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Recent Advances in Polymer-based Wound Dressings For the Treatment of

Diabetic Foot Ulcer: An Overview of State-of-the-art

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Current Drug Targets, 2017, 18, 000-000 1

REVIEW ARTICLE

Recent Advances in Polymer-based Wound Dressings for the Treatment of

Diabetic Foot Ulcer: An Overview of State-of-the-art

Zahid Hussain1,*, Hnin Ei Thu2, Ahmad Nazrun Shuid2, Haliza Katas3 and Fahad Hussain4

1
Department of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, Bandar Pun-
cak Alam 42300, Selangor, Malaysia; 2Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Ma-
laysia, Jalan Yaacob Latif, Bandar Tun Razak 56000 Cheras, Kuala Lumpur, Malaysia; 3Centre for Drug Delivery Re-
search, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz 50300, Kuala Lumpur,
Malaysia; 4Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Raiwind Road Lahore,
Punjab, Pakistan

ARTICLE HISTORY
Received: December 27, 2016
Revised: April 17, 2017
Accepted: May 16, 2017
DOI:
10.2174/1389450118666170704132523
Abstract: Diabetic foot ulcers (DFUs) are the chronic, non-healing complications of diabetic mellitus
which compels a significant burden to the patients and the healthcare system. Peripheral vascular dis-
ease, diabetic neuropathy, and abnormal cellular and cytokine/chemokine activity are among the
prime players which exacerbate the severity and prevent wound reapir. Unlike acute wounds, DFUs
impose a substantial challenge to the conventional wound dressings and demand the development of
novel and advanced wound healing modalities. In general, an ideal wound dressing should provide a
moist wound environment, offer protection from secondary infections, eliminate wound exudate and
stimulate tissue regeneration. To date, numerous conventional wound dressings are employed for the
management of DFUs but there is a lack of absolute and versatile choice. The current review was
aimed to summarize and critically discuss all the available evidence related to the pharmaceutical and
therapeutic viability of polymer-based dressings for the treatment of DFUs. A versatile range of natu-
rally-orignated polymers including chitosan (CS), hyaluronic acid (HA), cellulose, algninate, dextran,
collagen, gelatin, elatin, fibrin and silk fibroin have been utilized for the treatment of DFUs. These
polymers have been used in the form of hydrogels, films, hydrocolloids, foams, membranes, scaffolds,
microparticles, and nanoparticles. Moreover, the wound healing viability and clinical applicability of
various mutually modified, semi-synthetic or synthetic polymers have also been critically discussed.
In summary, this review enlightens most recent developments in polymer-based wound dressings with
special emphasis on advanced polymeric biomaterials, innovative therapeutic strategies and delivery
approaches for the treatment of DFUs.

Keywords: Diabetic foot ulcer, non-linear wound healing, conventional dressings, natural and synthetic polymers, efficacy-
upgradation.

1. INTRODUCTION prevalence of DM are expected to be the aging and the

Diabetes mellitus (DM) is one of the most prevalent
metabolic syndrome: in 2010, it was estimated that 285 mil-
lion adults worldwide had suffered from this metabolic dis-
orders and the prevalence is continuously escalating to be
expectedly increase to 439 million by 2030 [1, 2]. In North
America and Europe, the prevalence of diabetic population is
increased by 42.4% and 20% respectively, and a major burst
in Africa is predicted, with the number of adults with diabe-
tes is expected to increase by 98.1% from 2010 to 2030 [1,
2]. The prime dynamics responsible for this increasing
*Address correspondence to this author at the Department of Pharmaceutics,
Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus,
Bandar Puncak Alam 42300, Selangor, Malaysia; Tel: +6(0)102483089;
E-mail: zahidh85@yahoo.com
changes in lifestyle habits [1, 3].
Diabetic foot ulcer (DFU) is typically displayed as open
sore or wound and is usually employed as secondary compli-
cation of diabetes mellitus (DM) [4]. DFU lesions are re-
sponsible for more hospitalizations than any other complica-
tion of diabetes and are the leading cause of nontraumatic
lower extremity amputations in the United States. These
causative diseases have a significant impact on various vital
mechanisms of normal wound healing such as biochemical
signaling, extracellular matrix (ECM) deposition or cell mi-
gration which could result in impaired wound healing and
transformation to DFUs. For example, hyperglycemia in
diabetic patients may inhibit ECM deposition by up-
regulating the proteolytic action of matrix metalloproteinases
(MMPs) via increased levels of tumor necrosis factor-alpha

1389-4501/17 $58.00+.00 © 2017 Bentham Science Publishers

2 Current Drug Targets, 2017, Vol. 18, No. 11
(TNF-α) and interleukins (IL-1β) [5]. In addition, DFUs may
also impair keratinocyte migration and leukocyte function
leading to various infections. Moreover, depleted levels of
inorganic phosphate within diabetic patients could also result
in low levels of adenosine triphosphate (ATP), leading to a
significant attenuation of the immune response [5]. Signaling
molecules like epidermal growth factor (EGF) function nor-
mally to stimulate proliferation and migration of keratino-
cytes during wound closure; however, aging and metabolic
disease inhibit keratinocytes ability to respond to EGF and
other growth-promoting mitogens [6, 7]. The above mecha-
nisms contribute to impaired wound healing and are the fo-
cus of new therapeutic modalities that focus on incorporating
both ECM and various signaling molecules within chronic
wounds in order to promote regeneration and wound repair.
Impaired wound healing is one of the most prevalent
clinical problems in diabetes mellitus and results in failure to
completely heal DFUs, which may lead to lower extremity
amputations [4]. Chronic wounds seem to be detained in one
or more of the phases of wound healing. This is because
these wounds provide a significant burden to patients, health
care professionals and healthcare systems with 5.7 million
patients affected in the US alone costing an estimated 20
billion dollars annually [4, 8]. These types of wounds are
characterized by a prolonged or persistent inflammatory
phase, excessive infections, and the failure of epidermal or
dermal cells to respond to environmental insult [9]. As a
consequence, pro-inflammatory cells and cytokines at the
lesional site stimulate a proteolytic cascade which induces
degradation of growth factors (GFs) [10]. This would result
in inhibition of tissue growth and thus, delaying or impairing
the physiological mechanisms behind normal wound healing
[11]. Moreover, chronic wounds have also been proved to
show a high bacterial bioburden which can further compli-
cate wound restoration [12].
To date, numerous therapeutic strategies have been em-
ployed for the management of DFUs with the aim of acceler-
ating the healing process, avoiding secondary complications
and improving patient compliance. Various wound healing
approaches include; conventional wound dressings such as
hydrogel-, hydrocolloid-, foam-, and film-based dressings
and advanced standard procedures such as split-thickness
autografts, use of donor keratinocytes, cultured epithelial
autografts, and Biobrane dressings. Though, mild and acute
clinical cases can be managed with the conventional or stan-
dard therapies alone, chronic wounds and those appeared as
secondary complications of metabolic disorders might re-
quire intensive pharmaceutical care and pharmacotherapy.
In recent times, scientific orientation has been focused on
the use of polymeric delivery systems, modified advanced
biomaterials, and nanotechnology for optimising therapeutic
outcomes, patient adherence and compliance as well as
minimizing non-target adverse effects. The current review
therefore aims to summarize the most recent developments
in polymer-based wound dressings with special emphasis to
advanced polymeric biomaterials, innovative therapeutic
strategies and delivery approaches for the treatment of
DFUs. Recent results from in vitro and in vivo studies have
been included to underline the unique potential of polymer-
based wound dressings in the treatment of DFUs.
Hussain et al.
2. NON-LINEAR WOUND HEALING AND DFUs
Wound healing is an intricate process that involves the
simultaneous actuation of blood cells, soluble mediators,
parenchymal cells and extracellular matrix (ECM). This
complex wound healing process is completed through the
efficient collaboration of several phases: 1) the inflammatory
phase, which involves homeostasis/coagulation, and inflam-
matory cascades, 2) the proliferation phase, which involves
rebuilding new granulation tissues and the development of
new networks of blood vessels (angiogenesis) followed by
re-epithelialization (resurfacing of the wound with epithelial
cells), 3) the maturation phase, which is the final phase and
involves remodelling of collagen from type III to type I [13].
These phases are not typically associated with a rigorous and
well-defined period of time and may overlap and thus result
in non-linear or chronic wounds [14, 15]. The transition be-
tween phases usually depends on the maturation and differ-
entiation of mast cells, fibroblasts, keratinocytes and macro-
phages which play prime role in the wound healing process
[16-18].
Variuos complications associated with DM may cause
development of DFUs in diabetic patients. Diabetic neuropa-
thy or peripheral vascular diseases are two major problems
encountered with DM [19-22]. These two diseases may act
alone, together, or in combination with other pathological
and metabolic conditions such as biomechanical abnormali-
ties, microvascular disease and increased susceptibility to
infection [23, 24]. Besides, the development of chronic
wounds and their non-linear healing process can also be as-
sociated with the excessive and persistent activity of MMPs
and/or due to low levels of MMP inhibitors [25, 26]. In addi-
tion, the peripheral vascular disease may also tend to reduce
the healing capacity of an individual due to an insufficient
supply of oxygen and nutrients to the wounded area [27].
The impaired functioning of macrophages, granulocytes,
chemotactic mediators as well as deregulation of the neo-
vascularization phase might also prolong the healing process
and result into a DFUs [28, 29]. In addition other potential
reasons for the development of DFUs can be caused by the
impaired functioning of nitric oxide, collagen deposition,
anomalous proliferation and differentiation of fibroblasts and
keratinocytes [30], as well as the accumulation of ECM and
their subsequent remodeling by MMPs [31].
3. CLASSIFICATION AND MANAGEMENT OF DFU
Effectual therapeutic plan for a chronic stubborn wound
remains a challenge. However a better understanding of the
molecular biology and pathophysiology of chronic wounds
(DFUs) could result in more efficient and improved thera-
peutic paradigm for the management of chronic wounds.
Researchers believed that the wound healing process can be
actively promoted by amending the expression of prime bio-
logical mediators which are key parameters for the healing
process [32]. In general, it is already well-established that an
efficient and well-controlled healing process can be achieved
by adopting standard guidelines such as; (1) the wounded
area should be dressed with adequate biomaterials which can
prevent the contamination/infection of the affected area over
a long-term duration of wound management, (2) an ideal
moist environment needs to be provided to potentiate wound
Polymers-based Dressings for Diabetic Foot Ulcers
healing rate (wound closure) and prevent wound dissection
(3) use of such a medicated dressing which can provide a
sustained and proficient release of fabricated pharmacologi-
cal moieties and biomolecules and (4) prevent a rapid degra-
dation of medicated dressing and irregular releasing pattern
of fabricated drugs during the healing process [33, 34]. The
management plan for DFUs is defined based on the severity
and range of tissues affected. This can be assessed by classi-
fying DFUs according to Wagner’s system [35, 36]. In ac-
cordance with Wagneer’s classification system, DUFs can be
classified into various grades as follows: (1) “grade 0” indi-
cates no ulcers in affected tissues with high-risk of secondary
complications; (2) “grade-1” refers to a partial and/or full
thickness ulcer; (3) “grade-2” indicates a deep ulcer which
has penetrated down to the ligaments and muscle, but with
no bone involvement; (4) “grade-3” refers to a deep ulcer
with cellulitis or abscess formation, (5) “grade-4” indicates a
localized gangrene), and (6) “grade-5” indicates an extensive
and deep gangrene of the whole tissue [37]. The classifica-
tion of DFUs is imperative as it may facilitate selection of an
appropriate dressing depending on the wound type, severity
and on the phase of wound development [38]. DUFs have
also been classified based on clinical severity index and
menifestations (as shown in Table 1). The clinical presenta-
tion and the signs and symptoms of DFUs are presented in
(Fig. 1). Several conventional and advanced dressings have
been discussed in the following sections.
3.1. Polymer-based Conventional Dressings
3.1.1. Types and Ideal Characteristics of Polymer-based
Conventional Wound Dressings
Wound dressings were first developed to play only a pas-
sive and protective role in the healing process [39]. How-
ever, in recent decades several researchers have discovered
revolutionary findings, which suggest that moist dressings
can facilitate and accelerate the healing process [40]. Previ-
ous studies reported that the moistening of wound environ-
ment plays a pivotal role in stimulating proliferation and
migration of fibroblasts and keratinocytes at the site of injury
[41]. Moreover, it tends to enhance collagen synthesis which
leads to reduced scar formation [41, 42]. Taken together,
researchers also believe that besides facilitating optimum
moisture generation in the wounded area, the ideal wound
dressings should also: (1) allow gaseous exchange, thermal
insulation, and facilitate the removal of drainage and debris
in an attempt to promote the tissue reconstruction processes,
Table 1. Classification of DFU infections based on clinical severity.
Severity Index
Uninfected
Infection localized to the skin and subcutaneous tissue (cellulitis/erythema extends ≤ 2 cm around an ulcer) without evidence of sys-
Mild
More extensive local infection (i.e., local spread ≥ 2cm beyond an ulcer, lymphangitic streaking, abscess, gangrene, or involvement of
Moderate
deep soft tissue, muscle, fascia, tendon, joint or bone) without evidence systemic illness or severe metabolic derangements
Severe
* Infection is defined as the presence of purulent secretions (pus) or ≥ 2 signs or symptoms of inflammation (erythema, warmth, tenderness, induration, pain).
Current Drug Targets, 2017, Vol. 18, No. 11 3
(2) be non-toxic and should not provoke any immune or al-
lergic response, (3) prevent biofilm formation and secondary
infections, which could subsequently delay wound healing,
and (4) promote patient compliance, by facilitating self ap-
plication and removal without aggravating symptoms [39,
43]. However, due to the distinct severity and characteristics
of different types of wounds and healing phases involved,
there is no single dressing which can efficiently meet all the
needs for a particular wound and healing phase [44, 45]. The
particular characteristics, advantages and disadvantages of
the most commonly used polymers in the management of
DFUs are summarised in (Table 2).
3.2. Factors That Need to be Considered While Selecting
a Suitable Wound Dressing
Current focus on evidence-based practice and the needs
to ensure cost effectiveness and patient satisfaction have
changed the way wound dressings are prescribed. Healthcare
providers should aim, both at the time of prescribing and
while monitoring treatment thereafter, (1) to maximise effec-
tiveness, (2) to minimize associated risks, (3) to minimize
cost, and (4) to improve patient compliance. A holistic ap-
proach, considering the wider needs of the patient as well as
control of the wound environment, can maximize healing of
complex and chronic wounds. Hence, dressing selection
should be rational and based on the wound bed type.
Typically, DFU can be treated using passive or hydro-
active techniques [55]; however, the passive technique is
normally employed for the management of acute wounds (as
they absorb reasonable amounts of exudate and they can
ensure good protection). On the other hand, the hydro-active
technique is mostly employed for the management of chronic
wounds (such as DFUs) as they easily adapt to wounds and
are able to maintain a moist environment that can stimulate
the healing process [56].
4. RECENT PROGRESS IN POLYMER-BASED
WOUND DRESSINGS
The efficiency of wound healing is greatly dependent on
several parameters such as severity of the wound, patho-
physiological basis of the wound, patient health condition,
and the extent of tissues involved. The selection of appropri-
ate wound dressing, together with the inclusion of therapeu-
tic substances and healing enhancers (if employed) also
plays a pivotal role in the effective management of DFU.
Clinical Manifestations
Wound lacking purulence or any manifestations of inflammation
temic illness
Infection with systemic toxicity or severe metabolic derangements
4 Current Drug Targets, 2017, Vol. 18, No. 11
Fig. (1). Types of DFUs based on signs, symptoms, and clinical presentation.
As reported by many research groups [57, 58], the effi-
ciency of polymer based wound dressings, whether passive
or hydro-active, is largely based on the constituent polymeric
materials, physicochemical characteristics, biological re-
sponse, and extent of fabrication. Hence, one of the simplest
ways to differentiate these polymeric biomaterials is based
on their origin: synthetic or naturally based polymers and
copolymers [59]. Modified polymeric materials (those ob-
tained by chemical modification of naturally based poly-
mers) [60] or mixtures/combinations of different polymers
and copolymers [61] can also be considered. A wide variety
of polymer based wound dressings have gained remarkable
attention within the healthcare community for the manage-
ment of chronic wounds [62, 63]. The brief summary of most
commonly-used polymer-based materials and their wound
healing efficicies is presented in (Table 3).
4.1. Natural Polymers
Natural polymers are biomolecules that are originated
from natural sources such as microbial, animal or vegetable
sources [64]. Although natural polymers can closely simulate
the original cellular milieus and ECM, they are significantly
heterogeneous and may undergo significant biochemical
degradation that can modify their physicochemical character-
istics and and their behavior (releasing pattern, interaction
with surrounding tissues etc.) in the physiological environ-
ment [65]. Batch-to-batch variation in the quality attributes
of these polymers is often observed following isolation from
animal or vegetable sources, which can limit their useful in
wider wound care applications [66]. In addition, some nota-
ble risks of infectious diseases being transmitted have also
been reported for polymeric materials of natural origin,
which have been attributed due to their xenogenic or allo-
genic nature [67].
Other disadvantages of these naturally derived systems
include suboptimal mechanical performance and poor stabil-
ity, which also limit their wider application [67]. Interest-
ingly, several chemical modifications have been developed
in order to address these major shortcomings [68, 69]. Those
natural polymers used in wound dressings for the manage-
Hussain et al.
ment of DFUs are discussed in the sections of this report,
which follow.
4.1.1. Chitosan and Derivatives
Chitosan (CS) is a linear copolymer derived from chitin
which is the major component of the exoskeletons of crusta-
cea such as shrimp and crab (chemical structure shown in
Fig. 2). It is well-recognised for its heterogenic functionali-
ties such as its non-antigenicity, inertness, non-toxicity, bio-
degradability, biocompatibility, bio-adhesiveness, anti-
microbial properties, hemostatic effects and wound healing
characteristics [63, 70, 71]. Furthermore, CS is highly versa-
tile and is able to produce a variety of functionalised deriva-
tives through the chemical modification of amino and hy-
droxyl groups. These derivatives include N-carboxymethyl,
N-carboxybutyl, N-succinyl, N-acyl, N,O-(carboxymethyl),
N-N-dicarboxymethyl, N-carboxyethyl, O-succinyl, Ocar-
boxymethyl, and 5-methylpyrrolidinone CS derivatives
amongst others.
CS and its derivatives have been widely established as
delivery matrices for a number of pharmaceutical applica-
tions [60, 70, 72, 73]. It is soluble in weak organic acids,
whereby it interacts with negatively charged molecules such
as anionic polysaccharides, proteins, and nucleic acids,
which are usually present in skin [74]. CS and derivatives
have also been reported to exhibit mild gelation whilst dem-
onstrating the capacity to form films. It shows strong adhe-
sion to wound tissues and promotes blood coagulation and
wound healing [68, 75]. In particular, CS films with low
degree of deacetylation have already been proven effective
in the treatment of superficial wounds [76].
A recent study was conducted by Moura et al., (2014) to
evaluate the wound healing potential of 5-methyl pyrrolidi-
none CS (MPC) based dressing containing neurotensin, a
neuropeptide that acts as an inflammatory modulator in dia-
betic wounds [77]. Neurotensin (NT) is a bioactive neu-
ropeptide that is widely distributed in the brain and in several
peripheral tissues. NT interacts with leukocytes, mast cells,
dendritic cells and macrophages leading to cytokine release
and chemotaxis that can modulate the immune response.
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 5

Table 2. Summary of the polymer-based conventional wound dressings used for the management of DFUs.

Polymer(s) Features Indication Advantages Disadvantages Modality of Ref.

Application

Hydrogel 1. Available as cross- 1. Efficient for wounds 1. Non-adherent and can 1. Not efficient in wounds 1. Change [45-50]
linked polymer gels with minimal or no be applied or removed with excessive exudates every 1-3
in sheet form. exudates without seriously inter- which may require sec- days
fering with the wound ondary dressings.
2. Excellent in main- 2. Increased moisture bed.
taining a moist envi- content would facilitate 2. Not too absorptive,
ronment cleansing and autolytic 2. Effective in hydrating therefore, hydrogels or
debridement of necrotic wound surfaces and liq- hydrogel sheets may
3. Provide absorption, tissues. uefying necrotic tissue not be an appropriate
desloughing and de- on the wound surface. choice for moderate to
briding capacities to highly exudative
necrotic and fibrotic 3. Soothing effect improve wounds
tissue patient compliance.
Foam 1. Generally made up 1. Efficient for greatly 1. Comfortable and con- 1. Opaque and thus does 1. Change [45, 46,
of hydrophilic exudative wounds es- formable not allow the visualiza- every 3 49-51]
polyurethane pecially when drainage tion of wound bed. days
is at peak. 2. Easy application and
2. Capable of absorb- removal without inter- 2. Restricted to excessive
ing excessive wound 2. Deep cavity wounds - fering with wound bed exudative wounds only
exudates as packing to prevent or viable tissues fibers. and cannot be used on
premature closure dry wounds as it can
3. Improve patient while absorbing exu- 3. No dressing residue in cause excessive dryness.
compliance because dates and maintaining a the wound bed.
of less frequency of moist environment to
application and re- 4. Proposed as efficient
fasten healing rate. wound dressings for
moval.
severely chronic
wounds.
Hydrocolloid 1. Occlusive and adhe- 1. Efficiently manage 1. Conformable for easy 1. Moderate-to-severely 1. Can leave [47, 49,
sive wafer dressings granulating and epithe- application exudative wounds can in place up 52-54]
which combine ab- lialising wounds with cause messiness (ac- to 7 days or
sorbent colloidal mild-to-moderate drain- 2. Reduce pain, inflamma- cumulation of exudate) until fluid
materials with adhe- ing exudates tion and progression at beneath the dressings leaks.
sive elastomers. the wound site. usually within a few
2. Promote autoyltic de- days.
2. React with wound bridement of necrotic
exudates and form tissues by keeping 2. Degradation of the
gel-like covering wound moist dressing materials may
therefore protects produce a residue of
the wound bed and varying colors and pos-
maintains moist sible foul odor. This
wound environment. may reduce patient
compliance.
3. Powders and pastes
are also available
with increased ab-
sorptive capacity for
severely exudative
wounds.
Film 1. Transparent and 1. Efficient for wounds 1. Allow cyclic wound 1. May have potential risks 1. Can leave in [45, 46,
adhesive films are with mild-to-moderate inspections due to its of damaging wound bed place up to 7 49, 51]
typically semi- exudates. transparent nature. while removing film days or until
permeable mem- dressing because of its fluid or exu-
brane dressings. 2. Efficient for superficial 2. Water proof and gas adhesive nature. dates leaks.
pressure wounds. permeable.
2. Partially permeable 2. Non-absorptive and
to oxygen and water 3. Clinically used for 3. Maintain a moist will be overwhelmed
vapors. chronic wounds on el- wound environment by moderately exuda-
bows, heels and flat which helps to clear ne- tive wounds.
3. Impermeable and body surfaces. crotic debris and
prevents bacterial cleanse the wound bed.
contamination.
4. Economical and cost
4. Maintain a moist effective and thus im-
wound environment proves patient compli-
on chronic wound ance.
bed.
5. Facilitates cellular
migration and pro-
motes autolysis of
necrotic tissue by
trapping moisture on
the wound bed.
6 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

Table 3. Summary of efficacy of natural polymer-based dressings employed for the treatment of DFUs.

Study Experimental Polymer(s) Carrier System Active Moiety Main Findings Ref.
Design Model

In vivo STZ-induced dia- CS CS crosslinked collagen rhFGF 1. Faster wound healing process. [84]
studies betic rats
2. Promoted faster deposition of tissue
collagen, higher expression of tis-
sue growth factors and dermal cell
proliferation.

STZ-induced dia- Thiolated CS-oxidized _ 1. Non-toxic [85]

betic mice dextran hydrogel
2. Resistant to bio-degradation.

3. Accelerate tissue regeneration and

remodelling and subsequent wound
healing.

STZ-induced dia- CS + alginate + poly(c- _ 1. Stimulated wound healing process. [86]

betic rats glutamic acid) hydrogel
2. Higher intensity of collagen
accumulation.

3. Accelerated skin epithelialization.

4. Antibacterial activity to prevent

delaying of wound healing cas-
cades.

Clinical DFUs in human dia- CS CS Acetyl-glucosamine 1. Decreased wound size [87]

study betic patients oligomers
2. Accelerated angiogenesis and re-
epithelization.

3. Stimulated healing process.

In vivo db/db diabetic mice HA Poly-N-acetyl glucosa- _ 1. Faster rate of healing (90% closure [88]
studies mine (pGlcNAc) in 16.6 days).

2. Accelerated proliferation and vas-

cularization in granulation tissue.

db/db diabetic mice pGlcNAc membrane _ 1. Faster wound closure achieved by [89]
re-epithelialization and increased
keratinocyte migration.

2. Accelerated granulation tissue for-

mation, cell proliferation, and vas-
cularization.

3. Up-regulated levels of VEGF,

uPAR and MMP3 and MMP9.

STZ-induced dia- HA gel _ 1. Significant reduction of wound size. [90]

betic rats
2. Remarkable increased in number of
macrophages and fibroblast

3. Accelerated collagen deposition and

re-epithelization of the wounds.

STZ-induced dia- HA foam Arginine and EGF 1. Accelerated wound healing. [91]
betic rats
2. Significant reduction in wound size.

3. Increased re-epithelization.

(Table 3) contd….
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 7

Study Experimental Polymer(s) Carrier System Active Moiety Main Findings Ref.
Design Model

Clinical Non-healing chronic HA HA benzyl ester films Autologous human 1. Slow but consistent healing rate. [92]
studies wound in human keratinocytes
2. Healing of 79% of wound area
diabetic patients
achieved with 7-64 days.

3. Regeneration of dermal tissues.

®
Non-healing chronic Hyiodine Sodium hyaluronate- 1. Significantly faster healing rate. [93]
wound in human iodine complex
2. Faster wound closure.
diabetic patient

Non-healing ulcer in HA gel Mixture of amino 1. Significant reduction in ulcer area [94]
diabetic patient acids within 3 month of treatment.

2. Significant reduction in infective

complications.

In vivo db/db mice Cellulose deriva- Carboxymethyl cellulose Chestnut honey 1. Significant reduction of wound [95]
study tives hydrogel area.

2. Remarkable increase in tissue

granulation and tissue re-
epithelialization.

Clinical DFUs in human dia- Cellulose based dressing Silver-loaded NPs 1. Accelerated wound healing. [96]
studies betic patients
2. Significant reduction in the activity
of E. coli and of S. aureus by
99.99% in infected wounds.

DFUs in human dia- Collagen/oxidized regen- _ 1. Stimulated wound healing. [97]

betic patients erated cellulose foam
2. Significant reduction in ulcerative
area within 6 weeks of application.

Chronic, non-healing Microbial-derived cellu- PHMB 1. Significant improvement in healing [98]

ulcers in human pa- lose hydrogel process.
tient
2. Significant reduction in infectious
microbes.

3. Optimal moist healing environment

through the absorption of excess
fluid from exudative wounds.

4. Removal of necrosis debris.

DFUs in human dia- Collagen/oxidized regen- _ 1. Improved wound healing. [99]

betic patients erated cellulose foam
2. Significant decrease in the expres-
sion level of proteases, such as elas-
tase, plasmin, and gelatinase in
wound exudates.

Non-infected chronic Microbial cellulose _ 1. Accelerated wound healing within [100]

wound in human 32 days.
diabetic patients
2. Increased granulation and tissue re-
epithelialization.

Clinical Non-healing chronic Alginate Alginate hydrogel Phenytoin 1. Significant reduction in wound [101]
studies wound in human infection.
diabetic patients
2. Improved wound healing which led
to 60% of wound closure within 16
weeks of treatment.

3. Reduced pain

(Table 3) contd….
8 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

Study Experimental Polymer(s) Carrier System Active Moiety Main Findings Ref.
Design Model

DFU in human dia- Alginate gel Honey 1. Faster healing rate. [102]
betic patients
2. Stimulated tissue re-epithelization.

In vivo db/db mice Collagen/Gelatin Gelatin-based micro- FGF 1. Accelerated fibroblast proliferation [103]
studies spheres and capillary formation.

2. Reduced infection.

STZ-induced dia- Collagen matrix Glucose oxidase 1. Increased cellular proliferation [104]
betic rats
2. Accelerated wound closure.

db/db mice Collagen-gelatin bFGF 1. Faster wound healing. [105]

foam 2. Accelerated granulation tissue

formation and angiogenesis.

Clinical DFUs in human dia- Collagen based dressing _ 1. Remarkable improvement in wound [106]
studies betic patients healing with 60% of wound healed
within 2 weeks of treatment.

2. Significant reduction in infection by

bacteria

3. Increase in granulation tissue.

DFUs at high risk of Collagen matrix _ 1. Salvaged 46% of the limbs. [107]
amputation in human
2. Increased bacterial clearance.
patient
3. Greater granulation tissue forma-
tion.

In vivo STZ-induced dia- Fibrin Fibrin gel CD34+ cells 1. Stimulated wound healing rate. [62]
studies betic mice

Alloxan diabetic Fibrin scaffold AdeNOS 1. Faster rate of re-epithelialisation. [108]

rabbit
2. Enhanced wound healing, eNOS
expression and inflammatory re-
sponse.

Clinical Human patients with Combined single-donor _ 1. Accelerated wound closure. [109]
studies DFUs platelet gel and fibrin
2. Higher granulation tissue forma-
glue
tion.

Non-healing chronic Leucopatch® (naturally _ 1. Significant reduction in wound area [110]

wound in human coagulated fibrin) by 65% within only 12 weeks of
diabetic patients treatment.

2. Faster wound healing.

In vivo STZ diabetic rat Silk fibroin Fibroin film Aloe vera extract 1. Faster rate of wound healing. [111]
study
2. Higher granulation and re-
epithilialization.

Clinical Chronic wound in Dextran Dextran-allyl isocyanate- _ 1. Accelerated wound healing. [112]
study human patients ethylamine/polyethylene
2. Stimulated dermal regeneration,
glycol diacrylate hydro-
cell infiltration and migration.
gel

In vivo STZ-induced dia- Elastin Elastin-like peptides gel KGF 1. Faster healing. [113]
study betic mice
2. Enhanced re-epithelialization and
granulation tissue formation.
Abbreviation: CS, Chitosan; STZ, Streptozotocin; rhFGF, Recombinant human fibroblast growth factor; HA, Hyaluronic acid; VEGF, Vascular endothelial growth factor; uPAR,
Urokinase-type plasminogen activator; MMP3, metalloproteinases-3; MMP9, metalloproteinases-9; EGF, Epithelial growth factor; FGF, Fibroblasts growth factor; NPs, Nanoparti-
cles; PHMB, Polyhexamethylase biguanide; DFUs, Diabetic foot ulcer; KGF, Keratinocyte growth factor.
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 9

OH OH OH
OH HO O

CH2 O O
CH2 CH2 HO O O
O O O
HO O O O HO
OH NH OH
HO
HO
NH2 NH2 HO NH
O n
n O CH3
Chitosan Hyaluronic acid
H 3C
O-
OH O
HO OH
OH OH
O O
O O O
O O O O
*
HO OH HO HO
OH n
n O
m
O-
Cellulose
Alginate

O O O O O NH O
O
O O
OH O O NH OH
OH OH NH
HOHO HOHO OH NH NH
HOHO HOHO
O O O
n
Dextran Elastin

Fig. (2). Chemical structures of some natural polymers used for the treatment of DFUs.
In addition, NT affects microvascular tone, vessel permeabil-
ity, vasodilation/vasoconstriction and new vessel formation
which helps to improve angiogenesis during wound healing
processes. Moura and colleagues demonstrated that the NT
encapsulated MPC-based wound dressing greatly promoted
healing process and reduced the recovery time (Fig. 3) when
compared to other treatment groups. In the same study, an
increase in epidermis thickness was observed in all treatment
groups; being particularly prominent in NT-loaded MPC
treatments in diabetic skin for periods up to 3 days. How-
ever, on day-10 the epidermis thickness profile was similar,
but with a stronger effect in diabetic skin. Specific re-
epithelialization profiles were also observed: in control mice
with re-epithelialization occurring from the bottom to top
with basal cells in the epidermis covering the scar. In dia-
betic mice, re-epithelialization occurred over the granulation
inflammatory tissue while this was undergoing repair. No
correlation was observed with the applied treatments, in both
groups [77].
Different forms of CS including hydrogels, membranes,
scaffolds, microparticles, and nanoparticles have also been
employed to show wound healing potential [57, 77]. Li et al.,
(2013) investigated the wound healing potential of
poly(vinyl alcohol) (PVA) together with CS oligosaccharides
(COS) in the form of silver nanofibers (AgNPs) through
various in vivo experiments [78]. Silver has a long history of
medicinal use based on its antimicrobial effects. Microbial
burden can delay wound healing and makes silver an attrac-
tive local antiseptic for wounds affected this way, especially
as antibiotics have limitations. Whilst there is good evidence
in preclinical studies of the effects of silver on microbes and
on processes that delay wound healing, evidence for the
benefits of silver products on human wound healing is still
far from robust. However, Li and colleagues observed a
complete closure of wounds in all treatment groups within 14
days. The grafts prepared with nanofiber (PVA/CS-AgNPs)
scaffolds were well integrated into the surrounding skin. The
wound areas decreased gradually, reaching approximately
3% at day-14 after treatment with silver incorporated nanofi-
bers. In addition, the histological examination also high-
lighted the clinical superiority of PVA/CS-AgNPs nanofibers
in accelerating wound healing rate compared with control
groups. Seven days after grafting, the wounds treated with
control groups still displayed ulcerated surfaces, formation
of granulation tissue, and infiltration of inflammatory cells.
In contrast, the granulated tissue in the PVA/CS-nanofibers
treated group disappeared without capillary hyperplasia. On
day-14, newly synthesized fibrous tissue and sparse inflam-
matory cells in the dermis and subcutis were covered by
completely re-epithelialized epidermis in test groups. These
data confirm that the PVA/CS as nanofibrous membrane
could provide a suitable scaffold for wound healing.
The wound healing superiority of CS in combination
with adipose derived nucleated cell fractions (ADNCs) has
also been proposed by Mehrtash et al., (2015) using male
white Wistar rats [79]. Cell therapy is evident to increase
wound healing rate, reduce scar contracture, and minimize
donor-site morbidity in treatment of acute wound. In the
treatment of chronic wounds, attempts are made to convert
the wound bed into the environment where maximum wound
healing can be achieved by transplanting cells with an excel-
lent wound healing capacity to the wound bed. The adipose
tissue bears several properties that are advantageous for neu-
ronal sprouting and direction and has been used in different
areas of surgery in recent decades. In this study, Mehrtash
and colleagues demonstrated that ADNCs and CS combina-
tion resulted in a significant improvement of full thickness
wound healing. Significant differences were observed in
signs and symptoms of wounds treated with CS-ADNC
combination compared with other groups, particularly in
terms of cellular infiltration, acute hemorrhage, congestion,
edema, collagen production and density, reepithelialisation
10 Current Drug Targets, 2017, Vol. 18, No. 11
and neovascularisation. During the study period, scores for
re-epithelialization and neovascularization were significantly
higher in CS-ADNC rats than other groups were observed.
Polymorphonuclear (PMN) and mononuclear (MNC) cell
count, fibroblast cell proliferation and also Mean Rank of the
qualitative study of acute hemorrhage, edema and collagen
production score in CS-ADNC group were significantly
higher than those of other experimental groups.
Fig. (3). Wound size measurements for the MPC, NT and NT-
loaded MPC foam treatments in (A) control and (B) diabetic mice.
The wound size was determined on days 0, 1, 3, 5, 8 and 10 post-
wounding. The results are presented as means ± SEM of 7-18 inde-
pendent experiments. ∗∗p<0.01 MPC compared with PBS, ∗∗∗p<
0.001 MPC compared with PBS, ##p<0.01 MPC + NT compared
with PBS, ###p<0.001 MPC + NT compared with PBS [77]. Re-
printed with the permission by Acta Materialia Inc. Published by
Elsevier Ltd. (Copyright © 2013) through Copyright Clearance
Center.
Taken together, a well-known FDA approved dressing of
CS which is capable of stopping blood loss after injury and
can be used as a barrier for biofilm is HemCon® Bandage
[80, 81]. The bandage showed excellent wound healing,
granulation and fibrous connective tissue formation effect
compared to the control groups [81]. CS has also been re-
ported to provoke inflammatory functions of macrophages,
polymorphonuclear leukocytes, and neutrophils, and promote
tissue granulation to an undergone inflammatory cascade
[82]. Moreover, CS may also stimulate angiogenesis, fibro-
blasts proliferation, synthesis and accumulation of collagen
fibers which in turn improve tissue regeneration [75, 83].
Hence, the possible manipulation of the physicochemical
features of CS and/or derivatives could be accomplished to
design wound healing dressings with improved adherent and
anti-bacterial potential, increased exudate absorption capac-
ity, stimulation of angiogenesis and re-epithelialization of
Hussain et al.
skin tissue and collagen deposition and for the sustained de-
livery of fabricated therapeutic moieties. These and other
potential benefits of CS-based wound dressings; particularly
for chronic wounds, are presented in (Table 3).
4.1.2. Hyaluronic Acid and Derivatives
Hyaluronic acid (HA) is a natural polysaccharide with a
wide range of biological properties and wound healing po-
tential found in the ECM of mammalian tissue. Its composi-
tion is made up of disaccharide units consisting of glucuronic
acid and N-acetyl-glucosamine (chemical structure shown in
Fig. 2) [114]. HA is usually extracted from the synovial
fluid, umbilical cord, vitreous humor, or from rooster combs
[115]. It is non-allergic, non-toxic and biocompatible poly-
mer with wide range of activities [116, 117]. HA presents
many important physiological functions such as structural
and space-filling properties, lubrication, as well as tissue,
and ECM water sorption and retention abilities [116, 118].
Interestingly, HA is also well-known as potential natural
biomaterials for wound healing applications. Several reports
have highlighted the wound healing mechanism of HA as to
promote mesenchymal and epithelial cell migration and dif-
ferentiation, thus enhancing angiogenesis and collagen depo-
sition [117, 119, 120]. In addition, the metabolic degradation
products of HA have also been reported to stimulate endo-
thelial cell proliferation and migration, modulate the in-
flammatory processes and stimulate angiogenesis during
various wound healing stages [119, 121, 122].
HA is an interesting polymer for use in tissue engineering
as its biodegradation and biocompatibility support cell
growth and proliferation. It has been used extensively as a
drug delivery system for numerous therapeutic modalities
and as a biopolymer for structural support and stem cell de-
livery in bone regeneration [114]. Recent success in its use
as an in vitro culture template for proliferation of keratino-
cytes has made it an exciting new product for future use in
wound regeneration.
Studies by Turley & Torrance found that the biodegrada-
tion of HA produces byproducts that aid in epithelial cell
proliferation and migration [123]. A number of reported
studies found that enzymes involved in the degradation of
HA stimulate cell proliferation, providing further evidence
that HA must be broken down in order to promote cell
growth [124, 125]. The molecular structure of HA itself also
facilitates the movement of cells within the ECM providing a
substrate for cell migration and proliferation thus enhancing
dermal repair [126].
Interestingly, HA may play a significant role in angio-
genesis and the inflammatory response, further supporting
cellular growth. However, there was no significant difference
between the thicknesses of the epidermis treated with vi-
tronectin: growth factor alone and vitronectin growth factor
together with HA delivery vehicle. While the addition of HA
did not enhance all the cellular responses to vitronectin
growth factor.
The molecular weight of HA (MWHA) is also an impor-
tant factor when considering its role in wound regeneration
[127-129]. Specifically, studies by Campo and colleagues
found that breakdown products of low molecular weight HA
are pro-inflammatory leading to increased tissue damage
Polymers-based Dressings for Diabetic Foot Ulcers
[127]. Interestingly, high molecular weight HA (HMWHA)
may inhibit the nutrient supply to regenerate epithelial tissue
by blocking the formation of capillary networks. While
HMWHA may limit wound regeneration, some studies re-
vealed that in the presence of medium molecular weight HA
(MMWHA), wound repair could be enhanced [128]. Addi-
tionally, previous studies have found that MMWHA en-
hances wound closure through up-regulation of junctional
adhesion molecules at the epidermal diffusion border [128].
The limitations in wound repair with HA grafts are likely
related to co-morbidities found in high-risk patients. Arterial
occlusion and wound site infection also have a negative im-
pact on graft survival and wound repair.
The application of autologous human keratinocytes cul-
tured on membranes composed of benzyl ester of HA (Laser-
skin autograft) has shown greater potential to promote heal-
ing of DFUs. Keratinocytes, when applied to a wound, in-
duce and stimulate healing by releasing growth factors or
multiplying in situ, thereby enhancing the healing effect of
blood platelets. Theoretically, it is possible to amplify the
effects of the first steps of the wound healing cascade by
increasing the local concentration of platelets and keratino-
cytes which would then induce an increased production of
trophic and growth factors. A study with 14 patients by
Lobmann et al. found that 79% of DFU's treated with HA
template grafts fully healed between 7 and 64 days post-
procedure [130]. Interestingly, 3 of the grafts that failed to
survive had been grafted in patients with considerable arte-
rial occlusive disease or with concomitant infection [130].
Composite Laserskin graft is a HA derivative consisting of
micropores that support cell growth. Its use as a template for
cultured epithelial cell grafts has been studied extensively.
The efficiency of seeding the template with cultured epithe-
lial cells is dependent upon the use of a fibroblast feeder
layer.
Keratinocyte stem cell technology serves as a promising
adjuvant therapy to clinically close large cutaneous wounds
(e.g., DFU, burn wounds). However, the performance of
cultured keratinocyte depends primarily on the quality of the
bed to which they are applied. Clinical take rates for cultured
keratinocyte grafts are optimal when applied to a vascular-
ized dermal bed with minimal bacterial colonization. In the
absence of autologous dermis, staged reconstruction with a
dermal equivalent or dermal regeneration template is re-
quired. Myers et al. performed studies comparing the effi-
cacy of seeding composite Laserskin grafts with cultured
keratinocytes alone and with an allogenic fibroblast cell
layer. Laserskin's micropores are laser produced perforations
that are 40 µm in diameters which can deliver keratinocytes
which are roughly 20 µm thick. A 10 cm by 10 cm sheet of
Laserskin (along with a fibroblast feeding layer) can plate
about 4 million keratinocyte cells [131]. Laserskin, when
accompanied by allogenic fibroblasts, is a highly effective
human skin substitute, which can be used for wound resur-
facing. The comparative study reported by Lam and col-
leagues demonstrated that the seeding efficacy of human
keratinocytes on plain Laserskin was 75% while Laserskin
with the fibroblast layer boasted a 95% efficacy. The differ-
ence was even more pronounced in rat keratinocytes which
increased from 46% to 88% with the addition of the feeder
layer. Preliminary clinical data supported that composite
Current Drug Targets, 2017, Vol. 18, No. 11 11
Laserskin graft with a fibroblast cell layer was a powerful
tool with respect to its durability, biocompatibility, graft take
rate, low infection rate, and seeding efficacy [130]. A pleth-
ora of studies involving the use of HA, with or without bio-
active moieties, in the management of chronic wounds have
been summarized in (Table 3).
4.1.3. Cellulose and Derivatives
Cellulose is the primary structural component of plant
cell walls and is the most abundant organic polymer on
Earth. It is a renewable biomaterial, readily available at low
cost. Cellulose is a linear polymer constituted by b-1,4 linked
D-glucose units which are joined to form cellobiose repeat-
ing units (chemical structure shown in Fig. 2) [132]. Several
studies have reported that cellulose and its derivatives are
highly biocompatible due to their lesser inflammatory re-
sponse as foreign bodies [133, 134]. Moreover, resorption of
cellulose in tissues does not occur since cells are not able to
synthesize cellulases [134].
The wound healing activities of cellulose have been re-
ported in a number of studies which demonstrate that cellu-
lose accelerates wound healing through the release and main-
tenance of numerous growth factors at the site of injury such
as phosphodiesterase growth factor, epidermal growth factor
(EGF), and basic fibroblast growth factor (bFGF). These
growth factors stimulate the proliferation and migration of
dermal fibroblast and impede bacterial proliferation in
wounds [135, 136].
Growth factors (GF) are biologically active polypeptides
which are involved in cell growth, differentiation, prolifera-
tion, migration and metabolism. GF effects are a conse-
quence of the specific binding to their receptors which acti-
vates a cascade of molecular events. All stages of the healing
process are controlled by a wide variety of GFs and cytoki-
nes. This review sums up the major GFs involved in wound
healing and skin repair, particularly focusing on: EGF, plate-
let derived growth factor (PDGF), bFGF, transforming
growth factor-β (TGF-β), insulin-like growth factor (IGF)
and vascular endothelial growth factor (VEGF) families.
These biomolecules are considered especially important in
wound healing because GFs play an important role in stimu-
lating granulation tissue formation, modulating the inflam-
matory response and promoting angiogenesis. Further, GFs
are necessary for successful matrix formation, remodeling
and re-epithelisation process. In chronic wounds the GF lev-
els have been proven to decrease; thus, an interesting strat-
egy to promote healing is their external administration.
Based on these characteristics, a greater advancement has
been made in designing and manufacturing cellulose materi-
als-based wound healing dressings with antimicrobial agents
such as polyhexamethylase biguanide (PHMB) and/or silver
in recent decades.
Mu et al., (2016) recently evaluated the cutaneous wound
healing and cytokine response of nano-porous nitrocellulose
based liquid bandage (L-Bandage) using mouse model [137].
They synthesized a novel bandage containing a porous net-
work structure with mean diameter of 18 nm that could ef-
fectively prevent bacterial invasion, have favorable tensile
strength, facile elongation, and acceptable water vapor
transmission rate (WVTR). The L-Bandage treated wound
12 Current Drug Targets, 2017, Vol. 18, No. 11
exhibited accelerated healing, with reduced inflammation,
enhanced wound re-epithelialization, contraction, granula-
tion tissue formation, and rapid angiogenesis [137]. Taken
together, these data supported the wound healing potential of
nanoporous nitrocellulose L-bandages in terms of collagen
deposition. The resulting data demonstrated that both treated
and control wounds progressively deposited collagen over
the duration of the study, but L-Bandage treated wounds
produced significantly more collagen than control groups on
day-6 and day-8. Furthermore, after 12 days, L-Bandage
treated skin showed a very similar structure to normal skin,
where the collagen fibers became denser and regularly
aligned. These outcomes suggested that the application of L-
Bandage containing nanoporous nitrocellulose could pro-
mote collagen deposition in the wound and serve as a prom-
ising wound dressing [137].
The wound healing potential and biocompatibility of cel-
lulose-based materials in combination with other polymers
such as collagen have also been reported. An example of a
commercial cellulose-based dressing is Aquacel® Hydrofiber
wound dressing (ConvaTec, USA), which is an antimicrobial
carboxymethyl derivative of cellulose. After application on
the wound area, it absorbs wound exudate and creates a gel-
like network to maintain a moist wound environment and
thus accelerate the wound healing process. A large number
of studies reporting the clinical implication of cellulose and
derivatives based wound dressings have been summarized in
(Table 3).
4.1.4. Alginate
Alginate (or alginic acid) is one of the most studied and
applied natural polysaccharides in tissue engineering and
drug delivery applications. It is constituted by b-D-
mannuronate (M-residues) and a-L-guluronate (G-residues)
residues covalently linked in different alternating or random
sequences/blocks (chemical structure shown in Fig. 2) [132,
138]. Alginate has also been well-recognised as wound heal-
ing material and has high biocompatibility, low toxicity and
good mucoadhesive properties [132, 138]. Alginate-based
biomaterials are also pH sensitive and the release of bioac-
tive species from these materials at low pH conditions is
significantly reduced. This feature could be advantageous for
the development of a delivery system intended for near-
neutral pH conditions [138], although alginate-based hydro-
gels may present unpredictable and uncontrollable degrada-
tion and dissolution profiles after loss of the divalent cation
cross-linkers [139]. To overcome this issue, covalent/ionic
cross-linking can be employed with other biopolymers such
as gelatin [140], heparin [141], PVA [142] and CS [143].
The main disadvantage of alginate-based materials is
their inability to undergo efficient and rapid enzymatic deg-
radation in mammals. In addition, alginates are very hydro-
philic, which hinders its interactions with skin proteins
[138].
Calcium alginate-based dressings are recognized to have
the capacity to efficiently absorb wound exudates, hence
facilitating debridement and accelerating wound healing in
DFUs [144, 145]. This is evident that calcium has an estab-
lished role in the normal homeostasis of mammalian skin and
serves as a modulator in keratinocyte proliferation and dif-
Hussain et al.
ferentiation. Gradients of calcium concentration increasing
from 0.5 mM in the basal layer to > 1.4 mM in the stratum
granulosum are consistent with migration patterns in re-
sponse to minor abrasion (normal wear). Dermal fibroblasts
require calcium but are approximately 100 times less sensi-
tive than keratinocytes. Normal calcium metabolism in the
skin is dependent on cell membrane and cytosolic calcium
binding proteins (calmodulin, cadherins, etc.), but their
modulation through parathyroid hormone, vitamin D or
growth factors in normal or damaged tissue is not well
documented. In wound repair, calcium is predominantly in-
volved as Factor IV in the hemostatic phase, but it is ex-
pected to be required in epidermal cell migration and regen-
eration patterns in later stages of healing. Calcium alginate
dressings are designed to liberate calcium early in the acute
phase to promote hemostasis, but it is presently unclear
whether the supplementary calcium influences the intracellu-
lar environment at later stages of wound repair, notably dur-
ing the remodeling phase.
Alginate-based dressings have also been combined with
growth factors such as stromal derived factor-1 (SDF-1) or
drugs such as phenytoin, ibuprofen or clindamycin to im-
prove DFU treatment. Commercial products such as Medi-
honey (Derma Sciences Inc., Canada) which is an alginate
hydrocolloid wound dressing loaded with a minimum of
70% of active Leptospermum honey or Algisite M Calcium
Alginate Dressing (Smith and Nephew Inc., Australia) are
alginate-based dressings indicated for DFU treatment. These
and other examples of the application of alginate dressings
for DFU wound healing are summarized in (Table 3).
4.1.5. Collagen and Gelatin
Collagen is the most abundant protein of the ECMs natu-
rally present in human tissues (e.g. bone, skin, cartilage,
ligaments, and tendon etc.). It represents 25% of the total
protein body content [146, 147], providing strength and in-
tegrity to tissue matrices [148]. In addition, collagen can also
interact with cells and help essential cell signaling that will
regulate cell anchorage, migration, proliferation, differentia-
tion and survival [146-148].
Collagen has been well-studied as an ideal biomaterial
for developing wound healing dressings as well as for tissue
engineering. In addition, several recent studies have revealed
the clinical and in vivo efficacy of collagen and gelatin based
wound dressings for accelerating granular tissue formation,
improving healing rate, and angiogenesis as well as for de-
creasing infection by bacteria in chronic wounds [149-152].
These approaches include the incorporation of glucose oxi-
dase in a collagen matrix in order to achieve the sustained
delivery of reactive oxygen species (ROS), natural com-
pounds (such as polyphenols), growth factors (such as
bFGF), antibiotics (such as doxycycline and levofloxacin)
and ionic silver as antimicrobial agent.
Recently, Singh et al., (2011) conducted a clinical trial
with 120 patients having chronic wounds with exudative
lesions using collagen dressing in test groups [149]. For as-
sessment, the wound characteristics (size, edge, floor,
slough, granulation tissue, and wound swab or pus culture
sensitivity results) were evaluated. The appearance of granu-
lation tissue, healing rate, need for skin grafting, and pa-
Polymers-based Dressings for Diabetic Foot Ulcers
tients' satisfaction was also recorded in test groups. Result
indicated that collagen dressing avoid the need of skin graft-
ing, and provides additional advantage of patients' compli-
ance and comfort compared to conventional groups. Simi-
larly, Arul et al., (2012) had also highlighted the clinical
applicability of collagen based wound dressing for the man-
agement of chronic diabetic wounds [150]. They demon-
strated the pharmaceutical significance of collagen matrices
for the the sustained release of reactive oxygen species
(ROS) in diabetic dermal wound healing. Emerging data
favor the involvement of free radicals in the pathogenesis of
diabetic wound healing. In order to achieve the sustained
delivery of ROS in the wound bed, they incorporated glucose
oxidase in the collagen matrix (GOIC), which is applied to
the healing diabetic wound [150]. A significant increase in
ROS (p < 0.05) was observed in the fibroblast of GOIC
group during the inflammation period compared to the con-
trol groups. This elevated level up regulated the antioxidant
status in the granulation tissue cause significant improve-
ment in the granulation tissues and cellular proliferation in
the collagen based dressing treated group compared to con-
trol groups. Together, evidence from wound contraction and
histology also revealed faster healing rate in collagen treated
wounds compared to control groups [150].
The wound healing potential of a novel collagen-based
wound dressing consisting of 2,3-dihydroxybenzoic-acid-
modified gelatin microspheres loaded with doxycycline has
been highlighted by Adhirajan et al. [153]. It is well-
documented that chronic wounds are characterised by in-
creased levels of pro-inflammatory cytokines and proteases
that inhibit the healing process by disrupting essential mito-
genic activity. Doxycycline, which belongs to the tetracy-
cline group of antibiotics, promotes healing of the chronic
wound by inhibiting MMP production and action. There has
been a considerable amount of research into the effectiveness
of doxycycline and other tetracyclines in both animale and in
vitro studies. These studies have focused on a wide range of
conditions, including healing responses in intestinal anasto-
mosis in rats, corneal damage in rabbits from chemical war-
fare agents, extensive myocardial infarction in rats, impact
on healing after rotator cuff repair in rats, and damage to
human corneal epithelial cells. There have also been studies
in humans on a range of conditions; for example, osteoarthri-
tis, rheumatoid arthritis, and the use of doxycycline-releasing
sinus stents to prevent restenosis postoperatively. Adhirajan
and colleagues performed this study and found that a com-
plete healing of excisional wound was achieved by day-15,
compared to day-24 in the control group. Moreover, the in-
fection rate was significantly reduced (99.9% by day-9) in
collagen based dressing treated groups which resulted in
faster epidermal resurfacing and fibroplasias, in contrast to
the observation of severe inflammation in control groups due
to higher microbial load up to day-15. Thus, this study also
indicates that collagen based dressings may attenuate both
metalloprotease levels and wound bed infection and thus can
be a potential wound dressing to improve healing of chronic
wounds [153]. The clinical evaluation of collagen based
wound dressings has also been highlighted by other re-
searchers [151, 152].
Gelatin is a collagen derivative which is commonly used
as a hydrogel for pharmaceutical and biomedical applica-
Current Drug Targets, 2017, Vol. 18, No. 11 13
tions, mostly because of its good biodegradability
/biocompatibility in physiological medium and its good
processability [146, 154]. Therelatively low antigenicity of
gelatin also makes it a well established natural polymer used
in various biological applications [155, 156].
Gelatin has been employed in chronic wound healing ap-
plications by various researchers [151, 152]. Kawai and co-
workers (2005) conducted an in vivo analysis of bFGF-
impregnated gelatin microspheres into artificial dermis using
a pressure-induced decubitus ulcer model in genetically dia-
betic mice [151]. The results obtained clearly revealed a sig-
nificant improvement in angiogenesis and fibroblast prolif-
eration as well as reduction in wound bed infection when
using bFGF-impregnated gelatin microspheres compared to
the control groups.
Kanda et al., (2014) has recently conducted an in vivo
analysis to evaluate the wound healing potential of bFGF-
incorporated collagen-gelatin sponge in diabetic mouse
model [152]. The data obtained displayed a significant accel-
eration in granulation tissue formation and showed a signifi-
cant improvement in healing rate and angiogenesis compared
to control groups. Researchers further explained that colla-
gen-gelatin sponge might release positively charged growth
factors such as bFGF in a sustained manner which could
impart skin regeneration potential [152].
A large number of commercial collagen and gelatin based
dressings are already in commercial use for the effective
management of partial- and full-thickness pressure, venous,
vascular and diabetic ulcers. These products include BCG® ,
BIOSTEP®, Catrix®, CollaSorb® and PROMOGRAN
PRISMA® Matrix. The wound healing potential of collagen
and gelatin is presented in (Table 3).
4.1.6. Fibrin
Fibrin is a protein that is produced from fibrinogen and
hence can be autologously harvested from patients. It may
provide immunocompatible polymeric carriers for the deliv-
ery of bioactive molecules and/or cells in various biomedical
applications [146, 155].
Besides other biological applications, fibrin-based wound
dressings are also well-recognised in the management of
chronic ulcers [156, 157]. Breen et al., (2008) conducted an
in vivo experiment to evaluate the wound healing potential of
adenovirus encoding endothelial nitric oxide synthase
(eNOS) incorporated fibrin-based wound dressings using an
alloxan rabbit ear ulcer model [62]. Emerging evidence from
both animal and human studies indicates that nitric oxide
(NO) plays a key role in wound repair. The beneficial effects
of NO on wound repair may be attributed to its functional
influences on angiogenesis, inflammation, cell proliferation,
matrix deposition, and remodelig. Thus, various researchers
proposed the beneficical effect of eNOS in promoting syn-
thesis and release of NO endogenously which would facili-
tate healing mechanism and promot faster wound closure.
Breen and colleagues observed a significant improvement in
eNOS expression in the fibrin-based dressing treated group
at day-14 compared to control groups [62]. Moreover, the
test group treated with the fibrin-based dressing showed a
significantly faster rate of epithelialization, granulation tissue
formation and healing rate. The inflammatory cells were also
14 Current Drug Targets, 2017, Vol. 18, No. 11
reduced significantly in this group at day-14 and closure of
wounded area was also observed on day-14 which indicates
tissue remodelling [62].
Chen et al., (2010) highlighted the clinical significance
of fibrin-based dressing to facilitate the fixation of skin
grafts and to limit the risk of infection in chronic wounds in
fifteen patients [156]. The results revealed that the time
taken for complete wound healing to occur ranged from 3
weeks to 2 months with no rebound symptoms and no recur-
rence of ulcers within the 3- to 18-month follow-up period
[156].
The wound healing effects of fibrin gels incorporating
hematopoietic stem cells (CD34+), CD34+-derived endothe-
lial cells, or both were also reported by other researchers
[157]. Stem cells have a unique capability to differentiate
into various tissues in the body. Stem cells derived from
various sources such as bone marrow, peripheral blood, and
umbilical cord blood have been used for the healing of
chronic skin ulcers. Mesenchymal stem cells (MSCs) (also
known as multipotent mesenchymal stromal cells) possess
the capacity for self-renewal and multi-lineage differentia-
tion, and their ability to enhance cutaneous wound healing
has been well characterized. Acting via paracrine interac-
tions, MSCs accelerate wound closure, increase angiogene-
sis, promote resolution of wound inflammation, favorably
regulate extracellular matrix remodeling, and encourage re-
generation of skin with normal architecture and function.
The researchers indicated that the incorporated stem cells
were differentiated into fibroblasts, keratinocytes and endo-
thelial cells, which played an important role in accelerating
wound healing processes [157].
The use of enzymes to produce and deliver nitric oxide
(NO) has also been studied using fibrin-based dressings to
stimulate the inflammatory response and accelerate re-
epithelialization in the management of chronic skin ulcers
[158]. Data obtained clearly indicated a complete closure of
wounds within 12 weeks of treatment using Vivostat, a plate-
let-rich fibrin. Other wound healing benefits of fibrin-based
dressings were briefly summarized in (Table 3).
4.1.7. Silk Fibroin
Fibroin is an insoluble protein present in silk created by
spiders, the larvae of Bombyx mori, other moth genera such
as Antheraea, Cricula, Samia and Gonometa, and numerous
other insects. Silk in its raw state consists of two main pro-
teins including sericin and fibroin, with a glue-like layer of
sericin coating two singular filaments of fibroin called brins.
Owing to slow bio-degradability, bio-compatibility, and
hemo-compatibility [159, 160], it has been used in various
biomedical applications. It has been evident that silk fibroin
promotes epidermal cells and fibroblast attachment, cellular
proliferation, granular tissue formation and thus stimulates
wound healing processes [159, 160].
Numerous investigations revealed that aloe vera acceler-
ate wound healing by directly stimulating the activity of
macrophages and fibroblasts. Fibroblast activation by aloe
vera has been reported to increase collagen and proteoglycan
synthesis, thereby promoting tissue repair. Some of the ac-
tive principles appear to be polysaccharides composed of
several monosaccharides, predominantly mannose. It has
Hussain et al.
been suggested that mannose 6-phosphate, the principal
sugar component of aloe vera, may be partly responsible for
the wound healing properties of the gel. Mannose-6-
phosphate can bind to the growth factor receptors on the sur-
face of the fibroblasts and thereby enhance their activity.
Furthermore, acemannan, a complex carbohydrate isolated
from aloe leaves, has been shown to accelerate wound heal-
ing and reduce radiation-induced skin reactions.
Inpanya and co-workers (2012) highlighted the wound
healing effectiveness of an aloe gel extract incorporated in a
fibroin-based dressing in the treatment of chronic wounds
using streptozotocin-induced diabetic rats [160]. The result-
ing data revealed a significant increase in the proliferation
and differentiation of skin fibroblasts in the fibroin film
treated group compared to control groups. Furthermore, the
experimental animals treated with fibroin film showed partial
closure of the wound at day-7 compared to control groups.
Histological data showed that the fibroblast distribution and
collagen fiber organization was similar to normal rat skin.
These results clearly indicate that blended fibroin/aloe gel
films may stimulate wound healing and thus can be used as
potential alternative in the management of chronic diabetic
ulcers. These and other studies which reported wound heal-
ing potential of fibroin-based films in the management of
chronic wound are presented in (Table 3).
4.1.8. Dextran
Another natural polymer constituting strong hydrophilic-
ity, water solubility, biocompatibility and biological inert-
ness to but highly reactive through its reactive hydroxyl
groups, is dextran (chemical structure shown in Fig. 2) [161,
162]. It has widespread medical and biological applications
such as in dermal and subcutaneous healing as well as being
used as a drug delivery vehicle [161, 162]. It facilitates
wound healing by stimulating infiltration of inflammatory
cells and promoting angiogenic cell migration to the site of
lesions [163].
Sun et al., (2011) proposed that the application of dextran
hydrogel scaffolds augments angiogenic responses and
stimulates skin regeneration during chronic wound healing.
They have performed a clinical study allowing the dextran
scaffolds to remain intact and securely in place during the
entire healing period. Data indicated that the dextran hydro-
gel promoted dermal regeneration with skin appendages re-
growing within 3 weeks of treatment [163]. Further analysis
of the data revealed that the dextran scaffold enabled infiltra-
tion of inflammatory and angiogenic cells into the wounded
area. Endothelial cells homed into the hydrogel scaffolds to
enable neovascularization by day-7, resulting in a significant
increase in blood flow compared to the control groups. Fur-
thermore, a mature epithelial structure with fully developed
hair follicles and sebaceous glands were observed on day-21.
These results clearly demonstrate a considerable improve-
ment in wound healing processes in test groups treated with
dextran hydrogen scaffolds. These results were in agreement
with previous report by Parulkar et al., (1985) which also
indicated a positive role of dextran based biomaterials in
promoting chronic ulcers [164].
In the study undertaken by Paulkar et al (1985), chronic
wounds were applied with a thick layer of dextranomer, a
Polymers-based Dressings for Diabetic Foot Ulcers
dextran polymer, and were further covered with absorbent
gauze and non-occlusive bandage dressing [164]. Research-
ers observed a significant improvement in the wounded area
over an average period of 8 days. The effect of dextranomer
on the infected wound was rapid, leading to a remarkable
decrease of the inflammatory reaction around the wound
during the first day. Formation of healthy granulation tissue
occurred within a few days without pain, edema and tender-
ness [164]. It has further been proposed that the efficient
wound healing effect of dextran is associated with its ability
to cleanse the lesion by absorbing the wound exudate, facili-
tating tissue debriment and removing contaminantion from
the wound incluinding tissue degradation products, bacteria
and other contaminants, which in turn improve healing rate.
4.1.9. Elastin
Another natural polymer showing wound healing poten-
tial is elastin (chemical structure shown in Fig. 2). It is an
insoluble ECM protein and a major constituent of skin elastic
fibers [165, 166]. Generally, elastin is difficult to process
due to its highly insoluble nature; however, its soluble forms,
including tropoelastin (a soluble precursor form of elastin),
α-elastin (an oxalic acid derivative of elastin) and elastin-like
polypeptides have been recognized in broader applications
[166, 167]. These biomaterials enhance tissue regeneration
by promoting collagenase synthesis, fibroblast proliferation,
and increasing chemotactic activity [168].
The wound healing efficacy of elastin-based biomaterials
has been reported in a recent report by Koria et al., (2011)
[165]. They demonstrated that a protein gel comprised of
elastin-like peptides loaded with keratinocyte growth factor
(KGF) enhanced the re-epithelialization, neovascularization,
and granulation tissue formation in chronic diabetic wounds
[165]. These data clearly indicated that elastin-based polym-
H OH
O
n n
Poly(ethylene glycol) (PEG)
N O
H2
O C CH2 O
n n
Poly(vinyl pyrollidone) (PVP)
O O
OH
HO
CH3 n CH3
Poly(hydroxyethyle methacrylate) (PHEMA)
Fig. (4). Chemical structures of some synthetic polymers used for the treatment of DFUs.
Current Drug Targets, 2017, Vol. 18, No. 11 15
eric materials can be used as a potential alternative for pro-
moting wound healing processes.
4.2. Wound Healing Benefits of Synthetic Polymers
In recent decades, a wide diversity of synthetic biode-
gradable/non-biodegradable, biocompatible polymers and
copolymers have been developed [161]. The synthetic poly-
mers are claimed to overcome the limitations of natural
polymers by achieving consistent and reproducible chemical
and physical properties [154]. A vast majority of synthetic
polymers are insensitive to biological and enzymatic proc-
esses, and hence their physicochemical and biochemical be-
havior will not vary greatly from patient to patient [154]. The
wound healing potential of synthetic polymers and the de-
velopment of wound dressings is discussed in the subsequent
section.
4.2.1. Poly(ethylene glycol) (PEG)/Poly(ethylene oxide)
(PEO)
PEG is a polyether which is also known as poly(ethylene
oxide) (PEO) or as poly(oxyethylene) (POE) (as shown in
Fig. 4), depending on its molecular weight. It is a hydro-
philic, non-toxic, biocompatible and non-immunogenic ma-
terial that can be synthesized by anionic or cationic polym-
erization of ethylene oxide [139, 169]. PEG can also be
blended with other polymers such as CS, poly(lactic-co-
glycolic acid) (PLGA) and poly(propylene fumarate) (PPF)
in order to improve its inherent solubility, mechanical and
thermal properties as well as its viscosity and crystallinity
[170, 171].
The wound healing and tissue regeneration properties of
PEG and co-block-copolymers of PLGA-PEG have been
proposed by many researchers [172-177]. Lee and co-
workers (2007) designed a triblock copolymer (PEG-PLGA-
OH
Poly(vinyl alcohol) (PVA)
O
O
C NH CH2 NH C
Polyurethane (PU)
O
O H
O
n m
O
Poly(lactic-co-glycolic acid) (PLGA)
16 Current Drug Targets, 2017, Vol. 18, No. 11
PEG) as thermosensitive hydrogel scaffold and evaluated its
wound healing potential using diabetic mouse model [172].
They observed a significant engraftment in muscle-derived
stem cells (MDSCs) by 20- to 30-fold and a complete clo-
sure of wound in db/db mice treated with PEG-PLGA-PEG
until day-20. The increased engraftment resulted in improved
wound healing, as indicated by epithelium migration, higher
wound closure rate, and collagen deposition [172].
Yang et al., (2012) demonstrated the wound healing po-
tential of Poly(ethylene imine) and PEG plasmid in diabetic
rats [173]. Results obtained clearly revealed a gradual release
of incorporated bFGF and a significantly higher wound heal-
ing rate, enhanced collagen deposition, granulation tissue
formation, highly improved neovascularization, complete re-
epithelialization and regrowing skin appendages [173].
These results were in agreement with Huang et al., (2011)
who performed experiments to evaluate the wound healing
potential of PEGylated (PEG modified) rhFGF using dia-
betic mouse model [174]. They found that test animals
treated with PEGylated rhFGF exhibited superior therapeutic
effectiveness with faster healing rate, enhanced collagen
deposition and maturation, significant expression of TGF-β,
and higher dermal tissue regeneration, compared with con-
trol groups [174].
Choi et al., (2008) evaluated the wound healing efficacy
of poly(epsilon-caprolactone) (PCL)-PEG block copolymer
using diabetic animals with dermal wounds [176]. They ob-
served a significantly higher expression of keratinocyte-
specific genes in test animals treated with EGF-conjugated
nanofibers compared with control animals. The wound heal-
ing rate was significantly higher in test groups compared to
the control groups. The higher expression of EGF-receptor
(EGFR) using immune-histochemical staining also suggested
therapeutic superiority of EGF-conjugated nanofibers [176].
The wound healing potential of PEG and coblock copolymer
is summarized in (Table 4).
4.2.2. Poly(vinyl alcohol) (PVA)
PVA is a biodegradable, biocompatible, hydrophilic,
non-toxic and non-carcinogenic polymer obtained from vinyl
acetate by hydrolysis, alcoholysis, or aminolysis (chemical
structure shown in Fig. 4) [34, 47, 149]. PVA has been
widely used for tissue engineering and drug delivery applica-
tions, and besides its high hydrophilicity and water absorp-
tion capacity, it also presents an excellent capacity to be
processed in the form of particles, fibers, textiles, sponges
and films.
PVA has been used in the development of wound dress-
ings for the management of acute as well as chronic wounds.
Masters et al., (2002) evaluated the effect of NO releasing
PVA hydrogel wound dressings on the dermal wound heal-
ing using diabetic mice [178]. Emerging evidence from both
animal and human studies indicates that NO plays a key role
in wound repairs. The beneficial effects of NO on wound
repair may be attributed to its functional influences on angi-
ogenesis, inflammation, cell proliferation, matrix deposition,
and remodelig. Data obtained indicated a slow and consistent
release of NO release from the NO-modified hydrogel. A
significant improvement in wounds has been observed in
NO-modified hydrogel treated groups compared to control
Hussain et al.
groups [178]. The formation and deposition of granulation
tissue and an increase in wound closure rate was also ob-
served to be significantly higher in NO-modified hydrogel
treated wounds at day-8 and 15 compared to control groups.
These results suggest that NO induced treatment using the
PVA hydrogel system has the potential to modulate wound
healing processes [178].
Manju et al., (2010) also proposed the wound healing po-
tential of PVA based hydrogels [179]. In this study, PVA
based hydrogels were synthesized by polymerization with
aminophenyl boronic acid. An extended swelling of the hy-
drogel which was attributed to the strong affinity of the gel
for glucose and to the subsequent breaking of bonds formed
between PVA and boronic acid groups to releae ciproflox-
acin. Ciprofloxacin (CFX) is a synthetic broad-spectrum
antibiotic belonging to the fluoroquinolone class, and it is
effective against many gram-positive and gram-negative
bacteria, including some strains resistant to other agents such
as penicillins. The covalent insertion of CFX in the polym-
eric chains presents a strong antibacterial activity against S.
aureus and E. coli that commonly infects wounds. Thus re-
searchers proposed that the incorporation of CFX in poly-
mer-based dressing significantly improve wound healing
effects. On the basis of the strong affinity of PVA hydrogels
for binding with glucose, the researchers proposed that PVA
could be used in dressings for the management of wounds,
particularly diabetic wounds [179]. The wound healing ap-
plications of PVA based dressing and hydrogels are summa-
rized in (Table 4).
4.2.3. Poly(vinyl pyrrolidone) (PVP)
PVP is another biocompatible, hydrophilic, non-toxic and
non-carcinogenic material made from the monomer N-
vinylpyrrolidone (chemical structure shown in Fig. 4) and
has been extensively used for a wide variety of pharmaceuti-
cal and biomedical applications (including wound dressings).
Various researchers have proposed that this material is
very effectively used to fabricate wound dressings owing to
its strong water absorption and oxygen permeability proper-
ties [186, 187]. Yang and Ping (2010) recently evaluated the
wound healing potential of PVP used in the new NO delivery
platform, containing grafted S-nitrosothiols, derived from
endogenous glutathione (GSH) or its oligomeric derivatives
complexed with PVA [188]. This complex was shown to
provide consistent release rates of NO over a period of 10
days. Furthermore, the in vivo wound healing study demon-
strated that, with a single topical application, the sustained
release of NO delivery significantly accelerated wound heal-
ing when compared to the control group. Yang and Ping
(2010) proposed that these interpolymer complexes could be
potentially useful for the management of chronic exudative
diabetic wounds [188].
4.2.4. Polyurethanes (PUs)
PUs are highly versatile, easily processable, sterilizable,
non-toxic, non-carcinogenic, non-adherent and non-
allergenic polymers [181]. PUs are traditionally and most
commonly formed by reacting a di- or polyisocyanate with a
polyol (chemical structure shown in Fig. 4). Despite their
multi-functional potential, PU-based nanofibers have been
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 17

Table 4. Summary of efficacy of synthetic polymer-based dressings employed for the treatment of DFUs.

Study Experimental Polymer(s) Carrier System Active Moiety Main Findings Ref.
Design Model

In vivo Chronic wounds in PEG Poly(ethylene imine) and FGF 4. Significant increase in healing rate. [173]
studies diabetic rats PEG plasmid
5. Enhanced collagen deposition and
maturation
6. Fast complete re-epithelialization.
Non-healing chronic PEGylated fibres rhFGF 1. Accelerated wound closure. [174]
wounds in diabetic
rats 2. Significantly higher tissue collagen
formation and deposition.
3. Enhanced TGF-b expression.
DFUs in diabetic PCL-PEG block copoly- rhEGF 1. Faster rate of wound healing [176]
mice mer
2. Enhanced proliferation and differ-
entiation of keratinocytes at the
wounded area.
Non-healing chronic PEG-PCL nanofibers EGF + bFGF 1. Accelerated wound healing rate. [177]
wounds in diabetic
mice 2. Enhanced granulation tissue forma-
tion and collagen deposition.
In vivo DFUs in diabetic rats PVA PVA aminated hydrogel Nitric oxide 1. Remarkable increase in wound [178]
studies strength and quality of granulation
tissue formation.
2. Enhanced collagen formation and
deposition in wound area.
Clinical Chronic wounds in Aminophenyl boronic Ciprofloxacin 1. Significant improvement in healing [179]
studies human diabetic pa- acid + PVA rate.
tients
2. Reduced complication at the wound
area.
In vivo Non-healing wounds PVP Poly (vinyl methyl ether Nitric oxide 1. Faster healing rate. [180]
study in diabetic rats co-maleic anhydride) +
PVP 2. Significant reduction in secondary
complications in the wounded area.
Clinical Chronic exudative PU PU-based foam _ 1. Accelerated wound healing rate. [181]
study wound at lower ex-
tremity in human 2. Cleansing of exudative and dead
diabetic patient debriment tissues at the wounded
area.
In vivo Non-healing chronic Poly (α-esters) PLA fibres bFGF 1. Remarkable improvement in wound [182]
studies wounds in diabetic healing rate.
rats
2. Complete re-epithelialization,
granulation tissue formation,
neovascularization.
3. Regrown skin appendages.

STZ-induced PLGA microspheres rhEGF 1. Efficient wound healing rate. [183]

wounds in diabetic
rats 2. Significant improvement in fibro-
blast growth rate and granulation
tissue formation.
STZ-induced PCL nanofibers Curcumin 1. Accelerated closure of wounds. [184]
wounds in diabetic
mice 2. Enhanced wound healing rate.

STZ-induced dia- PLGA nanoparticles rhEGF 1. Significantly higher rate of wound [185]
betic rats healing.
2. Accelerated proliferation and
differentiation of fibroblasts.
Abbreviation: PEG, Polyethylene glycol; PVA, Poly(vinyl alcohol); PVP, Poly(vinyl pyrrolidone); PHEMA, Poly (hydroxyethyl methacrylate); PU, Polyurethanes; PLA, Polylac-
tide; PCL, Polycaprolactone; DFUs, Diabetic foot ulcer; STZ, Streptozotocin; rhFGF, Recombinant human fibroblast growth factor.
18 Current Drug Targets, 2017, Vol. 18, No. 11
evaluated for their efficient sorptive and fluid drainage prop-
erties, which are essential for wound dressings, whereby
these attributes prevent wound desiccation [189, 190].
Khil et al., (2003) suggested that efficient evaporative
water loss, coupled with considerable oxygen permeability
and the ability to drain wounds are the critical characteristics
of electrospun nanofibers, which determine wound healing
efficacy [189]. A significant increase in the rate of epithe-
lialization and formation of granulation tissue has been ob-
served for electrospun nanofibers used in the treatment of
wounds. Moreover, a number of researchers have demon-
strated accelerated wound healing when using PU-based
wound dressings [181, 191].
Recently, PU-based dressings have been patented as
wound dressings for the management of chronic DFUs [192].
In this regard, the commercial wound dressing Meliplex® Ag
(Molnlycke Health Care, Sweden) comprises a silicone
wound contact layer, an absorbent material (polyurethane
foam pad), an anti-microbial agent (silver sulfate) and a va-
por-permeable waterproof film which has been designed to
absorb wound exudates, whilst maintaining a moist wound
environment. It is well-recognised as an efficient wound
dressing for the effective management of chronic wounds
such as lower extremity ulcers, pressure ulcers, burn wounds,
and DFUs [193].
PU-based dressings have been reported to come loaded
with bioactive compounds, which are incorporated to pro-
mote rapid wound healing. A wound dressing containing an
antimicrobial therapeutic agent (e.g. penicillin, erythromy-
cin, chlorohexidine, triclosan), a pain-relieving substance
(e.g. ibuprofen) and protease inhibitors (e.g. MMP-9, elas-
tase, MMP-8, MMP-12) has been reported. In this system,
the active pharmaceutical ingredients are incorporated into a
barrier layer made of collagen/polylactide/polyglycolide or
polyurethane [181]. This layer degrades in contact with
wounds, releasing the therapeutic substances into the wound.
Recently, Pyun et al. (2015) evaluated PU-based foam
containing rhEGF as a dressing material for healing diabetic
wounds in Sprague-Dawley rats [194]. The result indicated
Fig. (5). Photographs of macroscopic appearance of infected wound treated with rhEGF/PUFs; (A) rhEGF(0)/PUF, (B) rhEGF(2.28)/PUF,
(C) rhEGF(4.58)/PUF, (D) rhEGF(8.4)/PUF [194]. Reprinted with the permission by Elsevier B.V. (Copyright © 2015) through Copyright
Clearance Center.
Hussain et al.
that compared with control groups, rhEGF-PU foam acceler-
ated wound healing by promoting wound contraction, re-
epithelialization, collagen deposition and the formation of a
skin appendage (as shown in Fig. 5). The clinical applica-
tions of of PU-based wound dressings have also been sum-
marized in (Table 4).
4.2.5. Poly(hydroxyethyl methacrylate) (PHEMA)
PHEMA-based polymers and copolymers are biocom-
patible, non-biodegradable materials that form hydrogels,
which can be employed in a range of different biomedical
and pharmaceutical applications [195]. The chemical, physi-
cal, sorption and permeability properties of PHEMA-based
polymers are dependent on the method of synthesis method
and the process conditions used in the manufacturing process
The composition of the polymer including the proportions of
the co-monomers and cross-linkers andthe final degree of
cross-linking also play an important role in determing the
material attributes [195].
PHEMA-based hydrogels have been used in the manu-
facture of artificial skin in addition to wound dressing appli-
cations [139, 170], with a range of many bioactive sub-
stances being incorporated into these materials. An interest-
ing example is the case of a hybrid dressing consisting of a
PHEMA core (containing a light-activated NO donor) and a
PU coating for use on chronic ulcers [196]. One major ad-
vantage of this material is the fact that NO release is affected
by light exposure. The dressing can be illuminated from time
to time to selectively deliver NO to the wound site, whilst
maintaining antiseptic conditions. This approach might be
superior to simple washing of the affected area with conven-
tional solutions such as hydrogen peroxide.
PHEMA and PEG have been combined to develop a hy-
drogel dressing that can bind covalently to MMP inhibitors
and promote the healing of chronic wounds. This patented
dressing ensures that MMPs in the chronic wound fluid are
inhibited (thus reducing their proteolytic content) while
guaranteeing that the necessary MMP levels for normal heal-
ing are not affected in the wound bed [197].
Polymers-based Dressings for Diabetic Foot Ulcers
4.2.6. Poly (a-esters) (PLA, PGA, PLGA, PCL)
Polylactide (PLA) is one of the most popular aliphatic
polyesters used in biomedical applications since it presents
relatively high strength and an appropriate degradation rate
for most drug delivery and tissue engineering systems [198].
In fact, PLA possesses good mechanical characteristics, con-
trolled degradability and excellent biocompatibility. How-
ever, its strong hydrophobicity limits some of its potential
applications [198-200].
Polyglycolic acid (PGA) is another poly(a-ester) which is
relatively hydrophilic and degrades faster than PLA in aque-
ous solutions and in vivo. To obtain intermediate degradation
rates between PGA and PLA, several copolymers of lactic
acid, glycolic acid (poly(lactic-co-glycolic acid) (PLGA))
can be synthesized [200, 201].
PLGA is also a biodegradable polymer with strong bio-
compatibility, controlled biodegradability and potential for
achieving sustained release of bioactive substances [202].
Furthermore, it can be processed into many different forms
including powders, pellets, fibers and nanoparticles.
PLGA microspheres loaded with rhEGF were demon-
strated to enhance the growth rate of fibroblasts, and it was
also observed that wounds in diabetic rats healed more effi-
ciently compared to the use pure rhEGF [202, 203].
Dong et al. [202] prepared PLGA microspheres loaded
with rhEGF by a solvent-evaporation technique. These mi-
crospheres were small in size and presented a high drug en-
capsulation capacity (86%). rhEGF-loaded microspheres
loaded into the wound site enhanced the growth rate of fi-
broblasts, and it was also observed that wounds in diabetic
rats healed more efficiently than when using pure rhEGF is
used. To this end, Chu et al. [203] used a modified double
emulsion method to prepare rhEGF-loaded PLGA nanoparti-
cles for use in treating diabetic ulcers. In diabetic rats, these
rhEGF-loaded nanoparticles promoted a faster healing rate
and enhanced fibroblast proliferation.
PLGA-based copolymers can be applied in skin tissue
regeneration and suture applications, and have been ap-
proved by the FDA for several biomedical and pharmaceuti-
cal applications [200]. The incorporation of drugs and other
bioactive substances into poly(a-hydroxy acids) has been
undertaken with DFU applications in mind. Xu et al. [204]
reported the incorporation of the hydrophilic antibiotic drug,
tetracycline hydrochloride (TCH), into an electrospun PEG-
PLA nanofibrous membrane. This drug-impregnated mem-
brane demonstrated sustained release of TCH over 6 days
and was effective at inhibiting growth of S. aureus.
As observed previously for other polymer-based dress-
ings, the loading of growth factors into PLA-based materials
to stimulate the wound healing is also an option for DFU
treatment. As an example, bFGF was embedded into ul-
trafine PLA fibers with a core-sheet structure [205]. An ini-
tial low burst release was achieved, followed by controlled
release for around 4 weeks, which might be useful for the
treatment in chronic ulcers. Results showed a higher wound
recovery rate with complete re-epithelialization, regeneration
of skin appendages, higher density and mature capillary ves-
sels in bFGF-loaded scaffolds when compared with fibers
Current Drug Targets, 2017, Vol. 18, No. 11 19
not containing bFGF. Moreover, enhanced collagen deposi-
tion and an ECM remodeling process were also observed
with the components of collagen fibers being similar to nor-
mal tissues.
Polycaprolactone (PCL) is another biodegradable and
biocompatible poly(a-ester) which has been evaluated for
tissue regeneration and wound healing applications. It pro-
motes faster healing and reduced inflammatory infiltration
[206]. However, PCL degrades at a significantly slower rate
than PLA, PGA and PLGA [207]. This slow degradation
makes PCL less attractive for this type of biomedical appli-
cation, but more attractive for sutures, long term implants
and controlled-release applications [207].
Merrel et al. [206] developed PCL nanofibers as a deliv-
ery vehicle for curcumin for diabetic wound healing applica-
tions. Curcumin is a natural phenolic compound with anti-
oxidant and anti-inflammatory properties. It has been re-
ported that curcumin acts as an antiproliferative, anti-
invasive, and antiangiogenic agent; as a mediator of
chemoresistance and radioresistance; as a chemopreventive
agent; and as a therapeutic agent in wound healing in dia-
betic and cardiovascular ailments. Curcumin increased cellu-
lar proliferation and collagen synthesis at the wound site.
Curcumin treated wounds were found to heal much faster as
indicated by improved rates of epithelialisation, wound con-
traction and increased tensile strength. To this end, Merrel
and colleagues demonstrated that the prepared curcumin-
loaded nanofibers reduced inflammatory induction from
mouse monocyte macrophages. In addition they increased
the rate of wound closure in a STZ-induced diabetic mouse
model [206].
SUMMARY
Chronic wounds include, but are not limited, to diabetic
foot ulcers, venous leg ulcers, and pressure ulcers. Effective
management of chronic wounds presents major clinical bur-
dens to the patients, healthcare providers and the healthcare
system around the globe. This review discusses the patho-
physiology of DFU, a complex chronic wound, factors that
need to be focussed while selecting a suitable dressing, and
the polymeric modalities currently available to achieve heal-
ing in DFU patients. Among various therapeutic modalities,
conventional wound dressings have greater recognition in the
management of chronic wounds; however in most instances,
the treatment of DFUs impose a substantial challenge to the
conventional wound dressings and demand the development
of novel and advanced wound healing modalities. New and
recent alternatives to conventional dressings have been de-
veloped; these include mixing different polymers and using
more efficient cross-linking methods to create improved ma-
terials that guarantee an optimal wound environment. Natu-
ral (CS, HA, cellulose, alginate, collagen, fibrin) and syn-
thetic (PVA, PEG, PVP, PU, PHEMA, poly(aesters)) poly-
mers have been combined or cross-linked (with either
genipin, oxidized dextran or glutaraldehyde) for the devel-
opment of new polymer-based wound dressings with im-
proved therapeutic outcomes and patient compliance. These
polymers have been used in the form of hydrogels, films,
hydrocolloids, foams, membranes, scaffolds, microparticles,
and nanoparticles. The critical analysis of the literature sug-
20 Current Drug Targets, 2017, Vol. 18, No. 11
gested that advanced polymeric dressings employed for the
treatment of DFUs results in enhanced tissue regeneration by
promoting collagenase synthesis and collagen formation,
proliferation and differentiation of fibroblast and keratino-
cytes, enhanced granulation tissue formation, re-
epithelialization, and neovascularization, increased chemo-
tactic activity, bacterial clearance, and upregulated expres-
sion of various protein biomarkers.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
The authors would like to acknowledge Universiti
Teknologi MARA for providing LESTARI grant (600-
IRMI/DANA 5/3/LESTARI (0007/2016)) and support in
writing this review article.
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