Title:  Pancreatic Islet Microphysiology System for Disease Modeling of Type 2 Diabetes 

Abstract: Diabetes has become an increasingly prominent global issue afflicting 10% of world’s population where type 2 diabetes (T2D) comprises the majority of those diagnosed. T2D correlates with a toxic bioenvironment that leads to the body’s inability to properly self-regulate blood glucose due to the dysfunction of insulin producing pancreatic islets. While the outcome of T2D is well recognized, the pathogenesis of the disease still requires greater understanding with most studied mechanisms having a non-human basis.  Additionally, current disease models fail to fully replicate disease conditions for drug testing leading to only 10% success in clinical trials. To bridge the gap and more accurately replicate human disease, microphysiological systems (MPS) have risen as a viable alternative since they combine microfluidics and tissue engineering to mimic the in vivo micro-environment.

This dissertation focuses on the development of an islet-MPS that utilizes both primary and stem cell-derive tissue to simulate the pathogenesis and drug testing for T2D. In this pursuit, we developed the pancreatic islet (PANIS) system that was able to sustain a healthy islet environment with glucose sensitive insulin secretion from both primary and stem cell-derived islets for more than two weeks. Disease induction was tested by subjecting the primary islet PANIS to toxic conditions correlated with T2D, such as hyperglycemia and/or high free fatty acids (lipotoxicity). The effects of these combinations were studied thoroughly using viability and functionality assays along with RNA sequencing to determine how each toxic factor affected islets and what toxic condition would most closely replicate T2D. This toxic conditioned islet MPS was able to test drug efficacy with dose dependent trials using the anti-oxidant drug, Resveratrol. Additionally, innate immune cell interactions were studied by co-culturing the primary and stem cell-derived islets with neutrophils while simulating disease conditions. The result of this dissertation ultimately provides a robust islet MPS that can be used to model islet-specific disease induction and drug treatment with the capabilities for personalized medicine using human stem cells.

Chair:

Dr. Ipsita Banerjee

Department of Chemical and Petroleum Engineering, University of Pittsburgh

Committee Members:

 Dr. Harvey S. Borovetz

Department of Chemical and Petroleum Engineering, University of Pittsburgh

Dr. Tagbo Niepa

Department of Chemical and Petroleum Engineering, University of Pittsburgh

Dr. Ioannis Zervantonakis

Department of Bioengineering, University of Pittsburgh

Dr. Yong Fan

Department of Biological Sciences, Carnegie Mellon University