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  • 1.
    Greuel, Selina
    et al.
    Charite Univ Med Berlin, Germany.
    Hanci, Guengoer
    Charite Univ Med Berlin, Germany.
    Boehme, Mike
    Charite Univ Med Berlin, Germany.
    Miki, Toshio
    Univ Southern Calif, CA USA.
    Schubert, Frank
    StemCell Syst GmbH, Germany.
    Sittinger, Michael
    Charite Univ Med Berlin, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Zeilinger, Katrin
    Charite Univ Med Berlin, Germany.
    Freyer, Nora
    Charite Univ Med Berlin, Germany.
    Effect of inoculum density on human-induced pluripotent stem cell expansion in 3D bioreactors2019In: Cell Proliferation, ISSN 0960-7722, E-ISSN 1365-2184, Vol. 52, no 4, article id e12604Article in journal (Refereed)
    Abstract [en]

    Objective For optimized expansion of human-induced pluripotent stem cells (hiPSCs) with regards to clinical applications, we investigated the influence of the inoculum density on the expansion procedure in 3D hollow-fibre bioreactors. Materials and Methods Analytical-scale bioreactors with a cell compartment volume of 3 mL or a large-scale bioreactor with a cell compartment volume of 17 mL were used and inoculated with either 10 x 10(6) or 50 x 10(6) hiPSCs. Cells were cultured in bioreactors over 15 days; daily measurements of biochemical parameters were performed. At the end of the experiment, the CellTiter-Blue (R) Assay was used for culture activity evaluation and cell quantification. Also, cell compartment sections were removed for gene expression and immunohistochemistry analysis. Results The results revealed significantly higher values for cell metabolism, cell activity and cell yields when using the higher inoculation number, but also a more distinct differentiation. As large inoculation numbers require cost and time-extensive pre-expansion, low inoculation numbers may be used preferably for long-term expansion of hiPSCs. Expansion of hiPSCs in the large-scale bioreactor led to a successful production of 5.4 x 10(9) hiPSCs, thereby achieving sufficient cell amounts for clinical applications. Conclusions In conclusion, the results show a significant effect of the inoculum density on cell expansion, differentiation and production of hiPSCs, emphasizing the importance of the inoculum density for downstream applications of hiPSCs. Furthermore, the bioreactor technology was successfully applied for controlled and scalable production of hiPSCs for clinical use.

  • 2.
    Christoffersson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Aronsson, Christopher
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Jury, Michael
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device2019In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 11, no 1, article id 015013Article in journal (Refereed)
    Abstract [en]

    Liver cell culture models are attractive in both tissue engineering and for development of assays for drug toxicology research. To retain liver specific cell functions, the use of adequate cell types and culture conditions, such as a 3Dorientation of the cells and a proper supply of nutrients and oxygen, are critical. In this article, we show how extracellular matrix mimetic hydrogels can support hepatocyte viability and functionality in a perfused liver-on-a-chip device. A modular hydrogel system based on hyaluronan and poly(ethylene glycol) (HA-PEG), modified with cyclooctyne moieties for bioorthogonal strain-promoted alkyne-azide 1, 3-dipolar cycloaddition (SPAAC), was developed, characterized, and compared for cell compatibility to hydrogels based on agarose and alginate. Hepatoma cells (HepG2) formed spheroids with viable cells in all hydrogels with the highest expression of albumin and urea in alginate hydrogels. By including an excess of cyclooctyne in theHA backbone, azide-modified cell adhesion motifs (linear and cyclicRGDpeptides) could be introduced in order to enhance viability and functionality of human induced pluripotent stem cell derived hepatocytes (hiPS-HEPs). In the HA-PEG hydrogels modified with cyclicRGDpeptides hiPS-HEPs migrated and grew in 3D and showed an increased viability and higher albumin production compared to when cultured in the other hydrogels. This flexible SPAAC crosslinked hydrogel system enabled fabrication of perfused 3D cell culture of hiPS-HEPs and is a promising material for further development and optimization of liver-on-a-chip devices.

  • 3.
    Gustavsson, Robert
    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.
    Löfgren, S.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Scheper, T.
    Leibniz Univ Hannover, Germany.
    Lindner, P.
    Leibniz Univ Hannover, Germany.
    In situ microscopy as online tool for detecting microbial contaminations in cell culture2019In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 296, p. 53-60Article in journal (Refereed)
    Abstract [en]

    Microbial contamination in mammalian cell cultures causing rejected batches is costly and highly unwanted. Most methods for detecting a contamination are time-consuming and require extensive off-line sampling. To circumvent these efforts and provide a more convenient alternative, we used an online in situ microscope to estimate the cell diameter of the cellular species in the culture to distinguish mammalian cells from microbial cells depending on their size. A warning system was set up to alert the operator if microbial cells were present in the culture. Hybridoma cells were cultured and infected with either Candida utilis or Pichia stipitis as contaminant. The warning system could successfully detect the introduced contamination and alert the operator. The results suggest that in situ microscopy could be used as an efficient online tool for early detection of contaminations in cell cultures.

  • 4.
    Roch, Patricia
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Sellberg, Anton
    Lund Univ, Sweden.
    Andersson, Niklas
    Lund Univ, Sweden.
    Gunne, Matthias
    Sanofi Aventis Deutschland GmbH, Germany.
    Hauptmann, Peter
    Sanofi Aventis Deutschland GmbH, Germany.
    Nilsson, Bernt
    Lund Univ, Sweden.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Model-based monitoring of industrial reversed phase chromatography to predict insulin variants2019In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 35, no 4, article id UNSP e2813Article in journal (Refereed)
    Abstract [en]

    Downstream processing in the manufacturing biopharmaceutical industry is a multistep process separating the desired product from process- and product-related impurities. However, removing product-related impurities, such as product variants, without compromising the product yield or prolonging the process time due to extensive quality control analytics, remains a major challenge. Here, we show how mechanistic model-based monitoring, based on analytical quality control data, can predict product variants by modeling their chromatographic separation during product polishing with reversed phase chromatography. The system was described by a kinetic dispersive model with a modified Langmuir isotherm. Solely quality control analytical data on product and product variant concentrations were used to calibrate the model. This model-based monitoring approach was developed for an insulin purification process. Industrial materials were used in the separation of insulin and two insulin variants, one eluting at the product peak front and one eluting at the product peak tail. The model, fitted to analytical data, used one component to simulate each protein, or two components when a peak displayed a shoulder. This monitoring approach allowed the prediction of the elution patterns of insulin and both insulin variants. The results indicate the potential of using model-based monitoring in downstream polishing at industrial scale to take pooling decisions.

  • 5.
    Greuel, Selina
    et al.
    Charite Univ Med Berlin, Germany.
    Freyer, Nora
    Charite Univ Med Berlin, Germany.
    Hanci, Gungor
    Charite Univ Med Berlin, Germany.
    Bohme, Mike
    Charite Univ Med Berlin, Germany.
    Miki, Toshio
    Univ Southern Calif, CA USA.
    Werner, Johannes
    Stem Cell Syst GmbH, Germany.
    Schubert, Frank
    Stem Cell Syst GmbH, Germany.
    Sittinger, Michael
    Charite Univ Med Berlin, Germany.
    Zeilinger, Katrin
    Charite Univ Med Berlin, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Online measurement of oxygen enables continuous noninvasive evaluation of human-induced pluripotent stem cell (hiPSC) culture in a perfused 3D hollow-fiber bioreactor2019In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 13, no 7, p. 1203-1216Article in journal (Refereed)
    Abstract [en]

    For clinical and/or pharmaceutical use of human-induced pluripotent stem cells (hiPSCs), large cell quantities of high quality are demanded. Therefore, we combined the expansion of hiPSCs in closed, perfusion-based 3D bioreactors with noninvasive online monitoring of oxygen as culture control mechanism. Bioreactors with a cell compartment volume of 3 or 17 ml were inoculated with either 10 x 10(6) or 50 x 10(6) cells, and cells were expanded over 15 days with online oxygen and offline glucose and lactate measurements being performed. The CellTiter-Blue (R) Assay was performed at the end of the bioreactor experiments for indirect cell quantification. Model simulations enabled an estimation of cell numbers based on kinetic equations and experimental data during the 15-day bioreactor cultures. Calculated oxygen uptake rates (OUR), glucose consumption rates (GCR), and lactate production rates (LPR) revealed a highly significant correlation (p amp;lt; 0.0001). Oxygen consumption, which was measured at the beginning and the end of the experiment, showed a strong culture growth in line with the OUR and GCR data. Furthermore, the yield coefficient of lactate from glucose and the OUR to GCR ratio revealed a shift from nonoxidative to oxidative metabolism. The presented results indicate that oxygen is equally as applicable as parameter for hiPSC expansion as glucose while providing an accurate real-time impression of hiPSC culture development. Additionally, oxygen measurements inform about the metabolic state of the cells. Thus, the use of oxygen online monitoring for culture control facilitates the translation of hiPSC use to the clinical setting.

  • 6.
    Christoffersson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Meier, Florian
    Boehringer Ingelheim Pharma GmbH and Co. KG, Nonclinical Drug Safety Germany, D-88397 Biberach an der Riss, Germany.
    Kempf, Henning
    Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
    Schwanke, Kristin
    Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
    Coffee, Michelle
    Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
    Beilmann, Mario
    Boehringer Ingelheim Pharma GmbH and Co. KG, Nonclinical Drug Safety Germany, D-88397 Biberach an der Riss, Germany.
    Zweigerdt, Robert
    Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    A Cardiac Cell Outgrowth Assay for Evaluating Drug Compounds Using a Cardiac Spheroid-on-a-Chip Device2018In: Bioengineering, E-ISSN 2306-5354, Vol. 5, no 2, p. 1-13, article id 36Article in journal (Refereed)
    Abstract [en]

    Three-dimensional (3D) models with cells arranged in clusters or spheroids have emerged as valuable tools to improve physiological relevance in drug screening. One of the challenges with cells cultured in 3D, especially for high-throughput applications, is to quickly and non-invasively assess the cellular state in vitro. In this article, we show that the number of cells growing out from human induced pluripotent stem cell (hiPSC)-derived cardiac spheroids can be quantified to serve as an indicator of a drug’s effect on spheroids captured in a microfluidic device. Combining this spheroid-on-a-chip with confocal high content imaging reveals easily accessible, quantitative outgrowth data. We found that effects on outgrowing cell numbers correlate to the concentrations of relevant pharmacological compounds and could thus serve as a practical readout to monitor drug effects. Here, we demonstrate the potential of this semi-high-throughput “cardiac cell outgrowth assay” with six compounds at three concentrations applied to spheroids for 48 h. The image-based readout complements end-point assays or may be used as a non-invasive assay for quality control during long-term culture.

  • 7.
    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.

  • 8.
    Pasitka, Laura
    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.
    Lim, Wanyoung
    Sungkyunkwan Univ, South Korea.
    Park, Sungsu
    Sungkyunkwan Univ, South Korea.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    A Microbore Tubing Based Spiral for Multistep Cell Fractionation2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 21, p. 12909-12916Article in journal (Refereed)
    Abstract [en]

    Cells were separated with the aid of a multistep spiral fractionation device, utilizing hydrodynamic forces in a spiral tubing. The spiral was fabricated using "off-the-shelf microbore tubing, allowing for cheap and fast prototyping to achieve optimal cell separation. As a first step, a model system with 20 and 40 mu m beads was used to demonstrate the effectiveness of the multistep separation device. With an initial purity of 5%, a separation purity of 83% was achieved after a two-step separation with the addition of 0.1% polyethylene glycol (PEG)-8000. Next, doxorubicinresistant polyploid giant breast cancer cells (MDA-MB-231) were separated from doxorubicin-sensitive monoploid small breast cancer cells in the same fashion as the beads, resulting in a purity of around 40%, while maintaining a cell viability of more than 90%. Combined with basic cell analytical methods, the hydrodynamic separation principle of the device could be envisaged to be useful for a variety of cell fractionation needs in cell biology and in clinical applications.

  • 9.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Advances in Micro-Bioreactor Design for Organ Cell Studies2018In: Bioengineering (Basel, Switzerland), ISSN 2306-5354, Vol. 5, no 3, article id 64Article in journal (Other academic)
  • 10.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Conceptual Design of Micro-Bioreactors and Organ-on-Chips for Studies of Cell Cultures2018In: Bioengineering (Basel, Switzerland), ISSN 2306-5354, Vol. 5, no 3, article id 56Article, review/survey (Refereed)
    Abstract [en]

    Engineering design of microbioreactors (MBRs) and organ-on-chip (OoC) devices can take advantage of established design science theory, in which systematic evaluation of functional concepts and user requirements are analyzed. This is commonly referred to as a conceptual design. This review article compares how common conceptual design principles are applicable to MBR and OoC devices. The complexity of this design, which is exemplified by MBRs for scaled-down cell cultures in bioprocess development and drug testing in OoCs for heart and eye, is discussed and compared with previous design solutions of MBRs and OoCs, from the perspective of how similarities in understanding design from functionality and user purpose perspectives can more efficiently be exploited. The review can serve as a guideline and help the future design of MBR and OoC devices for cell culture studies.

  • 11.
    Christoffersson, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Aronsson, Christopher
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Jury, Michael
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device2018In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 11, no 1, p. 1-13, article id 015013Article in journal (Refereed)
    Abstract [en]

    Liver cell culture models are attractive in both tissue engineering and for development of assays for drug toxicology research. To retain liver specific cell functions, the use of adequate cell types and culture conditions, such as a 3D orientation of the cells and a proper supply of nutrients and oxygen, are critical. In this article, we show how extracellular matrix mimetic hydrogels can support hepatocyte viability and functionality in a perfused liver-on-a-chip device. A modular hydrogel system based on hyaluronan and poly(ethylene glycol) (HA-PEG), modified with cyclooctyne moieties for bioorthogonal strain-promoted alkyne-azide 1, 3-dipolar cycloaddition (SPAAC), was developed, characterized, and compared for cell compatibility to hydrogels based on agarose and alginate. Hepatoma cells (HepG2) formed spheroids with viable cells in all hydrogels with the highest expression of albumin and urea in alginate hydrogels. By including an excess of cyclooctyne in the HA backbone, azide-modified cell adhesion motifs (linear and cyclic RGD peptides) could be introduced in order to enhance viability and functionality of human induced pluripotent stem cell derived hepatocytes (hiPS-HEPs). In the HA-PEG hydrogels modified with cyclic RGD peptides hiPS-HEPs migrated and grew in 3D and showed an increased viability and higher albumin production compared to when cultured in the other hydrogels. This flexible SPAAC crosslinked hydrogel system enabled fabrication of perfused 3D cell culture of hiPS-HEPs and is a promising material for further development and optimization of liver-on-a-chip devices.

  • 12.
    Randek, Judit
    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.
    On-line soft sensing in upstream bioprocessing2018In: Critical reviews in biotechnology, ISSN 0738-8551, E-ISSN 1549-7801, Vol. 38, no 1, p. 106-121Article, review/survey (Refereed)
    Abstract [en]

    This review provides an overview and a critical discussion of novel possibilities of applying soft sensors for on-line monitoring and control of industrial bioprocesses. Focus is on bio-product formation in the upstream process but also the integration with other parts of the process is addressed. The term soft sensor is used for the combination of analytical hardware data (from sensors, analytical devices, instruments and actuators) with mathematical models that create new real-time information about the process. In particular, the review assesses these possibilities from an industrial perspective, including sensor performance, information value and production economy. The capabilities of existing analytical on-line techniques are scrutinized in view of their usefulness in soft sensor setups and in relation to typical needs in bioprocessing in general. The review concludes with specific recommendations for further development of soft sensors for the monitoring and control of upstream bioprocessing.

  • 13.
    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, article id 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.

  • 14.
    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, p. 956-966Article 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.

  • 15.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Challenges for bioreactor design and operation2016In: Bioreactors: design, operation and novel applications / [ed] Carl-Fredrik Mandenius, Weinheim: Wiley-VCH Verlagsgesellschaft, 2016, p. 1-34Chapter in book (Other academic)
  • 16.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Design-of-experiments for development and optimization of bioreactor media2016In: Bioreactors: design, operation and novel applications / [ed] Carl-Fredrik Mandenius, Weinheim: Wiley-VCH Verlagsgesellschaft, 2016, p. 421-451Chapter in book (Other academic)
  • 17.
    Roch, Patricia
    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.
    On-line monitoring of downstream bioprocesses2016In: CURRENT OPINION IN CHEMICAL ENGINEERING, ISSN 2211-3398, Vol. 14, p. 112-120Article in journal (Refereed)
    Abstract [en]

    Downstream bioprocessing can benefit significantly from using on-line monitoring methods for surveillance, control and optimisation. Timely information on critical operational and product quality parameters provided by on-line monitoring may contribute to high product quality, more efficient process operation and better production economy. Here, recent advances in analytical techniques and tools are critically reviewed and assessed based on their capability to meet typical needs and requirements in the biotechnology industry. Soft sensors, which merge the signals generated from on-line monitoring devices into mathematical models, are highlighted for accessing critical information in downstream processing.

  • 18.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Gustavsson, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
    Soft sensor design for bioreactor monitoring and control2016In: Bioreactors: design, operation and novel application / [ed] Carl-Fredrik Mandenius, Weinheim: Wiley-VCH Verlagsgesellschaft, 2016, p. 391-420Chapter in book (Other academic)
  • 19.
    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.

  • 20.
    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.

  • 21.
    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

  • 22.
    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.

  • 23.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Gustavsson, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Mini-review: soft sensors as means for PAT in the manufacture of bio-therapeutics2015In: Journal of chemical technology and biotechnology (1986), ISSN 0268-2575, E-ISSN 1097-4660, Vol. 90, no 2, p. 215-227Article, review/survey (Refereed)
    Abstract [en]

    This mini-review discusses how soft sensors can contribute to accomplish FDAs process analytical technology (PAT) ambitions in the manufacture of bio-therapeutics. Focus is on applications with protein-based drugs (proteins, antibodies), but also gene therapy vectors as well as cell cultures are considered where chemical and bio-analytical as well as mathematical and statistical methods are used as tools. An overview of existing soft sensor alternatives and how these can be configured to meet typical industrial needs is provided. It is noted how several of these needs coincide with the PAT regulatory incentives but do also address process economic aspects of bio-therapeutic manufacture. Evaluation of soft sensor alternatives is highlighted in relation to the production targets, quality attributes and the specification of these as well as shortcomings and needs for further improvements.

  • 24.
    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.

  • 25.
    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.

  • 26.
    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.

  • 27.
    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.

  • 28.
    Paulsson, Dan
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    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.
    A Soft Sensor for Bioprocess Control Based on Sequential Filtering of Metabolic Heat Signals2014In: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 14, no 10, p. 17864-17882Article in journal (Refereed)
    Abstract [en]

    Soft sensors are the combination of robust on-line sensor signals with mathematical models for deriving additional process information. Here, we apply this principle to a microbial recombinant protein production process in a bioreactor by exploiting bio-calorimetric methodology. Temperature sensor signals from the cooling system of the bioreactor were used for estimating the metabolic heat of the microbial culture and from that the specific growth rate and active biomass concentration were derived. By applying sequential digital signal filtering, the soft sensor was made more robust for industrial practice with cultures generating low metabolic heat in environments with high noise level. The estimated specific growth rate signal obtained from the three stage sequential filter allowed controlled feeding of substrate during the fed-batch phase of the production process. The biomass and growth rate estimates from the soft sensor were also compared with an alternative sensor probe and a capacitance on-line sensor, for the same variables. The comparison showed similar or better sensitivity and lower variability for the metabolic heat soft sensor suggesting that using permanent temperature sensors of a bioreactor is a realistic and inexpensive alternative for monitoring and control. However, both alternatives are easy to implement in a soft sensor, alone or in parallel.

  • 29.
    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).

  • 30.
    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.

  • 31.
    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.

  • 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.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Meyer, Thomas
    MultiChannel Systems GmbH, Reutlingen, Germany.
    High-throughput screening assays to evaluate the cardiotoxic potential of drugs2013In: High-throughput screening methods in toxicity testing / [ed] Pablo Steinman, John Wiley & Sons, 2013, p. 403-420Chapter in book (Other academic)
    Abstract [en]

    "High-throughput assays are part of a paradigm shift, to more cost-effective and reliable methods, in the testing of chemical and drug safety. This book covers methods, data generation, data analysis, and applications in risk assessment for major toxicological assays to help toxicologists apply and understand the benefits and limits of high-throughput testing assays. Each chapter describes method principles and includes detailed information on data generation, data analysis, and applications in risk assessment. The topic is especially timely given Europe's REACH legislation and the US National Research Council"-- 

    "This book describes the high-throughput in vitro methods available for toxicity testing, serving as a guide to scientists working in toxicity evaluation and risk assessment of chemicals and drugs"-- 

  • 34.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    J Titchener-Hooker, N
    Lund University, Sweden .
    Measurement, Monitoring, Modelling and Control of Bioprocesses Preface2013Other (Refereed)
    Abstract [en]

    n/a

  • 35.
    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.

  • 36.
    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.

  • 37.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Biomechatronics for designing bioprocess monitoring and control systems: Application to stem cell production2012In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 162, no 4, p. 430-440Article in journal (Refereed)
    Abstract [en]

    Stem cell production systems need elaborate monitoring and control for meeting requirements on the final cell product. In this article, the use of biomechatronic design methodology for supporting these efforts is described. Biomechatronic design, which is based on a fundamental systematical design approach originating from mechanical engineering, is here applied for investigating how monitoring and control systems can be configured in stem cell manufacturing processes. Results are provided that demonstrate how the biomechatronic design tools are used to compare different process analytical instrumentation resulting in a design layout for the monitoring system for derivation of hepatocytes from human embryonic stem cells. The results can be extrapolated to other stem cell production processes using the same methodology.

  • 38.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Design of Monitoring and Sensor Systems for Bioprocesses by Biomechatronic Methodology2012In: Chemical Engineering & Technology, ISSN 0930-7516, E-ISSN 1521-4125, Vol. 35, no 8, p. 1412-1420Article in journal (Refereed)
    Abstract [en]

    Biomechatronic design methodology is discussed for the design of monitoring and sensor systems for biotechnological processes. The bioprocess monitoring systems are examples of complex biomechatronic systems between electronic, mechanical, and biological subsystems, and where in particular the biological parts, through active microbial or cellular components, influence the design solutions in a complex manner. The biomechatronic approach facilitates configuration of the monitoring and sensor systems with production and quality needs in focus, and can by that lead to more efficient design solutions.

  • 39.
    Luttmann, Reiner
    et al.
    Hamburg University of Appl Science, Germany .
    Bracewell, Daniel G.
    UCL, England .
    Cornelissen, Gesine
    Hamburg University of Appl Science, Germany .
    Gernaey, Krist V.
    Technical University of Denmark, Denmark .
    Glassey, Jarka
    Newcastle University, England .
    Hass, Volker C.
    University of Appl Science Bremen, Germany .
    Kaiser, Christian
    Richter Helm GmbH, Germany .
    Preusse, Christian
    Siemens AG, Germany .
    Striedner, Gerald
    University of Nat Resources and Life Science, Austria .
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Editorial Material: Soft sensors in bioprocessing: A status report and recommendations2012In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 7, no 8, p. 1040-1048Article in journal (Other academic)
    Abstract [en]

    The following report with recommendations is the result of an expert panel meeting on soft sensor applications in bioprocess engineering that was organized by the Measurement, Monitoring, Modelling and Control (M3C) Working Group of the European Federation of Biotechnology - Section of Biochemical Engineering Science (ESBES). The aim of the panel was to provide an update on the present status of the subject and to identify critical needs and issues for the furthering of the successful development of soft sensor methods in bioprocess engineering research and for industrial applications, in particular with focus on biopharmaceutical applications. It concludes with a set of recommendations, which highlight current prospects for the extended use of soft sensors and those areas requiring development.

  • 40.
    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.

  • 41.
    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.

  • 42.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Björkman, Mats
    Linköping University, Department of Management and Engineering, Manufacturing Engineering. Linköping University, The Institute of Technology.
    Scale-up of cell culture bioreactors using biomechatronic design2012In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 7, no 8, p. 1026-1039Article in journal (Refereed)
    Abstract [en]

    Scale-up of cell culture bioreactors is a challenging engineering work that requires wide competence in cell biology, mechanical engineering and bioprocess design. In this article, a new approach for cell culture bioreactor scale-up is suggested that is based on biomechatronic design methodology. The approach differs from traditional biochemical engineering methodology by applying a sequential design procedure where the needs of the users and alternative design solutions are systematically analysed. The procedure is based on the biological and technical functions of the scaled-up bioreactor that are derived in functional maps, concept generation charts and scoring and interaction matrices. Basic reactor engineering properties, such as mass and heat transfer and kinetics are integrated in the procedure. The methodology results in the generation of alternative design solutions that are thoroughly ranked with help of the user needs. Examples from monoclonal antibodies and recombinant protein production illuminate the steps of the procedure. The methodology provides engineering teams with additional tools that can significantly facilitate the design of new production methods for cell culture processes.

  • 43.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Biomechatronic Design for Sensors: Biomechatronic Methodology2011In: GIT Laboratory Journal, ISSN 1434-2634, Vol. 15, no 11-12, p. 24-25Article in journal (Other academic)
    Abstract [en]

    Biomechatronic design combines mechanical and electric product design principles with biotechnology [1]. Systematic conceptual design, used for decades in product development for mechanical products is here adapted to cope with the complexity of biological systems and processes. Typical examples are bioreactors and biosensors. The biomechatronic design facilitates and coordinates the product development work by using a few simple procedures, tools and models. In this report these tools and models are applied on the design of sensor systems used for monitoring and controlling biotechnology production processes.

  • 44.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
    Björkman, Mats
    Linköping University, Department of Management and Engineering, Assembly technology. Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Biomechatronic Design in Biotechnology: A Methodology for Development of Biotechnological Products2011Book (Other academic)
    Abstract [en]

    This cutting-edge guide on the fundamentals, theory, and applications of biomechatronic design principles.

    Biomechatronic Design in Biotechnology presents a complete methodology of biomechatronics, an emerging variant of the mechatronics field that marries biology, electronics, and mechanics to create products where biological and biochemical, technical, human, management-and-goal, and information systems are combined and integrated in order to solve a mission that fulfills a human need. A biomechatronic product includes a biological, mechanical, and electronic part. Beginning with an overview of the fundamentals and theory behind biomechatronic technology, this book describes how general engineering design science theory can be applied when designing a technical system where biological species or components are integrated. Some research methods explored include schemes and matrices for analyzing the functionality of the designed products, ranking methods for screening and scoring the best design solutions, and structuring graphical tools for a thorough investigation of the subsystems and sub-functions of products. This insightful guide also:

    • Discusses tools for creating shorter development times, thereby reducing the need for prototype testing and verification
    • Presents case study-like examples of the technology used such as a surface plasmon resonance sensor and a robotic cell culturing system for human embryonic stem cells
    • Provides an interdisciplinary and unifying approach of the many fields of engineering and biotechnology used in biomechatronic design

    By combining designs between traditional electronic and mechanical subsystems and biological systems, this book demonstrates how biotechnology and bioengineering design can utilize and benefit from commonly used design tools-- and benefit humanity itself.

  • 45.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Steel, Daniella
    Cellartis AB, Gothenburg, Sweden.
    Noor, Fozia
    Biochemical Engineering, Saarland University, Saarbruecken, Germany.
    Meyer, Thomas
    MultiChannel Systems GmbH, Reutlingen, Germany.
    Heinzle, Elmar
    Biochemical Engineering, Saarland University, Saarbruecken, Germany.
    Asp, Julia
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Sweden.
    Arain, Sarina
    PerSens GmbH, Regensburg, Germany.
    Kraushaar, Udo
    Natural and Medical Sciences Institute at the University of Tübingen, Germany.
    Bremer, Susanne
    ECVAM, Institute for Health and Consumer Protection (IHCP), European Commission Joint Research Center, Ispra, Italy.
    Class, Reiner
    Pharmacelsus GmbH, Saarbruecken, Germany.
    Sartipy, Peter
    Cellartis AB, Gothenburg, Sweden.
    Cardiotoxicity testing using pluripotent stem cell-derived human cardiomyocytes and state-of-the-art bioanalytics: a review2011In: JOURNAL OF APPLIED TOXICOLOGY, ISSN 0260-437X, Vol. 31, no 3, p. 191-205Article, review/survey (Refereed)
    Abstract [en]

    In this article, recent progress in cardiotoxicity testing based on the use of immortalized cell lines or human embryonic stem cell (hESC) derived cardiomyocytes in combination with state-of-the-art bioanalytical methods and sensors is reviewed. The focus is on hESC-derived cells and their refinement into competent testing cells, but the access and utility of other relevant cell types are also discussed. Recent developments in sensor techniques and bioanalytical approaches for measuring critical cardiotoxicity parameters are highlighted, together with aspects of data evaluation and validation. Finally, recommendations for further research are given.

  • 46.
    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.

  • 47.
    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.

  • 48.
    Mandenius, Carl-Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Andersson, Tommy B
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm.
    Alves, Paula M
    IBET, Oeiras, Portugal .
    Batzl-Hartmann, Christine
    Pharmacelsus GmbH, Saarbrücken, Germany.
    Björquist, Petter
    Cellartis AB, Göteborg, Sweden.
    Carrondo, Manuel J. T.
    IBET, Oeiras, Portugal .
    Chesne, Christophe
    BioPredic SA, Rennes, France.
    Coecke, Sandra
    ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra, Italy.
    Edsbagge, Josefina
    Cellartis AB, Göteborg, Sweden.
    Fredriksson, J. Magnus
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Gerlach, Jörg C.
    Experimental Surgery, Charité Universitätsmedizin, Berlin, Germany.
    Heinzle, Elmar
    Biochemical Engineering, Saarland University, Saarbrücken, Germany.
    Ingelman- Sundberg, Magnus
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm.
    Johansson, Inger
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm.
    Kuppers-Munther, Barbara
    Cellartis AB, Göteborg, Sweden.
    Mueller-Vieira, Ursula
    Pharmacelsus GmbH, Saarbrücken, Germany.
    Noor, Fozia
    Biochemical Engineering, Saarland University, Saarbrücken, Germany.
    Zeilinger, Katrin
    Experimental Surgery, Charité Universitätsmedizin, Berlin, Germany.
    Toward Preclinical Predictive Drug Testing for Metabolism and Hepatotoxicity by Using In Vitro Models Derived from Human Embryonic Stem Cells and Human Cell Lines - A Report on the Vitrocellomics EU-project2011In: ATLA-ALTERNATIVES TO LABORATORY ANIMALS, ISSN 0261-1929, Vol. 39, no 2, p. 147-171Article in journal (Refereed)
    Abstract [en]

    Drug-induced liver injury is a common reason for drug attrition in late clinical phases, and even for post-launch withdrawals. As a consequence, there is a broad consensus in the pharmaceutical industry, and within regulatory authorities, that a significant improvement of the current in vitro test methodologies for accurate assessment and prediction of such adverse effects is needed. For this purpose, appropriate in vivo-like hepatic in vitro models are necessary, in addition to novel sources of human hepatocytes. In this report, we describe recent and ongoing research toward the use of human embryonic stem cell (hESC)-derived hepatic cells, in conjunction with new and improved test methods, for evaluating drug metabolism and hepatotoxicity. Recent progress on the directed differentiation of human embryonic stem cells to the functional hepatic phenotype is reported, as well as the development and adaptation of bioreactors and toxicity assay technologies for the testing of hepatic cells. The aim of achieving a testing platform for metabolism and hepatotoxicity assessment, based on hESC-derived hepatic cells, has advanced markedly in the last 2-3 years. However, great challenges still remain, before such new test systems could be routinely used by the industry. In particular, we give an overview of results from the Vitrocellomics project (EU Framework 6) and discuss these in relation to the current state-of-the-art and the remaining difficulties, with suggestions on how to proceed before such in vitro systems can be implemented in industrial discovery and development settings and in regulatory acceptance.

  • 49.
    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.

  • 50.
    Warth, Benedikt
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Rajkai, Gyorgy
    Belach Biotekn AB.
    Mandenius, Carl-Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Biotechnology . Linköping University, The Institute of Technology.
    Evaluation of software sensors for on-line estimation of culture conditions in an Escherichia coli cultivation expressing a recombinant protein2010In: JOURNAL OF BIOTECHNOLOGY, ISSN 0168-1656, Vol. 147, no 1, p. 37-45Article in journal (Refereed)
    Abstract [en]

    Software sensors for monitoring and on-line estimation of critical bioprocess variables have mainly been used with standard bioreactor sensors, such as electrodes and gas analyzers, where algorithms in the software model have generated the desired state variables. In this article we propose that other on-line instruments, such as NIR probes and on-line HPLC, should be used to make more reliable and flexible software sensors Five software sensor architectures were compared and evaluated. (1) biomass concentration from an on-line NIR probe. (2) biomass concentration from titrant addition, (3) specific growth rate from titrant addition. (4) specific growth rate from the NIR probe, and (5) specific substrate uptake rate and by-product rate from on-line HPLC and NIR probe signals. The software sensors were demonstrated on an Escherichia colt cultivation expressing a recombinant protein, green fluorescent protein (GFP), but the results could be extrapolated to other production organisms and product proteins. We conclude that well-maintained on-line instrumentation (hardware sensors) can increase the potential of software sensors This would also strongly support the intentions with process analytical technology and quality-by-design concepts

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