Microsphere-embedded dual-network hydrogel with fatigue resistance, drug release, and chondrogenesis for potential...

To address the challenges on repair of articular cartilage defects in clinic, drug-loaded bioactive hydrogels remain desirable for cartilage support and simulate the cellular microenvironment. However, the reconstruction of cartilage through all-in-one advanced drug delivery hydrogel system is still limited. Herein, we fabricated biocompatible PVA-SF hydrogel composites embedding dual-drug loaded recombinant human collagen microspheres (MS), which were engineered to internally encapsulate Kartogenin (KGN) and externally conjugated Transforming Growth Factor-beta 1 (TGF-β1) via activated heparin. The optimized hydrogel composite (PS-2MS@K-T) loaded with 2 wt% MS, exhibited favorable porous architecture with enhanced compressive strength of 0.59 MPa and Young's modulus of 1.28 MPa, alongside fatigue resistance (>87% retention). This hierarchical structure could establish dual-barrier system for long-term controllable drug release up to >28 days. In vitro studies indicated compatibility of hydrogel composites to support robust cell activity and proliferation. The sustained co-delivery of KGN and TGF-β1 could orchestrate synergistic effect, to upregulate expression of chondrogenic gene, whereas simultaneously suppressing the hypertrophic gene induced by TGF-β1. This cell-free platform provides a promising strategy for functional cartilage regeneration by combining mechanical support, controlled drug release, and biomimetic signaling.