Constructing functionalized cartilage organoids by preserving mitochondrial homeostasis to accelerate cartilage repair

Due to the lack of blood vessels and nerves in cartilage tissue, its regeneration and repair has always been a clinical challenge. Cartilage organoids (COs) are miniature cartilage tissues cultivated using stem cells or chondrocytes, which have a broad application prospect in the field of cartilage regeneration and repair. However, prolonged scaffold-based culture of COs is often accompanied by chondrocyte hypertrophy and excessive reactive oxygen species (ROS) accumulation, which may compromise the maintenance of a stable cartilage phenotype. In this study, transcriptomic analysis of COs cultured for up to 8 weeks revealed stage-dependent changes in stress- and matrix-related programs and suggested that altered mitochondrial homeostasis may be associated with phenotypic deterioration. To address this problem, this study constructed a MnO 2 -Melatonin@DNA-SF hydrogel (Mn-Me@DSH) bioink matrix by loading MnO 2 nanoparticles and Melatonin on DNA-SF hydrogels. Subsequently, we bioprinted BMSCs with Mn-Me@DSH using a DLP system to produce a functionalized COs that could maintain mitochondrial homeostasis. These engineered COs effectively repaired cartilage defects in rats within 6 weeks. This study breaks through the limitations of the traditional COs in the oxidative stress microenvironment through the ROS scavenging, and provides a new solution for the construction of functionalized COs and cartilage regeneration.