Coordination chemistry-driven dynamic crosslinked hydrogel platform with ROS/pH responsiveness and photothermal activity for osteoporotic bone defect repair

Despite significant advancements in biomaterial-guided in situ bone regeneration, treating osteoporotic bone defects remains a substantial challenge in clinical practice. The imbalance in osteoblast/osteoclast function, coupled with attenuated vascularization, leads to delayed bone repair or even nonunion, whereas the acidic, hydrogen peroxide (H₂O₂)-rich osteoporotic microenvironment dampens macrophage immunological responses, creating a vicious cycle of inflammation and oxidative stress that inhibits bone regeneration. To address these challenges, a versatile coordination chemistry-driven tannic acid-functionalized calcium carbonate microsphere (TCM) was tailored and incorporated into 3,4-dihydroxyphenylalanine-modified hyaluronic acid (HA-DOPA)/phenylboronic acid-modified alginate (Alg-PBA)-based dynamically crosslinked hydrogel (HDAP/TCM) to promote the reconstruction of osteoporotic bone defects through integrated immune regulation, osteoblast/osteoclast homeostasis, and revascularization. Owing to the dual-crosslinking strategy of dynamic boronate bonds and metal coordination bonds, the resulting hydrogel exhibited an interconnected porous structure, injectability, tissue adhesion, self-healing behavior, enhanced mechanical properties, and pH/ROS-responsive degradation and release under the tested conditions. The TCM incorporated into the hydrogel functions as a naturally derived photothermal stimulator to induce osteogenesis, vascular network reconstruction, and M2 macrophage polarization, as well as to neutralize acidic inflammatory conditions in the osteoporotic bone microenvironment. Moreover, the developed HDAP/TCM hydrogel platform can respond intelligently to the pathological microenvironment (pH and ROS) of osteoporosis for the on-demand release of bioactive agents (i.e., polyphenols and Ca²⁺), combine spatiotemporally controlled mild local hyperthermia with synergistic free-radical scavenging, alleviate inflammation, protect osteoblasts and endothelial cells from oxidative stress damage, and inhibit excessive osteoclast activation in the alkaline microenvironment generated by TCM degradation. Transcriptomic analysis revealed that HDAP/TCM improved the inflammatory microenvironment by inhibiting NF-κB signaling and altering inflammation- and macrophage polarization-related gene expression in LPS-stimulated RAW264.7 cells, thereby significantly accelerating the repair and functional reconstruction of osteoporotic bone defects. In conclusion, these findings suggest that injectable microenvironment-responsive HDAP/TCM hydrogels can be promising alternative materials for the treatment of osteoporotic bone defects.