Current trends in the development of wound ... - Future Science

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Current trends in the development of wound dressings, biomaterials and devices Claire Martin*1,2, Wan Li Low3, Mohd Cairul Iqbal Mohd Amin4, Iza Radecka2,3, Prem Raj1 & Ken Kenward1 Wound management covers all aspects of patient care from initial injury, treatment of infection, fluid loss, tissue regeneration, wound closure to final scar formation and remodeling. There are many wound-care products available including simple protective layers, hydrogels, metal ion-impregnated dressings and artificial skin substitutes, which facilitate surface closure. This review examines recent developments in wound dressings, biomaterials and devices. Particular attention is focused on the design and manufacture of hydrogelbased dressings, their polymeric constituents and chemical modification. Finally, topical negative pressure and hyperbaric oxygen therapy are considered. Current wound-management strategies can be expensive, time consuming and labor intensive. Progress in the multidisciplinary arena of wound care will address these issues and be of immense benefit to patients, by improving both clinical outcomes and their quality of life.

Background

The greatest challenges in managing the chronic wound environment are insuring adequate delivery of drug or antimicrobial agent and controlling exudate fluid levels [1]. Other issues include the maintenance of bioavailability at microbiocidal concentrations, reducing the risk of uneven antimicrobial deposition at the wound site and the ease of application [1]. The uneven distribution of drug or exposure to sub-lethal antimicrobial concentrations can lead to development of resistance among wound infecting pathogens. In addition, uneven drug deposition may also induce toxic side effects to healthy cells, thus leading to tissue necrosis. Wound dressings act as a barrier to reduce external microbial infection, absorb or donate fluid and can deliver antimicrobial agent(s) [1,2]. In recent years, there have been increasing reports on the emergence of resistant microorganisms such as methicillin-resistant Staphylococcus aureus, vancomycinresistant enterococci and extended spectrum b-lactamase strains of Escherichia coli and Klebsiella pneumoniae [3]. Increased life expectancy has led to a much greater size and longevity of the elderly population who are especially prone to chronic diseases such as diabetes, obesity and hypertension. When combined with a sedentary lifestyle, such chronic diseases can lead to the development and persistence of slow nonhealing ulcers and wounds. Efficient control of infection can improve rates of healing in chronic wounds and lessen frequency of dressing changes, as well as minimize pain and discomfort. Topical application of antimicrobial agents is a popular approach since effective concentrations may be difficult to achieve with systemic drugs as wound trauma may impede delivery of the agent into the wound [4,5].

10.4155/PPA.13.18 © 2013 Future Science Ltd

Pharm. Pat. Analyst (2013) 2(3), 341–359

Department of Pharmacy, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, UK 2 Research Institute in Healthcare Science, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, UK 3 Department of Biology, Geography & the Environment, School of Applied Sciences, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, UK 4 Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd Aziz, 50300 Kuala Lumpur, Malaysia *Author for correspondence: E-mail: [email protected] 1

ISSN 2046-8954

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Key terms

Martin, Low, Amin, Radecka, Raj & Kenward

■ Wound healing

Wound healing is a dynamic proAntimicrobial: Chemical or cess involving cellular, enzymatic biological compounds used to and biochemical pathways, spanprevent microbial proliferation ning from the time the skin is dam(microbiostatic agents) or reduce the microbial load (microbiocidal) aged until the wound is completely in the wound bed. healed [1,6]. The events in wound healing are divided into four main Dressings: Protective covering stages, namely exudative (including layer applied to wounds to absorb excess exudate, prevent fluid loss hemostasis), resorptive (inflammaand ingress of microbes. Dressing tion), proliferative and regenerative components can be plain fabric or [7–9], as shown in Figure 1. These impregnated with antimicrobial highly integrated phases need to ocagents to treat wound infections. cur in an orderly and timely manner, to promote healing, minimize scarring and reduce the risk of a nonhealing chronic wound developing [10]. The first stage of the exudative phase starts immediately upon wounding to stop bleeding, eliminate microbial invasion, reduce further mechanical damage and exposure of tissues to the environment [8]. The ruptured cells and vessels at wound edges release signals to initiate vasoconstriction, trigger platelet-mediated inflammatory response (cytokines, chemokines and growth factors) and activate the clotting cascade [7,9]. Clot formation stops regional hemorrhage, triggers the release of inflammatory mediators and acts as a provisional matrix, providing support for the infiltrating inflammatory cells [9]. During the resorptive phase the wound site becomes progressively more inflamed, resulting in localized heat and swelling due to increased vasodilation, which allows the escape of plasma proteins and fluid into the interstitial space; pain and loss of function result that serves to reduce further damage to the injured site [8]. The increased vascular permeability helps to facilitate the leakage of neutrophils, macrophages and fibroblasts [7], which release nitric oxide, oxygen free radicals, serine proteases and matrix metalloproteinase (MMP) into the wound site. This aids in the elimination of bacterial cells, removal of damaged extracellular matrix as well as inflammatory debris to facilitate further the migration of tissue repair molecules [7,9,10]. In addition, the accumulation of macrophage-derived growth factors, such as TNF-a and IL-1, influences the migration of fibroblasts, keratinocytes and endothelial cells into the wound site [7]. Wound healing continues with a series of overlapping events that occur between the resorptive and proliferative phase. Macrophages phagocytize debris, release growth factors (e.g., VEGF) and induce the clearing of inflammatory cells from the wound site, to promote development of the proliferative phase [10]. Cell proliferation begins with keratinocytes

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migrating over the damaged dermis to form a provisional wound matrix [7,11]. The macrophage initiated influx of fibroblasts also helps to induce the production of glycosamino glycans (e.g., hyaluronic acid), proteoglycans and collagen, which are required for the formation of granulation tissue to replace the fibrin matrix [6,11]. The formation of new blood vessels (angiogenesis) occurs to provide oxygen and nutrients to the rapidly growing granulation tissue, which is composed of randomly deposited type III collagen, ground substance, capillaries and fibroblasts [7,11]. Continuous replacement of fibrin and the provisional wound matrix with collagen-rich granulation tissue increases the tensile strength of the wound [8]. Wound closure initiates when fibroblasts differentiate into contractile cells (myofibroblasts); the interaction of fibroblasts, myofibroblasts and continuous migration of keratinocytes and endothelial cells from the wound edge eventually results in wound closure [9,11]. During re-epithelialization, the final stage of wound healing, full closure of the wound occurs and a scar is formed. In this regenerative phase, newly constructed blood vessels are refined to form a functional network whilst inflammatory cells (neutrophils and macrophages) leave the site [9]. Tissue remodeling takes place to arrange the type III collagen into a thicker, stronger and well-organized matrix composed of type I collagen, to restore the normal architecture of the dermis and increase tensile strength [7]. Wound dressings

The concept of moist wound healing is now widely accepted, and in practice is associated with more rapid rates of healing, reduced pain, better infection control, decreased scarring and a reduction in associated healthcare costs [2]. When compared with dry wounds, a moist wound environment enhances re-epithelialization, eases movement of matrix material and increases growth factor activity, all of which promote the healing process [12]. Wound dressings are generally classified into three groups based on their function: absorb exudate, maintain moisture or donate moisture [2]. The choice of dressing will depend on the type, condition (wound healing phase) and location of the wound. Several wounds, including venous leg ulcers, are associated with the production of large amounts of exudate, which need to be managed appropriately. Excessive contact between wound surface and exudate can result in maceration of the surrounding tissue [13], saturation of dressings and soiling of the patient’s clothing. Dressings that absorb exudate to prevent fluid accumulation around the wound need to be highly absorbent with a high capacity for both absorption and

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Pharm. Pat. Analyst (2013) 2(3)

Platelets

Cytokines

K

K

Lymph vessel

Blood vessel

Proliferative phase

Lymph vessel

Blood vessel

Plug

K

K

K

Keratinocytes

Plug

Fibrin

Localized swelling

Pharm. Pat. Analyst © Future Science Group (2013)

Collagen

Microorganisms

Scar-thickened epidermis

Growth factors

Lymph vessel

Blood vessel

Regenerative phase

Lymph vessel

Blood vessel

Inflammation phase

Chemokines

D

B

Macrophages

Platelet plug

Clot formation

Provisional matrix

Neutrophils

Exudative phase (hemostasis) External trauma

Figure 1. The four stages of wound healing: exudative, resorptive, proliferative and regenerative. (A) Hemostasis and clot formation provides support for infiltrating inflammatory cells while triggering the release of inflamatorry mediators, including cytokines, chemokines and growth factors. (B) Leakage of neutrophils and macrophages into the wound site helps to destroy bacteria, remove infammatory debris and facilitate conditions for angiogenesis. (C) Proliferative phase involves the migration of epithelial cells from the wound edge to close the wound, accompanied by angiogenesis, deposition of granulation tissue and formation of a provisional matrix. (D) The wound fully closes, infmmatory response resolves and tissue remodelling occurs. Provisional matrix is gradually replaced with type I collagen and blood vessels within the scar matures into a functional network [7–9].

C

A

Current trends in the development of wound dressings, biomaterials & devices

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maintenance of wound fluid. Such exudate absorbing dressings include those prepared from alginate and various foams. Dressings that maintain hydration at the wound site are of particular importance during the granulation phase and generation of connective tissue, that generally occurs with a concurrent decrease in wound exudate production. Highly absorbent dressings are not particularly applicable during these stages as they can dehydrate the wound tissues, thus restricting granulation and other tissue regenerative processes. To maintain moisture levels around a wound in this phase, hydrocolloid dressings and transparent films are the best option. The

final classification of dressings are those that donate moisture to the wound, which is particularly important where autolytic debridement is required to clear the area of dead (necrotic), dried tissues. The process of autolytic debridement involves the removal of dead cells and other material by phagocytes, and requires a moist environment to facilitate the activity of the cells. Wound dressings that have a relatively high content of water, such as hydrogels, wafers or amorphous gel structures, can donate moisture to the wound environment. An overview of the most appropriate choice of dressings for various wound stages is presented in Table 1 [14–19].

Table 1. Description of various wound stages and the possible choice of dressing used for treatment. Stage of wound

Description

Possible dressing option

Example of commercially available products

Stage I

Intact skin Areas of nonblanchableredness Generally localized over a bony prominence Darkly pigmented skin’s color can differ from surrounding area

Hydrocolloids

Karayahesive® DuoDERM™ Comfeel® Cutinova® Restore™ Tegasorb™

Transparent films

Bioclusive™ Polyskin™

[15]

Alginates (if exudate present)

Sorbsan® AlgisiteM® Algosteril® Sorbalgon® Kaltocarb® Kaltostat® Sorbsan Melgisorb® Seasorb® Kaltogel®

[15,19]

Foams

Curafoam® ALLEVYN™ Flexan® LyoFoam™ MitraFlex™

Hydrocolloids

Karayahesive DuoDERM Comfeel Cutinova Restore Tegasorb

[15–18]

Hydrogels

NU-GEL® Carrasyn® Geliperm® Intrasite™ Gel Vigilon®

[15,17]

Transparent films

Bioclusive Polyskin

Stage II

Partial-thickness dermis loss Shallow open ulcer Red-pink wound bed, without slough Alternatively, develops as a serum-filled blister (can be intact or open/ruptured)

Ref. [15–18]

[17]

[15]

Data from [14,15].

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Table 1. Description of various wound stages and the possible choice of dressing used for treatment (cont.). Stage of wound

Description

Possible dressing option

Example of commercially available products

Ref.

Stage III

Full-thickness tissue loss Subcutaneous fat may be visible; bone, tendonand/or muscle not exposed Slough may be present but depth of tissue lossis not obscured Features can include undermining and tunnelling

Alginates (if exudate present), foams, hydrocolloids and hydrogels

Sorbsan AlgisiteM Algosteril Sorbalgon Kaltocarb Kaltostat Sorbsan Melgisorb Seasorb Kaltogel Curafoam ALLEVYN Flexan LyoFoam MitraFlex Karayahesive DuoDERM Comfeel Cutinova Restore Tegasorb NU-GEL Carrasyn Geliperm Intrasite Gel Vigilon

[15–19]

Stage IV

Full-thickness tissue loss Exposed bone, tendon and/or muscle slough or eschar may be present Features often include undermining and tunnelling

Alginates (if exudate present), foams, hydrocolloids and hydrogels

Same as above column for ‘Stage III’

[15–19]

Wound fillers (e.g., gauze)

Curity gauze sponges (Curity™) KERLIX super sponge (KERLIX™) KLING gauze rolls (KLING®) Nu gauze packing strips (NU GAUZE™)

[17]

Data from [14,15].

■■ Hydrogels

Hydrogels are water-rich, malleable materials that can absorb excess wound fluids while releasing medicinal; agents, such as antimicrobials and those that promote wound healing. Hydrogels dressings can be formulated to provide controlled, targeted release of antimicrobial agents that are facilitated by bioadhesive, stimuli (wound)-responsive characteristics. Topical hydrogels are biocompatible and gentle to the wound area, plus they also provide a biologically friendly support scaffold for tissue regenerating cells. Additionally, controlling the amount of agent delivered to the wound bed can avoid overloading at the site of infection while allowing effective antimicrobial activity. This may reduce possible side effects due to localized toxicity. Such systems also play a role in sealing the wound surface


to prevent further infection and discharge, as well as responding to the wound environment by absorbing and/or releasing materials at different stages of the wound life cycle. Several polymers and biopolymers have been explored in recent years for their application in wound responsive hydrogel dressings. These include chitosan [20,21], alginate [22,23], gelatine [24,25], collagen [26,27], soy protein [28], sterculia (karaya) gum [29], glucan [30], poly(vinyl alcohol) [31], poly(lactic-co-glycolic acid) [32], hyperbranched polyglycerol [33] and silk [25,34]. Chitosan

Chitosan is a partially deacetylated form of chitin, a linear homopolymer of 1,4b-linked N-acetyl-b-d-glucosamine that gradually degrades by depolymerization


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to liberate monomers that stimulate fibroblast proliferation, hyaluronate synthesis and collagen deposition at wound sites [35]. The polycationic polymer forms a viscous gel when dispersed in acidified (acetic acid) aqueous solutions and can be readily crosslinked with anionic donor species [36] or gelled with other natural and synthetic polymers [37]. In addition to dressings prepared with chitosan alone [20,21], blended chitosanpolymer hydrogels reported in the literature include combinations with PVA [38], alginate [36,37,39], agarose [40], gelatine [41], polyamine [42], chitosan (thiolated) and poly(N-isopropyl acrylamide) [43,44], poly(g-glutamic acid) [45], poly(ethylene glycol diacrylate) [46], poloxamer [37] and hyaluronate [47]. Table 2 highlights the various wound healing processes facilitated by chitosan alone and chitosan-polymer blend dressings [25,28,46–50]. Alginate

Currently, alginate is used in several hydrogel wound dressings and is extensively described in investigations of responsive hydrogel and hydrocolloid-based dressings in the literature [22,23]. Alginate is a biocompatible, biodegradable natural polysaccharide composed of b-(1–4)-linked d-mannuronic acid and a-(1–4) linked l-guluronic acid. Crosslinked with calcium chloride, hydrophilic alginate hydrogel properties can be tailored to control both the rate and degree of swelling, hence regulating the uptake of wound exudate and subsequent drug (antimicrobial agent) release [51]. In common with chitosan, the medical applications of alginate include cellular scaffolds and wound dressings as well as controlled drug delivery systems including hydrogels and microparticles. The moist, flexible wound healing micro-environment created by alginate dressings is able to promote the formation of granulation tissue and re-epithelialization [23]. Carboxymethylcellulose

Hydrogels and biopolymers have been incorporated in a variety of dressing inventions in a plethora of

different forms [101–107]. Gel-forming fibers composed of carboxymethylcellulose (CMC) or one of its derivatives were formulated to become transparent upon contact with wound exudate and incorporated into a dressing [108]. The woven or nonwoven carboxymethylated cellulosic fabric with a preferable substitution value of 0.12 –0.35 was chosen to increase the absorbency of the material. The dressing also included an absorbent layer with low lateral wicking rate to decrease maceration of the healthy skin surrounding the wound. Bishop et al. described a three-layered wound dressing designed for application to high exudate wounds [109]. These consisted of a wound contacting layer that transmits the exudate to an absorbent exudate-retaining core, thus limiting lateral spread of fluid, and a final outer layer with a high moisture vapor transmission rate. These dressings were specified as being able to absorb and retain between 6 and 20 g of exudate per 10 cm2 dressing over a 24-h period [109]. This compares well with the commercially available ALLEVYN™, which can handle 4.5 g per 10 cm2 over a 24-h period. Qin and Gilding describe a dressing with a hydrogelfelt layer structure, which would be of particular interest for the treatment of heavily exuding wounds, including burns [110]. The first (contact) layer of the dressing had an optimum thickness of 50–1000 µm. The second dressing layer is required to be up to five-times more hydrophilic than the first layer and have an optimum thickness of 1000–5000 µm. The increased hydrophilicity of the second layer pulls exudate from the contact layer, thus increasing the time taken for the first layer to become saturated with fluid. The first layer can be constructed from a range of materials with a multiplicity of functions, for example: provision of clotting by agglutination (e.g., calcium alginate); wound debridement (e.g., pectin); and ion, drug or antimicrobial delivery (e.g., zinc alginate, silver alginate and chitosan). The second highly hydrophilic layer can employ a range of materials in the form of a felt including alginate salts and salt or alginate-CMC blends. The proposed dual

Table 2. The various wound healing processes facilitated by chitosan and chitosan–polymer blend dressings. Properties of chitosan and chitosan-polymer blend dressings that may facilitate wound healing

Ref.

A bacteriostatic barrier to the ingress of colonizing bacteria into the wound Controlled release delivery of antimicrobials (e.g., minocylcine and silver) and antioxidants (e.g., quercetin)

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[48] [25,49,50]

Absorption of excessive wound exudate

[47]

Formation of a protective film over the wound surface

[49]

Hemostatic function to minimize hemorrhaging from the wound site

[28]

Cellular scaffold for dermal reconstruction

[46]




layered dressing is also able to capture proteins and growth factors. Spider silk

Recombinant spider silk has been examined for its application in wound dressings, scaffolding for various nerve and tissue repairs, artificial tissue structures including joints, tendons, and ligaments, as well as prosthetic devices [34,52]. Spider silk is a biocompatible natural protein with non-irritant and non-inflammatory properties that can promote cell adhesion and proliferation [52,53]. Baoyong et al. described the use of silk as a dressing material for deep second-degree burns in a rat model [34]. The authors found that the recombinant spider silk dressings increased the secretion of b-FGF, which is associated with the promotion of angiogenesis at the wound site. The silk dressings were also found to enhance the wound content of hydroxyproline, which is a major amino acid component of collagen fibers and protein. The use of silk in both wound and biomedical applications has recently been described [111–113]. As mentioned above, spider silk can be used as a scaffold for the regeneration of damaged tissues; Johansson et al. describe a method for the preparation of polymers of isolated spider silk proteins of between 170 and 600 amino acid residues [111]. The resulting silk polymers could be manufactured into fibers, films, foams, nets or meshes, which could be applied to wound dressing materials. A specific wound healing system designed by Zhang et al. incorporated silk fibroin and poly(ethylene oxide) in ratios of 2:1 or 4:1 to produce a blend of materials for dressings [112]. In a further development, drug loaded silk dressings have incorporated the polymeric cationic antimicrobial polyhexamethylene biguanide (PHMB) [113] to provide prolong microbiocidal activity at the infected wound site. Electrospun nanofibers

Nanotechnological approaches have also been applied to wound dressing developments in the form of electrospun nanofibers that can be composed of a diverse range of materials including hyperbranched polyglycerol [33], alginate-PVA-zinc oxide nanoparticle composites [54], collagen-chitosan [55], poly(urethane)-dextran [56] and silk fibroin [52]. Tojo et al. describe the preparation of a nanofiber layered sheet manufactured from polymeric nanofibers composed of a water soluble (e.g., natural and synthetic polymers) and water insoluble coat (e.g., completely saponified PVA, oxazoline-modified silicones, zein and poly[lactic acid]) [114]. Other approaches have involved incorporating nano- or microparticles (with modifications such as


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grafted functional groups or responsive coating materials), into hydrogels or scaffolds, for example polymerxerogel composites [57], modified gelatine microspheres in a collagen scaffold [24] and silver sulfadiazine-loaded chitosan microparticles in poly(ethylene glycol)-fibrin gels [58]. Costache et al. developed a polymer–xerogel composite wound dressing, which encapsulated silicon oxide sol-gel (xerogel) microparticles in a tyrosinepoly(ethylene glycol)–poly(ether carbonate) copolymer matrix [57]. The authors reported that one of the biggest advantages of using xerogel microparticles, rather than traditional biodegradable polymers such as poly(lactic acid) or poly(lactide-co-glycolic acid), is that they are more flexible and can liberate neutral, non-inflammatory degradation products. Drug release could be tailored to zero-order by modifying the copolymer’s hydrophile:lipophile balance, the porosity, weight ratio or drug loading of the xerogel microparticles [57]. The combination of the absence of inflammatory, acidic degradation products and the ease of control over drug release behavior, make these polymer-xerogel composites an attractive material for wound dressings. Recently, wound dressings have been developed with both non-occlusive regions (moisture-vapor permeable >2.0 g/cm2/24 h) and occlusive regions (reduced moisture-vapor permeable 1 atm) [214], or alternatively, pure, super-atmospheric oxygen can be applied directly to the wound site [86]. In common with TNPWT, the positive oxygen pressure can be applied in a cyclical manner, either continuously or intermittently to stimulate localized circulation and reduce edema. In addition, because the oxygen is applied via a hermetically sealed device, wound healing progresses in a moist environment [88]. The topical application of HOT allows the gas to penetrate into and through the skin via a number of different routes. As oxygen is a small molecule, it can easily pass through the pores of the skin such as the eccrine sweat gland pore, which are present across the


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full thickness of skin as a tissue. Alternatively, it is possible for oxygen to traverse transmembrane proteins such as aquaporin, which has a channel structure to allow the transport of gaseous molecules [89]. When the surface of the skin is damaged, as in the case of wounds (whether acute or chronic), much of the barrier functions of this region have been substantially compromised; in these areas the transport of oxygen into the affected region is much less tortuous. HOT facilitates re-epithelialization and angiogenesis within the wound bed. It is also associated with minimal levels of scarring [88], wound reopening risks and may also have analgesic effects [90]. A disadvantage of HOT for wounds is that it requires patients to undertake in-hospital treatment, where a typical treatment regimen consists of super-atmospheric, humidified oxygen treatment of the affected area (usually a distal limb) for up to 3 h, twice a day [88]. Wounds are generally covered with traditional noncompression, non-adhesive dressings between treatments, but may still require debriding and/or cleaning after each HOT session. Commercially available topical wound oxygen therapy devices include AOTI Hyper-box™ (AOTI Ltd, Galway, Ireland), topical pressurized oxygen therapy chamber (Therapeutic Surface Solutions, Inc., ON, Canada), Inotec® TOT Velox™ (Inotec AMD Ltd, Fowlmere, UK) and O2 Boot® (GWR Medical, Inc. PA, USA). HOT is credited with a range of clinical effects including: decreasing wound tissue hypoxia and edema, increasing perfusion, down-regulating inflammatory cytokines, facilitating fibroblast proliferation, modulating neutrophil reactive oxygen species-mediated microbial death and collagen production, and enhancing angiogenesis [91–93]. In terms of antimicrobial activity, the elevated presence of oxygen free radicals leads to bacterial protein and membrane lipid oxidation, as well as damage to DNA and inhibition of metabolic functions. HOT enhances the oxygen-dependent transmembrane transport of certain antibiotics, as well as leukocyte activation via the peroxidise system and is especially active against anaerobic bacteria [90,93]. With respect to the underlying tissues, HOT is able to magnify oxygen gradients at the periphery of ischemic wounds; this in turn promotes oxygen-dependent collagen matrix deposition, which underpins angiogenesis and the maintenance of tissue viability while the healing process proceeds [94]. When normal tissues become hyperoxic following HOT they vasoconstrict rapidly. Conversely in ischemic tissues the vasoconstriction that results from hyperoxia is mitigated by an increase in plasma oxygen and microvascular blood flow as well as a reduction in the occurrence of edema; there is also a decrease in

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ATP production and lactate accumulation [91,95]. All of these activities make the application of HOT an extremely promising treatment for diabetic foot ulcers: not only can oxygenation of the limb be improved by a non-invasive technique, but the concurrent decrease in edema, reduction in infection and enhanced healing response will speed up closure of the wound. Randomized controlled trials revealed that HOT decreased the rate of amputation related to diabetic foot ulcers and may improve healing up to 12 months [1]. HOT of burns, it is believed to act by reducing the resultant hemoconcentration, coagulation and vascular damage, in addition to the cascade of effects that follow hyperoxic vasoconstriction [94]; however, there is a lack of controlled clinical studies to confirm the effects [96] While the core concept behind HOT remains unchanged, the main advances have included developments in portable devices [165–167], disposable devices and integrated HOT dressings [168–170]. In terms of enhanced portability of the equipment, Loori and Hovorka described a modification to the device in the form of a collapsible bag, which could be applied to an isolated limb, rather than requiring the patient to undergo whole body HOT. The bag is described as consisting of two sealed sheets of fluid impervious material that enable gas (hyperbaric oxygen) to inflate the cavity to a rigid state and maintain it during pressure cycling (hyperbaric to ambient). ■■ Smart/indicator dressings

Smart technology wound dressings that indicate the presence of pathogenic bacteria, such as S. aureus and P. aeruginosa, have been described by Zhou et al. [97]. Using the self-quenching dye carboxyfluorescein encapsulated in vesicles that lyze in the presence of bacterial toxins, the authors reported the development and testing of a dressing in which vesicles were bound to polypropylene fabric. The bacterial toxins responsible for lysing the vesicles were hemolysin or PLA 2, both of which are secreted by common wound infecting pathogens. Fluorescence was clearly seen on the fabric dressing in the presence of pathogenic S. aureus and P. aeruginosa , but absent in the presence of E. coli Dh5a, which does not secrete lytic toxins. This ‘sensor’ dressing allows easy identification of wound infection status without the need for costly and untimely swabs, cultures and blood tests to confirm the presence of pathogenic bacteria. Future perspective

An ideal wound dressing should: maintain a moist environment; provide mechanical protection, thermal insulation and pH control; minimize the development




of infection; be easily removable without causing pain or trauma to the area; sequester excess exudate and debris; allow the exchange of gases; control wound odor; be hypoallergenic; be cosmetically acceptable; be cost effective; and promote tissue reconstruction. Many currently marketed products meet a selection of these criteria, but the most challenging aspects of wound management, namely the maintenance of an environment conducive to wound healing and the effective treatment of infection, are yet to be addressed. In recent years, materials that can function more efficiently as hydrogels, while also delivering anti microbial agents within the therapeutic range have been explored. There is renewed interest in biopolymers such as alginates, chitosan, hyaluronates and cellulose derivatives for their ability not only to provide a moist environment for wound healing (by virtue of their high water imbibing properties), but also to function as cellular scaffolds for tissue regeneration. Advances in novel hydrogel preparation techniques have sought to increase porosity within the structure, hence increasing the available surface area for moisture absorption and retention. Varying porosity

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and crosslinking density also enables the kinetics of drug release to be controlled, which is particularly beneficial in avoiding side effects and toxicity associated with many antimicrobial agents. In addition, incorporating more than one antimicrobial into the hydrogel, possibly in a gradient-loaded pattern (from high to low concentration at the wound surface) could enhance infection treatment strategies. There is also renewed interest in alternative micro biocides including metal ions, essential oils and other natural products [98], as well as combinations of traditional therapies [4,13]. Another noteworthy development is the rapidly expanding field of ionic liquids and their potential as novel antimicrobials; with potential to be ‘designer’ antimicrobial agents due to the feasibility of altering chemical properties to suit desirable features in efforts to reduced incidence of resistance development [99]. Once any infection has been cleared from the wound bed and the inflammatory response is beginning to subside, the next issue becomes the timely closure of the lesion. Skin substitutes are a commercial reality and are set to become much more prevalent in the clinic with the recent expansion of stem cell

Executive summary Background Wound management is a prolonged, labor-intensive and costly process which is continuously developing in response to clinical need. Consideration of underlying medical conditions, the specific type of wound, detection and treatment of infection, as well as patient needs all play an important role in effective, timely wound management. Wound dressings Hydrogels are water-rich, malleable materials that can absorb excess wound fluids while releasing medicinal agents, such as antimicrobials. They are biocompatible and gentle to the wound area, provide a biologically-friendly support scaffold for tissue regenerating cells and can seal the wound surface to prevent further infection and discharge. Hydrogel-based wound dressings can be formulated from a range of materials including chitosan, alginates, spider silk and electrospun materials such as hyperbranched polyglycerol and polyurethane-dextran. Antimicrobial dressings have the potential to combine the exudate management properties of traditional dressing systems with effective antimicrobial delivery for the treatment of infected wounds. Antimicrobial agents such as silver, zinc, honey and iodine are often incorporated into a range of commercially available dressings, for example, alginate hydrogels, hydrocolloids, foams and gauzes. Biomaterials & engineered skin substitutes Biomaterials can be derived from a variety of sources including animal and microbial culture and can be used to functionalize the dressing / wound surface. Biomaterials commonly used in wound dressings include collagen, hyaluronan, chitosan and extracellular matrix proteins. Skin substitutes are a diverse and rapidly expanding area within the field of wound management and include cultured and noncultured autologous skin substitutes, nonconfluent and confluence cultured skin substitutes as well as seeded and nonseeded dermal supports. Devices Topical negative pressure wound therapy involves the application of sub-atmospheric pressure to increase blood flow and angiogenesis, stimulate granulation tissue formation, induce cell proliferation, as well as promoting wound contraction. In hyperbaric oxygen therapy the wound is exposed to 100% super-atmospheric oxygen, which facilitates re-epithelialization and angiogenesis in the wound bed, minimizes scarring and can also have analgesic effects. An exciting new area of wound device development is the emergence of smart technology dressings, which can indicate the presence of pathogenic bacteria. This sensor dressing allows the status/extent of wound infection to be confirmed without the need for swabs, cultures and blood tests.



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research. In addition, the diverse range of applications for human amniotic membrane components may also have potential to enhance tissue regeneration and wound closure. Both topical TNPWT and HOT have received renewed attention, especially in light of greater understanding of their precise mechanism of action on and around the wound site. As with all wound healing interventions, patient convenience, acceptability and, hence, compliance are extremely important. Current arrangements of equipment for both TNPWT and HOT often take the form of bulky, immobile chambers that must be utilized within a hospital setting. As manufacturing techniques improve, the potential to make both forms of therapy portable so that they can be used in a community setting as

well as developments in disposable wound contact components will undoubtedly increase patient approval of these therapies. In addition, TNPWT and HOT dressing combinations will also grow in prevalence, especially if they can be combined with the advantageous properties of smart hydrogels that can deliver microbiocides and tissue stimulating molecules such as growth factors. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

References Papers of special note have been highlighted as: of interest of considerable interest n

n n

1

Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: a practical approach to the care of non-healing wounds and wound care dressings. J. Am. Acad. Dermatol. 58(2), 185–206 (2008).

2

Ovington LG. Advances in wound dressings. Clin. Dermatol. 25(1), 33–38 (2007).

3

Kumarasamy KK, Toleman MA, Walsh TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect. Dis. 10(9), 597–602 (2010).

4

Glasser JS, Guymon CH, Mende K, Wolf SE, Hospenthal DR, Murray CK. Activity of topical antimicrobial agents against multidrug-resistant bacteria recovered from burn patients. Burns 36(8) 1172–1184 (2010).

5

Toy LW, Macera L. Evidence-based review of silver dressing use on chronic wounds. J. Am. Acad. Nurse Prac. 23(4), 183–192 (2011).

6

Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J. Surg. Res. 153(2), 347–358 (2009).

7

Stojadinovic A, Carlson JW, Schultz GS, Davis TA, Elster EA. Topical advances in wound care. Gynecol. Oncol. 111(Suppl. 2), S70–S80 (2008).

8

Wild T, Rahbarnia A, Kellner M, Sobotka L, Eberlein T. Basics in nutrition and wound healing. Nutrition 26 (9), 862–866 (2010).

9

Shaw TJ, Martin P. Wound repair at a glance. J. Cell Sci. 122(18), 3209–3213 (2009).

10 Guo S, DiPietro LA. Factors affecting wound healing. J. Dent. Res. 89(3), 219–229 (2010).

356

11 Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature 453(7193), 314–321 (2008). 12 Mouës CM, Heule F, Hovius SER. A review of topical negative pressure therapy in wound healing: sufficient evidence? T. Am. J. Surg. 201(4), 544–556 (2011). n n

Very thorough, far-reaching review of the application of topical negative pressure wound therapy in wound management, analyzing the clinical and scientific basis for the various claims.

13 Morton LM, Phillips TJ. Wound healing update. Semin. Cutan. Med. Surg. 31(1), 33–37 (2012). 14 Lagana G, Anderson HA. Moisture dressing: the new standard in wound care. J. Nurse Prac. 6(5), 366–370 (2010). 15 Hanna JR, Giacopelli JA. A review of wound healing and wound dressing products. J. Foot Ankle Surg. 36(1), 2–14 (1997). 16 Fujimoto Y, Shimooka N, Ohnishi Y-I, Yoshimine T. Clinical evaluation of hydrocolloid dressings for neurosurgical wounds. Surg. Neurol. 70(2), 217–220 (2008). 17 Cuzzell J. Choosing a wound dressing. Geriat. Nurs. 18(6), 260–265 (1997). 18 Stashak TS, Farstvedt E, Othic A. Update on wound dressings: Indications and best use. Clin. Tech. Equine Pract. 3(2), 148–163 (2004). 19 Knill CJ, Kennedy JF, Mistry J et al. Alginate fibers modified with unhydrolysed and hydrolysed chitosans for wound dressings. Carbohyd. Polym. 55(1), 65–76 (2004). 20 Hofman D. The autolytic debridement of venous leg ulcers. Wound Essent. 2, 68–73 (2007).


21 Aoyagi S, Onishi H, Machida Y. Novel chitosan wound dressing loaded with minocycline for the treatment of severe burn wounds. Int. J. Pharm. 330(1–2), 138–145 (2007). 22 Ong S-Y, Wu J, Moochhala SM, Tan M-H, Lu J. Development of a chitosan-based wound dressing with improved hemostatic and antimicrobial properties. Biomaterials 29(32), 4323–4332 (2008). 23 Sikareepaisan P, Ruktanonchai U, Supaphol P. Preparation and characterization of asiaticoside-loaded alginate films and their potential for use as effectual wound dressings. Carbohyd. Polym. 83(4), 1457–1469 (2011). 24 Thu H-E, Zulfakar MH, Ng S-F. Alginate based bilayer hydrocolloid films as potential slow-release modern wound dressing. Int. J. Pharm. 434(1–2), 375–383 (2012). 25 Adhirajan N, Shanmugasundaram N, Shanmuganathan S, Babu M. Functionally modified gelatin microspheres impregnated collagen scaffold as novel wound dressing to attenuate the proteases and bacterial growth. Eur. J. Pharm. Sci. 36(2–3), 235–245 (2009). 26 Kanokpanont S, Damrongsakkul S, Ratanavarporn J, Aramwit P. An innovative bi-layered wound dressing made of silk and gelatin for accelerated wound healing. Int. J. Pharm. 436(1–2), 141–153 (2012). 27 Chen J-P, Lee W-L. Collagen-grafted temperature-responsive nonwoven fabric for wound dressing. Appl. Surf. Sci. 255(2), 412–415 (2008). 28 Chikazu D, Taguchi T, Koyama H et al. Improvement in wound healing by a novel synthetic collagen-gel dressing in genetically diabetic mice. Asian J. Oral Maxillofac. Surg. 22(2), 61–67 (2010). 29 Peles Z, Zilberman M. Novel soy protein wound dressings with controlled antibiotic



release: mechanical and physical properties. Acta Biomater. 8(1), 209–217 (2012). 30 Singh B, Pal L. Development of sterculia gum based wound dressings for use in drug delivery. Eur. Polym. J. 44(10), 3222–3230 (2008). 31 Huang M-H, Yang M-C. Evaluation of glucan/poly(vinyl alcohol) blend wound dressing using rat models. Int. J. Pharm. 346(1–2), 38–46 (2008). 32 Kokabi M, Sirousazar M, Hassan ZH. PVA-clay nanocomposite hydrogels for wound dressing. Eur. Polym. J. 43(3), 773–781 (2007). 33 Elsner JJ, Egozi D, Ullmann Y, Berdicevsky I, Shefy-Peleg A, Zilberman M. Novel biodegradable composite wound dressings with controlled release of antibiotics: results in a guinea pig burn model. Burns 37(5), 896–904 (2011). 34 Torres Vargas EA, do Vale Baracho NC, de Brito J, de Queiroz AA. Hyperbranched polyglycerol electrospun nanofibers for wound dressing applications. Acta Biomater. 6(3), 1069–1078 (2010). 35 Baoyong L, Jian Z, Denglong C, Min L. Evaluation of a new type of wound dressing made from recombinant spider silk protein using rat models. Burns 36(6), 891–896 (2010). n n

Describes an elegant series of experiments investigating the use of silk as a dressing material for deep second degree burns.

36 Jayakumar R, Prabaharan M, Kumar PTS, Nair SV, Tamura H. Biomaterials based on chitin and chitosan in wound dressing applications. Biotechnol. Adv. 29(3), 322–337 (2011).

42 Wang T, Zhu X-K, Xue X-T, Wu D-Y. Hydrogel sheets of chitosan, honey and gelatin as burn wound dressings. Carbohyd. Polym. 88(1), 75–83 (2012). 43 Fouda MMG, Wittke R, Knittel D, Schollmeyer E. Use of chitosan/polyamine biopolymer based cotton as a model system to prepare antimicrobial wound dressing. Int. J. Diabetes Mellit. 1(1), 61–64 (2009). 44 Chen J-P, Kuo C-Y, Lee W-L. Thermoresponsive wound dressings by grafting chitosan and poly(N-isopropylacrylamide) to plasma-induced graft polymerization modified non-woven fabrics. App. Surf. Sci. 262, 95–101 (2012). 45 Radhakumary C, Antonty M, Sreenivasan K. Drug loaded thermoresponsive and cytocompatible chitosan based hydrogel as a potential wound dressing. Carbohyd. Polym. 83(2), 705–713 (2011). 46 Tsao CT, Chang CH, Lin YY et al. Evaluation of chitosan/g-poly(glutamic acid) polyelectrolyte complex for wound dressing materials. Carbohyd. Polym. 84(2), 812–819 (2011). 47 Zhang X, Yang D, Nie J. Chitosan/ polyethylene glycol diacrylate films as potential wound dressing materials. Int. J. Biol. Macromol. 43(5), 456–462 (2008). 48 Rossi S, Faccendini A, Bonferoni MS et al. ‘Sponge-like’ dressings based on biopolymers for the delivery of platelet lysate to skin chronic wounds. Int. J. Pharm. 440(2), 207–215 (2012). 49 Deng C-M, He L-Z, Zhao M, Yang D, Liu Y. Biological properties of the chitosan-gelatin sponge wound dressing. Carbohyd. Polym. 69(3), 583–589 (2007).

37 Murakami K, Aoki H, Nakamura S et al. Hydrogel blends of chitin/chitosan, fucoidan and alginate as healing-impaired wound dressings. Biomaterials 31(1), 83–90 (2010).

50 Lu S, Gao W, Gu HY. Construction, application and biosafety of silver nanocrystalline chitosan wound dressing. Burns 34(5), 623–628 (2008).

38 Pawar HV, Tetteh J, Boateng JS. Preparation, optimization and characterization of novel wound healing film dressings loaded with streptomycin and diclofenac. Colloids Surf. B 102, 102–110 (2013).

51 Kim JO, Park JK, Kim JH et al. Development of polyvinyl alcohol-sodium alginate gel-matrix-based wound dressing system containing nitrofurazone. Int. J. Pharm. 359(1–2), 79–86 (2008).

39 Sung JH, Hwang M-R, Kim JO et al. Gel characterization and in vitro evaluation of minocylcine-loaded wound dressing with enhanced wound healing using polyvinyl alcohol and chitosan. Int. J. Pharm. 392(1–2), 232–240 (2010).

52 Schneider A, Wang XY, Kaplan DL, Garlick JA, Egles C. Biofunctionalised electrospun silk mats as a topical bioactive dressing for accelerated wound healing. Acta Biomater 5(7), 2570–2578 (2009).

40 Dong Y, Liu HZ, Xu L et al. A novel CHS/ ALG bi-layer composite membrane with sustained antimicrobial efficacy used as wound dressing. Chinese Chem. Lett. 21(8), 1011–1014 (2010). 41 Dias AMA, Braga MEM, Seabra IJ, Ferreira P, Gil MH, de Sousa HC. Development of natural-based wound dressings impregnated with bioactive compounds and using supercritical carbon dioxide. Int. J. Pharm. 408(1–2), 9–19 (2011).


Patent Review

as wound dressing. Colloid Surf. A 313–314, 183–188 (2008). 56 Unnithan AR, Barakat AM, Tirupathi Pichiah PB et al. Wound-dressing materials with antimicrobial activity from electrospun polyurethane-dextran nanofiber mats containing ciprofloxacin HCl. Carbohyd. Polym. 90(4), 1786–1793 (2012). 57 Costache MC, Qu H, Ducheyne P, Devore DI. Polymer-xerogel composites for controlled release wound dressings. Biomaterials 31(24), 6336–6343 (2010). 58 Seetharaman S, Natesan S, Stowers RS et al. A PEGylated fibrin-based wound dressing with antimicrobial and angiogenic activity. Acta Biomater. 7(7), 2787–2796 (2011). 59 Aziz Z, Abu SF, Chong NJ. A systematic review of silver-containing dressings and topical silver agents (used with dressings) for burn wounds. Burns 38(3), 307–318 (2012). n n

Excellent, comprehensive review of the application of silver-based dressings in burn wound management.

60 Yang J-Y, Huang C-Y, Chuang S-S, Chen C-C. A clinical experience of treating exfoliative wounds using nanocrystalline silver-containing dressings (Acticoat®). Burns 33(6), 793–797 (2007). 61 Visavadia BG, Honeysett J, Danford MH. Manuka honey dressing: an effective treatment for chronic wound infections. Br. J. Oral Maxillofac. Surg. 46(1), 55–56 (2008). 62 Vermeulen H, Westerbos SJ, Ubbink DT. Benefit and harm of iodine in wound care: a systematic review. J. Hosp. Infect. 76(3), 191–199 (2010). n

Interesting analysis of the clinical application of iodine-based formulations in wound management.

63 Atemnkeng MA, Plaizier-Vercammen J, Schuermans A. Comparison of free and bound iodine and iodide species as a function of the dilution of three commercial povidone-iodine formulations and their microbicidal activity. Inter. J. Pharm. 317(2), 161–166 (2006). 64 Selvaggi G, Monstrey S, Van Landuyt K, Hamdi M, Blondeel PH. The role of iodine in antisepsis and wound management: a reappraisal. Acta Chir. Belg. 103(3), 241–247 (2003).

53 Vasconcelos A, Gomes AC, Cavaco-Paulo A. Novel silk fibroin/elastin wound dressings. Acta Biomater 8(8), 3049–3060 (2012).

65 Noda Y, Fujii K, Fujii S. Critical evaluation of cadexomer-iodine ointment and povidoneiodine sugar ointment. Intern. J. Pharm. 372(1–2), 85–90 (2009).

54 Shalumon KT, Anulekha KH, Nair SV, Nair SV, Chennazhi KP, Jayakumar R. Sodium alginate/poly(vinyl alcohol)/nano ZnO composite nanofibers for antibacterial wound dressings. Int. J. Biol. Macromol. 49(3), 247–254 (2011).

66 Zhou J, Tun TN, Hong S-H et al. Development of a prototype wound dressing technology which can detect and report colonization by pathogenic bacteria. Biosens. Bioelectron. 30(1), 67–72 (2011).

55 Chen J-P, Chang G-Y, Chen J-K. Electrospun collagen/chitosan nanofibrous membrane


67 Böttcher-Haberzeth S, Biedermann T, Reichmann E. Tissue engineering of skin. Burns 36(4), 450–460 (2010).

357

Patent Review


68 Boyce ST, Goretsky MJ, Greenhalgh DG, Kagan RJ, Rieman MT, Warden GD. Comparative assessment of cultured skin substitutes and native skin autograft for treatment of full-thickness burns. Ann. Surg. 222(6), 743–752 (1995).

80 Kirsner RS, Marston WA, Snyder RJ, Lee TD, Cargill DI, Slade HB. Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a Phase 2, multicentre, double-blind, randomized, placebo-controlled trial. Lancet 380(9846), 977–985 (2012).

92 Banks PG, Stokes LB. A novel topical oxygen treatment for chronic and difficult to heal wounds: case studies. J. Spinal Cord Med. 31(3), 297–301 (2008).

81 Natesan S, Wrice NL, Baer DG, Christy RJ. Debrided skin as a source of autologous stem cells for wound repair. Stem Cells 29(8), 1219–1230 (2011).

94 Massey PR, Sakran JV, Miller AM et al. Hyperbaric oxygen therapy in necrotizing soft tissue infections. J. Surg. Res. 177(1), 146–151 (2012).

70 Boyce ST, Williams ML. Lipid supplemented medium induces lamellar bodies and precursors of barrier lipids in cultured analogues of human skin. J. Invest. Dermatol. 101(2), 180–184 (1993).

82 Natesan S, Baer DG, Walters TJ, Babu M, Christy RJ. Adipose-derived stem cell delivery into collagen gels using chitosan microspheres. Tissue Eng. Part A 16(4), 1369–1384 (2010).

95 Chen C-E, Ko J-Y, Fong C-Y, Juhn R-J. Treatment of diabetic foot infection with hyperbaric oxygen therapy. Foot Ankle Surg. 16(2), 91–95 (2010).

71 Boyce ST, Supp AP, Harriger MD, Greenhalgh DG, Warden GD. Topical nutrients promote engraftment and inhibit wound contraction of cultured skin substitutes in athymic mice. J. Invest. Dermatol. 104(3), 345–349 (1995).

83 Seetharaman S, Natesan S, Stowers RS et al. A PEGylated fibrin-based wound dressing with antimicrobial angiogenic activity. Acta Biomater. 7(7), 2787–2796 (2011).

69 Boyce ST, Kagan RJ, Yakuboff KP et al. Cultured skin substitutes reduce donor skin harvesting for closure of excised, fullthickness burns. Ann. Surg. 235(2), 269–279 (2002).

72 Boyce ST, Warden GD, Holder IA. Noncytotoxic combinations of topical antimicrobial agents for use with cultured skin substitutes. Antimicrob. Agents Chemother. 39(6), 1324–1328 (1995). 73 Wood FM, Stoner ML, Fowler BV, Fear MW. The use of non-cultured autologous cell suspension and Integra® dermal regeneration template to repair full-thickness skin wounds in a porcine model: a one step process. Burns 33(6), 693–700 (2007). 74 Wood FM, Giles N, Stevenson A, Rea S, Fear M. Characterisation of the cell suspension harvested from the dermal epidermal junction using a ReCell® kit. Burns 38(1), 44–51 (2012). 75 Campanella SD, Rapley P, Ramelet A-S. A randomized controlled pilot study comparing Mepitel® and SurfaSoft ® on pediatric donor sites treated with ReCell®. Burns 37(8), 1334–1342 (2011). 76 Wood F, Martin L, Lewis D et al. A prospective randomized clinical pilot study to compare the effectiveness of Biobrane® synthetic wound dressing, with or without autologous cell suspension, to the local standard treatment regimen in pediatric scald injuries. Burns 38(6), 830–839 (2012). 77 Solanki NS, Nowak KM, Mackie IP, Greenwood JE. Using biobrane: techniques to make life easier. Eplasty 10, 586–591 (2010). 78 Gravante G, Di Fede MC, Araco A et al. A randomized trial comparing ReCell® system of epidermal cells delivery versus classical skin grafts for the treatment of deep partial thickness burns. Burns 33(8), 966–972 (2007). 79 Anderson JR, Fear MW, Phillips JK et al. A preliminary investigation of the reinnervation and return of sensory function in burn patients treated with INTEGRA®. Burns 37(7), 1101–1108 (2011).

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84 Mohammadi AA, Jafari SMS, Kiasat M et al. Effect of fresh human amniotic membrane dressing on graft take in patients with chronic burn wounds compared with conventional methods. Burns 39(2), 349–353 (2012). n

Interesting clinical report on the rapid re-epithelialization and bacteriostatic activity of human amniotic membrane-based dressings for burn wounds.

85 Chua AWC, Ma DR, Song IC, Phan TT, Lee ST, Song C. In vitro evaluation of fibrin mat and Tegaderm™ wound dressing for the delivery of keratinocytes – implications of their use to treat burns. Burns 34(2), 175–180 (2008). 86 Allen-Hoffmann BL, Schlosser SJ, Ivarie CAR, Sattler CA, Meisner LF, O’Connor SL. Normal growth and differentiation in a spontaneously immortalized near-diploid human keratinocyte cell line, NIKS. J. Invest. Dermatol. 114(3), 444–455 (2000). 87 Barker JA, Carlson GL. Managing the open wound: indications for topical negative pressure therapy. Surgery 29(10), 507–512 (2011). 88 Ubbink DT, Westerbos SJ, Evans DL, Vermeulen LH. Topical negative pressure for treating chronic wounds. Cochrane Database Syst. Rev. 3, CD001898 (2008).

93 Lipsky BA, Berendt AR. Hyperbaric oxygen therapy for diabetic foot wounds. Diabetes Care 33 (5), 1143–1145 (2010).

96 Gill AL, Bell CAN. Hyperbaric oxygen: its uses, mechanisms of action and outcomes. Q JM 97(7), 385–395 (2004). n

Excellent review of the role of hyperbaric oxygen therapy in a variety of clinical conditions including infected skin grafts and noting ambiguous results with respect to thermal burns.

97 Wasiak J, Bennett M, Cleland HJ. Hyperbaric oxygen as adjuvant therapy in the management of burns: can evidence guide clinical practice? Burns 32 (5), 650–652 (2006). 98 Low WL, Martin C, Hill DJ, Kenward MA. Antimicrobial efficacy of silver ions in combination with tea tree oil against Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Int. J. Antimicrob. Agents 37(2), 162–165 (2011). 99 Cole MR, Li M, El-Zahab B, Janes ME, Hayes D, Warner IM. Design, synthesis, and biological evaluation of b-lactam antibioticbased imidazolium- and pyridinium-type ionic liquids. Chem. Biol. Drug Des. 78(1), 33–41 (2011).

■■ Patents 101 Chi2Gel Ltd: US8153612 (2012). 102 Zimmer, Inc.: US8110242 (2012). 103 Taiwan Textile Research Institute: US8173171 (2012). 104 Bayer Material Science AG: US7947863 (2011). 105 Zimmer GmbH: US7985781 (2011).

89 Tawfick W, Sultan S. Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU)? A parallel observational comparative study. Eur. J. Vasc. Endovasc. Surg. 38(1), 125–132 (2009).

106 Incept LLC: US8105622 (2012).

90 Roe DF, Gibbins BL, Ladizinsky DA. Topical dissolved oxygen penetrates skin: model and method. J. Surg. Res. 159(1), e29–e36 (2010).

110 Advanced Medical Solutions Ltd: US8158845 (2012).

91 Landau Z, Sommer A, Miller EB. Topical hyperbaric oxygen and low-energy laser for the treatment of chronic ulcers. Eur. J. Intern. Med. 17 (4), 272–275 (2006).

112 Trustees of Tufts College and University of Massachusetts Foundation, Inc.: WO008842 (2011).


107 Zimmer, Inc.: US7731988 (2010). 108 Convatec Technologies Inc.: US7759539 (2012). 109 Convatec Technologies Inc.: US7759537 (2010).

111 Spiber Technologies AB: EP2243792 (2010).



113 Spintec Engineering GmbH: EP2253336 (2010).

Patent Review

144 Shiseido Company, Ltd: US7645595 (2010).

■■ Websites

114 KAO Corporation: US0259518 (2011).

145 Worcester Polytechnic Institute: US0171180 (2011).

201 British National Formulary Online. www.bnf.org

115 Polyremedy, Inc.: US8237007 (2012).

146 Medivas, LLC: US7794706 (2010).

116 Pure Bioscience: US7732486 (2010).

147 Stratatech Corporation: US7955790 (2011).

117 3M Innovative Properties Company: US8192764 (2012).

148 Stratech Corporation: US6846675 (2005).

202 Ecolab Videne® Antiseptic Solution. www.uk.ecolab.eu/all-applications/hand-andskin-care/skin-hygiene/category/antisepticsskin/product/videneR-antiseptic-solution. html

118 Tissue Technologies, LLC : US8187626 (2012). 119 Exciton Technologies Inc.: US7687076 (2010). 120 Paul Hartmann AG: US8118792 (2012). 121 Argentum Medical, LLC: US8118791 (2012). 122 Kimberly-Clark Worldwide, Inc.: US8203029 (2012).

149 National Defense Medical Center: US8097274 (2012). 150 Technische Universiteit Eindhoven: EP2317489 (2011). 151 The Thailand Research Fund, The Prince of Songkla University & Axis IP Holding PTE Ltd: WO154569 (2009). 152 Woodroof EA, Enright MK: US7815931 (2010).

203 Ecolab Videne® Alcoholic Tincture. www.uk.ecolab.eu/all-applications/hand-andskin-care/skin-hygiene/category/antisepticsskin/product/videneR-alcoholic-tincture.html 204 Betadine® Cream. www.mundipharma.com.ph/multipage_ uploads/1307/11081/Betadine_cream.pdf

123 Brennen Medical, Inc.: US8231894 (2012).

153 Wisconsin Alumni Research Foundation: US7935364 (2011).

124 Feng Chia University: US7803424 (2010).

154 Stratatech Corp.: US0258001 (2006).

205 BetaisodonaTM Ointment. www.mundipharma.de/fileadmin/ mundipharma.de/mundipharma/public/pdf/ gebrauchsinformationen/GI_Beta_Salbe.pdf

125 Chung Shan Institute of Science and Technology, Armaments Bureau, MND: US7462753 (2008).

155 Tyco Healthcare Group LP: US8257328 (2012).

206 Savlon® Dry. www.savlon.co.uk

156 George F: WO011148 (2010).


157 Stryker Corporation: US8226586 (2012).

207 Savlon® Dry. www.medicinescomplete.com/mc/bnf/ current/PHP8158-savlon-dry.htm#PHP8158savlon-dry

127 Coloplast A/S: US7329417 (2008). 128 Ossur, HF: US7459598 (2008). 129 Vomaris Innovations, Inc.: US7813806 (2010). 130 Tyco Healthcare Group LP: US7799965 (2010). 131 Waikatolink Ltd: EP1237561 (2004). 132 Brightwake Ltd: WO010399 (2010). 133 Manuka Medical Ltd: US0269879 (2012).

158 Tyco Healthcare Group LP: US0253302 (2012). 159 Tyco Healthcare Group LP: WO138514 (2012). 160 Hyperbaric Technologies, Inc.: US0144599 (2011). 161 Hyperbaric Technologies, Inc.: US0172612 (2011). 162 Greener B, Hicks J, Hartwell EY: WO156709 (2009).

134 Repsco LLP: US7871646 (2011).

163 Boehringer Technologies, LP: US7857806 (2010).

135 Wood, Herron & Evans, LLP: US0287223 (2005).


136 Tissuetech, Inc.: US7494802 (2009).

165 Lewis PA: WO102380 (2009).

137 Peyman GA: US0031471 (2007).

166 Lewis PA: US0210239 (2008).

138 Tissuetech, Inc.: US8153162 (2012).

167 Aoti, Inc.: US7540283 (2009).

139 TissueTech, Inc.: WO094247 (2006). 140 International Centre for Cardio Thoracic and Vascular Disease: WO044408 (2009).

168 Trustees of the University of Pennsylvania, Velazquez OC & Gallagher KA: WO118370 (2008).

141 Osiris Therapeutics, Inc.: WO103455 A1 (2011).

169 Inotec AMD Ltd, Vinton MF & Hurst A: WO020759 (2010).

142 Osiris Therapeutics, Inc: US0256202 (2011).

170 Inotec AMD Ltd & Vinton MF: US0046603 (2012).

143 Tissue Tech, Inc.: US8182841 B2 (2012).



208 Ayrton Saunders. www.ayrtons.com 209 Betadine®. www.medicinescomplete.com/mc/bnf/ current/PHP8157-betadine.htm?q=betadine &t=search&ss=text&p=1#PHP8157-betadine 210 Prevail® Cardinal Health. www.cardinal.com/us/en/ distributedproducts/ASP/4VAIL. asp?cat=med_surg-orig 211 Inadine® Systagenix. www.systagenix.com/our-products/letsprotect/inadine-33 212 Smith & Nephew. IODOSORB: Cadexomer Matrix with Iodine. http://global.smith-nephew.com/master/ IODOSORB_27565.htm 213 Wound Source. IODOFLEX* Pad Absorbent Antimicrobial. www.woundsource.com/product/iodoflexpad-absorbent-antimicrobial 214 Undersea and Hyperbaric Medical Society. http://membership.uhms.org/?page=Indicati ons&hhSearchTerms=hyperbaric+and+oxyge n+and+therapy

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