Clinical REVIEW Role of collagen in wound management Collagen is structurally and functionally a key protein of the extracellular matrix which is also involved in scar formation during the healing 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 tissue, 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 Wound healing down first, with the proportion of type growth factors Dressings I increasing as scar formation progresses 8 Interactions between enzymes 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 injury, gradually ollagen is the unique, triple reaching a maximum of 70% of that of Collagen in chronic wound 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, fibronectin, 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 fibroblasts, at least unwounded tissue strength. Trengrove et al, 1999; Hansen et al, 21 genetically distinct collagens 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 54 Wounds UK, 2011, Vol 7, No 2 Leaper/Harding.indd 2 16/06/2011 12:21 Clinical REVIEW 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 (antibiotics) antimicrobials is pivotal to preparation of the wound bed, before 8 Cellular differentiation, angiogenesis 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 macrophages, neutrophils) 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 Cell 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 capillary 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 dressing 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 fibroblast production abdominal wound repair (Holl-Allen, can form abnormal scars, 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