A Human Muscle-Bone Organoid-on-Chip to Study Bone Mechano- Adaptation via Optogenetic Control

Objective

Fragility fractures and osteoporosis erode independence and drive healthcare costs. Muscle activity supports bone through mechanical strain and myokines such as irisin, but current models cannot separate these signals or recombine them with the precision needed to design effective, human-relevant regimens. What is missing is a platform that can measure, predict, and actively steer osteogenesis. BONE-TUNE builds that link. It develops a human muscle-bone organoid-on-a-chip where mechanical loading and muscle-derived biochemical cues are delivered either independently or synchronised, while a bone microtissue reports its state in real time. It integrates optogenetic muscle rings for light-controlled contractions and a biodegradable, microstructured bone microtissue under perfusion to enhance biological fidelity. Using calibrated inputs and live readouts, a compact computational model is trained to translate any candidate “exercise recipe” into a single osteogenic index. The model then closes the loop, automatically adjusting loading and myokine pulses to hold the tissue in an anabolic window as properties evolve, an adaptive “exercise machine on a chip.” The objectives are to quantify how muscle-derived strain and myokines act alone and together; to deliver a validated guidance tool that predicts outcomes for unseen regimens and yields a mechanics×myokines×timing response map; and to demonstrate real-time control that outperforms the best open-loop schedule. Outputs include a reusable chip and dataset, open software with look-ups from target strain to actuator settings, and practical dosing rules, including rest, that rehabilitation and preclinical teams can test. By shifting mechanobiology from description to prescription, BONE-TUNE provides human-relevant, model-guided mechanotherapy protocols, helps reduce exploratory animal use in line with the 3Rs, and accelerates progress toward smarter rehabilitation and exercise–drug regimens to curb bone loss.