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A bioartificial pancreas (BAP) encapsulating high pancreatic islets concentration is a promising alternative for type 1 diabetes therapy. However, the main limitation of this approach is O2 supply, especially until graft neovascularization. Here, we described a methodology to design an optimal O2-balanced BAP using statistical design of experiment (DoE). A full factorial DoE was first performed to screen two O2-technologies on their ability to preserve pseudo-islet viability and function under hypoxia and normoxia. Then, response surface methodology was used to define the optimal O2-carrier and islet seeding concentrations to maximize the number of viable pseudo-islets in the BAP containing an O2-generator under hypoxia. Monitoring of viability, function and maturation of neonatal pig islets for 15 days in vitro demonstrated the efficiency of the optimal O2-balanced BAP. The findings should allow the design of a more realistic BAP for humans with high islets concentration by maintaining the O2 balance in the device. [ABSTRACT FROM AUTHOR]

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. Mouré et al. adress the O2 limitation in a bioartificial pancreas, composed of neonate pig islets encapsulated in an alginate hydrogel, by combining an O2 generator (silicone‐CaO2) with an extracellular hemoglobin O2‐carrier. By increasing the O2 diffusivity in the alginate hydrogel and neutralising reactive O2 species produced by the silicone‐CaO2, the hemoglobin aims to improve the integration of the O2 generator into the device and the adaptation of the bioartificial pancreas to the varying O2 tensions encountered after transplantation. [ABSTRACT FROM AUTHOR]

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 2 supply after transplantation remains a major challenge. In this study, we address the O 2 limitation by combining silicone-encapsulated CaO 2 (silicone-CaO 2 ) to generate O 2 with an extracellular hemoglobin O 2 -carrier coencapsulated with islets. We showed that the hemoglobin improved by 37% the O 2 -diffusivity through an alginate hydrogel and displayed antioxidant properties neutralizing deleterious reactive O 2 species produced by silicone-CaO 2 . While the hemoglobin alone failed to maintain alginate macroencapsulated neonate pig islets under hypoxia, silicone-CaO 2 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 2 alone on murine pseudo-islet viability in normoxia and hypoxia. For the first time, our results show the interest of combining an O 2 provider with hemoglobin as an effective strategy to overcome O 2 limitations in tissue engineering., (© 2018 Wiley Periodicals, Inc.)