Bellofatto, K.; Lebreton, F.; Hassany, M.; Hanna, R.; Bignard, J.; Marteyn, A.; Mar Fonseca, L.; Campo, F.; Olgasi, C.; Wolf-van Buerck, L.; Honarpisheh, M.; MARTINEZ DE TEJADA WEBER, B.; Follenzi, A.; Citro, A.; Piemonti, L.; THAUNAT, O.; Seissler, J.; COMPAGNON, P.; cohen, m.; BERISHVILI, E.; VANGUARD consortium,

Beta cell replacement therapy for type 1 diabetes is hindered by poor graft survival and suboptimal function, largely due to inadequate vascularization and lack of supportive microenvironment. To address these challenges, we developed a clinically scalable, extracellular matrix (ECM) mimetic hydrogel, termed Amniogel, derived from human amniotic membrane via streamlined, clinically compliant process. Coencapsulation of pancreatic islets with blood outgrowth endothelial cells (BOECs) within Amniogel facilitated the formation of prevascularized endocrine constructs (VECs). These constructs demonstrated enhanced {beta}-cell viability and function through ECM bound prosurvival signals, rapid self-assembly of perfusable endothelial networks enabling efficient glucose sensing, and deposition of laminin-rich basement membranes enhancing {beta}-cell coupling and insulin secretion kinetics. In preclinical diabetic mouse models, VECs rapidly integrated with the host vasculature and provided sustained glycemic control when implanted subcutaneously. This integrative approach, combining a scalable, cost-effective biological scaffold with autologous vascularization potential, represents a significant advancement toward durable and clinically translatable {beta}-cell replacement therapies for T1DM.