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  • 1.
    Andersson, Henrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Monitoring of troponin release from cardiomyocytes during exposure to toxic substances using surface plasmon resonance biosensing2010In: ANALYTICAL AND BIOANALYTICAL CHEMISTRY, ISSN 1618-2642, Vol. 398, no 3, 1395-1402 p.Article in journal (Refereed)
    Abstract [en]

    Troponin T (TnT) is a useful biomarker for studying drug-induced toxicity effects on cardiac cells. We describe how a surface plasmon resonance (SPR) biosensor was applied to monitor the release of TnT from active HL-1 cardiomyocytes in vitro when exposed to cardiotoxic substances. Two monoclonal human TnT antibodies were compared in the SPR immunosensor to analyse the TnT release. The detection limit of TnT was determined to be 30 ng/ml in a direct assay set-up and to be 10 ng/ml in a sandwich assay format. Exposure of the cardiomyocytes to doxorubicin, troglitazone, quinidine and cobalt chloride for periods of 6 and 24 h gave significant SPR responses, whereas substances with low toxicity showed insignificant effects (ascorbic acid, methotrexate). The SPR results were verified with a validated immunochemiluminescence method which showed a correlation of r(2)=0.790.

  • 2.
    Andersson, Henrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Steel, Daniella
    Cellartis AB, Gothenburg, Sweden .
    Asp, Julia
    University of Gothenburg.
    Dahlenborg, Kerstin
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Jonsson, Marianne
    University of Gothenburg.
    Jeppsson, Anders
    Sahlgrens University Hospital.
    Lindahl, Anders
    University of Gothenburg.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Sartipy, Peter
    Cellartis AB, Gothenburg, Sweden .
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Assaying cardiac biomarkers for toxicity testing using biosensing and cardiomyocytes derived from human embryonic stem cells2010In: JOURNAL OF BIOTECHNOLOGY, ISSN 0168-1656, Vol. 150, no 1, 175-181 p.Article in journal (Refereed)
    Abstract [en]

    Human embryonic stem cell (hESC) derived cardiomyocytes are in the present study being used for testing drug-induced cardiotoxicity in a biosensor set-up. The design of an in vitro testing alternative provides a novel opportunity to surpass previous methods based on rodent cells or cell lines due to its significantly higher toxicological relevance. In this report we demonstrate how hESC-derived cardiomyocytes release detectable levels of two clinically decisive cardiac biomarkers, cardiac troponin T and fatty acid binding protein 3, when the cardiac cells are exposed to the well-known cardioactive drug compound. doxorubicin. The release is monitored by the immuno-biosensor technique surface plasmon resonance, particularly appropriate due to its capacity for parallel and high-throughput analysis in complex media.

  • 3.
    Arding, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Sensory evaluation and quality assessment of an alternative inner coating film in yogurt cartons2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The dairy food industry is continuously striving towards products with higher quality and longer shelf-life available to the customer at low prices. Arla Foods in Linköping, Sweden, is currently investigating the possibilities of changing the material in yogurt packaging containers by replacing the currently used carton with a different and cheaper alternative. A successful switch will give the company an economical advantage without affecting the sensory attributes (smell, taste, sight, and consistency), aroma profile or other important trademarks of the yogurt. This study is designed to examine and compare yogurt that has been stored in different packaging cartons, one coated with a single-layered low-density polyethylene (LDPE) and one coated with a currently used multi-layered ethylene-vinyl alcohol (EVOH).

    The study was based on the analysis and measurement of sensory attributes performed by experts, physical properties in laboratory and chemical composition in GC-FID/MS together with a discriminative test where a group of people would identify any difference between the yogurts. Together, these analyses would provide an explanation about any differences between the packaging materials by connecting physical, chemical and/or sensory characteristics. The collected results would give a better and more comprehensive picture than each analysis would do separately.

    The results from the study show that there is a difference between yogurts stored in LDPE-based containers and yogurts stored in EVOH-based containers and that the product was chemically affected, mainly by the level of oxygen in contact with the food. The overall assessment is that the largest difference was discovered in the taste.

  • 4. Bachinger, T.
    et al.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Physiologically motivated monitoring of fermentation processes by means of an electronic nose2001In: Chemical Engineering & Technology, ISSN 0930-7516, E-ISSN 1521-4125, Vol. 24, no 7, 33-42 p.Article in journal (Refereed)
    Abstract [en]

    An on-line approach of non-invasive monitoring of the physiological changes in fermentation processes is presented. In yeast batch and bacterial fed-batch fermentations it is shown that metabolic state changes can be revealed using an electronic nose. The transient responses of the gas sensors to the changes in the composition of the volatiles emitted from the cell cultures during fermentation are used to retrieve a semi-quantitative representation of the physiological state of the cultures. With the sensor responses of the electronic nose it is shown that physiological variables such as rates of growth, substrate uptake and product formation can be depicted. The non-invasive method thus seems as a pertinent alternative to conventional bioreactor monitoring methods.

  • 5. Bachinger, T.
    et al.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Striedner, G.
    Clementschitsch, F.
    Dürrschmid, E.
    Cserjan-Puschmann, M.
    Doblhoff-Dier, O.
    Bayer, K.
    Non-invasive detection of the metabolic burden on recombinant microorganisms during fermentation processes2001In: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 76, 885-889 p.Article in journal (Refereed)
  • 6. Bachinger, T.
    et al.
    Riese, U.
    Eriksson, R.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Electronic nose for estimation of product concentration in mammalian cell cultivation2000In: Bioprocess engineering (Berlin. Print), ISSN 0178-515X, E-ISSN 1432-0797, Vol. 23, no 6, 637-642 p.Article in journal (Refereed)
    Abstract [en]

    The off-gas composition from perfusion cultivation of a CHO-cell line producing recombinant human blood coagulation Factor VIII is monitored with an electronic nose. It is shown that the electronic nose in combination with an artificial neural network can be used for on-line estimation of the Factor VIII concentration in production-scale cultivations. The obtained prediction error (1s) for the Factor VIII concentration was 1.1 IU/ml. The potential of the electronic nose for estimation of viable cell count is outlined in laboratory-scale Factor VIII cultivations. The obtained prediction error (1s) for the viable cell count was 0.4 ╫ 106 cells/ml. The results show that this non-invasive method is potentially useful for on-line bioprocess monitoring.

  • 7. Bachinger, T.
    et al.
    Riese, U.
    Cell Culture Production, Pharmacia and Upjohn Inc., S-112 87, Stockholm, Sweden.
    Eriksson, R.
    Cell Culture Production, Pharmacia and Upjohn Inc., S-112 87, Stockholm, Sweden.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Monitoring cellular state transitions in a production-scale CHO-cell process using an electronic nose2000In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 76, no 1, 61-71 p.Article in journal (Refereed)
    Abstract [en]

    An electronic nose is used to monitor the bioreactor off-gas composition in perfused cultivations of a CHO-cell line producing recombinant human blood coagulation factor VIII. The applicability of the electronic nose for monitoring cellular state transitions and process control is explained. It is shown that the instrument can reveal characteristic process states related to product and lactate formation, and detect microbial infections in a very early stage of the infection. The visualization of ideal process conditions is realized by using principal component analysis (PCA) and the on-line applicability of this method is outlined. The results illustrate the potential of the electronic nose as on-line sensor for ensuring product and process quality in production-scale bioprocesses. Copyright (C) 2000 Elsevier Science B.V.An electronic nose is used to monitor the bioreactor off-gas composition in perfused cultivations of a CHO-cell line producing recombinant human blood coagulation factor VIII. The applicability of the electronic nose for monitoring cellular state transitions and process control is explained. It is shown that the instrument can reveal characteristic process states related to product and lactate formation, and detect microbial infections in a very early stage of the infection. The visualization of ideal process conditions is realized by using principal component analysis (PCA) and the on-line applicability of this method is outlined. The results illustrate the potential of the electronic nose as on-line sensor for ensuring product and process quality in production-scale bioprocesses.

  • 8. Bachinger, T.
    et al.
    Riese, U.
    Cell Culture Production, Pharmacia AB, S-112 87 Stockholm, Sweden.
    Eriksson, R.K.
    Cell Culture Production, Pharmacia AB, S-112 87 Stockholm, Sweden.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Gas sensor arrays for early detection of infection in mammalian cell culture2002In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 17, no 5, 395-403 p.Article in journal (Refereed)
    Abstract [en]

    The detection of bacterial infections in a mammalian cell culture process is realised using a gas sensor array. In production-scale and laboratory-scale cultivations of a perfused recombinant CHO-cell culture producing human blood coagulation Factor VIII, we show that the gas sensor array identifies bacterial contamination earlier than conventional methods. The sensitivity of the instrument is verified by inoculation of a blank cell culture medium with defined bacterial cell counts. © 2002 Elsevier Science B.V. All rights reserved.

  • 9. Bachinger, Th
    et al.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Searching for process information in the aroma of cell cultures2000In: Trends in Biotechnology, ISSN 0167-7799, E-ISSN 1879-3096, Vol. 18, no 12, 494-500 p.Article in journal (Refereed)
    Abstract [en]

    Aroma emissions from living cells can provide valuable information about the metabolic and physiological condition of those cells. Electronic noses are chemical gas-sensor arrays that use artificial neural network models to evaluate aromas. They can interpret the complex aroma information emitted from cultures of bacteria, yeast cells and animal cells. Potential applications for electronic noses range from medical diagnosis to industrial bioprocessing. Copyright (C) 2000 Elsevier Science Ltd.

  • 10.
    Benselfelt, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Flow Cytometry Sensor System Targeting Escherichia Coli as an Indicator of Faecal Contamination of Water Sources2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Poor water quality is a global health concern affecting one billion people around the world. It is important to monitor water sources in order to maintain the quality of our drinking water and to avoid disease outbreaks. Targeting Escherichia coli as a faecal indicator is a widely used procedure, but the current methods are time consuming and not adequate to prevent spreading of faecal influence.

     

    This Master thesis demonstrates the development of a near infrared fluorescence flow cytometer sensor system targeting Escherichia coli, using fluorescently labeled chicken IgY antibodies. The near infrared light was chosen to avoid fluorescence from blue-green algae that are present in the water source.

     

    The hardware was developed with a 785  nm laser line to detect Alexa Fluor 790 labeled antibodies, using a photomultiplier tube or two different CMOS cameras. The antibodies were labeled using a commercial labeling kit, and evaluated using antibody binding assays and the developed hardware.

     

    The IgY antibodies were successfully labeled with Alexa Fluor 790 and the function was maintained after the labeling process. The result demonstrates the principles of the sensor system and how it solved to the problem with fluorescence from blue-green algae. An aperture was used to overcome the suboptimal laser and filter setup, and to increase the sensitivity of the system. However, only a small fraction of the cells could be detected, due to challenges with the focal depth and loss of sensitivity in the photomultiplier tube at near infrared wavelengths. Further development is required to create a working product.

  • 11.
    Berg, Sofia
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Biology . Linköping University, The Institute of Technology.
    Christianou, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Jonsson, Tomas
    Research centre for Systems Biology, Univ. of Skövde, Sweden.
    Ebenman, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Biology . Linköping University, The Institute of Technology.
    Using sensitivity analysis to identify keystone species and keystone links in size-based food webs2011In: Oikos, ISSN 0030-1299, E-ISSN 1600-0706, Vol. 120, no 4, 510-519 p.Article in journal (Refereed)
    Abstract [en]

    Human-induced alterations in the birth and mortality rates of species and in the strength of interactions within and between species can lead to changes in the structure and resilience of ecological communities. Recent research points to the importance of considering the distribution of body sizes of species when exploring the response of communities to such perturbations. Here, we present a new size-based approach for assessing the sensitivity and elasticity of community structure (species equilibrium abundances) and resilience (rate of return to equilibrium) to changes in the intrinsic growth rate of species and in the strengths of species interactions. We apply this approach on two natural systems, the pelagic communities of the Baltic Sea and Lake Vättern, to illustrate how it can be used to identify potential keystone species and keystone links. We find that the keystone status of a species is closely linked to its body size. The analysis also suggests that communities are structurally and dynamically more sensitive to changes in the effects of prey on their consumers than in the effects of consumers on their prey. Moreover, we discuss how community sensitivity analysis can be used to study and compare the fragility of communities with different body size distributions by measuring the mean sensitivity or elasticity over all species or all interaction links in a community. We believe that the community sensitivity analysis developed here holds some promise for identifying species and links that are critical for the structural and dynamic robustness of ecological communities.

  • 12.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Exploring the SPR methodology for monitoring of critical attributes in toxicity testing and bioproduction2012Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Analysis of biological components is central in bioprocess monitoring, process control, product quality control and cell based toxicity assaying. One of these themes that is pursued in this thesis is the use of biosensors for monitoring of molecular markers, exploiting the natural selectivity of biomolecules. Another is the use of glycoconjugates to monitor the activity of biomolecules in a flu vaccine process is studied and were the sensor is based on the concept of weak affinity giving fast response time for the sensor.

    A third theme is monitoring of cell cultures used for toxicity testing different protein markers is of interest.

    When developing biosensor surfaces for new antigens commercial preparations of antibodies are often used. In this work we have chosen to look at lactate dehydrogenase (LDH) and describe the preparation and characterisation of antibody used in biosensor surface development.

    The design of a sensor surface is important for the characteristics of a sensor. By binding antibodies in an oriented manner to the surface a better control of the properties of the antibodies is achieved. The demonstrated method also has the advantage of in situ purification and provides a flexible platform for antibody evaluation and sensor development.

    In one sentence this thesis explores the possibility of utilizing recognition elements of a biosensor surface. In particular, surface plasmon resonance (SPR) is used as the primary biosensing tool, however most findings in are relevant for other biosensors.

    Moreover, the thesis approaches existing bioanalytical impediments, such as purity and accessibility of the recognition elements on the sensor surface and preparation strategies to achieve this.

    List of papers
    1. Monitoring of influenza virus hemagglutinin in process samples using weak affinity ligands and surface plasmon resonance
    Open this publication in new window or tab >>Monitoring of influenza virus hemagglutinin in process samples using weak affinity ligands and surface plasmon resonance
    Show others...
    2008 (English)In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 623, 66-75 p.Article in journal (Refereed) Published
    Abstract [en]

    Surface plasmon resonance (SPR) was used to screen the interaction between a variety of affinity ligands and hemagglutinin (HA) from human influenza virus, with the aim of identifying low affinity ligands useful for the development of a rapid bioanalytical sensor. Three sialic acid-based structures and four lectins were evaluated as sensor ligands. The sialic acid-based ligands included a natural sialic acid-containing glycoprotein, human α1-acid glycoprotein (α1-AGP), and two synthetic 6′-sialyllactose-conjugates, with varying degree of substitution. The interaction of HA with the four lectin-based ligands, concanavalin A (Con A), wheat germ agglutinin (WGA), Maackia amurensis lectin (MAL), and Sambucus nigra agglutinin (SNA), showed a wide variation of affinity strengths. Affinity and kinetics data were estimated. Strong affinities were observed for Con A, WGA, α1-AGP, and a 6′-sialyllactose-conjugate with a high substitution degree, and low affinities were observed for MAL and a 6′-sialyllactose-conjugate with low substitution.

    The main objective, to identify a low affinity ligand which could be used for on-line monitoring and product quantification, was met by a 6′-sialyllactose–ovalbumin conjugate that had 0.6 mol ligand per mol carrier protein. The apparent affinity of this ligand was estimated to be 1.5 ± 0.03 μM (KD) on the SPR surface. Vaccine process samples containing HA were analyzed in the range 10–100 μg HA mL−1 and correlated with single-radial immunodiffusion. The coefficient of variation on the same chip was between 0.010 and 0.091.

    Place, publisher, year, edition, pages
    Elsevier, 2008
    Keyword
    Influenza virus hemagglutinin; Affinity ligand; Surface plasmon resonance; Low affinity; Weak affinity
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-44210 (URN)10.1016/j.aca.2008.06.005 (DOI)76040 (Local ID)76040 (Archive number)76040 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. Initial development towards in vitro toxicity assay for lactate dehydrogenase using surface plasmon resonance
    Open this publication in new window or tab >>Initial development towards in vitro toxicity assay for lactate dehydrogenase using surface plasmon resonance
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Work with initial development towards in vitro toxicity assay for lactate dehydrogenase (LDH) using surface plasmon resonance is described. LDH is one of the important versatile biomarkers in in vitro hepatotoxicity. In this report LDH is detected by surface plasmon resonance using antibodies directly immobilized to the sensor surface. The assay is further extended with protein G immobilized to the surface to capture the antibody ligand. This has the advantage of simultaneously and on site purify and orient antibody ligand.

    Keyword
    Lactate dehydrogenase, surface plasmon resonance, in vitro toxicity, biosensor, protein G
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-73409 (URN)
    Available from: 2012-01-03 Created: 2012-01-03 Last updated: 2012-01-03Bibliographically approved
    3. Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips
    Open this publication in new window or tab >>Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips
    2011 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 158, no 1, 265-270 p.Article in journal (Refereed) Published
    Abstract [en]

    A surface plasmon resonance (SPR) sensor chip with immobilized protein G was used for simultaneously capturing, purifying and orienting antibody ligands. The ligands were further stabilized by chemical cross-linking. This procedure of designing the sensor chip improved efficient use of the ligands and could prolong the analytical use. less thanbrgreater than less thanbrgreater thanThe procedure was evaluated on standard dextran-coated sensor chips onto which commercial semi-purified antibodies towards human serum albumin and human troponin where captured and used for analysing their antigens. less thanbrgreater than less thanbrgreater thanThe procedure demonstrates a general design approach for presenting the biorecognition element on a biosensor surface which enhances sensitivity, stability and selectivity at the same time as an impure ligand is purified.

    Place, publisher, year, edition, pages
    Elsevier, 2011
    Keyword
    Biosensor, Affinity interaction, SPR, Biacore, Protein G, Sensor chip
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-71770 (URN)10.1016/j.snb.2011.06.017 (DOI)000295500200037 ()
    Note

    Funding Agencies|European Commission|LSHB-CT-2007-037636|

    Available from: 2011-11-04 Created: 2011-11-04 Last updated: 2017-12-08
  • 13.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Microfluidic biosensor systems for cardiotoxicity assaying2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Toxicity screening is an important part of pharmaceutical development and early detection of toxic side effects provide the opportunity for early redesign or termination of unfeasible projects. Today toxicity testing is relying on experiments on animals. Ethical concerns, high costs and problems with interspecies variability in animal experiments have introduced incentives for cell-based toxicity assays. The recent development of stem cell technology have raised the hope for toxicity testing with higher predictivity that can reduce the amount of animals sacrificed, increase the patient safety and reduce the costs in pharmaceutical development.

    Cell development and behavior is to a large extent dependent on the microenvironment. Microfluidic techniques can be used to build small-sized structures that provide the opportunity to introduce a high degree of control of the cell culture environment with features in cell sizes. In this thesis is demonstrated two different methods for infusing cells into microfluidic cell culture devices using either cells clustered in cardiac bodies during differentiation or cells pre-seeded in microporous carriers prior to infusion.

    Microfluidic cell culture devices are well suited for optical  evaluation. Demonstrated in this thesis is fluorescent staining in combination with confocal microscopy as well as automated imaging with evaluation of beating frequency of cardiomyocyte cell clusters can be used to assess toxicity of cells cultured in microfluidic devices.

    Biosensors use biological recognition elements to measure the presence of a chemical substance, for example low concentrations of biomarkers secreted by cells in a toxicity assay. Especially capacitive biosensors have shown very low limit of detection. In addition, protein G is demonstrated as an affinity ligand to capture IgG antibodies used as recognition element in a biosensor application or used for antibody screening.

    List of papers
    1. Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips
    Open this publication in new window or tab >>Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips
    2011 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 158, no 1, 265-270 p.Article in journal (Refereed) Published
    Abstract [en]

    A surface plasmon resonance (SPR) sensor chip with immobilized protein G was used for simultaneously capturing, purifying and orienting antibody ligands. The ligands were further stabilized by chemical cross-linking. This procedure of designing the sensor chip improved efficient use of the ligands and could prolong the analytical use. less thanbrgreater than less thanbrgreater thanThe procedure was evaluated on standard dextran-coated sensor chips onto which commercial semi-purified antibodies towards human serum albumin and human troponin where captured and used for analysing their antigens. less thanbrgreater than less thanbrgreater thanThe procedure demonstrates a general design approach for presenting the biorecognition element on a biosensor surface which enhances sensitivity, stability and selectivity at the same time as an impure ligand is purified.

    Place, publisher, year, edition, pages
    Elsevier, 2011
    Keyword
    Biosensor, Affinity interaction, SPR, Biacore, Protein G, Sensor chip
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-71770 (URN)10.1016/j.snb.2011.06.017 (DOI)000295500200037 ()
    Note

    Funding Agencies|European Commission|LSHB-CT-2007-037636|

    Available from: 2011-11-04 Created: 2011-11-04 Last updated: 2017-12-08
    2. Macroporous microcarriers for introducing cells into a microfluidic chip
    Open this publication in new window or tab >>Macroporous microcarriers for introducing cells into a microfluidic chip
    2014 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 14, no 18, 3502-3504 p.Article in journal (Refereed) Published
    Abstract [en]

    Macroporous gelatin beads (CultiSpher™ microcarriers) provide a convenient method for rapidly and reliably introducing cells cultured ex situ into a microfluidic device, where the spheres create a 3D environment for continued cell proliferation. We demonstrate the usefulness of this technique with a proof-of-concept viability analysis of cardiac cells after treatment with doxorubicin. © 2014 the Partner Organisations.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2014
    National Category
    Biological Sciences Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-109971 (URN)10.1039/c4lc00693c (DOI)000340474300008 ()25068539 (PubMedID)2-s2.0-84905837163 (Scopus ID)
    Funder
    Swedish Research Council, 2008-7537 2011-6404
    Note

    Acknowledgements

    The primary embryonic cardiomyocytes were provided byJordi Altimiras, Department of Physics, Chemistry andBiology, Linköping University. The authors thank the SwedishResearch Council (Vetenskapsrådet) for fundingviagrants 2008-7537 and 2011-6404

    Available from: 2014-08-29 Created: 2014-08-29 Last updated: 2017-12-05Bibliographically approved
    3. Capacitive biosensor for detection of toxicity biomarkers
    Open this publication in new window or tab >>Capacitive biosensor for detection of toxicity biomarkers
    2015 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Microfluidic devices are rapidly gaining importance for in vitro toxicity testing. Biomarker detection in microfluidic assays are however challenging due to small sample sizes and low analyte concentration. Capacitive electrochemical biosensors have been reported to have high sensitivity and properties that are amenable for implementation into microfluidic devices.

    In this work a biosensor application for troponin T (TnT) is presented. The sensor showed linear response to analyte over five orders of magnitude with the lowest detectable signal at 10-13 M. The sensor proved to be able to detect TnT spiked in cell culture media at concentrations relevant for cell cultures.

    National Category
    Biological Sciences Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-118293 (URN)
    Available from: 2015-05-26 Created: 2015-05-26 Last updated: 2015-05-26
    4. Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging
    Open this publication in new window or tab >>Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging
    Show others...
    2015 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 15, no 15, 3242-3249 p.Article in journal (Refereed) Published
    Abstract [en]

    Beating in vivo-like human cardiac bodies (CBs) were used in a microfluidic device for testing cardiotoxicity. The CBs, cardiomyocyte cell clusters derived from induced pluripotent stem cells, exhibited typical structural and functional properties of the native human myocardium. The CBs were captured in niches along a perfusion channel in the device. Video imaging was utilized for automatic monitoring of the beating frequency of each individual CB. The device allowed assessment of cardiotoxic effects on the 3D clustered cardiomyocytes from the drug substances doxorubicin, verapamil and quinidine. Beating frequency data recorded over a period of 6 hours are presented and compared to literature data. The results indicate that this microfluidic setup with imaging of CB characteristics provides a new opportunity for label-free, non-invasive investigation of toxic effects in a 3D microenvironment.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2015
    National Category
    Biological Sciences Physical Sciences
    Identifiers
    urn:nbn:se:liu:diva-118294 (URN)10.1039/c5lc00449g (DOI)000358022900017 ()
    Available from: 2015-05-26 Created: 2015-05-26 Last updated: 2017-12-04Bibliographically approved
  • 14.
    Bergström, Gunnar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Christoffersson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Schwanke, Kristin
    Hannover Medical School, Leibniz Research Laboratories for Biotechnology and Artificial Organs -LEBAO-, Hannover, Germany.
    Zweigerdt, Robert
    Hannover Medical School, Leibniz Research Laboratories for Biotechnology and Artificial Organs -LEBAO-, Hannover, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging2015In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 15, no 15, 3242-3249 p.Article in journal (Refereed)
    Abstract [en]

    Beating in vivo-like human cardiac bodies (CBs) were used in a microfluidic device for testing cardiotoxicity. The CBs, cardiomyocyte cell clusters derived from induced pluripotent stem cells, exhibited typical structural and functional properties of the native human myocardium. The CBs were captured in niches along a perfusion channel in the device. Video imaging was utilized for automatic monitoring of the beating frequency of each individual CB. The device allowed assessment of cardiotoxic effects on the 3D clustered cardiomyocytes from the drug substances doxorubicin, verapamil and quinidine. Beating frequency data recorded over a period of 6 hours are presented and compared to literature data. The results indicate that this microfluidic setup with imaging of CB characteristics provides a new opportunity for label-free, non-invasive investigation of toxic effects in a 3D microenvironment.

  • 15.
    Bergström, Gunnar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Kuusk, Ave
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Capacitive biosensor for detection of toxicity biomarkers2015Manuscript (preprint) (Other academic)
    Abstract [en]

    Microfluidic devices are rapidly gaining importance for in vitro toxicity testing. Biomarker detection in microfluidic assays are however challenging due to small sample sizes and low analyte concentration. Capacitive electrochemical biosensors have been reported to have high sensitivity and properties that are amenable for implementation into microfluidic devices.

    In this work a biosensor application for troponin T (TnT) is presented. The sensor showed linear response to analyte over five orders of magnitude with the lowest detectable signal at 10-13 M. The sensor proved to be able to detect TnT spiked in cell culture media at concentrations relevant for cell cultures.

  • 16.
    Bergström, Gunnar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Initial development towards in vitro toxicity assay for lactate dehydrogenase using surface plasmon resonanceManuscript (preprint) (Other academic)
    Abstract [en]

    Work with initial development towards in vitro toxicity assay for lactate dehydrogenase (LDH) using surface plasmon resonance is described. LDH is one of the important versatile biomarkers in in vitro hepatotoxicity. In this report LDH is detected by surface plasmon resonance using antibodies directly immobilized to the sensor surface. The assay is further extended with protein G immobilized to the surface to capture the antibody ligand. This has the advantage of simultaneously and on site purify and orient antibody ligand.

  • 17.
    Bergström, Gunnar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips2011In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 158, no 1, 265-270 p.Article in journal (Refereed)
    Abstract [en]

    A surface plasmon resonance (SPR) sensor chip with immobilized protein G was used for simultaneously capturing, purifying and orienting antibody ligands. The ligands were further stabilized by chemical cross-linking. This procedure of designing the sensor chip improved efficient use of the ligands and could prolong the analytical use. less thanbrgreater than less thanbrgreater thanThe procedure was evaluated on standard dextran-coated sensor chips onto which commercial semi-purified antibodies towards human serum albumin and human troponin where captured and used for analysing their antigens. less thanbrgreater than less thanbrgreater thanThe procedure demonstrates a general design approach for presenting the biorecognition element on a biosensor surface which enhances sensitivity, stability and selectivity at the same time as an impure ligand is purified.

  • 18.
    Bergström, Gunnar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, K.
    Percell Biolytica AB, Åstorp, Sweden.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Robinson, Nathaniel D
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, The Institute of Technology.
    Macroporous microcarriers for introducing cells into a microfluidic chip2014In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 14, no 18, 3502-3504 p.Article in journal (Refereed)
    Abstract [en]

    Macroporous gelatin beads (CultiSpher™ microcarriers) provide a convenient method for rapidly and reliably introducing cells cultured ex situ into a microfluidic device, where the spheres create a 3D environment for continued cell proliferation. We demonstrate the usefulness of this technique with a proof-of-concept viability analysis of cardiac cells after treatment with doxorubicin. © 2014 the Partner Organisations.

  • 19.
    Bisson, Isabelle
    et al.
    Guys Hospital, England.
    Green, Emma
    Guys Hospital, England.
    Sharpe, Michaela
    Guys Hospital, England.
    Herbert, Chris
    Guys Hospital, England.
    Hyllner, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology. Guys Hospital, England.
    Mount, Natalie
    Guys Hospital, England.
    Landscape of current and emerging cell therapy clinical trials in the UK: current status, comparison to global trends and future perspectives2015In: Regenerative Medicine, ISSN 1746-0751, E-ISSN 1746-076X, Vol. 10, no 2, 169-179 p.Article in journal (Refereed)
    Abstract [en]

    Cell Therapy Clinical Trial and Preclinical Research databases have been established by the Cell Therapy Catapult to document current and future cell therapy clinical trials in the UK. We identified 41 ongoing trials in April 2014, an increase of seven trials from April 2013. In addition, we identified 45 late-stage preclinical research projects. The majority of the clinical trials are early phase, primarily led by academic groups. The leading therapeutic areas are cancer, cardiology and neurology. The trends in the UK are also seen globally. As the field matures, more later phase and commercial studies will emerge and the challenges will likely evolve into how to manufacture sufficient cell quantities, manage complex logistics for multi-center trials and control cost.

  • 20.
    Borestrom, Cecilia
    et al.
    University of Gothenburg, Sweden .
    Simonsson, Stina
    University of Gothenburg, Sweden .
    Enochson, Lars
    University of Gothenburg, Sweden .
    Bigdeli, Narmin
    University of Gothenburg, Sweden .
    Brantsing, Camilla
    University of Gothenburg, Sweden .
    Ellerstrom, Catharina
    Cellectis Biores, Sweden .
    Hyllner, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Lindahl, Anders
    University of Gothenburg, Sweden .
    Footprint-Free Human Induced Pluripotent Stem Cells From Articular Cartilage With Redifferentiation Capacity: A First Step Toward a Clinical-Grade Cell Source2014In: STEM CELLS TRANSLATIONAL MEDICINE, ISSN 2157-6564, Vol. 3, no 4, 433-447 p.Article in journal (Refereed)
    Abstract [en]

    Human induced pluripotent stem cells (iPSCs) are potential cell sources for regenerative medicine; however, clinical applications of iPSCs are restricted because of undesired genomic modifications associated with most reprogramming protocols. We show, for the first time, that chondrocytes from autologous chondrocyte implantation (Ad) donors can be efficiently reprogrammed into iPSCs using a nonintegrating method based on mRNA delivery, resulting in footprint-free iPSCs (no genome-sequence modifications), devoid of viral factors or remaining reprogramming molecules. The search for universal allogeneic cell sources for the ACI regenerative treatment has been difficult because making chondrocytes with high matrix-forming capacity from pluripotent human embryonic stem cells has proven challenging and human mesenchymal stem cells have a predisposition to form hypertrophic cartilage and bone. We show that chondrocyte-derived iPSCs can be redifferentiated in vitro into cartilage matrix-producing cells better than fibroblast-derived iPSCs and on par with the donor chondrocytes, suggesting the existence of a differentiation bias toward the somatic cell origin and making chondrocyte-derived iPSCs a promising candidate universal cell source for ACI. Whole-genome single nucleotide polymorphism array and karyotyping were used to verify the genomic integrity and stability of the established iPSC lines. Our results suggest that RNA-based technology eliminates the risk of genomic integrations or aberrations, an important step toward a clinical-grade cell source for regenerative medicine such as treatment of cartilage defects and osteoarthritis.

  • 21.
    Bracewell, Daniel
    et al.
    UCL.
    V Gernaey, Krist
    Technical University of Denmark.
    Glassey, Jarka
    University of Newcastle.
    C Hass, Volker
    University of Applied Science, Bremen, Germany .
    Heinzle, Elmar
    University of Saarland.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Olsson, Ing-Marie
    MKS Umetrics AB.
    Racher, Andy
    Lonza Biol Inc.
    Staby, Arne
    Novo Nordisk AS.
    Titchener-Hooker, Nigel
    UCL.
    Report and recommendation of a workshop on education and training for measurement, monitoring, modelling and control ((MC)-C-3) in biochemical engineering2010In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 5, no 4, 359-367 p.Article in journal (Other academic)
  • 22. Brandgård, J.
    et al.
    Nordberg, Å.
    Schnürer, A.
    Sundh, I.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Mathisen, B.
    Monitoring growth of the methanogenic archaea Methanobacterium formicicum using an electronic nose2001In: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 23, no 4, 241-248 p.Article in journal (Refereed)
    Abstract [en]

    Growth of the methanogenic archaea, Methanobacterium formicicum, in pure culture was monitored by analysing samples from the gas phase with an array of chemical gas sensors (an 'electronic nose'). Analyses of the methane and protein formation rates were used as independent parameters of growth, and the data obtained from the electronic nose were evaluated using principal component analysis (PCA). We found that different growth phases can be distinguished with the electronic nose followed by PCA evaluation. The fast response of the sensors in combination with the high correlations with other parameters measuring growth show that the electronic nose can be a useful tool to rapidly determine methanogenic growth.

  • 23.
    Brink, Mattias
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Skoglund, Anders
    Iggesund Paperboard AB.
    On-line predictions of the aspen fibre and birch bark content in unbleached hardwood pulp, using NIR spectroscopy and multivariate data analysis2010In: CHEMOMETRICS AND INTELLIGENT LABORATORY SYSTEMS, ISSN 0169-7439, Vol. 103, no 1, 53-58 p.Article in journal (Refereed)
    Abstract [en]

    An on-line fibre-based near-infrared (NIR) spectrometric analyser was adapted for on-site process analysis at an integrated paperboard mill. The analyser uses multivariate techniques for the quantitative predication of the aspen fibre (aspen) and the birch bark contents of sheets of unbleached hardwood pulp. The NIR analyser is a prototype constructed from standard NIR components. The spectroscopic data was processed by using principal component analysis (PCA) and partial least square (PLS) regression. Three sample sets were collected from three experimental designs, each composed of known pulp contents of birch, aspen and birch bark. Sets I and 2 were used for model calibration and set 3 was used to validate the models. The PLS model that produced the best predictions gave an error of prediction (RMSEP) of 13% for aspen and less than 2% for birch bark. Eight components resulted in an (RX)-X-2 of 99.3%, (RY)-Y-2 of 99.6%. and Q(2) of 95.3%. For additional validation of aspen, three unbleached hardwood samples from the mills production were calculated to lie between -7% and +6%, regarding to the PIS model. When vessel cells were counted under a light microscope a value for the aspen content of 4.7% was obtained. The predictive models evaluated were suitable for quality assessments rather than quantitative determination.

  • 24.
    Bruening, Simone
    et al.
    University of Appl Science Bremen, Germany.
    Gerlach, Inga
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. University of Appl Science Bremen, Germany.
    Poertner, Ralf
    Hamburg University of Technology, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Hass, Volker C.
    Furtwangen University, Germany.
    Modeling Suspension Cultures of Microbial and Mammalian Cells with an Adaptable Six-Compartment Model2017In: Chemical Engineering & Technology, ISSN 0930-7516, E-ISSN 1521-4125, Vol. 40, no 5, 956-966 p.Article in journal (Refereed)
    Abstract [en]

    Process models can be used for model-based control strategies, but model development is a time-consuming and laborious task. To reduce the modeling effort, a new structured compartment model was developed, which may easily be adapted to different cultivation processes. The proposed six-compartment model was used to describe the time courses of cultivations of bacteria, yeast, fungi, and mammalian cell lines, namely, Escherichia coli,Lactobacillus delbrueckii, Saccharomyces cerevisiae, Cyathus striatus, and a hybridoma mammalian cell line. The model can describe the time courses of important state variables and can be adapted to the cultivation processes by parameterization. This reduces the modeling effort for a new process significantly.

  • 25.
    C Stummann, Tina C
    et al.
    JRC.
    Beilmann, Mario
    Boehringer Ingelheim Pharma GmbH & Co KG.
    Duker, Goran
    AstraZeneca R&D.
    Dumotier, Berengere
    Novartis Institute Biomed Research.
    Fredriksson, J Magnus
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Jones, Robin L
    Royal Marsden Hospital.
    Hasiwa, Marina
    JRC.
    Kang, Y James
    University of Louisville.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Meyer, Thomas
    Multi Channel Syst MCS GmbH.
    Minotti, Giorgio
    University G dAnnunzio.
    Valentin, Y Jean-Pierre
    AstraZeneca.
    Zuenkler, Bernd J
    Federal Institute Drugs & Medical Devices.
    Bremer, Susanne
    JRC.
    Report and Recommendations of the Workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity2009In: CARDIOVASCULAR TOXICOLOGY, ISSN 1530-7905, Vol. 9, no 3, 107-125 p.Article, review/survey (Other academic)
    Abstract [en]

    Cardiotoxicity is among the leading reasons for drug attrition and is therefore a core subject in non-clinical and clinical safety testing of new drugs. European Centre for the Validation of Alternative Methods held in March 2008 a workshop on "Alternative Methods for Drug-induced Cardiotoxicity" in order to promote acceptance of alternative methods reducing, refining or replacing the use of laboratory animals in this field. This review reports the outcome of the workshop. The participants identified the major clinical manifestations, which are sensitive to conventional drugs, to be arrhythmias, contractility toxicity, ischaemia toxicity, secondary cardiotoxicity and valve toxicity. They gave an overview of the current use of alternative tests in cardiac safety assessments. Moreover, they elaborated on new cardiotoxicological endpoints for which alternative tests can have an impact and provided recommendations on how to cover them.

  • 26.
    Christoffersson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    van Noort, Danny
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Developing organ-on-a-chip concepts using bio-mechatronic design methodology2017In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 9, no 2, 025023Article in journal (Refereed)
    Abstract [en]

    Mechatronic design is an engineering methodology for conceiving, configuring and optimising the design of a technical device or product to the needs and requirements of the final user. In this article, we show how the basic principles of this methodology can be exploited for in vitro cell cultures-often referred to as organ-on-a-chip devices. Due to the key role of the biological cells, we have introduced the term bio-mechatronic design, to highlight the complexity of designing a system that should integrate biology, mechanics and electronics in the same device structure. The strength of the mechatronic design is to match the needs of the potential users to a systematic evaluation of overall functional design alternative. It may be especially attractive for organs-on-chips where biological constituents such as cells and tissues in 3D settings and in a fluidic environment should be compared, screened and selected. Through this approach, design solutions ranked to customer needs are generated according to specified criteria, thereby defining the key constraints of the fabrication. As an example, the bio-mechatronic methodology is applied to a liver-on-a-chip based on information extrapolated from previous theoretical and experimental knowledge. It is concluded that the methodology can generate new fabrication solutions for devices, as well as efficient guidelines for refining the design and fabrication of many of todays organ-on-a-chip devices.

    The full text will be freely available from 2018-05-26 14:30
  • 27. Cimander, C.
    et al.
    Bachinger, T.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Assessment of the performance of a fed-batch cultivation from the preculture quality using an electronic nose2002In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 18, no 2, 380-386 p.Article in journal (Refereed)
    Abstract [en]

    An electronic nose, a gas-phase multisensor system, was used to monitor precultivations of a recombinant tryptophan-producing Escherichia coli strain. The electronic nose signals showed a high correlation toward the main stages of the precultivations, namely, exponential growth, oxygen-limited growth, and glucose depletion. Principal component analysis (PCA) of the electronic nose signals was performed and shown to be useful for monitoring preculture progression. More importantly, PCA also allowed a qualitative assessment of the preculture performance during subsequent fed-batch cultivations. The electronic nose signals from the precultures showed, furthermore, a high correlation to the time of phosphate limitation and the tryptophan yield coefficient of the subsequent fed-batch cultivations, which allowed an accurate prediction of these process variables using partial least squares (PLS). The results demonstrate on data from 12 cultivations how the electronic nose can be a useful tool for the assessment of inoculum quality, thereby providing means of reducing batch-to-batch variation and increasing the productivity of bioprocesses.

  • 28. Cimander, C.
    et al.
    Bachinger, T.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Integration of distributed multi-analyzer monitoring and control in bioprocessing based on a real-time expert system2003In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 103, no 3, 237-248 p.Article in journal (Refereed)
    Abstract [en]

    A computer system solution for integration of a distributed bioreactor monitoring and control instrumentation on the laboratory scale is described. Bioreactors equipped with on-line analyzers for mass spectrometry, near-infrared spectroscopy, electrochemical probes and multi-array gas sensors and their respective software were networked through a real-time expert systems platform. The system allowed data transmission of more than 1800 different signals from the instrumentation, including signals from gas sensors, electrodes, spectrometer detectors, balances, flowmeters, etc., and were used for processing and carrying out a number of computational tasks such as partial least-square regression, principal component analysis, artificial neural network modelling, heuristic decision-making and adaptive control. The system was demonstrated on different cultivations/fermentations which illustrated sensor fusion control, multivariate statistical process monitoring, adaptive glucose control and adaptive multivariate control. The performance of these examples showed high operational stability and reliable function and meet typical requirements for production safety and quality. © 2003 Elsevier B.V. All rights reserved.

  • 29. Cimander, C.
    et al.
    Carlsson, M.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Sensor fusion for on-line monitoring of yoghurt fermentation2002In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 99, no 3, 237-248 p.Article in journal (Refereed)
    Abstract [en]

    Measurement data from an electronic nose (EN), a near-infrared spectrometer (NIRS) and standard bioreactor probes were used to follow the course of lab-scale yoghurt fermentation. The sensor signals were fused using a cascade neural network: a primary network predicted quantitative process variables, including lactose, galactose and lactate, a secondary network predicted a qualitative process state variable describing critical process phases, such as the onset of coagulation or the harvest time. Although the accuracy of the neural network prediction was acceptable and comparable with the off-line reference assay, its stability and performance were significantly improved by correction of faulty data. The results demonstrate that on-line sensor fusion with the chosen analyzers improves monitoring and quality control of yoghurt fermentation with implications to other fermentation processes. ⌐ 2002 Elsevier Science B.V. All rights reserved.

  • 30. Cimander, C
    et al.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Bioprocess control from a multivariate process trajectory2004In: Bioprocess and biosystems engineering (Print), ISSN 1615-7591, E-ISSN 1615-7605, Vol. 26, no 6, 401-411 p.Article in journal (Refereed)
    Abstract [en]

    A multivariate bioprocess control approach, capable of tracking a pre-set process trajectory correlated to the biomass or product concentration in the bioprocess is described. The trajectory was either a latent variable derived from multivariate statistical process monitoring (MSPC) based on partial least squares (PLS) modeling, or the absolute value of the process variable. In the control algorithm the substrate feed pump rate was calculated from on-line analyzer data. The only parameters needed were the substrate feed concentration and the substrate yield of the growth-limiting substrate. On-line near-infrared spectroscopy data were used to demonstrate the performance of the control algorithm on an Escherichia coli fed-batch cultivation for tryptophan production. The controller showed good ability to track a defined biomass trajectory during varying process dynamics. The robustness of the control was high, despite significant external disturbances on the cultivation and control parameters.

  • 31. Cimander, C.
    et al.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Online monitoring of a bioprocess based on a multi-analyser system and multivariate statistical process modelling2002In: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 77, no 10, 1157-1168 p.Article in journal (Refereed)
    Abstract [en]

    Multivariate statistical process control (MSPC) was for the first time applied to analyse data from a bioprocess on-line multi-analyser system consisting of an electronic nose (EN), a near-infrared spectroscope (NIRS), a mass spectrometer (MS) and standard bioreactor probes. One hundred and fifty sensor signals from the electronic nose, 1050 wavelength signals from the NIRS, carbon dioxide evolution rate calculated from mass spectrometer signals and standard bioreactor data (eg amount of substrate fed) were interrogated for their ability to model a bioprocess using MSPC. The models obtained were validated on a recombinant Escherichia coli fed-batch process for tryptophan production. Limiting trajectories were defined in the MSPC models for warning, action, and process experience with respect to biomass and tryptophan concentrations. The results showed the capacity and robustness of MSPC models for monitoring with multi-analysers and allowed a comparison of the different analysers' suitability for this kind of data processing. Furthermore, the results demonstrate that MSPC models provide a functional and versatile framework for coping with large information flows and are also suited to a variety of other bioprocessing monitoring and control tasks. ⌐ 2002 Society of Chemical Industry.

  • 32.
    Cimander, Christian
    et al.
    Novozymes Biopharma AB.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Bioprocess control from a multivariate process trajectory.2004Article in journal (Refereed)
    Abstract [en]

    A multivariate bioprocess control approach, capable of tracking a pre-set process trajectory correlated to the biomass or product concentration in the bioprocess is described. The trajectory was either a latent variable derived from multivariate statistical process monitoring (MSPC) based on partial least squares (PLS) modeling, or the absolute value of the process variable. In the control algorithm the substrate feed pump rate was calculated from on-line analyzer data. The only parameters needed were the substrate feed concentration and the substrate yield of the growth-limiting substrate. On-line near-infrared spectroscopy data were used to demonstrate the performance of the control algorithm on an Escherichia coli fed-batch cultivation for tryptophan production. The controller showed good ability to track a defined biomass trajectory during varying process dynamics. The robustness of the control was high, despite significant external disturbances on the cultivation and control parameters.

  • 33.
    Darkins, Christopher Luke
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology. Loughborough University, UK.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Design of large-scale manufacturing of induced pluripotent stem cell derived cardiomyocytes2014In: Chemical engineering research & design, ISSN 0263-8762, E-ISSN 1744-3563, Vol. 92, no 6, 1142-1152 p.Article in journal (Refereed)
    Abstract [en]

    A new approach for design of large-scale manufacture of stem cell derived cells by using the biomechatronic methodology and computer-aided-design tools is described. The systematic conceptual design methodology for systems composed of active mechanical, electronic and biological components, here referred to as biomechatronics, is combined with the methodology for computer-aided design of bioprocesses. The objective has been to systematically investigate and compare by the combination of the methodologies what are favourable design alternatives in terms of equipment configuration and economic parameters. A demonstration case has been used for the manufacture of cardiomyocytes from human induced pluripotent stem cells. The results show how certain configurations are more favourable than others under given boundary conditions. The study indicates that the approach is possible to apply on other related bio-manufacturing systems.

  • 34.
    de Peppo, G. M.
    et al.
    New York Stem Cell Foundation, New York, NY, USA.
    Thomsen, P.
    University of Gothenburg, Sweden .
    Karlsson, C.
    University of Gothenburg, Sweden .
    Strehl, R.
    BIOMATCELL VINN Excellence Centre Biomat and Cell Ther, Gothenburg, Sweden.
    Lindahl, A.
    BIOMATCELL VINN Excellence Centre Biomat and Cell Ther, Gothenburg, Sweden.
    Hyllner, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Human Progenitor Cells for Bone Engineering Applications2013In: Current molecular medicine, ISSN 1566-5240, E-ISSN 1875-5666, Vol. 13, no 5, 723-734 p.Article in journal (Refereed)
    Abstract [en]

    In this report, the authors review the human skeleton and the increasing burden of bone deficiencies, the limitations encountered with the current treatments and the opportunities provided by the emerging field of cell-based bone engineering. Special emphasis is placed on different sources of human progenitor cells, as well as their pros and cons in relation to their utilization for the large-scale construction of functional bone-engineered substitutes for clinical applications. It is concluded that, human pluripotent stem cells represent a valuable source for the derivation of progenitor cells, which combine the advantages of both embryonic and adult stem cells, and indeed display high potential for the construction of functional substitutes for bone replacement therapies.

  • 35.
    Dong, Jia
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Lübberstedt, Marc
    Urbaniak, Thomas
    Nüssler, Andreas K. N.
    Knobeloch, Daniel
    Gerlach, Jörg C.
    Zeilinger, Katrin
    Evaluation and optimization of hepatocyte culture media factors by design of experiments (DoE) methodology2008In: Cytotechnology (Dordrecht), ISSN 0920-9069, E-ISSN 1573-0778, Vol. 27, 251-261 p.Article in journal (Refereed)
  • 36.
    Duong-Thi, Minh-Dao
    et al.
    Linnaeus Univ, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Bergstrom, Maria
    Linnaeus University, Sweden .
    Fex, Tomas
    University of Gothenburg, Sweden .
    Ohlson, Sten
    Nanyang Technology University, Singapore .
    Comparison of weak affinity chromatography and surface plasmon resonance in determining affinity of small molecules2014In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 461, 57-59 p.Article in journal (Refereed)
    Abstract [en]

    In this study, we compared affinity data from surface plasmon resonance (SPR) and weak affinity chromatography (WAC), two established techniques for determination of weak affinity (mM-mu M) small molecule-protein interactions. In the current comparison, thrombin was used as target protein. In WAC the affinity constant (K-D) was determined from retention times, and in SPR it was determined by Langmuir isotherm fitting of steady-state responses. Results indicate a strong correlation between the two methods (R-2 = 0.995, P less than 0.0001).

  • 37.
    Ekblad, Tobias
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Bergström, Gunnar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Ederth, Thomas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Conlan, Sheelagh L.
    Liu, Yunli
    Zhao, Qi
    DSouza, Fraddry
    Donnelly, GlenT.
    Willemsen, Peter R.
    Pettitt, Michala E.
    Callow, Maureen E.
    Callow, James A.
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Poly(ethylene glycol)-Containing Hydrogel Surfaces for Antifouling Applications in Marine and Freshwater Environments2008In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 9, no 10, 2775-2783 p.Article in journal (Refereed)
    Abstract [en]

       

  • 38.
    Fritzsche, Michael
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Fredriksson, Magnus
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Carlsson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    A cell-based sensor system for toxicity testing using multiwavelength fluorescence spectroscopy2009In: ANALYTICAL BIOCHEMISTRY, ISSN 0003-2697, Vol. 387, no 2, 271-275 p.Article in journal (Refereed)
    Abstract [en]

    A novel cell-based fluorometric sensor system for toxicity monitoring is described, which uses functional spontaneously contracting cardiomyocytes (HL-1 cell line) as the biological recognition element. Based on these highly specialized cells, it has the potential of providing a sensitive and relevant analytical in vitro toxicity testing method. The system was configured by propagating the surface-attaching HL-1 cardiomyocytes in the wells of a 96-well microtiter plate and connecting the plate via an optical fiber to a fluorescence spectrometer capable of excitation-emission matrix scanning. The fluorescence data were analyzed using a conventional spectral analysis software program. The performance of the system for detection of general cytotoxicity to the cells was evaluated using three well-known drugs: verapamil, quinidine, and acetaminophen. The dose-response curves were assessed and the EC50 values were determined (0.10 +/- 0.007, 0.23 +/- 0.025, and 12.32 +/- 2.40 mM, respectively). Comparison with in vitro and in vivo reference data for the drugs showed good correlations, suggesting that this cell-based sensor system Could be a useful tool in pharmacological in vitro drug testing.

  • 39.
    Fritzsche, Michael
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Fritzsche, Joachim
    University of Gothenburg, Sweden .
    Tegenfeldt, Jonas O.
    Lund University, Sweden .
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    A highly UV-transparent fused silica biochip for sensitive hepatotoxicity testing by autofluorescence2014In: BioChip Journal, ISSN 1976-0280, Vol. 8, no 2, 115-121 p.Article in journal (Refereed)
    Abstract [en]

    Fabrication and application of a non-fluorescent and UV-transparent microfluidic biochip in fused silica that allows sensitive autofluorescence detection are described. The biochip is particularly useful in cell-based assays where the most informative autofluorescence signals from the cells reside in the ultraviolet spectral range and where plastic labware materials commonly used in cell culture work severely disturb such measurements. In this study the fused silica biochip was used for measuring intrinsic autofluorescence from liver cells in order to assess hepatotoxic effects of drugs. The assessment assay was carried out with the human liver cell line HepG2 under perfusion conditions in the microfluidics of the biochip. The autofluorescence from the.liver cells exposed to quinidine was readily recorded without background disturbance and correlated well with reference toxicity data.

  • 40.
    Fritzsche, Michael
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Fluorescent cell-based sensing approaches for toxicity testing2010In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 398, no 1, 181-191 p.Article, review/survey (Refereed)
    Abstract [en]

    Fluorimetric cell-based sensing methods have attracted increasing interest in toxicity testing of pharmaceuticals, pathogens, environmental pollutants, and other chemicals. The objective of this review is to summarise the variety of approaches reported up to now and to present recent developments in this area. The different approaches are described in relation to their underlying mechanism and, especially, to the role of the fluorophore involved. The methods discussed include the use of fluorescent or fluorogenic indicators, fluorescence-based testing for membrane integrity, approaches based on fluorescence labelling, inducible fluorescent protein expression, and analysis of cellular autofluorescence. Several of these approaches have been shown to be advantageous in comparison with non-fluorescence methods and have potential in high-throughput screening, for example in drug discovery and safety pharmacology.

  • 41.
    Gerlach, Inga
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Operator Training Simulators towards Industrial Biotechnology2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biotechnological processes are carried out by applying advanced and demanding process strategies. Thus, fundamental understanding and knowledge about the applied microorganism is required to achieve high productivity and profitability. Therefore, computer-based simulation has been integrated into training methodologies for supplementing and expanding academic education and industrial operator training, in order to provide more effective as well as cost- and time-efficient training.

    Operator training simulators (OTS) are computer-based training tools that represent the real laboratory or plant within an interactive, virtual environment. Trainees can learn about cause-and-effect relationships during the virtual process to improve process understanding. Also, trainees and operators get the opportunity to develop, maintain and improve their operational skills. The virtual environment allows delayed operational actions and operational faults, as they are not interfering with the real process. Acceleration of the simulation speed makes training more effective. For instance, different procedures such as start-up and shut-down can be trained in a limited period of training time. Incident and trouble-shooting training can be realized in a safe, virtual environment without exposing the operator to potential risks. So far, OTS are mainly used in military, aviation, medicine and chemical industries. However, there are only a few examples where OTS are applied in biotechnological process applications.

    The aim of this thesis is to expose the benefits of using OTS for biotechnological process applications in academic education and industrial operator training. For this purpose, the feasibility of developing and applying OTS was investigated and discussed. Three OTS for the production of bio-ethanol and recombinant protein production were developed in order to investigate the benefits and their requirements as well as to assess the training effectiveness of these. To visualize the technical system including equipment and distributed control system (DCS), graphical user interfaces (GUIs) were designed, allowing the user to interact with the simulator. Mathematical models were developed and implemented in the OTS to ensure dynamic simulation of the process, where cause-and-effect relationships are realistically described. The essential part of an OTS for biotechnological process applications is the embedded sub-model which describes the biological production system. It is important that the cell growth behaviour within a bioreactor can be  simulated with sufficient accuracy in order to ensure high training effectiveness.

    In the assessment of the training effectiveness in academic education, it was observed that the students’ capability of understanding and controlling complex biotechnological processes improved after OTS training. Students showed better performance in laboratory experiments after participating in OTS pre-training. Moreover, the development of an OTS for an industrial, large-scale bio-ethanol plant illuminates the needs of OTS in biotechnological process industries. It was shown how the conceptual design methodology can be applied in designing an OTS, based on training needs from the industrial user perspective. Also, construction of the OTS including the formulation of mathematical models, the model structure which is embedded in the OTS and the design of the GUIs is covered in this thesis. Whether the use of the OTS will become cost-effective and assure maximum transfer of training depends on long term evaluation. However, application and evaluation of the developed OTS reveal the benefits and training effectiveness of these systems. The findings of the thesis might considerably facilitate the introduction of OTS into academic education and industrial operator training for biotechnological process applications.

    List of papers
    1. Virtual bioreactor cultivation for operator training and simulation: application to ethanol and protein production
    Open this publication in new window or tab >>Virtual bioreactor cultivation for operator training and simulation: application to ethanol and protein production
    2013 (English)In: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 88, no 12, 2159-2168 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUNDDuring recent years several computer-based operator training simulators (OTS) have been developed that are suitable for the virtual training of operators and other professionals. In the field of bioprocess engineering OTS are rarely used. Furthermore, the effects of using training simulators in bioprocess applications have not been evaluated. less thanbrgreater than less thanbrgreater thanRESULTSThe OTS BioProcessTrainer was applied to bioreactor operations for two biological processes, Saccharomyces cerevisiae, for ethanol production, and recombinant Escherichia coli, for production of green fluorescence protein (GFP). The simulator used a multi-shell model platform that described the biological and physical conditions of the bioreactor for the two bioprocess systems. The simulator enabled the user to plan, operate and control the processes in real or accelerated time. The training resulted in improved ability to manage the whole bioreactor procedure for the two processes. less thanbrgreater than less thanbrgreater thanCONCLUSIONThe study showed that the simulator can be an efficient tool for training of operation, optimization and control of bioprocesses. The mathematical model framework of the simulator can be adapted to a variety of industrial bioprocesses. Thus, it appears likely that this type of OTS may serve as a useful resource in industry for training and continuing education of plant operators and engineers.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2013
    Keyword
    operator training simulators, bioprocess models, bioengineering training, educational benefit
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-102072 (URN)10.1002/jctb.4079 (DOI)000326462900005 ()
    Note

    Funding Agencies|Linkoping University||

    Available from: 2013-12-03 Created: 2013-11-29 Last updated: 2017-12-06
    2. Operator training in recombinant protein production using a structured simulator model
    Open this publication in new window or tab >>Operator training in recombinant protein production using a structured simulator model
    Show others...
    2014 (English)In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 177, 53-59 p.Article in journal (Refereed) Published
    Abstract [en]

    Model-based operator training simulators ( OTS) could be powerful tools for virtual training of operational procedures and skills of production personnel in recombinant protein processes. The applied model should describe critical events in the bioprocess so accurately that the operators ability to observe and alertly act upon these events is trained with a high degree of efficiency. In this work is shown how this is accomplished in a structured multi-compartment model for the production of a recombinant protein in an Escherichia coli fed-batch process where in particular the induction procedure, the stress effects and overflow metabolism were highlighted. The structured model was applied on the OTS platform that virtually simulated the operational bioreactor procedures in real or accelerated time. Evaluation of training using the model-based OTS showed that trained groups of operators exhibited improved capability compared with the untrained groups when subsequently performing real laboratory scale cultivations. The results suggest that this model-based OTS may provide a valuable resource for enhancing operator skills in large scale recombinant protein manufacturing.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    Keyword
    Training simulator; Recombinant protein production; Cultivation; Modelling
    National Category
    Bioprocess Technology
    Identifiers
    urn:nbn:se:liu:diva-106511 (URN)10.1016/j.jbiotec.2014.02.022 (DOI)000333811200007 ()2-s2.0-84896536648 (Scopus ID)
    Available from: 2014-05-12 Created: 2014-05-09 Last updated: 2017-12-05Bibliographically approved
    3. Operator training simulation for integrating cultivation and homogenisation in protein production
    Open this publication in new window or tab >>Operator training simulation for integrating cultivation and homogenisation in protein production
    2015 (English)In: Biotechnology Reports, ISSN 2215-017X, Vol. 6, 91-99 p.Article in journal (Refereed) Published
    Abstract [en]

    Operating training simulators (OTS) are virtual simulation tools used for training of process operators in industry in performing procedures and running processes. Based on structured mathematical models of the unit operations of a bioprocess an OTS can train a process operator by visualising changing conditions during the process, allow testing operator actions, testing controller settings, experience unexpected technical problems and getting practice in using prescribed standard procedures for a plant. This work shows the design of an OTS where two sequential steps of a recombinant protein production process, a fed-batch cultivation and a high-pressure homogenisation, are integrated. The OTS was evaluated on a user test group and showed that the OTS promoted and developed their understanding of the process, their capability to identify parameters influencing process efficiency and the skills of operating it.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keyword
    Training simulator, Recombinant protein production, Cultivation, Homogenisation, Integrated process
    National Category
    Bioprocess Technology
    Identifiers
    urn:nbn:se:liu:diva-121472 (URN)10.1016/j.btre.2015.03.002 (DOI)
    Available from: 2015-09-21 Created: 2015-09-21 Last updated: 2015-10-15Bibliographically approved
    4. Conceptual Design of an Operator Training Simulator for a Bio-Ethanol Plant
    Open this publication in new window or tab >>Conceptual Design of an Operator Training Simulator for a Bio-Ethanol Plant
    2015 (English)In: Processes, ISSN 2227-9717, Vol. 3, no 3, 664-683 p.Article in journal (Refereed) Published
    Abstract [en]

    Conceptual design methodology for the configuration and procedural training with an operating training simulator (OTS) in a large-scale plant for commercial bio-ethanol production is described. The aim of the study is to show how the methodology provides a powerful way for finding the best configuration and training structure of the OTS before constructing and implementing the software of the OTS. The OTS principle, i.e., to use a computer-based virtual representation of the real process plant intended for efficient training of process operators, has long since been applied in aviation and process industries for more efficient and flawless operations. By using the conceptual design methodology (sometimes referred to as bio-mechatronics) a variety of OTS configurations with this capacity was generated. The systematic approach of for targeting the users’ (i.e., the plant management and process operators) needs resulted in better understanding and efficiency in training of hands-on skills in operating the plant. The training included general standard operating procedures for running the plant under normal operation conditions with different starch materials, handling of typical frequent disturbances as well as acting in situations not described in the standard operation procedures and applying trouble-shooting

    Place, publisher, year, edition, pages
    MPDI Open Access Publishing, 2015
    Keyword
    Conceptual design; systematic design; bio-refinery; bioprocess engineering; bio-mechatronics
    National Category
    Bioprocess Technology
    Identifiers
    urn:nbn:se:liu:diva-121473 (URN)10.3390/pr3030664 (DOI)
    Available from: 2015-09-21 Created: 2015-09-21 Last updated: 2015-10-15Bibliographically approved
    5. Operator training simulator for an industrial bio-ethanol plant
    Open this publication in new window or tab >>Operator training simulator for an industrial bio-ethanol plant
    2015 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The development of a software-based operator training simulators (OTS) for an industrial bioethanol plant is described. OTS are used in the process industry for training of process operators since several years but few examples are reported for their use in biochemical and biotechnological industry. This study describes the implementation of an OTS at a large-scale bio-plant producing ethanol. The study includes the implementation of models and graphical user interfaces of the OTS as well as the experience of the operator training with it. The OTS encompasses the whole process, i.e. the sections for hydrolysis, fermentation, separation and distillation. The implementation was carried out on the commercial process control software WinErs. The graphical user interfaces, including all essential distributed control systems of the plant, show high fidelity with the real system. Dynamic process models were able to efficiently train operators in running and controlling the process under standard, start-up, shut-down and critical conditions. The models show a sufficient accuracy and robustness at different simulation speeds. Experiences of applying the OTS in the industrial operator environment of the large-scale plant implies that the OTS can be a useful tool for making operator training more time- and cost-efficient in the biochemical and biotechnological industry.

    Keyword
    Training simulator; Recombinant protein production; Cultivation; Modellin
    National Category
    Bioprocess Technology
    Identifiers
    urn:nbn:se:liu:diva-121474 (URN)
    Available from: 2015-09-21 Created: 2015-09-21 Last updated: 2015-09-21Bibliographically approved
  • 42.
    Gerlach, Inga
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology. University of Applied Sciences, Bremen, Germany.
    Bruening, Simone
    University of Applied Sciences, Bremen, Germany .
    Gustavsson, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Hass, Volker C.
    University of Applied Sciences Furtwangen, Villingen-Schwenningen, Germany .
    Operator training in recombinant protein production using a structured simulator model2014In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 177, 53-59 p.Article in journal (Refereed)
    Abstract [en]

    Model-based operator training simulators ( OTS) could be powerful tools for virtual training of operational procedures and skills of production personnel in recombinant protein processes. The applied model should describe critical events in the bioprocess so accurately that the operators ability to observe and alertly act upon these events is trained with a high degree of efficiency. In this work is shown how this is accomplished in a structured multi-compartment model for the production of a recombinant protein in an Escherichia coli fed-batch process where in particular the induction procedure, the stress effects and overflow metabolism were highlighted. The structured model was applied on the OTS platform that virtually simulated the operational bioreactor procedures in real or accelerated time. Evaluation of training using the model-based OTS showed that trained groups of operators exhibited improved capability compared with the untrained groups when subsequently performing real laboratory scale cultivations. The results suggest that this model-based OTS may provide a valuable resource for enhancing operator skills in large scale recombinant protein manufacturing.

  • 43.
    Gerlach, Inga
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology. University of Appl Science Bremen, Germany .
    Hass, Volker C.
    University of Appl Science Furtwangen, Germany .
    Bruening, Simone
    University of Appl Science Bremen, Germany .
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Virtual bioreactor cultivation for operator training and simulation: application to ethanol and protein production2013In: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 88, no 12, 2159-2168 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUNDDuring recent years several computer-based operator training simulators (OTS) have been developed that are suitable for the virtual training of operators and other professionals. In the field of bioprocess engineering OTS are rarely used. Furthermore, the effects of using training simulators in bioprocess applications have not been evaluated. less thanbrgreater than less thanbrgreater thanRESULTSThe OTS BioProcessTrainer was applied to bioreactor operations for two biological processes, Saccharomyces cerevisiae, for ethanol production, and recombinant Escherichia coli, for production of green fluorescence protein (GFP). The simulator used a multi-shell model platform that described the biological and physical conditions of the bioreactor for the two bioprocess systems. The simulator enabled the user to plan, operate and control the processes in real or accelerated time. The training resulted in improved ability to manage the whole bioreactor procedure for the two processes. less thanbrgreater than less thanbrgreater thanCONCLUSIONThe study showed that the simulator can be an efficient tool for training of operation, optimization and control of bioprocesses. The mathematical model framework of the simulator can be adapted to a variety of industrial bioprocesses. Thus, it appears likely that this type of OTS may serve as a useful resource in industry for training and continuing education of plant operators and engineers.

  • 44.
    Gerlach, Inga
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Hass, Volker C.
    Hochschule Furtwangen, University of Applied Sciences Furtwangen, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Conceptual Design of an Operator Training Simulator for a Bio-Ethanol Plant2015In: Processes, ISSN 2227-9717, Vol. 3, no 3, 664-683 p.Article in journal (Refereed)
    Abstract [en]

    Conceptual design methodology for the configuration and procedural training with an operating training simulator (OTS) in a large-scale plant for commercial bio-ethanol production is described. The aim of the study is to show how the methodology provides a powerful way for finding the best configuration and training structure of the OTS before constructing and implementing the software of the OTS. The OTS principle, i.e., to use a computer-based virtual representation of the real process plant intended for efficient training of process operators, has long since been applied in aviation and process industries for more efficient and flawless operations. By using the conceptual design methodology (sometimes referred to as bio-mechatronics) a variety of OTS configurations with this capacity was generated. The systematic approach of for targeting the users’ (i.e., the plant management and process operators) needs resulted in better understanding and efficiency in training of hands-on skills in operating the plant. The training included general standard operating procedures for running the plant under normal operation conditions with different starch materials, handling of typical frequent disturbances as well as acting in situations not described in the standard operation procedures and applying trouble-shooting

  • 45.
    Gerlach, Inga
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering. Department of Environmental- and Bio-Technology, Hochschule Bremen University of Applied Sciences Bremen, Bremen, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Hass, Volker C.
    Faculty of Medical and Life Sciences, Hochschule Furtwangen University of Applied Sciences Furtwangen, Germany.
    Operator training simulation for integrating cultivation and homogenisation in protein production2015In: Biotechnology Reports, ISSN 2215-017X, Vol. 6, 91-99 p.Article in journal (Refereed)
    Abstract [en]

    Operating training simulators (OTS) are virtual simulation tools used for training of process operators in industry in performing procedures and running processes. Based on structured mathematical models of the unit operations of a bioprocess an OTS can train a process operator by visualising changing conditions during the process, allow testing operator actions, testing controller settings, experience unexpected technical problems and getting practice in using prescribed standard procedures for a plant. This work shows the design of an OTS where two sequential steps of a recombinant protein production process, a fed-batch cultivation and a high-pressure homogenisation, are integrated. The OTS was evaluated on a user test group and showed that the OTS promoted and developed their understanding of the process, their capability to identify parameters influencing process efficiency and the skills of operating it.

  • 46.
    Gerlach, Inga
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology. University of Applied Sciences, Bremen, Germany.
    Tholin, Sören
    Lantmännen Reppe AB, Lidköping, Sweden.
    Hass, Volker C.
    Hochschule Furtwangen University of Applied Sciences Furtwangen, Villingen- Schwenningen, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Operator training simulator for an industrial bio-ethanol plant2015Manuscript (preprint) (Other academic)
    Abstract [en]

    The development of a software-based operator training simulators (OTS) for an industrial bioethanol plant is described. OTS are used in the process industry for training of process operators since several years but few examples are reported for their use in biochemical and biotechnological industry. This study describes the implementation of an OTS at a large-scale bio-plant producing ethanol. The study includes the implementation of models and graphical user interfaces of the OTS as well as the experience of the operator training with it. The OTS encompasses the whole process, i.e. the sections for hydrolysis, fermentation, separation and distillation. The implementation was carried out on the commercial process control software WinErs. The graphical user interfaces, including all essential distributed control systems of the plant, show high fidelity with the real system. Dynamic process models were able to efficiently train operators in running and controlling the process under standard, start-up, shut-down and critical conditions. The models show a sufficient accuracy and robustness at different simulation speeds. Experiences of applying the OTS in the industrial operator environment of the large-scale plant implies that the OTS can be a useful tool for making operator training more time- and cost-efficient in the biochemical and biotechnological industry.

  • 47.
    Gernaey, Krist V
    et al.
    Technical University of Denmark, Denmark .
    Baganz, Frank
    UCL, England .
    Franco-Lara, Ezequiel
    TU Braunschweig University, Germany .
    Kensy, Frank
    M2p Labs GmbH, Germany .
    Kruehne, Ulrich
    Technical University of Denmark, Denmark .
    Luebberstedt, Marc
    Charite, Germany .
    Marx, Uwe
    Technical University of Berlin, Germany .
    Palmqvist, Eva
    Novo Nordisk AS, Denmark .
    Schmid, Andreas
    TU Dortmund University, Germany .
    Schubert, Frank
    Stem Cell Syst GmbH, Germany .
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Monitoring and control of microbioreactors: An expert opinion on development needs2012In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 7, no 10, 1308-1314 p.Article in journal (Refereed)
    Abstract [en]

    This perspective article is based on an expert panel review on microbioreactor applications in biochemical and biomedical engineering that was organized by the M3C (measurement, monitoring, modelling and control) Working Group of the European Section of Biochemical Engineering Science (ESBES) in the European Federation of Biotechnology (EFB). The aim of the panel was to provide an updated view on the present status of the subject and to identify critical needs and issues for furthering the successful development of microbioreactor monitoring and control. This will benefit future bioprocess development and in vitro toxicity testing. The article concludes with a set of recommendations for extended use and further development of microbioreactors.

  • 48.
    Glassey, Jarka
    et al.
    Newcastle University.
    Gernaey, Krist V
    Technical University Denmark.
    Clemens, Christoph
    Boehringer Ingelheim Pharma GmbH and Co KG.
    Schulz, Torsten W
    Boehringer Ingelheim Pharma GmbH and Co KG.
    Oliveira, Rui
    FCT University Nova Lisboa.
    Striedner, Gerald
    University Nat Resources and Appl Life Science.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Process analytical technology (PAT) for biopharmaceuticals2011In: BIOTECHNOLOGY JOURNAL, ISSN 1860-6768, Vol. 6, no 4, 369-377 p.Article in journal (Refereed)
    Abstract [en]

    Process analytical technology (PAT), the regulatory initiative for building in quality to pharmaceutical manufacturing, has a great potential for improving biopharmaceutical production. The recommended analytical tools for building in quality, multivariate data analysis, mechanistic modeling, novel models for interpretation of systems biology data and new sensor technologies for cellular states, are instrumental in exploiting this potential. Industrial biopharmaceutical production has gradually become dependent on large-scale processes using sensitive mammalian cell cultures. This further emphasizes the need for improved PAT solutions. We summarize recent progress in this area based on an expert workshop held at the 8(th) European Symposium on Biochemical Engineering Sciences (Bologna, 2010), and highlight new opportunities for exploiting PAT when applied in biopharmaceutical production. We conclude with recommendations for advancing PAT applications in the biopharmaceutical industry.

  • 49.
    Gustavsson, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    On-line control of glucose feeding in an Escherichia coli fed-batch cultivation expressing a recombinant protein.2011Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Soft sensors have been suggested as potent tools for on-line estimations of critical bioprocess variables to be able to control the biological process in an as high extent as possible. The formation of inhibitory by-products in the form of organic acids, caused by an overflow of glucose, is a problem in most bioprocesses expressing recombinant proteins. 

     

    In this project a new method of controlling the glucose feeding in an Escherichia coli fed-batch cultivation expressing the green fluorescent protein (GFP) was investigated. The new controller system implemented in the software controlled the feed rate based on on-line HPLC measurements of the concentration of organic acids.   

     

    The results showed that the controller managed to down-regulate the inhibitory organic acids to a low level as it tried to keep the glucose uptake rate at an optimum for maximum cell growth. The results suggested that the controller could be a powerful tool to create a more secure reproducibility and to generate high product yields in recombinant protein productions.   

  • 50.
    Gustavsson, Robert
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Lukasser, Cornelia
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Control of specific carbon dioxide production in a fed-batch culture producing recombinant protein using a soft sensor2015In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 200, 44-51 p.Article in journal (Refereed)
    Abstract [en]

    The feeding of a fed-batch cultivation producing recombinant protein was controlled by a soft sensor setup. It was assumed that the control approach could be based on the cells production of carbon dioxide and that this parameter indicates the metabolic state occurring at induced protein expression. The soft sensor used the on-line signals from a carbon dioxide analyser and a near-infrared (NIR) probe for biomass to estimate the specific production rate (q(CO2)). Control experiments were carried out with various q(CO2) set-points where we observe that the feeding of nutrients to the culture could easily be controlled and resulted in a decreased variability compared to uncontrolled cultivations. We therefore suggest that this control approach could serve as an alternative to other commonly applied methods such as controlling the cells overflow metabolism of acetate or the cells specific growth rate. However, further studies of the internal metabolic fluxes of CO2 during protein expression would be recommended for a more precise characterization of the relationship between q(CO2) and protein expression in order to fully interpret the control behaviour.

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