Microencapsulated human islets as a therapy for type 1 diabetes
Microencapsulating human islets is a means being explored to overcome the immune mediated destruction of the graft without toxic immunosuppression. Despite promising studies in various animal models, encapsulated human islet transplantation has so far not made an impact in the clinical setting. Many non-immunological and immunological factors such as limited islet availability, reduced immunoprotection, effect of the encapsulation process, hypoxia and inflammatory response hinder the successful application of this promising technology. In this study, strategies were designed to overcome the above factors which should enhance the survival and function of encapsulated human islets. The study demonstrated that human islets can be shipped safely over long distances and encapsulated without affecting cell survival and function, thus overcoming its limited availability. A strategy to reduce the pore size of the microcapsules by increasing the gelling time was unsuccessful and produced brittle capsules. The microcapsules produced were stable and biocompatible in rodents but not in the baboon. The encapsulation process had little or no effect on the cellular transcriptome of human islets and on their ability to function both in vitro and in vivo. The study showed that encapsulated human islets placed in the peritoneal cavity experience hypoxia in the immediate post-transplantation period. Pre-treating encapsulated islets with desferrioxamine enhanced expression of hypoxia inducible factor-1α and vascular endothelial growth factor, and reduced the number of encapsulated islets needed to normalize blood glucose levels from 2,000 to as few as 750 IEQs. Allo- and xeno- transplantation of encapsulated insulin producing cells into immunocompetent rats resulted in a dense pericapsular fibrotic overgrowth. Coating heparin on the microcapsules reduced the fibrotic overgrowth in the allo- but not the xeno- graft model. The absence of dense pericapsular fibrotic overgrowth in the allografted humanized mouse suggests that accelerated efforts are needed to develop a suitable preclinical animal model. In summary, this thesis shows that microencapsulating human islets is safe and illustrates strategies to overcome hypoxia and reduce pericapsular fibrosis. However, further modifications to the microcapsule are required to prevent the fibrotic overgrowth, if encapsulated human islets or beta cell surrogates are to become a viable option as a therapy for type 1 diabetes in humans.
Islet transplantation, Microencapsulation
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