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Abstract Extracellular vesicles (EVs) secreted by stem cells have become a promising cell‐free approach in regenerative medicine, with significant potential for the repair and treatment of musculoskeletal tissues and disorders. However, the limited bioactivity and scalability of EV production pose significant challenges for commercial production and clinical translation. To overcome these challenges, researchers have started exploring how the cellular microenvironment can modulate EV characteristics and enhance their therapeutic efficacy. While the microenvironment's biochemical facets have been the primary focus of prior investigations, the influence of biophysical factors on EV characteristics remains relatively underexplored. This review consolidates the existing research investigating the effects of biophysical features of the cellular microenvironment on EV production and function, with a particular emphasis on applications in musculoskeletal regeneration. By providing a comprehensive understanding of how biophysical factors impact EVs, this review seeks to enhance the development of effective strategies that harness the power of EVs for large‐scale production and their successful application in regenerative therapies for musculoskeletal disorders. Ultimately, such insights could greatly assist patients who require innovative, cell‐free regenerative treatments, thereby propelling advancements in musculoskeletal tissue engineering and in regenerative medicine.
Xu et al. (Tue,) studied this question.