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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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DOI: 10.2174/1389450118666170704132523

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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

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
ARTICLE HISTORY
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
Received: December 27, 2016
Revised: April 17, 2017 management of DFUs but there is a lack of absolute and versatile choice. The current review was
Accepted: May 16, 2017 aimed to summarize and critically discuss all the available evidence related to the pharmaceutical and
DOI: therapeutic viability of polymer-based dressings for the treatment of DFUs. A versatile range of natu-
10.2174/1389450118666170704132523
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


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

(TNF-α) and interleukins (IL-1β) [5]. In addition, DFUs may 2. NON-LINEAR WOUND HEALING AND DFUs
also impair keratinocyte migration and leukocyte function
Wound healing is an intricate process that involves the
leading to various infections. Moreover, depleted levels of
simultaneous actuation of blood cells, soluble mediators,
inorganic phosphate within diabetic patients could also result
parenchymal cells and extracellular matrix (ECM). This
in low levels of adenosine triphosphate (ATP), leading to a
significant attenuation of the immune response [5]. Signaling complex wound healing process is completed through the
efficient collaboration of several phases: 1) the inflammatory
molecules like epidermal growth factor (EGF) function nor-
phase, which involves homeostasis/coagulation, and inflam-
mally to stimulate proliferation and migration of keratino-
matory cascades, 2) the proliferation phase, which involves
cytes during wound closure; however, aging and metabolic
rebuilding new granulation tissues and the development of
disease inhibit keratinocytes ability to respond to EGF and
new networks of blood vessels (angiogenesis) followed by
other growth-promoting mitogens [6, 7]. The above mecha-
nisms contribute to impaired wound healing and are the fo- re-epithelialization (resurfacing of the wound with epithelial
cells), 3) the maturation phase, which is the final phase and
cus of new therapeutic modalities that focus on incorporating
involves remodelling of collagen from type III to type I [13].
both ECM and various signaling molecules within chronic
These phases are not typically associated with a rigorous and
wounds in order to promote regeneration and wound repair.
well-defined period of time and may overlap and thus result
Impaired wound healing is one of the most prevalent in non-linear or chronic wounds [14, 15]. The transition be-
clinical problems in diabetes mellitus and results in failure to tween phases usually depends on the maturation and differ-
completely heal DFUs, which may lead to lower extremity entiation of mast cells, fibroblasts, keratinocytes and macro-
amputations [4]. Chronic wounds seem to be detained in one phages which play prime role in the wound healing process
or more of the phases of wound healing. This is because [16-18].
these wounds provide a significant burden to patients, health
Variuos complications associated with DM may cause
care professionals and healthcare systems with 5.7 million
patients affected in the US alone costing an estimated 20 development of DFUs in diabetic patients. Diabetic neuropa-
thy or peripheral vascular diseases are two major problems
billion dollars annually [4, 8]. These types of wounds are
encountered with DM [19-22]. These two diseases may act
characterized by a prolonged or persistent inflammatory
alone, together, or in combination with other pathological
phase, excessive infections, and the failure of epidermal or
and metabolic conditions such as biomechanical abnormali-
dermal cells to respond to environmental insult [9]. As a
ties, microvascular disease and increased susceptibility to
consequence, pro-inflammatory cells and cytokines at the
lesional site stimulate a proteolytic cascade which induces infection [23, 24]. Besides, the development of chronic
wounds and their non-linear healing process can also be as-
degradation of growth factors (GFs) [10]. This would result
sociated with the excessive and persistent activity of MMPs
in inhibition of tissue growth and thus, delaying or impairing
and/or due to low levels of MMP inhibitors [25, 26]. In addi-
the physiological mechanisms behind normal wound healing
tion, the peripheral vascular disease may also tend to reduce
[11]. Moreover, chronic wounds have also been proved to
the healing capacity of an individual due to an insufficient
show a high bacterial bioburden which can further compli-
cate wound restoration [12]. supply of oxygen and nutrients to the wounded area [27].
The impaired functioning of macrophages, granulocytes,
To date, numerous therapeutic strategies have been em- chemotactic mediators as well as deregulation of the neo-
ployed for the management of DFUs with the aim of acceler- vascularization phase might also prolong the healing process
ating the healing process, avoiding secondary complications and result into a DFUs [28, 29]. In addition other potential
and improving patient compliance. Various wound healing reasons for the development of DFUs can be caused by the
approaches include; conventional wound dressings such as impaired functioning of nitric oxide, collagen deposition,
hydrogel-, hydrocolloid-, foam-, and film-based dressings anomalous proliferation and differentiation of fibroblasts and
and advanced standard procedures such as split-thickness keratinocytes [30], as well as the accumulation of ECM and
autografts, use of donor keratinocytes, cultured epithelial their subsequent remodeling by MMPs [31].
autografts, and Biobrane dressings. Though, mild and acute
clinical cases can be managed with the conventional or stan- 3. CLASSIFICATION AND MANAGEMENT OF DFU
dard therapies alone, chronic wounds and those appeared as
secondary complications of metabolic disorders might re- Effectual therapeutic plan for a chronic stubborn wound
quire intensive pharmaceutical care and pharmacotherapy. remains a challenge. However a better understanding of the
molecular biology and pathophysiology of chronic wounds
In recent times, scientific orientation has been focused on (DFUs) could result in more efficient and improved thera-
the use of polymeric delivery systems, modified advanced peutic paradigm for the management of chronic wounds.
biomaterials, and nanotechnology for optimising therapeutic Researchers believed that the wound healing process can be
outcomes, patient adherence and compliance as well as actively promoted by amending the expression of prime bio-
minimizing non-target adverse effects. The current review logical mediators which are key parameters for the healing
therefore aims to summarize the most recent developments process [32]. In general, it is already well-established that an
in polymer-based wound dressings with special emphasis to efficient and well-controlled healing process can be achieved
advanced polymeric biomaterials, innovative therapeutic by adopting standard guidelines such as; (1) the wounded
strategies and delivery approaches for the treatment of area should be dressed with adequate biomaterials which can
DFUs. Recent results from in vitro and in vivo studies have prevent the contamination/infection of the affected area over
been included to underline the unique potential of polymer- a long-term duration of wound management, (2) an ideal
based wound dressings in the treatment of DFUs. moist environment needs to be provided to potentiate wound
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 3

healing rate (wound closure) and prevent wound dissection (2) be non-toxic and should not provoke any immune or al-
(3) use of such a medicated dressing which can provide a lergic response, (3) prevent biofilm formation and secondary
sustained and proficient release of fabricated pharmacologi- infections, which could subsequently delay wound healing,
cal moieties and biomolecules and (4) prevent a rapid degra- and (4) promote patient compliance, by facilitating self ap-
dation of medicated dressing and irregular releasing pattern plication and removal without aggravating symptoms [39,
of fabricated drugs during the healing process [33, 34]. The 43]. However, due to the distinct severity and characteristics
management plan for DFUs is defined based on the severity of different types of wounds and healing phases involved,
and range of tissues affected. This can be assessed by classi- there is no single dressing which can efficiently meet all the
fying DFUs according to Wagner’s system [35, 36]. In ac- needs for a particular wound and healing phase [44, 45]. The
cordance with Wagneer’s classification system, DUFs can be particular characteristics, advantages and disadvantages of
classified into various grades as follows: (1) “grade 0” indi- the most commonly used polymers in the management of
cates no ulcers in affected tissues with high-risk of secondary DFUs are summarised in (Table 2).
complications; (2) “grade-1” refers to a partial and/or full
thickness ulcer; (3) “grade-2” indicates a deep ulcer which 3.2. Factors That Need to be Considered While Selecting
has penetrated down to the ligaments and muscle, but with a Suitable Wound Dressing
no bone involvement; (4) “grade-3” refers to a deep ulcer Current focus on evidence-based practice and the needs
with cellulitis or abscess formation, (5) “grade-4” indicates a to ensure cost effectiveness and patient satisfaction have
localized gangrene), and (6) “grade-5” indicates an extensive changed the way wound dressings are prescribed. Healthcare
and deep gangrene of the whole tissue [37]. The classifica- providers should aim, both at the time of prescribing and
tion of DFUs is imperative as it may facilitate selection of an while monitoring treatment thereafter, (1) to maximise effec-
appropriate dressing depending on the wound type, severity tiveness, (2) to minimize associated risks, (3) to minimize
and on the phase of wound development [38]. DUFs have cost, and (4) to improve patient compliance. A holistic ap-
also been classified based on clinical severity index and proach, considering the wider needs of the patient as well as
menifestations (as shown in Table 1). The clinical presenta- control of the wound environment, can maximize healing of
tion and the signs and symptoms of DFUs are presented in complex and chronic wounds. Hence, dressing selection
(Fig. 1). Several conventional and advanced dressings have should be rational and based on the wound bed type.
been discussed in the following sections.
Typically, DFU can be treated using passive or hydro-
3.1. Polymer-based Conventional Dressings active techniques [55]; however, the passive technique is
normally employed for the management of acute wounds (as
3.1.1. Types and Ideal Characteristics of Polymer-based they absorb reasonable amounts of exudate and they can
Conventional Wound Dressings ensure good protection). On the other hand, the hydro-active
Wound dressings were first developed to play only a pas- technique is mostly employed for the management of chronic
sive and protective role in the healing process [39]. How- wounds (such as DFUs) as they easily adapt to wounds and
ever, in recent decades several researchers have discovered are able to maintain a moist environment that can stimulate
revolutionary findings, which suggest that moist dressings the healing process [56].
can facilitate and accelerate the healing process [40]. Previ-
ous studies reported that the moistening of wound environ- 4. RECENT PROGRESS IN POLYMER-BASED
ment plays a pivotal role in stimulating proliferation and WOUND DRESSINGS
migration of fibroblasts and keratinocytes at the site of injury The efficiency of wound healing is greatly dependent on
[41]. Moreover, it tends to enhance collagen synthesis which several parameters such as severity of the wound, patho-
leads to reduced scar formation [41, 42]. Taken together, physiological basis of the wound, patient health condition,
researchers also believe that besides facilitating optimum and the extent of tissues involved. The selection of appropri-
moisture generation in the wounded area, the ideal wound ate wound dressing, together with the inclusion of therapeu-
dressings should also: (1) allow gaseous exchange, thermal
tic substances and healing enhancers (if employed) also
insulation, and facilitate the removal of drainage and debris
plays a pivotal role in the effective management of DFU.
in an attempt to promote the tissue reconstruction processes,

Table 1. Classification of DFU infections based on clinical severity.

Severity Index Clinical Manifestations

Uninfected Wound lacking purulence or any manifestations of inflammation

Infection localized to the skin and subcutaneous tissue (cellulitis/erythema extends ≤ 2 cm around an ulcer) without evidence of sys-
Mild
temic illness

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 with systemic toxicity or severe metabolic derangements


* Infection is defined as the presence of purulent secretions (pus) or ≥ 2 signs or symptoms of inflammation (erythema, warmth, tenderness, induration, pain).
4 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

Fig. (1). Types of DFUs based on signs, symptoms, and clinical presentation.

As reported by many research groups [57, 58], the effi- ment of DFUs are discussed in the sections of this report,
ciency of polymer based wound dressings, whether passive which follow.
or hydro-active, is largely based on the constituent polymeric
materials, physicochemical characteristics, biological re- 4.1.1. Chitosan and Derivatives
sponse, and extent of fabrication. Hence, one of the simplest Chitosan (CS) is a linear copolymer derived from chitin
ways to differentiate these polymeric biomaterials is based which is the major component of the exoskeletons of crusta-
on their origin: synthetic or naturally based polymers and cea such as shrimp and crab (chemical structure shown in
copolymers [59]. Modified polymeric materials (those ob- Fig. 2). It is well-recognised for its heterogenic functionali-
tained by chemical modification of naturally based poly- ties such as its non-antigenicity, inertness, non-toxicity, bio-
mers) [60] or mixtures/combinations of different polymers degradability, biocompatibility, bio-adhesiveness, anti-
and copolymers [61] can also be considered. A wide variety microbial properties, hemostatic effects and wound healing
of polymer based wound dressings have gained remarkable characteristics [63, 70, 71]. Furthermore, CS is highly versa-
attention within the healthcare community for the manage- tile and is able to produce a variety of functionalised deriva-
ment of chronic wounds [62, 63]. The brief summary of most tives through the chemical modification of amino and hy-
commonly-used polymer-based materials and their wound droxyl groups. These derivatives include N-carboxymethyl,
healing efficicies is presented in (Table 3). N-carboxybutyl, N-succinyl, N-acyl, N,O-(carboxymethyl),
N-N-dicarboxymethyl, N-carboxyethyl, O-succinyl, Ocar-
4.1. Natural Polymers boxymethyl, and 5-methylpyrrolidinone CS derivatives
Natural polymers are biomolecules that are originated amongst others.
from natural sources such as microbial, animal or vegetable CS and its derivatives have been widely established as
sources [64]. Although natural polymers can closely simulate delivery matrices for a number of pharmaceutical applica-
the original cellular milieus and ECM, they are significantly tions [60, 70, 72, 73]. It is soluble in weak organic acids,
heterogeneous and may undergo significant biochemical whereby it interacts with negatively charged molecules such
degradation that can modify their physicochemical character- as anionic polysaccharides, proteins, and nucleic acids,
istics and and their behavior (releasing pattern, interaction which are usually present in skin [74]. CS and derivatives
with surrounding tissues etc.) in the physiological environ- have also been reported to exhibit mild gelation whilst dem-
ment [65]. Batch-to-batch variation in the quality attributes onstrating the capacity to form films. It shows strong adhe-
of these polymers is often observed following isolation from sion to wound tissues and promotes blood coagulation and
animal or vegetable sources, which can limit their useful in wound healing [68, 75]. In particular, CS films with low
wider wound care applications [66]. In addition, some nota- degree of deacetylation have already been proven effective
ble risks of infectious diseases being transmitted have also in the treatment of superficial wounds [76].
been reported for polymeric materials of natural origin,
which have been attributed due to their xenogenic or allo- A recent study was conducted by Moura et al., (2014) to
genic nature [67]. evaluate the wound healing potential of 5-methyl pyrrolidi-
none CS (MPC) based dressing containing neurotensin, a
Other disadvantages of these naturally derived systems neuropeptide that acts as an inflammatory modulator in dia-
include suboptimal mechanical performance and poor stabil- betic wounds [77]. Neurotensin (NT) is a bioactive neu-
ity, which also limit their wider application [67]. Interest- ropeptide that is widely distributed in the brain and in several
ingly, several chemical modifications have been developed peripheral tissues. NT interacts with leukocytes, mast cells,
in order to address these major shortcomings [68, 69]. Those dendritic cells and macrophages leading to cytokine release
natural polymers used in wound dressings for the manage- 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- scaffolds were well integrated into the surrounding skin. The
ity, vasodilation/vasoconstriction and new vessel formation wound areas decreased gradually, reaching approximately
which helps to improve angiogenesis during wound healing 3% at day-14 after treatment with silver incorporated nanofi-
processes. Moura and colleagues demonstrated that the NT bers. In addition, the histological examination also high-
encapsulated MPC-based wound dressing greatly promoted lighted the clinical superiority of PVA/CS-AgNPs nanofibers
healing process and reduced the recovery time (Fig. 3) when in accelerating wound healing rate compared with control
compared to other treatment groups. In the same study, an groups. Seven days after grafting, the wounds treated with
increase in epidermis thickness was observed in all treatment control groups still displayed ulcerated surfaces, formation
groups; being particularly prominent in NT-loaded MPC of granulation tissue, and infiltration of inflammatory cells.
treatments in diabetic skin for periods up to 3 days. How- In contrast, the granulated tissue in the PVA/CS-nanofibers
ever, on day-10 the epidermis thickness profile was similar, treated group disappeared without capillary hyperplasia. On
but with a stronger effect in diabetic skin. Specific re- day-14, newly synthesized fibrous tissue and sparse inflam-
epithelialization profiles were also observed: in control mice matory cells in the dermis and subcutis were covered by
with re-epithelialization occurring from the bottom to top completely re-epithelialized epidermis in test groups. These
with basal cells in the epidermis covering the scar. In dia- data confirm that the PVA/CS as nanofibrous membrane
betic mice, re-epithelialization occurred over the granulation could provide a suitable scaffold for wound healing.
inflammatory tissue while this was undergoing repair. No
The wound healing superiority of CS in combination
correlation was observed with the applied treatments, in both with adipose derived nucleated cell fractions (ADNCs) has
groups [77].
also been proposed by Mehrtash et al., (2015) using male
Different forms of CS including hydrogels, membranes, white Wistar rats [79]. Cell therapy is evident to increase
scaffolds, microparticles, and nanoparticles have also been wound healing rate, reduce scar contracture, and minimize
employed to show wound healing potential [57, 77]. Li et al., donor-site morbidity in treatment of acute wound. In the
(2013) investigated the wound healing potential of treatment of chronic wounds, attempts are made to convert
poly(vinyl alcohol) (PVA) together with CS oligosaccharides the wound bed into the environment where maximum wound
(COS) in the form of silver nanofibers (AgNPs) through healing can be achieved by transplanting cells with an excel-
various in vivo experiments [78]. Silver has a long history of lent wound healing capacity to the wound bed. The adipose
medicinal use based on its antimicrobial effects. Microbial tissue bears several properties that are advantageous for neu-
burden can delay wound healing and makes silver an attrac- ronal sprouting and direction and has been used in different
tive local antiseptic for wounds affected this way, especially areas of surgery in recent decades. In this study, Mehrtash
as antibiotics have limitations. Whilst there is good evidence and colleagues demonstrated that ADNCs and CS combina-
in preclinical studies of the effects of silver on microbes and tion resulted in a significant improvement of full thickness
on processes that delay wound healing, evidence for the wound healing. Significant differences were observed in
benefits of silver products on human wound healing is still signs and symptoms of wounds treated with CS-ADNC
far from robust. However, Li and colleagues observed a combination compared with other groups, particularly in
complete closure of wounds in all treatment groups within 14 terms of cellular infiltration, acute hemorrhage, congestion,
days. The grafts prepared with nanofiber (PVA/CS-AgNPs) edema, collagen production and density, reepithelialisation
10 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

and neovascularisation. During the study period, scores for skin tissue and collagen deposition and for the sustained de-
re-epithelialization and neovascularization were significantly livery of fabricated therapeutic moieties. These and other
higher in CS-ADNC rats than other groups were observed. potential benefits of CS-based wound dressings; particularly
Polymorphonuclear (PMN) and mononuclear (MNC) cell for chronic wounds, are presented in (Table 3).
count, fibroblast cell proliferation and also Mean Rank of the
qualitative study of acute hemorrhage, edema and collagen 4.1.2. Hyaluronic Acid and Derivatives
production score in CS-ADNC group were significantly Hyaluronic acid (HA) is a natural polysaccharide with a
higher than those of other experimental groups. 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
Fig. (3). Wound size measurements for the MPC, NT and NT- as an in vitro culture template for proliferation of keratino-
loaded MPC foam treatments in (A) control and (B) diabetic mice. cytes has made it an exciting new product for future use in
The wound size was determined on days 0, 1, 3, 5, 8 and 10 post- wound regeneration.
wounding. The results are presented as means ± SEM of 7-18 inde-
pendent experiments. ∗∗p<0.01 MPC compared with PBS, ∗∗∗p< Studies by Turley & Torrance found that the biodegrada-
0.001 MPC compared with PBS, ##p<0.01 MPC + NT compared tion of HA produces byproducts that aid in epithelial cell
with PBS, ###p<0.001 MPC + NT compared with PBS [77]. Re- proliferation and migration [123]. A number of reported
printed with the permission by Acta Materialia Inc. Published by studies found that enzymes involved in the degradation of
Elsevier Ltd. (Copyright © 2013) through Copyright Clearance HA stimulate cell proliferation, providing further evidence
Center. that HA must be broken down in order to promote cell
growth [124, 125]. The molecular structure of HA itself also
Taken together, a well-known FDA approved dressing of facilitates the movement of cells within the ECM providing a
CS which is capable of stopping blood loss after injury and substrate for cell migration and proliferation thus enhancing
can be used as a barrier for biofilm is HemCon® Bandage dermal repair [126].
[80, 81]. The bandage showed excellent wound healing,
granulation and fibrous connective tissue formation effect Interestingly, HA may play a significant role in angio-
compared to the control groups [81]. CS has also been re- genesis and the inflammatory response, further supporting
ported to provoke inflammatory functions of macrophages, cellular growth. However, there was no significant difference
polymorphonuclear leukocytes, and neutrophils, and promote between the thicknesses of the epidermis treated with vi-
tissue granulation to an undergone inflammatory cascade tronectin: growth factor alone and vitronectin growth factor
[82]. Moreover, CS may also stimulate angiogenesis, fibro- together with HA delivery vehicle. While the addition of HA
blasts proliferation, synthesis and accumulation of collagen did not enhance all the cellular responses to vitronectin
fibers which in turn improve tissue regeneration [75, 83]. growth factor.
Hence, the possible manipulation of the physicochemical The molecular weight of HA (MWHA) is also an impor-
features of CS and/or derivatives could be accomplished to tant factor when considering its role in wound regeneration
design wound healing dressings with improved adherent and [127-129]. Specifically, studies by Campo and colleagues
anti-bacterial potential, increased exudate absorption capac- found that breakdown products of low molecular weight HA
ity, stimulation of angiogenesis and re-epithelialization of are pro-inflammatory leading to increased tissue damage
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 11

[127]. Interestingly, high molecular weight HA (HMWHA) Laserskin graft with a fibroblast cell layer was a powerful
may inhibit the nutrient supply to regenerate epithelial tissue tool with respect to its durability, biocompatibility, graft take
by blocking the formation of capillary networks. While rate, low infection rate, and seeding efficacy [130]. A pleth-
HMWHA may limit wound regeneration, some studies re- ora of studies involving the use of HA, with or without bio-
vealed that in the presence of medium molecular weight HA active moieties, in the management of chronic wounds have
(MMWHA), wound repair could be enhanced [128]. Addi- been summarized in (Table 3).
tionally, previous studies have found that MMWHA en-
hances wound closure through up-regulation of junctional 4.1.3. Cellulose and Derivatives
adhesion molecules at the epidermal diffusion border [128]. Cellulose is the primary structural component of plant
The limitations in wound repair with HA grafts are likely cell walls and is the most abundant organic polymer on
related to co-morbidities found in high-risk patients. Arterial Earth. It is a renewable biomaterial, readily available at low
occlusion and wound site infection also have a negative im- cost. Cellulose is a linear polymer constituted by b-1,4 linked
pact on graft survival and wound repair. D-glucose units which are joined to form cellobiose repeat-
The application of autologous human keratinocytes cul- ing units (chemical structure shown in Fig. 2) [132]. Several
tured on membranes composed of benzyl ester of HA (Laser- studies have reported that cellulose and its derivatives are
skin autograft) has shown greater potential to promote heal- highly biocompatible due to their lesser inflammatory re-
ing of DFUs. Keratinocytes, when applied to a wound, in- sponse as foreign bodies [133, 134]. Moreover, resorption of
duce and stimulate healing by releasing growth factors or cellulose in tissues does not occur since cells are not able to
multiplying in situ, thereby enhancing the healing effect of synthesize cellulases [134].
blood platelets. Theoretically, it is possible to amplify the The wound healing activities of cellulose have been re-
effects of the first steps of the wound healing cascade by ported in a number of studies which demonstrate that cellu-
increasing the local concentration of platelets and keratino- lose accelerates wound healing through the release and main-
cytes which would then induce an increased production of tenance of numerous growth factors at the site of injury such
trophic and growth factors. A study with 14 patients by as phosphodiesterase growth factor, epidermal growth factor
Lobmann et al. found that 79% of DFU's treated with HA (EGF), and basic fibroblast growth factor (bFGF). These
template grafts fully healed between 7 and 64 days post- growth factors stimulate the proliferation and migration of
procedure [130]. Interestingly, 3 of the grafts that failed to dermal fibroblast and impede bacterial proliferation in
survive had been grafted in patients with considerable arte- wounds [135, 136].
rial occlusive disease or with concomitant infection [130].
Composite Laserskin graft is a HA derivative consisting of Growth factors (GF) are biologically active polypeptides
micropores that support cell growth. Its use as a template for which are involved in cell growth, differentiation, prolifera-
cultured epithelial cell grafts has been studied extensively. tion, migration and metabolism. GF effects are a conse-
The efficiency of seeding the template with cultured epithe- quence of the specific binding to their receptors which acti-
lial cells is dependent upon the use of a fibroblast feeder vates a cascade of molecular events. All stages of the healing
layer. process are controlled by a wide variety of GFs and cytoki-
nes. This review sums up the major GFs involved in wound
Keratinocyte stem cell technology serves as a promising healing and skin repair, particularly focusing on: EGF, plate-
adjuvant therapy to clinically close large cutaneous wounds let derived growth factor (PDGF), bFGF, transforming
(e.g., DFU, burn wounds). However, the performance of growth factor-β (TGF-β), insulin-like growth factor (IGF)
cultured keratinocyte depends primarily on the quality of the and vascular endothelial growth factor (VEGF) families.
bed to which they are applied. Clinical take rates for cultured These biomolecules are considered especially important in
keratinocyte grafts are optimal when applied to a vascular- wound healing because GFs play an important role in stimu-
ized dermal bed with minimal bacterial colonization. In the lating granulation tissue formation, modulating the inflam-
absence of autologous dermis, staged reconstruction with a matory response and promoting angiogenesis. Further, GFs
dermal equivalent or dermal regeneration template is re- are necessary for successful matrix formation, remodeling
quired. Myers et al. performed studies comparing the effi- and re-epithelisation process. In chronic wounds the GF lev-
cacy of seeding composite Laserskin grafts with cultured els have been proven to decrease; thus, an interesting strat-
keratinocytes alone and with an allogenic fibroblast cell egy to promote healing is their external administration.
layer. Laserskin's micropores are laser produced perforations Based on these characteristics, a greater advancement has
that are 40 µm in diameters which can deliver keratinocytes been made in designing and manufacturing cellulose materi-
which are roughly 20 µm thick. A 10 cm by 10 cm sheet of als-based wound healing dressings with antimicrobial agents
Laserskin (along with a fibroblast feeding layer) can plate such as polyhexamethylase biguanide (PHMB) and/or silver
about 4 million keratinocyte cells [131]. Laserskin, when in recent decades.
accompanied by allogenic fibroblasts, is a highly effective
human skin substitute, which can be used for wound resur- Mu et al., (2016) recently evaluated the cutaneous wound
facing. The comparative study reported by Lam and col- healing and cytokine response of nano-porous nitrocellulose
leagues demonstrated that the seeding efficacy of human based liquid bandage (L-Bandage) using mouse model [137].
keratinocytes on plain Laserskin was 75% while Laserskin They synthesized a novel bandage containing a porous net-
with the fibroblast layer boasted a 95% efficacy. The differ- work structure with mean diameter of 18 nm that could ef-
ence was even more pronounced in rat keratinocytes which fectively prevent bacterial invasion, have favorable tensile
increased from 46% to 88% with the addition of the feeder strength, facile elongation, and acceptable water vapor
layer. Preliminary clinical data supported that composite transmission rate (WVTR). The L-Bandage treated wound
12 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

exhibited accelerated healing, with reduced inflammation, ferentiation. Gradients of calcium concentration increasing
enhanced wound re-epithelialization, contraction, granula- from 0.5 mM in the basal layer to > 1.4 mM in the stratum
tion tissue formation, and rapid angiogenesis [137]. Taken granulosum are consistent with migration patterns in re-
together, these data supported the wound healing potential of sponse to minor abrasion (normal wear). Dermal fibroblasts
nanoporous nitrocellulose L-bandages in terms of collagen require calcium but are approximately 100 times less sensi-
deposition. The resulting data demonstrated that both treated tive than keratinocytes. Normal calcium metabolism in the
and control wounds progressively deposited collagen over skin is dependent on cell membrane and cytosolic calcium
the duration of the study, but L-Bandage treated wounds binding proteins (calmodulin, cadherins, etc.), but their
produced significantly more collagen than control groups on modulation through parathyroid hormone, vitamin D or
day-6 and day-8. Furthermore, after 12 days, L-Bandage growth factors in normal or damaged tissue is not well
treated skin showed a very similar structure to normal skin, documented. In wound repair, calcium is predominantly in-
where the collagen fibers became denser and regularly volved as Factor IV in the hemostatic phase, but it is ex-
aligned. These outcomes suggested that the application of L- pected to be required in epidermal cell migration and regen-
Bandage containing nanoporous nitrocellulose could pro- eration patterns in later stages of healing. Calcium alginate
mote collagen deposition in the wound and serve as a prom- dressings are designed to liberate calcium early in the acute
ising wound dressing [137]. phase to promote hemostasis, but it is presently unclear
The wound healing potential and biocompatibility of cel- whether the supplementary calcium influences the intracellu-
lar environment at later stages of wound repair, notably dur-
lulose-based materials in combination with other polymers
ing the remodeling phase.
such as collagen have also been reported. An example of a
commercial cellulose-based dressing is Aquacel® Hydrofiber Alginate-based dressings have also been combined with
wound dressing (ConvaTec, USA), which is an antimicrobial growth factors such as stromal derived factor-1 (SDF-1) or
carboxymethyl derivative of cellulose. After application on drugs such as phenytoin, ibuprofen or clindamycin to im-
the wound area, it absorbs wound exudate and creates a gel- prove DFU treatment. Commercial products such as Medi-
like network to maintain a moist wound environment and honey (Derma Sciences Inc., Canada) which is an alginate
thus accelerate the wound healing process. A large number hydrocolloid wound dressing loaded with a minimum of
of studies reporting the clinical implication of cellulose and 70% of active Leptospermum honey or Algisite M Calcium
derivatives based wound dressings have been summarized in Alginate Dressing (Smith and Nephew Inc., Australia) are
(Table 3). alginate-based dressings indicated for DFU treatment. These
and other examples of the application of alginate dressings
4.1.4. Alginate for DFU wound healing are summarized in (Table 3).
Alginate (or alginic acid) is one of the most studied and
4.1.5. Collagen and Gelatin
applied natural polysaccharides in tissue engineering and
drug delivery applications. It is constituted by b-D- Collagen is the most abundant protein of the ECMs natu-
mannuronate (M-residues) and a-L-guluronate (G-residues) rally present in human tissues (e.g. bone, skin, cartilage,
residues covalently linked in different alternating or random ligaments, and tendon etc.). It represents 25% of the total
sequences/blocks (chemical structure shown in Fig. 2) [132, protein body content [146, 147], providing strength and in-
138]. Alginate has also been well-recognised as wound heal- tegrity to tissue matrices [148]. In addition, collagen can also
ing material and has high biocompatibility, low toxicity and interact with cells and help essential cell signaling that will
good mucoadhesive properties [132, 138]. Alginate-based regulate cell anchorage, migration, proliferation, differentia-
biomaterials are also pH sensitive and the release of bioac- tion and survival [146-148].
tive species from these materials at low pH conditions is
Collagen has been well-studied as an ideal biomaterial
significantly reduced. This feature could be advantageous for
for developing wound healing dressings as well as for tissue
the development of a delivery system intended for near-
engineering. In addition, several recent studies have revealed
neutral pH conditions [138], although alginate-based hydro- the clinical and in vivo efficacy of collagen and gelatin based
gels may present unpredictable and uncontrollable degrada-
wound dressings for accelerating granular tissue formation,
tion and dissolution profiles after loss of the divalent cation
improving healing rate, and angiogenesis as well as for de-
cross-linkers [139]. To overcome this issue, covalent/ionic
creasing infection by bacteria in chronic wounds [149-152].
cross-linking can be employed with other biopolymers such
These approaches include the incorporation of glucose oxi-
as gelatin [140], heparin [141], PVA [142] and CS [143].
dase in a collagen matrix in order to achieve the sustained
The main disadvantage of alginate-based materials is delivery of reactive oxygen species (ROS), natural com-
their inability to undergo efficient and rapid enzymatic deg- pounds (such as polyphenols), growth factors (such as
radation in mammals. In addition, alginates are very hydro- bFGF), antibiotics (such as doxycycline and levofloxacin)
philic, which hinders its interactions with skin proteins and ionic silver as antimicrobial agent.
[138].
Recently, Singh et al., (2011) conducted a clinical trial
Calcium alginate-based dressings are recognized to have with 120 patients having chronic wounds with exudative
the capacity to efficiently absorb wound exudates, hence lesions using collagen dressing in test groups [149]. For as-
facilitating debridement and accelerating wound healing in sessment, the wound characteristics (size, edge, floor,
DFUs [144, 145]. This is evident that calcium has an estab- slough, granulation tissue, and wound swab or pus culture
lished role in the normal homeostasis of mammalian skin and sensitivity results) were evaluated. The appearance of granu-
serves as a modulator in keratinocyte proliferation and dif- lation tissue, healing rate, need for skin grafting, and pa-
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 13

tients' satisfaction was also recorded in test groups. Result tions, mostly because of its good biodegradability
indicated that collagen dressing avoid the need of skin graft- /biocompatibility in physiological medium and its good
ing, and provides additional advantage of patients' compli- processability [146, 154]. Therelatively low antigenicity of
ance and comfort compared to conventional groups. Simi- gelatin also makes it a well established natural polymer used
larly, Arul et al., (2012) had also highlighted the clinical in various biological applications [155, 156].
applicability of collagen based wound dressing for the man-
Gelatin has been employed in chronic wound healing ap-
agement of chronic diabetic wounds [150]. They demon-
plications by various researchers [151, 152]. Kawai and co-
strated the pharmaceutical significance of collagen matrices
workers (2005) conducted an in vivo analysis of bFGF-
for the the sustained release of reactive oxygen species
impregnated gelatin microspheres into artificial dermis using
(ROS) in diabetic dermal wound healing. Emerging data
a pressure-induced decubitus ulcer model in genetically dia-
favor the involvement of free radicals in the pathogenesis of betic mice [151]. The results obtained clearly revealed a sig-
diabetic wound healing. In order to achieve the sustained
nificant improvement in angiogenesis and fibroblast prolif-
delivery of ROS in the wound bed, they incorporated glucose
eration as well as reduction in wound bed infection when
oxidase in the collagen matrix (GOIC), which is applied to
using bFGF-impregnated gelatin microspheres compared to
the healing diabetic wound [150]. A significant increase in
the control groups.
ROS (p < 0.05) was observed in the fibroblast of GOIC
group during the inflammation period compared to the con- Kanda et al., (2014) has recently conducted an in vivo
trol groups. This elevated level up regulated the antioxidant analysis to evaluate the wound healing potential of bFGF-
status in the granulation tissue cause significant improve- incorporated collagen-gelatin sponge in diabetic mouse
ment in the granulation tissues and cellular proliferation in model [152]. The data obtained displayed a significant accel-
the collagen based dressing treated group compared to con- eration in granulation tissue formation and showed a signifi-
trol groups. Together, evidence from wound contraction and cant improvement in healing rate and angiogenesis compared
histology also revealed faster healing rate in collagen treated to control groups. Researchers further explained that colla-
wounds compared to control groups [150]. gen-gelatin sponge might release positively charged growth
factors such as bFGF in a sustained manner which could
The wound healing potential of a novel collagen-based
impart skin regeneration potential [152].
wound dressing consisting of 2,3-dihydroxybenzoic-acid-
modified gelatin microspheres loaded with doxycycline has A large number of commercial collagen and gelatin based
been highlighted by Adhirajan et al. [153]. It is well- dressings are already in commercial use for the effective
documented that chronic wounds are characterised by in- management of partial- and full-thickness pressure, venous,
creased levels of pro-inflammatory cytokines and proteases vascular and diabetic ulcers. These products include BCG® ,
that inhibit the healing process by disrupting essential mito- BIOSTEP®, Catrix®, CollaSorb® and PROMOGRAN
genic activity. Doxycycline, which belongs to the tetracy- PRISMA® Matrix. The wound healing potential of collagen
cline group of antibiotics, promotes healing of the chronic and gelatin is presented in (Table 3).
wound by inhibiting MMP production and action. There has
been a considerable amount of research into the effectiveness 4.1.6. Fibrin
of doxycycline and other tetracyclines in both animale and in Fibrin is a protein that is produced from fibrinogen and
vitro studies. These studies have focused on a wide range of hence can be autologously harvested from patients. It may
conditions, including healing responses in intestinal anasto- provide immunocompatible polymeric carriers for the deliv-
mosis in rats, corneal damage in rabbits from chemical war- ery of bioactive molecules and/or cells in various biomedical
fare agents, extensive myocardial infarction in rats, impact applications [146, 155].
on healing after rotator cuff repair in rats, and damage to
human corneal epithelial cells. There have also been studies Besides other biological applications, fibrin-based wound
in humans on a range of conditions; for example, osteoarthri- dressings are also well-recognised in the management of
tis, rheumatoid arthritis, and the use of doxycycline-releasing chronic ulcers [156, 157]. Breen et al., (2008) conducted an
sinus stents to prevent restenosis postoperatively. Adhirajan in vivo experiment to evaluate the wound healing potential of
and colleagues performed this study and found that a com- adenovirus encoding endothelial nitric oxide synthase
plete healing of excisional wound was achieved by day-15, (eNOS) incorporated fibrin-based wound dressings using an
compared to day-24 in the control group. Moreover, the in- alloxan rabbit ear ulcer model [62]. Emerging evidence from
fection rate was significantly reduced (99.9% by day-9) in both animal and human studies indicates that nitric oxide
collagen based dressing treated groups which resulted in (NO) plays a key role in wound repair. The beneficial effects
faster epidermal resurfacing and fibroplasias, in contrast to of NO on wound repair may be attributed to its functional
the observation of severe inflammation in control groups due influences on angiogenesis, inflammation, cell proliferation,
to higher microbial load up to day-15. Thus, this study also matrix deposition, and remodelig. Thus, various researchers
indicates that collagen based dressings may attenuate both proposed the beneficical effect of eNOS in promoting syn-
metalloprotease levels and wound bed infection and thus can thesis and release of NO endogenously which would facili-
be a potential wound dressing to improve healing of chronic tate healing mechanism and promot faster wound closure.
wounds [153]. The clinical evaluation of collagen based Breen and colleagues observed a significant improvement in
wound dressings has also been highlighted by other re- eNOS expression in the fibrin-based dressing treated group
searchers [151, 152]. at day-14 compared to control groups [62]. Moreover, the
test group treated with the fibrin-based dressing showed a
Gelatin is a collagen derivative which is commonly used significantly faster rate of epithelialization, granulation tissue
as a hydrogel for pharmaceutical and biomedical applica- formation and healing rate. The inflammatory cells were also
14 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

reduced significantly in this group at day-14 and closure of been suggested that mannose 6-phosphate, the principal
wounded area was also observed on day-14 which indicates sugar component of aloe vera, may be partly responsible for
tissue remodelling [62]. the wound healing properties of the gel. Mannose-6-
phosphate can bind to the growth factor receptors on the sur-
Chen et al., (2010) highlighted the clinical significance
of fibrin-based dressing to facilitate the fixation of skin face of the fibroblasts and thereby enhance their activity.
Furthermore, acemannan, a complex carbohydrate isolated
grafts and to limit the risk of infection in chronic wounds in
from aloe leaves, has been shown to accelerate wound heal-
fifteen patients [156]. The results revealed that the time
ing and reduce radiation-induced skin reactions.
taken for complete wound healing to occur ranged from 3
weeks to 2 months with no rebound symptoms and no recur- Inpanya and co-workers (2012) highlighted the wound
rence of ulcers within the 3- to 18-month follow-up period healing effectiveness of an aloe gel extract incorporated in a
[156]. fibroin-based dressing in the treatment of chronic wounds
using streptozotocin-induced diabetic rats [160]. The result-
The wound healing effects of fibrin gels incorporating
ing data revealed a significant increase in the proliferation
hematopoietic stem cells (CD34+), CD34+-derived endothe-
and differentiation of skin fibroblasts in the fibroin film
lial cells, or both were also reported by other researchers
treated group compared to control groups. Furthermore, the
[157]. Stem cells have a unique capability to differentiate
into various tissues in the body. Stem cells derived from experimental animals treated with fibroin film showed partial
closure of the wound at day-7 compared to control groups.
various sources such as bone marrow, peripheral blood, and
Histological data showed that the fibroblast distribution and
umbilical cord blood have been used for the healing of
collagen fiber organization was similar to normal rat skin.
chronic skin ulcers. Mesenchymal stem cells (MSCs) (also
These results clearly indicate that blended fibroin/aloe gel
known as multipotent mesenchymal stromal cells) possess
films may stimulate wound healing and thus can be used as
the capacity for self-renewal and multi-lineage differentia-
tion, and their ability to enhance cutaneous wound healing potential alternative in the management of chronic diabetic
ulcers. These and other studies which reported wound heal-
has been well characterized. Acting via paracrine interac-
ing potential of fibroin-based films in the management of
tions, MSCs accelerate wound closure, increase angiogene-
chronic wound are presented in (Table 3).
sis, promote resolution of wound inflammation, favorably
regulate extracellular matrix remodeling, and encourage re- 4.1.8. Dextran
generation of skin with normal architecture and function.
The researchers indicated that the incorporated stem cells Another natural polymer constituting strong hydrophilic-
were differentiated into fibroblasts, keratinocytes and endo- ity, water solubility, biocompatibility and biological inert-
thelial cells, which played an important role in accelerating ness to but highly reactive through its reactive hydroxyl
wound healing processes [157]. groups, is dextran (chemical structure shown in Fig. 2) [161,
162]. It has widespread medical and biological applications
The use of enzymes to produce and deliver nitric oxide such as in dermal and subcutaneous healing as well as being
(NO) has also been studied using fibrin-based dressings to
used as a drug delivery vehicle [161, 162]. It facilitates
stimulate the inflammatory response and accelerate re-
wound healing by stimulating infiltration of inflammatory
epithelialization in the management of chronic skin ulcers
cells and promoting angiogenic cell migration to the site of
[158]. Data obtained clearly indicated a complete closure of
lesions [163].
wounds within 12 weeks of treatment using Vivostat, a plate-
let-rich fibrin. Other wound healing benefits of fibrin-based Sun et al., (2011) proposed that the application of dextran
dressings were briefly summarized in (Table 3). hydrogel scaffolds augments angiogenic responses and
stimulates skin regeneration during chronic wound healing.
4.1.7. Silk Fibroin They have performed a clinical study allowing the dextran
scaffolds to remain intact and securely in place during the
Fibroin is an insoluble protein present in silk created by
spiders, the larvae of Bombyx mori, other moth genera such entire healing period. Data indicated that the dextran hydro-
gel promoted dermal regeneration with skin appendages re-
as Antheraea, Cricula, Samia and Gonometa, and numerous
growing within 3 weeks of treatment [163]. Further analysis
other insects. Silk in its raw state consists of two main pro-
of the data revealed that the dextran scaffold enabled infiltra-
teins including sericin and fibroin, with a glue-like layer of
tion of inflammatory and angiogenic cells into the wounded
sericin coating two singular filaments of fibroin called brins.
area. Endothelial cells homed into the hydrogel scaffolds to
Owing to slow bio-degradability, bio-compatibility, and
hemo-compatibility [159, 160], it has been used in various enable neovascularization by day-7, resulting in a significant
increase in blood flow compared to the control groups. Fur-
biomedical applications. It has been evident that silk fibroin
thermore, a mature epithelial structure with fully developed
promotes epidermal cells and fibroblast attachment, cellular
hair follicles and sebaceous glands were observed on day-21.
proliferation, granular tissue formation and thus stimulates
These results clearly demonstrate a considerable improve-
wound healing processes [159, 160].
ment in wound healing processes in test groups treated with
Numerous investigations revealed that aloe vera acceler- dextran hydrogen scaffolds. These results were in agreement
ate wound healing by directly stimulating the activity of with previous report by Parulkar et al., (1985) which also
macrophages and fibroblasts. Fibroblast activation by aloe indicated a positive role of dextran based biomaterials in
vera has been reported to increase collagen and proteoglycan promoting chronic ulcers [164].
synthesis, thereby promoting tissue repair. Some of the ac-
In the study undertaken by Paulkar et al (1985), chronic
tive principles appear to be polysaccharides composed of
several monosaccharides, predominantly mannose. It has wounds were applied with a thick layer of dextranomer, a
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 15

dextran polymer, and were further covered with absorbent eric materials can be used as a potential alternative for pro-
gauze and non-occlusive bandage dressing [164]. Research- moting wound healing processes.
ers observed a significant improvement in the wounded area
over an average period of 8 days. The effect of dextranomer 4.2. Wound Healing Benefits of Synthetic Polymers
on the infected wound was rapid, leading to a remarkable
decrease of the inflammatory reaction around the wound In recent decades, a wide diversity of synthetic biode-
gradable/non-biodegradable, biocompatible polymers and
during the first day. Formation of healthy granulation tissue
copolymers have been developed [161]. The synthetic poly-
occurred within a few days without pain, edema and tender-
mers are claimed to overcome the limitations of natural
ness [164]. It has further been proposed that the efficient
polymers by achieving consistent and reproducible chemical
wound healing effect of dextran is associated with its ability
and physical properties [154]. A vast majority of synthetic
to cleanse the lesion by absorbing the wound exudate, facili-
tating tissue debriment and removing contaminantion from polymers are insensitive to biological and enzymatic proc-
esses, and hence their physicochemical and biochemical be-
the wound incluinding tissue degradation products, bacteria
havior will not vary greatly from patient to patient [154]. The
and other contaminants, which in turn improve healing rate.
wound healing potential of synthetic polymers and the de-
4.1.9. Elastin velopment of wound dressings is discussed in the subsequent
section.
Another natural polymer showing wound healing poten-
tial is elastin (chemical structure shown in Fig. 2). It is an 4.2.1. Poly(ethylene glycol) (PEG)/Poly(ethylene oxide)
insoluble ECM protein and a major constituent of skin elastic (PEO)
fibers [165, 166]. Generally, elastin is difficult to process
PEG is a polyether which is also known as poly(ethylene
due to its highly insoluble nature; however, its soluble forms,
including tropoelastin (a soluble precursor form of elastin), oxide) (PEO) or as poly(oxyethylene) (POE) (as shown in
Fig. 4), depending on its molecular weight. It is a hydro-
α-elastin (an oxalic acid derivative of elastin) and elastin-like
philic, non-toxic, biocompatible and non-immunogenic ma-
polypeptides have been recognized in broader applications
terial that can be synthesized by anionic or cationic polym-
[166, 167]. These biomaterials enhance tissue regeneration
erization of ethylene oxide [139, 169]. PEG can also be
by promoting collagenase synthesis, fibroblast proliferation,
blended with other polymers such as CS, poly(lactic-co-
and increasing chemotactic activity [168].
glycolic acid) (PLGA) and poly(propylene fumarate) (PPF)
The wound healing efficacy of elastin-based biomaterials in order to improve its inherent solubility, mechanical and
has been reported in a recent report by Koria et al., (2011) thermal properties as well as its viscosity and crystallinity
[165]. They demonstrated that a protein gel comprised of [170, 171].
elastin-like peptides loaded with keratinocyte growth factor
The wound healing and tissue regeneration properties of
(KGF) enhanced the re-epithelialization, neovascularization,
and granulation tissue formation in chronic diabetic wounds PEG and co-block-copolymers of PLGA-PEG have been
proposed by many researchers [172-177]. Lee and co-
[165]. These data clearly indicated that elastin-based polym-
workers (2007) designed a triblock copolymer (PEG-PLGA-

H OH
O

n n

Poly(ethylene glycol) (PEG) OH

Poly(vinyl alcohol) (PVA)

N O O
O
H2
O C CH2 O C NH CH2 NH C

n n

Poly(vinyl pyrollidone) (PVP) Polyurethane (PU)

O
O O
OH O H
HO O
n m

CH3 n CH3 O

Poly(hydroxyethyle methacrylate) (PHEMA) Poly(lactic-co-glycolic acid) (PLGA)

Fig. (4). Chemical structures of some synthetic polymers used for the treatment of DFUs.
16 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

PEG) as thermosensitive hydrogel scaffold and evaluated its groups [178]. The formation and deposition of granulation
wound healing potential using diabetic mouse model [172]. tissue and an increase in wound closure rate was also ob-
They observed a significant engraftment in muscle-derived served to be significantly higher in NO-modified hydrogel
stem cells (MDSCs) by 20- to 30-fold and a complete clo- treated wounds at day-8 and 15 compared to control groups.
sure of wound in db/db mice treated with PEG-PLGA-PEG These results suggest that NO induced treatment using the
until day-20. The increased engraftment resulted in improved PVA hydrogel system has the potential to modulate wound
wound healing, as indicated by epithelium migration, higher healing processes [178].
wound closure rate, and collagen deposition [172].
Manju et al., (2010) also proposed the wound healing po-
Yang et al., (2012) demonstrated the wound healing po- tential of PVA based hydrogels [179]. In this study, PVA
tential of Poly(ethylene imine) and PEG plasmid in diabetic based hydrogels were synthesized by polymerization with
rats [173]. Results obtained clearly revealed a gradual release aminophenyl boronic acid. An extended swelling of the hy-
of incorporated bFGF and a significantly higher wound heal- drogel which was attributed to the strong affinity of the gel
ing rate, enhanced collagen deposition, granulation tissue for glucose and to the subsequent breaking of bonds formed
formation, highly improved neovascularization, complete re- between PVA and boronic acid groups to releae ciproflox-
epithelialization and regrowing skin appendages [173]. acin. Ciprofloxacin (CFX) is a synthetic broad-spectrum
These results were in agreement with Huang et al., (2011) antibiotic belonging to the fluoroquinolone class, and it is
who performed experiments to evaluate the wound healing effective against many gram-positive and gram-negative
potential of PEGylated (PEG modified) rhFGF using dia- bacteria, including some strains resistant to other agents such
betic mouse model [174]. They found that test animals as penicillins. The covalent insertion of CFX in the polym-
treated with PEGylated rhFGF exhibited superior therapeutic eric chains presents a strong antibacterial activity against S.
effectiveness with faster healing rate, enhanced collagen aureus and E. coli that commonly infects wounds. Thus re-
deposition and maturation, significant expression of TGF-β, searchers proposed that the incorporation of CFX in poly-
and higher dermal tissue regeneration, compared with con- mer-based dressing significantly improve wound healing
trol groups [174]. effects. On the basis of the strong affinity of PVA hydrogels
for binding with glucose, the researchers proposed that PVA
Choi et al., (2008) evaluated the wound healing efficacy
could be used in dressings for the management of wounds,
of poly(epsilon-caprolactone) (PCL)-PEG block copolymer
particularly diabetic wounds [179]. The wound healing ap-
using diabetic animals with dermal wounds [176]. They ob-
served a significantly higher expression of keratinocyte- plications of PVA based dressing and hydrogels are summa-
rized in (Table 4).
specific genes in test animals treated with EGF-conjugated
nanofibers compared with control animals. The wound heal- 4.2.3. Poly(vinyl pyrrolidone) (PVP)
ing rate was significantly higher in test groups compared to
the control groups. The higher expression of EGF-receptor PVP is another biocompatible, hydrophilic, non-toxic and
(EGFR) using immune-histochemical staining also suggested non-carcinogenic material made from the monomer N-
therapeutic superiority of EGF-conjugated nanofibers [176]. vinylpyrrolidone (chemical structure shown in Fig. 4) and
The wound healing potential of PEG and coblock copolymer has been extensively used for a wide variety of pharmaceuti-
is summarized in (Table 4). cal and biomedical applications (including wound dressings).
Various researchers have proposed that this material is
4.2.2. Poly(vinyl alcohol) (PVA)
very effectively used to fabricate wound dressings owing to
PVA is a biodegradable, biocompatible, hydrophilic, its strong water absorption and oxygen permeability proper-
non-toxic and non-carcinogenic polymer obtained from vinyl ties [186, 187]. Yang and Ping (2010) recently evaluated the
acetate by hydrolysis, alcoholysis, or aminolysis (chemical wound healing potential of PVP used in the new NO delivery
structure shown in Fig. 4) [34, 47, 149]. PVA has been platform, containing grafted S-nitrosothiols, derived from
widely used for tissue engineering and drug delivery applica- endogenous glutathione (GSH) or its oligomeric derivatives
tions, and besides its high hydrophilicity and water absorp- complexed with PVA [188]. This complex was shown to
tion capacity, it also presents an excellent capacity to be provide consistent release rates of NO over a period of 10
processed in the form of particles, fibers, textiles, sponges days. Furthermore, the in vivo wound healing study demon-
and films. strated that, with a single topical application, the sustained
release of NO delivery significantly accelerated wound heal-
PVA has been used in the development of wound dress-
ings for the management of acute as well as chronic wounds. ing when compared to the control group. Yang and Ping
(2010) proposed that these interpolymer complexes could be
Masters et al., (2002) evaluated the effect of NO releasing
potentially useful for the management of chronic exudative
PVA hydrogel wound dressings on the dermal wound heal-
diabetic wounds [188].
ing using diabetic mice [178]. Emerging evidence from both
animal and human studies indicates that NO plays a key role 4.2.4. Polyurethanes (PUs)
in wound repairs. The beneficial effects of NO on wound
repair may be attributed to its functional influences on angi- PUs are highly versatile, easily processable, sterilizable,
ogenesis, inflammation, cell proliferation, matrix deposition, non-toxic, non-carcinogenic, non-adherent and non-
and remodelig. Data obtained indicated a slow and consistent allergenic polymers [181]. PUs are traditionally and most
release of NO release from the NO-modified hydrogel. A commonly formed by reacting a di- or polyisocyanate with a
significant improvement in wounds has been observed in polyol (chemical structure shown in Fig. 4). Despite their
NO-modified hydrogel treated groups compared to control 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 Hussain et al.

evaluated for their efficient sorptive and fluid drainage prop- that compared with control groups, rhEGF-PU foam acceler-
erties, which are essential for wound dressings, whereby ated wound healing by promoting wound contraction, re-
these attributes prevent wound desiccation [189, 190]. epithelialization, collagen deposition and the formation of a
skin appendage (as shown in Fig. 5). The clinical applica-
Khil et al., (2003) suggested that efficient evaporative
water loss, coupled with considerable oxygen permeability tions of of PU-based wound dressings have also been sum-
marized in (Table 4).
and the ability to drain wounds are the critical characteristics
of electrospun nanofibers, which determine wound healing 4.2.5. Poly(hydroxyethyl methacrylate) (PHEMA)
efficacy [189]. A significant increase in the rate of epithe-
lialization and formation of granulation tissue has been ob- PHEMA-based polymers and copolymers are biocom-
served for electrospun nanofibers used in the treatment of patible, non-biodegradable materials that form hydrogels,
wounds. Moreover, a number of researchers have demon- which can be employed in a range of different biomedical
strated accelerated wound healing when using PU-based and pharmaceutical applications [195]. The chemical, physi-
wound dressings [181, 191]. cal, sorption and permeability properties of PHEMA-based
polymers are dependent on the method of synthesis method
Recently, PU-based dressings have been patented as and the process conditions used in the manufacturing process
wound dressings for the management of chronic DFUs [192]. The composition of the polymer including the proportions of
In this regard, the commercial wound dressing Meliplex® Ag the co-monomers and cross-linkers andthe final degree of
(Molnlycke Health Care, Sweden) comprises a silicone cross-linking also play an important role in determing the
wound contact layer, an absorbent material (polyurethane material attributes [195].
foam pad), an anti-microbial agent (silver sulfate) and a va-
por-permeable waterproof film which has been designed to PHEMA-based hydrogels have been used in the manu-
absorb wound exudates, whilst maintaining a moist wound facture of artificial skin in addition to wound dressing appli-
environment. It is well-recognised as an efficient wound cations [139, 170], with a range of many bioactive sub-
dressing for the effective management of chronic wounds stances being incorporated into these materials. An interest-
such as lower extremity ulcers, pressure ulcers, burn wounds, ing example is the case of a hybrid dressing consisting of a
and DFUs [193]. PHEMA core (containing a light-activated NO donor) and a
PU coating for use on chronic ulcers [196]. One major ad-
PU-based dressings have been reported to come loaded vantage of this material is the fact that NO release is affected
with bioactive compounds, which are incorporated to pro- by light exposure. The dressing can be illuminated from time
mote rapid wound healing. A wound dressing containing an to time to selectively deliver NO to the wound site, whilst
antimicrobial therapeutic agent (e.g. penicillin, erythromy- maintaining antiseptic conditions. This approach might be
cin, chlorohexidine, triclosan), a pain-relieving substance
superior to simple washing of the affected area with conven-
(e.g. ibuprofen) and protease inhibitors (e.g. MMP-9, elas-
tional solutions such as hydrogen peroxide.
tase, MMP-8, MMP-12) has been reported. In this system,
the active pharmaceutical ingredients are incorporated into a PHEMA and PEG have been combined to develop a hy-
barrier layer made of collagen/polylactide/polyglycolide or drogel dressing that can bind covalently to MMP inhibitors
polyurethane [181]. This layer degrades in contact with and promote the healing of chronic wounds. This patented
wounds, releasing the therapeutic substances into the wound. dressing ensures that MMPs in the chronic wound fluid are
inhibited (thus reducing their proteolytic content) while
Recently, Pyun et al. (2015) evaluated PU-based foam
guaranteeing that the necessary MMP levels for normal heal-
containing rhEGF as a dressing material for healing diabetic ing are not affected in the wound bed [197].
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.
Polymers-based Dressings for Diabetic Foot Ulcers Current Drug Targets, 2017, Vol. 18, No. 11 19

4.2.6. Poly (a-esters) (PLA, PGA, PLGA, PCL) not containing bFGF. Moreover, enhanced collagen deposi-
tion and an ECM remodeling process were also observed
Polylactide (PLA) is one of the most popular aliphatic
with the components of collagen fibers being similar to nor-
polyesters used in biomedical applications since it presents
mal tissues.
relatively high strength and an appropriate degradation rate
for most drug delivery and tissue engineering systems [198]. Polycaprolactone (PCL) is another biodegradable and
In fact, PLA possesses good mechanical characteristics, con- biocompatible poly(a-ester) which has been evaluated for
trolled degradability and excellent biocompatibility. How- tissue regeneration and wound healing applications. It pro-
ever, its strong hydrophobicity limits some of its potential motes faster healing and reduced inflammatory infiltration
applications [198-200]. [206]. However, PCL degrades at a significantly slower rate
than PLA, PGA and PLGA [207]. This slow degradation
Polyglycolic acid (PGA) is another poly(a-ester) which is makes PCL less attractive for this type of biomedical appli-
relatively hydrophilic and degrades faster than PLA in aque-
cation, but more attractive for sutures, long term implants
ous solutions and in vivo. To obtain intermediate degradation
and controlled-release applications [207].
rates between PGA and PLA, several copolymers of lactic
acid, glycolic acid (poly(lactic-co-glycolic acid) (PLGA)) Merrel et al. [206] developed PCL nanofibers as a deliv-
can be synthesized [200, 201]. ery vehicle for curcumin for diabetic wound healing applica-
tions. Curcumin is a natural phenolic compound with anti-
PLGA is also a biodegradable polymer with strong bio-
oxidant and anti-inflammatory properties. It has been re-
compatibility, controlled biodegradability and potential for
ported that curcumin acts as an antiproliferative, anti-
achieving sustained release of bioactive substances [202].
invasive, and antiangiogenic agent; as a mediator of
Furthermore, it can be processed into many different forms
chemoresistance and radioresistance; as a chemopreventive
including powders, pellets, fibers and nanoparticles.
agent; and as a therapeutic agent in wound healing in dia-
PLGA microspheres loaded with rhEGF were demon- betic and cardiovascular ailments. Curcumin increased cellu-
strated to enhance the growth rate of fibroblasts, and it was lar proliferation and collagen synthesis at the wound site.
also observed that wounds in diabetic rats healed more effi- Curcumin treated wounds were found to heal much faster as
ciently compared to the use pure rhEGF [202, 203]. indicated by improved rates of epithelialisation, wound con-
traction and increased tensile strength. To this end, Merrel
Dong et al. [202] prepared PLGA microspheres loaded
with rhEGF by a solvent-evaporation technique. These mi- and colleagues demonstrated that the prepared curcumin-
loaded nanofibers reduced inflammatory induction from
crospheres were small in size and presented a high drug en-
mouse monocyte macrophages. In addition they increased
capsulation capacity (86%). rhEGF-loaded microspheres
the rate of wound closure in a STZ-induced diabetic mouse
loaded into the wound site enhanced the growth rate of fi-
model [206].
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 SUMMARY
emulsion method to prepare rhEGF-loaded PLGA nanoparti- Chronic wounds include, but are not limited, to diabetic
cles for use in treating diabetic ulcers. In diabetic rats, these foot ulcers, venous leg ulcers, and pressure ulcers. Effective
rhEGF-loaded nanoparticles promoted a faster healing rate management of chronic wounds presents major clinical bur-
and enhanced fibroblast proliferation. dens to the patients, healthcare providers and the healthcare
PLGA-based copolymers can be applied in skin tissue system around the globe. This review discusses the patho-
regeneration and suture applications, and have been ap- physiology of DFU, a complex chronic wound, factors that
proved by the FDA for several biomedical and pharmaceuti- need to be focussed while selecting a suitable dressing, and
cal applications [200]. The incorporation of drugs and other the polymeric modalities currently available to achieve heal-
bioactive substances into poly(a-hydroxy acids) has been ing in DFU patients. Among various therapeutic modalities,
undertaken with DFU applications in mind. Xu et al. [204] conventional wound dressings have greater recognition in the
reported the incorporation of the hydrophilic antibiotic drug, management of chronic wounds; however in most instances,
tetracycline hydrochloride (TCH), into an electrospun PEG- the treatment of DFUs impose a substantial challenge to the
PLA nanofibrous membrane. This drug-impregnated mem- conventional wound dressings and demand the development
brane demonstrated sustained release of TCH over 6 days of novel and advanced wound healing modalities. New and
and was effective at inhibiting growth of S. aureus. recent alternatives to conventional dressings have been de-
veloped; these include mixing different polymers and using
As observed previously for other polymer-based dress- more efficient cross-linking methods to create improved ma-
ings, the loading of growth factors into PLA-based materials terials that guarantee an optimal wound environment. Natu-
to stimulate the wound healing is also an option for DFU ral (CS, HA, cellulose, alginate, collagen, fibrin) and syn-
treatment. As an example, bFGF was embedded into ul- thetic (PVA, PEG, PVP, PU, PHEMA, poly(aesters)) poly-
trafine PLA fibers with a core-sheet structure [205]. An ini- mers have been combined or cross-linked (with either
tial low burst release was achieved, followed by controlled genipin, oxidized dextran or glutaraldehyde) for the devel-
release for around 4 weeks, which might be useful for the opment of new polymer-based wound dressings with im-
treatment in chronic ulcers. Results showed a higher wound proved therapeutic outcomes and patient compliance. These
recovery rate with complete re-epithelialization, regeneration polymers have been used in the form of hydrogels, films,
of skin appendages, higher density and mature capillary ves- hydrocolloids, foams, membranes, scaffolds, microparticles,
sels in bFGF-loaded scaffolds when compared with fibers and nanoparticles. The critical analysis of the literature sug-
20 Current Drug Targets, 2017, Vol. 18, No. 11 Hussain et al.

gested that advanced polymeric dressings employed for the [16] Rodero MP, Khosrotehrani K. Skin wound healing modulation by
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[17] Schreml S, Szeimies R, Prantl L, Landthaler M, Babilas P. Wound
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diabetic neuropathy. Am Fam Physician 2005; 71: 2123-8.
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The authors declare no conflict of interest, financial or neuropathies. Diabetes Care 2004; 27: 1458-86.
[23] Rathur HM, Bloulton AJM. Recent advances in the diagnosis and
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