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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, p. 1395-1402Article 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, p. 175-181Article 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. 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, p. 33-42Article 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.

  • 4. 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, p. 885-889Article in journal (Refereed)
  • 5. 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, p. 637-642Article 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.

  • 6. 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, p. 61-71Article 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.

  • 7. 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, p. 395-403Article 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.

  • 8. 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, p. 494-500Article 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.

  • 9.
    Bengtsson, Katarina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, Faculty of Science & Engineering. LunaMicro AB, Linköping, Sweden.
    Christoffersson, Jonas
    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.
    Robinson, Nathaniel D
    Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, Faculty of Science & Engineering. LunaMicro AB, Linköping, Sweden.
    A clip-on electroosmotic pump for oscillating flow in microfluidic cell culture devices2018In: Microfluidics and Nanofluidics, ISSN 1613-4982, E-ISSN 1613-4990, Vol. 22, no 3, article id 27Article in journal (Refereed)
    Abstract [en]

    Recent advances in microfluidic devices put a high demand on small, robust and reliable pumps suitable for high-throughput applications. Here we demonstrate a compact, low-cost, directly attachable (clip-on) electroosmotic pump that couples with standard Luer connectors on a microfluidic device. The pump is easy to make and consists of a porous polycarbonate membrane and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) electrodes. The soft electrode and membrane materials make it possible to incorporate the pump into a standard syringe filter holder, which in turn can be attached to commercial chips. The pump is less than half the size of the microscope slide used for many commercial lab-on-a-chip devices, meaning that these pumps can be used to control fluid flow in individual reactors in highly parallelized chemistry and biology experiments. Flow rates at various electric current and device dimensions are reported. We demonstrate the feasibility and safety of the pump for biological experiments by exposing endothelial cells to oscillating shear stress (up to 5 dyn/cm2) and by controlling the movement of both micro- and macroparticles, generating steady or oscillatory flow rates up to ± 400 μL/min.

  • 10.
    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, p. 3242-3249Article 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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    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, p. 265-270Article 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.

  • 14.
    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, p. 3502-3504Article 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.

  • 15.
    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, p. 359-367Article in journal (Other academic)
  • 16. 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, p. 241-248Article 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.

  • 17.
    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, p. 53-58Article 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.

  • 18.
    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, p. 107-125Article, 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.

  • 19. 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, p. 380-386Article 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.

  • 20. 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, p. 237-248Article 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.

  • 21. 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, p. 237-248Article 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.

  • 22. 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, p. 401-411Article 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.

  • 23. 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, p. 1157-1168Article 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.

  • 24.
    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.

  • 25.
    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, p. 1142-1152Article 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.

  • 26.
    Derelöv, Micael
    et al.
    Linköping University, Department of Management and Engineering, Assembly technology . Linköping University, The Institute of Technology.
    Detterfelt, Jonas
    Linköping University, Department of Management and Engineering, Assembly technology . Linköping University, The Institute of Technology.
    Björkman, Mats
    Linköping University, Department of Management and Engineering, Assembly technology . Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Engineering Design Methodology for Bio-Mechatronic Products2008In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 4, no 1, p. 232-244Article in journal (Refereed)
    Abstract [en]

    Four complex biotechnology products/product systems (a protein purification system, a bioreactor system, a surface plasmon resonance biosensor, and an enzymatic glucose analyzer) are analyzed using conceptual design principles. A design model well-known in mechanical system design, the Hubka-Eder (HE) model, is adapted to biotechnology products that exemplify combined technical systems of mechanical, electronic, and biological components, here referred to as bio-mechatronic systems. The analysis concludes that an extension of the previous HE model with a separate biological systems entity significantly contributes to facilitating the functional and systematic analyses of bio-mechatronic systems.

  • 27.
    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, p. 251-261Article in journal (Refereed)
  • 28.
    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, p. 57-59Article 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).

  • 29.
    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, p. 271-275Article 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.

  • 30.
    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, p. 115-121Article 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.

  • 31.
    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, p. 181-191Article, 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.

  • 32.
    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, p. 53-59Article 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.

  • 33.
    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, p. 2159-2168Article 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.

  • 34.
    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, p. 664-683Article 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

  • 35.
    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, p. 91-99Article 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.

  • 36.
    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.

  • 37.
    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, p. 1308-1314Article 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.

  • 38.
    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, p. 369-377Article 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.

  • 39.
    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, p. 44-51Article 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.

  • 40.
    Gustavsson, Robert
    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.
    Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed-batch cultivation producing green fluorescence protein2013In: Bioprocess and biosystems engineering (Print), ISSN 1615-7591, E-ISSN 1615-7605, Vol. 36, no 10, p. 1375-1384Article in journal (Refereed)
    Abstract [en]

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

  • 41. Ivansson, D.
    et al.
    Bayer, K.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Quantitation of intracellular recombinant human superoxide dismutase using surface plasmon resonance2002In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 456, no 2, p. 193-200Article in journal (Refereed)
    Abstract [en]

    An immunosensor assay for the quantitation of intracellular recombinant human superoxide dismutase (rhSOD) in Escherichia coli cultivations based on detection with surface plasmon resoance (SPR) is described. A monoclonal antibody for rhSOD was immobilized on a SPR dextran gold chip. Bacterial samples were sonicated and centrifugated prior to injection over the antibody chip for SPR detection. The assay time was 7min and allowed quantitation in the range of 1-64nM SOD in lysate samples with a precision of 1.1-3.4%. The assay was applied to monitor the concentration of rhSOD during E. coli bioreactor cultivations where the rhSOD production was induced by iso-propyl-b-D-thiogalactoside (IPTG). The assay allowed accurate monitoring of the production of rhSOD where the important phases in the product formation were possible to see. The report also discusses influence from sample preparation, SPR selectivity and sensitivity and quantitation limits. The assay proved to be fast, sensitive and accurate with low background effects from the dextran matrix of the SPR chip. ⌐ 2002 Published by Elsevier Science B.V.

  • 42.
    J T Carrondo, Manuel J T
    et al.
    IBET, Portugal University of Nova Lisboa, Portugal .
    Alves, Paula M
    IBET, Portugal University of Nova Lisboa, Portugal .
    Carinhas, Nuno
    IBET, Portugal University of Nova Lisboa, Portugal .
    Glassey, Jarka
    Newcastle University, England .
    Hesse, Friedemann
    University of Appl Science, Germany .
    Merten, Otto-Wilhelm
    Genethon, France .
    Micheletti, Martina
    UCL, England .
    Noll, Thomas
    University of Bielefeld, Germany .
    Oliveira, Rui
    IBET, Portugal University of Nova Lisboa, Portugal .
    Reichl, Udo
    Max Planck Institute Dynam Complex Technical Syst, Germany .
    Staby, Arne
    Lund University, Sweden Novo Nordisk AS, Denmark .
    Teixeira, Ana P
    IBET, Portugal University of Nova Lisboa, Portugal .
    Weichert, Henry
    Sartorius Stedim Biotech GmbH, Germany .
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    How can measurement, monitoring, modeling and control advance cell culture in industrial biotechnology?2012In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 7, no 12, p. 1522-1529Article in journal (Refereed)
    Abstract [en]

    This report highlights the potential of measurement, monitoring, modeling and control ((MC)-C-3) methodologies in animal and human cell culture technology. In particular, state-of-the-art of (MC)-C-3 technologies and their industrial relevance of existing technology are addressed. It is a summary of an expert panel discussion between biotechnologists and biochemical engineers with both academic and industrial backgrounds. The latest ascents in (MC)-C-3 are discussed from a cell culture perspective for industrial process development and production needs. The report concludes with a set of recommendations for targeting (MC)-C-3 research toward the industrial interests. These include issues of importance for biotherapeutics production, miniaturization of measurement techniques and modeling methods.

  • 43.
    Johansson, Leif B. G.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bergström, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Eriksson, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Prokop, Stefan
    Charite, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Heppner, Frank L.
    Charite, Germany.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    An azide functionalized oligothiophene ligand - A versatile tool for multimodal detection of disease associated protein aggregates2015In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 63, p. 204-211Article in journal (Refereed)
    Abstract [en]

    Ligands for identifying protein aggregates are of great interest as such deposits are the pathological hallmark of a wide range of severe diseases including Alzheimers and Parkinsons disease. Here we report the synthesis of an azide functionalized fluorescent pentameric oligothiophene that can be utilized as a ligand for multimodal detection of disease-associated protein aggregates. The azide functionalization allows for attachment of the ligand to a surface by conventional click chemistry without disturbing selective interaction with protein aggregates and the oligothiophene-aggregate interaction can be detected by fluorescence or surface plasmon resonance. In addition, a methodology where the oligothiophene ligand is employed as a capturing molecule selective for aggregated proteins in combination with an antibody detecting a distinct peptide/protein is also presented. We foresee that this methodology will offer the possibility to create a variety of multiplex sensing systems for sensitive and selective detection of protein aggregates, the pathological hallmarks of several neurodegenerative diseases.

  • 44.
    Jungar, Christina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology.
    Neoglycoconjugates as affinity ligands in surface plasmon resonance analysis2001In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 449, no 1-2, p. 51-58Article in journal (Refereed)
    Abstract [en]

    Neoglycoconjugates, i.e. de novo synthesized conjugates of glycosides and carrier molecules such as proteins or polylipids, were used as affinity ligands in a surface plasmon resonance (SPR) biosensor assay. The affinity of the glycoconjugates, normally in the lower affinity range, was influenced by increasing the number of glycosides bound per carrier protein, the coupling chemistry, and the assay temperature. As a model system, albumin-conjugated A- and B-active blood group oligosaccharides with suitable linker molecules were chosen. Specific monoclonal antibodies were used as analytes to verify the interactive performance. Affinity kinetics of the systems were evaluated from the SPR biosensor data. The results demonstrate that neoglycoconjugates are a good alternative in presenting affinity ligands of small, specific molecules in SPR-based assays with retained specificity and bioavailability. ⌐ 2001 Elsevier Science B.V. All rights reserved.

  • 45.
    Jungar, Christina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Strandh, M
    University of Kalmar, Kalmar, Sweden.
    Ohlson, S
    University of Kalmar, Kalmar, Sweden.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology.
    Analysis of carbohydrates using liquid chromatography-surface plasmon resonance immunosensing systems2000In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 281, no 2, p. 151-158Article in journal (Refereed)
    Abstract [en]

    An immunosensing system based on surface plasmon resonance (SPR) was used for on-line detection and characterization of carbohydrate molecules separated by high-performance liquid chromatography. These analytes, with or without serum, were continuously separated and analyzed in the combined liquid chromatography-surface plasmon resonance (LC-SPR) system. By using weak and readily reversible monoclonal antibodies, the SPR system allowed specific on-line monitoring of the substances. To increase the specificity of the immunosensor, nonrelevant antibodies were used as reference in a serial flow cell. The sensitivity of the LC-SPR system was dependent on molecular weight of the carbohydrate, affinity of binding, and design of the sensor. (C) 2000 Academic Press.

  • 46. Komaraiah, P.
    et al.
    Kishor PB, Kavi
    Carlsson, Maria
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Enhancement of anthraquinone accumulation in Morinda citrifolia suspension cultures2005In: Plant Science, ISSN 0168-9452, E-ISSN 1873-2259, Vol. 168, no 5, p. 1337-1344Article in journal (Refereed)
    Abstract [en]

    Enhancement of accumulation of anthraquinones in Morinda citrifolia (Noni fruit) suspension cultures was accomplished by treatment with elicitors, by ultrasonication and by controlled feeding of the carbon source in the growth medium. The elicitation was attained by additions of polyunsaturated fatty acids (linoleic acid, α-linolenic acid, arachidonic acid), methyl jasmonate, salicylate and nitric oxide (by addition of sodium nitroprusside to the medium) at different concentrations. The accumulation of anthraquinones in the elicited cultures ranged from 5 to 12 mg/g dry weight of cells, which was two to three-fold of what was attained in control cultures. Treatment by short pulses of ultrasonication enhanced the accumulation up to 2.5-fold after 16 s of sonication. A synergistic effect was achieved by simultaneously applying elicitation and controlled addition of sucrose, that increased the anthraquinone production to 16.74 mg/g of dry weight, which was more than a four-fold increase above the control cultures. The accumulation of the anthraquinones in the M. citrifolia cells was confirmed by confocal laser fluorescence microscopy. Minor fluorescence was observed from the cells in the lag phase (1-3 days), while substantially higher fluorescence was observed at late exponential and stationary phase (10-14 days). Rounder spherical cells emitted less fluorescence than elongated slender cells. The fluorescence was assumed to be a result of autofluorescent properties of the aromatic anthraquinone molecules. © 2005 Elsevier Ireland Ltd. All rights reserved.

  • 47. Komaraiah, P.
    et al.
    Navratil, M.
    Carlsson, Maria
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Jeffers, P.
    Ctr. for Synthesis and Chem. Biology, Department of Chemical Engineering, University College Dublin, Belfield, Dublin 4, Ireland.
    Brodelius, M.
    Dept. of Chem. and Biomed. Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden.
    Brodelius, P.E.
    Dept. of Chem. and Biomed. Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden.
    Kieran, P.M.
    Ctr. for Synthesis and Chem. Biology, Department of Chemical Engineering, University College Dublin, Belfield, Dublin 4, Ireland.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Growth behavior in plant cell cultures based on emissions detected by a multisensor array2004In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 20, no 4, p. 1245-1250Article in journal (Refereed)
    Abstract [en]

    The use of a multisensor array based on chemical gas sensors to monitor plant cell cultures is described. The multisensor array, also referred to as an electronic nose, consisted of 19 different metal oxide semiconductor sensors and one carbon dioxide sensor. The device was used to continuously monitor the off-gas from two plant cell suspension cultures, Morinda citrifolia and Nicotiana tabacum, cultivated under batch conditions. By analyzing the multiarray responses using two pattern recognition methods, principal component analysis and artificial neural networks, it was possible to monitor the course of the cultivations and, in turn, to predict (1) the biomass concentration in both systems and (2) the formation of the secondary metabolite, antraquinone, by M. citrifolia. The results identify the multisensor array method as a potentially useful analytical tool for monitoring plant process variables that are otherwise difficult to analyze on-line.

  • 48.
    Komaraiah, Palle
    et al.
    St.Jude Children´s Reserarch Hospital.
    Navratil, Marian
    Linköpings universitet.
    Carlsson, Maria
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology.
    Jeffers, Paul
    University College Dublin.
    Brodelius, Maria
    University of Kalmar.
    Brodelius, Peter E.
    University of Kalmar.
    Kieran, Patricia M.
    University of Kalmar.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology.
    Growth Behavior in Plant Cell Cultures Based on Emissions Detected by a Multisensor Array2004In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 20, p. 1245-1250Article in journal (Refereed)
  • 49.
    Kreij, Karl
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    Clemente, Joao J.
    Cunha, Antonio Eduardo
    Monteiro, Sandra M.S.
    Carrondo, Manuel J.T.
    Hesse, Friedemann
    de los Milagros Bassani Molinas, Maria
    Wagner, Roland
    Merten, Otto-Wilhelm
    Geny-Fiamma, Cecile
    Leger, Wolfgang
    Wiesinger-Mayr, Herbert
    Müller, Dethard
    Katinger, Hermann
    Mårtensson, Per
    Bachinger, Thomas
    Mitrovics, Jan
    On-line detection of microbial contaminations in animal cell reactor cultures using an electronic nose device2005In: Cytotechnology (Dordrecht), ISSN 0920-9069, E-ISSN 1573-0778, Vol. 48, no 1-3, p. 41-58Article in journal (Refereed)
    Abstract [en]

    An electronic nose (EN) device was used to detect microbial and viral contaminations in a variety of animal cell culture systems. The emission of volatile components from the cultures accumulated in the bioreactor headspace, was sampled and subsequently analysed by the EN device. The EN, which was equipped with an array of 17 chemical gas sensors of varying selectivity towards the sampled volatile molecules, generated response patterns of up to 85 computed signals. Each 15 or 20 min a new gas sample was taken generating a new response pattern. A software evaluation tool visualised the data mainly by using principal component analysis. The EN was first used to detect microbial contaminations in a Chinese hamster ovary (CHO) cell line producing a recombinant human macrophage colony stimulating factor (rhM-CSF). The CHO cell culture was contaminated by Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida utilis which all were detected. The response patterns from the CHO cell culture were compared with monoculture references of the microorganisms. Second, contaminations were studied in an Sf-9 insect cell culture producing another recombinant protein (VP2 protein). Contaminants were detected from E. coli, a filamentous fungus and a baculovirus. Third, contamination of a human cell line, HEK-293, infected with E. coli exhibited comparable results. Fourth, bacterial contaminations could also be detected in cultures of a MLV vector producer cell line. Based on the overall experiences in this study it is concluded that the EN method has in a number of cases the potential to be developed into a useful on-line contamination alarm in order to support safety and economical operation for industrial cultivation. © Springer 2005.

  • 50. Lidén, H.
    et al.
    Bachinger, T.
    Gorton, L.
    Mandenius, Carl-Fredrik
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biotechnology .
    On-line determination of non-volatile or low-concentration metabolites in a yeast cultivation using an electronic nose2000In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 125, no 6, p. 1123-1128Article in journal (Refereed)
    Abstract [en]

    An electronic nose was used for on-line gas phase monitoring of key metabolites in a Saccharomyces cerevisiae cultivation. The metabolites were either non-volatile or present at very low concentrations and therefore not detectable in the gas phase by the sensors in the electronic nose. It was found that it is still possible to make a prediction based on the off-gas emission. Artificial neural networks (ANNs) were trained using data acquired by the gas sensors and reference data obtained from on-line HPLC analyses, from a total of six cultivations to estimate concentrations of the metabolites glucose, glycerol, acetate and acetaldehyde. The ANNs were subsequently validated on an independent set of cultivation data resulting in a prediction accuracy described by the root mean square error (RMSE) of 0.13 (in the range 0-7.33), 0.015 (0.08-0.15), 0.012 (0-0.20) and 0.004 (0-0.11) g L-1, respectively. Data from a cultivation with higher initial glucose concentration were added to the original data and the extended set was used for training an ANN to determine concentration variables at higher concentration ranges than in the first study. The RMSE was 1.2 (0-9.31), 0.016 (0.09-0.20), 0.026 (0-0.19) and 0.010 (0-0.15) g L-1, respectively, when validating the ANNs.

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