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 study aimed to develop a novel hydrogel, termed dual cross‐linked alendronate (ALN)‐Ca2+/Mg2+‐doped sulfated hyaluronic acid (SHA@CM) hydrogel, using a one‐step mixing injection molding in situ method known as the “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 Ca2+/Mg2+ and ALN, promoting enhanced osteogenic activities and providing additional mechanical reinforcement to the hydrogel. Our experimental data demonstrated 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 Mg2+ within the SHA@CM hydrogel exhibited pro‐angiogenic effects, while the controlled release of nanoparticles formed by Ca2+/Mg2+ and ALN further enhanced the osteogenesis of the hydrogel. These findings were supported by an in vivo study using a rat cranial defect model, wherein the SHA@CM hydrogel demonstrated enhanced therapeutic efficacy in bone defect repair. Overall, our results indicate that the SHA@CM hydrogel holds significant potential as a platform for the clinical translation of BTE.This article is protected by copyright. All rights reserved