<p>Smart responsive hydrogels have emerged as a promising class of biomaterials in bone tissue engineering, offering dynamic and adaptive therapeutic strategies for complex bone defects. These hydrogels can perceive and respond to microenvironmental cues, such as pH fluctuations, oxidative stress, enzymatic activity, mechanical forces, and thermal or photic changes, to achieve controlled drug release, modulate cellular behavior, and reconstruct the local tissue milieu. This review systematically summarizes recent advances in various categories of smart hydrogels, including enzyme-responsive, reactive oxygen species-responsive, pH-responsive, thermo-/photo-responsive, mechanically responsive, and multi-responsive systems. Emphasis is placed on their mechanisms of action and their roles in immunomodulation, angiogenesis, osteogenesis, and microenvironment remodeling. Furthermore, the review highlights representative design innovations that integrate multi-stimuli sensitivity with intelligent feedback regulation, enhancing clinical adaptability and regenerative efficacy. Despite remarkable progress, challenges such as complex synthesis procedures, limited response precision, biosafety concerns, and translational standardization remain to be addressed. Future research directions are discussed, focusing on logical material design, interdisciplinary integration, and the development of next-generation hydrogels with immunoregulatory, self-adaptive, and programmable regenerative capabilities for clinical translation in bone repair.</p>

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Multi-stimuli responsive hydrogels in bone tissue engineering: microenvironmental cues and biofunctional strategies

  • Tingting Yang,
  • Yuemeng Zhu,
  • Junjie Jiao,
  • Jingjie Zhai,
  • Quan Lin

摘要

Smart responsive hydrogels have emerged as a promising class of biomaterials in bone tissue engineering, offering dynamic and adaptive therapeutic strategies for complex bone defects. These hydrogels can perceive and respond to microenvironmental cues, such as pH fluctuations, oxidative stress, enzymatic activity, mechanical forces, and thermal or photic changes, to achieve controlled drug release, modulate cellular behavior, and reconstruct the local tissue milieu. This review systematically summarizes recent advances in various categories of smart hydrogels, including enzyme-responsive, reactive oxygen species-responsive, pH-responsive, thermo-/photo-responsive, mechanically responsive, and multi-responsive systems. Emphasis is placed on their mechanisms of action and their roles in immunomodulation, angiogenesis, osteogenesis, and microenvironment remodeling. Furthermore, the review highlights representative design innovations that integrate multi-stimuli sensitivity with intelligent feedback regulation, enhancing clinical adaptability and regenerative efficacy. Despite remarkable progress, challenges such as complex synthesis procedures, limited response precision, biosafety concerns, and translational standardization remain to be addressed. Future research directions are discussed, focusing on logical material design, interdisciplinary integration, and the development of next-generation hydrogels with immunoregulatory, self-adaptive, and programmable regenerative capabilities for clinical translation in bone repair.