Ivins v2.indd

Wound healing is a dynamic and complex biological process involving highly organised overlapping phases, including coagulation, inflammation, epithelialisation, matrix deposition, angiogenesis, proliferation, cellular remodelling and wound contraction (Clark, 1985; Mast and Schultz, 1996). For completion of each stage of wound healing, complex interactions must occur between various biological factors, e.g. growth factors and cell types (Nwomeh et al, 1998). Together these processes result in the restoration of tissue integrity and functional healing (Hackam and Ford, 2002). A variety of factors influence wound healing adversely, including the presence of infection, necrotic tissue, impaired tissue perfusion, and clinical conditions such as venous and arterial insufficiency, advanced age, steroid administration and diabetes (Hackam and Ford, 2002). The majority of cells playing a role in wound healing require matrix metalloproteinases (MMPs) to perform their normal physiological role. As part of the inflammatory response, macrophages and neutrophils produce and utilise MMPs for debridement of necrotic tissue, whilst all cells require expression of surface MMPs to allow them to dissect a migratory pathway through extracellular matrix (ECM). MMPs are produced by fibroblasts to remodel ECM which strengthens scar tissue following wound closure (Gibson et al, 2009). MMPs thus play a role in inflammation, granulation tissue formation, re-epithelialisation and re-modelling during normal healing, although their levels decrease rapidly as healing proceeds (Tarlton et al, 1997). In acute wounds, a burst of protease activity is seen at the start of wound healing, which peaks about day 3 and starts to reduce by day 5 (Gibson et al, 2009). In chronic wounds, however, an imbalance of MMPs is associated with impaired wound healing (Schultz and Wysocki, 2009). In these non-healing wounds, MMPs reach higher levels and persist for longer, which may lead to the degradation of the ECM, prevention of cellular migration and cause tissue destruction (Trengove et al, 1999). A prolonged high protease activity may be stimulated by the presence of damaged tissue, foreign material, bacteria and biofilms (International Consensus, 2011). The gelatinases MMP-2 and MMP-9 digest a number of ECM molecules including type IV, V and XI collagens, laminin, aggrecan core protein, while MMP-2, but not MMP-9, digests collagens I, II and III (Nagase et al, 2006). High levels of activated MMPs, including MMP-2 and MMP-9, are seen in non-healing wounds and this may play a major role in chronic wounds failing to close (Wysocki et al, 1993). Elevated levels of MMP-9