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