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A mechanistic model of erythroblast growth inhibition providing a framework for optimisation of cell therapy manufacturing

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journal contribution
posted on 06.03.2018 by Katie Glen, Elizabeth Cheeseman, Adrian J. Stacey, Rob Thomas
Manufacture of Red Blood Cell based products in vitro requires highly efficient erythroblast culture for economic viability. It has previously been shown that efficiency of erythroblast culture in scalable bioreactors is not primarily limited by mass transfer, availability of medium components, or commonly recognised inhibitory metabolites or cytokines. We have developed a dynamic mechanistic model that describes an autocrine feedback loop in which a cell-derived factor accumulates in culture medium resulting in reversible erythroblast growth inhibition. Cells exhibited two phases of growth: a relatively uninhibited followed by an inhibited phase. Cell cycle analysis during inhibition identified slight accumulation of cells in S phase, distinct from the G1 accumulation anticipated in growth factor or nutrient deprivation. Substantial donor to donor growth rate variability (mean 0.047 h−1, standard deviation 0.008 h−1) required the growth rate parameter to be refitted for different donors. The model could then be used to predict growth behaviour with full medium exchange, but showed some reduced predictive ability after partial medium exchange. The model could predict the growth inflexion point over a range of phenotypic maturities from early to late maturity erythroblasts; however the secondary phase of growth differed substantially with less inhibition observed in more mature cells. The model provided a framework to optimise culture economics based on cost of production time and input consumables. It also provided a framework to evaluate the benefits of biological process engineering in medium design or cell modification vs. operational optimisation depending on the specific cost scenario of a process developer.

Funding

Engineering and Physical Sciences Research Council Fellowship grant (EP/K00705X/1) and Wellcome Trust Translational Fund grant (102610/Z/13/Z).

History

School

  • Mechanical, Electrical and Manufacturing Engineering

Published in

Biochemical Engineering Journal

Volume

133

Pages

28 - 38

Citation

GLEN, K.E. ... et al, 2018. A mechanistic model of erythroblast growth inhibition providing a framework for optimisation of cell therapy manufacturing. Biochemical Engineering Journal, 133, pp.28-38.

Publisher

Elsevier © The Author(s)

Version

VoR (Version of Record)

Publisher statement

This work is made available according to the conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) licence. Full details of this licence are available at: http://creativecommons.org/licenses/ by/4.0/

Acceptance date

27/01/2018

Publication date

2018-01-31

Notes

This is an Open Access Article. It is published by Elsevier under the Creative Commons Attribution 4.0 International Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/

ISSN

1369-703X

Language

en

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