Decellularized matrix scaffold integrating hyaluronic acid-celecoxib modulates inflammation and promotes regenerative meniscus remodeling.

Meniscus injuries present dual challenges, including limited regenerative capacity due to avascularity and a persistent inflammatory microenvironment following injury. Herein, we reported a decellularized meniscus extracellular matrix (dmECM) scaffold functionalized with a hyaluronic acid (HA) and celecoxib (CLX) grafted (dmECM-HC) through carbodiimide chemistry. This design integrates acute immunomodulation with long-term regenerative support. The dmECM scaffold recapitulated the ECM architecture of the native meniscus, while the HA-CLX enhanced its elasticity and immunomodulatory capacity. The dmECM-HC scaffold exhibited superior mechanical performance retention during 1000 cyclic compression cycles and demonstrated sustained release of CLX for up to 7 weeks in vitro. It promoted M2 polarization of lipopolysaccharide (LPS)-stimulated macrophages and effectively modulated acute inflammation through Toll-like receptor, tumor necrosis factor (TNF), and Nuclear factor kappa-B (NF-κB) signaling pathways. Together with its robust antioxidant capacity, the dmECM-HC scaffold provided a pro-regenerative microenvironment. Furthermore, it significantly facilitated stem cell recruitment and ECM deposition. In a rabbit meniscus defect model, the dmECM-HC scaffold promoted tissue repair by activating NF-κB and calcium signaling pathways. At 12 weeks, it significantly enhanced tissue maturation and collagen arrangement in the defect area and mitigated cartilage degeneration. This strategy guides meniscus healing with a dual function by modulating the inflammatory environment while providing biomimetic structural support.