Wound Healing Collagen

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Wounds UK , 2011, Vol 7, No 2

Role of collagen in

wound management

Aravindan Rangaraj, Keith Harding, David Leaper

Aravindan Rangaraj is Clinical Research Fellow; KeithHarding is Head of Section of Wound Healing; DavidLeaper is Visiting Professor; all at Department ofDermatology and Wound Healing, School of Medicine,Cardiff University, Cardiff

Collagen is structurally and functionally a key protein of the extracellular matrix which is also involved inscar formation during the healing of connective tissues. Many collagen dressings have been developed toenhance wound repair, particularly of non-infected, chronic, indolent skin ulcers. The use of collagen dressingsis supported by relatively sparse and insufcient scientic data. This review identies the supporting evidencefor the use of the dressings which are available, often with widely different claimed advantages and modes ofaction, and considers future developments and assessment of collagen dressings.

C ollagen is the unique, triplehelix protein molecule, whichforms the major part of theextracellular dermal matrix (ECM),

together with the glycosaminoglycans,proteoglycans, laminin, bronectin, elastinand cellular components (Hopkinson,1992a, b; Berry et al, 1998; Enoch andLeaper, 2008). Collagen is the mostabundant protein in animal tissues andaccounts for 7080% of the dry weightof the dermis (Hopkinson, 1992a).Mainly produced by broblasts, at least21 genetically distinct collagens havecurrently been identied, with six of

these being present in the skin. Collagen type I comprises approximately 70% ofcollagen in the skin, with type III being10%, and trace amounts of collagen typeIV, V, VI and VII (Uitto et al, 1989; Hay,1991).

8 Protein synthesis in the extracellularmatrix (ECM)

8 Synthesis and release ofinammatory cytokines andgrowth factors

8 Interactions between enzymes whichremodel the ECM, including matrixmetalloproteinases (MMPs) and their

tissue inhibitors (TIMPs), which aresummarised in Table 1 .

Collagen in chronic wound healingIn chronic wounds involving skin, denedas those which do not heal in optimalconditions within six weeks (Mustoeet al, 2006), the complex interactiveprocesses described above arederanged. Conversely, there is not a lackof normal healing but often hyperactivitywhich is out of phase, non-progressive,and with a persistent, uncoordinated,mixed acute and chronic inammatoryresponse (Schultz and Mast, 1998;Trengrove et al, 1999; Hansen et al,2003; Kim et al, 2003; Diegelmann andEvans, 2004), which has also been wellsummarised at molecular level (Agrenand Werthen, 2007). The most commoncause of this hard-to-heal chronicity isinfection, which can be hard to deneand range from increasing microbialcolonisation, which is inevitable in openwounds healing by secondary intention,

through to increasing contamination andclinically overt infection. The concept ofcritical colonisation, or alternatively anexcessive local bioburden, which acts asa prequel to infection, is widely accepted

KEY WORDS

CollagenWound healingDressingsChronic wounds

The principal function of collagen is to act as a scaffold in connective tissue,mostly in its type I, II and III forms. Inearly healing wounds, type III is laiddown rst, with the proportion of typeI increasing as scar formation progressesand is remodelled. Collagen depositionand remodelling contribute to theincreased tensile strength of the wound,which is approximately 20% of normalby three weeks after injury, graduallyreaching a maximum of 70% of that ofnormal skin (Desmouliere et al, 1995).Although epithelial structures can healby regeneration, connective tissuescannot and depend on the processof repair mostly by the formation ofcollagenous scar tissue (Berry et al,1998), predominantly of type I, whichserves to restore tissue continuity,strength and function. Collagen is abrittle substitute for unwounded tissue,and scar tissue rarely exceeds 70% ofunwounded tissue strength.

In embryos, it has been shown thatcutaneous wounds can heal without ascar (Rowlatt et al, 1979; Moulin et al,2005; Redd et al, 2004), but this has yet

to be translated into a tissue engineeredalternative solution. In addition to being

the main component of scar tissue,collagen has a key role in:8 The control of the inammatory

response to injury and subsequentrepair with functions that inuencecellular mitogenesis, differentiationand migration


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but is not accurately measurable (Whiteand Cutting, 2008). Nevertheless, controlof colonisation and infection throughlocal, topical (antiseptics) and systemic(antibiotics) antimicrobials is pivotal topreparation of the wound bed, beforewound closure following contraction

through formation of healthy granulation tissue and epithelialisation. Other factorscritical to the successful preparationof the wound bed include scrupulousdebridement of non-viable tissue andforeign material, by all methodologiesavailable (including sharp surgicaldebridement and topical negativepressure [TNP] therapy) (Wolcott etal, 2009). This can only be achieved inconjunction with optimal holistic care;again through local (such as attention

to adequate arterial supply or pressurerelief) and systemic (such as diabeticcontrol) interventions. Once thesecriteria are met, with a prepared woundbed and control of any underlyingpathological processes, successful healingcan occur. It is at this stage that collagenor collagen-derived dressings may have arole in wound healing strategies.

Along with the critical collagenfunctions listed in Table 1 , several otherfactors relating to poor wound healing,directly affect collagen metabolism.Included among the extrinsic factorsis diabetes, in which hyperglycaemiareduces normal collagen productionand induces non-enzymatic glycosylationof collagen and keratin, leading toformation of abnormal rigid collagenand adding to tissue breakdown (Blacket al, 2003). Collagen over production

can form abnormal scars, which impedewound healing (Gault, 1999). A chronicwound burden among the elderly hasbeen documented (Wilkinson et al,1993), and much of this age-related,delayed wound healing is causedby impaired collagen synthesis andincreased degradation (Ashcroft et al,2002). Smoking affects the synthesisrates of collagen, MMP and TIMP1levels in the skin, leading to imbalancesin collagen turnover (Knuutinen et

al, 2002). Intrinsic factors includevariations in oxygen tension whichcan alter broblast proliferation andcollagen production, and also enhance

the structural support required for

Table 1

Inuence of collagen in the inammatory response to injury

8 Cellular differentiation, angiogenesis and mitogenesis

8 Protein synthesis and ECM deposition

8 Cellular migration (keratinocytes and epithelialisation, broblasts, monocyte/ macrophages, neutrophils)

8 Induction of collagenases

8 Wound contraction

8 Platelet aggregation and induction clotting cascades

8 Induction of growth factors and cytokines through degradation products

8 Cell surface receptors (integrins) in cell-signalling and induction of other ECM moleculesand proteins

References:Doillon and Silver, 1986; Montesano et al, 1983; Albini and Adelman-Grill, 1985; Newman and T1990; Petersen et al, 1990; Shaw et al, 1990; Klein et al, 1991; Schiro et al, 1991; Hynes, 1992; Mand Marx, 1992; Scharfetter-Kochanek et al, 1992; Sudbeck et al, 1994; Krieg, 1995; Clark, 1996Schultz and Mast, 1998; Pilcher et al, 1997, 1999; Feng et al, 1999; Davis et al, 2000; Steffensen al, 2001; Armstrong and Jude, 2002; Ruszczak, 2003; Diegelmann and Evans, 2004; Mirastschijsal, 2004; Schultz et al, 2005; Ulrich et al, 2005; Agren and Werthen, 2007; Cavallini, 2007; Clark2007; Hodde and Johnson, 2007; DiCosmo, 2009; Schultz and Wysocki, 2009

capillary angiogenesis (Hunt and Pai,1975), and an abnormal excessivelocal inammatory response leading

to abnormal, hypertrophic or keloidscarring (Wang et al, 2007).

Collagen dressings in wound managementThe use of collagen dressings may seemattractive in view of their functions to:8 Inhibit or deactivate MMPs8 Increase broblast production

and permeation8 Aid in the uptake and bioavailability

of bronectin8 Help to preserve leukocytes,

macrophages, broblasts, andepithelial cells

8 Assist in the maintenance of the chemical and thermostaticmicroenvironment of the wound(Burton et al, 1978; Doillon et al,1984, 1986, 1988; Palmieri, 1992;Brett, 2008).

These data suggest a compelling theoretical role for collagen as a dressingin wound management, but are relativelylimited, being derived from experimental

data and non-comparative casereports. The use of collagen in woundmanagement has not yet been clearly

translated into a platform for widespreadclinical use, as these studies only offerevidence for collagen as a dressing matrixand not as an active agent.

By comparison, the use of collagenmaterials as a scaffold in hernia andabdominal wound repair (Holl-Allen,

1984; Buinewicz and Rosen, 2004; Parkeret al, 2006; Baillie et al, 2007; Jehle et al,2007) seems to be clinically and cost-effective, but their use as a dressing inhealing indolent chronic skin wounds,healing by secondary intention, has yet

to be convincingly proven, despite thefact that there are many such productsalready available (Table 2 ).

This review looks at thecurrently available data to explore

and substantiate any case for thedevelopment and clinical use of collagensheet dressings, paste or eece for thestimulation of closure in indolent hard-

to-heal chronic wounds.


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Skin, with its inherent epidermis anddermis, provides the ideal cover for anywound. For this reason, a whole rangeof autologous skin graft techniques areavailable to replace lost skin, from split-

thickness skin grafts to complex pedicleor free microvascular myocutaneousaps, but these may not be sufcient tocover the widespread skin loss whichmay occur after extensive burns (Purnaand Babu, 2000). All these grafts giveprimary cover with an optimal chance ofhealing, and have also been widely used

to cover chronic wounds in which healingis stalled despite adequate preparationof the wound bed to optimise closure bysecondary intention. Nevertheless, thesegrafted wounds are at risk of failure orinfection (of both donor and recipientsites), with considerable subsequentmorbidity. Several techniques havebeen designed to extend the area ofsplit-thickness grafts available, such asmeshing, or to make harvest simpler andaccessible, as in pinch grafting, but theystill inict an injury to healthy, intact skin(Horch et al, 2005).

The use of dermal allografts stillhas a place (Pianigiani et al, 2004), butprogress has turned to the evolution of

tissue engineering from the developmentof monolayer culture of keratinocytes

through to the use of collagen,hyaluronic acid or synthetic polymersas carriers of live, human-derivedbroblasts and keratinocytes (Horchet al, 2000). Even freeze-dried cellulardressings with a carrier matrix have beenshown to be effective in healing woundsof diverse origins (Nanchahal and Ward,

1992; Gentzkow et al, 1996; Munster,1996; Sabolinski et al, 1996; Leigh etal, 1987; Polak et al, 1997; Falanga andSabolinsky, 1999; Tay et al, 2000; Veves etal, 2002; Bello and Falabella, 2002; Omaret al, 2002; Curran and Plosker, 2002;Caravaggi et al, 2003; Krishnamoorthyet al, 2003; Ehrlich, 2004; Harding et al,2005; Cavorsi et al, 2006; Shealy andDeLoach, 2006; Ehrenreich and Ruszczak,2006; Vanschiedt et al, 2007).

These advances in the productionof articial skin substitutes have thepotential to replace lost functional cells,which can also successfully orchestrate

the dysfunctional wound healing process

compromised. While it is appreciated that the gold standard of complete healinghas to be replaced by surrogates ofhealing rates (Gelfand et al, 2002) using,for example, computerised planimetry,

there is often too much emphasis onpoor clinical assessments of presence ofinfection or inammation, pain, handlingof exudate, odour, numbers of dressingchanges and dressing acceptability or

tolerance, and inadequate add-onattempts at cost-effectiveness (althoughone study, using a Markov-basedhealth economic analysis did suggest

that Promogran may be cost-effective;Ghatnekar et al, 2002). These are, ofcourse, criticisms that can be levelledat almost all trials involving the healingof chronic ulcers and, ideally, more highquality research is genuinely needed.

Nevertheless, there is a consistencyin the clinical trials involving Promogran

to faster healing rates and betteroutcomes. Like so many other dressings,it has also been combined with silver toimprove control of bioburden.

Other collagen acellular dermal matrix dressingsThere have been several sources ofcollagen for use as a dermal matrix ( Table2 ). Some have been used as temporarydressings in burn care therapy for manyyears to optimise the wound healingprocess or improve post-burn scarring(Robson et al, 1973; Purna and Baboo,2000; Ehrenreich and Rusczak, 2006;Shores et al, 2007). The dermal skinsubstitute Integra (Integra Life Sciences),which is a bi-layer bovine collagenand polysiloxane dressing, has been

extensively used for this purpose, but there have been few prospective RCTscomparing it with other available skinsubstitutes (Nguyen and Dickson, 2006).

AlloDerm (Life CellCorp), anacellular dermal matrix derived fromcadaveric skin, and Biobrane, (Smithand Nephew), a porcine collagen with alayer of silicone, have also been widelyused for burn management (McHugh etal, 1986; Wainwright, 1995). Adequate

trials studying their use, and othersimilar dressings, in different wound

types other than burns are also awaited.All these biological dressings, includingporcine and bovine collagen as well

57Wounds UK , 2011, Vol 7, No 2

found in chronic wounds. However, they come at an expensive price forintroduction into wide clinical practiceand it could be argued that much moreextensive evidence is needed for theiradoption. It has also been argued that

there is no replacement for an autograft(Paul, 2008). The application of theseskin substitutes vary from simple directapplication as cell monolayers to polymer,or animal-derived collagen scaffolds, and

their diversity deserves a separate review.The interaction of collagen alone within

the wound is also considerable and is thebasis of this review.

Collagen and acellular dermal skinsubstitute dressingsPromogran (Systagenix)This product deserves special interest, asit has been the subject of prolonged andin-depth research and marketing. It is amatrix dressing containing regeneratedcellulose and collagen which has beenshown experimentally to modulateproteases, metalloproteinases andelastase in open wounds (Cullen et al,2002a; Hart et al, 2002) by protectingplatelet-derived growth factor (PDGF)and other growth factors in the wound.There is also clinical trial evidence thatPromogran may be able to handleexudate and accelerate healing in venousand diabetic ulcers (Vin et al, 2002; Veveset al, 2002), but the clinical signicanceof this is open to doubt (Cullen et al,2002b). There is a plethora of casereports and small patient series, whichare supportive, but these have a high riskof publication bias.

In the authors opinion, the difcultywith the clinical studies and attempts atrandomised controlled trials (RCTs)is that:8 They are underpowered, with

randomisation which is poor ornot dened

8 They often compare the dressingwith an ineffective standard therapy(often bland Vaseline gauze)

8 Evaluations are unblinded andsubjective (and therefore biased),

and made by untrained, unvalidatedobservers and methodology.

Often there are high dropout rates so that assessment even up to 12 weeks is


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Table 2Currently available acellular collagen and dermal matrix products for wound care(the list is not exhaustive)

Permacol porcine dermis Tissue Science Laboratroies

Integra bovine tendon/synthetic polysiloxane Integra Lifesciences

Puracol Bovine collagen Medline Industries

Promogran collagen/regenerated cellulose Systagenix

Fibracol collagen/alginate Systagenix

Promogran Prisma collagen/Ag Systagenix

Oasis porcine small intestine submucosa Cook Biotech

Biostep porcine collagen/alginate/CMC +/- Ag Smith and Nephew

Colactive porcine collagen/alginate +/- AgSmith and Nephew

Catrix bovine carilage (powder) Lescarden Inc

Cellerate bovine collagen Wound Care Innovations

Collieva bovine collagen CollMed Laboratories

Medil bovine collagen gel BioCore

Skintemp bovine collagen BioCore

Matriderm collagen/elastin Suwelak

Decutastar equine collagen ADL

Septocoll E collagen eece/gentamicin BiometColladerm bovine/equine/gentamicin Innocoll

AlloDerm human cadaver de-epithelialised skinLifeCell Corp

Cymetra particulate alloderm LifeCell Corp

Mediskin porcine dermis Brennan Medical

EZ-Derm aldehyde linked porcine dermis Brennan Medical

Biobrane porcine collagen/silicone membraneSmith and Nephew

GraftJacket human cadaver dermal matrix Wright Medical Technology

* Dermagraft (Advance Tissue Sciences) is freeze dried bovine collagen used as a carrier forhuman broblasts

* Apligraf (Organogenesis) is a bi-layered dressing of cultured human epidermis bonded to bovinecollagen containing human broblasts

has been experimentally studied as anECM graft with subsequent successfuluse in multicentre clinical trials (Mostowet al, 2005; Niezgoda et al, 2005).

Although showing a difference inhealing rates, favouring the ECM matrixdressing, both studies were relativelyunderpowered. The rst involved 120patients with relatively small venousulcers and reached a statisticallysignicant difference compared withstandard compression alone (p


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of producing a new collagen dressing,or evaluating collagen dressings fur ther,ideally supported by a multicentre,randomised, controlled trial? From

a cost point of view alone, it wouldbe prohibitive; let alone the logisticsof mounting such a trial to show anyclear-cut advantage. There are several,possibly already too many, collagendressings available, so why shouldanother, which offers no particularlyspecial or extra effectiveness or priceadvantage be worth marketing? Somecollagen products have been widelyexposed in symposia or special issuesof journals, presented throughout thisreview, without becoming integratedinto wound management in general,and may follow the fate of the widerange of growth factors and cellular/skin substitutes that are hardly enjoyingwidespread use (Fu et al, 2005).

There is, in addition, considerablepressure from the need for evidence-based medicine to prove the valueof drugs and devices. The Cochranesystematic review has proven to beunhelpful in the eld of wound care,with each foray into different aspectscoming up with the conclusion that moreresearch is needed (Leaper, 2009). Forsimilar reasons, it is unlikely that guidelinescan be expected from institutions suchas the National Institute of Health andClinical Evidence (NICE) or the ScottishIntercollegiate Guidelines Network(SIGN). The likely lack of any forthcomingguidelines for the use of collagendressings in clinical wound managementalso militates against the introduction ofanother to an already crowded eld.

In the eld of a bioengineeredskin substitute, collagen is provingeffective for skin constructs (suchas Dermagraft and Apligraf ). Theauthors foresee this as the future forcollagen-based wound management.Nevertheless, the compellingexperimental data around the value andpotential inuence of collagen in thehealing of stalled traumatic and surgical

wounds, or hard-to-heal chronic ulcersof all types, including diabetic, venousleg and pressure ulcers, clearly remainsattractive for many scientic groupsand manufacturers.

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Key points

8 Collagen is a key protein inconnective tissue and in theprocess of wound healing byrepair and formation of scar.

8 Collagen is intimatelyinvolved in many tissuephysiological processes.

8 Collagen dressings,particularly to promote

healing in chronic wounds,are clearly attractive andseveral experimentaland clinical studies haveshown promise.

8 The evaluation of collagendressings with an unequivocalresult in adequately powered,randomised clinical trials maybe prohibitive.

Wound Healing Collagen

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