Membrane based macroencapsulation devices for improved pancreatic islet survival and function

The research presented in this thesis is about the development of novel membrane based macroencapsulation devices for improved pancreatic islet survival and function. To improve pancreatic islets functionality by avoiding their aggregation within macroencapsulation devices, we developed a novel microwell membrane based encapsulation device, where the islets are seeded in separate microwells avoiding their fusion and clustering. The membrane porosity is tailored to achieve shielding of the islets from the host immune cells without compromising their secretory responses. The non-degradable, microwell membranes are composed of poly (ether sulfone)/polyvinylpyrrolidone (PES/PVP) and manufactured via phase separation micromolding. The encapsulated islets maintain their glucose responsiveness demonstrating the potential of this novel device for islet transplantation. Moreover, we fabricated porous, micropatterned PES/PVP membranes and investigated the effect of patterns on human umbilical vein endothelial cell (HUVEC) alignment and interconnection as a first step towards the development of a stable prevascularized layer in vitro. The micropatterned surface, applied as lid for the microwell macroencapsulation device, would support cell organization during the development of a prevascularized layer on the outside of the device. Providing encapsulated islets with close proximity to blood vessels is important for their survival and function. Additionally, in order to mimic the β-cell relation with endothelial cells in native islets, we created stable composite aggregates by co-culture of mouse insulinoma MIN6 cells with HUVECs on a non-adherent agarose microwell platform. These composite aggregates maintain their function after encapsulation within our microwell PES/PVP device and show better insulin release than encapsulated pure MIN6 aggregates, indicating that providing the β-cells with a connection to the endothelial cells within an encapsulation device can improve the encapsulated cells’ functionality. As alternative for the flat configuration, we developed new PES/PVP multibore hollow fiber membranes for islet macroencapsulation. The fiber consists of seven bores and has high mechanical stability offering good protection to the encapsulated islets. Human islets encapsulated within the fiber bores retain their glucose responsiveness. Our new multibore hollow fiber membranes have higher islet encapsulation capacity than single-bore fibers and allow for easier up-scaling, which are important factors for the development of a clinically applicable bioartificial pancreas.