Bone defects, as one of the most urgent problems in the orthopedic clinic, have attracted much attention from the biomedical community and society. Hydrogels have been widely used in the biomedical field for tissue engineering research because of their excellent hydrophilicity, biocompatibility, and degradability. Stimulus-responsive hydrogels, as a new type of smart biomaterial, have more advantages in sensing external physical (light, temperature, pressure, electric field, magnetic field, etc.), chemical (pH, redox reaction, ions, etc.), biochemical (glucose, enzymes, etc.) and other different stimuli. They can respond to stimuli such as the characteristics of the 3D shape and solid–liquid phase state, and exhibit special properties (injection ability, self-repair, shape memory, etc.), thus becoming an ideal material to provide cell adhesion, proliferation, and differentiation, and achieve precise bone defect repair. This review is focused on the classification, design concepts, and research progress of stimulus-responsive hydrogels based on different types of external environmental stimuli, aiming at introducing new ideas and methods for repairing complex bone defects.

The significant efforts being made towards the utilization of artificial soft materials holds considerable promise for developing tissue engineering scaffolds for bone-related diseases in clinics. However, most of these biomaterials cannot simultaneously satisfy the multiple requirements of high mechanics, good compatibility, and biological osteogenesis. In this study, an osteogenic hybrid hydrogel between the amine-functionalized bioactive glass (ABG) and 4-armed poly(ethylene glycol) succinimidyl glutarate-gelatin network (SGgel) is introduced to flexibly adhere onto the defective tissue and to subsequently guide bone regeneration. Relying on the rapid ammonolysis reaction between amine groups (-NH₂) of gelatin and ABG components and N-hydroxysuccinimide (NHS)-ester of tetra-PEG-SG polymer, the hydrogel networks were formed within seconds, offering a multifunctional performance, including easy injection, favorable biocompatibility, biological and mechanical properties (compressive strength: 4.2 MPa; storage modulus: 10⁴ kPa; adhesive strength: 56 kPa), which could facilitate the stem cell viability, proliferation, migration and differentiation into osteocytes. In addition, the integration between the SGgel network and ABG moieties within a nano-scale level enabled the hybrid hydrogel to form adhesion to tissue, maintain the durable osteogenesis and accelerate bone regeneration. Therefore, a robust approach to the simultaneously satisfying tough adhesion onto the tissue defects and high efficiency for bone regeneration on a mouse skull was achieved, which may represent a promising strategy to design therapeutic scaffolds for tissue engineering in clinical applications.