{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:32:52Z","timestamp":1776213172567,"version":"3.50.1"},"reference-count":126,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T00:00:00Z","timestamp":1621209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/BIO\/04565\/2019"],"award-info":[{"award-number":["UID\/BIO\/04565\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/EQU-EQU\/29653\/2017"],"award-info":[{"award-number":["PTDC\/EQU-EQU\/29653\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/EQU-EQU\/3853\/2020"],"award-info":[{"award-number":["PTDC\/EQU-EQU\/3853\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/128376\/2017"],"award-info":[{"award-number":["PD\/BD\/128376\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Programa Operacional Regional de Lisboa 2020","award":["007317"],"award-info":[{"award-number":["007317"]}]},{"name":"Programa Operacional Regional de Lisboa 2020","award":["PAC\u2014PRECISE\u2014LISBOA-01-0145-FEDER-016394, SAICTPAC\/0021\/2015"],"award-info":[{"award-number":["PAC\u2014PRECISE\u2014LISBOA-01-0145-FEDER-016394, SAICTPAC\/0021\/2015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Research on human stem cells, such as pluripotent stem cells and mesenchymal stromal cells, has shown much promise in their use for regenerative medicine approaches. However, their use in patients requires large-scale expansion systems while maintaining the quality of the cells. Due to their characteristics, bioreactors have been regarded as ideal platforms to harbour stem cell biomanufacturing at a large scale. Specifically, single-use bioreactors have been recommended by regulatory agencies due to reducing the risk of product contamination, and many different systems have already been developed. This review describes single-use bioreactor platforms which have been used for human stem cell expansion and differentiation, along with their comparison with reusable systems in the development of a stem cell bioprocess for clinical applications.<\/jats:p>","DOI":"10.3390\/bioengineering8050068","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T04:25:07Z","timestamp":1621225507000},"page":"68","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Single-Use Bioreactors for Human Pluripotent and Adult Stem Cells: Towards Regenerative Medicine Applications"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2346-8485","authenticated-orcid":false,"given":"Diogo E.S.","family":"Nogueira","sequence":"first","affiliation":[{"name":"Department of Bioengineering and iBB\u2014Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-5845","authenticated-orcid":false,"given":"Joaquim M.S.","family":"Cabral","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and iBB\u2014Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9645-1591","authenticated-orcid":false,"given":"Carlos A.V.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and iBB\u2014Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"ref_1","first-page":"32","article-title":"The future of multihospital systems","volume":"18","author":"Kaiser","year":"1992","journal-title":"Top. Health Care Financ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"421","DOI":"10.7326\/0003-4819-149-6-200809160-00009","article-title":"Whither prometheus\u2019 liver? Greek myth and the science of regeneration","volume":"149","author":"Power","year":"2008","journal-title":"Ann. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/432451a","article-title":"Regenerative medicine: Prometheus unbound","volume":"432","author":"Schneider","year":"2004","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1126\/science.282.5391.1145","article-title":"Embryonic stem cell lines derived from human blastocysts","volume":"282","author":"Thomson","year":"1998","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1126\/science.1151526","article-title":"Induced pluripotent stem cell lines derived from human somatic cells","volume":"318","author":"Yu","year":"2007","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rowe, R.G., and Daley, G.Q. (2019). Induced pluripotent stem cells in disease modelling and drug discovery. Nat. Rev. Genet.","DOI":"10.1038\/s41576-019-0100-z"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1177\/1535370220959598","article-title":"Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects","volume":"246","author":"Dame","year":"2021","journal-title":"Exp. Biol Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lancaster, M.A., and Huch, M. (2019). Disease modelling in human organoids. Dis Model. Mech, 12.","DOI":"10.1242\/dmm.039347"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","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. Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jocit.2014.12.001","article-title":"Mesenchymal stem cells: Immunomodulatory capability and clinical potential in immune diseases","volume":"2","author":"Zhao","year":"2016","journal-title":"J. Cell. Immunother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3057624","DOI":"10.1155\/2018\/3057624","article-title":"Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application","volume":"2018","author":"Wang","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2062","DOI":"10.1038\/cddis.2015.327","article-title":"Mesenchymal stem cells and immunomodulation: Current status and future prospects","volume":"7","author":"Gao","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Han, Y., Li, X., Zhang, Y., Han, Y., Chang, F., and Ding, J. (2019). Mesenchymal Stem Cells for Regenerative Medicine. Cells, 8.","DOI":"10.3390\/cells8080886"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41536-019-0083-6","article-title":"Mesenchymal stem cell perspective: Cell biology to clinical progress","volume":"4","author":"Pittenger","year":"2019","journal-title":"NPJ Regen. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8031718","DOI":"10.1155\/2018\/8031718","article-title":"Mesenchymal Stromal\/Stem Cells in Regenerative Medicine and Tissue Engineering","volume":"2018","author":"Fitzsimmons","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.3389\/fimmu.2020.01091","article-title":"MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy","volume":"11","author":"Moll","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/sctm.19-0202","article-title":"Trends in mesenchymal stem cell clinical trials 2004-2018: Is efficacy optimal in a narrow dose range?","volume":"9","author":"Kabat","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1097\/MIB.0000000000000441","article-title":"Human Placenta-derived Cells (PDA-001) for the Treatment of Moderate-to-severe Crohn\u2019s Disease: A Phase 1b\/2a Study","volume":"21","author":"Melmed","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S1474-4422(17)30046-7","article-title":"Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial","volume":"16","author":"Hess","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/10_2008_27","article-title":"Large scale production of stem cells and their derivatives","volume":"114","author":"Zweigerdt","year":"2009","journal-title":"Eng. Stem Cells"},{"key":"ref_22","first-page":"3015","article-title":"Deconstructing the third dimension: How 3D culture microenvironments alter cellular cues","volume":"125","author":"Baker","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1634\/stemcells.2007-0230","article-title":"Disruption of apical-basal polarity of human embryonic stem cells enhances hematoendothelial differentiation","volume":"25","author":"Krtolica","year":"2007","journal-title":"Stem Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1007\/s10295-017-1927-y","article-title":"High-performance recombinant protein production with Escherichia coli in continuously operated cascades of stirred-tank reactors","volume":"44","author":"Schmideder","year":"2017","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/BF00170567","article-title":"Continuous production of baculovirus in a cascade of insect-cell reactors","volume":"33","author":"Vlak","year":"1990","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/bit.25352","article-title":"Scaled-up manufacturing of recombinant antibodies produced by plant cells in a 200-L orbitally-shaken disposable bioreactor","volume":"112","author":"Raven","year":"2015","journal-title":"Biotechnol. Bioeng."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/btpr.1647","article-title":"Impact of aeration strategy on CHO cell performance during antibody production","volume":"29","author":"Tarrant","year":"2013","journal-title":"Biotechnol. Prog."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.5966\/sctm.2015-0253","article-title":"Impact of Feeding Strategies on the Scalable Expansion of Human Pluripotent Stem Cells in Single-Use Stirred Tank Bioreactors","volume":"5","author":"Kropp","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1076","DOI":"10.1002\/term.2435","article-title":"Scalable stirred suspension culture for the generation of billions of human induced pluripotent stem cells using single-use bioreactors","volume":"12","author":"Kwok","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1002\/bit.26359","article-title":"Process development of human multipotent stromal cell microcarrier culture using an automated high-throughput microbioreactor","volume":"114","author":"Rafiq","year":"2017","journal-title":"Biotechnol. Bioeng."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Rotondi, M., Grace, N., Betts, J., Bargh, N., Costariol, E., Zoro, B., Hewitt, C.J., Nienow, A.W., and Rafiq, Q.A. (2021). Design and development of a new ambr250(R) bioreactor vessel for improved cell and gene therapy applications. Biotechnol. Lett.","DOI":"10.1007\/s10529-021-03076-3"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jbiotec.2017.01.014","article-title":"Bioprocess integration for human mesenchymal stem cells: From up to downstream processing scale-up to cell proteome characterization","volume":"248","author":"Cunha","year":"2017","journal-title":"J. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/elsc.201300134","article-title":"Scale-up of adipose tissue-derived mesenchymal stem cell production in stirred single-use bioreactors under low-serum conditions","volume":"14","author":"Schirmaier","year":"2014","journal-title":"Eng. Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.procbio.2016.05.010","article-title":"Multiphase mixing characteristics in a microcarrier-based stirred tank bioreactor suitable for human mesenchymal stem cell expansion","volume":"51","author":"Grein","year":"2016","journal-title":"Process. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.bej.2016.11.020","article-title":"Process development for expansion of human mesenchymal stromal cells in a 50 L single-use stirred tank bioreactor","volume":"120","author":"Lawson","year":"2017","journal-title":"Biochem. Eng. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jbiotec.2012.06.025","article-title":"A novel automated bioreactor for scalable process optimisation of haematopoietic stem cell culture","volume":"161","author":"Ratcliffe","year":"2012","journal-title":"J. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"64","DOI":"10.2174\/1874120700701010064","article-title":"Cultivation and Differentiation of Encapsulated hMSC-TERT in a Disposable Small-Scale Syringe-Like Fixed Bed Reactor","volume":"1","author":"Weber","year":"2007","journal-title":"Open Biomed. Eng. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1177\/039139881003300802","article-title":"Expansion of human mesenchymal stem cells in a fixed-bed bioreactor system based on non-porous glass carrier\u2013part A: Inoculation, cultivation, and cell harvest procedures","volume":"33","author":"Weber","year":"2010","journal-title":"Int. J. Artif. Organs."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/btpr.1707","article-title":"Efficient expansion of mesenchymal stromal cells in a disposable fixed bed culture system","volume":"29","author":"Mizukami","year":"2013","journal-title":"Biotechnol. Prog."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1007\/s10529-012-1033-1","article-title":"Scale-up of human embryonic stem cell culture using a hollow fibre bioreactor","volume":"34","author":"Roberts","year":"2012","journal-title":"Biotechnol. Lett."},{"key":"ref_42","first-page":"9704945","article-title":"Laminin as a Potent Substrate for Large-Scale Expansion of Human Induced Pluripotent Stem Cells in a Closed Cell Expansion System","volume":"2019","author":"Morrissey","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.omtm.2018.05.006","article-title":"GMP Production and Scale-Up of Adherent Neural Stem Cells with a Quantum Cell Expansion System","volume":"10","author":"Tirughana","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1111\/trf.14805","article-title":"Characterization and cost-benefit analysis of automated bioreactor-expanded mesenchymal stem cells for clinical applications","volume":"58","author":"Russell","year":"2018","journal-title":"Transfusion"},{"key":"ref_45","first-page":"1","article-title":"Culture expansion of adipose derived stromal cells. A closed automated Quantum Cell Expansion System compared with manual flask-based culture","volume":"14","author":"Follin","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-019-1202-4","article-title":"A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells","volume":"10","author":"Mennan","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.bej.2018.02.018","article-title":"Technologies for large-scale umbilical cord-derived MSC expansion: Experimental performance and cost of goods analysis","volume":"135","author":"Mizukami","year":"2018","journal-title":"Biochem. Eng. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s12015-017-9787-4","article-title":"A Fully-Closed and Automated Hollow Fiber Bioreactor for Clinical-Grade Manufacturing of Human Mesenchymal Stem\/Stromal Cells","volume":"14","author":"Mizukami","year":"2018","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.jcyt.2016.05.013","article-title":"Large-scale progenitor cell expansion for multiple donors in a monitored hollow fibre bioreactor","volume":"18","author":"Lambrechts","year":"2016","journal-title":"Cytotherapy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s11064-019-02925-y","article-title":"Large-Scale Automated Hollow-Fiber Bioreactor Expansion of Umbilical Cord-Derived Human Mesenchymal Stromal Cells for Neurological Disorders","volume":"45","author":"Vymetalova","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1080\/00365513.2018.1462082","article-title":"Development of large-scale manufacturing of adipose-derived stromal cells for clinical applications using bioreactors and human platelet lysate","volume":"78","author":"Juhl","year":"2018","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.bbrc.2012.11.001","article-title":"Good manufacturing practice-compliant animal-free expansion of human bone marrow derived mesenchymal stroma cells in a closed hollow-fiber-based bioreactor","volume":"430","author":"Nold","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jneumeth.2012.04.005","article-title":"Beta-adrenoceptor pathway enhances mitochondrial function in human neural stem cells via rotary cell culture system","volume":"207","author":"Chiang","year":"2012","journal-title":"J. Neurosci. Methods"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/jor.20566","article-title":"Rotating three-dimensional dynamic culture of adult human bone marrow-derived cells for tissue engineering of hyaline cartilage","volume":"27","author":"Sakai","year":"2009","journal-title":"J. Orthop. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3390\/bioengineering1040231","article-title":"Characterization and Application of a Disposable Rotating Bed Bioreactor for Mesenchymal Stem Cell Expansion","volume":"1","author":"Neumann","year":"2014","journal-title":"Bioengineering"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"50","DOI":"10.2174\/1874120701307010050","article-title":"Large scale expansion of human umbilical cord cells in a rotating bed system bioreactor for cardiovascular tissue engineering applications","volume":"7","author":"Reichardt","year":"2013","journal-title":"Open Biomed. Eng. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1177\/2472630318760745","article-title":"Automated Closed-System Expansion of Pluripotent Stem Cell Aggregates in a Rocking-Motion Bioreactor","volume":"23","author":"Davis","year":"2018","journal-title":"SLAS Technol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s13770-018-00174-8","article-title":"Tissue Regeneration of Human Mesenchymal Stem Cells on Porous Gelatin Micro-Carriers by Long-Term Dynamic In Vitro Culture","volume":"16","author":"Nguyen","year":"2019","journal-title":"Tissue Eng. Regen. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.procbio.2019.06.004","article-title":"Improving wave-induced motion bioreactor performance for human mesenchymal stromal cell expansion","volume":"84","author":"Mizukami","year":"2019","journal-title":"Process Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"107693","DOI":"10.1016\/j.bej.2020.107693","article-title":"Mesenchymal stromal cells maintain the major quality attributes when expanded in different bioreactor systems","volume":"161","author":"Severino","year":"2020","journal-title":"Biochem. Eng. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1089\/ten.tec.2011.0207","article-title":"Ultra-high-yield manufacture of red blood cells from hematopoietic stem cells","volume":"17","author":"Timmins","year":"2011","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Silva, T.P., Sousa-Luis, R., Fernandes, T.G., Bekman, E.P., Rodrigues, C.A.V., Vaz, S.H., Moreira, L.M., Hashimura, Y., Jung, S., and Lee, B. (2021). Transcriptome profiling of human pluripotent stem cell-derived cerebellar organoids reveals faster commitment under dynamic conditions. Biotechnol. Bioeng.","DOI":"10.1101\/2021.01.27.428468"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","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_64","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1002\/jctb.5738","article-title":"Scalable culture of human induced pluripotent cells on microcarriers under xeno-free conditions using single-use vertical-wheel (TM) bioreactors","volume":"93","author":"Rodrigues","year":"2018","journal-title":"J. Chem. Technol. Biotechnol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1002\/sctm.19-0406","article-title":"Optimized serial expansion of human induced pluripotent stem cells using low-density inoculation to generate clinically relevant quantities in vertical-wheel bioreactors","volume":"9","author":"Borys","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-020-02109-4","article-title":"Overcoming bioprocess bottlenecks in the large-scale expansion of high-quality hiPSC aggregates in vertical-wheel stirred suspension bioreactors","volume":"12","author":"Borys","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bej.2017.12.011","article-title":"Aggregation of Culture Expanded Human Mesenchymal Stem Cells in Microcarrier-based Bioreactor","volume":"131","author":"Yuan","year":"2018","journal-title":"Biochem. Eng. J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e1800716","DOI":"10.1002\/biot.201800716","article-title":"Scalable Manufacturing of Human Mesenchymal Stromal Cells in the Vertical-Wheel Bioreactor System: An Experimental and Economic Approach","volume":"14","author":"Bandeiras","year":"2019","journal-title":"Biotechnol. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"553444","DOI":"10.3389\/fcell.2020.553444","article-title":"Scalable Production of Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Under Serum-\/Xeno-Free Conditions in a Microcarrier-Based Bioreactor Culture System","volume":"8","author":"Bernardes","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Lembong, J., Kirian, R., Takacs, J.D., Olsen, T.R., Lock, L.T., Rowley, J.A., and Ahsan, T. (2020). Bioreactor Parameters for Microcarrier-Based Human MSC Expansion under Xeno-Free Conditions in a Vertical-Wheel System. Bioengineering, 7.","DOI":"10.3390\/bioengineering7030073"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1002\/btpr.2158","article-title":"Production of oncolytic adenovirus and human mesenchymal stem cells in a single-use, Vertical-Wheel bioreactor system: Impact of bioreactor design on performance of microcarrier-based cell culture processes","volume":"31","author":"Sousa","year":"2015","journal-title":"Biotechnol. Prog."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/btpr.124","article-title":"Can shear stress direct stem cell fate?","volume":"25","author":"Stolberg","year":"2009","journal-title":"Biotechnol. Prog."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1089\/ten.teb.2012.0641","article-title":"Mechanobiology of human pluripotent stem cells","volume":"19","author":"Earls","year":"2013","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1089\/ten.tec.2010.0320","article-title":"Agitation can induce differentiation of human pluripotent stem cells in microcarrier cultures","volume":"17","author":"Leung","year":"2011","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"713","DOI":"10.2217\/rme.10.60","article-title":"Shear stress induces osteogenic differentiation of human mesenchymal stem cells","volume":"5","author":"Yourek","year":"2010","journal-title":"Regen. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0032-9592(00)00272-7","article-title":"The studies on the oxygen mass transfer coefficient in a bioreactor","volume":"36","author":"Gayik","year":"2001","journal-title":"Process Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Nienow, A.W. (2009). Scale-up, Stirred Tank Reactors. Encyclopedia of Industrial Biotechnology: Bioprocess., Bioseparation, and Cell Technology, John Wiley & Sons.","DOI":"10.1002\/9780470054581.eib535"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bej.2016.07.006","article-title":"Application of Euler-Lagrange CFD for quantitative evaluating the effect of shear force on Carthamus tinctorius L. cell in a stirred tank bioreactor","volume":"114","author":"Liu","year":"2016","journal-title":"Biochem. Eng. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.stemcr.2019.06.004","article-title":"Continuous WNT Control Enables Advanced hPSC Cardiac Processing and Prognostic Surface Marker Identification in Chemically Defined Suspension Culture","volume":"13","author":"Halloin","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s11746-001-0329-5","article-title":"Enzymatic conversion of waste edible oil to biodiesel fuel in a fixed-bed bioreactor","volume":"78","author":"Watanabe","year":"2001","journal-title":"J. Am. Oil. Chem. Soc."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1016\/j.procbio.2010.05.004","article-title":"Synthesis of biodiesel in column fixed-bed bioreactor using the fermented solid produced by Burkholderia cepacia LTEB11","volume":"45","author":"Salum","year":"2010","journal-title":"Process Biochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/S0360-3199(02)00130-1","article-title":"Biohydrogen production with fixed-bed bioreactors","volume":"27","author":"Chang","year":"2002","journal-title":"Int. J. Hydrogen Energy"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/ees.2000.17.257","article-title":"Fixed-bed bioreactor treating perchlorate-contaminated waters","volume":"17","author":"Kim","year":"2000","journal-title":"Environ. Eng. Sci"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3434","DOI":"10.1016\/j.procbio.2005.04.002","article-title":"Immobilized cell fixed-bed bioreactor for wastewater decolorization","volume":"40","author":"Chen","year":"2005","journal-title":"Process Biochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13568-014-0025-z","article-title":"Assessment of packed bed bioreactor systems in the production of viral vaccines","volume":"4","author":"Rajendran","year":"2014","journal-title":"AMB Express"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/gt.2017.91","article-title":"Optimization of lentiviral vector production for scale-up in fixed-bed bioreactor","volume":"25","author":"Valkama","year":"2018","journal-title":"Gene Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1089\/hgtb.2016.021","article-title":"Development and Optimization of AAV hFIX Particles by Transient Transfection in an iCELLis((R)) Fixed-Bed Bioreactor","volume":"27","author":"Powers","year":"2016","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1023\/A:1008085932764","article-title":"Development of a fixed bed bioreactor for the expansion of human hematopoietic progenitor cells","volume":"30","author":"Meissner","year":"1999","journal-title":"Cytotechnology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nbt0602-592","article-title":"Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells","volume":"20","author":"Simonsen","year":"2002","journal-title":"Nat. Biotechnol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/978-1-4939-3584-0_23","article-title":"GMP-Compliant Expansion of Clinical-Grade Human Mesenchymal Stromal\/Stem Cells Using a Closed Hollow Fiber Bioreactor","volume":"1416","author":"Barckhausen","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1749-6632.2001.tb03845.x","article-title":"Effect of flow configuration and membrane characteristics on membrane fouling in a novel multicoaxial hollow-fiber bioartificial liver","volume":"944","author":"MacDonald","year":"2001","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.vaccine.2013.11.044","article-title":"Production of high-titer human influenza A virus with adherent and suspension MDCK cells cultured in a single-use hollow fiber bioreactor","volume":"32","author":"Tapia","year":"2014","journal-title":"Vaccine"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0022-1759(01)00388-X","article-title":"Mammalian expression and hollow fiber bioreactor production of recombinant anti-CEA diabody and minibody for clinical applications","volume":"253","author":"Yazaki","year":"2001","journal-title":"J. Immunol. Methods"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.jbiotec.2008.04.006","article-title":"Expression of SEAP (secreted alkaline phosphatase) by baculovirus mediated transduction of HEK 293 cells in a hollow fiber bioreactor system","volume":"135","author":"Jardin","year":"2008","journal-title":"J. Biotechnol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/0043-1354(94)90037-X","article-title":"Hollow fibre bioreactor for wastewater treatment using bubbleless membrane aeration","volume":"28","author":"Pankhania","year":"1994","journal-title":"Water Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8799","DOI":"10.1016\/j.biortech.2011.07.014","article-title":"Experimental study of the anaerobic urban wastewater treatment in a submerged hollow-fibre membrane bioreactor at pilot scale","volume":"102","author":"Gimenez","year":"2011","journal-title":"Bioresour. Technol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.memsci.2016.04.032","article-title":"Development of a hollow fiber membrane micro-reactor for biocatalytic production of formate from CO2","volume":"514","author":"Wang","year":"2016","journal-title":"J. Membr. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/j.procbio.2007.07.002","article-title":"Sucrose conversion into palatinose with immobilized Serratia plymuthica cells in a hollow-fibre bioreactor","volume":"42","author":"Krastanov","year":"2007","journal-title":"Process Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3448","DOI":"10.1111\/trf.15483","article-title":"Gaps in the knowledge of human platelet lysate as a cell culture supplement for cell therapy: A joint publication from the AABB and the International Society for Cell & Gene Therapy","volume":"59","author":"Bieback","year":"2019","journal-title":"Transfusion"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.stemcr.2019.10.006","article-title":"Effects of Spaceflight on Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Structure and Function","volume":"13","author":"Wnorowski","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1007\/s11626-998-0008-y","article-title":"Simulated microgravity conditions enhance differentiation of cultured PC12 cells towards the neuroendocrine phenotype","volume":"34","author":"Lelkes","year":"1998","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"ref_102","first-page":"S49","article-title":"Responses of gravity level variations on the NASA\/JSC bioreactor system","volume":"35","author":"Tsao","year":"1992","journal-title":"Physiologist"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"F12","DOI":"10.1152\/ajprenal.2001.281.1.F12","article-title":"Optimized suspension culture: The rotating-wall vessel","volume":"281","author":"Hammond","year":"2001","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/(SICI)1097-0290(19990705)64:1<14::AID-BIT2>3.0.CO;2-R","article-title":"Characterization of bimodal cell death of insect cells in a rotating-wall vessel and shaker flask","volume":"64","author":"Cowger","year":"1999","journal-title":"Biotechnol. Bioeng."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.procbio.2016.07.004","article-title":"Production of \u03b2-glucosidase from wheat bran and glycerol by Aspergillus niger in stirred tank and rotating fibrous bed bioreactors","volume":"51","author":"Abdella","year":"2016","journal-title":"Process Biochem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.biortech.2013.01.088","article-title":"Enhanced cellulase production by Trichoderma viride in a rotating fibrous bed bioreactor","volume":"133","author":"Lan","year":"2013","journal-title":"Bioresour. Technol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"6293","DOI":"10.1039\/C7RA12997A","article-title":"Enhanced biodegradation of phenol in a novel cyclic activated sludge integrated with a rotating bed bioreactor in anoxic and peroxidase-mediated conditions","volume":"8","author":"Pourakbar","year":"2018","journal-title":"RSC Advances"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.biortech.2015.08.047","article-title":"High-rate biological denitrification in the cyclic rotating-bed biological reactor: Effect of COD\/NO3(-), nitrate concentration and salinity and the phylogenetic analysis of denitrifiers","volume":"197","author":"Jafari","year":"2015","journal-title":"Bioresour. Technol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/jbm.a.30965","article-title":"Cultivation of MC3T3-E1 cells on a newly developed material (Sponceram) using a rotating bed system bioreactor","volume":"80","author":"Suck","year":"2007","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1023\/A:1008025016272","article-title":"Disposable bioreactor for cell culture using wave-induced agitation","volume":"30","author":"Singh","year":"1999","journal-title":"Cytotechnology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/btpr.516","article-title":"Experimental characterization of flow conditions in 2- and 20-L bioreactors with wave-induced motion","volume":"27","author":"Kalmbach","year":"2011","journal-title":"Biotechnol. Prog."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1002\/aic.15734","article-title":"Fluid dynamic characterization of a laboratory scale rocked bag bioreactor","volume":"63","author":"Marsh","year":"2017","journal-title":"AIChE J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ces.2018.08.017","article-title":"Study of hydrodynamics in wave bioreactors by computational fluid dynamics reveals a resonance phenomenon","volume":"193","author":"Zhan","year":"2019","journal-title":"Chem. Eng. Sci."},{"key":"ref_114","unstructured":"da Silva, C.L., Chase, L.G., and Diogo, M.M. (2016). Novel Single-Use Bioreactors for Scale-Up of Anchorage-Dependent Cell Manufacturing for Cell Therapies In Stem Cell Manufacturing, Elsevier."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/(SICI)1097-0290(19970505)54:3<191::AID-BIT1>3.0.CO;2-A","article-title":"Inducing single-cell suspension of BTI-TN5B1-4 insect cells: I. The use of sulfated polyanions to prevent cell aggregation and enhance recombinant protein production","volume":"54","author":"Dee","year":"1997","journal-title":"Biotechnol. Bioeng."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1021\/bp0000353","article-title":"The growth factor inhibitor suramin reduces apoptosis and cell aggregation in protein-free CHO cell batch cultures","volume":"16","author":"Zanghi","year":"2000","journal-title":"Biotechnol. Prog."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.actbio.2016.06.001","article-title":"Vascularization of three-dimensional engineered tissues for regenerative medicine applications","volume":"41","author":"Kim","year":"2016","journal-title":"Acta Biomater"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"49","DOI":"10.5731\/pdajpst.2015.01001","article-title":"Extractables analysis of single-use flexible plastic biocontainers","volume":"69","author":"Marghitoiu","year":"2015","journal-title":"PDA J. Pharm. Sci. Technol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/btpr.1869","article-title":"A cytotoxic leachable compound from single-use bioprocess equipment that causes poor cell growth performance","volume":"30","author":"Hammond","year":"2014","journal-title":"Biotechnol. Prog."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"123","DOI":"10.5731\/pdajpst.2013.00905","article-title":"Identification of a leachable compound detrimental to cell growth in single-use bioprocess containers","volume":"67","author":"Hammond","year":"2013","journal-title":"PDA J. Pharm. Sci. Technol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1002\/rcm.7021","article-title":"Ambient analysis of leachable compounds from single-use bioreactors with desorption electrospray ionization time-of-flight mass spectrometry","volume":"28","author":"Liu","year":"2014","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1002\/btpr.1934","article-title":"Verification of a new biocompatible single-use film formulation with optimized additive content for multiple bioprocess applications","volume":"30","author":"Jurkiewicz","year":"2014","journal-title":"Biotechnol. Prog."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jclepro.2012.09.048","article-title":"An environmental life cycle assessment comparison of single-use and conventional process technology for the production of monoclonal antibodies","volume":"41","author":"Pietrzykowski","year":"2013","journal-title":"J. Clean. Prod."},{"key":"ref_124","first-page":"40","article-title":"Single-use technology and modular construction","volume":"11","author":"Levine","year":"2013","journal-title":"BioProcess Int."},{"key":"ref_125","unstructured":"Rogge, P., M\u00fcller, D., and Schmidt, S.R. (2015). The single-use or stainless steel decision process. BioProcess Int., 13."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nbt.3525","article-title":"Quality cell therapy manufacturing by design","volume":"34","author":"Lipsitz","year":"2016","journal-title":"Nat. Biotechnol."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/8\/5\/68\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:02:24Z","timestamp":1760162544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/8\/5\/68"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,17]]},"references-count":126,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["bioengineering8050068"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering8050068","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,17]]}}}