Development of an Immunoisolated Endovascular Islet Cell Stent to Treat Type I Diabetes Mellitus

Introduction and Objectives: Despite recent advances in cell sources and immunosuppression protocols, islet cell transplantation has had limited clinical success in achieving long-term freedom from exogenous insulin therapy for individuals with type 1 diabetes. Currently, islet cell transplants are performed via the infusion of islet cells into the recipient's portal vein. Approximately 60% of transplanted cells die within 3 days of transplantation due to ischemic injury. ⁷ Significant immunosuppression is needed to avoid rejection but is also toxic to islet cells, and the use of immunosuppression remains a barrier to more widespread use of islet cell transplantation. To address these challenges, we developed an endovascular biologic stent-graft, IsletStent, which is designed to utilize semipermeable membranes to protect transplanted islets from immune cell attack and prevent ischemic injury through endovascular deployment. Methods: Semipermeable cell chambers in stent-grafts were fabricated from ePTFE with a pore size of 0.22 µm. The cell chamber was seeded with islet cells harvested from 6–8-week-old male BALB/c mice (Jackson Laboratories, Bar Harbor, ME). Human islets were obtained courtesy of an institutional islet isolation GMP facility. A benchtop normothermic machine perfusion circuit was used to model intravascular deployment. Within the perfusion circuit, devices were exposed to varying glucose concentrations in the perfusion media, and samples were drawn for insulin analysis. Insulin levels were measured via ELISA. Results: In murine islet cells, there were significantly increased levels of insulin secretion after exposure to high-glucose media. After 3 hours of low glucose exposure (2.8 mM), the average insulin concentration was 83 ± 8 mIU/ml, and after 3 hours of high glucose exposure (28 mM), the average insulin concentration was 145 ± 20 mIU/ml. The insulin concentration under high-glucose conditions was significantly greater than the insulin concentration under low-glucose conditions (p = 0.02; α = 0.05). The rate of insulin secretion was significantly greater under high-glucose conditions than under low-glucose conditions (6759 ± 503 mIU/h vs. 5344 ± 144 mIU/hr, p = 0.008, α = 0.05). After 3 hours of low glucose exposure (2.8 mM), the average insulin concentration was 229 ± 13 mIU/dL, and after 3 hours of high glucose exposure (28 mM), the average insulin concentration was 300 ± 17 mIU/dl. The insulin concentration under high-glucose conditions was significantly greater than the insulin concentration under low-glucose conditions (p = 0.014; α = 0.05). Conclusions: The IsletStent is a novel biologic endovascular device that enables islet cell function and survival within a semipermeable cell chamber placed intravascularly. However, further in-vivo studies are needed to understand the immune response to the graft.