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Cell encapsulation represents a promising therapeutic strategy for many hormone-deficient diseases such as type 1 diabetes (T1D). However, adequate oxygenation of the encapsulated cells remains a challenge, especially in the poorly oxygenated subcutaneous site. Here, we present an encapsulation system that generates oxygen (O2) for the cells from their own waste product, carbon dioxide (CO2), in a self-regulated (i.e., “inverse breathing”) way. We leveraged a gas-solid (CO2–lithium peroxide) reaction that was completely separated from the aqueous cellular environment by a gas permeable membrane. O2 measurements and imaging validated CO2-responsive O2 release, which improved cell survival in hypoxic conditions. Simulation-guided optimization yielded a device that restored normoglycemia of immunocompetent diabetic mice for over 3 months. Furthermore, functional islets were observed in scaled-up device implants in minipigs retrieved after 2 months. This inverse breathing device provides a potential system to support long-term cell function in the clinically attractive subcutaneous site. 

Transplantation of stem cell–derived β (SC-β) cells represents a promising therapy for type 1 diabetes (T1D). However, the delivery, maintenance, and retrieval of these cells remain a challenge. Here, we report the design of a safe and functional device composed of a highly porous, durable nanofibrous skin and an immunoprotective hydrogel core. The device consists of electrospun medical-grade thermoplastic silicone-polycarbonate-urethane and is soft but tough (~15 megapascal at a rupture strain of >2). Tuning the nanofiber size to less than ~500 nanometers prevented cell penetration while maintaining maximum mass transfer and decreased cellular overgrowth on blank (cell-free) devices to as low as a single-cell layer (~3 micrometers thick) when implanted in the peritoneal cavity of mice. We confirmed device safety, indicated as continuous containment of proliferative cells within the device for 5 months. Encapsulating syngeneic, allogeneic, or xenogeneic rodent islets within the device corrected chemically induced diabetes in mice and cells remained functional for up to 200 days. The function of human SC-β cells was supported by the device, and it reversed diabetes within 1 week of implantation in immunodeficient and immunocompetent mice, for up to 120 and 60 days, respectively. We demonstrated the scalability and retrievability of the device in dogs and observed viable human SC-β cells despite xenogeneic immune responses. The nanofibrous device design may therefore provide a translatable solution to the balance between safety and functionality in developing stem cell–based therapies for T1D. 

Implanted cell‐containing grafts require a robust and functional vasculature to supply oxygen and nutrients, as well as clear metabolic waste products. However, it remains challenging to fabricate tunable, vascular‐promoting scaffolds without incorporating additional biologics. Here, a biphasic gel consisting of a highly porous aerogel and a degradable fibrin hydrogel for inducing vascularization is presented. The highly porous (>90%) and stable aerogel is assembled from short microfibers by being dispersed in an aqueous solution that can be 3D printed into various configurations. The biphasic gel demonstrates good compression‐resistance: 70.30% Young's modulus is recovered over 20 cycles of 65% compression under water. Furthermore, it is confirmed that tissue cells and blood vessels can penetrate a thick (≈3 mm) biphasic gel in the subcutaneous space of mice. Finally, the biphasic gel doubles the vascular ingrowth compared to a composite of a commercial surgical polyester felt and a fibrin hydrogel upon subcutaneous implantation in mice after 4 weeks. The design of this biphasic gel may advance the development of vascularized scaffolds.