A number of topical interventions that reduce the inflammatory response have been tried in an attempt to reduce scarring in adult skin wounds, particularly to reduce the presence of TGF-P1 and 2, or create a more fetal-like ECM.
Hepatocyte growth factor (HGF) is an important growth factor in liver regeneration (Chapter 7). HGF has angiogenic, angioprotective, anti-inflammatory and antifibrotic activities (Matsumoto and Nakamura, 1996), but its expression has not been studied in healing skin wounds. However, injecting rat incisional skin wounds with a combination of rhFGF-2 protein (FiblastTM) and a plasmid expressing the HGF gene resulted in elevated fibroblast apoptosis in the granulation tissue and less extensive scarring than observed with either agent alone (Ono et al., 2004). The mechanism by which the antifibrotic effect was achieved is not clear, but the rhFGF-2 may have had an apoptotic effect and the HGF an anti-inflammatory effect at early stages of repair.
Chitosan, a high-molecular-weight, positively charged polysaccharide extracted from the chitin of crab shells, has a significant positive effect on the repair of subcutaneous wounds in rats (Diegelman et al., 1996). Chitosan prolongs the presence of neutrophils and delays the appearance of macrophages, thus reducing TGF-P1 and 2 production, capillary ingrowth, fibro-blast migration, and collagen deposition. The collagen produced was in the form of fine reticulin-like fibrils rather than the mature bands of dense collagen seen in controls. N-O carboxymethylchitosan (N-O-CMC, a GAG hydrogel derivative of chitin) has ECM-like properties that prevent or minimize fibrosis and adhesions when applied topically to the injured caecum of rats (Krause et al., 1996). The mechanisms of action of chitosan and N-O-CMC are unclear. Chitosan has blood clotting activity that is independent of the normal platelet-dependent cascade (Malette et al., 1983) and might modulate platelet function, thus altering the inflammatory phase of repair. N-O-CMC is hydrophilic and would have low affinity for fibronectin, thus preventing hydrophilic interactions between the molecules involved in the formation of adhesions.
Reduction of TGF-P1 in wounds reduces scarring. The enzyme cyclooxygenase-2 (COX-2) catalyzes the conversion of arachadonic acid to prostaglandins during the inflammatory response. Prostaglandins induce collagen production in adult wounds (Talwar et al., 1996), and PGE2 induces scar formation in fetal wounds (Wilgus et al., 2003). Daily treatment of excisional wounds in mice with the COX-2 inhibitor, celicoxib, decreased PGE2 by 50% and TGF-P1 by one-third at 48-hr postwounding (Wilgus et al., 2003). These decreases were associated with a later reduction in scar tissue formation without disrupting re-epithelialization or decreasing tensile strength of the repair tissue. The mean collagen content and scar width was only half that of controls.
Studies in vivo and in vitro have shown that reducing the levels of TGF-P1 by topical application of neutralizing antibodies, or the application of TGF-P3 immediately after wounding reduces scarring in skin wounds (FIGURE 4.1) (Shah et al., 1994; Houghton et al., 1995). Anti-TGF-P1 antibodies are currently being developed commercially as agents to reduce scarring during skin wound repair (Ferguson and O'Kane, 2004).
Biointeractive hydrogel films composed of cross-linked hyaluronic acid and chondroitin sulfate were tested on full-thickness skin wounds of mice to determine their efficacy in reducing scarring (Kirker et al., 2002). HA is present in much higher quantities in fetal skin than in adult skin and is associated with the ability of fetal skin to regenerate. The films did not effect any changes in the inflammatory response or degree of wound contraction, but there was a significant increase in re-epithelialization and in the amount of dermal collagen, as well as organization of the collagen.
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