Application of heat compensation calorimetry to an E. coli fed-batch process.

The application of biocalorimetry to fermentation processes offers advantageous insights, while being less complex compared to other, sophisticated PAT solutions. Although the general concept is established, calorimetric methods vary in detail. In this work, a special approach, called heat compensation calorimetry, was applied to an E. coli fed-batch process. Much work has been done for batch processes, proving the validity and accuracy of this calorimetric mode. However, the adaption of this strategy to fed-batch processes has some implications. In the first section of this work, batch fermentations were performed, comparing heat capacity calorimetry to the compensation mode. Both processes showed very good agreement by means of growth behavior. The heat related differences, e.g. temperature profiles, were obvious. In addition, the impact of the chosen mode on the calculation of in-process heat transfer coefficients was shown. Finally, a fed-batch fermentation was performed. The compensation mode was kept sufficiently, up to the point where the metabolic heat production accelerated strongly. Controller tuning was a neuralgic point, which would have needed further optimization under these conditions. Nevertheless, in the present work it was possible to realize a working compensation process while demonstrating critical aspects that must be considered when establishing such approach.

[1]  E. Gnaiger,et al.  Anaerobic metabolism in aerobic mammalian cells: information from the ratio of calorimetric heat flux and respirometric oxygen flux. , 1990, Biochimica et biophysica acta.

[2]  David F. Ollis,et al.  Biochemical Engineering Fundamentals , 1976 .

[3]  U von Stockar,et al.  Development of a large-scale biocalorimeter to monitor and control bioprocesses. , 2002, Biotechnology and bioengineering.

[4]  S. Lee,et al.  High cell-density culture of Escherichia coli. , 1996, Trends in biotechnology.

[5]  J. G. Kuenen,et al.  Continuous measurement of microbial heat production in laboratory fermentors , 1993, Biotechnology and bioengineering.

[6]  R. Gesthuisen,et al.  Simultaneous estimation of the heat of reaction and the heat transfer coefficient by calorimetry: estimation problems due to model simplification and high jacket flow rates—theoretical development , 2005 .

[7]  J. Büchs,et al.  Comparison of two methods for designing calorimeters using stirred tank reactors , 2013, Biotechnology and bioengineering.

[8]  H. Harms,et al.  Calorespirometric feeding control enhances bioproduction from toxic feedstocks—Demonstration for biopolymer production out of methanol , 2016, Biotechnology and bioengineering.

[9]  W. Deckwer,et al.  High cell density cultivation of Escherichia coli at controlled specific growth rate. , 1991, Journal of biotechnology.

[10]  A. Clamen,et al.  The relationship of substrate, growth rate, and maintenance coefficient to single cell protein production , 1973, Biotechnology and bioengineering.

[11]  Mustafa Türker,et al.  Development of biocalorimetry as a technique for process monitoring and control in technical scale fermentations , 2004 .

[12]  John R. Bourne,et al.  Heat transfer and power measurements in stirred tanks using heat flow calorimetry , 1981 .

[13]  K. Reichert,et al.  Temperature oscillation calorimetry in stirred tank reactors , 1996 .

[14]  Dieter Eibl,et al.  Development of a method for reliable power input measurements in conventional and single‐use stirred bioreactors at laboratory scale , 2017, Engineering in life sciences.

[15]  T. Maskow,et al.  Chip calorimetry and its use for biochemical and cell biological investigations , 2008 .

[16]  R. Biener,et al.  Calorimetric control of the specific growth rate during fed-batch cultures of Saccharomyces cerevisiae. , 2012, Journal of biotechnology.

[17]  Thomas Maskow,et al.  Real Time Insights into Bioprocesses Using Calorimetry: State of the Art and Potential , 2006 .

[18]  R. Gesthuisen,et al.  Determining the best reaction calorimetry technique: theoretical development , 2005, Comput. Chem. Eng..

[19]  R. Kemp “Fire burn and cauldron bubble” (W. Shakespeare): what the calorimetric–respirometric (CR) ratio does for our understanding of cells? , 2000 .

[20]  A C A Veloso,et al.  Monitoring of fed-batch E. coli fermentations with software sensors , 2009, Bioprocess and biosystems engineering.

[21]  C. Scali,et al.  Temperature oscillation calorimetry: Robustness analysis of different algorithms for the evaluation of the heat transfer coefficient , 2002 .

[22]  T. Maskow,et al.  What does calorimetry and thermodynamics of living cells tell us? , 2015, Methods.

[23]  J. Luong,et al.  Determination of the heat of some aerobic fermentations , 1980 .

[24]  F. Schäfer,et al.  Quantification of small enthalpic differences in anaerobic microbial metabolism—a calorimetry-supported approach , 1996 .

[25]  D. Wirz,et al.  Microbial growth and isothermal microcalorimetry: Growth models and their application to microcalorimetric data , 2013 .

[26]  I. Marison,et al.  Thermodynamics of microbial growth and metabolism: an analysis of the current situation. , 2006, Journal of biotechnology.

[27]  Richard Biener,et al.  Calorimetric control for high cell density cultivation of a recombinant Escherichia coli strain. , 2010, Journal of biotechnology.

[28]  Marvin J. Johnson,et al.  Energy Supply and Cell Yield in Aerobically Grown Microorganisms , 1967 .

[29]  Konrad Hungerbühler,et al.  Isothermal reaction calorimetry as a tool for kinetic analysis , 2004 .

[30]  G. Honderd,et al.  Using heat-flow measurements for the feed control of a fed batch fermentation of Saccharomyces cerevisiae , 1998 .

[31]  Thomas Maskow,et al.  Calorimetric bioprocess monitoring by small modifications to a standard bench-scale bioreactor. , 2007, Journal of biotechnology.

[32]  I. Marison,et al.  Calorimetric investigation of aerobic fermentations , 1987, Biotechnology and bioengineering.

[33]  Sang Jun Lee,et al.  Modified Escherichia coli B (BL21), a superior producer of plasmid DNA compared with Escherichia coli K (DH5alpha). , 2008, Biotechnology and bioengineering.

[34]  M. Eiteman,et al.  Overcoming acetate in Escherichia coli recombinant protein fermentations. , 2006, Trends in biotechnology.

[35]  I. Marison,et al.  On-line detection of baseline variations through torque measurements in isothermal reaction calorimeters☆ , 1995 .

[36]  A. Blomberg,et al.  Use of microcalorimetric monitoring in establishing continuous energy balances and in continuous determinations of substrate and product concentrations of batch‐grown Saccharomyces cerevisiae , 1991, Biotechnology and bioengineering.

[38]  C L Cooney,et al.  Measurement of heat evolution and correlation with oxygen consumption during microbial growth , 1969, Biotechnology and bioengineering.

[39]  A. Schiraldi Microbial growth and metabolism: Modelling and calorimetric characterization , 1995 .

[40]  J. Villadsen,et al.  Isothermal reaction calorimeters—I. A literature review , 1987 .