| High cell density induces spontaneous bifurcations of dissolved oxygen controllers during CHO cell fermentations. | |
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MedLine Citation:
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PMID: 12966579 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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High cell density cultures of CHO cells growing in a bioreactor under dissolved oxygen control were found to undergo spontaneous bifurcations and a subsequent loss of stability some time into the fermentation. This loss of stability was manifested by sustained and amplified oscillations in the bioreactor dissolved oxygen concentration and in the oxygen gas flow rate to the reactor. To identify potential biological and operational causes for the phenomenon, linear stability analysis was applied in a neighborhood of the experimentally observed bifurcation point. The analysis revealed that two steady state process gains, K(P1) and K(P2), regulated k(l)a and gas phase oxygen concentration inputs, respectively, and the magnitude of K(P1) was found to determine system stability about the bifurcation point. The magnitude of K(P1), and hence the corresponding open-loop steady state gain K(OL1), scaled linearly with the bioreactor cell density, increasing with increasing cell density. These results allowed the generation of a fermentation stability diagram, which partitioned K(C)-N operating space into stable and unstable regions separated by the loci of predicted critically stable controller constants, K(C,critical), as a function of bioreactor cell density. This consistency of this operating diagram with experimentally observed changes in system stability was demonstrated. We conclude that time-dependent increases in cell density are the cause of the observed instabilities and that cell density is the critical bifurcation parameter. The results of this study should be readily applicable to the design of a more robust controller. |
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Authors:
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John D Chung; Conway C Chang; James Ashley Groves |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biotechnology and bioengineering Volume: 84 ISSN: 0006-3592 ISO Abbreviation: Biotechnol. Bioeng. Publication Date: 2003 Oct |
Date Detail:
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Created Date: 2003-09-10 Completed Date: 2004-05-19 Revised Date: 2005-11-17 |
Medline Journal Info:
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Nlm Unique ID: 7502021 Medline TA: Biotechnol Bioeng Country: United States |
Other Details:
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Languages: eng Pagination: 224-32 Citation Subset: IM |
Copyright Information:
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Copyright 2003 Wiley Periodicals, Inc. |
Affiliation:
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Abgenix Inc, 6701 Kaiser Drive, Fremont, California 94555, USA. jchung@dendreon.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Algorithms Animals Bioreactors* CHO Cells Cell Count* Cell Division / drug effects, physiology Computer Simulation Cricetinae Cricetulus Fermentation* Kinetics Models, Theoretical Oxygen / metabolism*, pharmacology |
| Chemical | |
Reg. No./Substance:
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7782-44-7/Oxygen |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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