In the pancreas, islets are surrounded by a complex microenvironment that is not recapitulated during islet transplantation, resulting in limited islet function. Creating a proper microenvironment to support islet secretory function within an encapsulation device that protects the cells from the surrounding immune response is crucial for the success of this approach. To achieve this goal, we are developing: (1) a polyacrylamide (PA) islet microenvironment to better understand the microenvironment necessary to maintain islet function and (2) a nano-porous thin-film polycaprolactone (PCL) macro-encapsulation device that protects the islets from immune destruction.PA micro-well scaffolds at 0.1 kPa and 10 kPa were fabricated using standard photolithography to create 3D cell clusters from dissociated islets and beta cells. We show a significant stiffness-dependent increase in the glucose stimulated insulin response per cell for 3D beta cell clusters grown on 0.1kPa scaffolds in comparison to 10kPa scaffolds. Our data suggests that the physical interactions with the microenvironment regulate insulin processing through the MLCK and ROCK mechanosensing pathways. Furthermore, our data suggests active beta-catenin signaling is requires for stiffness dependent insulin regulation. To improve long-term in vivo islet viability we fabricated a thin-film device from PCL, a biodegradable polymer approved by the FDA for biomedical devices.  In vitro the device demonstrates unhindered insulin kinetics.  In vivo the device vascularizes and protects against allo-rejection, this suggests thin-film devices engraft and maintain alloimunity after a period of one month. Since our devices demonstrate cell viability at one-month, we predict that alloimunity can be maintained indefinitely. By understanding the role of microenvironment and designing a device that promotes improved islet function, viability and immune protection, we can better design the therapeutics necessary to treat diabetes.

Compliant polymeric scaffolds with nanofabricated membranes for improved pancreatic islet function and viability

248th National Meeting (2014)

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