Bioprocess monitoring

Harms, Peter D.; Kostov, Yordan; Rao, Govind

doi:10.1016/s0958-1669(02)00295-1

Cited by 148 publications

(100 citation statements)

References 37 publications

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“…Advances in optics and electronics have made optical sensors commercially available for the monitoring of such processes (Harms et al 2002). Specifically, real-time monitoring is advantageous for assessing growth rate, the state of bioreactions, and to obtain early indications of catastrophic events such as contamination or cessation of growth.…”

Section: Introductionmentioning

confidence: 99%

“…Optical-chemical sensing is also fast-the cell properties can be measured continuously during cell growth, and there is no delay between measurement and results. They also can be easily miniaturized with high precision and low cost (Ge et al 2003;Harms et al 2002). This allows measurement of the entire culture duration, batch or continuous, with no sampling required.…”

Section: Introductionmentioning

confidence: 99%

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Monitoring pH and dissolved oxygen in mammalian cell culture using optical sensors

2008

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Here, we have studied two parameters critical to process control in mammalian cell culture; dissolved oxygen (dO 2 ) and pH, measured with fluorescent sensors thus allowing the study of the metabolic state of cells in culture without removing or damaging cells during cultivation. Two cell lines, namely, NS0 and CHO were batch-grown in 24-well plates at different serum concentrations with the sensors implemented in the bottom of each well. The data showed a good relationship between the dO 2 and pH data obtained from fluorescent probes and the growth and death characteristics of cells. The method has provided a high throughput on-line multi-parametric analysis of mammalian cell cellular activity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Monitoring pH and dissolved oxygen in mammalian cell culture using optical sensors

2008

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“…Conventional monitoring methods mostly provide population averaged values (i.e., concentrations of metabolites and biomass, dissolved O 2 concentration, CO 2 production rate, etc. ), while single-cell analysis is usually limited to the determination of colonyforming units (Harms et al, 2002). The latter method is, however, tedious and the results become available with a time delay of 1 or more days.…”

Section: Introductionmentioning

confidence: 99%

Flow-cytometric detection of changes in the physiological state ofE. coli expressing a heterologous membrane protein during carbon-limited fedbatch cultivation

Looser

Hammes

Keller

et al. 2005

Biotechnol. Bioeng.

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The key to optimizing productivity during industrial fermentations is the ability to rapidly monitor and interpret the physiological state of single microbial cells in a population and to recognize and characterize different sub-populations. Here, a flow cytometry-based method for the reproducible detection of changes in membrane function and/or structure of recombinant E. coli JM101 (pSPZ3) expressing xylene monooxygenase (XMO), was developed. XMO expression led to compromised but not permeabilized cell membranes. This was deduced from the fact that recombinant cells only stained with ethidium bromide (EB) and not with propidium iodide (PI). During the glucose-limited fedbatch cultivation, an increase from 25% to 95% of EB-stained cells was observed, occurring between 2 and 5 h after induction. Control experiments confirmed that this increase was due to the recombinant protein production and not caused by any possible effects of varying substrate availability, high cell density, plasmid replication or the presence of the inducing agent. We hypothesize that the integration of the recombinant protein into the cell membrane physically disrupted the functionality of the efflux pumps, thus resulting in EB-staining of the recombinant cells. This method enabled us to detect changes in the physiological state of single cells 2-4 h before other indications of partial cell damage, such as unbalanced growth, acetate accumulation and an increased CO(2) production rate, were observed. This method therefore shows promise with respect to the further development of an early-warning system to prevent sudden productivity decreases in processes with recombinant E. coli expressing heterologous membrane proteins.

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“…The miniaturization of cultivation technology has been hampered by the lack of suitably durable, compact and relevant sensors, and by the limited ability to control parameters within small volumes (Harms et al, 2002;Scheller et al, 2001;Schugerl, 2001;Walther et al, 1994). Applicable sensor technology has been progressing steadily; methods employing microfabricated silicon-based sensors or optochemical sensing allow for the monitoring of parameters in many simultaneous experiments (Pons, 1993;Scheller et al, 2001;Zanzotto et al, 2002;Zhang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Microbioreactor arrays with parametric control for high‐throughput experimentation

Maharbiz

Holtz

Howe

et al. 2003

Biotech & Bioengineering

111

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A scalable array technology for parametric control of high-throughput cell cultivations is demonstrated. The technology makes use of commercial printed circuit board (PCB) technology, integrated circuit sensors, and an electrochemical gas generation system. We present results for an array of eight 250 microl microbioreactors. Each bioreactor contains an independently addressable suite that provides closed-loop temperature control, generates feed gas electrochemically, and continuously monitors optical density. The PCB technology allows for the assembly of additional off-the-shelf components into the microbioreactor array; we demonstrate the use of a commercial ISFET chip to continuously monitor culture pH. The electrochemical dosing system provides a powerful paradigm for reproducible gas delivery to high-density arrays of microreactors. Growth data are presented for Escherichia coli cultured in the array with varying microaerobic conditions using electrochemically generated oxygen. Additionally, we present data on carbon dioxide generation for pH dosing.

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Bioprocess monitoring

Cited by 148 publications

References 37 publications

Monitoring pH and dissolved oxygen in mammalian cell culture using optical sensors

Monitoring pH and dissolved oxygen in mammalian cell culture using optical sensors

Flow-cytometric detection of changes in the physiological state ofE. coli expressing a heterologous membrane protein during carbon-limited fedbatch cultivation

Microbioreactor arrays with parametric control for high‐throughput experimentation

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