Towards engineering a novel transplantation site for pancreatic islets

Intraportal pancreatic islet transplantation is a promising therapy for type 1 diabetes, but the liver is not an optimal site as it is associated with massive cell-death in the graft. Several alternative sites were investigated, but the human body does not contain an adequate islet transplantation site. This thesis describes the development of a novel optimal islet environment by using a scaffold that can be implanted in a readily accessible site such as under the skin. This alternative transplantation site has the advantage that it might provide fast revascularization of the islets to improve the availability of oxygen and nutrients, and insulin release directly after transplantation. The studies were done in a stepwise fashion. First a technology platform was developed to select a suitable polymer for the scaffold. The effects of poly(D,L-lactide-co-ε-caprolactone) (PDLLCL), poly(ethylene oxide terephthalate)/polybutylene terephthalate (PEOT/PBT) block copolymeer and polysulfone on functional islet survival was tested. Only PDLLCL supported in vitro functional survival of islets and induced a minor tissue response after 28 days of implantation. To allow blood vessels to grow into the scaffold, the scaffold was implanted under the skin of several diabetic animal models four weeks before transplantation. Transplantation of islets illustrated that our prevascularized, subcutaneous PDLLCL scaffold supported functional islet survival. An islet-titration study in mice showed that transplantation of 800 islets is enough to obtain normoglycemia. Further improvement of the vascularization may reduce this number, ultimately leading to improvement of the long-term success rate of islet transplantation as treatment for type 1 diabetes