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Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein
Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.
Linköpings universitet, Institutionen för fysik, kemi och biologi, Teknisk biologi. Linköpings universitet, Tekniska högskolan.ORCID-id: 0000-0001-9711-794X
2013 (engelsk)Inngår i: Bioprocess and biosystems engineering (Print), ISSN 1615-7591, E-ISSN 1615-7605, Vol. 36, nr 10, s. 1375-1384Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

A soft sensor approach is described for controlling metabolic overflow from mixed-acid fermentation and glucose overflow metabolism in a fed-batch cultivation for production of recombinant green fluorescence protein (GFP) in Escherichia coli. The hardware part of the sensor consisted of a near-infrared in situ probe that monitored the E. coli biomass and an HPLC analyzer equipped with a filtration unit that measured the overflow metabolites. The computational part of the soft sensor used basic kinetic equations and summations for estimation of specific rates and total metabolite concentrations. Two control strategies for media feeding of the fed-batch cultivation were evaluated: (1) controlling the specific rates of overflow metabolism and mixed-acid fermentation metabolites at a fixed pre-set target values, and (2) controlling the concentration of the sum of these metabolites at a set level. The results indicate that the latter strategy was more efficient for maintaining a high titer and low variability of the produced recombinant GFP protein.

sted, utgiver, år, opplag, sider
Springer Verlag (Germany) , 2013. Vol. 36, nr 10, s. 1375-1384
Emneord [en]
Soft sensors, Software sensors, Bioprocess monitoring and control, Fed-batch cultivation control, Overflow metabolism, Mixed-acid fermentation
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-98661DOI: 10.1007/s00449-012-0840-zISI: 000324214400005OAI: oai:DiVA.org:liu-98661DiVA, id: diva2:655273
Merknad

Funding Agencies|Linkoping University||

Tilgjengelig fra: 2013-10-10 Laget: 2013-10-10 Sist oppdatert: 2019-01-22bibliografisk kontrollert
Inngår i avhandling
1. Development of soft sensors for monitoring and control of bioprocesses
Åpne denne publikasjonen i ny fane eller vindu >>Development of soft sensors for monitoring and control of bioprocesses
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

In the manufacture of bio-therapeutics the importance of a well-known process is key for a high product titer and low batch to batch variations. Soft sensors are based on the concept that online sensor signals can be used as inputs to mathematical models to derive new valuable process information. This information could then be used for better monitoring and control of the bioprocess.

The aim of the present thesis has been to develop soft sensor solutions for upstream bioprocessing and demonstrate their usefulness in improving robustness and increase the batch-to-batch reproducibility in bioprocesses. The thesis reviews the potential and possibilities with soft sensors for use in production of bio-therapeutics to realize FDA´s process analytical technology (PAT) initiative. Modelling and hardware sensor alternatives which could be used in a soft sensor setup are described and critically analyzed. Different soft sensor approaches to control glucose feeding in fed-batch cultures of Escherichia coli are described. Measurements of metabolic fluxes and specific carbon dioxide production was used as control parameters to increase product yield and decrease the variability of produced recombinant proteins. Metabolic heat signals were used in uninduced cultures to estimate and control the specific growth rate at a desired level and thereby also estimate the biomass concentration online. The introduction of sequential filtering of the signal enabled this method to be used in a down-scaled system. The risk and high impact of contaminations in cell cultures are also described. An in situ microscope (ISM) was used as an online tool to estimate cell concentration and also to determine cell diameter size which enabled the detection of contaminant cells at an early stage.

The work presented in this thesis supports the idea that soft sensors can be a useful tool in the strive towards robust and reliable bioprocesses, to ensure high product quality and increased economic profit.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. s. 55
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1954
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-152439 (URN)10.3384/diss.diva-152439 (DOI)9789176852071 (ISBN)
Disputas
2018-10-26, Planck, Fysikhuset, Campus Valla, Linköping, 13:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2018-10-31 Laget: 2018-10-31 Sist oppdatert: 2019-09-30bibliografisk kontrollert

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