The DOI matches its Crossref record; 39 of the 40 references it cites were found in a registry or an index.
Expansion of 3D human induced pluripotent stem cell aggregates in bioreactors: Bioprocess intensification and scaling-up approaches
Abstract
Human induced pluripotent stem cells (hiPSC) are attractive tools for drug screening and disease modeling and promising candidates for cell therapy applications. However, to achieve the high numbers of cells required for these purposes, scalable and clinical-grade technologies must be established. In this study, we use environmentally controlled stirred-tank bioreactors operating in perfusion as a powerful tool for bioprocess intensification of hiPSC production. We demonstrate the importance of controlling the dissolved oxygen concentration at low levels (4%) and perfusion at 1.3day -1 dilution rate to improve hiPSC growth as aggregates in a xeno-free medium. This strategy allowed for increased cell specific growth rate, maximum volumetric concentrations (4.7×10 6 cell/mL) and expansion factors (approximately 19 in total cells), resulting in a 2.6-fold overall improvement in cell yields. Extensive cell characterization, including whole proteomic analysis, was performed to confirm that cells' pluripotent phenotype was maintained during culture. A scalable protocol for continuous expansion of hiPSC aggregates in bioreactors was implemented using mechanical dissociation for aggregate disruption and cell passaging. A total expansion factor of 1100 in viable cells was obtained in 11days of culture, while cells maintained their proliferation capacity, pluripotent phenotype and potential as well as genomic stability after 3 sequential passages in bioreactors.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The apparent under appreciation of reporting measured environmental parameters is exemplified by published bioreactor experiments that report only the target levels of environmental parameters (e.g., Karst et al., 2016; Abecasis et al., 2017).”
From Toward Best Practices for Controlling Mammalian Cell Culture Environments (2022) · cites this paper as Abecasis et al., 2017
Citations
Cites
Vascularized and functional human liver from an iPSC-derived organ bud transplant
Takebe, T., Sekine, K., Enomura, M., Koike, H., Kimura, M., Ogaeri, T., Zhang, R.-R., Ueno, Y., Zheng, Y.-W., Koike, N., et al. (2013) · Nature · doi:10.1038/nature12271 · Cited by 2,170
The promise of induced pluripotent stem cells in research and therapy
Robinton, D. A., & Daley, G. Q. (2012) · Nature · doi:10.1038/nature10761 · Cited by 1,150
Low O 2 tensions and the prevention of differentiation of hES cells
Ezashi, T., Das, P., & Roberts, R. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501283102 · Cited by 824
Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts
Varum, S., Rodrigues, A. S., Moura, M. B., Momcilovic, O., Easley, C. A., Ramalho-Santos, J., Van Houten, B., & Schatten, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020914 · Cited by 671
UCP2 regulates energy metabolism and differentiation potential of human pluripotent stem cells
Zhang, J., Khvorostov, I., Hong, J. S., Oktay, Y., Vergnes, L., Nuebel, E., Wahjudi, P. N., Setoguchi, K., Wang, G., Do, A., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.401 · Cited by 512
Metabolic Regulation in Pluripotent Stem Cells during Reprogramming and Self-Renewal
Zhang, J., Nuebel, E., Daley, G. Q., Koehler, C. M., & Teitell, M. A. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.10.005 · Cited by 477
Cho, Y. M., Kwon, S., Pak, Y. K., Seol, H. W., Choi, Y. M., Park, D. J., Park, K. S., & Lee, H. K. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.08.020 · Cited by 465
The promise of human induced pluripotent stem cells for research and therapy
Nishikawa, S., Goldstein, R. A., & Nierras, C. R. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2466 · Cited by 423
Process engineering of human pluripotent stem cells for clinical application
Serra, M., Brito, C., Correia, C., & Alves, P. M. (2012) · Trends in biotechnology · doi:10.1016/j.tibtech.2012.03.003 · Cited by 309
Self-citationScalable expansion of human pluripotent stem cells in suspension culture
Zweigerdt, R., Olmer, R., Singh, H., Haverich, A., & Martin, U. (2011) · Nature Protocols · doi:10.1038/nprot.2011.318 · Cited by 271
Flagged first, then by citations
1 of the 40 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 101–105 of 105
Shaping cell therapy manufacturing with metabolic understanding and control
Costa, C. M., Terrasso, A. P., Costa, M. H. G., Alves, P. M., & Serra, M. (2026) · Trends in biotechnology · doi:10.1016/j.tibtech.2026.03.006
Self-citationScalable process technologies for human pluripotent stem cells (hPSCs) expansion and differentiation
Cyrys, K., & Zweigerdt, R. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115904 · Cited by 1
Cyrys, K., Manstein, F., Triebert, W., Kriedemann, N., Hernandez-Bautista, C. A., & Zweigerdt, R. (2026) · Nature Protocols · doi:10.1038/s41596-026-01398-y
Salvador, W. O. S., Nogueira, D. E. S., Castillo, G. A. D., Karpiak, J. V., Rees, S. D., Cabral, J. M. S., Graumann, K., & Rodrigues, C. A. V. (2026) · Research Square · doi:10.21203/rs.3.rs-11065760/v1
van der Walle, C. F. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-45791-3.00006-8
Metadata
- Authors
- Abecasis, B., Aguiar, T., Arnault, É., Costa, R., Gomes-Alves, P., Aspegren, A., Serra, M., & Alves, P. M.
- Affiliations
- Instituto de Biologia Experimental e Tecnológica (PT)
- Takara (Sweden) (SE)
- Corresponding author
- Aspegren, Anders
- Serra, Margarida
- Venue
- Journal of Biotechnology
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 246
- Pages
- 81-93
- ISSN
- 0168-1656 (ISSN-L)
- OpenAlex
- W2580933284
- Cited by
- 100
- References
- 40
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 14 · 2023: 10 · 2022: 6 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 8 · 2017: 3
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação para a Ciência e Tecnologia (FCT)-funded projects CARDIOSTEM (MITP-TB/ECE/0013/2013)
- CardioRegen (HMSP-ICT/0039/2013)
- iNOVA4Health (UID/Multi/04462/2013)
- FCT (SFRH/BD/52475/2013)
- Vinnova Grant
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Physical Sciences › Chemical Engineering › Fluid Flow and Transfer Processes › Fluid Dynamics and Mixing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- human induced pluripotent stem cells, cell aggregates, stirred tank bioreactor, perfusion bioreactor, bioprocess intensification, low dissolved oxygen, cell expansion, mechanical dissociation, pluripotency maintenance, genome stability, cell therapy
- MeSH terms
- Cell Differentiation, Cells, Cultured, Humans, Oxygen, Phenotype, Cell Culture Techniques, Bioreactors, Proteomics, Genomic Instability, Cell Proliferation, Induced Pluripotent Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
