Stem Cell-Derived Extracellular Matrix Biofunctionalized Small Intestinal Submucosa for the Repair of Rotator Cuff Tears

Abstract Large to massive rotator cuff tears (RCTs) frequently lead to high retear rates, and small intestinal submucosa (SIS) has been applied in RCT repair but is limited by insufficient regenerative capacity. To enhance the tendon-bone healing potential of SIS, we modified it with extracellular matrix (ECM) derived from bone marrow−derived mesenchymal stem cells (BM-MSCs), generating a scaffold termed BME-SIS. The morphology, surface roughness, hydrophilicity, mechanical properties, and growth factor content of BME-SIS were systematically characterized. In vitro, the BME-SIS extract significantly promoted BM-MSC proliferation, migration, and the expression of osteogenic, chondrogenic, and tenogenic lineage-related differentiation markers, despite its slightly reduced mechanical strength. In a rat model of RCT, BME-SIS was implanted at the tendon-bone interface (TBI) and evaluated at four and eight weeks post surgery by gait analysis, biomechanical testing, microcomputed tomography, magnetic resonance imaging, and histological assessment. Compared with SIS, BME-SIS exhibited increased surface roughness, enhanced hydrophilicity, and enriched growth factors, which translated into superior biological performance. In vivo, BME-SIS markedly improved gait recovery, facilitated tendon-bone integration, and promoted cartilage regeneration at the TBI. Collectively, these results demonstrate that BM-MSC-derived ECM significantly augments the reparative potential of SIS, highlighting BME-SIS as a promising biomaterial for RCT repair.