Spatiotemporal Decoupling of Antimicrobial and Osteogenic Cues for Tissue Regeneration: Evidence, Design Windows, and a Validation Roadmap

Infected bone defects require two outcomes that can conflict at the same site: reduction of biofilm-associated bacterial burden, which usually needs high local antimicrobial exposure, and regeneration of vascularised bone, which needs viable progenitor cells and a resolving immune environment. Biomaterials that present antimicrobial and regenerative cues together are clinically established, but in some systems the exposure needed to act on biofilm may approach the tolerance of host cells. This targeted narrative review develops spatiotemporal decoupling, the separation of cues in time, location or activation condition, as a design hypothesis rather than a proven superior strategy. It (i) defines decoupling operationally and classifies published platforms accordingly; (ii) frames the therapeutic window as a measurable exposure problem, defines exposure metrics, and specifies what must be measured to compute them; (iii) maps four overlapping biological domains (bacterial burden, inflammation, vascular supply, bone formation) to cues, controls and readouts, with each design rule tagged by evidence status; (iv) examines the immuneosteogenic–vascular network as a hypothesis map; (v) positions bioactive glasses and glass-ceramics as a testable platform opportunity, separating what has been shown from what is inferred; and (vi) sets out validation gates and author-proposed reporting recommendations. Most evidence reviewed is mechanistic or preclinical, and matched comparisons against equal-payload co-delivery remain the decisive missing experiment.