{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T10:00:23Z","timestamp":1785060023454,"version":"3.55.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp; Bioengineering"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The use of perfusion systems for the continuous cultivation of animal cells at high cell density (HCD) for the production of recombinant proteins, viruses, and viral vectors has many advantages. Besides an enhancement of volumetric productivity and high cell viability, the product quality can be improved through a steady\u2010state environment. However, the establishment of such a process intensification method using stirred tank bioreactors (STRs) for cultivations at very high cell concentrations (&gt;\u200950\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    \u2009cells\u2009mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) can be challenging. In particular, limitations in the oxygen supply, CO\n                    <jats:sub>2<\/jats:sub>\n                    stripping, high viscosity, and excessive foam formation can impede cell viability and product yields. In this study, we investigated a novel membrane\u2010stirrer (MemStir) based bioreactor that employs multiple hollow\u2010fiber membrane sheets arranged in a device that facilitates efficient gas transfer through bubble\u2010free diffusion for HCD cultivations. We found that the oxygen transfer rates at different tip speeds and gas flow rates resulted in volumetric mass transfer coefficient (kLa) values of 10\u201330\u2009h\n                    <jats:sup>\u22121<\/jats:sup>\n                    enabling sufficient oxygen supply to support concentrations exceeding 50\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    cells mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    . The functionality of the membrane\u2010stirrer was benchmarked in batch mode against shake flasks and a conventional STR equipped with a pitched\u2010blade impeller and an\n                    <jats:sc>l<\/jats:sc>\n                    \u2010drilled hole sparger. Suspension growth of a human embryonic kidney 293 LTV (HEK\u2010LTV) cell in the MemStir system was comparable to the cell growth in a STR. Using pure oxygen for aeration, a maximum viable cell concentration of 7.6\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    cells mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    was achieved. As a starting point for further optimization, we investigated the impact of the MemStir system on viable cell concentration, cell viability, dissolved oxygen partial pressure, pH control and foam formation in HCD cultivations in perfusion mode. Using the MemStir system equipped with an alternating tangential flow system, HEK\u2010LTV cells reached concentrations of up to 92\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    \u2009cells\u2009mL\n                    <jats:sup>\u22121<\/jats:sup>\n                    with a specific growth rate of 0.022\u2009h\n                    <jats:sup>\u22121<\/jats:sup>\n                    in perfusion mode. Moreover, controlling the pH in the range 7.0 to 7.3 was easily achieved, and no foam formation was observed. Overall, these results suggest that the MemStir system is a viable option for HCD cultivation because it can overcome limitations of both aeration and foam formation.\n                  <\/jats:p>","DOI":"10.1002\/bit.70317","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T09:19:34Z","timestamp":1785057574000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High Cell Density Cultivation of HEK293 Cells Using a 2L Membrane\u2010Stirred Bioreactor"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4720-5743","authenticated-orcid":false,"given":"Lennart","family":"Jacobtorweihe","sequence":"first","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"van Heuvel","sequence":"additional","affiliation":[{"name":"BioThrust GmbH Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrina","family":"Scheiermann","sequence":"additional","affiliation":[{"name":"BioThrust GmbH Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2240-2671","authenticated-orcid":false,"given":"Patrick","family":"Bongartz","sequence":"additional","affiliation":[{"name":"BioThrust GmbH Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2652-5943","authenticated-orcid":false,"given":"Yvonne","family":"Genzel","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-1332","authenticated-orcid":false,"given":"Udo","family":"Reichl","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems Magdeburg Germany"},{"name":"Otto\u2010von\u2010Guericke\u2010University Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"Bauer I. T.Dreher D.Eibl et al. Recommendations for Process Engineering Characterisation of Single\u2010Use Bioreactors and Mixing Systems by Using Experimental Methods. Frankfurt am Main Germany: DECHEMA Gesellschaft f\u00fcr Chemische Technik und Biotechnologie eV. 2020."},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.bej.2018.10.029","article-title":"Modelling and Optimisation of Gas\u2010Liquid Mass Transfer in a Microporous Hollow Fiber Membrane Aerated Bioreactor Used to Produce Surfactin","volume":"145","author":"Berth A.","year":"2019","journal-title":"Biochemical Engineering Journal"},{"issue":"9","key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"3545","DOI":"10.1002\/bit.27822","article-title":"A Scalable Bubble\u2010Free Membrane Aerator for Biosurfactant Production","volume":"118","author":"Bongartz P.","year":"2021","journal-title":"Biotechnology and Bioengineering"},{"issue":"5","key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1002\/bit.28334","article-title":"A Novel Membrane Stirrer System Enables Foam\u2010Free Biosurfactant Production","volume":"120","author":"Bongartz P.","year":"2023","journal-title":"Biotechnology and Bioengineering"},{"key":"e_1_2_11_6_1","unstructured":"Bongartz P. M.Meyer andM.Wessling Gas\u2010Liquid Reactor for Bubble\u2010Free Gassing of a Process Liquid.2021a. patent DE102020102420A1."},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","DOI":"10.3389\/fbioe.2025.1684315","article-title":"Upscaling: Efficient Generation of Human Lung Organoids From Induced Pluripotent Stem Cells Using a Stirring Bioreactor","volume":"13","author":"Budeus B.","year":"2025","journal-title":"Frontiers in Bioengineering and Biotechnology"},{"issue":"3","key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1002\/btpr.1704","article-title":"Very High Density of CHO Cells in Perfusion by ATF or TFF in Wave Bioreactor. Part I. Effect of the Cell Density on the Process","volume":"29","author":"Clincke M. 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