In developing new therapies for diseases, a constant issue resides in the inadequacies of current animal models to accurately represent human physiology and diseases. This leads to many drugs that proved successful in animal studies to fail after entering clinical trials. A promising new approach to aid in more accurately predicting the effects of drugs is in the development of the human-on-a-chip model. In this model, organoids are implemented in a microfluidic device to create in vitro models for high throughput drug testing and disease modeling. A disease my lab has been focused on treating is diabetes. Diabetes is a widespread disease, wherein the body cannot properly produce necessary levels of insulin to meet its metabolic needs, leading to high levels of glucose. The onset of diabetes is caused the body forming a resistance to insulin (T2D) or from the autoimmune death of the insulin producing cells which reside in pancreatic islets (T1D). The aim of the current project is to develop an islet-on-a-chip model that can be used to better understand and treat diabetes.
The objective of this work will be achieved by reproducing a diabetic phenotype in an organ-on-a-chip model using human pluripotent stem cells (hPSCs). The model utilizes a two-chamber microfluidic device with individual inflow and outflow separated by a membrane. In initial studies, primary islets were incorporated in the device under direct, low flow conditions over extended culture periods. The isletâs 3D morphology was maintained through their encapsulation in an alginate gel, which additionally protected them from the high shear in glucose response testing. Under these conditions, the islets demonstrated high viability and glucose responsiveness over continued culture periods. hPSCs- derived islet organoids were further integrated into the device. The islet organoids were developed to more accurately represent primary islets through the incorporation of vascular cells to form an intra-islet vascular network, which exists in vivo in islets. The flow perfusing through the vascularized islet-mimetic organoids showed improved functionality. With the inclusion of hPSC derived cells, the future implementation of diabetes related genetic factors can be included.
