Chemistry: molecular biology and microbiology – Apparatus – Differentiated tissue perfusion or preservation apparatus
Patent
1992-01-14
1994-03-01
Warden, Robert J.
Chemistry: molecular biology and microbiology
Apparatus
Differentiated tissue perfusion or preservation apparatus
435285, 435287, 435311, C12M 300, C12M 304, C12M 100, C12M 112
Patent
active
052907007
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a continuous bulk cell culture device, or bioreactor, which makes it possible in particular to improve the preparation of the products of said cultures.
Several cell culture methods and devices are known at the present time.
Cells can be cultured on a smooth surface such as appropriate plastic or glass (dishes or tubes). Such cultures do not permit substantial cell growth and they require large amounts of nutriments.
In particular, U.S. Pat. Nos. 3,883,393 (USA), 3,997,396 (MONSANTO Co.), 4,087,327, 4,201,845 (MONSANTO Co.), 4,220,725 (USA) and 4,391,912 describe systems in which the cells are cultivated on or near hollow fibers.
U.S. Pat. No. 4,201,845 (MONSANTO Co.) describes in particular a cell culture reactor comprising a culture chamber in which a layer of hollow fibers for supplying gas is sandwiched between a microporous membrane for distributing the culture medium and a microporous membrane acting as a barrier to diffusion of the cells out of said chamber. The flow of medium is directed upwards and transversely to the plane of the fibers.
However, this device has a number of disadvantages; in particular, there are risks that the membrane distributing culture medium will clog because of the frontal attack on said membrane, this clogging resulting in local inequalities of flow rate and non-homogeneous nutriment distribution.
In some of these devices, and especially in the MONSANTO device, the distribution of the medium towards the cells is not effected homogeneously over the whole surface of the plate; this can cause disparities, which are difficult to control, in the metabolism of the cells, according to their position in the device, and difficulties in extrapolating the size of the device, especially in the context of industrial production.
The aim of the Applicant was consequently to provide a bioreactor, or cell culture device, which meets practical needs better than the devices of the prior art, especially by making it possible to produce culture products, continuously and in bulk, from cultures kept at a high cell concentration in excess of 5.10.sup.8 /cm.sup.3, over a long period, without causing clogging, i.e. without reducing the flow rate of nutriments in the whole of the cell space, and to use a cell space of large dimensions which is better suited to the industrial scale.
The present invention relates to a cell culture device, or bioreactor, especially for the production of metabolites, of the type comprising a cell culture space in which the cells are confined in a liquid medium--said space being delimited by walls of which at least three are selectively permeable, the first to the fresh nutrient medium, the second to the gaseous fluids and the last to the spent nutrient medium--and means of circulating the fluids in said device, characterized in that the first wall consists of a sheet of tubes whose wall is permeable to the fresh nutrient medium, said tubes being assembled in parallel between an inlet manifold and an outlet manifold in a closed-loop circuit including means of supplying said fresh nutrient medium, and fresh medium passing through each of said tubes, from end to end, at a flow rate which is several times greater than that passing through its wall.
In terms of the present invention, fresh medium is understood as meaning a nutriment-rich medium supplied to the cells for their needs and their growth.
Spent medium is understood as meaning a nutriment-impoverished medium containing the metabolites excreted by said cells.
According to one advantageous characteristic of this device, the flow rate of the medium passing through each tube corresponds to a flow velocity of the order of 1 dm/s, which guarantees the tangential filtration of the fresh medium through the wall of said tubes.
According to another characteristic of said device, said tubes are rigid and have a diameter of the order of a centimeter, their wall having pores whose diameter allows the nutriment molecules, and especially the molecules with a molecular weight of more than 150 kDa
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Tharakan, J. P., et al., (1986) Biotechnology and Bioengineering, vol. XVIII, pp. 329-342.
Binot Patrick
Cognard Dominique
Dufau Frederic
Hache Jean
Bertin & Cie.
Brunelle Jan P.
Dreger Walter H.
Kim Christopher Y.
Warden Robert J.
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