Advanced multifunctional thermo- and electro-stimulative hydrogels for bone regeneration

Bone defects caused by trauma, infection, tumors, osteoporosis, and diabetes disrupt skeletal integrity and impair regeneration. The healing process involves inflammatory hematoma formation, callus development, and remodeling, coordinated by diverse cells and signaling pathways. Conventional grafts and inorganic implants are limited by donor scarcity, immune rejection, and low bioactivity, necessitating more effective repair strategies. Recently, multifunctional smart hydrogels have emerged as a frontier in bone regeneration due to their biocompatibility, tunable structure, and ability to integrate diverse functionalities. This review systematically summarizes recent advances in thermotherapy- and electrotherapy-stimulative hydrogels for bone defect repair. Photothermal and magnetothermal hydrogels provide controlled thermal stimulation to activate Wnt/β-catenin, HIF-1α, and heat shock protein pathways, thereby promoting osteogenesis, angiogenesis, and immune modulation while exhibiting antibacterial and antitumor effects. Conductive and piezoelectric hydrogels reconstruct the native bioelectric microenvironment of bone, enhancing cellular activity and matrix mineralization through electrical or mechanoelectrical coupling. Finally, the review discusses the current challenges, design considerations, and future perspectives of advanced hydrogel systems in bone regeneration.