Preservation of chondrocyte microspheroids by local sustained hydrogen supply improves osteoarthritic cartilage repair.

The inflammatory pathological microenvironment of osteoarthritis (OA) degrades the cell state and function of stem cell-derived grafts and presents a major obstacle to developing effective cell therapies. Here, we show that the viability and hyaline cartilage phenotype of bone marrow-derived mesenchymal stem cell (BMSC)-derived chondrocyte microspheroids (CMSs) can be efficiently preserved during spheroidization with persistent H2 supply and in an OA microenvironment. We therefore developed TiSi2 nanosheets (TSN) that hydrolytically generate a sustained (> 2 months) high dose of H2 and construct a H2-releasing hydrogel transplant (TSN/CMS-Gel) by encapsulating TSN and CMSs within a photo-crosslinking hydrogel (Gel). Transplantation of TSN/CMS-Gel achieves a strong survival of chondrocytes in a rodent OA model and promotes the rapid and efficient repair of sheep osteoarthritic critical-size cartilage defects, as well as the reversal of osteoarthritic progression within 6 months. The proposed strategy of locally sustaining H2-mediated preservation of transplanted chondrocytes in the pathological microenvironment opens new opportunities to enhance cell transplantation outcomes.