Objective
The overall objective of this project is to develop a cell-based, bioartificial pancreas system that mimics the native pancreas, by providing an optimal three-dimensional environment to the transplanted insulin-producing cells. This environment is generated via a highly porous, biocompatible scaffold, which also serves as a multi-functional platform for the local delivery of bioactive agents, such as those that improve nutrient delivery to the cells and protect foreign cells from the immune system.
Background Rationale
Clinical islet transplantation (CIT) has shown significant promise in the treatment of Type I diabetes; however, the infusion of islets into the non-ideal site of the liver is plagued with significant islet loss following implantation, as well as the inability to retrieve or monitor the transplant. Therefore, there is a strong need to investigate alternative transplant sites and supporting scaffolds that could provide a means to bypass these significant inflammatory and mechanical stresses, as well as provide an optimal site for islet engraftment. Transplantation of devices within alternative sites, however, requires close intimacy with their surrounding environment and a high degree of blood vessel infiltration to permit optimal responsiveness of the islets to blood sugar levels. Furthermore, beta cells possess a high metabolic demand. Thus, optimal nutrient delivery to the transplant is necessary to prevent cell loss. Finally, given the immune response to the transplanted islets, the delivery of agents to protect beta cells from immune attack would be highly beneficial. To meet this need, we have fabricated a non-degradable macro-porous scaffold, which serves to distribute and mechanically protect the islets in 3-D, permit graft retrievability, and deliver complimentary agents. Of particular emphasis in this proposal is the incorporation of agents that release oxygen, to assist in supplementation of oxygen during engraftment, and immunomodulatory agents, to serve to dampen immune attack.
Description of Project
The development of treatment options for insulin-dependent diabetics that provide a highly regulated glucose sensing and insulin secreting closed loop system could result in dramatic improvements in quality of life and decrease disease management complications. Current artificial systems, however, lack the ability to provide this precise control. Clinical islet transplantation, the loading of donor islets into the liver, shows strong potential to provide this intimate control given that it transplants the very cells with this inherent glucose sensing/insulin secreting capacity. Limiting islet transplantation, however, is the significant loss and dysfunction of islets following implantation, due to poor engraftment environment and significant immunological attack. We have sought to address these roadblocks by developing a platform technology for optimizing the islet transplant environment within an alternative site. This platform seeks to: 1) house islets into an tailored 3-D scaffold environment that directs vascular in-growth; 2) deliver supplemental oxygen to the local graft site to support the cells; and 3) locally protect the foreign cells by adding a protective polymer to the cell surface and releasing agents capable of stopping immune attack. We have already engineered said devices and seek to complete definitive studies with these platforms to fully validate their potential for clinical translation. The final product of this proposal will be a device capable of nutritionally supporting a therapeutic dosage of insulin-producing cells for durable and elegant glycemic control with minimal dependency on external immunosuppressive drugs, while also allowing for ease in device implantation and retrieval.
Anticipated Outcome
With promising pre-clinical studies, we seek to generate a definitive bioactive scaffold that permits clinical translation within the extra-hepatic site of the omentum. We anticipate that these studies will provide a valuable new approach for increasing the success of islet transplantation for the treatment of Type 1 Diabetes, by creating a superior bioartificial pancreas device, requiring only a reasonable number of islets, scalability to humans, and with the added safety benefit of retrievability and monitoring.
Relevance to T1D
Cell-based therapy for T1D has to potential to provide glycemic control untenable via external glucose sensors and pump. By increasing the viability and function of the transplanted beta cells, we seek to minimize the number of cells required to achieve normoglycemia and increase the longevity of transplant efficacy. In addition, the technology developed in this project serves as a general platform for the transplantation of any insulin-secreting cell, thereby permitting the transition of this technology from current islet transplantation to alternative sources for insulin-secreting cells.