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Therapeutic Approaches - 6

Extra Cellular Matrix

ECM is composed of a mixture of collagen and elastin fibrils that provide strength and elasticity to skin. These proteins are co-mingled with proteoglycans which are protein-carbohydrate complexes characterised by their glycosaminoglycan (GAG) component. GAGs are highly charged sulphated and carboxylated polyanionic linear polysaccharides. Those most commonly present within the ECM are Hyaluronan (HA), Chondroitin Sulphate, Dermatan Sulphate, Heparan Sulphate and Keratan Sulphate.
Hyaluronan (HA), previously known as hyaluronic acid, consists of alternating glucuronic acid and N-acetylglucosamine units. It is synthesised by fibroblasts and is a major component of wound ECM and because of its high level of hydration confers viscosity to tissues and fluids. Its physicochemical properties modulate cell functions by acting as a hygroscopic osmotic buffer, by its chemical properties such as free radical scavenging, anti-oxidant effects and its ability to exclude enzymes from the local cellular environment. Additionally it may interact directly with cells via the RHAMM receptor (Receptor for HA Mediated Motility), the CD44 receptor and the ICAM-1 (Inter-Cellular Adhesion Molecule -1) receptor. Receptor interaction may be via a ligand receptor type interaction (CD44) or via a receptor blockade (ICAM-1) (Chen, 1999).

HA potentially plays a role in each phase of healing. During the inflammatory phase of healing wound tissue is rich in HA. It may play multiple roles promoting inflammation early in healing by enhancing leucocyte infiltration and also moderating the inflammatory response as healing progresses towards granulation tissue formation.

Granulation tissue is also rich in HA and here its role includes facilitation of cell migration (fibroblasts and endothelial cells) into the provisional matrix. Although HA has not been demonstrated to be mitogenic its oligosaccharide derivatives do stimulate endothelial cell proliferation (West, 1989).

HA is present in high concentrations in the basal layer of the epidermis in normal skin and co-localises with the CD44 receptor expressed by keratinocytes migrating over the provisional matrix of wound granulation tissue. Suppression of CD44 expression and consequential decreased HA binding results in defective inflammatory responses, decreased skin elasticity and impaired healing.

HA applied to the wound surface absorbs wound exudate to create a gel forming a HA rich moist wound environment that has been demonstrated to stimulate healing in human chronic wounds (Ortonne, 1996) and wound dressings are now available manufactured from the benzyl ester of HA. This slows down degradation by introducing the requirement for de-esterification to provide a slow release of HA into the wound environment (Benedetti, 1993). Treatment with this product has been demonstrated to produce a higher degree of wound closure for indolent neuropathic ulcers (Edmonds and Foster, 2000) and pilot study of 20 VLU indicates that it will promote healing of this lesion as 4/20 healed at 8 weeks of treatment and the remaining ulcers achieved a mean area reduction of 53% in wound area (Colleta et al, 2003).

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