Effects of Physical Stimulation and Bioactive Agents in Bone Regenerative Medicine: Recent Advances and Synergistic Approaches

Bone tissue regeneration represents a complex biological process regulated by 23 mechanical, biochemical, and cellular interactions. It remains a major challenge in 24 regenerative medicine due to the limited self-healing capacity of large or complex bone 25 defects. Recent advances have highlighted the pivotal role of biophysical stimuli, such as 26 mechanical loading, electromagnetic fields, ultrasound, and photobiomodulation, in 27 promoting osteogenic differentiation and tissue remodeling. At the same time, bioactive 28 substances, including growth factors, peptides delivered primarily via extracellular 29 vesicles, and biomaterial-based delivery systems, have shown a potential role in 30 enhancing cellular responses and modulating the microenvironment to promote 31 regeneration. This review aims to provide a comprehensive overview of the latest 32 progress in understanding how biophysical and bioactive stimuli converge to regulate 33 bone regeneration and to consider their synergistic approaches that integrate physical 34 stimulation with the controlled release of bioactive molecules. These combined strategies 35 are promising to improve tissue integration and reduce healing times and complications, 36 representing a future research direction.