Ginsenoside CK Hybrid Exosome Composited Injectable Macroporous Hydrogel Scaffold for Cartilage Regeneration via Endogenous Bone Marrow Mesenchymal Stem Cells Recruitment and Fate Modulation.

Abstract

Osteoarthritis (OA)-induced cartilage repair critically relies on bone marrow mesenchymal stem cells (BMSCs). Three key challenges persist in OA therapy: efficient recruitment of BMSCs to lesions, sustained retention in defects, and inhibition of chondrocyte hypertrophy under inflammatory conditions. This study proposes a multidimensional repair strategy coordinating the entire process of "endogenous BMSCs recruitment-retention/proliferation-differentiation-postdifferentiation fate-regulation." Accordingly, a ginsenoside CK (CK)-hybridized exosome (HyExo@CK) composite injectable microporous hydrogel scaffold (HyExo@CK/SiCH) is developed by integrating material strategies for multifunctional synergy. Detailly, the HyExo@CK enables endogenous BMSCs recruitment. The hydrogel scaffold, formed by in situ polysiloxane crosslinking of silane-modified recombinant collagen (functioning as surfactant-like foaming agent) and hyaluronic acid (serving as a high-viscosity rheological modifier and foam stabilizer), features interconnected macropores (171.40 ± 7.37 µm) that offer an optimal niche for BMSCs retention and proliferation. Cellular assays demonstrated HyExo@CK/SiCH significantly promoted BMSCs proliferation, migration, and chondrogenic differentiation. Computational modeling and OA-mimicking transcriptomic analysis revealed that CK competitively binds to the ligand-binding domain of SDF-1, effectively inhibiting the chondrocyte hypertrophy-associated SDF-1/CXCR4 signaling pathway to regulate BMSCs fate postdifferentiation. In rabbit OA cartilage defect models, HyExo@CK/SiCH achieved complete cartilage regeneration within 12 weeks postimplantation, demonstrating superior endogenous BMSCs recruitment and whole-cycle fate regulation capabilities.