ROS-responsive adhesive nanocomposite hydrogel promotes tendon-to-bone healing by modulating the inflammatory...

Natural functional regeneration of the tendon-bone interface in rotator cuff repair surgery remains a major challenge and requires the development of innovative therapeutic strategies. Hydrogels with biomechanical adaptability and regenerative microenvironment modulation are promising candidates for treating such injuries. In this study, an ROS-responsive adhesive nanocomposite hydrogel (TPGA@CZB) was developed to enhance tendon-to-bone interface repair by on-demand drug release to modulate the inflammatory microenvironment and promote cell differentiation. The hydrogel consisted of baicalin (Ba)-loaded Cu-Zn bimetallic-organic framework (CZB), N-[tris(hydroxymethyl) methyl] acrylamide (THMA), poly(ethylene glycol) diacrylate (PEGDA) and phenylboronic acid modified methacrylated gelatin (GelMA-CPBA). Owing to its multi-crosslinked structure, TPGA@CZB exhibits excellent adhesive properties (lap shear strength reaching 110.90 ± 15.38 kPa) and mechanical adaptability (compressive strain exceeding 80% and tensile strain of 196.24 ± 3.87%). Additionally, TPGA@CZB demonstrated favorable ROS-responsive release characteristics, with the cumulative release of Ba in H₂O₂ solution (63.90 ± 4.76% at 96 h) being significantly higher than that in PBS solution (48.39 ± 1.56% at 96 h). Furthermore, cellular experiments revealed that TPGA@CZB effectively scavenged intracellular ROS, inhibits the NF-κB signaling pathway, regulates macrophage polarization and promotes osteogenic differentiation and chondrogenesis. In vivo studies confirmed that TPGA@CZB treatment effectively optimized collagen remodeling, enhanced osteogenesis and cartilage formation, as well as modulated the inflammatory microenvironment at the injury site. In conclusion, this nanocomposite hydrogel integrates "mechanical support-controlled drug release-microenvironment regulation" into a single platform, offering a promising multifunctional therapeutic strategy for enhancing tendon-bone interface regeneration.