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Multivariate analysis of metabolic parameters and optimization of antibody production using high cell density hybridoma in hollow fiber bioreactors

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Abstract

Objectives

The relationships of manipulation of culture temperature and medium circulation rate on the metabolic parameters were regressed by multiple linear regression analysis in hollow fiber bioreactors (HFB).

Results

The high circulation rate could significantly enhance the oxygen consumption of the hybridoma cells and the medium’s oxidation–reduction potential. A mildly hypothermic condition of 36 °C and a circulation rate of 182.5 mL/min could support the hybridoma had the maximal antibody titer of 60.75 μg/mL for 20 days. When the ammonium ion was 65 ppm or lactate close to 2.6 g/L, the medium was replaced to maintain the stable and healthy cells at the high cell concentration of 3.33 × 108/mL for continuous antibody production. Two serum-free media could be successfully applied to this perfusion system and maintain hybridoma growth and antibody production.

Conclusion

The single-use HFBs could provide the advantages including high cell density, low shear stress, and continuous antibody production.

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Acknowledgements

We express gratitude to Ministry of Science and Technology (MOST 106-2221-E-182-050, 108-2221-E-182-039), Chang Gung University (BMRP 758) and Chang Gung Memorial Hospital (CMRPD2G0282, 2H0071, 2H0072) for funding and supporting this research. We thank the valuable suggestions for bioreactor operation from Frank R. H. Wang, at United BioPharma, Hsinchu, Taiwan.

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Authors and Affiliations

  1. Department of Chemical and Materials Engineering, Chang Gung University, 259, Wen-Hwa First Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC

    Chi-Hsien Liu & Monika Kumari

  2. Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, 261, Wen-Hwa First Road, Taoyuan, Taiwan, ROC

    Chi-Hsien Liu

  3. Department of Chemical Engineering, Ming Chi University of Technology, 84, Gung-Juan Road, New Taipei City, Taiwan, ROC

    Chi-Hsien Liu

  4. Department of Ophthalmology, Chang Gung Memorial Hospital, 5, Fu-Hsing Street, Taoyuan, Taiwan, ROC

    Chi-Hsien Liu & Wei-Chi Wu

  5. Graduate Institute of Biomedical Engineering, Chang Gung University, 259, Wen-Hwa First Road, Kwei-Shan, Tao-Yuan 333, Taiwan, ROC

    Yi-Xin Liu

  6. College of Medicine, Chang Gung University, 259, Wen-Hwa First Road, Taoyuan, Taiwan, ROC

    Wei-Chi Wu

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  1. Chi-Hsien Liu
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Correspondence to Chi-Hsien Liu.

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Liu, CH., Liu, YX., Kumari, M. et al. Multivariate analysis of metabolic parameters and optimization of antibody production using high cell density hybridoma in hollow fiber bioreactors. Biotechnol Lett 41, 963–977 (2019). https://doi.org/10.1007/s10529-019-02712-3

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  • DOI: https://doi.org/10.1007/s10529-019-02712-3

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