Injectable Composite Hydrogels Orchestrating Macrophage Reprogramming and Chondrogenesis to Promote Microfracture‐Assisted Cartilage Repair

ABSTRACT

Articular cartilage repair remains a major clinical challenge. Although microfracture (MF) is widely applied, it frequently results in fibrocartilaginous repair with limited mechanical durability and unsatisfactory long‐term outcomes. The persistent inflammatory microenvironment following cartilage injury disrupts tissue homeostasis and impairs chondrogenic differentiation of bone marrow stem cells (BMSCs), representing a major impediment to regeneration. Here, an injectable, thermosensitive composite hydrogel, constructed from a dopamine‐modified hyaluronic acid and Pluronic F127 network, which incorporates chlorogenic acid (CA) and ZIF‐8 nanoparticles encapsulated with kartogenin (KGN), is developed to establish a cascade repair strategy. Preferential release of CA can efficiently reprogram macrophages toward a pro‐regenerative M2 phenotype and improve anti‐inflammatory cytokine secretion, thereby creating a pro‐regeneration microenvironment. Subsequently, the sustained release of KGN further stimulates BMSCs chondrogenic differentiation within this optimized niche. Biological assays demonstrate that this synergistic mechanism enhances cartilage‐specific matrix synthesis and alleviates matrix degradation under inflammatory conditions. Furthermore, this composite hydrogel, combined with MF, improves cartilage tissue regeneration in a rat model, as evidenced by smooth defect filling, well‐organized extracellular matrix deposition, and reduced Matrix metalloproteinase 13‐mediated degradation. This work presents a synergistic immuno‐chondroregenerative platform that overcomes fundamental limitations of MF and offers a promising paradigm for functional cartilage regeneration.