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This review aims to identify and evaluate strategies to improve the yield and functionality of stem cell-derived extracellular vesicles for tendon and tendon-to-bone junction regeneration.

July 17, 2026Stem Cell Research & Therapy0 citationsOpen Access

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

HLHaining LiuChinese University of Hong Kong PLPauline Po Yee LuiChinese University of Hong Kong

Key Points

This review aims to identify and evaluate strategies to improve the yield and functionality of stem cell-derived extracellular vesicles for tendon and tendon-to-bone junction regeneration.
Systematic review of enhancement strategies for extracellular vesicles, including genetic engineering and 3D culture techniques.
Evaluation of both scaffold-free and scaffold-based methods to optimize extracellular vesicle production.
Discussion of molecular mechanisms that influence extracellular vesicle efficacy in tendon repair.
Enhanced extracellular vesicle yield through biophysical and biological preconditioning is promising for tendon regeneration.
3D culture techniques and surface modifications improved extracellular vesicle stability and functionality.
Preclinical data support the potential of tailored extracellular vesicles to address chronic tendinopathy.

Abstract

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. Created in BioRender. https://BioRender.com/198vi3b

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