Year 2

This early translational award is focused on creating a stem cell based therapy to improve healing in diabetic foot ulcers (DFU). DFU are probably the major complication of diabetes mellitus. It is estimated that between 15- 25 % of all patients who have diabetes will develop this complication, and this goes on to be the cause of an astounding 85% of all lower leg amputations. The incidence of diabetes is increasing worldwide, and sadly, California leads the US with the highest prevalence of DFU. New therapies using live cells have been marketed as major advances in the therapy of this devastating problem, but their success is limited. Here we have proposed to engineer a wound replacement tissue that is laden with bone marrow derived mesenchymal stem cells (MSC), that have been pre-treated using conditions that will optimize their ability to repair the wound.

In this funding period (year 2) we have met all the preset milestones for this work. In particular, we have developed a model of impaired skin wound healing in a diabetic mouse, and demonstrated that our combination therapy of preconditioning the MSC with a treatment of hypoxia (low oxygen tension) and a drug commonly used to block the beta adrenergic receptor can improve healing in this impaired healing model. The MSC are pretreated and then adhered to an extracellular matrix that forms a scaffold for cell attachment and tissue regeneration. Improvement of over 20% of healing rates have been achieved in this model. A second milestone of this year’s work was to initiate a model of impaired healing in pig skin, as this mirrors human skin wound healing much more closely. We show the development of this model, how multiple healing parameters are measured in this model, and how these metrics can show us the impairment of healing that occurs when the wound is infected with common wound pathogenic bacteria. Our plan is to test our pre-conditioned MSC/matrix device in these two models and to not only demonstrate efficacy, but also to understand the mechanisms by which the device improves healing. At the end of this three year funding period we hope to have sufficient data to lead to an IND submission to the FDA for initiation of a clinical trial in patients with DFU.