(631e) Islet-on-Chip Model for Type 2 Diabetes

Diabetes is an increasingly prominent disease that develops from the dysfunction of the insulin production within pancreatic islets. This dysfunction stems from autoimmune elimination of the insulin producing beta cells (Type 1) or a toxic environment that hinders insulin production or effectiveness (Type 2). Testing of possible treatments for preventing or mitigating the complications of diabetes is hindered by expensive and inadequate animal models. The human-on-chip project seeks to replace these models and aid in the transition from initial testing to clinical trials by mimicking the biochemical and biophysical environment of organs on a fluidic device. This project aims to develop a type 2 diabetic islet-on-a-chip model utilizing both primary islets and human induced pluripotent stem cells (hiPSCs).

The islet-on-chip platform is based on the commercially available Organ-on-Chip fluidic device from Micronit that utilizes three glass layers to form a 2-chamber system partitioned by a polyester membrane. The two chambers can be individually accessed through a dedicated perfusion channel that allows for customizable flow configurations through the system. The polyester membrane was designed for culturing adherent cells with the options of cell seeding either through perfusion flow or prior to chip assembly. This aspect of the base chip design is not conducive to culturing pancreatic islets, since retention of spheroidal islet architecture is critical for continued islet function. We introduced a novel strategy for culturing 3D spheroidal islets in the microfluidic device, by supporting the islets with a hydrogel substrate for its structural stability and micropatterning the hydrogel on the membrane. A COMSOL-based in silico flow field model informed this system design for optimizing flow rate and micropattern design to retain adequate oxygen level in the islet vicinity, while minimizing shear stress. Our islet-on-chip system retained high viability and function of glucose stimulated insulin secretion (GSIS) with primary human islets over an extended period of 28 days of perfusion culture under normal ‘fasting’ condition. We expect this extended culture of healthy islets will be instrumental in modeling disease conditions and tracking disease progression/ reversal over time. The progression of type 2 diabetes was modeled within the formed chip, by simulating the diseased states of glucotoxicity, lipotoxicity, and glucolipotoxicity through long term exposure to pathological glucose levels, elevated free fatty acids, and combinations of the two. With these methods, the resulting islets showed lower insulin expressing cells and loss in functional secretion of insulin in response to glucose changes, which is indicative of a diabetic state. In parallel to testing with primary islets, hiPSC-derived islet organoids were developed to replace the primary human islets as a regenerative cell source. As with the primary islets, the fluidic culture system maintained good survival and functional glucose-stimulated insulin responsiveness in the hiPSC-derived islets over a 14-day span. The end goal of this project is to test of type 2 diabetes treatments, such as Pioglitazone, to determine the reversibility of the toxic states and how well it simulates treatment of the disease in patients.