Piezoelectric hydrogel-based 3D bioprinting of cartilage-bone integrated organoids for osteochondral defect repair

Articular cartilage defects are inherently difficult to treat given the tissue's avascularity and minimal intrinsic regenerative capacity. Although stem cell-derived organoids offer promise for cartilage regeneration, insufficient dimensional scalability and poor host-tissue integration remain key limitations. Here, we developed a 3D-bioprinted piezoelectric cartilage-bone integrated organoid system using two functionally distinct bioinks: a chondrogenic matrix of methacrylated chondroitin sulfate (ChSMA), barium titanate (BTO) nanoparticles, and TGF-β and an osteogenic matrix of gelatin methacrylate (GelMA), BTO, and nano-hydroxyapatite (nHA). This bilayer design establishes compartment-specific microenvironments that guide bone marrow mesenchymal stem cell (BMSC) differentiation toward chondral and osseous lineages while maintaining spatial segregation between the two compartments. Incorporated BTO nanoparticles convert mechanical stimulation into localized bioelectrical cues, enhancing cellular responsiveness and tissue maturation. The biomimetic osseous layer provides structural anchorage at the defect site. Our results demonstrate stratified extracellular matrix formation with compartment-specific compositions, offering a mechanistically grounded approach for osteochondral defect repair.