Improving stem cell-derived extracellular vesicles for better tendon and tendon-to-bone junction regeneration:...

Chronic tendinopathy is a debilitating tendon overuse disorder characterized by localized tenderness, swelling, and pain, significantly impairing physical function. It is particularly common among the overuse and aging populations. Traditional treatment options, including conservative therapies and surgical interventions, often yield limited success. Recent studies indicate that extracellular vesicles (EV) derived from stem cells provide a promising therapeutic avenue for healing of tendon and tendon-to-bone junction (TBJ) injuries associated with chronic tendinopathy. Their unique properties, such as higher cargo stability and the ability to serve as carriers for targeted drug delivery, position them as ideal candidates for tendinopathy treatment. However, the low yield of EVs presents challenges for clinical applications. This review systematically review various strategies to enhance EV yield and function, including preconditioning stem cells through biophysical, biological, or chemical means; genetic engineering of stem cells; in vitro loading of proteins or drugs and surface modification of EVs; and modifying the stem cell culture environment, particularly through three-dimensional (3D) culture techniques. Emphasis is placed on scaffold-free methods, scaffold-based methods, 3D printing, spinner flasks, and bioreactors, which can potentially improve EV yield and functions for tendon and TBJ regeneration. The review also summarizes relevant preclinical data and explores the molecular mechanisms underlying enhanced EV yield and functions, as well as the mechanisms of EVs on tendon and TBJ repair. Future research directions include investigating various EV enhancement strategies in models of degenerative tendon injury, studying the underlying molecular mechanisms, establishing cost-effective methods for scalable EV production, optimizing EV treatment protocols for clinical translation, and exploring combination strategies to enhance therapeutic EV production and function.