A PROANGIOGENIC STRATEGY TO PROMOTE DIABETIC WOUND CLOSURE

Abstract

This dissertation seeks to repurpose two drugs 1)antifungal ciclopirox olamine(CPX) and 2)lysophospholipid sphingosine-1-phosphate(S1P) as a proangiogenic combination to promote diabetic skin wound contraction. Contraction involves compaction of collagen fibers in the granulation tissue which pulls the perilesional skin to reduce wound area. This process requires a robust angiogenesis. In diabetics, both angiogenesis and contraction are diminished, impairing wound healing. To emulate this pathology and address it pharmacologically, a wound healing model in diabetic ZDF rats is developed and topically treated with CPX+S1P. In vitro, CPX+S1P upregulates a crucial driver of angiogenesis, hypoxia-inducible factor-1. Injection of CPX+S1P into subcutaneously implanted sponges additively increased endothelial infiltration and vessel length. Identification of specific dorsal sites in diabetic rats allowed for incremental wound depths from 1mm (superficial) to 3mm (deep). While the effects of topical gel treatment of CPX+S1P were masked by rodent-characteristic dominant contraction in superficial wounds, they became evident in deep wounds.