Review

Emerging drugs for the treatment

of wound healing
Elizabeth R Zielins, Elizabeth A Brett, Anna Luan, Michael S Hu,
1. Background Graham G Walmsley, Kevin Paik, Kshemendra Senarath-Yapa,
David A Atashroo, Taylor Wearda, H Peter Lorenz, Derrick C Wan &
2. Medical need
Michael T Longaker†
3. Market review †
Stanford University School of Medicine, Division of Plastic Surgery, Department of Surgery, Hagey
4. Current research goals Laboratory for Pediatric Regenerative Medicine, Stanford, CA, USA
5. Scientific rationale
Introduction: Wound healing can be characterized as underhealing, as in the
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15

6. Competitive environment setting of chronic wounds, or overhealing, occurring with hypertrophic scar
7. Potential development issues formation after burn injury. Topical therapies targeting specific biochemical
8. Conclusion and molecular pathways represent a promising avenue for improving and,
in some cases normalizing, the healing process.
9. Expert opinion
Areas covered: A brief overview of both normal and pathological wound
healing has been provided, along with a review of the current clinical
guidelines and treatment modalities for chronic wounds, burn wounds and
scar formation. Next, the major avenues for wound healing drugs, along
with drugs currently in development, are discussed. Finally, potential
challenges to further drug development, and future research directions are
discussed.
For personal use only.

Expert opinion: The large body of research concerning wound healing

pathophysiology has provided multiple targets for topical therapies. Growth
factor therapies with the ability to be targeted for localized release in the
wound microenvironment are most promising, particularly when they
modulate processes in the proliferative phase of wound healing.

Keywords: adjuvant, burns, chronic wounds, developing drugs, scarring, wound healing

Expert Opin. Emerging Drugs [Early Online]

1. Background

Despite recent efforts, there currently remains no satisfactory method to treat or

prevent the underhealing or overhealing of wounds. The inundation of the wound
closure market with new products and drugs highlights the massive need for an ideal
wound healing therapy, and the absence of the existence of such a treatment.
Chronic wounds represent a significant and expanding biomedical burden, while
the global market for anti-fibrotic therapies is over 10 billion USD [1]. In addition
to their unpredictable and often inadequate efficacy, many current therapies carry
the disadvantages of painful application and/or difficulty of use [2]. Herein, we
review topical adjuvant therapies for use in wound healing, focusing particularly
on the most popular and promising strategies for improving healing in particularly
challenging wounds: chronic wounds and burns.

1.1 Wound healing

After an injury, multiple biological processes work in concert to ultimately repair
tissue via the accumulation of cells and the deposition of a relatively disorganized
collagen matrix. The quality of wound healing is dependent on multiple factors,
including the inflammatory response to injury, cytokines and growth factors
released and structural characteristics of the repaired tissues [3]. Cutaneous wound
healing is traditionally considered to occur in three overlapping stages:

10.1517/14728214.2015.1018176 © 2015 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 1

All rights reserved: reproduction in whole or in part not permitted
 E. R. Zielins et al.
inflammation, proliferation and remodeling [4]. Inflammation
begins with the extravasation of blood and clot formation
after injury, and lasts for ~ 48 h. This also leads to the release
of inflammatory cytokines, including TGF-b1, TNF-a and
the interleukins, which attract immune cells such as neutro-
phils and macrophages to the site of injury for debridement
of the wound [5].
In the proliferative stage, which begins 2 -- 10 days after
injury and lasts 1 -- 3 weeks, keratinocytes migrate from the
wound edges, proliferate and mature [3]. Angiogenesis occurs
with the formation of new blood vessels, and fibroblasts are
attracted to the wound and produce extracellular matrix
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
(ECM). At this stage, growth factors and other peptides are
critical in the recruitment and direction of cells. VEGF,
platelet-derived growth factor (PDGF) and the fibroblast
growth factor (FGF) family of proteins (notably, FGF-2) are
all well known to be associated with angiogenesis and tissue
repair [6,7]. More recently, other proteins such as angiotensin
II have been shown to be involved in cutaneous wound
healing at multiple levels [8]. Connective tissue growth factor
(CTGF) has been implicated in the formation of myofibro-
blasts, a specialized subset of contractile fibroblasts that have
features of smooth muscle cells. Myofibroblasts are thought
to play a role in fibrosis, including scar formation and
For personal use only.
contraction [9], by affecting collagen orientation [10].
The final, remodeling stage of wound healing can last for
over a year, and involves turnover of the ECM, ultimately
changing the collagen content of the wound to produce a
mature scar. Degradation and remodeling of the ECM is
regulated largely by MMPs, a family of zinc-dependent
proteinases that are inhibited by tissue-derived inhibitors of
metalloproteinases (TIMPs) [10].
1.2 Pathological wound healing
While the intricacies of the cutaneous wound healing process
make it effective in restoring the skin’s function as a barrier,
they also leave it vulnerable to disruption, particularly in the
setting of systemic diseases such as diabetes and vascular insuf-
ficiency, and/or local complications such as infection.
Chronic wounds, or ulcers, result from a failure of normal
progression through the wound healing process, leading to
delayed and incomplete healing [11]. Ulcers may be classified
by underlying etiology into arterial, venous, pressure and
diabetic ulcers. While each differs in its precise pathophysiol-
ogy, all varieties of chronic wounds share features such as local
tissue hypoxia and dysregulated inflammation [11].
In contrast to the ‘under-healing’ of chronic wounds, the
effort to restore tissue integrity may instead lead to dysfunc-
tional ‘over-healing’ and the formation of pathological scars.
Normotrophic scars are non-functional fibrotic tissue
composed mainly of fibroblasts and a disorganized collagen
matrix [3]. Pathological scars include hypertrophic scars and
keloids, both of which are characterized by altered cell prolif-
eration and increased ECM deposition [3]. Hypertrophic
scarring is particularly prevalent following burns [12], and
2 Expert Opin. Emerging Drugs (2015) 20(2)
aside from its aesthetic implications, can lead to debilitating
contractures [13]. Clinically, keloids are distinguished from
hypertrophic scars by proliferating beyond the borders of
the original lesion. Histologically, they also differ in collagen
density, with thickened collagen fibrils found in keloids in
comparison with the fine fibers of hypertrophic scars.
Additionally, keloids have higher numbers of myofibroblasts
than hypertrophic scars [14].
2. Medical need
2.1 Chronic wounds
Approximately 6.5 million people suffer from chronic
wounds each year in the USA, resulting in annual healthcare
costs of > US$25 billion dollars, a figure that reflects neither
the indirect costs accrued due to disability and loss of work,
nor the psychosocial costs and additional medical risks associ-
ated with having a non-healing wound [1]. Specifically,
delayed wound healing is associated with pain and functional
limitations, and increased risks of infection and malignant
transformation in the form of Marjolin’s ulcers [11].
The sizable socioeconomic burden of chronic wounds is
perpetuated by the growing incidences of conditions that
predispose patients to them -- namely, obesity and diabetes.
As of 2012, one-third of the US population is obese, and
12% diabetic [15,16]. Worldwide, 347 million people have dia-
betes, while, as of 2008, 1.4 billion adults are overweight [17,18].
These statistics are accompanied by an expanding elderly
population, who are further predisposed to cutaneous injury
owing to decreases in skin thickness and mechanical
integrity [19].
2.1.1 Existing treatments for chronic wounds
The overarching treatment strategy for chronic wounds is to
correct the dysregulated physiological state of the wound
and allow for healing to occur [20]. At a fundamental level,
this means attending to the patient’s nutritional and hydra-
tion status, and managing any co-morbidities that may have
contributed to and/or caused ulcer development. Infection
control, adequate wound oxygenation and debridement are
also paramount to maximizing wound healing potential, as
are the use of appropriate precautions to minimize excess
pressure and/or other mechanical stress on the wound [20-23].
Subsequent management is dependent on the type of chronic
wound present. In the case of arterial ulcers, treatment is pri-
marily surgical -- revascularization (either open or endovascu-
lar) in combination with debridement of non-viable tissue [20].
Diabetic ulcer treatment involves both debridement and basic
wound care principles, including wound cleansing and the use
of dressings that provide adequate moisture while simulta-
neously minimizing contact with wound exudates [23].
Similarly, venous and pressure ulcers are treated with standard
wound care practices, with the option for surgical treatments
such as primary closure or skin grafting if these prove
inadequate [21,22].

While the treatment paradigms for ulcers are medically
sound, they do not produce uniformly ideal outcomes, partic-
ularly when it comes to diabetic ulcers. These ulcers are often
multifactorial in etiology, stemming from ischemic peripheral
vascular disease, neuropathy and/or foot deformity leading to
excess pressure on an area and subsequent mechanical break-
down [23,24]. Rates of wound healing have been reported as
60%, while lower extremity ulcer recurrence rates range
from 8 to 59% [23,25].
With these figures in mind, additional treatment strategies
are often employed to aid and improve wound healing,
including negative pressure wound therapy (NPWT) and
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
hyperbaric oxygen therapy (HBO). NPWT is thought to be
beneficial to wound healing by clearing the wound of exudate
and potentially harmful bacterial products in addition to
mechanically stabilizing the wound, increasing tissue
perfusion and at the cellular level, promoting granulation
tissue formation [26]. However, evidence supporting the use
of NPWT in the setting of chronic wounds is mixed [27].
HBO is another strategy used to increase tissue oxygenation
and reduce inflammation, although it too has received incon-
sistent reports of efficacy [25,28,29].
Becaplermin (REGRANEX Gel, Smith & Nephew, Inc.,
Andover, MA, USA) is a topical formulation of recombinant
For personal use only.
human PDGF-BB, marketed as an adjuvant therapy for
diabetic neuropathic ulcers of the lower extremity [30]. How-
ever, when titrated against competing drugs (such as angioten-
sin analogue NorLeu3-A(1 -- 7)), becaplermin was seen to
have a poorer wound healing capacity in terms of accelerating
closure of full thickness wounds [31]. Additionally, becapler-
min should be used with caution in patients with malignan-
cies (and is contraindicated in those with malignancy at the
site of application); in general, increased mortality secondary
to malignancy is associated with use of three or more tubes
of gel [30].
2.2 Burns and scarring
According to the National Repository of Burns, burn patients
over 64 years old have a higher risk of hospital readmission
and death in the 2 years following injury [32]. Yet, while
aged individuals represent the target population for chronic
wound treatments, much of burn research concerns the pedi-
atric population [33]. In 2000, direct costs in the USA for care
of children with burns exceeded 211 million USD. In South
Africa, ~ 26 million USD is spent annually for care of burns
from kerosene cookstove injuries; in 2007, Norway spent in
excess of 10.5 million EUR for hospital burn care [34].
In addition to the morbidity and risk of mortality incurred
by the actual injury, the dysregulated immune response and
destruction of the physical barrier provided by the skin
predisposes burn patients to wound infections. In fact, wound
infections have been found to account for ~ 17% of burn
complications [35]. Even once wound healing is successfully
achieved, burn patients are at risk for hypertrophic scarring,
estimated to occur in 32 -- 72% of cases [35,36]. From an
Expert Opin. Emerging Drugs (2015) 20(2)
Emerging drugs for the treatment of wound healing
economic standpoint, morbidity resulting from fibrosis and
scarring is estimated to account for tens of billions of dollars
in healthcare costs [3]. Hypertrophic scars are often painful
and pruritic; scar contractures may lead to decreased function-
ality and, if formed across joints, can restrict growth in the
pediatric population [10,37-39]. Furthermore, the unaesthetic
appearance of hypertrophic scars, particularly if occurring in
visible regions such as the face, can have devastating psychoso-
cial effects [36].
2.2.1 Existing treatments for burns and scarring
Burn wound management relies on adequate tissue debride-
ment in conjunction with wound coverage -- the standard of
care for full-thickness burns (in which epidermis and entire
dermis are affected) remains surgical excision and graft-
ing [40,41]. Enzymatic debridement agents have long been
investigated as viable alternatives, particularly in difficult
anatomic regions such as the hand, and allow for preservation
of viable tissues that may have otherwise been surgically
excised [42]. This therapy, also used for removal of tissue in
chronic wounds, has been associated with increased repitheli-
alization rates [43]. In spite of their promise, the optimum
enzymatic debridement agent for clinical use has yet to be
determined/developed. Recently, SANTYL Ointment (Smith
& Nephew, Inc.), a commercially available collagenase
formulation, has been shown to be as effective as silver sulfa-
diazine (SSD) in treatment of partial thickness burns in a ran-
domized trial of pediatric patients [44]. This is particularly
interesting, as SSD is an antibacterial cream used to prevent
infections and maintain a moist wound environment in
partial and full-thickness burns; it relies more on autolysis
for eschar removal. Practically speaking, however, SSD was
found by nurses to be more difficult to apply during dressing
changes for partial thickness burns when compared with
collagenase ointment [45].
Although widely used in burn units, a further limitation of
SSD is that its application is precluded in patients with sulfa
drug allergies, in which case other topical antibiotics such as
bacitracin may be used [46]. Alternative therapies include the
use of antibacterial-loaded dressings, such as the silver-
containing foam, Mepilex Ag (M€olnlycke Health Care,
Norcross, GA, SA). Chitosan, a natural, cationic polymer
with broad-spectrum antimicrobial properties, has been used
in the fabrication of dressings for chronic and acute wounds,
including burns [47]. It is already used commercially in Celox
Gauze (Medtrade Products Ltd., Crewe, UK), a material
designed to rapidly clot hemorrhaging wounds, and in the
dressing KytoCel (Aspen Medical, Redditch, UK) [48].
While the ostensible goal of wound care is successful and
timely wound healing, in cases of deep dermal injury,
especially in the setting of burns and/or wound infection, out-
comes may be suboptimal, with hypertrophic scar or keloid
formation [49]. Considering the limited treatments available
for improving scars in general, such scars are especially prob-
lematic. Surgical excision unfortunately has high recurrence
3
 E. R. Zielins et al.
rates, and medical therapies are limited. Currently used
treatments include use of topical silicone, pressure garments,
intralesional steroid injections, radiotherapy and laser therapy,
none of which provides optimal results [50]. Silicone sheets,
which are readily available over-the-counter, are designed to
reduce mature scars (placement on non-epithelialized dermis
will not be effective), although evidence of their actual efficacy
is unclear [51]. While the exact mechanism of action is
unknown, the occlusive nature of silicone dressings seems to
have a hydrating effect on the skin [11,52,53].
The long-term outcome of intralesional injections of triam-
cinolone acetonide (TA) varies across patients. Pioneered in
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
1961, TA injections have shown to either improve scar
appearance, or be comparable to placebo [54]. Other topical
treatments for scarring include the use of various immune
modulators and chemotherapeutic agents, such as 5-fluoro-
uracil, a relatively established anti-scar therapy, and, more
recently, imiquimod 5% cream. Imiquimod, which stimulates
production of the proinflammatory cytokine interferon,
increases the breakdown of collagen within the scar [53,55].
Unfortunately, imiquimod use has been associated with
additional disfigurement due to both hyper- and hypopig-
mentation of treated skin [56,57]. Intralesional injection of
bleomycin, an antineoplastic agent, has been seen to decrease
For personal use only.
the surface area of large keloids and hypertrophic scars [58].
When used in combination with electroporation (short,
intense electrical pulses designed to transiently increase
membrane permeability to drugs), bleomycin was shown to
decrease scar size by > 50%, combined with a significant
reduction in erythema [59]. However, this combinatorial treat-
ment requires multiple sessions, and although initial results
for scar reduction are promising, it cannot yet be considered
an established treatment for keloids.
CO2 lasers have recently been shown to be efficacious in
recontouring keloids via fibroblast activation and collagen
fiber rearrangement, although multiple treatments are
required, with increased treatment frequency associated with
increased local erythema [60]. This principle was utilized as
part of a novel therapy for the treatment of hypertrophic scars
by Waibel et al., who used fractional laser treatments to
enhance topical triamcinolone delivery [61]. The combination
treatment resulted in improved scar hypertrophy and texture,
although improvement in scar color was not as appreciable [61].
Interestingly, topical application of FGF-2 (basic FGF) has
shown clinical success in improving scar color and texture in
the setting of multiple types of wounds, including: burns,
chronic wounds and split-thickness skin-grafted wounds [62].
While this treatment has shown much promise in Japan, it
is not yet available for clinical use in Europe or the USA.
3. Market review
There are several market constraints facing wound healing
drug development across different countries: lack of economic
and clinical evidence supporting a new pharmacology could
4 Expert Opin. Emerging Drugs (2015) 20(2)
hinder its growth and acceptance; sophisticated treatments
may not be an option for certain national healthcare budgets,
even if the treatments are accompanied by a decrease in hospi-
tal care. By 2019, the US target patient population in need of
dermal regenerative treatments is projected to reach 6.4
million, fuelling a market worth of ~ 24.3 billion USD [63].
The increasing incidences of diabetes and obesity, combined
with growth of the aged population, make growth of the
market for therapies targeted to the chronic wounds sector a
near certainty, while in 2010, the worldwide market for der-
mal anti-fibrotic drugs alone was estimated to be 12 billion
USD [1]. Wound healing drugs primarily consist of growth
factor therapies, which as of 2013 made up 3.4% of the global
wound care market, with a projected growth rate of over 25%
in the next 8 years [64].
4. Current research goals
While new wound healing drugs are being developed for a
variety of indications, most topical therapies, which we focus
on in this review, are growth factor therapies. That is, they
make use of cytokines known to be involved in wound healing
in order to either augment the normal wound healing process
or, in the case of chronic wounds and scarring, rescue it. Thus,
the goal of these therapies is to balance the speed of wound
closure with scar formation, as well as to ensure adequate
and controlled delivery to the target area.
4.1 Optimize debridement
As we have previously detailed, in spite of the promising
nature of enzymatic debridement, no optimum agent exists.
There is currently one enzymatic debridement agent in devel-
opment, NexoBrid (MediWound Ltd., Yavne, ISR), with a
Phase III trial planned for comparison of its efficacy against
collagenase ointment in the treatment of large burns [65]. A
honey-based gel/paste dressing, MEDIHONEY GEL
(Derma Sciences, Inc., Princeton, NJ, USA) is currently being
evaluated for its antibacterial properties and ability to improve
the speed of partial thickness burn healing, also in comparison
with collagenase ointment [66].
4.2 Increase angiogenesis
A survey of the current drugs in Phase II and III trials for
chronic wounds reveals some common themes, the largest of
which is an attempt to increase the speed of wound healing
by promoting wound angiogenesis. Perhaps the most estab-
lished methodology for this is the addition of the pro-
angiogenic growth factor PDGF. As previously mentioned,
PDGF is already commercially available as becaplermin,
although this topical agent is limited strictly to diabetic neu-
ropathic ulcer treatment, with no indications for use with
other ulcers, such as those due to pressure or venous stasis [30].
Other known pro-angiogenic growth factors being utilized in
wound healing therapies include hepatocyte growth factor
(HGF) and FGF-1. Interestingly, non-traditional means

Epidermis
Dermis
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
Cell growth and proliferation
- PDGF
- CTGF
- Angiotensin
Figure 1. Topical wound healing therapies target three key areas: debridement of necrotic tissue, angiogenesis and cellular
growth/proliferation.
CTGF: Connective tissue growth factor; FGF: Fibroblast growth factor; PDGF: Platelet-derived growth factor.
For personal use only.
such as wound-specific use of b-blockers are also being
employed in this setting for their beneficial effects
on microvasculature.
4.3 Alter cellular proliferation and growth
A further goal of emerging topical wound healing therapies is
alteration of the cellular kinetics of the wound environment.
In the case of chronic wounds, this is intimately linked to
angiogenesis, with PDGF additionally functioning as a
mitogen. Other dual-functioning agents, such as Tb4 and
angiotensin, are also being trialed for use as pro-angiogenic
factors that also serve to counterbalance the relatively
catabolic setting of the chronic wound [67]. The goal of these
treatments is somewhat different than the goals of anti-
fibrotic treatments, however. Anti-fibrotic topical therapies
are particularly focused on inhibiting cellular proliferation,
with a promising target (as evidenced by its incorporation
into multiple therapies) being inhibition of CTGF [68].
5. Scientific rationale
Wound healing is a complex process, and although a vast
body of knowledge currently exists, it does not indicate a
complete understanding of the events that restore tissue integ-
rity. In this section, we describe the major aspects of wound
healing that are being targeted by developing topical thera-
pies. It should also be noted here that several vulnerary agents,
particularly those formulated from botanical extracts, have
unclear/unknown mechanisms of action. Unfortunately, a
comprehensive description of all pathways targeted by
Expert Opin. Emerging Drugs (2015) 20(2)
Emerging drugs for the treatment of wound healing
Wound
Necrosis Angiogenesis
- PDGF
- VEGF
- FGF-2
- Angiotensin
developing drugs is beyond the scope of this review, although
we have highlighted three key areas of focus (Figure 1).
5.1 Debridement
Adequate wound debridement is paramount for the occur-
rence of normal wound healing and infection control,
especially in the setting of burns and chronic wounds, where
necrotic tissue can become abundant. Enzymatic debridement
agents allow for the removal of necrotic tissue without the
potential for blood loss, although they may cause pain and,
depending on whether the agent used is selective or non-
selective, damage to surrounding tissues [69]. The most
common proteolytic enzymes used for debridement are
collagenase, which specifically targets elastin fibers, and
papain (derived from the papaya), which targets fibrin [69].
Bromelain, originally described in the 1980s, is emerging as
a debridement agent [70]. A mixture of enzymes obtained
from the stem portion of pineapples, bromelain is useful in
wound debridement due to presence of escharase. Escharase
is non-proteolytic enzyme that allows for selective debride-
ment of non-viable tissue [71,72].
5.2 Angiogenesis
Insufficient blood supply can be both a causative and perpet-
uating factor in the case of chronic wounds. Tissue hypoxia
may be partially or fully due to large-vessel disease, in the
case of diabetic and arterial ulcers, or due to changes at the
microvascular level due to chronic venous insufficiency
(venous leg ulcers) or sustained application of a mechanical
load (pressure ulcers) [73-75]. Similarly, the inflammatory
response induced by burn injury disrupts tissue
5
 E. R. Zielins et al.
microvasculature by increasing vascular permeability via the
release of various factors, including reactive oxygen species,
nitric oxide and MMP-9 [76]. Once a wound is established,
local hypoxia impairs both healing and clearance of
pathogens; in fact, while all open wounds are colonized to
some degree, bacterial count has been shown to be inversely
correlated with wound oxygen levels [77].
Neovascularization is therefore essential to wound healing.
It begins relatively early in the process, during the inflamma-
tory stage. At this point, multiple cytokines are produced as
part of the immune response to injury, many of which will
stimulate angiogenesis and vasculogenesis, and include:
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
VEGF, PDGF, HGF, TGF-b, FGF-1 and -2, along with
angiogenin and angiopoietins [78,79]. The precise roles of these
cytokines in neovascularization are complex and have yet to be
fully elucidated, although levels of several -- particularly
PDGF, VEGF, TGF-b, and FGF-2 -- are decreased in the
setting of chronic wounds [5]. In our search of vulnerary
agents in Phase II and III trials, PDGF was the most common
growth factor utilized (Table 1). Initially secreted by platelets
during formation of a fibrin clot in response to injury,
PDGF plays a role in all stages of wound healing [80].
There are five isoforms of PDGF, which bind to the tyro-
sine kinase receptors PDGFR-a and -b [80]. Of the isoforms,
For personal use only.
PDGF-BB is most commonly implicated in wound healing.
PDGF-BB has been shown to stimulate neovascularization
in animal models of diabetic wound healing and in clinical
trials [81,82]. Specifically, PDGF-BB works to balance the
actions of VEGF in angiogenesis. VEGF induces new vessel
formation by endothelial sprouting -- an endothelial cell form-
ing the tip of a new vessel begins migrating towards a VEGF
gradient, while neighboring cells rearrange themselves and
begin proliferating to form the body of the capillary. This
process is concluded as PDGF-BB released by the tip endo-
thelial cell attracts pericytes, which serve to temper endothelial
proliferation and stabilize the newly formed vasculature [83].
Thus, it is the balance of PDGF-BB and VEGF levels that
facilitates normal neovascularization. Overexpression of these
factors has been observed in malignancies such as non-small-
cell lung cancer and breast cancer, rationalizing the limita-
tions/contraindications surrounding becaplermin use [84,85].
Hypertrophic scars have been characterized as hypervascular,
although in a 2011 study, van der Veer et al. did not observe
increased VEGF levels during hypertrophic scar formation as
compared with normotrophic scars. They did, however,
observe increases in other factors, such as angiopoietin-1
and -2 [86].
Additional functions of PDGF-BB include modulation of
wound levels of nitric oxide [80]. This is particularly impor-
tant, as nitric oxide is crucial for VEGF-mediated angiogene-
sis; PDGF-BB stimulates endothelial cell production of nitric
oxide, which works to direct capillary growth while also acting
via a negative feedback mechanism to decrease endothelial cell
proliferation [87]. Another player in VEGF-induced neovascu-
larization is angiotensin II. Angiotensin II acts at the
6 Expert Opin. Emerging Drugs (2015) 20(2)
microvascular level via two receptors with opposing functions:
AT1 and AT2. While AT1 stimulates VEGF activity, AT2
inhibits it via inhibition of endothelial nitric oxide synthe-
sis [88]. Independent of nitric oxide-directed endothelial cell
migration, Tb4, a small protein found in all nucleated cells,
stimulates angiogenesis by binding to elements of the
cytoskeleton to coordinate endothelial cell migration [89].
5.3 Cell proliferation and growth
Agents such as PDGF, angiotensin II and Tb4 are likely
proving to be good candidates for wound healing drugs due
to the diversity of their functions. As we have stated, PDGF
is expressed throughout the stages of wound healing. In
addition to promoting neovascularization, PDGF stimulates
fibroblast proliferation, resulting in increased ECM produc-
tion during the proliferative stage. This is counterbalanced
by PDGF’s actions in the remodeling stage of healing, during
which it promotes MMP production by fibroblasts [80].
Angiotensin II also affects the proliferative stage of wound
healing, again through the actions of receptors AT1 and
AT2. AT1 stimulates collagen synthesis and TIMP expression
by fibroblasts, while AT2 exerts the opposite effect. The
relative expression levels of these two receptors differ over
the course of the wound healing process [90]. While angioten-
sin II modulates TIMP expression, Tb4 modulates expression
of MMPs directly. Given their capacity to mechanically
modulate the wound environment by breaking down ECM,
MMPs are integral to healing, and can have powerful effects
on cell behavior, whether by influencing migration, pheno-
type or even cell survival [91]. Interestingly, tetracycline antibi-
otics such as doxycycline have been implicated in MMP
inhibition, giving them a dual function in wound healing
therapies [92].
Within the proliferative and remodeling stages of wound
healing, the most popular target for antiscar therapy (as
opposed to improvement in wound healing speed) appears
to be CTGF. CTGF, a downstream target of TGF-b signal-
ing, is involved in ECM synthesis, and has been found to be
upregulated in hypertrophic scar fibroblasts [93].
6. Competitive environment
The multifactorial nature of wound healing provides abun-
dant targets for potential therapies. Multiple clinical trials
have evaluated the efficacy of various growth factors for
wound healing therapies, and, although promising, many of
these agents are still in the earlier stages of development. In
fact, there are only four drugs currently in Phase III of clinical
trials, as evidenced in the competitive environment table
(Table 1).
6.1 Chronic wounds
As previously mentioned, PDGF is the most commonly eval-
uated vulnerary agent. The shortcomings of commercially
available becaplermin (PDGF-BB), which is only approved
 Emerging drugs for the treatment of wound healing

Table 1. Competitive environment table.

Compound Company Structure Indication Stage of Mechanism of action

development

Amnion-derived Cellular Stemnion Cytokine solution of Burns Phase II Mixture of growth

Cytokine Solution amnion-derived multipo- factors: PDGF, VEGF,
tent progenitor cells TGF-b2, angiogenin
MEDIHONEY GEL with Derma Sciences, Gel/paste Burns Unknown Antibacterial and pro-wound
active leptospermum Inc. healing effects of honey
honey
EscharEx, NexoBrid MediWound Bromelain Burns Launched Enzyme
Kur-212 Kuros Biosurgery PDGF analogue + fibrin Burns Phase II Fibrin matrix adheres graft to
AG matrix wound site; PDGF analogue
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15

is engineered for controlled

release
RPh-201 Regenera Pharma Botanical product Chronic Phase II Unknown
wounds
LL-37 Pergamum Cathelicidin LL-37 Chronic Phase II LL-37 is implicated in wound
wounds healing
ChronSeal Kringle Pharma rhHGF Chronic Phase II HGF agonist
wounds
Excellagen Excellarate Taxus Cardium Type 1 bovine collagen Chronic Phase III PDGF modified to bind
(GAM-501; Ad5PDGF-B) Pharmaceuticals with PDGF-B adenovirus wounds collagen
HO-03-03 Heal-Or Peptide Chronic Phase II PKC a activation, delta
wounds inhibition
BioChaperone PDGF-BB Adocia Recombinant PDGF-BB DFU Phase III Angiogenesis and cell
proliferation
Galnobax NovaLead Esmolol DFU Phase II b1-adrenoreceptor agonist
For personal use only.

NanoDOX Nanotherapeutics Doxycycline DFU Phase II MMP inhibitor

MEBO Wound Ointment Skingenix Multiple botanical DFU Phase II Unknown
extracts VLU
DSC-127 Derma Sciences NorLeu3-A(1 -- 7) DFU Phase III Angiotensin agonist
Scarring
Wound
healing
EXC-001 Pfizer Nucleic acid Scarring Phase II Reduce CTGF expression
RXI-109 RXi siRNA Scarring Phase II Reduce CTGF expression
Pharmaceuticals
Nexagon CoDa Therapeutics Anti-connexin VLU Phase II Downregulates proteins that
oligonucleotide form gap junctions
Oleogel-S10 Birken Birch bark extract Wound Phase III Unknown
healing
RGN-137 RegeneRx Thymosin b4 synthetic Wound Phase II Modulates MMP expression;
Biopharmaceuticals analogue healing stimulates angiogenesis
CVBT-141B CardioVascular FGF-1 Wound Phase II Angiogenesis stimulant,
BioTherapeutics healing FGF-1 agonist,
FGFR-1 agonist
Granexin FirstString ACT1 (peptide) Wound Phase II Stabilizes gap junctions of
Research healing endothelial cells

CTGF: Connective tissue growth factor; DFU: Diabetic foot ulcer; FGF: Fibroblast growth factor; HGF: Hepatocyte growth factor; PDGF: Platelet-derived
growth factor; VLU: Venous leg ulcer.

for use in neuropathic diabetic foot ulcers, make the develop-
ment of additional formulations a reasonable and desirable
goal. Thus, several PDGF-based therapies are currently in
clinical trials. BioChaperone PDGF-BB (Adocia, Lyons, FR)
is a recombinant PDGF-BB currently in Phase III of clinical
trials. GAM501 is a topically administered gel containing an
adenoviral vector that encodes PDGF-BB. The principle
behind this approach is that, rather than delivering PDGF-
BB itself, which may then become delocalized within the
wound microenvironment, the adenoviral vector facilitates
cell-specific production of the cytokine. Using a gene therapy
approach to PDGF delivery has also allowed for modification
of the encoded protein such that it binds to collagen, thus
facilitating sustained presence in the wound [94]. After success-
fully completing Phase I and II, GAM501 is now in Phase III
clinical trials for treatment of diabetic foot ulcers.
Other growth factor therapies for wound healing remain in
Phase II of clinical trials, with the exception of the angiotensin

Expert Opin. Emerging Drugs (2015) 20(2) 7

 E. R. Zielins et al.
agonist NorLeu3-A(1 -- 7) (DSC127) (Derma Sciences, Inc.).
NorLeu3-A(1 -- 7) is now in Phase III of clinical trials, after
demonstrating safety and efficacy in treatment of diabetic
foot ulcers. Notably, this angiotensin analogue had previously
been shown to outperform both angiotensin 1 -- 7 (A(1 -- 7))
and becaplermin. Angiotensin 1 -- 7 (A(1 -- 7)) itself has
proven to be just as efficacious, if not better, than angiotensin
II in improving the speed of wound healing [95].
6.2 Burns
The selective nature of bromelain makes it an attractive choice
as an enzymatic debridement agent. In fact, NexoBrid, a bro-
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
melain ointment, is the only enzymatic debridement agent
that is now beyond Phase I of clinical trials; it is currently in
Phase III clinical trials for use in both adult and pediatric burns.
Unfortunately, specialized drugs for treatment of burn
wounds are not abundantly in development. However, in an
effort to apply the benefits of PDGF administration to burn
wounds, Kuros Biosurgery AG has completed Phase II clinical
trials evaluating the use of a combination of fibrin gel and a
variant form of PDGF in enhancing the take of split thickness
skin grafts for partial thickness burn wounds. Kur-212 aims to
provide the wound healing enhancement afforded by PDGF,
while obviating the need for sutures/staples in skin graft place-
For personal use only.
ment. A more holistic approach to growth factor treatment of
burns can be seen in Amnion-derived Cellular Cytokine
Solution (Stemnion, Inc., Pittsburgh, PA, USA), a mixture
of cytokines derived from the culture supernatant of amion-
derived multipotent progenitor cells. This solution, consisting
of primarily pro-angiogenic growth factors (PDGF, VEGF,
angiogenin, TGF-b2), has been shown experimentally to
accelerate partial-thickness burn wound healing, and is now
in Phase III clinical trials [96].
6.3 Scarring
Scar therapies in Phase II and III of clinical trials are also
limited in number. However, two separate agents, EXC-001
(Pfizer, New York, NY, USA) and RXI-109 (RXi Pharma-
ceuticals, Marlborough, MA, USA) have been developed for
inhibition of CTGF and thus applications in reducing
scarring. EXC-001 has completed Phase II clinical trials,
demonstrating efficacy in improvement of both normo- and
hypertrophic scars. As an antisense oligonucleotide (single
strand nucleic acid), EXC-001 inhibits CTGF production at
the transcriptional level by interfering with the normal proc-
essing/functioning of mRNA [97,98]. Similarly, RXI-109 is a
small interfering RNA that inhibits CTGF by preventing
translation of CTGF mRNA [99]. It is currently in Phase II
clinical trials for improving outcomes of scar revision surgery.
7. Potential development issues
Development of effective wound healing drugs is a difficult
task, largely due to the multiple roles played by each growth
factor involved in the process. The modulation of angiogenic
8 Expert Opin. Emerging Drugs (2015) 20(2)
growth factors in the setting of chronic wounds illustrates
this difficulty perfectly. While upregulation of PDGF and
VEGF are logical solutions to correct the deficiencies seen in
chronic wounds, imbalances in growth factor levels produce
aberrant, and, as is unfortunately associated with becaplermin
use, sometimes fatal results. The need for precise dosing also
applies to the use of proliferative agents (including, again,
PDGF), in order to avoid the potential for excess scar forma-
tion. Thus, prior to implementing a growth factor therapy,
the appropriate drug dose must be titrated in order to
maximize beneficial physiologic effects while minimizing
adverse effects. To that end, a further consideration in drug
development is bioavailability: agents must not be so easily
degraded/transient that there is no time for their biological
effects to be realized. Drugs with short half-lives, such as
deferoxamine (a drug shown to improve diabetic wound
healing in murine studies, although it has not yet reached
clinical trials), can be delivered for a sustained amount of
time via incorporation into a specialized dressing that facili-
tates controlled release [100].
Thus, the primary development issue facing the advanced
wound care market is drug delivery. In the case of vulnerary
agents whose half-lives are not prohibitive, efforts to address
this can be seen when evaluating the use of selective enzymatic
debridement agents such as bromelain, for example, or when
examining PDGF-based treatments. Transient gene therapy
such as adenoviral-mediated delivery of PDGF-BB, combined
with use of recombinant forms of PDGF-BB designed to
localize to the wound, represent promising strategies to pre-
vent potential systemic toxicity by precisely targeting a region
of interest. RNA interference therapies, as we have described
as being in development for scar reduction, represent another
example of providing targeted, transient modulation of the
wound/scar microenvironment.
8. Conclusion
Wound healing therapies represent a large, rapidly-growing
market, particularly due to the ever-increasing global popula-
tion in conjunction with the rise of medical conditions such as
obesity and diabetes. Current guidelines for wound care rely
first and foremost on medical management of causative
conditions, and, when necessary, surgical intervention. The
development of more specialized, efficient treatments for
both acute and chronic wounds has been limited, largely
due to an incomplete knowledge of the molecular and cellular
mechanisms of healing.
However, the vast body of knowledge that we currently
possess has resulted in the identification of key target areas
for the improvement of wound healing: debridement, angio-
genesis and cell growth and proliferation. With the exception
of debridement, drugs affecting wound angiogenesis and
cellular behavior are primarily growth factor therapies, a mar-
ket sector expected to grow substantially in the coming years.
Yet, while there is no doubt that advances in both the life
 Emerging drugs for the treatment of wound healing

sciences and engineering will continue to facilitate the devel-
opment of more advanced, targeted drugs, those currently in
development show great promise for improving the precision
and efficacy of wound care.
9. Expert opinion
The ultimate goal of a wound healing drug is to be both med-
ically effective and cost-effective. Medical efficacy is linked to
both objective clinical outcomes as well as patient comfort lev-
els/satisfaction, while cost--effectiveness must balance
decreased hospital stay, need for surgery and other potential
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
whether causative, as in venous stasis ulcers, perpetuating, as
in the case of many chronic wounds, or simply a natural
response to injury, as in burns, is a critical force in wound
healing. While we acknowledge that many of the growth
factors/peptides detailed here do play roles either in the
inflammatory response to injury or in tempering its poten-
tially destructive outcomes, there are no therapies focused
on modulating the local inflammatory response to injury.
Given the complex interplay between the inflammatory
response to injury and its effects at the molecular and cellular
levels, this remains a highly challenging, though worthy goal.

results of improving wound treatment with the cost of

manufacturing and administering a new drug. As we have
mentioned earlier in the article, the costs of some new
therapies may preclude their use in countries with uncertain
economies, and should be taken into account as much as
possible during drug development.
The emerging drugs that we have reviewed herein show
promise for implementation one day into clinical practice.
Importantly, the continued investigation of PDGF variants
for use in chronic wounds is indicative that not only is it an
appropriate target for improvement of chronic wound heal-
ing, but that the proliferative stage of wound healing, which
For personal use only.
Acknowledgement
EA Brett and A Luan contributed equally to this work.
Declaration of interest
MT Longaker was supported by NIH grants U01 HL099776,
R01 DE021683-01, RC2 DE020771, the Oak Foundation
and Hagey Laboratory for Pediatric Regenerative Medicine.
HP Lorenz was supported by NIH grant GM087609, a Gift
from Ingrid Lai and Bill Shu in honor of Anthony Shu and

it plays a major role in, is a key target for the development
of additional treatment modalities. PDGF’s multiple roles in
wound healing further highlight the advantages of targeting
multiple processes in a single therapy. An exception to that
strategy, however, might be observed in anti-CTGF scar
treatments, although these too represent the future of wound
healing drugs, as they illustrate emerging means for precise
manipulation of signaling pathways.
One aspect of wound healing that appears to be less
addressed, at least among drugs currently in Phase II and III
clinical trials, is the inflammatory stage. Inflammation,
the Hagey Laboratory for Pediatric Regenerative Medicine
and Children’s Surgical Research Program. DC Wan was
supported by NIH grant 1K08DE24269, the ACS Franklin
H Martin Faculty research Fellowship, the Hagey Laboratory
for Pediatric Regenerative Medicine and the Stanford Univer-
sity Child Health Research Institute Faculty Scholar award.
The authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those
disclosed.

Bibliography
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
1. Sen CK, Gordillo GM, Roy S, et al.
Human skin wounds: a major and
snowballing threat to public health and
the economy. Wound Repair Regen
2009;17(6):763--71
2. Uzun H, Bitik O, Hekimoglu R, et al.
Angiotensin-converting enzyme inhibitor
enalapril reduces formation of
hypertrophic scars in a rabbit ear
wounding model. Plast Reconstr Surg
2013;132(3):361e--71e
regeneration. Nature
2008;453(7193):314--21
. Provides a detailed yet succinct
overview of the wound healing process.
4. Singer AJ, Clark RA. Cutaneous wound
healing. N Engl J Med
1999;341(10):738--46
5. Barrientos S, Stojadinovic O,
Golinko MS, et al. Growth factors and
cytokines in wound healing.
Wound Repair Regen
2008;16(5):585--601
6. Yun YR, Won JE, Jeon E, et al.
Fibroblast growth factors: biology,
7. Zakrzewska M, Marcinkowska E,
Wiedlocha A. FGF-1: from biology
through engineering to potential medical
applications. Crit Rev Clin Lab Sci
2008;45(1):91--135
8. Steckelings UM, Henz BM, Wiehstutz S,
et al. Differential expression of
angiotensin receptors in human
cutaneous wound healing. Br J Dermatol
2005;153(5):887--93
9. Estes JM, Vande Berg JS, Adzick NS,
et al. Phenotypic and functional features
of myofibroblasts in sheep fetal wounds.
Differentiation 1994;56(3):173--81

3. Gurtner GC, Werner S, Barrandon Y, function, and application for tissue 10. Hu MS, Maan ZN, Wu JC, et al. Tissue
Longaker MT. Wound repair and regeneration. J Tissue Eng engineering and regenerative repair in
2010;2010:218142 wound healing. Ann Biomed Eng
2014;42(7):1494--507

Expert Opin. Emerging Drugs (2015) 20(2) 9

 E. R. Zielins et al.
11. Menke NB, Ward KR, Witten TM,
et al. Impaired wound healing.
Clin Dermatol 2007;25(1):19--25
12. Bloemen MC, van der Veer WM,
Ulrich MM, et al. Prevention and
curative management of hypertrophic
scar formation. Burns 2009;35(4):463--75
13. Asuku ME, Ibrahim A, Ijekeye FO.
Post-burn axillary contractures in
pediatric patients: a retrospective survey
of management and outcome. Burns
2008;34(8):1190--5
14. Ehrlich HP, Desmouliere A,
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
Diegelmann RF, et al. Morphological
and immunochemical differences between
keloid and hypertrophic scar.
Am J Pathol 1994;145(1):105--13
15. Centers for Disease Control and
Prevention. National Diabetes Statistics
Report: Estimates of Diabetes and Its
Burden in the United States, 2014. US
Department of Health and Human
Services; Atlanta, GA: 2014
16. Ogden CL, Carroll MD, Kit BK,
Flegal KM. Prevalence of childhood and
For personal use only.
adult obesity in the United States,
2011-2012. JAMA 2014;311(8):806--14
17. World Health Organization. Diabetes:
fact sheet 312. November
2014. Available from: http://www.who.
int/mediacentre/factsheets/fs312/en/
[Cited 16 November 2014]
18. World Health Organization. Obesity and
overweight: fact sheet 311. August
2014. Available from: http://www.who.
int/mediacentre/factsheets/fs311/en/
[Cited 16 November 2014]
19. Farage MA, Miller KW, Elsner P,
Maibach HI. Characteristics of the Aging
Skin. Adv Wound Care 2013;2(1):5--10
20. Hopf HW, Ueno C, Aslam R, et al.
Guidelines for the treatment of arterial
insufficiency ulcers.
Wound Repair Regen
2006;14(6):693--710
21. Robson MC, Cooper DM, Aslam R,
et al. Guidelines for the treatment of
venous ulcers. Wound Repair Regen
2006;14(6):649--62
22. Whitney J, Phillips L, Aslam R, et al.
Guidelines for the treatment of pressure
ulcers. Wound Repair Regen
2006;14(6):663--79
23. Steed DL, Attinger C, Colaizzi T, et al.
Guidelines for the treatment of diabetic
ulcers. Wound Repair Regen
2006;14(6):680--92
10
24. Kavitha KV, Tiwari S, Purandare VB,
et al. Choice of wound care in diabetic
foot ulcer: a practical approach.
World J Diabetes 2014;5(4):546--56
25. Mulder G, Tenenhaus M, D’Souza GF.
Reduction of diabetic foot ulcer healing
times through use of advanced treatment
modalities. Int J Low Extrem Wounds
2014;13(4):335--46
26. Seo SG, Yeo JH, Kim JH, et al.
Negative-pressure wound therapy induces
endothelial progenitor cell mobilization
in diabetic patients with foot infection or
skin defects. Exp Mol Med 2013;45:e62
27. Beitz JM, van Rijswijk L. Developing
evidence-based algorithms for negative
pressure wound therapy in adults with
acute and chronic wounds: literature and
expert-based face validation results.
Ostomy Wound Manage
2012;58(4):50--69
28. Liu R, Li L, Yang M, et al. Systematic
review of the effectiveness of hyperbaric
oxygenation therapy in the management
of chronic diabetic foot ulcers.
Mayo Clin Proc 2013;88(2):166--75
29. Margolis DJ, Gupta J, Hoffstad O, et al.
Lack of effectiveness of hyperbaric
oxygen therapy for the treatment of
diabetic foot ulcer and the prevention of
amputation: a cohort study.
Diabetes Care 2013;36(7):1961--6
30. Regranex (becaplermin) Gel 0.01%.
Available from: http://www.regranex.
com/index.php [Cited 11 November
2014]
31. Rodgers K, Verco S, Bolton L,
Dizerega G. Accelerated healing of
diabetic wounds by NorLeu(3)-
angiotensin (1-7). Expert Opin
Investig Drugs 2011;20(11):1575--81
32. Sen S, Palmieri T, Greenhalgh D.
Review of burn research for the year
2013. J Burn Care Res
2014;35(5):362--8
33. Golshan A, Patel C, Hyder AA.
A systematic review of the epidemiology
of unintentional burn injuries in South
Asia. J Public Health (Bangkok)
2013;35(3):384--96
34. World Health Organization. Burns: fact
sheet 365. April
2014. Available from: http://www.who.
int/mediacentre/factsheets/fs365/en/
[Cited 11 November 2014]
35. Barajas-Nava LA, Lopez-Alcalde J,
Roque i Figuls M, et al. Antibiotic
Expert Opin. Emerging Drugs (2015) 20(2)
prophylaxis for preventing burn wound
infection. Cochrane Database Syst Rev
2013;6:CD008738
36. Lawrence JW, Mason ST, Schomer K,
Klein MB. Epidemiology and impact of
scarring after burn injury: a systematic
review of the literature. J Burn Care Res
2012;33(1):136--46
37. Shih B, Garside E, McGrouther DA,
Bayat A. Molecular dissection of
abnormal wound healing processes
resulting in keloid disease.
Wound Repair Regen
2010;18(2):139--53
38. Wadman M. Scar prevention: the healing
touch. Nature 2005;436(7054):1079--80
39. Hu MS, Rennert RC, McArdle A, et al.
The role of stem cells during scarless skin
wound healing. Adv Wound Care
2014;3(4):304--14
40. Sheridan RL. Comprehensive treatment
of burns. Curr Probl Surg
2001;38(9):657--756
41. Lewis GM, Heimbach DM, Gibran NS.
Evaluation of the burn wound:
management decisions. In: Herndon DN,
editor. Total burn care. 4th edition.
Elsevier, Inc; New York:
2012. p. 125--30
42. Krieger Y, Bogdanov-Berezovsky A,
Gurfinkel R, et al. Efficacy of enzymatic
debridement of deeply burned hands.
Burns 2012;38(1):108--12
43. Singer AJ, Taira BR, Anderson R, et al.
The effects of rapid enzymatic
debridement of deep partial-thickness
burns with Debrase on wound
reepithelialization in swine. J Burn
Care Res 2010;31(5):795--802
44. Ostlie DJ, Juang D, Aguayo P, et al.
Topical silver sulfadiazine vs collagenase
ointment for the treatment of partial
thickness burns in children: a prospective
randomized trial. J Pediatr Surg
2012;47(6):1204--7
45. Sharp NE, Aguayo P, Marx DJ, et al.
Nursing preference of topical silver
sulfadiazine versus collagenase ointment
for treatment of partial thickness burns
in children: survey follow-up of a
prospective randomized trial.
J Trauma Nurs 2014;21(5):253--7
46. Dai T, Huang YY, Sharma SK, et al.
Topical antimicrobials for burn wound
infections. Recent Patents Anti-Infect
Drug Disc 2010;5(2):124--51
 Emerging drugs for the treatment of wound healing

47. Jayakumar R, Prabaharan M,
Sudheesh Kumar PT, et al. Biomaterials
based on chitin and chitosan in wound
dressing applications. Biotechnol Adv
2011;29(3):322--37
48. Millner R, Lockhart AS, Marr R.
Chitosan arrests bleeding in major
hepatic injuries with clotting dysfunction:
an in vivo experimental study in a model
of hepatic injury in the presence of
moderate systemic heparinisation. Ann R
Coll Surg Engl 2010;92(7):559--61
49. Gauglitz GG, Korting HC, Pavicic T,
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
part 2 -- algorithms for scar prevention
and treatment. Dermatol Surg
2014;40(8):825--31
58. Naeini FF, Najafian J, Ahmadpour K.
Bleomycin tattooing as a promising
therapeutic modality in large keloids and
hypertrophic scars. Dermatol Surg
2006;32(8):1023--9; discussion 29-30
59. Manca G, Pandolfi P, Gregorelli C, et al.
Treatment of keloids and hypertrophic
scars with bleomycin and electroporation.
Plast Reconstr Surg
2013;132(4):621e--30e
69. Ayello EA, Cuddigan JE. Debridement:
controlling the necrotic/cellular burden.
Adv Skin Wound Care
2004;17(2):66--75; quiz 76-8
70. Houck JC, Chang CM, Klein G.
Isolation of an effective debriding agent
from the stems of pineapple plants. Int J
Tissue React 1983;5(2):125--34
71. Pavan R, Jain S, Shraddha Kumar A.
Properties and therapeutic application of
bromelain: a review. Biotechnol Res Int
2012;2012:976203
72. Rosenberg L, Krieger Y, Silberstein E,

et al. Hypertrophic scarring and keloids:
pathomechanisms and current and
emerging treatment strategies. Mol Med
2011;17(1-2):113--25
.
A detailed overview of the
pathophysiology of hypertrophic
scarring (and treatment modalities).
50. Ogawa R. The most current algorithms
for the treatment and prevention of
hypertrophic scars and keloids.
Plast Reconstr Surg 2010;125(2):557--68
51. O’Brien L, Jones DJ. Silicone gel
sheeting for preventing and treating
For personal use only.
60. Nicoletti G, De Francesco F, Mele CM,
et al. Clinical and histologic effects from
CO2 laser treatment of keloids.
Lasers Med Sci 2013;28(3):957--64
61. Waibel JS, Wulkan AJ, Shumaker PR.
Treatment of hypertrophic scars using
laser and laser assisted corticosteroid
delivery. Lasers Surg Med
2013;45(3):135--40
62. Akita S, Akino K, Hirano A. Basic
Fibroblast Growth Factor in Scarless
Wound Healing. Adv Wound Care
et al. Selectivity of a bromelain based
enzymatic debridement agent: a porcine
study. Burns 2012;38(7):1035--40
73. Bouten CV, Oomens CW, Baaijens FP,
Bader DL. The etiology of pressure
ulcers: skin deep or muscle bound?
Arch Phys Med Rehabil
2003;84(4):616--19
74. Mustoe TA, O’Shaughnessy K,
Kloeters O. Chronic wound pathogenesis
and current treatment strategies:
a unifying hypothesis.

2013;2(2):44--9 Plast Reconstr Surg

hypertrophic and keloid scars.
63.
Cochrane Database Syst Rev
2013;9:CD003826
52. Mustoe TA. Evolution of silicone
64.
therapy and mechanism of action in scar
management. Aesthetic Plast Surg
2008;32(1):82--92
53. Gauglitz GG. Management of keloids
and hypertrophic scars: current and
emerging options. Clin Cosmet
65.
Investig Dermatol 2013;6:103--14
54. Muneuchi G, Suzuki S, Onodera M,
et al. Long-term outcome of intralesional
injection of triamcinolone acetonide for
the treatment of keloid scars in Asian
patients. Scand J Plast Reconstr Surg
66.
Hand Surg 2006;40(2):111--16
55. Ud-Din S, Bayat A. Strategic
management of keloid disease in ethnic
skin: a structured approach supported by
the emerging literature. Br J Dermatol
2013;169(Suppl 3):71--81
67.
56. Qiu Y, Ma G, Lin X, et al. Treating
protruding infantile hemangiomas with
topical imiquimod 5% cream caused
68.
severe local reactions and disfiguring
scars. Pediatr Dermatol
2013;30(3):342--7
57. Gold MH, McGuire M, Mustoe TA,
et al. Updated international clinical
recommendations on scar management:
Zhang Z, Michniak-Kohn BB. Tissue
engineered human skin equivalents.
Pharmaceutics 2012;4(1):26--41
MedMarket Diligence LLC. Worldwide
Wound Management, Forecast to 2021:
Established and Emerging Products,
Technologies and Markets in the
Americas, Europe, Asia/Pacific and Rest
of World. 2013
MediWound Ltd. A study to evaluate the
efficacy and safety of nexobrid in subjects
with thermal burns. ClinicalTrialsgov
2014. Available from: http://clinicaltrials.
gov/show/NCT02148705 [Cited
11 November 2014]
Allegheny Singer Research Institute.
Medihoney and santyl for burn injuries
(MSBI). ClinicalTrialsgov
2014. Available from: http://clinicaltrials.
gov/ct2/show/record/NCT02250183
[Cited 11 November 2014]
Demling RH. Nutrition, anabolism, and
the wound healing process: an overview.
Eplasty 2009;9:e9
Grotendorst GR, Duncan MR.
Individual domains of connective tissue
growth factor regulate fibroblast
proliferation and myofibroblast
differentiation. FASEB J
2005;19(7):729--38
2006;117(7 Suppl):35S--41S
75. Smith PC. The causes of skin damage
and leg ulceration in chronic venous
disease. Int J Low Extrem Wounds
2006;5(3):160--8
76. Wiggins-Dohlvik K, Han MS,
Stagg HW, et al. Melatonin inhibits
thermal injury-induced hyperpermeability
in microvascular endothelial cells.
J Trauma Acute Care Surg
2014;77(6):899--905
77. Schreml S, Szeimies RM, Prantl L, et al.
Oxygen in acute and chronic wound
healing. Br J Dermatol
2010;163(2):257--68
78. Tonnesen MG, Feng X, Clark RA.
Angiogenesis in wound healing.
J Investig Dermatol Symp Proc
2000;5(1):40--6
79. Bevan D, Gherardi E, Fan TP, et al.
Diverse and potent activities of HGF/SF
in skin wound repair. J Pathol
2004;203(3):831--8
80. Kaltalioglu K, Coskun-Cevher S,
Tugcu-Demiroz F, Celebi N. PDGF
supplementation alters oxidative events in
wound healing process: a time course
study. Arch Dermatol Res
2013;305(5):415--22
81. Li H, Fu X, Zhang L, et al. Research of
PDGF-BB gel on the wound healing of

Expert Opin. Emerging Drugs (2015) 20(2) 11

 E. R. Zielins et al.
diabetic rats and its pharmacodynamics.
J Surg Res 2008;145(1):41--8
82. Smiell JM, Wieman TJ, Steed DL, et al.
Efficacy and safety of becaplermin
(recombinant human platelet-derived
growth factor-BB) in patients with
nonhealing, lower extremity diabetic
ulcers: a combined analysis of four
randomized studies.
Wound Repair Regen 1999;7(5):335--46
83. Gianni-Barrera R, Bartolomeo M,
Vollmar B, et al. Split for the cure:
VEGF, PDGF-BB and intussusception in
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by University of Victoria on 02/26/15
therapeutic angiogenesis.
Biochem Soc Trans 2014;42(6):1637--42
.. Provides an explanation of the
physiologic role of platelet-derived
growth factor-BB in the regulation
of angiogenesis.
84. Rykala J, Przybylowska K, Majsterek I,
et al. Angiogenesis markers quantification
in breast cancer and their correlation
with clinicopathological prognostic
variables. Pathol Oncol Res
2011;17(4):809--17
85. Liu J, Liu C, Qiu L, et al.
For personal use only.
Overexpression of both platelet-derived
growth factor-BB and vascular
endothelial growth factor-C and its
association with lymphangiogenesis in
primary human non-small cell lung
cancer. Diagn Pathol 2014;9:128
86. van der Veer WM, Niessen FB,
Ferreira JA, et al. Time course of the
angiogenic response during normotrophic
and hypertrophic scar formation in
humans. Wound Repair Regen
2011;19(3):292--301
87. Cudmore M, Ahmad S, Al-Ani B, et al.
VEGF-E activates endothelial nitric oxide
synthase to induce angiogenesis via
cGMP and PKG-independent pathways.
Biochem Biophys Res Commun
2006;345(4):1275--82
88. Takeda H, Katagata Y, Hozumi Y,
Kondo S. Effects of angiotensin II
receptor signaling during skin wound
healing. Am J Pathol
2004;165(5):1653--62
12
89. Sosne G, Qiu P, Goldstein AL,
Wheater M. Biological activities of
thymosin beta4 defined by active sites in
short peptide sequences. FASEB J
2010;24(7):2144--51
90. Min LJ, Cui TX, Yahata Y, et al.
Regulation of collagen synthesis in mouse
skin fibroblasts by distinct angiotensin II
receptor subtypes. Endocrinology
2004;145(1):253--60
91. Baker EA, Leaper DJ. Profiles of matrix
metalloproteinases and their tissue
inhibitors in intraperitoneal drainage
fluid: relationship to wound healing.
Wound Repair Regen
2003;11(4):268--74
92. Zaga-Clavellina V, Garcia-Lopez G,
Flores-Pliego A, et al. In vitro secretion
and activity profiles of matrix
metalloproteinases, MMP-9 and MMP-2,
in human term extra-placental
membranes after exposure to Escherichia
coli. Reprod Biol Endocrinol 2011;9:13
93. Colwell AS, Phan TT, Kong W, et al.
Hypertrophic scar fibroblasts have
increased connective tissue growth factor
expression after transforming growth
factor-beta stimulation.
Plast Reconstr Surg
2005;116(5):1387--90; discussion 91-2
94. Mulder G, Tallis AJ, Marshall VT, et al.
Treatment of nonhealing diabetic foot
ulcers with a platelet-derived growth
factor gene-activated matrix (GAM501):
results of a phase 1/2 trial.
Wound Repair Regen 2009;17(6):772--9
95. Balingit PP, Armstrong DG,
Reyzelman AM, et al. NorLeu3-A(1-7)
stimulation of diabetic foot ulcer healing:
results of a randomized, parallel-group,
double-blind, placebo-controlled
phase 2 clinical trial.
Wound Repair Regen
2012;20(4):482--90
96. Payne WG, Wachtel TL, Smith CA,
et al. Effect of amnion-derived cellular
cytokine solution on healing of
experimental partial-thickness burns.
World J Surg 2010;34(7):1663--8
Expert Opin. Emerging Drugs (2015) 20(2)
97. Farooqi AA, Rehman ZU, Muntane J.
Antisense therapeutics in oncology:
current status. Onco Targets Ther
2014;7:2035--42
98. Robert DG, Mark LJ, Jeff J, et al. An
antisense oligonucleotide (EXC-001)
targeting connective tissue growth factor
reduces skin scarring associated with
abdominoplasty and reduces CTGF
expression. Plast Reconstr Surg
2011;128:45
99. RXI-109 reduces a key component of
dermal scarring, connective tissue growth
factor mRNA, in a multidose
phase 1 clinical trial. J Am
Acad Dermatol 2014;70(5):AB196
100. Duscher D, Neofytou E, Wong VW,
et al. Transdermal deferoxamine prevents
pressure-induced diabetic ulcers.
Proc Natl Acad Sci USA
2015;112(1):94--9
Affiliation
Elizabeth R Zielins1 MD, Elizabeth A Brett1 MS,
Anna Luan1 MS,
Michael S Hu1-3 MD MS MPH,
Graham G Walmsley1,3 BA, Kevin Paik1 AB,
Kshemendra Senarath-Yapa1 MA MBBChir
MRCS, David A Atashroo1 MD,
Taylor Wearda1 BS, H Peter Lorenz1 MD,
Derrick C Wan1 MD &
Michael T Longaker†1,3 MD MBA
†
Author for correspondence
1
Stanford University School of Medicine,
Division of Plastic Surgery, Department of
Surgery, Hagey Laboratory for Pediatric
Regenerative Medicine, 257 Campus Drive,
Stanford, CA 94305-5148, USA
Tel: +1 650 736 1707;
Fax: +1 650 736 1705;
E-mail: longaker@stanford.edu
2
University of Hawai’i, John A. Burns School of
Medicine, Department of Surgery, Honolulu, HI,
USA
3
Stanford University, Institute for Stem Cell
Biology and Regenerative Medicine, Stanford,
CA, USA