Project

Back to overview

Fluid dynamics and mixing behavior in orbitally shaken bioreactors for mammalian cell cultivation

English title Fluid dynamics and mixing behavior in orbitally shaken bioreactors for mammalian cell cultivation
Applicant Wurm Florian
Number 125444
Funding scheme Sinergia
Research institution EPFL SV SV-DEC PH-SV AAB 1 46 (Bâtiment AAB) Station 19
Institution of higher education EPF Lausanne - EPFL
Main discipline Fluid Dynamics
Start/End 01.04.2009 - 31.08.2013
Approved amount 744'757.00
Show all

Keywords (10)

bioreactor; orbital shaking; mass transfer; computation fluid dynamics; mathematical modelling; mixing; mammalian cells; recombinant protein; shear stress; fluid velocity

Lay Summary (English)

Lead
Lay summary
Objective. The main objective of this project is to understand gas transfer and mixing in orbitally shaken bioreactors for the cultivation of mammalian cells in suspension. This will be done to improve the design and operating parameters in these reactors and to ultimately achieve predictable cell growth over a range of volumetric scales.Rationale and significance. Recombinant therapeutic proteins are frequently produced in mammalian cells cultivated in suspension in large-scale stirred tank bioreactors. However, stirred-tank bioreactors are expensive to purchase and maintain. Second, they have not been adapted to volumetric scales less than one liter, making small-scale studies difficult to extrapolate to large-scale. Third, non-homogeneous mixing and limited mass transfer capacity are frequently observed in these bioreactors. As an alternative, orbitally shaken bioreactors for suspension cultivation at scales of operation from a few milliliters to 1'000 liters are being developed. Orbital shaking is a scalable technology and it confers less shear stress on cells as compared to stirred-tank bioreactors. Unfortunately, there is very little known about the engineering characteristics of orbitally shaken bioreactors, and the optimal geometry and operating parameters have not been determined. The characterization of these bioreactors is necessary to support their establishment as alternatives to stirred-tank bioreactors for producing recombinant therapeutic proteins.Methods. The mass transfer rate, mixing time, homogeneity of mixing, and shear stress are important parameters for bioreactors. For orbitally shaken bioreactors, these factors depend on the geometry of the container, the shaking speed, the shaking diameter, and the liquid height to container diameter ratio. Numerical approaches based on Computational Fluid Dynamics (CFD) will be combined with experiments in fluid dynamics and cell cultivation to optimize mixing and mass transfer in shaken bioreactors. The project will be initiated by characterization of mass transfer and mixing in a shaken 30 liter cylindrical container. Mixing and mass transfer will be simulated by CFD, and the model will be compared to experimental measurements of fluid velocity, gas transfer, and mixing. A cell culture model based on the cultivation of mammalian cells in orbitally shaken containers will be generated and incorporated into the CFD model. Simulations of the validated CFD-derived model will be used to improve the geometric design of the 30 liter container to facilitate mixing, gas transfer, and cell growth. The most effective designs, as judged by simulations, will be validated experimentally.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Disposable 600-mL orbitally shaken bioreactor for mammalian cell cultivation in suspension
Monteil Dominique (2013), Disposable 600-mL orbitally shaken bioreactor for mammalian cell cultivation in suspension, in Biochemical Engineering Journal, 76, 6-12.
Numerical simulation of orbitally shaken viscous fluids with free surface
Discacciati Marco (2013), Numerical simulation of orbitally shaken viscous fluids with free surface, in INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS, 71, 294-315.
kLa as a predictor for successful probe-independent mammalian cell bioprocesses in orbitally shaken bioreactors
Tissot Stéphanie (2012), kLa as a predictor for successful probe-independent mammalian cell bioprocesses in orbitally shaken bioreactors, in New Biotechnology, 29(3), 387-394.
Efficient and reproducible mammalian cell bioprocesses without probes and controllers?
Tissot Stéphanie (2011), Efficient and reproducible mammalian cell bioprocesses without probes and controllers?, in New Biotechnology, 28, 382-390.
Determination of a scale-up factor from mixing time studies in orbitally shaken bioreactors
Tissot Stéphanie (2010), Determination of a scale-up factor from mixing time studies in orbitally shaken bioreactors, in Biochemical Engineering Journal, 52, 181-186.
Numerical approximation of internal discontinuity interface problems
Discacciati Marco, Numerical approximation of internal discontinuity interface problems, in SIAM Journal on Scientific Computing.

Collaboration

Group / person Country
Types of collaboration
Dr. Nicola Parolini, Laboratory of Modeling and Scientific Computing MOX, Politecnico di Milano Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Protein Expression in Animal Cells (PEACe) conference Poster 22.09.2013 Kananaskis, Alberta, Canada Wurm Florian; Hacker David; Monteil Dominique;
European Society for Animal Cell Technology Meeting Poster 23.06.2013 Lille, France Monteil Dominique; Wurm Florian; Hacker David;
European Society for Animal Cell Technology meeting Poster 23.06.2013 Lille, France Wurm Florian; Hacker David; Monteil Dominique;
European Society for Animal Cell Technology meeting Poster 23.06.2013 Lille, France Monteil Dominique; Wurm Florian; Hacker David;
OrbShake Technology meeting Talk given at a conference 21.09.2012 Monthey, Switzerland Farhat Mohamed; Redclari Martino;
Invited talk at Tohoku University Talk given at a conference 25.02.2012 Sendai, Japan Farhat Mohamed;
American Physical Society, 64rd annual meeting, Division of Fluid Dynamics Talk given at a conference 20.11.2011 Baltimore, United States of America Farhat Mohamed; Redclari Martino;
RMMM 2011 - Reliable methods of mathematical modeling Talk given at a conference 03.07.2011 Lausanne, Switzerland Quarteroni Alfio; Quinodoz Samuel;
European Society for Animal Cell Technology meeting Poster 15.05.2011 Vienna, Austria Hacker David; Wurm Florian; Monteil Dominique; Quinodoz Samuel; Quarteroni Alfio; Farhat Mohamed; Tissot Stéphanie;
European Society for Animal Cell Technology meeting Poster 15.05.2011 Vienna, Austria Hacker David; Wurm Florian; Tissot Stéphanie; Monteil Dominique;
16th International Conference on Finite Elements in Flow Problems Location Talk given at a conference 23.03.2011 Münich, Germany Quinodoz Samuel; Quarteroni Alfio;
American Physical Society, 63rd annual meeting, Division of Fluid Dynamics Talk given at a conference 21.11.2010 Long Beach, United States of America Farhat Mohamed; Redclari Martino;
ETW European Biotechnology Workshop Poster 12.09.2010 Ittingen, Switzerland Farhat Mohamed; Redclari Martino;
Centre International de Rencontres Mathématiques conference on fictitious domain methods for immersed boundary conditions Talk given at a conference 30.08.2010 Marseille, France Quarteroni Alfio; Quinodoz Samuel;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Orbital shaking: From Wine Swirling to Large Bioreactors International 2012
Video/Film "Oenodynamic": Hydrodynamic of wine swirling International 2011

Abstract

The main objective of this collaborative project is to understand transport phenomena (oxygen transfer and mixing) in orbitally shaken bioreactors in order to improve their design and operation and to ultimately achieve predictable cell growth profiles over a range of volumetric scales. Numerical approaches based on Computational Fluid Dynamics (CFD) will be combined with experiments in fluid dynamics and cell cultivation to simulate and optimize mixing and mass transfer in shaken bioreactors for the suspension cultivation of mammalian cells. The project will be initiated by characterization of mass transfer and mixing in a shaken 30 L cylindrical vessel, a medium-scale bioreactor suitable for the experimental and computational methods described here. Mixing and mass transfer in this vessel will be simulated by CFD, and the model will be compared to experimental measurements of fluid velocity, gas transfer, and mixing. At the same time, a cell culture model based on cultivation of Chinese hamster ovary (CHO) cells in orbitally shaken containers will be generated and incorporated into the CFD model. Simulations of the validated CFD-derived model (with and without cell growth) will be used to improve the geometric design of the 30 L cylindrical vessel to facilitate mixing, gas transfer, and cell growth. The most effective designs, as judged by simulations, will be validated experimentally. Finally, the scalability of shaken cylindrical vessels and vessels with other geometries will be determined through a combination of numerical and experimental methods.
-