Advisor:

Andrés García, PhD (Georgia Institute of Technology)

Committee Members:

Edward Botchwey, PhD (Georgia Institute of Technology)

Krishnendu Roy, PhD (Georgia Institute of Technology)

Ankur Singh, PhD (Georgia Institute of Technology)

Cristina Nostro, PhD (University of Toronto)

Synthetic Hydrogels for the Maturation and Engraftment of Stem Cell-Derived Beta Cells

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.