Subject-specific multivariate modeling for regenerative rehabilitation of bone healing

Rehabilitation can help promote functional restoration following surgical reconstruction of severe bone injuries, yet prescribed regimens are often conservative due to limited understanding of their impact on healing. This study examined rodent physical activity parameters, including wheel running duration, distance, bout frequency, bout duration, velocity, and rest time, assessing their combined impact on bone healing in 2 and 3 mm segmental defects. Artifical intelligence (AI)-based genetic programming generated high-accuracy nonlinear models, revealing a "goldilocks" phenomenon: some rehabilitation stimulates bone formation, but excessive activity is detrimental. Subject-specific finite element modeling showed that local defect compressive strains decreased only in injuries that achieved union and that the correlation between strain and healing evolved over time. These findings highlight the dynamic healing process, necessitating a subject-specific approach. While bone healing is often thought to be primarily driven by achieving optimal strain magnitudes, our results suggest a more complex reality. Bone healing depends not only on optimal strain magnitude but also on balancing activity and rest, which shifts with injury severity and healing progression. Overall, effective rehabilitation must consider injury stabilization, severity, and healing status while ensuring adequate rest to promote optimal bone regeneration.