Effects of Transplanted Islets Nano-Encapsulated with Hyperbranched Polyethylene Glycol and Heparin on Microenvironment Reconstruction and Glucose Control.

The microenvironment of pancreatic islets gets disrupted during enzyme digestion and causes islets to remain in a vulnerable state, leading to poor outcome in the initial days of transplantation. To avoid immune invasion while allowing the reconstruction of the microenvironment of the transplanted site, we propose immunoisolation polymers, which can nanoencapsulate islets quickly without cytotoxicity. Here, nonhuman primate (NHP) islets were nanoencapsulated with hyperbranched polyethylene glycol (hb-PEG) and heparin by layer-by-layer technology and transplanted into the kidney subcapsular space of diabetic C57BL/6 mice. An immunosuppressive drug protocol was applied to increase the survival time until the animals were sacrificed. The recipients of NHP islets exhibited high nonfasting blood glucose level (BGL) for 2-3 weeks, which was normalized afterward. Immunohistochemical (IHC) analysis revealed an immature vascular basement membrane and cell surface integrins directly associated with poor initial insulin production. The transplanted grafts regained their own microenvironment within a month without any outside stimuli. No lymphocyte infiltration was observed in the grafts at any time. Humoral and cell-mediated immune responses were prominently diminished by the hb-PEG/Heparin nanoencapsulated islets. Immunoisolation accompanied by an immunosuppressive drug protocol protects islets by helping them avoid immunogenesis while at the same time allowing them to reconstruct their microenvironment.