Objective
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. We hypothesize that the VEGF-delivering gel can be tuned to promote islet vascularization, survival, and function in the subcutaneous space, a site with high clinical potential in terms of accessibility, convenience, and ease of monitoring and retrieval if necessary. A major advantage of our strategy over encapsulation devices is direct vascularization of the transplanted islets for enhanced survival and glucose/insulin pharmacokinetics without fibrosis and diffusional limitations. This project will result in an injectable delivery vehicle for islets that promotes islet vascularization, engraftment and function and will provide validation results in a large animal model. Because this project focuses on islet vascularization and function, the studies will use allogeneic islet transplantation into immunosuppressed receipts. Notably, the hydrogel formulation can be combined in the future with other technologies for cell therapy, including immunomodulatory strategies, encapsulation devices, and scaffolds. This work will provide a solid foundation for future studies of this vasculogenic hydrogel vehicle in translational diabetic large animal model.
Background Rationale
Transplantation of allogeneic islets from cadaveric donors into the liver has emerged as a promising therapy for T1D. However, infusion of islets into the liver triggers instant blood-mediated inflammatory reaction, resulting in significant acute loss of islets, as many as 60-80% of the delivered dose, in hours to days following transplantation. Considerable interest has focused on establishing alternative extravascular sites for transplantation of islets to avoid this instant blood-mediated inflammatory reaction, including peritoneum, subcutaneous space, and omentum, but these remain limited in terms of low oxygenation, inadequate metabolic kinetics, and clinical utility. Inadequate re-vascularization of transplanted islets is a major cause for reduced islet viability and function. Delivery of pro-vascularization factors, such as vascular endothelial growth factor (VEGF), improves vascularization and islet function, but these strategies are hindered by insufficient and/or complex release kinetics and inadequate delivery matrices as well as technical and safety considerations. We have engineered synthetic injectable hydrogels with controlled VEGF delivery that promote re-vascularization and engraftment of transplanted islets in non-liver sites. 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. We hypothesize that the VEGF-delivering gel can be tuned to promote islet vascularization, survival, and function in the subcutaneous space, a site with high clinical potential in terms of accessibility, convenience, and ease of monitoring and retrieval if necessary. A major advantage of our strategy over encapsulation devices is direct vascularization of the transplanted islets for enhanced survival and glucose/insulin pharmacokinetics without fibrosis and diffusional limitations.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β-cells of the pancreas are destroyed. T1D affects 1.6 million children and adults in the US with >$16 billion annual healthcare costs. Standard therapy with exogenous insulin is burdensome, associated with a significant danger of hypoglycemia, and only partially efficacious in preventing long-term complications. Transplantation of allogeneic islets from cadaveric donors into the liver has emerged as a promising therapy for T1D. However, infusion of islets into the liver triggers instant blood-mediated inflammatory reaction, resulting in significant acute loss of islets, as many as 60-80% of the delivered dose, in hours to days following transplantation. Considerable interest has focused on establishing alternative extravascular sites for transplantation of islets to avoid this instant blood-mediated inflammatory reaction, including peritoneum, subcutaneous space, and omentum, but these remain limited in terms of low oxygenation, inadequate metabolic kinetics, and clinical utility. Inadequate re-vascularization of transplanted islets is a major cause for reduced islet viability and function. Delivery of pro-vascularization factors, such as vascular endothelial growth factor (VEGF), improves vascularization and islet function, but these strategies are hindered by insufficient and/or complex release kinetics and inadequate delivery matrices as well as technical and safety considerations. We have engineered synthetic injectable hydrogels with controlled VEGF delivery that promote re-vascularization and engraftment of transplanted islets in non-liver sites. 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. We hypothesize that the VEGF-delivering gel can be tuned to promote islet vascularization, survival, and function in the subcutaneous space, a site with high clinical potential in terms of accessibility, convenience, and ease of monitoring and retrieval if necessary. A major advantage of our strategy over encapsulation devices is direct vascularization of the transplanted islets for enhanced survival and glucose/insulin pharmacokinetics without fibrosis and diffusional limitations. This project will result in an injectable delivery vehicle for islets that promotes islet vascularization, engraftment and function and will provide validation results in a large animal model. Because this project focuses on islet vascularization and function, the studies will use allogeneic islet transplantation into immunosuppressed receipts. Notably, the hydrogel formulation can be combined in the future with other technologies for cell therapy, including immunomodulatory strategies, encapsulation devices, and scaffolds. This work will provide a solid foundation for future studies of this vasculogenic hydrogel vehicle in translational diabetic large animal model.
Anticipated Outcome
This project will result in an injectable delivery vehicle for islets that promotes islet vascularization, engraftment and function and will provide validation results in a large animal model. Because this project focuses on islet vascularization and function, the studies will use allogeneic islet transplantation into immunosuppressed receipts. Notably, the hydrogel formulation can be combined in the future with other technologies for cell therapy, including immunomodulatory strategies, encapsulation devices, and scaffolds. This work will provide a solid foundation for future studies of this vasculogenic hydrogel vehicle in translational diabetic large animal model.
Relevance to T1D
This project will result in an injectable delivery vehicle for pancreatic islets that promotes islet vascularization, engraftment and function and will provide validation results in a large animal model. Notably, the hydrogel formulation can be combined in the future with other technologies for cell therapy, including immunomodulatory strategies, encapsulation devices, and scaffolds. This work will provide a solid foundation for future studies of this vasculogenic hydrogel vehicle in translational diabetic large animal model. This strategy overcomes current limitations of islet delivery to the liver that results in high islet loss.