Developing a long-acting VEGF to improve wound healing in type 1 diabetes

Patients with diabetes exhibit delayed wound healing and the treatment of foot ulcers in diabetics present an enormous challenge for physicians. The lifetime incidence of a diabetic developing a foot-ulcer has been estimated at 15-25% and even with aggressive care approximately 14-24% of diabetics with a foot ulcer ultimately require an amputation. One cause of poor wound healing for diabetic patients is impaired blood flow to the extremities. For patients with severe blood flow problems there are surgical procedures which can provide relief. However, many patients would benefit from less invasive local therapy to increase blood flow around the ulcer which enhances the healing process. Previous research has shown that treatment with vascular endothelial growth factor (VEGF) can stimulate the growth of new blood vessels within the wound area to accelerate the healing process. However, the half-life of VEGF is quite short making it difficult to develop a useful therapy for patients. In our laboratory we developed a novel VEGF analogue which has a longer half-life and therefore may provide a more practical treatment option for patients suffering from painful ulcers.

First, we will need to determine the specific differences in half-life between the purified recombinant VEGF and our long-acting VEGF through a series of pharmacological experiments. Next, we will need to identify the carrying compound that will provide the best absorption of VEGF across the skin. We will study three potential carriers: saline, PEG polymer solution, and a petroleum-based gel. The goal will be to find the compound that allows VEGF to move slowly, but efficiently into the skin. Once we have optimized our topical VEGF treatment we will evaluate its effectiveness in two different wound healing models. Both models will use a common strain of laboratory mouse, C57Bl/J; however, some of the animals will be administered a chemical that causes Type 1 diabetes in the mice within 7-10 days. Both the diabetic mice and non-diabetic mice will undergo surgery to induce a standard-sized open wound on their backs. Mice will be randomized into one of 3 treatment groups: carrying compound alone, compound with recombinant VEGF, and compound with our long-acting VEGF. We will monitor the rate at which the wounds heal and also collect tissue samples to determine if treatment helps to increase blood vessel development within the wound. In previous studies the non-diabetic mice show full closure of the wound within 10 days and the diabetic mice require a longer time of approximately 2-3 weeks.