Year 1

In the United States, over 25 million people have diabetes, from which approximately 25% will develop a foot ulcer in their lifetime. These ulcers are a causal factor for amputations in about 30% of patients and of these patients with amputations, and the 5 year survival rate is less than 30%. This dire outcome is coupled with extensive US healthcare expenditures for diabetic leg ulcers, of over $43 billion a year. Yet, these expenditures for good standard of care result in healing of only 30% of patients with diabetic foot ulcers. This rather dismal cure rate has prompted vigorous research for therapeutic alternatives, and advanced wound care approaches including topical application of growth factors, extracellular matrix scaffold materials, bioengineered living tissue replacements, and scaffold/stem cell products, including ours, are now being developed.

Our CIRM-funded Development Candidate is a combination product consisting of a collagen-based scaffold for dermal regeneration (SDR, Integra™) in which human bone-marrow derived mesenchymal stem cells (MSC) that have been preconditioned under hypoxia and beta adrenergic antagonist pretreatment are embedded.

We have now completed our first Milestone, which was to generate 5 master cell banks, compare the expression of multiple factors between them, and choose the two optimal MSC batches from which to create larger working cell banks. Our tests included cell viability prior and after freezing, normal karyotype confirmation, normal expression of cell surface markers, normal differentiation potential, sterility (low endotoxin levels; absence of microorganisms), secretion of wound-repair related factors and capability to promote of migration of endothelial cells. Importantly in this first year we correlated potency assays for the different MSC batches with in vivo performance when seeded in the scaffold for dermal regeneration.

The two working cell banks were further tested and importantly show similar, significant disease-modifying activity in a murine model of diabetic skin wounds. We have optimized the wound model and are now poised to perform the dose-finding studies proposed in the milestones for year two.