Chitosan-ibuprofen conjugate-based short-fiber reinforced scaffold with sustained immunomodulation for meniscus regeneration.

Meniscus regeneration remains challenging due to insufficient mechanical support and complex inflammatory microenvironment. We developed a mechanically stable, immunomodulatory composite short-fiber scaffold, CSI-PE, for functional meniscus repair. The scaffold was engineered by incorporating homogenized poly-L-lactic acid (PLLA)/decellularized meniscus extracellular matrix (dmECM) short fibers (designated as PE fibers for PLLA/dmECM) into a chitosan-ibuprofen (CS-IBU) conjugate matrix, followed by glutaraldehyde cross-linking and lysine modification. CSI-PE exhibited an interconnected porous structure with a porosity greater than 80%, providing excellent fatigue resistance and withstanding 100 compression cycles, providing essential mechanical stability for early-stage tissue integration. It enabled sustained IBU release for up to 56 days (67 ± 5 μg/mg), effectively modulating the immune microenvironment by reducing reactive oxygen species (ROS) production and promoting macrophage polarization. This immunomodulatory microenvironment synergistically enhanced the proliferation, migration, and fibrocartilaginous differentiation of bone marrow mesenchymal stem cells (BMSCs) under adverse conditions. In vivo, CSI-PE significantly alleviated intra-articular inflammation and facilitated high-quality tissue regeneration with well-organized collagen deposition while preventing cartilage degeneration after 8 weeks. Transcriptomic analysis further associated this regeneration with immune regulation and extracellular matrix remodeling pathways. This strategy effectively harmonizes mechanical stability with immune homeostasis, positioning CSI-PE as a promising candidate for meniscus tissue engineering.