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Although MSC-derived EVs have been widely investigated for their regenerative potential, progress toward translational evaluation has been limited in part by challenges in scalable and reproducible manufacturing. We recently reported that human telomerase reverse transcriptase (hTERT)-immortalized MSCs reproducibly produce EVs that retain key characteristics of EVs derived from primary MSCs. Building on this work, three-dimensional (3D) culture systems have emerged as promising platforms for large-scale manufacturing. In this study, we compared the yield, molecular composition, and functional activity of EVs produced from hTERT-immortalized MSCs cultured in either a fixed-bed bioreactor or conventional two-dimensional (2D) flasks. Our data demonstrate that bioreactor culture results in increased EV yield as compared to an equivalent production from 2D cultures. Molecular analyses indicated that bioreactor-derived EVs were associated with a broader spectrum of cargo and were enriched with molecules that may contribute to enhanced reparative function. Importantly, bioreactor-derived EVs also exerted a more pronounced effect in cellular repair assays in vitro. Collectively, these results highlight the potential of fixed-bed bioreactors as scalable platforms for EV production, offering higher yields while preserving molecular composition and functional activity. This approach represents an important step toward achieving the reproducible, high-quality EV production required for research and future translational applications.<\/jats:p>","DOI":"10.3390\/cells15070654","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T07:25:12Z","timestamp":1775633112000},"page":"654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fixed-Bed Bioreactor Culture Enhances Yield and Reparative Properties of hTERT Mesenchymal Stem Cell Extracellular Vesicles"],"prefix":"10.3390","volume":"15","author":[{"given":"Zachary","family":"Cuba","sequence":"first","affiliation":[{"name":"American Type Culture Collection, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenny","family":"Godinho","sequence":"additional","affiliation":[{"name":"American Type Culture Collection, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata","family":"Choudhury","sequence":"additional","affiliation":[{"name":"American Type Culture Collection, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kajal","family":"Patil","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9049-2530","authenticated-orcid":false,"given":"Anastasia","family":"Williams","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-3597","authenticated-orcid":false,"given":"Weidong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6565-264X","authenticated-orcid":false,"given":"Marissa","family":"Howard","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya P.","family":"Aryal","sequence":"additional","affiliation":[{"name":"Meso Scale Diagnostics, LLC, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin A.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Meso Scale Diagnostics, LLC, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6200-5646","authenticated-orcid":false,"given":"David A.","family":"Routenberg","sequence":"additional","affiliation":[{"name":"Meso Scale Diagnostics, LLC, Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance A.","family":"Liotta","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Couch","sequence":"additional","affiliation":[{"name":"American Type Culture Collection, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9681-2780","authenticated-orcid":false,"given":"Fatah","family":"Kashanchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Branscome","sequence":"additional","affiliation":[{"name":"American Type Culture Collection, Manassas, VA 20110, USA"},{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1478-811X-9-12","article-title":"Different Populations and Sources of Human Mesenchymal Stem Cells (MSC): A Comparison of Adult and Neonatal Tissue-Derived MSC","volume":"9","author":"Hass","year":"2011","journal-title":"Cell Commun. 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