Biomaterial physicochemical properties govern immune activation and bone regeneration: a titanium-focused...

The host immune response is increasingly recognized as a critical determinant of implant performance and bone regeneration in craniofacial applications. In osteoimmunology, macrophages act as central regulators of the foreign body response by integrating material-derived cues with intracellular signaling pathways that control inflammation and tissue repair. In this context, biomaterials actively regulate the immune microenvironment. However, the integration of biomaterial physicochemical properties with immune signaling and regenerative outcomes remains incomplete. Here, a mechanistic and design-oriented perspective on osteoimmunological processes governing biomaterial-tissue interactions is provided, with a particular focus on macrophage polarization, cytokine signaling networks, and apoptosis pathways involved in bone remodeling. Special attention is given to titanium wear particles as key immunological stimuli that activate macrophages through NF-κB, MAPK, and STAT signaling pathways, as well as emerging mechanisms including inflammasome activation and immunometabolic reprogramming. A unified osteoimmunological framework is introduced that integrates biomaterial physicochemical properties with immune signaling pathways and regenerative outcomes. Within this framework, material-induced modulation of macrophage phenotypes and cytokine profiles is identified as a central design axis controlling the balance between inflammation and regeneration. Emerging immunomodulatory strategies are discussed, including surface nanoengineering, ion-releasing systems, bioactive coatings, and stimuli-responsive biomaterials enabling spatiotemporal control of immune responses. Key limitations, including the oversimplified classification of macrophage phenotypes and the limited translational relevance of in vitro models, are critically addressed. By integrating immunology with materials science, this review outlines design principles for next-generation immuno-instructive biomaterials. This perspective supports the rational design of immuno-instructive biomaterials with predictable regenerative outcomes.