Scaffold‐Guided Subchondral Bone Repair Enables Endogenous Stem Cell–Driven Cartilage Regeneration in Osteochondral Defects

Abstract Osteochondral defects involve concurrent damage to cartilage and the subchondral bone. Here, a cell‐free scaffold is presented, consisting of a 3D‐printed bioceramic base combined with a Gelatin methacryloyl (GelMA)‐Kartogenin (KGN) hydrogel. This dual induction scaffold is engineered to promote osteogenesis while simultaneously providing localized chondrogenic stimulation. The rabbit bone marrow‐derived mesenchymal stromal cells are added as a positive control, while the blank osteochondral defects without scaffold implantation are set as a negative control. It is hypothesized that effective regeneration of subchondral bone is a prerequisite for functional cartilage repair, with effective recruitment of endogenous skeletal stem cells (SSCs). In rabbit osteochondral defects, chondrogenic scaffolds alone regenerated cartilage but caused severe subchondral bone collapse and joint surface deformation persisting through 24 weeks. In contrast, combining osteogenic scaffolds with chondrogenic constructs preserved joint morphology by promoting Gli‐1⁺ and Sca‐1⁺ skeletal stem cell recruitment and proliferation. Interestingly, adding exogenous mesenchymal stromal cells offered no further benefit. Together, a scaffold capable of recruiting endogenous skeletal stem cells to regenerate subchondral bone is essential for effective osteochondral repair and demonstrates comparable efficacy to stem cell transplantation, demonstrating the viability of a scaffold‐only strategy for articular cartilage and subchondral bone tissue regeneration.