Articular Cartilage‐Derived Extracellular Matrix Material Promotes a Pro‐Regenerative Macrophage Phenotype to Support Chondrogenesis

ABSTRACT Articular cartilage (AC) repair remains a major clinical challenge due to its limited healing capacity and the inability of current treatment strategies to restore long‐term function. Biomaterial‐based strategies which support favorable immune responses and appropriate progenitor cell function have shown promise in enhancing cartilage regeneration. We and others have previously demonstrated the capacity of extracellular matrix (ECM)‐based materials to direct both innate immune cell behavior and progenitor cell differentiation, with these effects highly dependent on the ECM tissue of origin. Building on these observations, we now aim to further investigate the immunomodulatory properties of AC‐derived ECM (AC‐ECM) materials. Using primary human macrophages, we demonstrate that AC‐ECM material promotes a metabolically active mixed response in macrophages, with elevated expression of reparative growth factors conducive to chondrogenesis. Furthermore, AC‐ECM limits inflammatory activation of primary human macrophages, as demonstrated by reduced metabolic reprogramming and inflammatory cytokine production. Functionally, macrophages treated with AC‐ECM enhance cartilage regeneration by increasing chondrogenic marker expression in mesenchymal stem cells, while also suppressing angiogenic tube formation in endothelial cells. Overall, this work demonstrates that AC‐ECM biomaterials can direct macrophage phenotype toward a pro‐chondrogenic state, offering a promising strategy for the development of more effective and durable cartilage repair therapies.