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Biotechnol Bioeng. 2018 Dec 29. doi: 10.1002/bit.26913. [Epub ahead of print]

Extracellular hemoglobin combined with an O2 -generating material overcomes O2 limitation in the bioartificial pancreas.

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Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne Loire, Nantes, France.
Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France.
Service de Pédiatrie des Maladies Chroniques, CHU de Nantes, Nantes, France.
Department of Experimental Surgery, CRIP, Oniris, Nantes, France.
Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
Department of Process Engineering for Environment and Food Laboratory (GEPEA), UMR CNRS 6144, Oniris, Nantes, France.
Laboratoire Réactions et Génie des Procédés (LRGP), Université de Lorraine, CNRS, Nancy, France.


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 O2 supply after transplantation remains a major challenge. In this study, we address the O2 limitation by combining silicone-encapsulated CaO2 (silicone-CaO2 ) to generate O2 with an extracellular hemoglobin O2 -carrier coencapsulated with islets. We showed that the hemoglobin improved by 37% the O2 -diffusivity through an alginate hydrogel and displayed antioxidant properties neutralizing deleterious reactive O2 species produced by silicone-CaO2 . While the hemoglobin alone failed to maintain alginate macroencapsulated neonate pig islets under hypoxia, silicone-CaO2 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-CaO2 alone on murine pseudo-islet viability in normoxia and hypoxia. For the first time, our results show the interest of combining an O2 provider with hemoglobin as an effective strategy to overcome O2 limitations in tissue engineering.


Type 1 diabetes; bioartificial pancreas; extracellular hemoglobin; oxygen supply; pancreatic islet; tissue engineering


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