Islet transplantation (IT) may cure type-1 diabetes (T1D) but current protocols require life-long systemic immunosuppression (SI) to prevent graft rejection. SI is the main cause of adverse events associated with IT. In order to increase safety of the IT procedure and to treat young patients, an alternative and safer anti-rejection therapy needs to be implemented. Immunoisolation of pancreatic islets (PI) with biocompatible hydrogels through cell encapsulation allows transplantation in absence of SI in rodents but has failed in pre-clinical and clinical settings. Reasons for these failures are unknown. We hypothesize that the large size of conventional microcapsules along with in vivo instability of encapsulation materials are among the possible causes of failure. The large size of microcapsule (600-1000 µm) diameter reduces diffusion of oxygen and nutrients to enclosed cells and causes delay in insulin secretion. Also, large microcapsule size increases IT volume thus limiting the choices of transplant site to the peritoneal cavity, which is not ideal due to the non-optimal kinetics of insulin absorption and lack of vascularization. In addition to microcapsule size, conventional encapsulation materials like alginate are subjected to in vivo remodeling, including swelling and change in permeability and permselectivity to molecules that are involved in triggering immunological responses.

To address this we have developed and optimized a method to conformally coat islets by shrink-wrapping them with polyethylene glycol (PEG) hydrogels that minimizes capsule size and graft volume while controlling coating perm-selectivity and in vivo stability. We have shown that rodent islets can be completely coated with a thin (10-20µm) layer of hydrogel that does not affect islet viability and function in vitro (as assessed by live/dead and ROS staining, GSIR index and delta, perifusion up to 14 days) and in vivo in syngeneic murine models of islet transplantation (700 IEQ/mouse, kidney capsule). We have also shown that conformal coatings are immunoisolating and prevent rejection of fully MHC-mismatched pancreatic islets in mice in a bioengineered epididymal fat pad (EFP) site (1000 IEQ/mouse) without SI (100% protection from allorejection >100 days PTX vs. 100% rejection of naked islets at 9-12 days, n=2). In addition to this we have optimized conventional alginate microencapsulation by minimizing capsule size (450-550µm in diameter) and by using ultra-pure clinical grade materials that are highly biocompatible. Optimized microcapsules transplanted in a bioengineered EFP site reverse diabetes at day 1 PTX and maintain glucose homeostasis. We are currently comparing the safety and efficacy of conformal coating encapsulation with optimized alginate microencapsulation in vitro and in vivo in rodent models of islet allotransplantation.