SUMMARY

Stem cell-derived β-cells are positioned to be a transformative cure for type 1 diabetes (T1D) by replacing the insulin-producing β-cells destroyed by the autoimmune system. Human induced pluripotent stem cells (hiPSCs) can differentiate into insulin-producing cells that phenotypically and functionally resemble immature β-cells. While promising, fully functional in vitro differentiation of these hiPSCs into mature β-cells remains elusive. Current in vitro differentiation protocols of hiPSCs cannot provide the precise microenvironmental cues necessary for complete maturation. Consequently, in vivo implantation is often used to direct end-stage maturation of stem cells, resulting in an uncontrolled environment to direct β-cell maturation. Furthermore, there are few suitable delivery vehicles for transplantation to clinically-translatable extrahepatic sites. These challenges highlight the need for strategies that enhance the in vitro maturation of the hiPSC-derived β-cells and improve their engraftment and function in a clinically-translatable transplant site. The objective of this project is to engineer advanced synthetic hydrogels to direct in vitro maturation of hiPSC-derived β-cells and enhance engraftment in an extrahepatic murine site. In Aim 1, I demonstrate that engineered synthetic hydrogels support the viability and differentiation of encapsulated hiPSCs to a mature β-cell stage. In Aim 2, I demonstrate that an engineered vasculogenic synthetic hydrogel supports the engraftment of pancreatic progenitors and immature β-cells into the mouse fat pad. In Aim 3, I develop a novel hydrolytic hydrogel that demonstrates tunable in vivo degradation kinetics to promote enhanced stem cell engraftment and vascularization. This project will provide a significant foundation for translation of hiPSC-derived β-cells into more clinically-relevant sites and establish innovative materials that promote survival, engraftment, and function of hiPSC-derived β-cells.