A dynamic model linking cell growth to intracellular metabolism and extracellular by-product accumulation.

Abstract:

:Mathematical modeling of animal cell growth and metabolism is essential for the understanding and improvement of the production of biopharmaceuticals. Models can explain the dynamic behavior of cell growth and product formation, support the identification of the most relevant parameters for process design, and significantly reduce the number of experiments to be performed for process optimization. Few dynamic models have been established that describe both extracellular and intracellular dynamics of growth and metabolism of animal cells. In this study, a model was developed, which comprises a set of 33 ordinary differential equations to describe batch cultivations of suspension AGE1.HN.AAT cells considered for the production of α1-antitrypsin. This model combines a segregated cell growth model with a structured model of intracellular metabolism. Overall, it considers the viable cell concentration, mean cell diameter, viable cell volume, concentration of extracellular substrates, and intracellular concentrations of key metabolites from the central carbon metabolism. Furthermore, the release of metabolic by-products such as lactate and ammonium was estimated directly from the intracellular reactions. Based on the same set of parameters, this model simulates well the dynamics of four independent batch cultivations. Analysis of the simulated intracellular rates revealed at least two distinct cellular physiological states. The first physiological state was characterized by a high glycolytic rate and high lactate production. Whereas the second state was characterized by efficient adenosine triphosphate production, a low glycolytic rate, and reactions of the TCA cycle running in the reverse direction from α-ketoglutarate to citrate. Finally, we show possible applications of the model for cell line engineering and media optimization with two case studies.

journal_name

Biotechnol Bioeng

authors

Ramos JRC,Rath AG,Genzel Y,Sandig V,Reichl U

doi

10.1002/bit.27288

subject

Has Abstract

pub_date

2020-05-01 00:00:00

pages

1533-1553

issue

5

eissn

0006-3592

issn

1097-0290

journal_volume

117

pub_type

杂志文章
  • Methodological analysis for determination of enzymatic digestibility of cellulosic materials.

    abstract::Accurate measurement of enzymatic cellulose digestibility (X) is important in evaluating the efficiency of lignocellulose pretreatment technologies, assessing the performance of reconstituted cellulase mixtures, and conducting economic analysis for biorefinery processes. We analyzed the effect of sugars contained in e...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.21178

    authors: Zhang YH,Schell DJ,McMillan JD

    更新日期:2007-01-01 00:00:00

  • Characterization of human islet-like structures generated from pancreatic precursor cells in culture.

    abstract::This study addresses the characterization of human islet-like structures generated from a newly discovered sparse population of precursor cells (Petropavlovskaia and Rosenberg, 2002) in the human pancreas. These cells may be progenitor cells capable of producing pancreatic cells suitable for the treatment of type 1 di...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.20801

    authors: Bodnar CA,Sen A,Kallos MS,Behie LA,Petropavlovskaia M,Rosenberg L

    更新日期:2006-04-05 00:00:00

  • Effects of culture conditions on N-glycolylneuraminic acid (Neu5Gc) content of a recombinant fusion protein produced in CHO cells.

    abstract::CHO cells express glycoproteins containing both the N-acetylneuraminic acid (Neu5Ac) and minor amounts of the N-glycolylneuraminic acid (Neu5Gc) forms of sialic acid. As Neu5Gc is not expressed in humans and can be recognized as a foreign epitope, there is the potential for immunogenicity issues for glycoprotein thera...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.22644

    authors: Borys MC,Dalal NG,Abu-Absi NR,Khattak SF,Jing Y,Xing Z,Li ZJ

    更新日期:2010-04-15 00:00:00

  • A novel purification strategy for retrovirus gene therapy vectors using heparin affinity chromatography.

    abstract::Membrane separation and chromatographic technologies are regarded as an attractive alternative to conventional academic small-scale ultracentrifugation procedures used for retrovirus purification. However, despite the increasing demands for purified retroviral vector preparations, new chromatography adsorbents with hi...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.20301

    authors: Segura MM,Kamen A,Trudel P,Garnier A

    更新日期:2005-05-20 00:00:00

  • Analysis of noise and bias in fermentation oxygen uptake rate data.

    abstract::The calculation of many derived fermentation variables such as the respiratory quotient (RQ) and mass transfer coefficient (K(L)a) requires the differences between the molar percentages of oxygen and carbon dioxide in the fermentor inlet and exit gas, called the %OUR and %CER. Noise and bias in %CER data is of order t...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260400511

    authors: Royce PN,Thornhill NF

    更新日期:1992-08-01 00:00:00

  • On the estimation of average shear rate in bubble columns.

    abstract::Development of bioengineering using such biomaterials as plant tissues or genetically produced microorganisms makes it important to accurately estimate the prevailing shear rate in bioreactors because they are generally sensitive to shear. Various authors have discussed ways to estimate the average shear rate in a bub...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260370711

    authors: Nishikawa M

    更新日期:1991-03-25 00:00:00

  • Development of a multienzyme reactor for dopamine synthesis: I. enzymology and kinetics.

    abstract::The enzymology and kinetics of tyrosine phenol lyase (TPL) from Erwinia herbicola, and tyrosine decarboxylase (TDC) from Streptococcus faecalis have been investigated for potential use in a coimmobilized multienzyme biocatalytic system for the production of dopamine. In this multienzyme biotransformation using whole c...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260390711

    authors: Anderson WA,Moo-Young M,Legge RL

    更新日期:1992-03-25 00:00:00

  • Optimized release of recombinant proteins by ultrasonication of E. coli cells.

    abstract::The release kinetics of beta-galactosidase protein have been determined during small-scale ultrasonication of E. coli cells. Among several studied parameters, ionic strength and cell concentration have the least influence on the rate of protein recovery, whereas sample volume and acoustic power dramatically affect the...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0290(19980605)58:5<536::aid-bit

    authors: Feliu JX,Cubarsi R,Villaverde A

    更新日期:1998-06-05 00:00:00

  • Kinetic studies on hybridoma cells immobilized in fixed bed reactors.

    abstract::Cultures with immobilized hybridoma cells were performed in fixed bed systems. "Steady state" values for volume-specific substrate uptake and metabolite production rates were determined at various perfusion rates and superficial flow velocities of the medium within the carrier matrix. Data from fixed bed volumes betwe...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/(SICI)1097-0290(19970805)55:3<535::AID-BIT

    authors: Pörtner R,Rössing S,Koop M,Lüdemann I

    更新日期:1997-08-05 00:00:00

  • Physical modeling of animal cell damage by hydrodynamic forces in suspension cultures.

    abstract::Physical damage of animal cells in suspension culture, due to stirring and sparging, is coupled with complex metabolic responses. Nylon microcapsules, therefore, were used as a physical model to study the mechanisms of damage in a stirred bioreactor and in a bubble column. Microcapsule breaskage folowed first-order ki...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260401018

    authors: Lu GZ,Gray MR,Thompson BG

    更新日期:1992-12-05 00:00:00

  • Immobilized enzyme cellulose hollow fibers: II. Kinetic analysis.

    abstract::Immobilized enzyme hollow fibers may be useful in the purification or treatment of whole blood under clinical conditions. In this study, catalytically pure heparinase was immobilized to cellulose to analyze the feasibility for the removal of heparin's anticoagulant activity from whole blood. The kinetics of catalytica...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260341105

    authors: Comfort AR,Albert E,Langer R

    更新日期:1989-12-20 00:00:00

  • The kinetics of cometabolism.

    abstract::Experimental observations indicate that the rates of cometabolic transformation are linked to the consumption of growth substrate during growth and to the consumption of cell mass and/or energy substrate in the absence of growth substrate. Three previously proposed models (models 1 through 3) describing the kinetics o...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260411107

    authors: Criddle CS

    更新日期:1993-05-01 00:00:00

  • Optimization of batch processes involving simultaneous enzymatic and microbial reactions.

    abstract::Two general models for batch simultaneous enzymatic and microbial reaction (SEMR) processes are presented, the second derived from and simpler than the first and accounting for enzyme denaturation. Using the second model and parameter values from the literature, simulation was used to examine a range of enzyme additio...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260371114

    authors: Asenjo JA,Sun WH,Spencer JL

    更新日期:1991-05-01 00:00:00

  • Fluid mechanics of a spinner-flask bioreactor.

    abstract::Spinner-flask bioreactors have been used for the production of articular cartilage in vitro. The dynamic environment within bioreactors is known to significantly affect the growth and development of the tissue. The present research focuses on the experimental and numerical characterization of the flow field within a s...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.10788

    authors: Sucosky P,Osorio DF,Brown JB,Neitzel GP

    更新日期:2004-01-05 00:00:00

  • Analysis of endogenous process behavior in activated sludge.

    abstract::In this article, an autonomous four-compartment model that describes the endogenous respiration in an aerobic biodegradation process is proposed and analyzed theoretically. First, the multi-time scale of the system's behavior, to be taken into account in subsequent analyses, is emphasized. Then, an identifiability and...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0290(19980120)57:2<155::aid-bit

    authors: Keesman KJ,Spanjers H,van Straten G

    更新日期:1998-01-20 00:00:00

  • Process parameter shifting: Part I. Effect of DOT, pH, and temperature on the performance of Epo-Fc expressing CHO cells cultivated in controlled batch bioreactors.

    abstract::The impact of process environment changes on process performance is one of the most crucial process safety issues when cultivating mammalian cells in a bioreactor. In contrast, directed shifting of process parameters can also be used as an optimization tool providing higher cell and product yields. Compared to other s...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.21013

    authors: Trummer E,Fauland K,Seidinger S,Schriebl K,Lattenmayer C,Kunert R,Vorauer-Uhl K,Weik R,Borth N,Katinger H,Müller D

    更新日期:2006-08-20 00:00:00

  • A genetic time-delay circuitry in mammalian cells.

    abstract::Gene expression circuitries with time-delayed expression profiles regulate key events, such as oscillating systems, noise elimination, and coordinated multi-step processes, in all organisms from bacteria to mammalian cells. We present the rational synthesis of a genetic circuit displaying time-delayed expression in si...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.21463

    authors: Weber W,Kramer BP,Fussenegger M

    更新日期:2007-11-01 00:00:00

  • EGFR-targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells.

    abstract::Tumor-targeted Salmonella VNP20009 preferentially replicate within tumor tissue and partially suppress tumor growth in murine tumor models. These Salmonella have the ability to locally induce apoptosis when they are in direct contact with cancer cells but they lack significant bystander killing, which may correlate wi...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.26026

    authors: Quintero D,Carrafa J,Vincent L,Bermudes D

    更新日期:2016-12-01 00:00:00

  • Cellular reporoduction and extracellular polymer formation by Pseudomonas aeruginosa in continuous culture.

    abstract::The kinetics of cellular reproduction and the rate and extent of synthesis of extracellular polymeric substances (EPS) were investigated for P. aeruginosa growing in glucose-limited chemostats. mu(max) and K(s) estimates of 0.4 h(-1) and 2 mg glucose C/L, respectively, at 25 degrees C were obtained for this bacterium....

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260261203

    authors: Robinson JA,Trulear MG,Characklis WG

    更新日期:1984-12-01 00:00:00

  • Analysis of a framework using material balances in metabolic pathways to elucidate cellular metabolism.

    abstract::A framework using material balances in metabolic pathways to study cellular metabolism is examined and the results are discussed. Rate measurements on extracellular compounds alone were found to be not always sufficient to validate proposed unique intracellular mechanisms. The conditions to delineate among candidate m...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260340409

    authors: Niranjan SC,San KY

    更新日期:1989-08-05 00:00:00

  • Global gene expression of Dehalococcoides within a robust dynamic TCE-dechlorinating community under conditions of periodic substrate supply.

    abstract::A microarray targeting four sequenced strains in the Dehalococcoides (Dhc) genus was used to analyze gene expression in a robust long-term trichloroethene (TCE)-degrading microbial community (designated ANAS) during feeding cycles that involve conditions of periodic substrate supply. The Dhc transcriptome was examined...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.24819

    authors: West KA,Lee PK,Johnson DR,Zinder SH,Alvarez-Cohen L

    更新日期:2013-05-01 00:00:00

  • A reductionist metastasis-on-a-chip platform for in vitro tumor progression modeling and drug screening.

    abstract::Current animal and 2-D cell culture models employed in metastasis research and drug discovery remain poor mimics of human cancer physiology. Here we describe a "metastasis-on-a-chip" system allowing real time tracking of fluorescent colon cancer cells migrating from hydrogel-fabricated gut constructs to downstream liv...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.25950

    authors: Skardal A,Devarasetty M,Forsythe S,Atala A,Soker S

    更新日期:2016-09-01 00:00:00

  • Preparation of immobilized alpha-amylase covalently attached to granular polyacrylonitrile.

    abstract::In this report, alpha-Amylase originating from Bacillus subtilis (liquefying type) was immobilized on partially imidoesterized polyacrylonitrile (PAN) by covalent bonding. For the preparation of immobilized alpha-amylase, which has a high activity and high stability to repeated use, the optimum conditions for the prep...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260251212

    authors: Handa T,Hirose A,Akino T,Watanabe K,Tsuchiya H

    更新日期:1983-12-01 00:00:00

  • Mobile phase modifier effects in multimodal cation exchange chromatography.

    abstract::This study examines protein adsorption behavior and the effects of mobile phase modifiers in multimodal chromatographic systems. Chromatography results with a diverse protein library indicate that multimodal and ion exchange resins have markedly different protein binding behavior and selectivity. NMR results corrobora...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.23318

    authors: Holstein MA,Parimal S,McCallum SA,Cramer SM

    更新日期:2012-01-01 00:00:00

  • N-Acyl homoserine lactonase promotes prevention of Erwinia virulence with zwittermicin A-producing strain Bacillus cereus.

    abstract::Zwittermicin A (ZwA), a hybrid polyketide- peptide antibiotic, and N-acyl -homoserine-lactonase (AHL-lactonase), a kind of quorum-quenching enzyme, have the potential to prevent the virulence of Erwinia carotovora, which is a major pathogen of soft rot. The purpose of this study was to combine the two agents in one ho...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.21794

    authors: Zhao C,Zeng H,Yu Z,Sun M

    更新日期:2008-06-15 00:00:00

  • Analysis of metabolic networks of Streptomyces leeuwenhoekii C34 by means of a genome scale model: Prediction of modifications that enhance the production of specialized metabolites.

    abstract::The first genome scale model (GSM) for Streptomyces leeuwenhoekii C34 was developed to study the biosynthesis pathways of specialized metabolites and to find metabolic engineering targets for enhancing their production. The model, iVR1007, consists of 1,722 reactions, 1,463 metabolites, and 1,007 genes, it includes th...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.26598

    authors: Razmilic V,Castro JF,Andrews B,Asenjo JA

    更新日期:2018-07-01 00:00:00

  • Cellobiose hydrolysis using Pichia etchellsii cells immobilized in calcium alginate.

    abstract::The rate of celluose degradation, limited due to the inhibition by cellobiose, can be increased by the hydrolysis of cellobiose to glucose using immobilized beta-glucosidase. Production of beta-glucosidase in four yeasts was studied and a maximum activity of 1.22 IU/mg cells was obtained in cells of Pichia etchellsii ...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260260408

    authors: Jain D,Ghose TK

    更新日期:1984-04-01 00:00:00

  • Biofabrication of antibodies and antigens via IgG-binding domain engineered with activatable pentatyrosine pro-tag.

    abstract::We report the assembly of seven different antibodies (and two antigens) into functional supramolecular structures that are specifically designed to facilitate integration into devices using entirely biologically based bottom-up fabrication. This is enabled by the creation of an engineered IgG-binding domain (HG3T) wit...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.22238

    authors: Wu HC,Shi XW,Tsao CY,Lewandowski AT,Fernandes R,Hung CW,DeShong P,Kobatake E,Valdes JJ,Payne GF,Bentley WE

    更新日期:2009-06-01 00:00:00

  • Effect of metal ion concentration on a biological reactor.

    abstract::Saccharomyces cerevisiae (yeast) cells were employed as a source of alcohol dehydrogenase in the NAD(+)-to-NADH reaction. The cells were immobilized in calcium alginate monofilament fibers and used in a biological reactor. The alginate could not be heat sterilized since temperatures above 80 degrees C caused the polym...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/bit.260360706

    authors: Ibbotson PG,Spedding PL,Otterburn MS

    更新日期:1990-10-05 00:00:00

  • A rapid method for determining kinetic parameters of enzymes exhibiting nonlinear thermal inactivation behavior.

    abstract::A rapid method is developed to analyze the kinetics of thermal inactivation of enzymes that exhibit a nonlinear biphasic log(activity)-time relationship. Thermal destruction experiments on alcohol dehydrogenase from baker's yeast demonstrate the applicability of the method. The method is based on physical consideratio...

    journal_title:Biotechnology and bioengineering

    pub_type: 杂志文章

    doi:10.1002/(SICI)1097-0290(19960105)49:1<106::AID-BIT

    authors: Nath S

    更新日期:1996-01-05 00:00:00