title: A CMI (cell metabolic indicator)-based controller for achieving high growth rate Escherichia coli cultures.
abstract: A large fraction of biopharmaceuticals are produced in Escherichia coli, where each new product and strain currently requires a high degree of growth characterization in benchtop and industrial bioreactors to achieve economical production protocols. The capability to use a standard set of sensors to characterize a system quickly without the need to conduct numerous experiments to determine stable growth rate for the strain would significantly decrease development time. This paper presents a cell metabolic indicator (CMI) which provides better insight into the E. coli metabolism than a growth rate value. The CMI is the ratio of the oxygen uptake rate (OUR) of the culture and the base addition rate (BAR) required to keep pH at a desired setpoint. The OUR and BAR are measured using a off-gas sensor and pH probe, respectively, and thus the CMI can be computed online. Experimental results demonstrate the relationship between CMI and the different cell metabolic states. A previously published model is augmented with acid production dynamics, allowing for comparison of the CMI-based controller with an open-loop controller in simulation. The CMI-based controller required little a priori knowledge about the E. coli strain in order to achieve a high growth rate. Since many different types of cells exhibit similar behaviors, the CMI concept can be extended to mammalian and stem cells.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Pepper
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Ajay
authors.initials: A
authors.lastname: Padmakumar
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burg
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Harcum
authors.forename: Richard E
authors.initials: RE
authors.lastname: Groff
mesh_terms: D019149:Bioreactors; D046508:Culture Techniques; D004734:Energy Metabolism; D004926:Escherichia coli / Q000254:growth & development* / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction