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Beta cell replacement therapy (BCRT) for patients with type 1 diabetes (T1D) improves blood glucose regulation by replenishing the endogenous beta cells destroyed by autoimmune attack. Several limitations, including immune isolation, prevent this therapy from reaching its full potential. Cell encapsulation devices used for BCRT provide a protective physical barrier for insulin-producing beta cells, thereby protecting transplanted cells from immune attack. However, poor device engraftment posttransplantation leads to nutrient deprivation and hypoxia, causing metabolic strain on transplanted beta cells. Prevascularization of encapsulation devices at the transplantation site can help establish a host vascular network around the implant, increasing solute transport to the encapsulated cells. Here, we present a replenishable prevascularized implantation methodology (RPVIM) that allows for the vascular integration of replenishable encapsulation devices in the subcutaneous space. Empty encapsulation devices were vascularized for 14 days, after which insulin-producing cells were inserted without disrupting the surrounding vasculature. The RPVIM devices were compared with nonprevascularized devices (Standard Implantation Methodology [SIM]) and previously established prevascularized devices (Standard Prevascularization Implantation Methodology [SPVIM]). Results show that over 75% of RPVIM devices containing stem cell-derived insulin-producing beta cell clusters showed a signal after 28 days of implantation in subcutaneous space. Notably, not only was the percent of RPVIM devices showing signal significantly greater than SIM and SPVIM devices, but the intraperitoneal glucose tolerance tests and histological analyses showed that encapsulated stem-cell derived insulin-producing beta cell clusters retained their function in the RPVIM devices, which is crucial for the successful management of T1D.

Pancreatic islet transplantation is a promising treatment for type I diabetes, which is a chronic autoimmune disease in which the host immune cells attack insulin-producing beta cells. The impact of this therapy is limited due to tissue availability and dependence on immunosuppressive drugs that prevent immune rejection of the transplanted cells. These issues can be solved by encapsulating stem cell-derived insulin-producing cells in an immunoprotective device. However, encapsulation exacerbates ischemia, and the lack of vasculature at the implantation site post-transplantation worsens graft survival. Here, an encapsulation device that supplements nutrients to the cells is developed to improve the survival of encapsulated stem cell-derived insulin-producing cells in the poorly vascularized subcutaneous space. An internal compartment in the device is fabricated to provide zero-order release of alanine and glutamine for several weeks. The amino acid reservoir sustains viability of insulin-producing cells in nutrient limiting conditions in vitro. Moreover, the reservoir also increases cell survival by 30% after transplanting the graft in the subcutaneous space.