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|Inventor(s)||Ihsan A. Haddad · Alvin R. Arsenault ·|
Instrumentation Laboratory, Inc. ·
|Primary Examiner||Alvin E. Tanenholtz ·|
|Predicted expiration date||05/31/1993|
|U.S. Classifications||195/127 · 195/142 ·|
|International Classifications||C12B 100 ·|
|International Classifications||195127;139;142;109 ·|
|Related U.S. Application Data||This application is a continuation in part of our co-pending patent application Ser. No. 365,535, filed May 31, 1973 now U.S. Pat. No. 3,887,436, entitled "Fluid Handling".|
SUMMARY OF INVENTION
This invention relates to the growth of living cells, and more particularly to systems for such cell culture and chambers for use in such systems.
The culture of cells in monolayer films is well known and has permitted very rapid development of virological techniques and the manufacture of antiviral vaccines from viruses produced in vitro under reproducible and readily controllable conditions.
Numerous cell propagation arrangements have been proposed in which conditions are established which approach a cell environment in the intact animal. Such cell propagation arrangements include the use of stationery "Roux" flasks, and "roller" bottles, the tissue culture chambers typically being of glass or plastics materials. Another example of a proposed system is described in the article "Cell Propagation of Films of Polymeric Fluorocarbon as a Means to Regulate Pericellular pH and PO.sub.2 in Cultured Monolayers", Munder et al. FEBS Letters, Volume 15, No. 3, June 1971, page 191. A particular need exists for improved large scale cell culture systems.
An object of this invention is to provide a novel and improved cell culture system.
Another object of this invention is to provide an improved tissue culture or cell growth chamber for use in large scale culturing of cells or similar materials, for example cells of animal origin.
In accordance with a feature of the invention there is provided a replaceable, sterilizable, cell growth assembly comprising a chamber structure of gas permeable, liquid impermeable material having an inner surface to which cells are attachable. The chamber is of tubing configuration and is disposed in a plurality of layers in stacked relation. Spacer structure between the layers of tubing define a plurality of flow passages between the layers and enable a gaseous environment to bathe the majority of the external surface area of the tubing layers. The chamber also includes an inlet conduit for introducing culture media for flow through the plural layers of the chamber structure and an outlet conduit for receiving culture media from the chamber structure, and coupling structure for detachably connecting the inlet conduit to a source of culture media and the outlet conduit to an appropriate culture media receptacle.
In a particular embodiment, the sample chamber is an elongated tubular member disposed in spiral configuration and both the inlet and outlet conduits are of flexible resilient tubing, the ends of which provide the detachable coupling structure. The chaamber is made of a sheet of fluorinated ethylene-propylene copolymer, one surface of which has been chemically etched although other suitable gas permeable liquid impermeable materials may be used. The spacer structure may take a variety of forms, for example, a sheet member to which are secured on each side a multiplicity of uniformly spaced protrusions, an embossed sheet, or a sheet of "expanded metal" configuration. In a particular embodiment the spacer structure includes a convoluted strip member that is disposed between adjacent turns or layers of the spiral configuration chamber, providing positive support of those layers, maintaining them spaced from one another and defining a multiplicity of transverse flow passages extending along its length. The convolutions or other support portions of the spacer structure provide small and closely spaced support areas so that the chamber wall does not sag into contact with the spacer structure at points between the support portions and the majority of the external chamber surface area is spaced from the spacer structure, providing multiple gas flow paths across the external surfaces of each layer. Supplemental spacer portions are preferably provided along each edge of each interposed spacer sheet to maintain the stacked sheets of the spacer structure spaced from one another to provide the requisite gas flow paths. Thus nutrient media may be flowed through the chamber from the inlet conduit to the outlet conduit to bathe cells attached to the inner surfaces of the multilayer chamber and gases in the area surrounding the chamber diffuse through the chamber walls into the chamber.
This invention provides a replaceable culture chamber which provides particular convenience for use in arrangements adapted for large scale and efficient cell culture.
In accordance with another feature of the invention there is provided a cell culture system comprising a housing, a cell culture substrate in the housing, the cell culture substrate being of gas permeable, liquid impermeable material and having a first surface to which cells are attachable and an opposite surface exposed to the gaseous environment in the housing. A nutrient media circulation path includes supply and return conduits connected to the cell culture substrate, means for circulating nutrient media along the circulation path and across the surface of the cell culture substraate to which cells are attachable, a redox sensor for monitoring the reduction-oxidation potential of nutrient media in the circulation path, and a control responsive to the redox sensor for controlling the gaseous environment in the housing and specifically controlling the introduction of oxygen to the housing for flow across the opposite surface of the cell culture substrate to provide a controlled atmosphere conducive to cell growth on the substrate.
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