The Woodruff School

SUMMARY

Type 1 diabetes (T1D) is a chronic, debilitating disease characterized by the autoimmune destruction of insulin-producing b-cells located within pancreatic islets. The gold standard for T1D cell therapy is clinical islet transplantation (CIT), the infusion of islets through the hepatic portal vein. While CIT recipients demonstrate enhanced blood glucose control, the procedure is limited to a marginal subset of T1D patients, in part due to the inhospitable nature of the intrahepatic site Indeed, an expected >60% loss of therapeutic cargo is expected within three days following transplantation. Thus, there is a significant need to establish an alternative extrahepatic transplant site that supports the engraftment of islets.

The subcutaneous space is an attractive extrahepatic transplant site for T1D cell therapy given its high clinical potential in terms of surgical accessibility, ease of monitoring, and convenience for replenishment and/or retrieval of therapeutic cargo. However, the unmodified subcutaneous space lacks the adequate vascularization necessary to preserve functional islets. An elegant, facile strategy to promote neovascularization is the biomaterial-mediated delivery of proangiogenic factors such as vascular endothelial growth factor (VEGF). The objective of this project is to engineer injectable VEGF-delivering synthetic poly(ethylene glycol) [PEG] hydrogels that promote islet vascularization, engraftment, and function in the subcutaneous space. My central hypothesis is that the VEGF-delivering hydrogel can be tuned to do so.

To test my hypothesis, I will first identify VEGF-PEG hydrogel formulations that support islet vascularization using an in vitro platform of vascularized islets. Next, I will evaluate lead VEGF-PEG hydrogel formulations in their ability to promote allogeneic islet vascularization, engraftment, and function in the subcutaneous spaces of diabetic rats and nondiabetic pigs. My work will result in an optimized injectable hydrogel for islet vascularization, engraftment, and function. Most significantly, it will provide a solid foundation for future work in a translational diabetic large animal model.

SUBJECT:	Ph.D. Proposal Presentation

BY:	Michelle Quizon

TIME:	Tuesday, May 31, 2022, 11:00 a.m.

PLACE:	IBB Building, 1128

TITLE:	Synthetic hydrogels for islet vascularization and engraftment in the subcutaneous space

COMMITTEE:	Andrés J. García, Ph.D., Chair (ME) Edward A. Botchwey, Ph.D. (BME) Rebecca D. Levit, M.D. (Cardiology) Edward A. Phelps, Ph.D. (BME) Krishnendu Roy, Ph.D. (BME)

SUMMARY Type 1 diabetes (T1D) is a chronic, debilitating disease characterized by the autoimmune destruction of insulin-producing b-cells located within pancreatic islets. The gold standard for T1D cell therapy is clinical islet transplantation (CIT), the infusion of islets through the hepatic portal vein. While CIT recipients demonstrate enhanced blood glucose control, the procedure is limited to a marginal subset of T1D patients, in part due to the inhospitable nature of the intrahepatic site Indeed, an expected >60% loss of therapeutic cargo is expected within three days following transplantation. Thus, there is a significant need to establish an alternative extrahepatic transplant site that supports the engraftment of islets. The subcutaneous space is an attractive extrahepatic transplant site for T1D cell therapy given its high clinical potential in terms of surgical accessibility, ease of monitoring, and convenience for replenishment and/or retrieval of therapeutic cargo. However, the unmodified subcutaneous space lacks the adequate vascularization necessary to preserve functional islets. An elegant, facile strategy to promote neovascularization is the biomaterial-mediated delivery of proangiogenic factors such as vascular endothelial growth factor (VEGF). The objective of this project is to engineer injectable VEGF-delivering synthetic poly(ethylene glycol) [PEG] hydrogels that promote islet vascularization, engraftment, and function in the subcutaneous space. My central hypothesis is that the VEGF-delivering hydrogel can be tuned to do so. To test my hypothesis, I will first identify VEGF-PEG hydrogel formulations that support islet vascularization using an in vitro platform of vascularized islets. Next, I will evaluate lead VEGF-PEG hydrogel formulations in their ability to promote allogeneic islet vascularization, engraftment, and function in the subcutaneous spaces of diabetic rats and nondiabetic pigs. My work will result in an optimized injectable hydrogel for islet vascularization, engraftment, and function. Most significantly, it will provide a solid foundation for future work in a translational diabetic large animal model.