A Dual Reversible Cross‐Linked Hydrogel with Enhanced Mechanical Property and Capable of Proangiogenic and Osteogenic Activities for Bone Defect Repair

Abstract The clinical treatment of bone defects presents ongoing challenges. One promising approach is bone tissue engineering (BTE), wherein hydrogels have garnered significant attention. However, the application of hydrogels in BTE is severely limited due to their poor mechanical properties, as well as their inferior proangiogenic and osteogenic activities. To address these limitations, our develop a dual cross‐linked alendronate (ALN)‐Ca 2+ /Mg 2+ ‐doped sulfated hyaluronic acid (SHA@CM) hydrogel, using a one‐step mixing injection molding method known as “three‐in‐one” approach. This approach enabled the simultaneous formation of Schiff‐Base crosslinking and electric attraction‐based crosslinking within the hydrogel. The Schiff‐Base crosslinking contributed to the majority of the hydrogel's mechanical strength, while the electric attraction‐based crosslinking served as a release reservoir for Ca 2+ /Mg 2+ and ALN, promoting enhanced osteogenic activities and providing additional mechanical reinforcement to the hydrogel. These experimental data demonstrates several favorable properties of the SHA@CM hydrogel, including satisfactory injectability, rapid gelation, self‐healing capacity, and excellent cytocompatibility. Moreover, the presence of sulfated groups and Mg 2+ within the SHA@CM hydrogel exhibited pro‐angiogenic effects, while the controlled release of nanoparticles formed by Ca 2+ /Mg 2+ and ALN further enhanced the osteogenesis of the hydrogel. Overall, these results indicate that the SHA@CM hydrogel holds significant potential for the clinical translation of BTE.