Extracellular vesicles: From bone development to regenerative orthopedics.

Regenerative medicine aims to promote the replacement of tissues lost to damage or disease. While positive outcomes have been observed experimentally, challenges remain in their clinical translation. This has led to growing interest in applying extracellular vesicles (EVs) to augment or even replace existing approaches. Through the engineering of culture environments or direct/indirect manipulation of EVs themselves, multiple avenues have emerged to modulate EV production, targeting, and therapeutic potency. Drives to modulate release using material systems or functionalize implants for improved osseointegration have also led to outcomes that could have real-world impact. The purpose of this review is to highlight advantages in applying EVs for the treatment of skeletal defects, outlining the current state of the art in the field and emphasizing avenues for further investigation. Notably, the review identifies inconsistencies in EV nomenclature and outstanding challenges in defining a reproducible therapeutic dose. Challenges also remain in the scalable manufacture of a therapeutically potent and pure EV product, with a need to address scalable cell sources and optimal culture environments. Addressing these issues will be critical if we are to develop regenerative EV therapies that meet the demands of regulators and can be translated from bench to bedside.