Sophia Kioulaphides
BME PhD Proposal Presentation

Date: 2024-04-23
Time: 9am-11am
Location / Meeting Link: Suddath Seminar Room (IBB 1128) / https://gatech.zoom.us/j/98470971775?pwd=YWc5eDlyV0J4L2kyQXI5S2FWanIxQT09

Committee Members:
Andres J. Garcia, PhD (Advisor); Edward A. Botchwey, PhD; Julia E. Babensee, PhD; Jeffrey R. Millman, PhD; James F. Markmann, MD, PhD.


Title: Engineering synthetic, vasculogenic hydrogels to direct stem cell-derived islet maturation, engraftment, and function for Type 1 Diabetes

Abstract:
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β-cells, resulting in hyperglycemia. Nearly 1:400 adolescents are affected by T1D, and 15-20 years post-diagnosis there is a high risk of cardiovascular issues, which can lead to atherosclerosis, gangrene, retinopathy, neuropathy, and nephropathy. The most common treatment for T1D is exogenous insulin injections, but this method is costly and poses a risk of hypoglycemia. The most promising solution for insulin independence is the transplantation of islets from cadaveric donors to the hepatic portal vein. However, this treatment is only successful for 3-5 years, due to an instant blood-mediate immune response (IBMIR), poor engraftment in the intrahepatic site, and the need of chronic immunosuppression, resulting in 2-4 donors needed per recipient. There is a critical need to deliver a renewable source of insulin-producing cells that can successfully engraft in the body without the risk of adverse immune responses. The most promising renewable source of insulin-producing cells is stem cell-derived β (SC-β) cells, however, their marker expression and function pales in comparison to cadaveric islets. Additionally, there is a need for delivery carriers and clinically translatable transplant sites that result in successful engraftment of the SC-β cells without an adverse immune response. The gonadal fat pad (gFP) has shown promise as a transplant site for cadaveric islets, as it is highly vascularized and is like the omentum in larger mammals. The use of synthetic biomaterial platforms offers a promising solution to both present bioactive ligands that promote the differentiation of SC-β cells in vitro and deliver vasculogenic factors in vivo to promote engraftment. The objective of this project is to engineer a poly(ethylene glycol) (PEG) hydrogel that can promote the differentiation and maturation of SC-β cells in vitro and deliver them with vascular endothelial growth factor (VEGF) in vivo to promote their engraftment and function. My central hypothesis is that the PEG hydrogel tethered with bioactive ligands and vasculogenic factors will promote the differentiation of SC-β cells in vitro and engraftment and diabetes correction in vivo. My preliminary data gives strong scientific premise for this project. The project will be carried out with the following specific aims: 1) Screen synthetic hydrogels that support the in vitro survival, differentiation, and maturation of SC-β cells; 2) Engineer vasculogenic, synthetic hydrogels that support the in vivo survival and engraftment of SC-β cells in the gFP of non-diabetic immune deficient mice; and 3) Evaluate different doses of SC-β cells with and without a PEG-VEGF carrier in the gFP to restore normoglycemia in diabetic, immune deficient mice. Expected outcomes for this project include the development of synthetic hydrogel platforms that support 1) in vitro development of SC-β cells, and 2) in vivo cell survival, engraftment, and diabetes correction.