Accelerated cartilage regeneration through immunomodulation and enhanced chondrogenesis by an extracellular matrix hydrogel encapsulating Kartogenin.

• The adverse immune microenvironment ensuing from cartilage injury, coupled with the intrinsic property of the tissue characterized by limited cellularity, has posed a significant challenge to the reconstruction of cartilage defect. • Enzymatic treatment converts small intestinal submucosa (SIS) into a hydrogel form, not only providing a scaffold for cells engaged and achieving prolonged drug release, but also exhibiting excellent immunomodulatory effects. • Kartogenin (KGN) recruits the endogenous BMSCs of the host and directly enhances their chondrogenic differentiation, thereby achieving cartilage repair and regeneration without cell transplantation. • Leveraging the combined effects of the SIS hydrogel and KGN, this innovative composite material provides a simple yet effective method for expediting the repair and regeneration of cartilage defects. Articular cartilage is crucial for the functional integrity of joints yet vulnerable to a spectrum of injuries. The adverse immune microenvironment ensuing from injury, coupled with the intrinsic property of the tissue characterized by limited cellularity, poses a significant challenge to the reconstruction of cartilage defect. In this study, an extracellular matrix hydrogel derived from porcine small intestinal submucosa (SIS) with encapsulation of Kartogenin (KGN) has been designed for the cartilage repair and regeneration. The SIS hydrogel, which possessed a three-dimensional porous structure akin to the natural cartilage, has provided a scaffold essential for the progenitor cells engaged in the repair process and sustained release of KGN. As shown by in vitro experiments, the KGN could recruit host endogenous bone marrow-derived mesenchymal stem cells (BMSCs) and induce them to differentiate into chondrocytes, thus enabling in situ cartilage regeneration without cell transplantation. Notably, the bioactive component of SIS was further revealed to possess excellent immunomodulatory capacity to induce the phenotypic shift from M1 to M2 macrophages, which could enhance the chondrogenic differentiation of BMSCs indirectly. Additionally, in vivo experiments showed that the regenerated tissues of the composite SIS hydrogel group were close to the natural hyaline cartilage. Leveraging the combined effects of KGN and SIS hydrogel, this innovative composite material shows great potential as a biomaterial for effective cartilage repair and regeneration. [ABSTRACT FROM AUTHOR]