DESIGNING ADVANCED CELL ENCAPSULATION SYSTEMS FOR TYPE 1 DIABETES (T1D) TREATMENT

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which the patient’s own immune system attacks and destroys the insulin-producing beta cells in the pancreas. It is estimated that in the US alone there are as many as three million people with T1D, with approximately 80 newly diagnosed patients every day. One in every 400 children and adolescents in the US has T1D and the rate of T1D incidence among children under the age of 14 is estimated to increase by 3% annually worldwide. Current treatments include injections and infusion of exogenous insulin and require constant attention and strict patient compliance. The transplantation of pancreases or islets offers a better alternative. However, its wide application is limited by the need for long-term immunosuppression and a persistent shortage of donor organs. Cell encapsulation has been shown to hold promise for effective, long-term treatment of T1D. However, encapsulation systems developed to date still face various challenges. For example, alginate hydrogel capsules, despite their biocompatibility and function, are difficult to retrieve or replace completely due to the large number of capsules required for effective treatment and the complicated organ structures in the transplantation site (i.e. peritoneal space), contributing to risks and concerns in case of transplant failure or medical complications. On the other hand, macroscopic devices (e.g. planar diffusion chambers), although considered retrievable, are challenging to scale up to a clinically relevant capacity due to their small surface area for mass transfer. In this thesis, I present three independent yet correlated research projects developing advanced cell encapsulation systems. Firstly, I developed a novel method to fabricate toroidal particles. Alginate hydrogel toroidal particles have a shorter diffusion path within compared to conventional spherical alginate hydrogel particles, facilitating mass transport and benefiting encapsulated cells. Secondly, to enhance the mechanical robustness of the hydrogel and prevent cells from escaping, I engineered a novel nanofiber-enabled encapsulation device by combining electrospun nanofibers with biocompatible hydrogel. Last but not least, to further push cell encapsulation therapies toward clinical applications, I designed a retrievable and scalable device. I demonstrated the therapeutic potential of the device through the correction of chemically induced diabetes in C57BL/6 mice using rat islets for 3 months as well as in immunodeficient SCID-Beige mice using human islets for 4 months. I further showed, as a proof of concept, the scalability and retrievability of the device in dogs. In general, these projects may contribute to a cellular therapy for T1D.