Extracellular hemoglobin combined with an O -generating material overcomes O limitation in the bioartificial pancreas.

The bioartificial pancreas encapsulating pancreatic islets in immunoprotective hydrogel is a promising therapy for Type 1 diabetes. As pancreatic islets are highly metabolically active and exquisitely sensitive to hypoxia, maintaining O supply after transplantation remains a major challenge. In this study, we address the O limitation by combining silicone-encapsulated CaO (silicone-CaO ) to generate O with an extracellular hemoglobin O -carrier coencapsulated with islets. We showed that the hemoglobin improved by 37% the O -diffusivity through an alginate hydrogel and displayed antioxidant properties neutralizing deleterious reactive O species produced by silicone-CaO . While the hemoglobin alone failed to maintain alginate macroencapsulated neonate pig islets under hypoxia, silicone-CaO alone or combined to the hemoglobin restored islet viability and insulin secretion and prevented proinflammatory metabolism (PTGS2 expression). Interestingly, the combination took the advantages of the two individual strategies, improved neonate pig islet viability and insulin secretion in normoxia, and VEGF secretion and PDK1 normalization in hypoxia. Moreover, we confirmed the specific benefits of the combination compared to silicone-CaO alone on murine pseudo-islet viability in normoxia and hypoxia. For the first time, our results show the interest of combining an O provider with hemoglobin as an effective strategy to overcome O limitations in tissue engineering.