Microparticulate polymers and hydrogels for wound healing

Microparticulate polymers and hydrogels for wound healing

10

R. Ghadi1, A. Jain1, W. Khan1, A.J. Domb2 1National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India; 2The Hebrew University of Jerusalem and Jerusalem College of Engineering (JCE), Jerusalem, Israel

  

10.1  Introduction According to the Wound Healing Society, a wound is the consequence of disruption of the normal anatomic structure and function of a tissue. A dermal wound is defined as a disruption in the integrity of the skin, raised due to an external or internal harmful stimulus, which leads to an inadequate performance of the skin functions. It is therefore vital to reinstate skin integrity and consequently its functions as early as possible [1]. Wound healing is a dynamic interactive response to tissue injury that involves complex interactions of various resident cells and infiltrating leucocyte subtypes, extracellular matrix (ECM) molecules and soluble mediators. Wound healing progresses through a series of interdependent and overlapping stages with the primary aim to re-establish the integrity of damaged tissue and replacement of lost tissue [2]. Acute wounds heal in a very orderly and efficient manner characterized by four phases: haemostasis, inflammation, cell migration/proliferation and maturation (remodelling). A chronic wound arises after disruption of the acute wound healing process in one or more of its phases, impairing the re-establishment of anatomical and functional integrity of the affected tissue in a physiologically appropriate length of time. Multiple systemic diseases and topical factors can inhibit mechanisms of normal wound repair, which may lead to chronic nonhealing wounds [3]. Health care professionals face an increasing number of patients suffering from wounds which are difficult to treat and heal. Wounds may require diverse approaches to treat because of the erraticism in the type and degree of damage. Several dressings have been used for delivering drugs to acute and chronic wounds. These dressings could be classified in many ways, depending on the type of material used for healing [4] and the type of wound and physical state of dressings [5]. Active ingredients (antimicrobials, growth factors or other supplements) could be incorporated into medicated dressing which will be useful in wound healing either directly or indirectly [6]. Apart from incorporating drugs in the dressings, several pharmacological agents have been given by systemic route, locally or both to inhibit microbial growth or to improve the wound healing process. These agents include antibiotics [7], gene therapy and

Wound Healing Biomaterials - Volume 2. http://dx.doi.org/10.1016/B978-1-78242-456-7.00010-6 Copyright © 2016 Elsevier Ltd. All rights reserved.

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cytokines [8], growth factors [9–11], stem cells [12] and other drugs such as antioxidants [13], antihistamines [14], isoniazid [15], phenytoin [16], antisense gel [17] and traditional drugs [18]. Traditional treatment of open wounds engaged natural or synthetic bandages such as cotton wool, lint and gauzes with the primary function to keep the wound dry by allowing evaporation of wound exudate and prevention of the entry of harmful bacteria into the wound. Findings show that a warm, moist wound environment with proper wound healing material can achieve more rapid and successful wound healing; hence, polymer- and hydrogel-based wound dressings have become popular [6]. Hydrogel, a network of hydrophilic polymer chains with water dispersed inside the network, provides an excellent system for wound healing [19]. Polymers, be they from natural origin, such as polysaccharides [20–23], proteoglycans [24] and proteins [25] or from synthetic origins (polyglycolic acid [PGA], polylactic acid [PLA], polyacrylic acid, poly-ε-caprolactone, polyvinyl pyrrolidone [PVP], polyvinyl alcohol [PVA] and polyethylene glycol [PEG]) have exhibited in vitro and in vivo wound healing properties with enhanced epithelialization and display hydrogel-forming ability [26–29]. Micro- and nanoparticulate delivery systems designed with these polymers have also been reported for wound healing [30–34]. Furthermore, delivering polystyrene particles (5 μm) to the wound surface to induce an inflammatory response that enhances wound healing is a successful concept [35]. This chapter gives an overview on various polymers and hydrogels for wound healing, with recent advancement in terms of clinical trials, patents and marketed products. The different novel micro- and nanoparticulate delivery systems based on these polymers and hydrogels are also discussed. Finally, the chapter gives insight on the trends in wound healing dressings and materials which will help wound management in getting a new direction.

10.2  Wound management Effective wound management depends on the understanding of several different factors such as the underlying mechanism of wound formation, the type of wound, the healing process and the general condition of a patient in terms of health (eg, diabetes, advanced age). In addition to ensuring proper diagnosis of the wound, it is important to provide a favourable environment at the surface of the wound in which healing can take place in combination with a proper treatment strategy [5,6]. The presence of necrotic tissue or foreign material in a wound increases the risk of infection and sepsis. It also prolongs the inflammatory phase, which inhibits wound healing. It is therefore important to remove necrotic tissue or foreign material from areas around the wound using scalpel and scissors; hydrotherapy or wound irrigation and autolytic removal by rehydration of necrotic tissue; and enzymatic removal using bacterially derived collagenase, papain, fibrinolysin/DNAse, trypsin, streptokinase-streptodornase and subtilisin. There has been a resurgence of the ancient use of maggots. These insect larvae are now laboratory bred under aseptic conditions. In addition to removing necrotic tissue,

Microparticulate polymers and hydrogels for wound healing

205

maggots disinfect wounds by killing bacteria and also stimulate faster wound healing, especially in chronic wounds. It has been suggested that maggots also stimulate the production of granulation tissue [6,36]. Furthermore, depending on the wound type, its cause and position on the body, one or combination of several treatment options are involved: topical application of antibiotics, antiseptics or both; multiple dressing changes per day; and costly treatments involving the application of local mechanical stresses or energy to a wound such as – negative pressure wound therapy and mist ultrasound therapy [37,38]. Compared to the above-described physical methods for wound management, the use of modern polymer-based and hydrogel-based dressing materials is cheaper. Natural polymers or biopolymers such as polysaccharides, proteoglycans and proteins are extensively used in wound management because of their biocompatibility, biodegradability and similarity to macromolecules recognized by the human body. Similarly, some synthetic polymers obtained by the electrospinning technique, such as biomimetic ECM micro- and nanoscale fibres based on PGA, PLA, polyacrylic acid, poly-ε-caprolactone, PVP, PVA and PEG, exhibit in vivo and in vitro wound healing properties [39–43]. They provide a favourable microenvironment for cell proliferation, migration and differentiation, due to their biocompatibility, biodegradability, peculiar structure and good mechanical properties. Natural polymers show a relatively low mechanical strength compared to synthetic polymers. By cross-linking or blending with synthetic polymers, the mechanical properties of natural polymers are improved [44–47]. Both synthetic polymers and biopolymers are easily processed into the desired shape and design and stabilized using different techniques for extended shelf life. In addition, hydrogel-based dressings made from different polymers may be used as drug carriers [48].

10.3  Hydrogel- and polymer-based dressings for wound healing Hydrogels are three-dimensional hydrophilic polymer networks capable of swelling in water or biological fluids and retaining a large amount of fluids in the swollen state. The water content in equilibrium of swelling affects different properties of the hydrogels such as permeability, mechanical and surface properties, and biocompatibility. The value of hydrogels as biomaterials lies in the similarity of their physical properties to those of living tissues. This resemblance is based on their water content, soft and rubbery consistency and low interfacial tension with water or biological fluids [19,49]. Hydrogels aid wound healing because they create a permanent moist medium in the wound, thereby maintaining cellular activity. Rehydration of the wound bed softens and detaches the necrotic tissue, assists granulation tissue formation and facilitates epithelialization [50]. Furthermore, some hydrogels are capable of absorbing exudate. Simultaneously, this type of dressing does not adhere to the wound, which is an advantage for the patient. Similarly, hydrogels prevent bacterial contamination of the wounds, being able to even incorporate antibiotics. They are permeable to oxygen

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[6,51]. It has been observed that the placing of hydrogel frequently results in marked reduction in pain response. It is suggested that the high humidity protects the exposed neurons from dehydration and also produces acceptable changes in pH. A cooling effect lasting for up to 6 h, may contribute to analgesia. To attain satisfactory conditions at the wound site, the dressing should possess a suitable water vapour transmission rate. Studies conducted with experimental animals confirm that wound dressing based on hydrogels induced a significantly enhanced healing rate in the impaired wound [21,27,47,52]. The commercial hydrogel-type dressings are characterized by high water content, greater than 90% in weight in some cases (Table 10.1). There is a wide variety in terms of composition; they consist of carboxymethyl cellulose (CMC), polyurethane, polyacrylate, polyacrylamide, agar, cross-linked polymer derived from acrylates substituted with groups of amine and nitrile, chitosan and PVP, as well as with derivatives of hyaluronic acid (HA) with or without alginates. Other wound dressings consist of cross-linked hydrogels formed from blends of PVP with PEG and agar. PVA and PVP blended hydrogels, as well as PEO and PEO/PVA blend hydrogels for wound dressings, have also been prepared [53].

10.4  Natural polymers for wound healing Natural polymers are widely used in the regenerative medicine field for wound dressing because of their biocompatibility, biodegradability and similarity to the ECM. Natural polymers are involved in the repair of damaged tissues by inducing and stimulating the wound healing process [54]. Biomaterial hydrogels are used in the pharmaceutical and biomedical area, especially for wound management, tissue engineering, drug delivery and organ transplant due to their three-dimensional cross-linked polymeric networks that are soaked with water or biological fluids [55]. In addition, novel biomaterials based on renewable, nontoxic and biodegradable natural polymers are obtained through radiation processing. Hydrogels containing cross-linked natural polymers can therefore be used for wound management [56].

10.4.1  Polysaccharides Some polysaccharides are extensively used for the management of wounds when administered in the form of hydrogels: neutral (cellulose, dextran, β-glucan), acidic (alginic acid, HA), basic (chitin, chitosan) or sulphated polysaccharides (chondroitin sulphte, dermatan sulphate, heparin, keratan sulphate). The various polysaccharides which are used in wound healing are described in Table 10.2.

10.4.2  Glycosaminoglycans Glycosaminoglycans (GAGs) are important components of ECMs, essential to bone and skin regeneration. According to the structure (polymer length, degree of sulphation), they modulate the attraction of skin and bone precursor cells. Their potential in

Nonexhaustive list of clinically used hydrogel wound dressings

Product (manufacturer)

Main constituents

Main characteristics

Aquaflo (Covidien)

PEG and propylene glycol

Granugel (Convatec)

Pectin, CMC and propylene glycol

Intrasite gel (Smith & Nephew)

Modified CMC (2.3%) and propylene glycol (20%) Sterile hydrogel formulation of preserved PVP Sodium CMC, calcium alginate and more than 90% of water

Unique disc shape that maximizes wound coverage and helps to fill shallow cavities. Translucent gel that allows wound visualization. A clear, viscous hydrogel for the management of partial- and full-thickness wounds. May be used as a filler for dry cavity wounds to provide a moist healing environment. Amorphous sterile hydrogel dressing for use in shallow and deep open wounds. Indicated for dry, light and moderately exuding partial- and full-thickness wounds, except for third-degree burns. Indicated for dry and sloughy necrotic wounds, as well as wounds with a mix of necrotic and granulated tissue such as leg ulcers, pressure ulcers, noninfected diabetic foot ulcers and first- and second-degree burns. Can be used throughout the healing process to provide a moist healing environment. Dressing contains a superabsorbent polymeric gel able to absorb bacteria and retain them in its structure. Described as a wound ‘kick-starter’ patch for chronic wounds, it can also be used as a secondary absorbent.

Nu-gel (Systagenix) Purilon gel (Coloplast)

Woundtab (First water)

Sulphonated copolymer, CMC, glycerol and water

Microparticulate polymers and hydrogels for wound healing

Table 10.1 

207

Polysaccharides used in wound healing dressings in alphabetical order

Polysaccharide

Description

Agar and agarose

• Smooth

Alginates

Carrageenan

Cellulose

Chitin and chitosan

α-Glucans β-Glucans

Wound Healing Biomaterials

Dextrans

and homogeneous agarose fibres have a very important water swelling capacity (400–500%) and tensile strength (30–50 MPa) • Geliperm® hydrogel provides optimal physiological conditions for wound healing. The hydrogel in granular form represents a coherent material which could be used in deep fissured wounds and for the treatment of injuries with a large amount of exudation and contamination [57] • Alginate-based wound dressings are commonly used for their haemostatic properties in exudation/bleeding wounds and burns • Alginate can absorb water/body fluids up to 20 times its weight; during this process, resulting hydrophilic gel provides a moist wound healing environment [48] • PVP-kappa carrageenan hydrogel could absorb the fluid effectively, exhibit high elasticity, be pleasant in touch and painless on removal and also had good mechanical strength and good transparency, allowing observation of the healing process [58] • Microbial cellulose biosynthesized in high amounts by Acetobacter xylinum (Acetobacteraceae), used as a wound healing scaffold for severely damaged skin and for small-diameter blood vessel replacement [61−65] • Porous nanofibrous bacterial nanocellulose membranes could be used for tissue repairing and remodelling or for large area skin transplantation [66–68] • β-Chitin/nanosilver composite scaffolds were developed for wound healing applications using β-chitin hydrogel with silver nanoparticles; the scaffolds were bactericidal against Escherichia coli and Staphylococcus aureus and showed good blood clotting ability as well [59] • Microporous chitosan hydrogel-nanofibrin composite bandage for skin tissue regeneration [60] • Carboxymethyl benzyl amide sulfonate dextran, a soluble polymer structurally similar to glycosaminoglycan heparin, stimulates wound healing in various in vivo experimental models; controls the proliferation of S. aureus biofilm; and affects proliferation and metabolism of tumour cells, smooth muscle cells and endothelial cells [69] • A superabsorbent hydrogel based on pullulan derivate as antibacterial release wound dressing • Remarkable water absorption property (swelling ratio up to 4000%) • Offered quick haemostatic ability and prevention of the wound bed dehydration [34] • Highly purified yeast-derived insoluble β(1 → 3)-d-glucan (glucan #300) strongly inhibited adipogenic differentiation, supported wound healing and significantly lowered skin irritation [70,71]

208

Table 10.2 

Microparticulate polymers and hydrogels for wound healing

209

tissue engineering for wounds and burns is well known. HA is a naturally occurring non-immunogenic linear polysaccharide made from N-acetyl-d-glucosamine and glucuronic acid. It exhibits remarkable effects in scar-free wound healing, supporting angiogenesis and neurite outgrowth/repair. Directing tissue regeneration has been achieved using HA hydrogel scaffolds. Cross-linked HA hydrogel films have been produced for the use as polymeric drug delivery platforms with improved exploitation characteristics. HA and silver sulfadiazine–impregnated polyurethane foams are used for wound dressing applications [72]. Chondroitin sulphate is an important structural component of cartilage. Materials made from this GAG are biocompatible and nonimmunogenic. Chondroitin sulphate acts as a surrogate ECM, serving as a repository for cytokines and growth factors, important bioentities for the healing process, and they provide structural frameworks for fibroblasts during epithelial regeneration [73,74]. Heparin-coated aligned nanofibers increased endothelial cell infiltration in threedimensional scaffolds and tissue remodelling in vitro and in vivo, in full-thickness dermal wound models. Heparin was also incorporated into noncovalently assembled, polymeric hydrogel networks based on its interactions with known heparin-­interacting peptides and proteins. PEG star polymers functionalized with heparin-binding peptide motifs have been reported to assemble with heparin into viscoelastic solutions with tuneable properties. These can also be mixed with star-PEG-heparin conjugates to form noncovalent hydrogels capable of growth factor delivery via hydrogel erosion. Such erosion strategies, although passive, may offer opportunities to modulate growth factor activity via co-release of the growth factor with heparinized macromolecules [75].

10.4.3  Proteins and peptides Among proteins, collagen and hydrolysate derivatives (ie, gelatins) show vast potential for efficient wound treatment as dressings and drug delivery systems. Collagen is the most abundant protein in the human body and in the skin. It is primarily produced by fibroblasts and other connective tissue cells. Collagen dressings formulated from bovine, porcine or avian sources are recommended for the treatment of partial-thickness and full-thickness wounds with minimal-to-moderate exudation. It is contraindicated for third-degree skin burns and for sensitive/allergic patients. There are numerous studies concerning the application of different collagen dressing formulations for wound healing: collagen sponges in the healing of experimental deep skin wounds [76,77] and collagen-alginic acid cross-linked thermostable and biodegradable biopolymer as a wound dressing material [78]. Similarly, collagen-minocycline–based hydrogels potentially applicable for the treatment of cutaneous wound infections have been explored [79]. The biological half-life and mechanical properties of collagen can be increased by glutaraldehyde cross-linking, which reduces the collagen material immunogenicity and enzymatic susceptibility. Gelatin is a natural polymer derived from collagen. In the biomedical field gelatin is used for the production of biocompatible and biodegradable drug delivery systems and wound dressings. Pectin/gelatin-based hydrogel membranes were developed by

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solution casting method and cross-linked with glutaraldehyde. Characterization and evaluation of hydrogel membranes reveal that the swelling percentage is more than 100%, which confirms that hydrogels are superabsorbent in nature. Water vapour transmission rate analysis shows the moisture retentive nature of the membranes. Hydrogels are also cytocompatible. Thus, the blend membrane has proven to be a successful application in moist wound dressing applications [80]. Biopolymers are efficient in the tissue repair processes only to a certain extent, being limited in interactions at the molecular level with wound pathogens. These natural macromolecules have attracted attention as dressing materials due to their biodegradability, where material degradation and the new tissue formation should be parallel processes (normally the case in the treatment of acute wounds). The situation with chronic wounds is more complicated due to low stability of these biomaterials in contact with the fluids containing elevated levels of hydrolytic enzymes; eg, lysozyme cleaves chitosan-based materials [81], whereas collagen is a natural substrate of several matrix metalloproteinases. Moreover, the use of biopolymers in wound management has not yet been clearly translated into a platform for widespread clinical use.

10.5  Synthetic polymers for wound healing Hydrogels in their swollen state exhibit weak mechanical strength; hence, they are unsuitable for application under load. To overcome this problem the mechanical properties can be, in principle, increased by developing hydrogels with stronger polymer network, such as synthetic polyurethane block copolymer, polyacrylate and polyacrylamide. Synthetic polymers show a superior mechanical strength compared to natural macromolecules; thus, by their cross-linking or blending, the mechanical properties of the natural macromolecules are improved. Synthetic polymers are used mainly as platforms for actuation and delivery of active agents, but they also provide an optimal microenvironment for cell proliferation, migration and differentiation when used in dressings and biosynthetic skin grafts. Biodegradability of synthetic polymers is desired when localized delivery of active compounds from temporary dressings/templates is required. Besides functionalization with both organic and inorganic active agents, synthetic polymers are often used in a combination with biopolymers and further processed in different dressing designs [48]. Features of some of the most used synthetic polymers in wound healing are summarized below. Polyurethanes (PUs) are copolymers with repetitive urethane groups in their structures. This class of synthetic polymers has gained receipt in the biomedical field due to exceptional strength and biocompatibility. The physical properties of PUs vary from brittle to very elastic. Biomedically acceptable PUs are nontoxic and have elastomeric properties accompanied by good toughness, tear resistance and abrasion resistance. Such materials favour epithelialization during wound healing. PUs possess good barrier properties and oxygen permeability. It has been studied extensively as a material for wound dressing [82].

Microparticulate polymers and hydrogels for wound healing

211

PVA hydrogels have been prepared for wound dressing application by freeze-thawing because of their desirable clinical features. PVA possesses desirable properties such as nontoxicity, biocompatibility and high hydrophilicity; relatively easier film-forming ability and chemical and mechanical resistance. The importance of the polymer blending with PVA has increased due to blended polymeric materials that have desired and improved physical properties, such as the low cost of basic polymer materials, enhanced processing of film formation and biological acceptability. Accordingly, some blended polymers have been used with PVA to improve the clinical properties of obtained polymeric membranes for wound dressing applications, such as alginate, dextran and chitosan [83]. PVP is a well-known polymer with good biocompatibility; hence, it can be used as one of the main components of hydrogel preparations for temporary skin covers or wound dressings. PVP is used in the production of medicines, and it serves as a blood substitute and blood detoxifier. PVP hydrogel itself does not exhibit good swelling properties, but when blended with polysaccharides such as CMC, chitosan or other polysaccharides such as agar or alginate, the swelling properties improve [19]. PVP is an excellent binder for active agents to dressing materials [84].

10.6  Micro- and nanoparticulate delivery systems in wound healing The mechanism for the controlled delivery of drugs from polymeric dressings must be considered. Effective dressings should have properties and delivery characteristics that are optimized for specific wound types with minimal or no inconvenience to the patient and at reasonable cost. To achieve such objectives, manipulation of the physical characteristics of the identified systems is necessary. As with any new product, often the race to introduction into clinical use precedes adequate controlled study, and efficacy is defined by clinical experience. Various attempts have been made in these contexts as discussed in the following. • Genta et al. evaluated the wound healing properties of chitosan microspheres in vivo and concluded that the chitosan microspheres may have wound healing properties [85]. • Kawai et al. evaluated the effect of incorporating basic fibroblast growth factor (FGF)– impregnated gelatin microspheres into an artificial dermis in guinea pig full-thickness excision wounds. They concluded that the efficacy of FGF was improved when incorporated into gelatin microspheres compared with free FGF. The positive effects were attributed to the sustained release achieved by the gelatin microspheres [86]. • Lee et al. studied a laminin-modified composite collagen membrane containing silver sulfadiazine (AgSD)-HA microparticles. The AgSD-HA microparticles were incorporated into two outer collagen layers at 50 mg/cm2. The composite collagen membrane dressing lowered inflammation, increased vessel proliferation and reduced wound size compared with the PU film control [87]. • Yerushalmi et al. carried out molecular and cellular studies of HA-modified liposomes as bioadhesive carriers for delivery of drugs to wounds. HA was bound to the surface of the liposomes by carbodiimide. It was concluded that the HA-modified liposomes act as site-adherent depots [88].

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• Thomas et al. investigated Ag nanoparticle formation within poly(acrylamide-co-acrylic acid) hydrogels. The antibacterial potency against E. coli increased with the concentration of AgNO3 used in the composite hydrogel synthesis and the acrylic acid content because negatively charged acrylic acid promoted Ag+ binding and Ag nanoparticles nucleation, and with decreasing composite hydrogel size, which represents a larger surface area [89]. Similarly, Travan et al. investigated the formation and stabilization of Ag nanoparticles in chitosan-derived hydrogels. They found a potent antimicrobial effect against Gram-positive and Gram-negative bacteria, but low eukaryotic cell toxicity [90]. Along the same line, Sahiner et al. prepared hydrogel particles by emulsion polymerization of 4-vinylpyridine. Although the hydrogel particles themselves displayed modest antibacterial activity on S. aureus, Pseudomonas aeruginosa, Bacillus subtilis and E. coli, incorporation of either Ag or Cu nanoparticles substantially increased antibacterial potency [91]. • For the treatment of severely painful skin wounds, topically applied morphine is an option. Heilmann et al. prepared Poloxamer 407 (25%) hydrogel for sustained release and percutaneous absorption of the opioid. Due to the sustained release the number of painful dressing changes and need for systemic opioids could be reduced [92]. •  Gong et al. prepared curcumin-loaded micelles into thermosensitive poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) hydrogel composite (Cur-M-H). The Cur-M-H composite was converted into a gel at body temperature, adhered to the tissue and released curcumin over an extended period. The antioxidant bioactivity of curcumin in linear incisions and excisional wounds in rats could be demonstrated only when incorporated into the composite. The Cur-M-H dressing also improved several wound healing characteristics compared with the controls. Overall, the results suggest that the in situ gel-forming composite with curcumin is a potential wound dressing [93]. • Rutin is a flavonol with antioxidant and cytoprotective effects. Rutin was released in a sustained manner when conjugated to a chitosan-poly(ethylene glycol)-tyramine hydrogel that stimulated fibroblast proliferation and collagen production. The hydrogel was tested in 8-mm excisional wounds in five rats [94].

10.7  Hydrogel/polymer-based wound healing dressings in the market More than 3000 dressing types overwhelm the wound management market. The characteristics of the various types of dressings depend on the intrinsic properties of the polymers used for their preparation. The resulting products may be used individually or in combination to absorb exudate, combat odour and infection, relieve pain, promote autolytic debridement and/or provide and maintain a moist environment at the wound surface. A wide range of polymer-based materials are available to match particular wound requirements. Unfortunately, no single dressing can accomplish all these goals. Thus, the selection of the appropriate dressing to a specific wound type is a difficult task and depends on factors related to the product itself, the patient’s health status, wound type and location and economic considerations. Modern wound dressings frequently include a combination of polymeric layers with different functions that provide particular characteristics to the dressing. Table 10.3 presents an overview of the most frequent hydrogel/polymer-based wound dressings available.

Microparticulate polymers and hydrogels for wound healing

213

Table 10.3 

Hydrogel- and polymer-based commercial wound dressings in alphabetical order within each dressing category Wound dressings

Commercial name

Manufacturer

Polymer

Hydrogels

Aquafloa

Covidien

Aquaform Bionect Carrasyn Hydrogel Curasol Flexigel Granugela Intrasite gela Nu-gela Purilon gela Regranex gel Sterigel Tegaderm Bioclusive Blisterfilm Cutifilm C-View Flexipore Mepore

Robert Bailey Dara Carrington Healthpoint Smith & Nephew Convatec Smith & Nephew Johnson & Johnson Coloplast Smith & Nephew Seton 3M Healthcare Systagenix Covidien Smith & Nephew Aspen Medical Activeheal

Polyoxyethylene glycol Propylene glycol Biosciences HA Acemannan

OpSite plus Polyskin II Release Skintact Cica-Care Mepiform Mepilex BGC matrix

Smith & Nephew Covidien Johnson & Johnson Robinson Smith & Nephew Mölnlycke Health Care Mölnlycke Health Care Brennan Medical

Biopad Biostep collagen matrix Cellerate RX gel

Angelini Pharma Smith & Nephew

Polymer films

Silicone

Collagen

aProducts

described in detail in Table 10.1.

Wound Care Innovations

CMC Sodium alginate CMC CMC Hemicellulose Guar gum Polyurethane Polyurethane Polyurethane Polyurethane Mölnlycke Health Care Viscose (cellulose) xanthane Polyurethane Ethyl-methyl acrylate Silicone Silicone Silicone Collagen and β-glucan Type I collagen Collagen Type I collagen

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10.8  Clinical trials and patents related to hydrogel/ polymer-based wound dressings Table 10.4 gives an insight on the various clinical trials conducted. Table 10.5 gives an overview on the various patents associated with polymer/ hydrogel-based wound dressings.

10.9  Accelerating wound healing with active agents: future therapeutic trends Major emphasis on advanced wound care has been focused on the development of new dressings capable of accelerating wound healing by erasing chronicity factors and combining many functional properties into one [6]. Managing chronic or nonhealing ulcers in particular requires a systematic multiprofessional approach and a willingness to consider the patient’s perspective to promote the most favourable conditions for healing. Despite all hydrogel/polymer-based materials that promote wound repair to a certain extent, these materials exploit only the intrinsic properties of the matrix itself without any active agents to interact with the chronicity factors at the molecular level. The multifactorial nature of virtually all non-healing wounds requires biochemical stimuli to halter the events governing the ECM breakdown and impaired healing. Such effects can be expected only in case of controlled application of bioactive molecules, eg, antimicrobials, enzyme inhibitors and growth factors. An orderly, predictable sequence of wound regeneration is driven by numerous cellular mediators, ie, cytokines/growth factors. Advanced wound dressing products thus intend to accelerate the repair processes by promoting/augmenting the activities of these mediators in nonhealing conditions (Fig. 10.1). Although in many cases the role of these hydrogels/polymers in such dressings and products is merely to provide a structural support, they are also crucial to maintain a moist environment and crucial in the wound bed to promote growth factors, cytokines and migration of cells [82]. Table 10.6 gives insight into the various advanced polymer and hydrogel dressings containing active agents in the market.

10.10  Advanced PolyHeal™ technology for wound healing PolyHeal™ technology has an innovative approach that uses negatively charged microspheres (NCM). This technology consists of synthetic, nonbiodegradable, medical grade polystyrene microspheres (0.025%, 5 μm) in a suspension of serum-free nutrient medium. The NCM provides a scaffold and surface to which cells and macromolecules attach. This creates a microenvironment where the cells and molecules can interact and participate in the wound healing process, including the natural generation of collagen and other components of the ECM (Fig. 10.2).

Clinical trials associated with polymer/hydrogel-based wound dressing

Official title

Condition

Type of dressing

NCT no

Status

Efficacy of Myskin patch for the healing of cut injuries and abrasions: a randomized controlled trial Open, noncomparative, single center investigation exploring the clinical utility of a new silver gel for use on chronic wounds

Wounds and injuries, abrasions, cut injuries

Hydrogel and polyurethane film

NCT01573234

Completed

Chronic wounds

NCT01442103

Completed

Clinical comparative trial of a modified polyurethane dressing and aquacel A Phase IIa, single-centre, randomized, observer-blinded trial with intraindividual comparison of treated vs untreated to assess the wound healing efficacy of topical Tyrosur gel Double-blind randomized controlled trial of recombinant human platelet-derived growth factor-BB gel (Regranex gel) vs hydrogel (Duoderm hydrogel) for healing of Martorell’s hypertensive leg ulcers. Eran trial.

Epithelialization of skin graft donor sites Abrasive wounds induced on the forearm of healthy volunteers by sterile hand brush

Normlgel Ag is an opaque, amorphous hydrogel containing a high water content, water-soluble polymer chains and an antimicrobial silver compound Modified polyurethane film dressing Gel containing the antibiotic tyrothricin

NCT01055925

Completed

NCT01227759

Completed

Sodium CMC aqueous-based becaplermin gel

NCT00970697

Completed

Hypertensive leg ulcers

Microparticulate polymers and hydrogels for wound healing

Table 10.4 

215

Patents associated with polymer/hydrogel-based wound dressings Patent no.

Description

Spray hydrogel wound dressings

WO 2003063923 A1

Wound healing compositions comprising biocompatible cellulose hydrogel membranes and methods of use thereof

US 20120231038 A1

Hydrogels useful in wound healing and antiadhesion applications

US 5505952 A

Fluorinated polymerizable hydrogels for wound dressings and methods of making same

US 20150018433 A1

In situ–forming hydrogel wound dressings containing antimicrobial agents

EP 2590689 A2

Hydrogel tattoo protection and aftercare system

WO 2014145714 A1

Composition is provided that forms a dressing in situ on a wound. The liquid composition is sprayed onto the wound, whereupon it polymerizes or otherwise thickens to form a hydrogel wound dressing [95]. The invention provides a wound healing composition comprising a biocompatible cellulose hydrogel membrane, wherein the cellulose hydrogel membrane possesses desirable properties, including one or more of the following: high water content, high transparency, high permeability, high biocompatibility, high tensile strength and an optimal thickness [96]. This invention relates to modified, synthetic, cross-linked amino acid polymers which are useful in forming hydrogels particularly for wound healing and antiadhesion applications [97]. The invention provides a hydrogel formed of a cross-linked polymer containing a pendant fluorine group. The fluorines allow the hydrogel to dissolve oxygen, which can later be released from the hydrogel to an area of low oxygen concentration such as wound [98]. Composition comprising a macromer that can be in situ polymerized into a hydrogel wound dressing directly on a wound and one or more antimicrobial agents intended to achieve bacteriostasis and/or be bactericidal. The antimicrobial agent is released upon application and trapped in the hydrogel upon its formation and also released over time into the wound [99]. The invention consists of spreadable hydrogel matrix treated with a film forming mist to form a flexible membrane over a tattoo or wound. It improves wound healing for a freshly applied tattoo as well as reduces the formation of exudative crusting and reduces ink loss. It also absorbs exudate, adheres to the moist wound surface and can be removed with little or no pain at the wounded skin surface [100].

Wound Healing Biomaterials

Title

216

Table 10.5 

Microparticulate polymers and hydrogels for wound healing

Antimicrobials antiseptics

Growth factors

HO HO

O

OH

NH2

O HO

O NH2

Enzyme inhibitory agents

Supplements antioxidants

Cytokines

OH

Synthetic polymers

217

OH O

O HO

Biopolymers/ natural polymers

OH

NH2

n

Processing

Nanoformulations/ novel formulations

Hydrogels/ thermosensitive hydrogels

Accelerated wound healing

Figure 10.1  Concept of advanced wound healing hydrogel/polymer dressings.

Table 10.6  Advanced Commercial name

wound healing dressings with active agents

Manufacturer

Active agent

Category/role

Acticoat Aquacel Ag hydrofiber Biatain Ag Cutisorb

Smith & Nephew ConvaTec

Nanocrystalline silver Silver

Antimicrobial Antimicrobial

Coloplast BSN Medical

Silver Dialkylcarbamoyl chloride

Promogran prisma

Systagenix (Acelity)

Regranex

Smith & Nephew

Oxidized regenerated cellulose (ORC), collagen and 1% silver-ORC Becaplermin

Antimicrobial Hydrophobic interaction with microorganisms Antimicrobial, protease-modulating matrix

Silvercel Suprasorb X + PHMB

Systagenix (Acelity) Lohmann & Rauscher

Silver Polyhexamethylene biguanide (PHMB)

Platelet-derived growth factor-BB Antimicrobial Antiseptic

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3RO\+HDO70

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Figure 10.2  PolyHeal technology. Adopted from the website: http://www.polyheal.com/clinical-evidence/clinical-studies/.

PolyHeal™ has demonstrated clinical benefits in hard-to-heal wounds within 4 weeks in one randomized controlled study [35], in three open-label studies, and when tested in more than 400 patients in Europe and Israel. In the randomized controlled, prospective, double-blind study, PolyHeal™ was compared to daily treatment with saline in gauze in therapy-resistant wounds (30.4 cm2 in size and 16.6 months old) of different etiologies (36% venous leg ulcers) in 58 patients [35]. During the subsequent follow-up phase, all patients received standard therapy. PolyHeal™ treatment

Microparticulate polymers and hydrogels for wound healing

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increased granulations (p  =  0.01) and reduced wound size significantly (39.0% vs 14.9, p = 0.02) compared with placebo after 4 weeks. After 12 weeks, 11 of 32 wounds had healed with PolyHeal™ compared with 8 of 26 placebo-treated wounds. Physicians preferred PolyHeal™ over saline gauze treatment.

10.11  Conclusion and future perspectives Wound dressings are a significant part of the medical and pharmaceutical wound management market worldwide. Despite the wide range of products already available, complex non-healing wounds are still a challenge to manage and accordingly attract a great deal of interest among the research community. Their treatment represent a huge health burden and drain on healthcare resources due to the extensive medical intervention required. Furthermore, as elderly individuals become the fastest-growing segment of the population, complex wounds occurrence will have an even more pronounced economic impact in the future. Therefore, new solutions such as novel micro- and nanoparticulate polymer and hydrogel-based dressings to facilitate chronic wound healing are needed. The advanced wound care market is constantly growing and includes an array of competing technologies and solutions that can be classified according to the materials from which they are produced. Polymer-based and hydrogel-based dressings are its largest sector. They also include few bioactive dressings and skin substitutes on the market that combine polymers with various therapeutics, antimicrobials, enzyme inhibitors, biological supplements and/or cells acting on specific molecular targets in the wound environment. In near future, it is expected that polymers will be exploited more efficiently, since they can be easily modified via chemical or biochemical techniques. Permanent functionalization of polymer matrices with bioactive agents will allow their action from the polymer matrix, without being released to the wound, thus avoiding risk of overdose and associated adverse effects. Polymers in the form of dressings and pharmaceutical formulations are already an integral part of modern wound care. Synthetic polymers have good mechanical properties; near-limitless supply and are easy to process into suitable designs for wound repair, including appropriate pore size and scaffold geometry. These advantages are countered by their minimal intrinsic bioactive properties. Biopolymer dressings, in contrast, interact with dermal tissue and cells to accelerate the acute healing process, but they have no or minimal effect on the healing of complex wounds. Therefore, advanced wound repair is currently directed towards stimulation of physiological repair at the molecular level. Combining synthetic and/or biopolymer dressing with the therapeutic potential of bioactive molecules has emerged as an exciting field of research for enhanced wound repair. The rationale for the development of these next generation composites lies in their superior efficacy in preclinical models relative to the application of their components alone. Many approaches for assembling polymers with therapeutically relevant compounds and cells are established technologies, with a few already commercialized based on the clinical evidence. Nevertheless, the extensive research being conducted is likely to result in additional approvals, and more advanced polymer-based dressings will certainly reach the market in the next few years.

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List of abbreviations AgSD CMC ECM FGF HA NCM PEG PGA PLA PU PVA PVP

Silver sulfadiazine Carboxymethyl cellulose Extracellular matrix Fibroblast growth factor Hyaluronic acid Negatively charged microspheres Polyethylene glycol Polyglycolic acid Polylactic acid Polyurethane Polyvinyl alcohol Polyvinyl pyrrolidone

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