Self-assembled meniscus-specific ECM membrane promotes cell migration and vascular ingrowth for meniscus repair and reconstruction

Background The knee meniscus has limited intrinsic repair and regenerative capacity. Safe and effective biotherapeutic products remain lacking, and enhancing cell migration and angiogenesis remains a major challenge. This study aimed to develop a novel self-assembled meniscus-specific extracellular matrix membrane (saECM-M) and evaluate its performance in scaffold-free meniscus repair and scaffold-guided whole-meniscus reconstruction, in comparison with chemically processed decellularized ECM (cpd-ECM). Methods Meniscal fibrochondrocytes (MFCs) were cultured under membrane-inducing conditions to generate saECM-M in vitro . Its bioactivity was evaluated by cell migration and endothelial network formation assays in vitro and by a scaffold-free meniscus defect repair model in vivo . For whole-meniscus reconstruction, saECM-M was integrated with a biomimetic 3D-printed poly(ε-caprolactone) (PCL) scaffold to guide ECM alignment and provide mechanical support. PCL scaffolds seeded with MFCs alone or combined with cpd-ECM served as controls. Meniscus regeneration was assessed in a rabbit meniscectomy model using imaging, histological, and biomechanical analyses, including chondroprotective evaluation. Transcriptomic profiling and proteomics were performed to investigate molecular pathways associated with saECM-M-mediated cell migration and vascular ingrowth. Results saECM-M was characterized as a cell-laden membrane enriched with native meniscus-like ECM components. In vitro , saECM-M significantly enhanced cell migration and endothelial network formation compared with cpd-ECM (approximately 1.2-fold and 2-fold, respectively; P < 0.05), accompanied by increased collagen deposition. In vivo , isolated saECM-M promoted superior meniscus defect repair. When integrated with the biomimetic PCL scaffold, saECM-M further promoted aligned collagen organization, vascular ingrowth, and robust meniscus regeneration. Compared with the PCL-cpd-ECM group, the PCL-saECM-M group showed improved host tissue integration on MRI (WORMS score: 10 ± 1 vs 32.3 ± 2.1), enhanced tensile mechanical properties (79 ± 2 MPa vs 64 ± 7.8 MPa), and superior chondroprotective effects (Mankin score: 1.67 ± 0.58 vs 6.67 ± 0.58) ( P < 0.05). Transcriptomic and proteomic analyses identified enrichment of ECM-receptor interaction- and PI3K-AKT signaling-related pathways associated with saECM-M-enhanced cell migration and vascular ingrowth. Conclusion saECM-M functions as an intrinsically bioactive meniscus-derived matrix capable of promoting both scaffold-free repair and scaffold-guided reconstruction. Compared with cpd-ECM, saECM-M more effectively supports cell migration, angiogenesis, and organized collagen remodeling, leading to superior regenerative outcomes. The translational potential of this article saECM-M addresses an unmet clinical need as a cell-secreted, additive-free bioactive matrix. It may serve as a simple biologic augmentation for arthroscopic repair, while integration with an FDA-approved PCL scaffold offers a promising strategy for meniscus replacement with improved bioactivity and biocompatibility.