Despite the promise of the Edmonton protocol, the need to use immunosuppressive drugs and the severe shortage of human islets remain major barriers to clinical islet transplantation. An attractive strategy to overcome these two barriers is the technique of microencapsulation of islets prior to transplantation. Still, there are a number of issues that need to be resolved before this approach can become a clinical reality. Microencapsulated islet transplantation is currently performed in the unmodified peritoneal cavity because of the need for a large space to accommodate the large graft volume for which conventional islet transplant sites, such as the liver, are not suitable. The relatively large surface-to-volume ratio of microcapsules and the absence of a blood supply in the peritoneal cavity pose challenges to adequate supply of oxygen and nutrients to the encapsulated islets as well as exchange of glucose and insulin between the encapsulated islets and the systemic circulation. We will test the hypothesis that neovascularization of encapsulated islet transplants would enhance the viability of the islets because of adequate supply of oxygen and nutrients. The specific aims of this proposal are: 1) To design an optimum delivery system for angiogenic proteins to induce neovascularization around alginate microcapsules. After encapsulating the novel HBGAM-R136K angiogen in either of the alginate layers of alginate-polyornithine- alginate microcapsules, we will first study its release kinetics in vitro and the nature and level of microvasculature in vitro using fluorescence and image processing techniques. We will then examine tissue angiogenic and fibrotic responses to the protein in in vivo studies. 2) To determine the function of islets encapsulated and transplanted with the angiogenic protein to induce neovascularization. Using an isograft model of normal Lewis rat islet donors and Streptozotocin-diabetic Lewis rat recipients, we will co- encapsulate islets with angiogenic protein, and will assess blood glucose and insulin levels for 90 days after transplantation in omentum pouches of recipients. 3) To determine the efficacy of the optimized model of this bioartificial pancreas in a rat allograft. We will isolate and encapsulate islets from normal Wistar-Furth rats and transplant them in diabetic Lewis rats. 4) To assess the bioartificial pancreas function in xenograft animal models - first, human islets transplanted in diabetic Lewis rats for 90 days;and second, human islet transplants in diabetic monkeys for 180 days. PUBLIC HEALTH RELEVANCE: It is now clear that islet transplantation provides the best treatment option for individuals afflicted with Type 1 diabetes. However, the shortage of human islets and the need to use risky drugs to prevent transplant rejection remain major obstacles to routine use of islet transplantation in diabetic patients. The purpose of this project is to develop a viable strategy to overcome these two barriers and make islet transplantation a more appealing and widely used treatment option for diabetic patients.

R01DK080897

2009-09-05

2012-08-31