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LIFE - Transcriptomics Group

Bioinformatik Uni Leipzig

http://www.life.uni-leipzig.de

Growth optimization of MDCK-cells on Microcarriers: A modelling approach


Dirk Drasdo, Nick Jagiella
Interdisciplinary Centre for Bioinformatics
University of Leipzig

Cooperation:
Udo Reichl
Max-Planck-Inst. for Complex Technical Systems
Magdeburg


Background: One of the most important and well established systems for the production of vaccines is the growth of attenuated viruses in Madin-Darby kidney cells (MDCK). Current manufacturing processes utilizing these cells rely on the use of serum supplemented medium. One of the subjects of the MPI for the Dynamics of Complex Technical Systems is the development and optimization of integrated concepts to design and control vaccine production processes. This implies an optimization of virus yield which in turn implies to optimize the yield of MDCK-cells growing on microcarriers in the roller bottles (Figs. 1,2). The cells are administered into the growth medium where they attach at the microcarriers on which they grow and divide until eventually the microcarriers are covered by cells. Cells may detach from the microcarriers and undergo apoptosis. The growth kinetics depends on the initial density of cells in the reactor, the attachment and detachment rate, the growth rate, the proliferation depth, the density of microcarries in the bioreactor, the size of the microcarriers etc.


Figure 1: Scheme of virus production (Prof. Reichl): A) cells are cultured in roller bottles, (B) infected by virus, and eventally (C) downstream processing.
Fig. 2: Microcarrier populated by MDCK-cells


Model: The model considers cells as polygons on a sphere (Fig. 3) and uses the same modelling technique as for monolayers growing on flat substrates (Drasdo, 2005). The complete stochastic process consisting of attachment, growth etc. in modelled by a master equation and numerically integrated.

Fig. 3: The cells (blue circles in (B)) on a spherical microcarrier are modelled as polygons on a sphere. (A).
Results: The efficient modeling technique permits to perform computer simulation over wide parameter ranges. First comparisons with experiments show a good agreement.

Benefit and outlook: Eventually the project aims at predicting optimal conditions for the growth of MDCK cells on microcarriers. So far the models used are based on differential equations. They include parts of the metabolic reactions but neglect the influence of space. Eventually, the model aims at including space and metabolism.


Fig. 4: Mathematical growth model for adherent Madin Darby Canine Kidney Cells on microcarrier, Moehler, L., bock, A. and Reichl, U., in preparation.


Publications:
Drasdo, D. (2005)
Coarse graining in simulated cell populations.
Adv. Complex Syst., 2 & 3, 319-364.
Galle, J., Aust, G., Schaller, G., Beyer, T., Drasdo, D. (2005)
Individual cell-based models of the spatio-temporal organisation of multicellular systems - achievements and limitations.
Cytometry, accepted.
Drasdo D, Höhme, S.
A single-cell based model of tumor growth in vitro: monolayers and spheroids.
Phys. Biol. 2005; 2:133-147.

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