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Clinical REVIEW Role of in wound management

Collagen is structurally and functionally a key protein of the which is also involved in formation during the of connective tissues. Many collagen dressings have been developed to enhance wound repair, particularly of non-infected, chronic, indolent skin ulcers. The use of collagen dressings is supported by relatively sparse and insufficient scientific data. This review identifies the supporting evidence for the use of the dressings which are available, often with widely different claimed advantages and modes of action, and considers future developments and assessment of collagen dressings.

Aravindan Rangaraj, Keith Harding, David Leaper

The principal function of collagen is 8 Protein synthesis in the extracellular KEY WORDS to act as a scaffold in connective , matrix (ECM) mostly in its type I, II and III forms. In 8 Synthesis and release of Collagen early healing wounds, type III is laid inflammatory cytokines and down first, with the proportion of type growth factors Dressings I increasing as scar formation progresses 8 Interactions between which Chronic wounds and is remodelled. Collagen deposition remodel the ECM, including matrix and remodelling contribute to the metalloproteinases (MMPs) and their increased tensile strength of the wound, tissue inhibitors (TIMPs), which are which is approximately 20% of normal summarised in Table 1. by three weeks after , gradually ollagen is the unique, triple reaching a maximum of 70% of that of Collagen in healing helix protein molecule, which normal skin (Desmouliere et al, 1995). In chronic wounds involving skin, defined Cforms the major part of the Although epithelial structures can heal as those which do not heal in optimal extracellular dermal matrix (ECM), by regeneration, connective tissues conditions within six weeks (Mustoe together with the glycosaminoglycans, cannot and depend on the process et al, 2006), the complex interactive proteoglycans, laminin, , elastin of repair mostly by the formation of processes described above are and cellular components (Hopkinson, collagenous scar tissue (Berry et al, deranged. Conversely, there is not a lack 1992a, b; Berry et al, 1998; Enoch and 1998), predominantly of type I, which of normal healing but often hyperactivity Leaper, 2008). Collagen is the most serves to restore tissue continuity, which is out of phase, non-progressive, abundant protein in animal tissues and strength and function. Collagen is a and with a persistent, uncoordinated, accounts for 70–80% of the dry weight brittle substitute for unwounded tissue, mixed acute and chronic inflammatory of the dermis (Hopkinson, 1992a). and scar tissue rarely exceeds 70% of response (Schultz and Mast, 1998; Mainly produced by , at least unwounded tissue strength. Trengrove et al, 1999; Hansen et al, 21 genetically distinct have 2003; Kim et al, 2003; Diegelmann and currently been identified, with six of In embryos, it has been shown that Evans, 2004), which has also been well these being present in the skin. Collagen cutaneous wounds can heal without a summarised at molecular level (Agren type I comprises approximately 70% of scar (Rowlatt et al, 1979; Moulin et al, and Werthen, 2007). The most common collagen in the skin, with type III being 2005; Redd et al, 2004), but this has yet cause of this ‘hard-to-heal’ chronicity is 10%, and trace amounts of collagen type to be translated into a tissue engineered infection, which can be hard to define IV, V, VI and VII (Uitto et al, 1989; Hay, alternative solution. In addition to being and range from increasing microbial 1991). the main component of scar tissue, colonisation, which is inevitable in open collagen has a key role in: wounds healing by secondary intention, Aravindan Rangaraj is Clinical Research Fellow; Keith 8 The control of the inflammatory through to increasing contamination and Harding is Head of Section of Wound Healing; David response to injury and subsequent clinically overt infection. The concept of Leaper is Visiting Professor; all at Department of repair with functions that influence ‘critical colonisation”, or alternatively an Dermatology and Wound Healing, School of Medicine, cellular mitogenesis, differentiation excessive local bioburden, which acts as Cardiff University, Cardiff and migration a prequel to infection, is widely accepted

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but is not accurately measurable (White and Cutting, 2008). Nevertheless, control Table 1 of colonisation and infection through Influence of collagen in the inflammatory response to injury local, topical (antiseptics) and systemic () antimicrobials is pivotal to preparation of the wound bed, before 8 Cellular differentiation, and mitogenesis wound closure following contraction through formation of ‘healthy’ granulation 8 Protein synthesis and ECM deposition tissue and epithelialisation. Other factors 8 Cellular migration (keratinocytes and epithelialisation, fibroblasts, monocyte/ critical to the successful preparation , ) of the wound bed include scrupulous debridement of non-viable tissue and 8 Induction of collagenases foreign material, by all methodologies 8 Wound contraction available (including sharp surgical debridement and topical negative 8 Platelet aggregation and induction clotting cascades pressure [TNP] therapy) (Wolcott et 8 Induction of growth factors and cytokines through degradation products al, 2009). This can only be achieved in conjunction with optimal holistic care; 8 surface receptors (integrins) in cell-signalling and induction of other ECM molecules again through local (such as attention and proteins to adequate arterial supply or pressure References: relief) and systemic (such as diabetic Doillon and Silver, 1986; Montesano et al, 1983; Albini and Adelman-Grill, 1985; Newman and Tucci, control) interventions. Once these 1990; Petersen et al, 1990; Shaw et al, 1990; Klein et al, 1991; Schiro et al, 1991; Hynes, 1992; Madri criteria are met, with a prepared wound and Marx, 1992; Scharfetter-Kochanek et al, 1992; Sudbeck et al, 1994; Krieg, 1995; Clark, 1996; bed and control of any underlying Schultz and Mast, 1998; Pilcher et al, 1997, 1999; Feng et al, 1999; Davis et al, 2000; Steffensen et pathological processes, successful healing al, 2001; Armstrong and Jude, 2002; Ruszczak, 2003; Diegelmann and Evans, 2004; Mirastschijski et can occur. It is at this stage that collagen al, 2004; Schultz et al, 2005; Ulrich et al, 2005; Agren and Werthen, 2007; Cavallini, 2007; Clark et al, or collagen-derived dressings may have a 2007; Hodde and Johnson, 2007; DiCosmo, 2009; Schultz and Wysocki, 2009 role in wound healing strategies.

Along with the critical collagen functions listed in Table 1, several other angiogenesis (Hunt and Pai, data and non-comparative case factors relating to poor wound healing, 1975), and an abnormal excessive reports. The use of collagen in wound directly affect collagen metabolism. local inflammatory response leading management has not yet been clearly Included among the extrinsic factors to abnormal, hypertrophic or keloid translated into a platform for widespread is diabetes, in which hyperglycaemia scarring (Wang et al, 2007). clinical use, as these studies only offer reduces normal collagen production evidence for collagen as a matrix and induces non-enzymatic glycosylation Collagen dressings in wound management and not as an active agent. of collagen and keratin, leading to The use of collagen dressings may seem formation of abnormal rigid collagen attractive in view of their functions to: By comparison, the use of collagen and adding to tissue breakdown (Black 8 Inhibit or deactivate MMPs materials as a scaffold in hernia and et al, 2003). Collagen over production 8 Increase production abdominal wound repair (Holl-Allen, can form abnormal , which impede and permeation 1984; Buinewicz and Rosen, 2004; Parker wound healing (Gault, 1999). A chronic 8 Aid in the uptake and bioavailability et al, 2006; Baillie et al, 2007; Jehle et al, wound burden among the elderly has of fibronectin 2007) seems to be clinically and cost- been documented (Wilkinson et al, 8 Help to preserve leukocytes, effective, but their use as a dressing in 1993), and much of this age-related, macrophages, fibroblasts, and healing indolent chronic skin wounds, delayed wound healing is caused epithelial cells healing by secondary intention, has yet by impaired collagen synthesis and 8 Assist in the maintenance of to be convincingly proven, despite the increased degradation (Ashcroft et al, the chemical and thermostatic fact that there are many such products 2002). Smoking affects the synthesis microenvironment of the wound already available (Table 2). rates of collagen, MMP and TIMP1 (Burton et al, 1978; Doillon et al, levels in the skin, leading to imbalances 1984, 1986, 1988; Palmieri, 1992; This review looks at the in collagen turnover (Knuutinen et Brett, 2008). currently available data to explore al, 2002). Intrinsic factors include and substantiate any case for the variations in oxygen tension which These data suggest a compelling development and clinical use of collagen can alter fibroblast proliferation and theoretical role for collagen as a dressing sheet dressings, paste or fleece for the collagen production, and also enhance in wound management, but are relatively stimulation of closure in indolent ‘hard- the structural support required for limited, being derived from experimental to-heal’ chronic wounds.

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Skin, with its inherent epidermis and found in chronic wounds. However, compromised. While it is appreciated that dermis, provides the ideal cover for any they come at an expensive price for the gold standard of complete healing wound. For this reason, a whole range introduction into wide clinical practice has to be replaced by surrogates of of autologous skin graft techniques are and it could be argued that much more healing rates (Gelfand et al, 2002) using, available to replace lost skin, from split- extensive evidence is needed for their for example, computerised planimetry, thickness skin grafts to complex pedicle adoption. It has also been argued that there is often too much emphasis on or free microvascular myocutaneous there is no replacement for an autograft poor clinical assessments of presence of flaps, but these may not be sufficient to (Paul, 2008). The application of these infection or , pain, handling cover the widespread skin loss which skin substitutes vary from simple direct of exudate, odour, numbers of dressing may occur after extensive burns (Purna application as cell monolayers to polymer, changes and dressing acceptability or and Babu, 2000). All these grafts give or animal-derived collagen scaffolds, and tolerance, and inadequate ‘add-on’ primary cover with an optimal chance of their diversity deserves a separate review. attempts at cost-effectiveness (although healing, and have also been widely used The interaction of collagen alone within one study, using a Markov-based to cover chronic wounds in which healing the wound is also considerable and is the health economic analysis did suggest is stalled despite adequate preparation basis of this review. that Promogran may be cost-effective; of the wound bed to optimise closure by Ghatnekar et al, 2002). These are, of secondary intention. Nevertheless, these Collagen and acellular dermal skin course, criticisms that can be levelled grafted wounds are at risk of failure or substitute dressings at almost all trials involving the healing infection (of both donor and recipient Promogran® (Systagenix) of chronic ulcers and, ideally, more high sites), with considerable subsequent This product deserves special interest, as quality research is genuinely needed. morbidity. Several techniques have it has been the subject of prolonged and been designed to extend the area of in-depth research and marketing. It is a Nevertheless, there is a consistency split-thickness grafts available, such as matrix dressing containing regenerated in the clinical trials involving Promogran meshing, or to make harvest simpler and cellulose and collagen which has been to faster healing rates and better accessible, as in pinch grafting, but they shown experimentally to modulate outcomes. Like so many other dressings, still inflict an injury to healthy, intact skin proteases, metalloproteinases and it has also been combined with silver to (Horch et al, 2005). elastase in open wounds (Cullen et al, improve control of bioburden. 2002a; Hart et al, 2002) by ‘protecting’ The use of dermal allografts still platelet-derived (PDGF) Other collagen acellular dermal matrix dressings has a place (Pianigiani et al, 2004), but and other growth factors in the wound. There have been several sources of progress has turned to the evolution of There is also clinical trial evidence that collagen for use as a dermal matrix (Table tissue engineering from the development Promogran may be able to handle 2). Some have been used as temporary of monolayer culture of keratinocytes exudate and accelerate healing in venous dressings in burn care therapy for many through to the use of collagen, and diabetic ulcers (Vin et al, 2002; Veves years to optimise the wound healing or synthetic polymers et al, 2002), but the clinical significance process or improve post-burn scarring as carriers of live, human-derived of this is open to doubt (Cullen et al, (Robson et al, 1973; Purna and Baboo, fibroblasts and keratinocytes (Horch 2002b). There is a plethora of case 2000; Ehrenreich and Rusczak, 2006; et al, 2000). Even freeze-dried cellular reports and small patient series, which Shores et al, 2007). The dermal skin dressings with a carrier matrix have been are supportive, but these have a high risk substitute Integra® (Integra Life Sciences), shown to be effective in healing wounds of publication bias. which is a bi-layer bovine collagen of diverse origins (Nanchahal and Ward, and polysiloxane dressing, has been 1992; Gentzkow et al, 1996; Munster, In the authors’ opinion, the difficulty extensively used for this purpose, but 1996; Sabolinski et al, 1996; Leigh et with the clinical studies and attempts at there have been few prospective RCTs al, 1987; Polak et al, 1997; Falanga and randomised controlled trials (RCTs) comparing it with other available skin Sabolinsky, 1999; Tay et al, 2000; Veves et is that: substitutes (Nguyen and Dickson, 2006). al, 2002; Bello and Falabella, 2002; Omar 8 They are underpowered, with et al, 2002; Curran and Plosker, 2002; randomisation which is poor or AlloDerm® (Life CellCorp), an Caravaggi et al, 2003; Krishnamoorthy not defined acellular dermal matrix derived from et al, 2003; Ehrlich, 2004; Harding et al, 8 They often compare the dressing cadaveric skin, and Biobrane®, (Smith 2005; Cavorsi et al, 2006; Shealy and with an ineffective ‘standard’ therapy and Nephew), a porcine collagen with a DeLoach, 2006; Ehrenreich and Ruszczak, (often bland Vaseline gauze) layer of silicone, have also been widely 2006; Vanschiedt et al, 2007). 8 Evaluations are unblinded and used for burn management (McHugh et subjective (and therefore biased), al, 1986; Wainwright, 1995). Adequate These advances in the production and made by untrained, unvalidated trials studying their use, and other of artificial skin substitutes have the observers and methodology. similar dressings, in different wound potential to replace lost functional cells, types other than burns are also awaited. which can also successfully orchestrate Often there are high dropout rates so All these biological dressings, including the dysfunctional wound healing process that assessment even up to 12 weeks is porcine and bovine collagen as well

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has been experimentally studied as an Table 2 ECM graft with subsequent successful Currently available acellular collagen and dermal matrix products for wound care use in multicentre clinical trials (Mostow (the list is not exhaustive) et al, 2005; Niezgoda et al, 2005). Although showing a difference in

® healing rates, favouring the ECM matrix Permacol porcine dermis Tissue Science Laboratroies dressing, both studies were relatively Integra® bovine tendon/synthetic polysiloxane Integra Lifesciences underpowered. The first involved 120 patients with relatively small venous Puracol Bovine collagen Medline Industries ulcers and reached a statistically Promogran® collagen/regenerated cellulose Systagenix significant difference compared with standard compression alone (p<0.02); Fibracol® collagen/alginate Systagenix but the second, involving 73 patients Promogran Prisma® collagen/Ag Systagenix with diabetic foot ulcers, did not reach Oasis® porcine small intestine submucosa Cook Biotech significance compared with topically- applied platelet-derived growth factors Biostep® porcine collagen/alginate/CMC +/- Ag Smith and Nephew (PDGF). In the venous leg ulcer study, Colactive porcine collagen/alginate +/- Ag Smith and Nephew more healed ulcers remained healed at six months after treatment with the ® Catrix bovine carilage (powder) Lescarden Inc ECM matrix dressing, compared with the Cellerate® bovine collagen Wound Care Innovations patients treated with compression alone.

™ Collieva bovine collagen CollMed Laboratories The use of growth factors has Medifil® bovine collagen gel BioCore proven to be inconsistent, and seems to have fallen off the wound healing Skintemp bovine collagen BioCore formulary (Fu et al, 2005). However, Matriderm® collagen/elastin Suwelak the clinical evaluation of collagen Decutastar® equine collagen ADL still promises that there may be a therapeutic role to orchestrate the Septocoll® E collagen fleece/gentamicin Biomet healing of ‘hard-to-heal’, uninfected, Colladerm bovine/equine/gentamicin Innocoll chronic wounds which have a prepared wound bed. The many interactions with ® AlloDerm human cadaver de-epithelialised skin LifeCell Corp the ECM (Table 1) suggest that collagen Cymetra® particulate alloderm LifeCell Corp is a suitable candidate to initiate healing or restore the cellular milieu in stalled Mediskin porcine dermis Brennan Medical wounds (Agren and Werthen, 2007). EZ-Derm™ aldehyde linked porcine dermis Brennan Medical Again, more research is needed, but the cost of further adequate RCTs in Biobrane® porcine collagen/silicone membrane Smith and Nephew multicentre trials for clear scientific GraftJacket® human cadaver dermal matrix Wright Medical Technology proof and meta-analysis is prohibitive. There are plenty of case reports or * Dermagraft® (Advance Tissue Sciences) is freeze dried bovine collagen used as a carrier for short patient series that have evaluated human fibroblasts collagen matrix dressings to heal chronic ulcers, indicating success (Sabolinski, ® * Apligraf (Organogenesis) is a bi-layered dressing of cultured human epidermis bonded to bovine 1996; Yamada et al, 1999; Shealy and collagen containing human fibroblasts DeLoach, 2006).

Conclusions Functionally, collagen has a pivotal role as that from human origin, have been as silver and gentamicin. There are by means of its wide-ranging functions, refined and prepared through several several types of availability ranging from spanning the spectrum of processes different processes of purification to fleeces, sponges, films and pastes to bi- involved in a healing wound. However, render them non-antigenic and sterile layered sheet dressings, which have all collagen dressings have only been (Huang et al, 2004; Rosales et al, 2004; been previously well-reviewed (Shores scientifically proven to be effective Rudnick, 2006; Nataraj et al, 2007). et al, 2007; Brett, 2008). exogenously, as a substrate and viable Like Promogran, they have since been biomaterial. Its appealing endogenous linked with other materials, for example, The use of pig, small intestinal, functions by means of a dressing are yet alginates and antimicrobial agents, such submucosa (Oasis® Wound Matrix) to be proven. Is it then worth the effort

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of producing a new collagen dressing, References Cullen B, Watt PW, Lundqvist C, et al or evaluating collagen dressings further, (2000a) The role of oxidised regenerated Agren MS, Werthen M (2007) The ideally supported by a multicentre, cellulose/collagen in chronic wound repair extracellular matrix in wound healing: and its potential mechanism of action. Int J randomised, controlled trial? From a closer look at therapeutics for chronic Biochem Cell Biol 1307: 1–13 a cost point of view alone, it would wounds. Lower Extremity Wounds 6: 82–97 Cullen B, Smith R, McCulloch E, et al be prohibitive; let alone the logistics Albini A, Adelman-Grill BC (1985) (2002b) Mechanism of action of Promogran, of mounting such a trial to show any Collagenolytic cleavage products of collagen a protease modulating matrix, for the clear-cut advantage. There are several, type I as chemoattractants for human dermal treatment of diabetic foot ulcers. Wound Rep possibly already too many, collagen fibroblasts. Eur J Cell Biol 36: 104–7 Regen 10: 16–25 dressings available, so why should Armstrong DG, Jude EB (2002) The role of Curran MP, Plosker GL (2002) Bilayered another, which offers no particularly matrix metalloproteinases in wound healing. bioengineered skin substitute (Apligraf). A Am Podiatrists Med Assoc 92: 12–18 special or extra effectiveness or price review of its use in the treatment of venous leg ulcers and diabetic foot ulcers. Biodrugs advantage be worth marketing? 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