CHOlife@Interzell

Novel Production Processes and Multi-Scale Analysis, Modelling and Design of Cell-Cell and Cell-Bioreactor Interactions (SPP2170)

 

Contactperson: M.Sc. Sebastian Hofmann 

Financing: German Research Foundation (DFG) 

Duration: Since 2019

Partners:

Prof. Dr.-Ing. Ralf Takors, US, Institute of Biochemical Engineering (IBVT);

Prof. Dr. Georg Sprenger, US, Institute of Microbiology (IMB);

Prof. Dr. rer. nat. Miriam Agler-Rosenbaum, Leibniz-HKI;

Prof. Dr.-Ing. Jochen Büchs, RWTH, Biochemical Engineering (AVT);

Dr. Meike Baumgart, FZ Jülich, Institute of Bio- and Geosciences (IBG);

Prof. Dr. Dietrich Kohlheyer, FZ Jülich, Institute of Bio- and Geosciences (IBG);

Dr.-Ing. Christian Dusny , Helmholtz UFZ;

Dr.-Ing. Stephan Noack, FZ Jülich, Institute of Bio- and Geosciences (IBG);

Prof. Dr.-Ing. Alexander Grünberger, UB, Multiscale Bioengineering;

Prof. Dr.-Ing. Heiko Briesen, TUM, Process Systems Engineering (SVT);

Dr. Anna-Lena Heins, TUM, Biochemical Engineering (BioVT);

Prof. Dr.-Ing. Andreas Kremling, TUM, Systems Biotechnology (SBT);

Dr. Katharina Pflüger-Grau, TUM, Systems Biotechnology (SBT);

Prof. Dr.-Ing. Dirk Weuster-Botz, TUM, Biochemical Engineering (BioVT);

 

Motivation


Nowadays, the production of basic and fine chemicals or pharmaceutical proteins is established by pure cultures from bacteria, yeasts, fungi, mammalian cells, like CHO (Chinese Hamster Ovary) or phototrophic cells, like microalgae. However, in the natural environment these usually grow in consortia and use symbiotic mechanisms to enhance cell structure, catalytic pathways and population growth to generally benefit from each other. More than 95 percent of the microbial ora cannot be cultivated in pure culture, but only in mixed culture (biological dark matter). If it were possible to produce microbial ora in such mixed cultures, this would have enormous potential for the production of new biotechnological products. The positive results can only be roughly estimated by knowing the outcome of pure culture cultivation, which is dominating the market so far. Additionally, current synthetic biology methods over new possibilities for constructing entire biological consortia in such way that only this very co-culture is able to take over the production of a target product in an effcient way.

Once the bioprocesses are developed the performance data will be transferred from the laboratory scale to large-volume production scale. Obviously, this requires a profound understanding of the interactions between the production cells and the partially harsh production conditions inside a fermenter. The priority program InterZell therefore aims to establish the synthetic mixed culture as a new microbial production process. Furthermore, the researchers will be transfering the results from the laboratory to the technical production scale without loss of performance. InterZell is contributing to sustainable production ways and bringing together the natural and engineering sciences. Thus, this program with all its 21 PhDs and their group leaders from multiple universities and research facilities will strengthen the quality and visibility of Germany as a research location in the long term. Moreover, InterZell aims particularly at the networking of engineers and natural scientists. The main idea is to achieve a close interaction between engineering and natural sciences by combining theory and experiments cross-group wise.


Goals


In order to understand the cultivation processes it is indispensable to get deep insights into the overall and local hydrodynamics with high spatial and temporal resolution. Velocity and concentration gradients (such as pH, O2, CO2), differences in shear stress as well as the mass transfer performance need to be measured and characterized in a system without cells to transfer the gained knowledge eventually to a system with cells. Furthermore the timescale, a cell would be exposed to certain conditions, is of tremendous importance.

On the one hand, in aerated stirred bioreactors, the local hydrodynamics is dominated by stirring and additionally in induced by the buoyancy driven flow induced by rising gas bubbles, which makes the prediction of flow structures in large scale bioreactors even more difficult.

On the other hand, multi-stage arrangements may lead to the formation of compartments within the reactor, even though each stage has a well-mixed radial zone around the impeller with two stable toroidal vortices. Consequently, mixing time increases under certain conditions and mass transfer between occurring zones is limited axially and hindering optimal fermentation results. In close collaboration with the Institute of Biochemical Engineering (IBVT) at the University of Stuttgart a novel scale-up simulator will be developed, in which mentioned compartments can be mimicked in a small scale and results taken into account for test trials in a 12,000 L bioreactor at the Institute of Multiphase Flows (IMS) at the Hamburg University of Technology. Furthermore, three dimensional streamlines of particles of different sizes will be measured to determine areas of strong acceleration, local mixing time distributions and dead zones inside a reactor. Another main goal will be developing free-floating sensors, which will measure process conditions wirelessly during a cultivation to create a reliable and predictable picture of a fermentation of different scales. Our sub-project is called CHOLife, which means summarized a multi-scale experimental analysis and further simulation of lifelines (streamlines of cells) in bioreactors to study their impact on the cultivation performance of CHO cells. Thanks to the nancing of the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) we have the quite unique possibility to prove a novel approach as successful over the next six years - with the condensed knowledge of multiphase flows, biochemistry, microelectronics, mechanical and process engineering.