{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:24:00Z","timestamp":1767831840874,"version":"3.49.0"},"reference-count":24,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,3,28]],"date-time":"2020-03-28T00:00:00Z","timestamp":1585353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Allogeneic cell therapy products, such as therapeutic cells derived from pluripotent stem cells (PSCs), have amazing potential to treat a wide variety of diseases and vast numbers of patients globally. However, there are various challenges related to the manufacturing of PSCs in large enough quantities to meet commercial needs. This manuscript addresses the challenges for the process development of PSCs production in a bioreactor, and also presents a scalable bioreactor technology that can be a possible solution to remove the bottleneck for the large-scale manufacturing of high-quality therapeutic cells derived from PSCs.<\/jats:p>","DOI":"10.3390\/bioengineering7020031","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T13:27:19Z","timestamp":1585661239000},"page":"31","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Challenges and Solutions for Commercial Scale Manufacturing of Allogeneic Pluripotent Stem Cell Products"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4451-3831","authenticated-orcid":false,"given":"Brian","family":"Lee","sequence":"first","affiliation":[{"name":"PBS Biotech, Inc., Camarillo, CA 93012, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2220-4568","authenticated-orcid":false,"given":"Breanna S.","family":"Borys","sequence":"additional","affiliation":[{"name":"Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4, Canada"}]},{"given":"Michael S.","family":"Kallos","sequence":"additional","affiliation":[{"name":"Department of Chemical and Petroleum Engineering, Schulich School of Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4, Canada"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-1591","authenticated-orcid":false,"given":"Carlos A. V.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Ibb\u2014Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Lisboa 1049-001, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5039-703X","authenticated-orcid":false,"given":"Teresa P.","family":"Silva","sequence":"additional","affiliation":[{"name":"Ibb\u2014Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Lisboa 1049-001, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-5845","authenticated-orcid":false,"given":"Joaquim M. S.","family":"Cabral","sequence":"additional","affiliation":[{"name":"Ibb\u2014Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Lisboa 1049-001, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1242\/dev.092551","article-title":"Induced Puripotent Stem Cells in Medicine and Biology","volume":"140","author":"Takahashi","year":"2013","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nrd.2016.245","article-title":"Induced Pluripotent Stem Cell Technology: A Decade of Progress","volume":"16","author":"Shi","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/bit.25008","article-title":"Allogeneic Cell Therapy Bioprocess Economics and Optimization: Single-Use Cell Expansion Technologies","volume":"111","author":"Simaria","year":"2014","journal-title":"Biotechnol. Bioeng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.biotechadv.2011.06.009","article-title":"Stem Cell Cultivation in Bioreactors","volume":"29","author":"Rodrigues","year":"2011","journal-title":"Biotechnol. Adv."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cabral, J.M.S. (2018). Chapter 2\u2014Bioreactors for Human Pluripotent Stem Cell Expansion and Differentiation. Bioreactors for Stem Cell Expansion and Differentiation, CRC Press.","DOI":"10.1201\/9780429453144"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.stem.2013.12.005","article-title":"Human Pluripotent Stem Cell Culture: Considerations for Maintenance, Expansion, and Therapeutics","volume":"14","author":"Chen","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s13036-019-0204-1","article-title":"Strategies for The Expansion of Human Induced Pluripotent Stem cells as Aggregates in Single-Use Vertical-Wheel Bioreactors","volume":"13","author":"Nogueira","year":"2019","journal-title":"J. Biol. Eng."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1634\/stemcells.2008-0183","article-title":"Control of Human Embryonic Stem Cell Colony and Aggregate Size Heterogeneity Influences Differentiation Trajectories","volume":"26","author":"Bauwens","year":"2008","journal-title":"Stem Cells"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-14325-9","article-title":"Controlled Self-Assembly of Stem Cell Aggregates Instructs Pluripotency and Lineage Bias","volume":"7","author":"Xie","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1159\/000330691","article-title":"Mass transfer limitations in embryoid bodies during human embryonic stem cell differentiation","volume":"196","author":"Gates","year":"2012","journal-title":"Cells Tissues Organs"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wu, J., Rostami, M.R., Cadavid Olaya, D.P., and Tzanakakis, E.S. (2014). Oxygen Transport and Stem Cell Aggregation in Stirred-Suspension Bioreactor Cultures. PLos ONE, 9.","DOI":"10.1371\/journal.pone.0102486"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nogueira, D.E.S., Rodrigues, C.A.V., Hashimura, Y., Jung, S., Lee, B., and Cabral, J.M.S. (2019). Suspension Culture of Human Induced Pluripotent Stem Cells in Single-Use Vertical-Wheel Bioreactors Using Aggregate and Microcarrier Culture Systems. Methods Mol. Biol., in press.","DOI":"10.1007\/7651_2020_287"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/s12015-010-9149-y","article-title":"Suspension Culture of Undifferentiated Human Embryonic Stem Cells and Induced Pluripotent Stem Cells","volume":"6","author":"Amit","year":"2010","journal-title":"Stem Cell Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16978","DOI":"10.1073\/pnas.0905550106","article-title":"Microwell-Mediated Control of Embryoid Body Size Regulates Embryonic Stem Cell Fate via Differential Expression of WNT5a and WNT11","volume":"106","author":"Hwang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1002\/biot.201400846","article-title":"Spatial and Temporal Control of Cell Aggregation Efficiently Directs Human Pluripotent Stem Cells Towards Neural Commitment","volume":"10","author":"Miranda","year":"2015","journal-title":"Biotechnol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1089\/scd.2013.0088","article-title":"Generation of Functional Hepatocyte-Like Cells from Human Pluripotent Stem Cells in a Scalable Suspension Culture","volume":"22","author":"Vosough","year":"2013","journal-title":"Stem Cells Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.addr.2015.11.016","article-title":"Large-Scale Production of Human Pluripotent Stem Cell Derived Cardiomyocytes","volume":"96","author":"Kempf","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1089\/ten.teb.2011.0040","article-title":"The Multiparametric Effects of Hydrodynamic Environments on Stem Cell Culture","volume":"17","author":"Kinney","year":"2011","journal-title":"Tissue Eng. Part B"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1021\/bp0498488","article-title":"Bioprocess Equipment: Characterization of Energy Dissipation Rate and its Potential to Damage Cells","volume":"20","author":"Mollet","year":"2004","journal-title":"Biotechnol. Prog."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Minin, O. (2011). Chapter 4\u2014CFD for Characterizing Standard and Single-Use Stirred Cell Culture Bioreactors. Computational Fluid Dynamics Technologies and Applications, IntechOpen.","DOI":"10.5772\/686"},{"key":"ref_21","unstructured":"Cabral, J.M.S., Lobato de Silva, C., Chase, L.G., and Diogo, M.M. (2016). Chapter 5\u2014Novel Single-Use Bioreactors for Scale-Up of Anchorage-Dependent Cell Manufacturing for Cell Therapies. Stem Cell Manufacturing, Elsevier, B.V."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Borys, B.S., So, T., Colter, J., Dang, T., Roberts, E.L., Revay, T., Larijani, L., Krawetz, R., Lewis, I., and Argiropoulos, B. (2020). Optimized Serial Expansion of Human Induced Pluripotent Stem Cells Using Low Density Inoculation to Generate Clinically Relevant Quantities in Vertical-Wheel Bioreactors. Stem Cells Transl. Med., in press.","DOI":"10.1002\/sctm.19-0406"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Silva, T.P., Fernandes, T.G., Nogueira, D.E.S., Rodrigues, C.A.V., Bekman, E.P., Hashimura, Y., Jung, S., Lee, B., Carmo-Fonseca, M., and Cabral, J.M.S. (2020). Scalable Generation of Mature Cerebellar Organoids from Human Pluripotent Stem Cells and Characterization by Immunostaining. JoVE, in press.","DOI":"10.3791\/61143-v"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.bej.2018.02.005","article-title":"Scale-Up of Embryonic Stem Cell Aggregate Stirred Suspension Bioreactor Culture Enabled by Computational Fluid Dynamics Modeling","volume":"133","author":"Borys","year":"2018","journal-title":"Biochem. Eng. J."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/7\/2\/31\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:12:40Z","timestamp":1760173960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/7\/2\/31"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,28]]},"references-count":24,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["bioengineering7020031"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering7020031","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,28]]}}}