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.