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Extracellular vesicles (EVs) hold promise for tissue regeneration, but their low yield and limited therapeutic efficacy hinder clinical translation. Bioreactors provide a larger culture surface area and stable environment for large-scale EV production, yet their ability to enhance EV therapeutic efficacy is limited. Physical stimulation, by inducing cell differentiation and modulating EV cargo composition, offers a more efficient, cost-effective, and reproducible approach compared to the cargo loading of EVs and biochemical priming of parental cells. Herein, the effects of a 3D-printed perfusion bioreactor with a topographical cue on the macrophage EV yield and bioactivity were assessed. The results indicate that the bioreactor increased the EV yield 12.5-fold and enhanced bioactivity in promoting osteogenic differentiation and angiogenesis via upregulated miR-210-3p. Mechanistically, fluid shear stress activates Piezo1, triggering Ca 2+ influx and Yes-associated protein (YAP) nuclear translocation, promoting EV secretion and enhancing macrophage M2 polarization in conjunction with morphological changes guided by aligned topography. Moreover, a porous electrospun membrane–hydrogel composite scaffold loaded with bioreactor-derived EVs exhibited outstanding efficacy in promoting osteogenic differentiation and angiogenesis in a rat cranial defect model. This study presents a scalable, cost-effective, and stable platform for the production of therapeutic EVs, potentially overcoming key challenges in translating EV-based therapies to the clinic.
Huang et al. (Tue,) studied this question.