Regulatory network–oriented design of stimuli-responsive biomaterials for oral and craniofacial bone regeneration

Oral and craniofacial bone regeneration is regulated by a dynamically evolving defect microenvironment in which microbial dysbiosis, persistent inflammation, oxidative stress, extracellular matrix degradation, and altered mechanical signaling are closely interconnected. These convergent pathological cues act on shared regulatory pathways coupling immune activation with bone remodeling, resulting in sustained osteoclastogenesis and impaired osteogenic differentiation. Conventional biomaterials, primarily designed for structural support, have limited capacity to modulate this temporally shifting signaling network. Stimuli-responsive biomaterials provide a microenvironment-adaptive intervention strategy by sensing pathological alterations and translating them into defined biological responses. Responsiveness to chemical and physical cues enables spatiotemporal regulation of interconnected processes governing inflammation, osteoclast activity, immunometabolic homeostasis, and mechanotransductive signaling. Modulation of these regulatory pathways supports restoration of osteoimmune balance and regenerative remodeling. This review establishes a network-based framework linking microenvironmental pathology to pathway-level material design in oral and craniofacial bone repair. Responsive systems are organized according to activation mechanisms and regulatory targets, and translational considerations related to response precision, long-term safety, and scalable manufacturing are critically assessed.