Nanofiber‐Reinforced Self‐Adaptive Hydrogels with Desired Sequential Delivery Capability of Bioactive Factors and Magnesium for Vascularized Osteochondral Regeneration

Abstract The limited ability of cartilage regeneration, the complexity of joint defects, and the lack of stem cells have plagued the reconstruction of osteochondral defects with tissue engineering scaffolds. This study develops a multifunctional hydrogel for vascularized osteochondral regeneration by incorporating transforming growth factor‐β3 (TGF‐β3)‐loaded Mg‐based nanosheets into nanofiber‐reinforced self‐adaptive hydrogel loaded with platelet‐derived growth factor‐BB (PDGF‐BB). This strategy successfully integrates self‐adaptive and self‐healing properties, reactive oxygen species (ROS) scavenging ability, and adhesion properties within a single scaffold, rendering it suitable for joint repair applications. The β‐sheet‐rich silk nanofibers enhance the mechanical strength of the dynamic hydrogel. Mg‐based nanosheets with high loading efficiency achieve sustainable release of TGF‐β3 and Mg 2+ . The sequential release of PDGF‐BB and TGF‐β3/Mg 2+ from the scaffold stimulates cell migration, tube formation, and differentiation of stem cells. Upon implantation into the osteochondral defect models, the scaffold offers the required stimulus to promote cell recruitment and angiogenesis, and enhance the directed differentiation of stem cells, ultimately achieving satisfactory osteochondral regeneration. Transcriptome analysis in vivo further confirms that the upregulation of relevant genes and signaling pathways is associated with the cell recruitment, angiogenesis, osteogenesis, chondrogenesis, and potential inflammatory regulation, aligning with the findings. These findings suggest that the scaffold provides an optimal 3D microenvironment for osteochondral repair.