Chiara Villa

ype 1 Diabetes mellitus (T1D) is a chronic autoimmune disease caused by the attack of T lymphocytes on pancreatic β-cells, leading to absolute insulin deficiency. For T1D patients, exogenous insulin injections are a lifesaving treatment, but it does not prevent hypoglycemia daily risk. Pancreatic islet transplantation is one of the therapeutic approaches in case of severe hypoglycemic unawareness, but it requires life-long systemic immunosuppression, causing several side effects. Moreover, most patients show insulin-independence and early graft function lost, due to immunological and physiological limitations of the transplant site. Alginate encapsulation represents an alternative providing a physical barrier from the host immune system attack, and it has been evaluated in pre-clinical and clinical settings. The successful use of alginate microcapsules has been hampered by 1) the large diameters, and 2) the mechanical instability. The large capsule size constitutes an oxygen and nutrient diffusion barrier and limits the choice of transplant sites to areas not conceived for cell survival, such as the peritoneal cavity. Conventional alginate microencapsulation has been optimized by minimizing capsule size (450-550μm in diameter), increasing the cell loading density (nearly 3%), and by using highly biocompatible Ultra-Pure medium viscosity sodium alginate (UP-MVG). This allowed for transplantation of microencapsulated islets in the well-vascularized epididymal fat pad (EFP), engineered with a fibrin matrix to promote graft engraftment. Under physiological conditions alginate capsules show swelling and pore size increase. To protect the cells, the capsule must therefore be carefully designed, especially with respect to mechanical stability. Thus, novel alginate-based capsules have been designed to improve in vivo stability of alginate: 1) hybrid microcapsules (MicroMix) using an electrostatic droplet generator method by mixing UP-MVG with Polyethylene Glycol (Peg) 2) UP-MVG microcapsules double coated (Double) with Peg through an emulsification process. One of the main challenges has been to ensure in vivo long term alginate capsule stability, with the hope that a complete knowledge of alginate-based capsule biocompatibility, mechanical properties and permselectivity will be useful for successful clinical transplantation.