Constructing hypoxia and bioshield inhibits neurovascularized endochondral ossification for stable cartilage regeneration

Cartilage regeneration by bone marrow stromal cells (BMSCs) has become a promising therapeutic approach. However, the BMSC-engineered cartilage (BEC) is highly prone to ossification once implanted in vascularized and innervated subcutaneous microenvironments, ultimately leading to failure of cartilage regeneration. Herein, we innovatively developed a living cell-based encapsulation coating technique (designated as EC@GelMA) aimed at creating a biophysical barrier for BMSCs to maintain their stability in cartilage regeneration within an ectopic non-neurovascularized microenvironment. In vitro experimental results confirm that, both technically and theoretically, EC@GelMA could provide a hypoxic and biologically active biomimetic cartilage microenvironment for internally encapsulated BMSCs. In vivo experiments confirmed that EC@GelMA can provide BMSCs with a biomimetic cartilage microenvironment that isolates blood vessels and nerves, achieving stable cartilage regeneration of BMSCs in the ectopic microenvironment. All our results provide an effective solution for repairing cartilage defects in subcutaneous ectopic microenvironments, such as ear and nasal cartilage, using BMSCs, and facilitates its clinical translation.