Activities at the division of Biotechnology
The research and education at the division of biotechnology focus on industrial applications in biotechnology. We regard biotechnology as the engineering of biology, emphasizing that we engineer biological systems by using the fundamental principles and unfolding tools of engineering. The LiTH master program (civilingenjörsprogram) in Engineering Biology conceives this into a coherent education and engineering degree.
Worldwide, industrial biotechnology research is synonymous with the integration of engineering and biosciences for production purposes (IUPAC). The scientific breakthroughs during the past century in molecular biology have unfolded an exceptional industrial development and realisation in the use of microorganisms and cell cultures, biopharmaceuticals, pluripotent stem cells, biosensors, DNA microarrays, protein science and bioprocessing
In Linköping and at IFM we dedicate much of our research to apply physics into biotechnology. We combine physics with engineering of metabolic, protein, cellular and organ systems to support production of biologics and fabrication of devices with the prime task to provide new and better industrial applications.
Core capabilities of the division of Biotechnology
Design of cell-based assays
To develop safe, efficient and competitive new medicines remain very demanding and require substantial time in the biopharmaceutical industry. Our ambition is to contribute to shorten the development time by inventing new cell-based assays with higher accuracy and speed at lower cost per analysis. In recent years we have actively exploited pluripotent stem cells and advanced sensor methods for developing better assay methodology for safety and efficacy testing. This has included development of new cell-based assays for cardiac and liver cells, together with several large and SME pharma companies within the EU-projects StemBANCC (www.stembancc.org/), Vitrocellomics and Invitroheart, as well as in various national projects (see examples below). Our capabilities are available for new projects and collaborations.
• Cader Z, Graf M, Burcin M, Mandenius CF, Ross J (2018) Cell-based assays using differentiated human induced pluripotent cells. (Eds. Ross JD, Mandenius CF) Springer Nature Protocols in Molecular Biology in press
• Mandenius CF, Steel D, Noor F, Meyer T, Heinzle E, Asp J, Arain S, Kraushaar U, Bremer S, Class R, Sartipy S (2011) Cardiotoxicity testing using pluripotent stem cell derived human cardiomyocytes and state-of-the-art bioanalytics: a review. J. Appl. Toxicol. 31, 191-205.
• Christoffersson J, Meier F, Kempf H, Schwanke K, Coffee M, Beilmann M, Zweigerdt R, Mandenius CF (2018) A cardiac cell outgrowth assay for evaluating drug compounds using a cardiac spheroid-on-a-chip device. Bioengineering 5, 36.
Bioprocess monitoring and control by fused sensors
The biotechnology industry lacks real-time sensors for critical quality parameters. We develop methods based on soft sensors to accomplish online monitoring, modelling and control of bio
processes with the purpose to enhance better product quality, higher productivity and more sustainable processes, in compliance with the Process Analytical Technology (PAT) principles.
Examples of projects we pursue are integrated soft sensors with mechanistic models, fused sensors for adaptive control, calorimetric sensors, fibre-optical real-time sensors and sensor design for downstream processing. We take part in several national and international projects (e.g. the EU-Marie Curie project on rapid bioprocess development, www.bio-rapid.eu/ and the VINNOVA program on biological production).
• Mandenius CF, Gustavsson R (2016) Soft sensor design for bioreactor monitoring and control. In: Bioreactors: Design, Operation and Novel Applications (Editor C.F. Mandenius) Wiley VCH, Weinheim, Germany.
• Randek J, Mandenius CF (2018) On-line soft sensing in upstream bioprocessing. Critical Review Biotechnology 38, 106-121.
• Roch P, Mandenius CF (2016) On-line monitoring of downstream bioprocesses. Current Opinion in Chemical Engineering 14, 112–120.
Microfluidics and organ-on-a-chip
Organ-on-a-Chip and microfluidics are by FDA and other regulatory organisations examples of microphysiological systems with high potential for providing more relevant and accurate disease and drug models. This could solve many of today’s shortcomings encountered in drug development and environmental medicine. Our main ambition is to provide small micro-designed systems with stem cell-derived organ cells. We are involved in several projects aiming at the development of cell-based sensors for in vitro testing and analysis. At present, the research has two directions: Cancer cell fractionation in microfluidic (microbore) devices (in collaboration with Korea) and heart-on-a-chips for testing of cardiac drugs. We believe we have a unique capacity of merge sensor technology, microsystems technology and bioengineering into new designs of benefit for healthcare and environment.
• Bergström G, Christoffersson J, Zweigerdt R, Schwanke K, Mandenius CF (2015) Stem cell derived cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging. Lab Chip 15, 3242-3249.
• Pasitka L, van Noort D, Lim W, Park S, Mandenius CF (2018). A microbore tubing-based spiral for multi-step cell fractionation. Anal Chem 90, 21, 12909-12916.
Conceptual design for biotechnology applications
The biotechnology industry can speed up its development of new products and processes by applying systematic and efficient design methodology. We call this conceptual design because we use a conceptual and functional thinking in the design process before we start resource-demanding engineering and prototyping work. We call the methodology Biomechatronics to highlight that design in biotechnology is extremely complex because it involves three diverse areas: bio(logy), mecha(nics), and (elec)tronics. Biomechatronics is applicable to many kinds of bioproducts, such as bioprocesses, protein purification systems, bioreactors, biosensors, micro arrays, biochips, microfluidics and PAT. Several publications are available from our research and new projects are constantly launched.
• Christoffersson J, van Noort D, Mandenius CF (2017) Developing organ-on-a-chip concepts using bio-mechatronic design methodology. Conceptual design of an Organ-on-a-Chip. Biofabrication 9, 025023.
• Mandenius CF, Björkman M. 2011. Biomechatronic Design in Biotechnology: a Methodology for Development of Biotechnology Products. John Wiley & Sons, Inc., Hoboken, New Jersey, USA.
Operator Training Simulators
Good Manufacture Practice (GMP) of bioprocesses requires efficient training and education of process operators and engineers. With computer power this can be achieved by creating virtual operator environments for simulator training. This is often done within other areas (e.g. flight simulators) but the complexity of biology makes it a challenge for biotechnology applications. We have developed Operator Training Simulators for large-scale bioproduction plants as well as for engineering education that significantly enhance efficiency in training of process technicians and engineering students.
• Gerlach I, Hass VC, Brüning S, Mandenius CF (2013) Virtual bioreactor cultivation for operator training and simulation: Application to ethanol and protein production. J. Chem. Technol. Biotechnol. 88, 2159–2168.