Topical Stem and Progenitor Cell Therapy for Diabetic Foot Ulcers

Abstract

The prevalence of diabetes mellitus is increasing to epidemic proportions worldwide. Diabetic foot ulceration can affect up to 25 percent of people with diabetes mellitus throughout their lives. The most significant complication of foot ulceration is lower limb amputation, which arises from pre-existing ulcers in the majority of cases. Despite current clinical care protocols for ulcer treatment, there exists a high amputation rate. This presents a major burden for individual patients’ health and well-being in addition to significant financial cost for health care systems. There is an urgent need for new medicinal products to treat diabetic ulcers. Cell-based therapies offer a novel treatment strategy to augment diabetic wound healing, increase ulcer healing rate and prevent amputation. The field of tissue engineering has developed commercially available skin substitutes for diabetic cutaneous wound repair. These products have incorporated somatic cells delivered in a bioengineered scaffold. However, having been available for the last decade, the majority have demonstrated only moderate clinical benefit in small clinical trials. In comparison, stem and progenitor cell therapy offer the potential for accelerated wound repair in addition to structural skin regeneration with functional recovery. Stem cells have the ability to self-renew and differentiate into other cell types and are classified into adult stem and progenitor cells, embryonic stem cells and induced pluripotent stem cells. The mechanisms of action of stem and progenitor cells are not fully elucidated but include 1) differentiation to specialised cells e.g. skin cells of the dermis and epidermis 2) acting by paracrine or autocrine effects through the secretion of trophic factors e.g. the production of soluble mediators for neo-angiogenesis and 3) immuno-modulatory functions. Much research endeavour is determining the benefit of stem cell treatment on diabetic cutaneous wound healing with encouraging results in animal models. Regenerative medicine and tissue engineering specialties are rapidly elucidating the mechanisms of action of stem cells and translating the results of in-vitro and in-vivo experiments to human clinical trials. The requirements for success will be patient safety, clinical efficacy and convenience of use. The focus of this chapter is to review the area of topical stem and progenitor cell therapy as a treatment for non-healing diabetic foot ulcers. It will focus on adult stem cells as these are nearer to use in human trials and do not pose the ethical constraints associated with the use of embryonic stem cells. Topical treatment with endothelial progenitor cell (EPC) and mesenchymal stem cell (MSC) therapy is presented in this review, and more specifically the delivery of these cells using biomaterial scaffolds. The currently available cell therapy