Multi-stimuli Responsive Hydrogels in Bone Tissue Engineering: Microenvironmental Cues and Biofunctional Strategies

• • Hydrogels with water content exceeding 90% mimic native ECM, providing an ideal 3D niche for BMSC adhesion, proliferation, and osteogenic differentiation, which is critical for spatially organized bone regeneration. • • Multi-stimuli responsive hydrogels integrate enzyme-, ROS-, pH-, thermo-/photo-, and mechano-responsiveness, enabling precise spatiotemporal control over drug release and cellular behavior, addressing the complexity of bone defect microenvironments. • • Representative designs, such as MgFe-LDH nanosheet-incorporated thermo-responsive hydrogels, demonstrate controllable growth factor release, achieving enhanced bone regeneration with tunable degradation and release kinetics. • • Despite progress, clinical translation is hindered by complex synthesis, limited response precision, and biosafety concerns; standardization of fabrication and evaluation protocols is essential for regulatory approval.