Exogenous physical stimulation as a programmable input to bone immunometabolism: mechanisms, materials, and controversies

Bone repair materials are shifting from passive mechanical support toward active modulation of the host immune microenvironment, with immunometabolism linking material cues, macrophage state and bone regeneration. This non-registered, PRISMA-informed scoping review examines whether electrical and piezoelectric, ultrasound-driven piezoelectric or mechanical, near-infrared photothermal, photobiomodulation and magnetic stimulation can be regarded as programmable inputs to bone immunometabolism. Europe PMC, OpenAlex, PubMed, Web of Science and Scopus were searched from January 2021 to October 2026. The five database exports yielded 4,146 records; DOI/title de-duplication removed 1,957 duplicates, leaving 2,189 records screened. Screening retained 104 candidates; 102 full texts were verified. 85 primary research articles and 17 contextual records. Seventy-four primary articles contributed 75 input-class entries; only one delivered two independent inputs. Evidence connects stimulation, metabolic change, immune phenotype and bone outcome, but not within one validated causal chain. Only three studies reported both an extracellular flux/OCR measurement and immunophenotyping in macrophages, with attribution limited by separate experiments, co-delivery or assessment at only the selected dose. No study measured flux and phenotype across multiple matched doses. Clinical evidence remains uncertain because a network meta-analysis produced imprecise estimates and the TRUST trial found no acceleration of radiographic healing or functional recovery with low-intensity pulsed ultrasound. Four methodological problems persist: incompatible dose windows, incomplete causal attribution, over-reliance on M1/M2 labels and interpretation of pathway-protein changes as metabolic flux. Across 18 ultrasound-driven piezoelectric and 21 near-infrared photothermal entries, intensity was reported in 15 and 20, duration in 11 and 19, and temperature in 0 and 12; no entry reported CEM43. Programmable control therefore remains a hypothesis until target-site dose or field exposure, flux and function are measured together and reporting is standardized.