UCSF

The goal of this dissertation is to develop a bioartificial pancreas device consisting of silicon nanopore membrane (SNM)-encapsulated insulin-producing pancreatic islets under convective transport to treat Type 1 Diabetes (T1D). Problems associated with islet transplantation for T1D such as shortage of donor cells, and use of immunosuppressive drugs remain as major challenges. Immune isolation using encapsulation may circumvent the use of immunosuppressants and prolong the longevity of transplanted islets. The encapsulating membrane must block the passage of host’s immune components while providing sufficient exchange of glucose, insulin and other small molecules.

This research effort investigated the feasibility of encapsulating islets with SNM to provide: (1) middle molecule selectivity against pro-inflammatory cytokines; and (2) sufficient nutrients and oxygen with convective transport to overcome the mass transfer limitations associated with diffusion through nanometer-scale pores. The selectivity analysis revealed 80% reduction in cytokines passage through SNM under convective transport. Moreover, the SNM protected encapsulated islets from infiltrating cytokines and retained islet viability and remained responsive to changes in glucose levels unlike non-encapsulated controls. The glucose-stimulated insulin response showed that membrane-encapsulation of islets with convection outperformed the diffusive conditions in terms of the magnitude of insulin secreted (1.49-fold increase in stimulation index & 3.86-fold decrease in shut-down index) and the rate of insulin production during high (1.19-fold increase) and low glucose (6.45-fold decrease) challenges. As a result of these data, the small-scale SNM-based intravascular bioartificial pancreas (iBAP) device was presented to support high cell viability and function at clinically relevant islet densities utilizing convective mass transfer both in vitro and in vivo. The hemocompatibility of the iBAP blood flow path after intravascular implantation was also demonstrated in the porcine model. These studies address the critical challenges faced by macroencapsulation and pave the way for the development of a full-scale SNM-encapsulated iBAP to treat T1D in the future.