High‐Efficiency, Prevascularization‐Free Macroencapsulation System for Subcutaneous Transplantation of Pancreatic Islets for Enhanced Diabetes Treatment

Pancreatic islet macroencapsulation systems for subcutaneous transplantation have garnered significant attention as a therapy for Type I diabetes due to their minimal invasiveness and low complication rates. However, the low vascular density of subcutaneous tissue threatens the long‐term survival of islets. To address this issue, prevascularized systems are introduced but various challenges remain, including system complexity and vascular‐cell immunogenicity. Here, a novel prevasculature‐free macroencapsulation system designed as a multilayer sheet, which ensures sufficient mass transport even in regions with sparse vasculature, is presented. Islets are localized in top/bottom micro‐shell layers (≈300 µm thick) to maximize proximity to the surrounding host vasculature. These sheets, fabricated via bioprinting using rat islets and alginate‐based bio‐ink, double islet viability and optimize islet density, improving insulin secretion function by 240%. The subcutaneous transplantation of small islet masses (≈250 islet equivalent) into diabetic nude mice enable rapid (<1 day) recovery of blood glucose, which remain stable for >120 days. Additionally, antifibrotic drug‐loaded multilayer sheets facilitate blood glucose regulation by rat islets at the subcutaneous sites of diabetic immunocompetent mice for >35 days. Thus, this macroencapsulation system can advance the treatment of Type I diabetes and is also effective for islet xenotransplantation in subcutaneous tissue.