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However, the development of such immunotherapies requires the manufacture of large numbers of T\u2010cells, which remains a major translational and commercial bottleneck due to the manual, small\u2010scale, and often static culturing systems used for their production. Such systems are used because there is an unsubstantiated concern that primary T\u2010cells are shear sensitive, or prefer static conditions, and therefore do not grow as effectively in more scalable, agitated systems, such as stirred\u2010tank bioreactors, as compared with T\u2010flasks and culture bags. In this study, we demonstrate that not only T\u2010cells can be cultivated in an automated stirred\u2010tank bioreactor system (ambr\u00ae 250), but that their growth is consistently and significantly better than that in T\u2010flask static culture, with equivalent cell quality. Moreover, we demonstrate that at progressively higher agitation rates over the range studied here, and thereby, higher specific power inputs (P\/M W\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ), the higher the final viable T\u2010cell density; that is, a cell density of 4.65\u2009\u00b1\u20090.24\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    viable cells ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    obtained at the highest P\/M of 74\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    \u2009W\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    in comparison with 0.91\u2009\u00b1\u20090.07\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    viable cells ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    at the lowest P\/M of 3.1\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    W\u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    . We posit that this improvement is due to the inability at the lower agitation rates to effectively suspend the Dynabeads\u00ae, which are required to activate the T\u2010cells; and that contact between them is improved at the higher agitation rates. Importantly, from the data obtained, there is no indication that T\u2010cells prefer being grown under static conditions or are sensitive to fluid dynamic stresses within a stirred\u2010tank bioreactor system at the agitation speeds investigated. Indeed, the opposite has proven to be the case, whereby, the cells grow better under higher agitation speeds while maintaining their quality. This study is the first demonstration of primary T\u2010cell ex vivo manufacture activated by Dynabeads\u00ae in an automated stirred\u2010tank bioreactor system such as the ambr\u00ae 250 and the findings have the potential to be applied to multiple other cell candidates for advanced therapy applications.\n                  <\/jats:p>","DOI":"10.1002\/bit.27088","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T05:20:40Z","timestamp":1560230440000},"page":"2488-2502","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Establishing the scalable manufacture of primary human T\u2010cells in an automated stirred\u2010tank bioreactor"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-5684","authenticated-orcid":false,"given":"Elena","family":"Costariol","sequence":"first","affiliation":[{"name":"Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Rotondi","sequence":"additional","affiliation":[{"name":"Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arman","family":"Amini","sequence":"additional","affiliation":[{"name":"Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Hewitt","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Aston Medical Research Institute Aston University  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin W.","family":"Nienow","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences, Aston Medical Research Institute Aston University  Birmingham UK"},{"name":"School of Chemical Engineering University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.J.","family":"Heathman","sequence":"additional","affiliation":[{"name":"Hitachi Chemical Advanced Therapeutics Solutions (HCATS)  Allendale New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Micheletti","sequence":"additional","affiliation":[{"name":"Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4400-9106","authenticated-orcid":false,"given":"Qasim A.","family":"Rafiq","sequence":"additional","affiliation":[{"name":"Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,9]]},"reference":[{"key":"e_1_2_7_1_2_1","unstructured":"Alliance for Regenerative Medicine. 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