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The effect of dextrin–rhEGF on the healing of full-thickness, excisional wounds in the (db/db) diabetic mouse

Hardwicke, Joseph T., Hart, Jeff, Bell, Andrea, Duncan, Ruth, Thomas, David W., Moseley, Ryan
Journal of controlled release 2011 v.152 no.3 pp. 411-417
alpha-amylase, angiogenesis, blood, dextrins, epidermal growth factor, fibroblasts, granulation tissue, humans, keratinocytes, mice, models, polymers, proteolysis, therapeutics, tissue repair
Chronic wounds, such as ulceration of the lower limb, represent a significant clinical challenge in today's ageing society. With the aim of identifying improved therapeutics, we have previously described a bioresponsive, dextrin–recombinant human epidermal growth factor conjugate (dextrin–rhEGF), that (i) protects rhEGF against proteolytic degradation by human chronic wound fluid; and (ii) mediates rhEGF release by α-amylase, capable of stimulating increased proliferation/migration in normal dermal and chronic wound fibroblasts; and keratinocytes, in vitro. The aim of this study was to extend these findings, by investigating the effects of dextrin–rhEGF on wound healing in the (db/db) diabetic mouse, a widely used in vivo model of delayed wound healing. Standardised, full-thickness excisional wounds, created in the dorsal flank skin, were treated topically with succinoylated dextrin (50μg/mL), rhEGF (10μg/mL) or dextrin–rhEGF (1 or 10μg/mL). Treatments were applied immediately after injury and subsequently on post-wounding, days 3 and 8. Wound healing was assessed macroscopically, in terms of initiation of neo-dermal tissue deposition and wound closure (including wound contraction and re-epithelialisation), over a 16day period. Wound healing was assessed histologically, in terms of granulation tissue formation/maturity; cranio-caudal wound contraction and wound angiogenesis (CD31 immuno-staining), using tissues harvested at day 16. Blood samples were also analysed for α-amylase and rhEGF concentrations. In this established impaired wound healing model, the topically-applied dextrin–rhEGF significantly accelerated wound closure and neo-dermal tissue formation at the macroscopic level; and significantly increased granulation tissue deposition and angiogenesis at the histological level (p<0.05), relative to untreated, succinoylated dextrin and rhEGF alone controls. Overall, these findings support the further development of bioresponsive polymer conjugates, for tissue repair.