Bioengineering of the implantable vascularized endocrine constructs for insulin delivery suitable for clinical upscaling

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,

doi:10.1101/2025.04.19.647461

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bioRxiv · 10.1101/2025.04.19.647461

Bioengineering of the implantable vascularized endocrine constructs for insulin delivery suitable for clinical upscaling

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Abstract

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. Co-encapsulation 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 pro-survival 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. One Sentence SummaryA clinically scalable, biological hydrogel based vascularized endocrine constructs show sustained diabetes reversal.

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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,. 2025-04-23. Bioengineering of the implantable vascularized endocrine constructs for insulin delivery suitable for clinical upscaling. https://doi.org/10.1101/2025.04.19.647461

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