Novel Cell-Based Therapies for the Treatment of Diabetic Ulceration
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The focus of this research is on developing novel cell based therapies for the treatment of non-healing diabetic foot ulceration. The thesis begins with a concise review of the diabetic foot ulcers. The burden associated with non-healing diabetic foot ulceration in humans is presented. The biology of the diabetic ulcer is reviewed and the scientific rationale for pursuing the development of a stem and progenitor cell-based therapy is emphasised. Cell transplantation using biomaterials is reviewed. The first cell type that is investigated is the early endothelial progenitor cell or circulating angiogenic cell. A cell-scaffold treatment was developed using collagen. A preclinical model of diabetic wound healing was validated. The model is the alloxan induced diabetic rabbit ear ulcer model. Subsequently autologous circulating angiogenic cells exposed to the matricellular protein osteopontin were applied to a full thickness cutaneous ulcer. The cells were delivered via a collagen scaffold and the percentage wound closure was assessed after one week. Circulating angiogenic cells exposed to osteopontin and seeded on a collagen scaffold displayed significantly increased percentage wound closure as compared to other groups. Stereological analysis of wounds demonstrated a superior vascular network in wounds treated with circulating angiogenic cells exposed to osteopontin. The secretome of human circulating angiogenic cells was assessed with diabetic CACs demonstrating less angiogenesis in vitro. Topical treatment of ulcers with allogeneic non-diabetic mesenchymal stem cells was assessed in the same preclinical model. A dose escalation protocol was carried out. Wounds treated with 1,000,000 MSCs seeded in a collagen scaffold augmented wound healing as compared to untreated wounds. Stereological analysis demonstrated a superior neovasculature in wounds treated with 1,000,000 MSCs The outcome of this research is the demonstration of the therapeutic efficacy of topically applied circulating angiogenic cells and mesenchymal cells in diabetic cutaneous ulceration.