Animal cell bioreactors

J. Tramper. Oxygen gradients in animal-cell bioreactors. Animal Cell Technol 883-891, 1995. 

In low shear, there is low mixing which means the bioreactor can be used for growing plant and animal cells. 

Surface interactions play an important role in the ability of certain animal cells to grow and produce the desired bioproducts. An understanding of the dynamics of cell surface interactions in these "anchorage-dependent" cells (cells that function well only when attached to a surface) will be needed, for example, to improve the design of bioreactors for growing animal cells. 

Three major intellectual frontiers for chemical engineers in bioprocessing are the design of bioreactors for the culture of plant and animal cells, the development of control systems along with the needed biosensors and analytical instraments, and the development of processes for separating and purifying products. A critical component in each of these three research areas is the need to relate the micro-scale to the mesoscale. 

One problem mentioned earlier is that certain animal cells are anchorage-dependent. Also, plant and animal cells are easily raptured by mechanical shear. Bioreactors for handhng such cells must be designed so that the contents of the reactor can be mixed without disrupting the cells. A similar problem exists in the design of systems to transfer the cells from one vessel to another. 

Special reactors are required to conduct biochemical reactions for the transformation and production of chemical and biological substances involving the use of biocatalysts (enzymes, immobilised enzymes, microorganisms, plant and animal cells). These bioreactors have to be designed so that the enzymes or living organisms can be used under defined, optimal conditions. The bioreactors which are mainly used on laboratory scale and industrially are roller bottles, shake flasks, stirred tanks and bubble columns (see Table 1). 

Kalogerakis, N., and Behie, L. A., Oxygenation Capabilities of New Generation Three Phase - Two Region Bioreactors for Microcarrier Cultures of Animal Cells, Fluidization VIII, (C. Laguerie, and J. F. Large, eds.), p. 441, Engineering Foundation, Tours, France (1995)... 

Figure 5.9 Design of a generalized microbial cell fermentation vessel (a) and an animal cell bioreactor (b). Animal cell bioreactors display several structural differences compared with microbial fermentation vessels. Note in particular (i) the use of a marine-type impeller (some animal cell bioreactors-air lift fermenters-are devoid of impellers and use sparging of air-gas as the only means of media agitation) (ii) the absence of baffles (iii) curved internal surfaces at the bioreactor base. These modifications aim to minimize damage to the fragile animal cells during culture. Note that various additional bioreactor configurations are also commercially available. Reprinted with permission from Proteins Biochemistry and Biotechnology (2002), J. Wiley Sons...

Different animal cell types display different properties pertinent to their successful culture. Those used to manufacture biopharmaceuticals are invariably continuous (transformed) cell lines. Such cells will grow relatively vigorously and easily in submerged culture systems, be they roller bottle or bioreactor based. 

Master and working banks of both the viral vector and the animal cell line will have been constructed during the drug development process (see Chapter 4). Manufacture of a batch of vector, therefore, will be initiated by the culture of packing cells in suitable animal cell bioreactors. The... 

Stirred bioreactors are common in animal cell culture, as they offer a homogenous enviroiunent, representative sampling, better access to process control and an increased oxygen transfer. Several of these techniques (spinner flasks and stirred vessel bioreactors) have been tested successfully for the cultivation of hematopoietic cells [58,64-67]. 

Tokashiki M, Yokoyama S (1997) Bioreactor designed for animal cells. In Hanser H, Wagner R (eds) Mammalian cell biotechnology in protein prodnction. Walter de Gruyter, Berlin, p 279... 

Helmrich, A. Barnes, D. (1998). Animal cell culture equipment and techniques. Methods Cell Biol. 57, 3-17. Houdebine, L. (2000). Transgenic animal bioreactors. Transgen. Res. 9(4-5), 305-320. 

Commercial manufacturing operations in biotechnology usually employ bioreactors or fermentors for product expression. In this discussion, the term fermentor will refer to bacterial or fungal processes and the term bioreactor to animal cell cultures. While extensive description of the operation... 

The impact of hydrodynamic stress on animal cells has been reviewed extensively (29,43). Most of the work reported in the literature on cell damage in agitated bioreactors has been done at bench-scale. Kunas and Papoutsakis (44) reported that in 1-2 L bioreactors equipped with a 7 cm diameter pitched-blade impeller, cell damage was not observed until the impeller rate was raised to above 700 rpm (tip speed 513cm/s), as long as air entrapment did not occur. However, it is not clear how these bench-scale observations translate into damaging impeller rates at manufacturing scale. 

Papoutsakis ET. Fluid-mechanical damage of animal cells in bioreactors. Trends Biotechnol 1991 9 427-437. 

Hua J, Erickson LE, Yiin T-Y, Glasgow LA. A review of the effects of shear and interfacial phenomena on cell viability. Grit Rev Biotechnol 1993 13(4) 305-328. Tramper J, de Gooijer KD, Vlak JM. Scale-up considerations and bioreactor development for animal cell cultivation. Bioprocess Technol 1993 17 139-177. Griffiths B, Looby D. Scale-up of suspension and anchorage-dependent animal cells. Methods Mol Biol 1997 75 59-75. 

Kunas K, Papoutsakis ET. Damage mechanisms of suspended animal cells in agitated bioreactors with and without bubble entrainment. Biotechnol Bioeng 1990 36 476-483. 

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