledged the major advances made over the
last decade. Considerable regulatory and scientific barriers still remain, which have slowed
down development. To address the regulatory delays, the group expressed strong interest in
development of a collaborative dialogue with the FDA to facilitate evaluation and future
availability of novel burn therapies. The need for skin substitutes that contain all of the
essential elements of the skin including an epidermal barrier, a durable yet elastic collagen
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based dermal matrix, pigment cells, blood vessels, nerves, hair follicles, sebaceous glands,
sweat glands and immune cells was reemphasized. Availability of a multi-layered, multi-
component, non-immunogenic, off-the-shelve, universal skin substitute remains one of the
most important objectives of burn wound management.

Together, the participants in the roundtable discussion on burn wound healing and tissue
engineering identified these several objectives as areas in which active research may

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improve outcomes for burn patients during the next ten years and beyond. With a perspective
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on the momentum of burn research since the 2006 State of the Science conference to the
present, it can be predicted with confidence that most, if not all, of the topics discussed here
will be addressed, and that new knowledge will generate additional reductions in mortality
and morbidity from burn injuries in the years ahead.

Acknowledgments
The 2016 State of the Science Meeting, Progress in Burn Research Acute & Rehabilitative Care (Feb 22 – 23, 2016,
Mandarin Oriental Hotel, Washington, D.C.) was made possible through the support of the American Burn
Association, the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR), and
Shriners Hospitals for Children. NIDILRR is a Center within the Administration for Community Living (ACL),
Department of Health and Human Services (HHS). The contents of this publication do not necessarily represent the
policy of NIDILRR, ACL, HHS, and you should not assume endorsement by the Federal Government.

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