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.