Development of a Bioartificial Vascular Pancreas for Type 1 Diabetes Treatment

Edward Xu Han, Yale University Graduate School of Arts and Sciences


Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic islets and is a growing and chronic health problem. Although exogenous insulin injections can help T1D patients manage their blood glucose levels, constant patient vigilance and compliance is required. Less than 40% of diabetic patients can maintain their therapeutic targets. As a result, around 30% of patients older than 40 years of age have diabetes related complications. Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type I diabetes. However, transplantation of islets into either the portal vein or the subcutaneous/intraperitoneal spaces can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations are magnified when increasing transplanted islet numbers dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vessel as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular blood vessel using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. To prove the capabilities of the BVP design, the work in this thesis aims to: 1) Utilize in silico modeling to create a simulation of the BVP that incorporates equations to account for oxygen diffusion and islet oxygen consumption; 2) Create a repeatable process for the creation of BVPs and test the constructs in bioreactor settings mimicking in vivo conditions; 3) Implant BVPs into diabetic rats and pigs to demonstrate in vivo efficacy at restoring normoglycemia; 4) Assess the possibility of using genetically modified cells in the BVP and pave the way for creating BVPs using insulin secreting induced pluripotent stems cells. For Aim 1, simulations were performed using finite element analysis in COMSOL Multiphysics to predict oxygen concentrations and demonstrate that the BVP design can provide adequate oxygenation to enable islet survival. In Aim 2, BVPs were created using decellularized umbilical artery, rat islets, and bovine fibrin. Testing these tissues in bioreactor settings demonstrated that luminal flow through the BVP enables increased islet survival and insulin secretion functionality. Building off of this, in Aim 3, BVPs were implanted as end-to-end abdominal aorta grafts in nude rats. Implanted BVPs restored normoglycemia in diabetic rats over the course of 90 days, and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Lastly, Aim 4 established the use of other cell types in the BVP. Specifically, fibroblasts genetically modified to secrete erythropoietin (EPO) are created using the BVP design. Transplantation of these EPO secreting tissues into rats increased blood EPO levels and generated an expected physiological effect on hemoglobin and hematocrit. Overall, this dissertation combines bioengineering from in silico, in vitro, and in vivo work to show that the BVP can be a solution enabling the transplantation of pancreatic islets to treat or cure type I diabetes.