A pragmatic review on the property, role and significance of polymers in treating diabetic foot ulcer

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A pragmatic review on the property, role and significance of polymers in treating diabetic foot ulcer Esther Jemima Paul ⇑, Padmapriya B Department of Biomedical Engineering, PSG College of Technology, Coimbatore 641004, India

a r t i c l e

i n f o

Article history: Received 10 April 2019 Received in revised form 8 July 2019 Accepted 14 July 2019 Available online xxxx Keywords: Diabetic foot ulcer Polymeric scaffolds Delivery mechanisms Cellular and acellular therapy Commercial dressings Smart automated dressings

a b s t r a c t Diabetic Foot Ulcer (DFU) is one of the traumatic complications and addressing the associated impediments is important to attain a wholesome treatment. Though various treatment methods have been employed, search for novel dressings are still on the rise to address factors such as promoting tissue regeneration, effective drug delivery, rapid wound closure and biodegradability. This review emphasizes the contribution of natural and synthetic polymers in standard and smart wound dressings. Through extensive study on the prognostic stages and the role of individual polymers, strategic management to alleviate the conditions of the challenging DFU could be made possible. Ó 2019 Elsevier Ltd. Peer-review under responsibility of the scientific committee of the Advanced Materials for Clean Energy and Health Applications (AMCEHA).

1. Introduction Foot Ulcer (FU) is one of the leading causes for severe mortality and morbidity in diabetic patients and the economic burden due to hospitalization associated with it is felt more in the developing countries [1,2]. Reports confer that in 2010, 285 millions had diabetes mellitus and it is likely to cross 360 million in 2030 [3]. The probability of such patients to develop FU during their life span is 15–25% and the risk of lower extremity amputations is 17–40 times greater in diabetic patients than their counterparts [4–7]. Increased number of male patients, obese individuals contributed the affected list [2,6]. It is also reported that one-third of the elderly diabetic individuals contract FU because of chronic sensorimotor neuropathy [5,8]. Impediments in foot arise in both type I and type II diabetic patients [2]. The prognostic stage of DFU is represented in Fig. 1. The clinical diagnosis includes the presence of exudates with a foul odor, accumulation of necrotic tissues and severe infection (aerobic and anaerobic) due to venous insufficiency and weakened cellular response. Early diagnosis prevents further prognosis of the conditions and helps render proper wound care [7,9,10]. In addition, recurring ulcers also pose worsening effects [2]. A multifaceted approach specifically glycemic control, debridement, appropriate contemporary dressing and off-loading systems ⇑ Corresponding author. E-mail address: [email protected] (E.J. Paul).

for treating DFU is mandatory along with the other adjunct therapies [2,3]. The pertinent dressing types are chosen based on the causes, wound site, wound margin, extent of penetration, presence of exudates and extent of infection. Further the choice extends to the maximum facilitation of repair, preventing microbial invasion and wound closure [2,6]. Changes resulting in the margin of the wound, planimetry of the wound area are to be assessed during the wound healing studies [9]. Several research have been carried out and numerous dressing materials have been proposed. Reports on other treatment modalities depicted in Fig. 2 are also studied extensively. Though hyperbaric oxygen therapy [11–13], electrical stimulation [14,15], negative pressure wound therapy [16–19], bioengineered skin and administering growth factors also are few of the proven adjunct therapies in treating DFU with ample evidences and is reviewed elsewhere [3,12,20–22]. Employing polymeric dressing on the other hand offers several advantages including mimicking of the extra cellular matrix (ECM) of the host, ability to achieve controlled drug delivery, rapid degradation rate, comfort, affordability and versatile [23]. The next generation treatment of DFU should include combinatorial effect to achieve wholesome rapid healing rate [24]. The smart and automated dressings and their components with passive and active drug release mechanisms have also been reviewed recently [25] and so are not in the scope here. This review focusses on the contribution of natural and synthetic polymeric materials [26–28], composite forms and the role of incorporating bioactive molecules such as growth factors [29],

https://doi.org/10.1016/j.matpr.2019.07.406 2214-7853/Ó 2019 Elsevier Ltd. Peer-review under responsibility of the scientific committee of the Advanced Materials for Clean Energy and Health Applications (AMCEHA).

Please cite this article as: E. J. Paul and B. Padmapriya, A pragmatic review on the property, role and significance of polymers in treating diabetic foot ulcer, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.07.406

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Fig. 1. The prognostic stages in DFU.

Fig. 2. Various Treatment Modalities for DFU.

Please cite this article as: E. J. Paul and B. Padmapriya, A pragmatic review on the property, role and significance of polymers in treating diabetic foot ulcer, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.07.406

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cytokines, chemokines, their properties [20,30–32] and delivery mechanisms in standard and smart wound dressing for diabetic ulcers. 2. Methods The study selection and data extraction were from reviews and trials from Cochrane library, American medical association, database of abstracts listed in NCBI site, Google scholar website and the bibliography of each of the identified articles with diabetes, diabetic ulcer, tissue engineering, diabetic foot ulcer, polymers in wound regeneration, polymers (natural, synthetic, composite) in DFU treatment, dressing materials for chronic wounds as the key words. 3. Sole of the foot and ulcer etiology The layers of the skin in the sole of the foot exhibits a distinct contrast from the thin skin present elsewhere in the body [33]. A non-invasive high frequency ultrasonography of the sole of the foot revealed that the skin in the sole of the foot is thick and hairless to adapt increased pressure and surface resistance. The histology of the sole discloses the presence of an additional layer of cells stratum lucidum surfacing between stratum granulosum and stratum corneum, the latter being thicker in the sole contributing to the mean increased epidermal thickness of 1.46 mm at the heel when compared to the thin skin epidermis. The epidermal layer region is adequately defined whereas the dermal – subcutaneous margin is poorly defined. Further massive eccrine sweat glands penetrate from epidermis to dermis, higher microvascularization with the pilosebaceous gland absent. The dermatoglyphics suggests that it requires water for its plasticity and collagen provides hydration. The hypodermal region is sparsely populated and is well vascularised containing areolar connective tissues and numerous adipose tissues, which act as shock and stress absorbers [34–36]. A DFU can be aptly defined as a chronic, non-healing wounds with irregular contours extending through the dermis below the ankle [25]. DU unlike other wounds pose multiple challenges including high exudate discharge, necrotic tissues, lack of gaseous exchange, impaired wound healing due to lack of angiogenesis, abnormal toe brachial index (TBI), higher infection on site, poor inflammatory

3

response, variations in pH and temperature [28,36–38]. Matrix metallo proteinase (MMP) 9, an endopeptidase also delays the wound healing process significantly [39]. Hence addressing these concerns are prime to attain wholesome treatment in DFU [40]. Various challenges to be addressed in treating DFU is represented in Fig. 3. 4. Polymer substitutes in wound dressing A team of plastic surgeons have accounted that not all the commercially available dermal matrices brings out similar clinical performance and it is very vital to study their role and benefits [41]. Polymer based skin substitutes have proven advantages of reducing the rate of morbidity [42]. Polymers can be broadly categorized into natural – collagen, gelatin, alginate, fibrin, keratin, albumin, gluten, elastin, fibroin, hyaluronic acid, cellulose, chitosan, pectin, galactan, gellan, levan, emulsan, pullulan, dextran, heparin, silk, chondroitin-6-sulphate, poly hydroxy alkanoates and synthetic – poly lactic acid (PLA), poly e-capro lactone (PCL), poly(lactic-coglycolic acid) (PLGA), poly glutaric acid (PGA), and polyurethanes (mainly from the polyester family). Their nature of interaction with the biomolecules are weak van der Waal’s interaction, hydrogen and covalent bonds (affects the drug delivery rate although provides stability) [26,43–46]. The choice of the polymeric forms at different stages of wound has been reviewed previously [45]. A list of commercial dressings with the various polymers/bioactives used with the possible wound healing mechanism is discussed in Table 1. Their rate of degradation depends on its design, hydrophilicity, processing parameters, co-polymerizing agents and molecular mass. In turn, the degraded products affect the compatability of the polymer [40,47–49]. Hence a cautious study on the choice of polymer is essential because the formation of new tissues and the marginal tissues are site specific. (See Table 2). 4.1. Natural polymeric forms 4.1.1. Collagen Collagen (Type I), the most abundant is a natural polymer and structural protein which provides elasticity, mechanical strength to bones, cartilages, tendon, ligament and skin and trigger angiogenesis. Collagen has been obtained from bovine, porcine and marine sources [28,50–52]. They are facilitated in various forms such

Fig. 3. Challenges to be addressed in a foot with DU.

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S. No.

Contemporary Dressing

Polymers/Bioactives Used

Proposed wound healing mechanism

Advantages

Disadvantages

Ref

1.

GraftJacket (Wright Medical Technology, Inc., USA) Integra (Integra Life Sciences Corp., USA)

Acellular premeshed human dermis

Promotes revascularization and cellular infiltration; Reduces inflammation

It offers a permanent cover at the wound site

Changing of dressings (1/day); To be used with a non-adherent dressing; Allergic against polysorbate 20

[21]

Dual Layer Acellular scaffold with bovine collagen, Chondroitin-6-sulfate, poly siloxane layer Acellular cadaveric dermis

Prevents shearing forces, minimizes development of hematoma and seroma

Very high engraftment rate and patient satisfaction, with no serious complication upto 3 year follow-up Injectable micronized version is also available

Several changing of dressings (15 times in place of 2–3 of DermACELL) required

[41,99,100]

Constraint by size, shape and mechanical strength; Allergic reactions against few antibiotics Cannot be a skin substitute because of the presence of nylon Preparation, evaluation of the dressing materials is complex Risk of infection; Several dressing changes (1–4/week) Allergic reactions against few antibiotics

[101–103]

2.

3.

AlloDerm (LifeCell Corporation, NJ)

4.

Biobrane (UDL Labs, USA) DermACELL (LifeNet Health, Inc., USA) EZ Derm (Brennen Medical, Inc., USA) GammaGraft (Promethean LifeSciences, Inc., USA) Pelnac (Gunze Ltd, Japan)

Acellular cadaveric dermis (Irradiated) template

Reduces immune response on site due to the absence of viable cells and their DNA Direct application of wound promotes reepithelialization Fibroblasts and vascular tissue proliferation on the template

Acellular Collagen sponge (Porcine) with silicone

Promotes infiltration of fibroblasts and revascularization

9.

OASIS Ultra (Cook Biotech Inc., USA)

Tri-layered acellular small intestine submucosal ECM (Porcine)

Delivers GFs and promote cell migration & angiogenesis

10.

45S5 Bioglass

PLGA incorporated Glass

11.

Terudermis (Olympus Terumo Biomaterial Corp., Japan) Promogran (KCL, Acelity, USA) Apligraf (Graftskin) Organogenesis Inc., USA Orcel (Ortec International, Inc., USA) Hyaff

Bovine collagen sponge adhering to silicone layer

Promotes hypoxia inducible factor (HIF) 1a, VEGF expression; stimulates revascularization; heals full thickness wound Promote cell migration & angiogenesis

5. 6. 7.

8.

12. 13.

14.

15. 16.

17.

18.

Hyalograft (Fidia Advanced Biopolymers, Italy) Laserskin (Fidia Advanced Biopolymers, Italy) (Vivoderm) Dermagraft (Advanced BioHealing, Inc.,

Acellular collagen (porcine) scaffold of silicone film and 3D nylon filament Acellular human dermis allograft Acellular collagen scaffold (porcine)

Matrix with collagen and oxidized regenerative cellulose Bilayered cellular scaffold with type I collagen (Bovine), human allogenic neonatal fibroblasts & keratinocytes Type-I bovine collagen sponge/neonatal allogenic fibroblasts/keratinocytes Semi permeable silicone layer with esters of HA HA scaffold with cultured fibroblasts

HA (Esterified) with autologous keratinocytes

Polyglactin scaffold with human neonatal fibroblasts from foreskin cultured (Biobrane seeded with neonatal fibroblasts)

Promotes angiogenesis and fibroblast infiltration in wounds Promotes infiltration of fibroblasts

Reduces activity of MMP, increases IL-1; release of GFs Effective migration of immune response, infiltration and proliferation Top non-porous collagen layerkeratinocytes & bottom porous collagen layer – fibroblast Promotes endogenic healing; mediates neoplasm of cells and angiogenesis Promotes proliferation, migration of TGFb, IL-6, 8, Hepatocyte (HGF) & Keratinocyte GF (KGF) Same as Hyalograft

Secretion of collagen, ECM proteins, GFs, cytokines on the scaffold

Risk of antigenicity and infection; Expensive Increased healing rate and wound closure Reduced healing time and pain Reduced antigenic response because it is acellular

[42,104,105] [41] [104,106] [100,103,107]

Infection rates cannot be controlled

[65,66,108]

Cross linking of matrix renders cytotoxic effects

[42,100,109,110]

Borate treated bioglass resulted in severe nephropathic issues

[111–113]

Can be treated for deeper burns; promotes regeneration; acts on trauma induced wounds

Same as OASIS Ultra

[95]

Rapid healing rate because less proteases and increased GFs Rapid healing rate; reduced risk of amputation; Improved cosmetic outcome Can be applied onto burn injuries; well tolerated with minimum irritation; faster wound healing Has been effective on dorsal hard-toheal ulcers Highly recommended when total off loading cast (TCC) cannot be used; Treats dorsal DFU. Scarless wound healing; Highly recommended suggested when TCC cannot be used.

Additional contact layer has to be made along with the matrix Effective treatment for epidermal and dermal full thickness ulcers only

[98,95]

Can act on acute burns and skin defects; skin grafted patients; patients with necrotizing fasciitis Faster healing, wound closure rate; reduce the activity of MMP and other endogenous proteases Faster healing rate

Rapid healing rate; Faster reepithelialization; Biocompatible

[22,24,98,114]

[98,115]

Skin grafts with tissue replacements to be made for lesser amputation; Allergic reactions towards few antibiotics Degree of resorption and esterification is different Cannot be a perfect skin substitute as a bilayered tissue graft

[21,100,103,107, 116,118,119]

Same as Hyalograft

[100,103,116]

15 times costlier than Biobrane

[3,42,98,120]

[116,117]

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Please cite this article as: E. J. Paul and B. Padmapriya, A pragmatic review on the property, role and significance of polymers in treating diabetic foot ulcer, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.07.406

Table 1 Polymers/bioactives used with the possible wound healing mechanisms in commercial dressings.

[130]

[95,129]

[126–128] AlloPatch (MTF, NJ)

TheraSkin (Soluble Systems, LLC, USA) Procellera

21.

22.

23.

EpiFix (MiMedx, GA) 20.

Single layer absorbent polyester with moisture activated microcell batteries (provides monophasic DC)

Broad spectrum antimicrobial protection; effective against biofilms

Healing rate is high even at elevated HbA1c levels Faster healing rate due to excess collagen Resistance development for antibiotics need not be dealt Allows infiltration of the tissues and remain a temporary graft Provides GFs, cytokines, human collagen

Wastage is more since no unique wound margin orientation Allergic reactions against few antibiotics Minor rashes and skin irritation

[115,123–125] Amniotic collagen are structural rigidity, ECM and bioactive cells promote superior healing rate Contains numerous ECM proteins, GFs, cytokines, and other specialty proteins

Dehydrated single layer epithelial cells scaffold with amniotic and chorionic membrane, non-vascular connective tissue matrix Aseptically processed human dermis (papillary and reticular portion) Human cadaveric ECM

[121–123]

Longer regeneration phase (almost 3 weeks) hence has to be used with dermal substitutes Skin grafts along with tissue replacements had to be made for lesser amputation rate Very low risk of rejection Serves as permanent skin replacement USA) (TransCyte) Epicel (Genzyme Biosurgery, USA) 19.

Autologous keratinocytes on petrolatum gauze

Ref Disadvantages Advantages Proposed wound healing mechanism Polymers/Bioactives Used Contemporary Dressing S. No.

Table 1 (continued)

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as sponge, foam, gel and as nanofibrous scaffolds using electrospinning and electrospraying techniques [53–55]. Collagen hydrogels promote absorption of wound exudate, controlled release of bioactive substances and aids in epithelialization. The scaffolds provide high porosity and help in migration and proliferation of keratinocytes and fibroblasts respectively at the wound site [45,49,51,56,57]. Reports have shown that seeding of fibroblasts, keratinocytes and GFs to the collagen sponge have accelerated the granulation and wound healing with minimum irritation [28,52]. Collagen peptides nano fabricated with poly3hydroxy butyrate-co-4-hydroxy butyrate showed increased cell proliferation and rapid wound closure apart from possessing higher wettability [58]. Cellulose-collagen matrix reduces the level and effect of MMPs and promote fibroblast proliferation and collagen deposition [59,60]. 4.1.2. Gelatin Gelatin aids in cell–cell adhesion and tissue migration. Instances with gelatin loaded microspheres crosslinked with tetracycline hydrochloride exhibited good stability, possessed mechanical property and was successful in sustained release of GFs for tissue regeneration [61–63]. Crosslinking of interleukin (IL) 8 and macrophage inflammatory protein-3a with the gelatin hydrogel exhibited rapid wound healing effects on diabetic rats by promoting neovascularization [30,44]. Gelatin – starch and borax crosslinked foams has been authenticated to possess mechanical stability and antimicrobial properties [64]. Collagen-gelatin sponges also have been reported to have reduced the time of repair and regeneration and could achieve sustained release of fibroblast growth factor (FGF) for over a period of ten days in animal models [65,66]. 4.1.3. Silk Electrospun silk fibres with alginate hydrogels incorporated with amniotic fluid was a biocompatible bioactive dressing which promoted cellular migration, proliferation and rapid wound healing property [67,68]. Green electrospinning of silk and manuka honey composite fibrous matrix was biocompatible and possessed anti-inflammatory and anti-bacterial characteristics apart from wound healing properties [68]. 4.1.4. Chitin/chitosan Chitin (b(1-) poly-N-acetyl-D- glucosamine) is the second most abundant polysaccharide and has been extensively studied for its wound healing property and various clinical applications including nano drug delivery carriers [61,69,70] as its structure resembles glycosaminoglycans (GAGs) of the ECM [27]. A dressing mat with chitin-chitosan-glucan was thermostable, anti-bacterial, cytocompatable and enhanced the wound healing rate [71]. The chitin/chitosan dressing though had better structural strength, did not remove exudate. Rather than chitin/chitosan, chitinoligosaccharides with poly vinyl alcohol (PVA) at definite ratios showed higher wound healing potential [72]. 4.1.5. Cellulose Cellulose aims at developing tougher materials and has improved biodegradability. Citric acid crosslinked with carboxy methyl cellulose (CMC) hybrid with poly ethylene glycol was described to be superaborbent, biodegradable and possessed high cell viablilty ration [73,74]. CMC hydrogel with ZnO impregnated mesporous silica exhibited high swelling ratio with good gaseous permeability, antimicrobial property and sustained drug delivery [56,75]. Micro cellulose regardless of the source, possess high tensile strength, water absorbing ability, crystallinity and offers a good dressing moiety. The microfibrils trap the platelets and GFs between them and so the epithelialization, granulation and the

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healing time has been faster when employed [76,77]. The presence of CMC in PVP hydrogels increased the sweeling ratio and stabilized the Ag nanoparticles thereby intensifying the reepithelialization and neovascularization processes [78].

pattern thus promoting high infiltration of tissues and rapid wound healing [94].

4.1.6. Hyaluronic acid (HA) A polysaccharide belonging to GAG family, HA has been studied extensively for its activity against necrosis, wound repair and healing [38,79,80]. HA-PVA with ampicillin has been cytocompatible, antimicrobial and absorbing wound dressing [79]. Cellulose nanocrystals-HA-gelatin dressing material was a spongy absorbent hydrogel which promoted adherence, growth and proliferation of fibroblast thereby aiding in wound closure [81]. Chitosan-HA sponge exhibited controlled release of vascular endothelial growth factor (VEGF) with enhanced swelling ratio. Further it was cytocompatible and biodegradable and promoted angiogenesis [82].

Probability of cell proliferation and regeneration is high when employing a suitable dressing material triad which contains a porous scaffold (cross-linked or modified) serving as a temporary substrate, an appropriate signaling biomolecule that regulates the synthesis of various proteins and growth factors (GFs) and appropriate cells derived either from the host or a synthetically prepared mimic [45]. The matrix of the scaffold primarily being biocompatible, aims to deliver these cells effectively and at high loading rate promote proliferation at the intended site without causing severe immune response [3,28,32,40]. The porosity of the substrate scaffold determines the extent of spreadability of the newly forming cells, the rate of permeation of drugs, infiltration, exudate removal and gaseous diffusion. Though highly porous structures yield poor mechanical strength, it is reported that fibroblast cells thrive better in the scaffold with 186–200 mm pore diameter and when the contact angle is between 50° and 70° [43]. Whereas, Gelatin coated PCL electrospun nanofiber when studied for the fibroblast proliferation, the optimal contact angle was 0° [95]. When alginate, an hydrophilic polymer and electrospun silk fibroin was used, the contact angle maintained was 28° and was still reduced when amniotic fluid was incorporated to the matrix and better spreadability of fibroblasts was achieved. A change in shape from round to spindle shaped fibroblasts was also observed in the latter trial [67].

4.2. Synthetic polymeric forms 4.2.1. Poly lactic acid (PLA) A wound patch dressing constituting of PLA with hyperbranched poly glycerol loaded with curcumin had high swelling and drug uptake ratio with controlled release properties. It was cytocompatible, promoting adhesion, proliferation of fibroblasts and promoted effective wound closure [83]. Chitosan-PLA-poly ethylene glycol (PEG)-glutamic acid (GA) hydrogel nanofibrous mat was exhibited to absorb wound exudate and permeable for gaseous exchange and promoted wound healing apart from being antibacterial [84]. 4.2.2. Poly e-caprolactone (PCL) PCL is an extensively studied wound dressing material owing to its various biomedical applications [38,85]. Insulin loaded with chitosan coated onto 1:1 collagen-PCL electrospun matrix when applied onto full thickness excision wound model exhibited 45% wound constriction in 14 days [86]. Chitosan nanoparticle-PCL nanofiber composite was non-cytotoxic and absorbed aqueous wound exudate and promoted fibroblast proliferation on the composite matrix aiding in wound closure [27]. Rate of degradation of PCL, a rubbery polymer which has got a high crystalline structure is slower (approx 2 years in vivo) because of the limited infiltration rate [47,87]. 4.2.3. Poly(lactic-co-glycolic acid) (PLGA) Lipid nanoparticles of composite fibrous PLGA-aloe vera extracts was demonstrated to possess improved wound healing by affecting FGF and the proliferation of fibroblasts [88]. PLGA-HA-chitosan electrospun composite nanofiber was an effective anti-bacterial, cytocompatible and promoted wound healing by allowing fibroblast adhesion and proliferation on its matrix both in vivo and in vitro [89]. PLGA-gelatin-epidermal growth factor (EGF) nanofibrous scaffold demonstrated sustained release pattern with blood clotting and platelet adhesion property [90]. Further fibroblast infiltration and higher gene expression for the synthesis of type I and III collagen was also observed thereby making it a desirable dressing material [90]. Hydrogel loaded with anti-oxidant compounds rendered effective anti-microbial property [91]. 4.2.4. Polyurethanes (PU) The hydrophilic poly urethane foam dressing membrane as an adjunct with proper management, debridement, antimicrobial, off-loading and vascularizing agents, demonstrated complete wound healing in 63.5% patients in a significantly less time [38,92,93]. Recombinant Human EGF-PU foams enhanced wound constriction by the expression of transforming growth factor (TGF), platelet derived growth factor and EGF in sustained release

5. Biopolymeric scaffolds

Table 2 Significance of Polymers in wound healing. Significance in wound healing

Choice of polymer

References

Re-epithelialization

CMC Collagen PVP CMC Gelatin HA PU Collagen Cellulose Collagen Silk HA PLA PCL PLGA PU Gelatin Gelatin PCL Gelatin Silk HA PLA PLGA Gelatin Cellulose PLGA Chitin/chitosan Collagen Chitin/chitosan Cellulose HA Gelatin Silk PVA HA Cellulose

[78] [52] [78] [78] [30,44] [82] [94] [28,52] [76,77] [51,57] [67,68] [81] [83] [27] [89] [94] [61–63] [30,44] [47,87] [64] [68] [79] [84] [90] [65,66] [56,75] [90] [61,69,70] [52] [71] [73,74] [79] [61–63] [67,68] [72] [38,79,80] [78]

Neo-vascularization and Angiogenesis

Granulation Proliferation of fibroblasts and keratinocytes

Cell-cell adhesion Mechanical stability Anti-microbial property

Sustained drug delivery

Drug delivery carriers Cytocompatability

Promoting migration of cells Aiding in wound closure Anti-necrotic Combat MMPs

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E.J. Paul, B Padmapriya / Materials Today: Proceedings xxx (xxxx) xxx Table 3 Wound Healing Markers and their Significance. Marker

Significance

Low

High

Severe

pH

Infection rate/Damaged Skin

–

Epidermal Damage

Temperature

–

Moisture

Local Blood Flow; Lymphocyte extravasation; Infection; Chronicity Capillary Injury/Exudate

Oxygen

Wound Healing Rate

Electrical Signal (Magnitude independent of wound size)

Cell Migration and Healing

Colonization/Angiogenesis, Fibrosis Higher Vascularization; Proliferation Angiogenesis (Controversy); Wound Healing Raw wound

Infection & Biofilm formation Infection/Wound Healing Lead to infection

6. Smart/automated dressings Wound healing process is complex and physiological process of the environment varies over a period of time between patients. In such cases, parameters such as temperature, pH, enzyme concentration, moisture, oxygen, mechanical stability and electrical signals can act as markers for the healing process [25]. Assessing variations in these and timely addressing will help check the prognosis of DFU and thereby the cost associated with it. Incorporation of sensors in wound management is an effective technique to monitor the disease conditions provided they conform to the contours of the wound bed. Inference from the sensors about the wound status is tabulated in Table 3. The release of drug from such a dressing can be passive or active. Sensor based dressings offer several advantages including close monitoring of the healing status and decision making process concerned and achieve sustained drug delivery. On the other hand, they are prone to corrode due to the varying pH, proteins and enzyme concentration which may affect the sensitivity and compatibility [25,96]. 7. Concluding remarks and discussion Though lowering and maintaining the glycosylated hemoglobin (HbA1C) levels to below 7% has resulted in decreased microvascular complications, neuropathy and peripheral arterial disease in most of the reports [97], it is vital to manage and treat the DFU already incurred. An ideal dressing material ought to provide adequate moisture, regulation of endogenous protease, stimulation of growth factors, anti-microbial activity, permeable to gaseous exchange, promote autolytic debridement thereby infiltration of granulation tissues and re-epithelialization [3]. Technological advancements in the physical, chemical and morphological nature of polymeric dressing materials, ability to incorporate cellular factors and the associated cellular responses, intended drug release patterns are effective milestones attained in treating the chronic hard-to-heal DFU with the polymers. Polymeric hydrogels have proven to be superior in providing ideal conditions for rapid wound healing such as moistening, absorption of exudates, controlled delivery achievement. Collagen, mimicking the ECM closely supplemented with cellulose is a viable polymeric form of epithelial wound dressing. Incorporating collagen alone or in combination in the wound dressing of any form has been found superior in healing the DFU and hence has to be taken into account to achieve healing. Further in order to increase the stability, thermal and mechanical properties physical cross linking can be carried out. TCC treated as the gold standard treatment for DFU should not be neglected by the podiatrists and patients and should be prescribed along with the dressings received [98]. Patient specific approach on the wound filling can be essentially considered after extensive study on the occurrence, prognosis, severity and the cellular responses observed to strategically manage the challenging etiology of the DFU. Inclusion of flexible sensors technology with polymer substrates as the dressing material

Slower remodelling Angiogenesis (Controversy) Moderate – Healing wound

– –

for accurate and timely diagnosis of healing status of the wound and sustained delivery of the drug through active or passive means is a challenge to be addressed. Acknowledgements The financial support extended by the All India Council for Technical Education, India to Esther Jemima Paul, a National Doctoral Fellow, is gratefully acknowledged. The authors thank the management of PSG College of Technology for the support and the facility rendered. References [1] W.H. Organization. Global report on diabetes, 2016. [2] A. Trikkalinou, A.K. Papazafiropoulou, A. Melidonis, Type 2 diabetes and quality of life, World J. Diabetes 8 (2017) 120. [3] L. Yazdanpanah, M. Nasiri, S. Adarvishi, Literature review on the management of diabetic foot ulcer, World J. Diabetes 6 (2015) 37. [4] N. Singh, D.G. Armstrong, B.A. Lipsky, Preventing foot ulcers in patients with diabetes, JAMA 293 (2005) 217–228. [5] J.F. Guest, G.W. Fuller, P. Vowden, Diabetic foot ulcer management in clinical practice in the UK: costs and outcomes, Int. Wound J. 15 (2018) 43–52. [6] A.S. Fard, M. Esmaelzadeh, B. Larijani, Assessment and treatment of diabetic foot ulcer, Int. J. Clin. Pract. 61 (2007) 1931–1938. [7] A. Spichler, B.L. Hurwitz, D.G. Armstrong, B.A. Lipsky, Microbiology of diabetic foot infections: from Louis Pasteur to ‘crime scene investigation’, BMC Med. 13 (2015) 2. [8] M. Edmonds, Diabetic foot ulcers, Drugs 66 (2006) 913–929. [9] N. Schaper, Diabetic foot ulcer classification system for research purposes: a progress report on criteria for including patients in research studies, Diabetes/Metab. Res. Rev. 20 (2004) S90–S95. [10] M.S. Bader, Diabetic foot infection, Am. Fam. Physician 78 (2008) 71–79. [11] P. Kranke, M.H. Bennett, M. Martyn-St James, A. Schnabel, S.E. Debus, S. Weibel, Hyperbaric oxygen therapy for chronic wounds, Cochrane Database Syst. Rev. (2015). [12] C.-Y. Chen, R.-W. Wu, M.-C. Hsu, C.-J. Hsieh, M.-C. Chou, Adjunctive hyperbaric oxygen therapy for healing of chronic diabetic foot ulcers, J. Wound Ostomy Continence Nurs. 44 (2017) 536–545. [13] W.J. Ennis, E.T. Huang, H. Gordon, Impact of hyperbaric oxygen on more advanced wagner grades 3 and 4 diabetic foot ulcers: matching therapy to specific wound conditions, Adv. Wound Care 7 (2018) 397–407. [14] P.G. Wirsing, A.D. Habrom, T.M. Zehnder, S. Friedli, M. Blatti, Wireless micro current stimulation–an innovative electrical stimulation method for the treatment of patients with leg and diabetic foot ulcers, Int. Wound J. 12 (2015) 693–698. [15] Y. Turan, B.M. Ertugrul, B.A. Lipsky, K. Bayraktar, Does physical therapy and rehabilitation improve outcomes for diabetic foot ulcers?, World J Exp. Med. 5 (2015) 130. [16] M.K. Imran, P. Sreeramulu, C. Shashirekha, P. Dave, Efficacy of negative pressure wound therapy using suction drain in the management of chronic wounds, Int. Surg. J. 5 (2018) 2256–2263. [17] M. Meloni, V. Izzo, E. Vainieri, L. Giurato, V. Ruotolo, L. Uccioli, Management of negative pressure wound therapy in the treatment of diabetic foot ulcers, World J. Orthopedics 6 (2015) 387. [18] Z. Liu, J.C. Dumville, R.J. Hinchliffe, N. Cullum, F. Game, N. Stubbs, et al., Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus, Cochrane Database Syst. Rev. (2018). [19] S. Liu, C-z He, Y-t Cai, Q-p Xing, Y-z Guo, Z-l Chen, et al., Evaluation of negative-pressure wound therapy for patients with diabetic foot ulcers: systematic review and meta-analysis, Therapeutics Clin. Risk Manage. 13 (2017) 533. [20] H. Cho, M.R. Blatchley, E.J. Duh, S. Gerecht, Acellular and cellular approaches to improve diabetic wound healing, Adv. Drug Deliv. Rev. (2018). [21] Der Hautschaden FT. Advanced Therapies of Skin Injuries.

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Please cite this article as: E. J. Paul and B. Padmapriya, A pragmatic review on the property, role and significance of polymers in treating diabetic foot ulcer, Materials Today: Proceedings, https://doi.org/10.1016/j.matpr.2019.07.406