Retrievable "sea-island" microstructured zwitterionic-silicone hydrogel devices: augmented oxygen transport and anti-fibrosis for sustaining islet survival.

Abstract

Islet encapsulation is a transformative strategy for type 1 diabetes (T1D) cellular therapy, enabling islet transplantation without lifelong immunosuppression. However, macroscale encapsulation faces prominent challenges: poor surgical retrieval, hypoxia, and foreign body response (FBR)-induced fibrosis, which severely compromise clinical translation. Herein, we develop a sea-island microstructured zwitterionic-silicone hydrogel device via copolymerization of siloxane monomer SiGMA, zwitterionic monomer carboxybetaine acrylamide (CBAA), and hydrogen-bonding monomer N-acryloyl glycinamide (NAGA). Notably, NAGA enhances hydrogel structural stability via strong H-bonds, reinforcing network and mechanical integrity to facilitate safe retrieval; importantly, NAGA's hydrogen bonding crosslinks allow the hydrogel device to be heat-sealed, preventing cell leakage and maintaining immunoisolation. The incorporation of SiGMA induces hydrophobic phase separation, generating silicone-rich polymer microdomains that enhance oxygen permeability to alleviate islet hypoxia, while zwitterionic CBAA significantly improves antifouling performance and mitigates fibrotic encapsulation by suppressing the host FBR. After 8 weeks of implantation in mice and beagle dogs, the device exhibits minimal fibrotic encapsulation and can be readily retrieved. Notably, even without pre-vascularization or immunosuppression, the transplanted islets in diabetic mice sustain normoglycemia for up to 400 days. These results demonstrate a robust retrievable encapsulation device that addresses key bottlenecks in islet transplantation, advancing its potential translation for T1D.