Automated, multicompartmental cell culture system

• US 5,612,188 A
• Filed: 02/10/1994
• Issued: 03/18/1997
• Est. Priority Date: 11/25/1991
• Status: Expired due to Term

• Current Assignee: Cornell Research Foundation Incorporated (Cornell University)
• Original Assignee: Cornell Research Foundation Incorporated (Cornell University)
• Inventors: Sweeney, Lisa M., Babish, John G., Johnson, Brian E., Shuler, Michael L.
• Primary Examiner(s): Beisner, William H.
• Application Number:
  US08/194,792
• Time in Patent Office: 1,132 Days
• Field of Search: 364/413.1, 364/413.01, 435/313-315, 435/284, 435/286, 435/287, 435/291, 435/299, 435/32, 435/29, 435/285, 435/240.2, 435/3, 435/284.1, 435/286.5, 435/286.6, 435/287.1, 435/289.1 , 435/294.1, 435/297.2, 435/297.4, 435/303.1, 435/1.1, 435/1.2, 435/33, 436/63
• US Class Current: 435/29
• CPC Class Codes: C12M 21/08 for producing artificial tissue or for ex-vivo cultivation of tissue prostheses A61F2/00, grafts A61L27/00
• CPC Class Codes: C12M 23/58 Reaction vessels connected in series or in parallel combinations of bioreactors with other apparatus, C12M43/00
• CPC Class Codes: C12M 29/14 Pressurized fluid
• CPC Class Codes: C12M 35/08 Chemical, biochemical or biological means, e.g. plasma jet, co-culture
• CPC Class Codes: C12M 37/00 Means for sterilizing, maintaining sterile conditions or avoiding chemical or biological contamination C12M23/38 takes precedence; filtration in general and filters per se B01D24/00-B01D41/00; autoclaves B01J3/04; treatment of microorganisms with electrical or wave energy C12N13/00
• CPC Class Codes: C12M 41/34 of gas
• CPC Class Codes: C12M 41/48 Automatic or computerized control automatic analysis G01N35/00
• CPC Class Codes: G01N 33/5082 Supracellular entities, e.g. tissue, organisms
• CPC Class Codes: G16H 10/40 for data related to laboratory analysis, e.g. patient specimen analysis

Abstract

The present invention relates to an in vitro system for physiological and metabolic evaluation of substances for use in living beings. The system includes one or more cell culture chambers, each containing cells in a culture medium and a gas-liquid exchange device for contacting the culture medium with oxygen-containing gas so that the culture medium absorbs that gas and desorbs carbon dioxide-containing gas. The conduit system conducts culture medium between the gas-liquid exchange device and the cell culture chambers. A circulation mechanism is used to circulate culture medium through the conduit system, the cell culture chambers, and the gas-liquid exchange device. In use, the substance to be evaluated is added to the culture medium of the system and circulated through the system. The cells in each of the cell culture chambers are then evaluated for effects resulting from the presence of the substance.

Claims

1. An in vitro system which maintains different cell types in a viable state comprising:

a plurality of cell culture chambers each containing the different cell types in a culture medium containing a substance to be evaluated;

a gas-liquid exchange device;

a conduit system to conduct culture medium between said gas-liquid exchange device and said plurality of cell culture chambers;

a circulation mechanism for circulating culture medium through said conduit system, said plurality of cell culture chambers, and said gas-liquid exchange device, including circulating culture medium between said plurality of cell culture chambers, wherein the substance to be evaluated contacts the different cell types, thereby producing either metabolites of the substance to be evaluated or metabolites of the different cell types; and

a microprocessor to control operation of said gas-liquid exchange device and said circulation mechanism, wherein said plurality of cell culture chambers, said conduit system, and said circulation mechanism are configured such that the metabolites of the different cell types or the metabolites of the substance to be evaluated are exchanged between said plurality of cell culture chambers.

2. An in vitro system according to claim 1, wherein one of said plurality of cell culture chambers contains lung cells.

3. An in vitro system according to claim 2, wherein said conduit system connects the cell culture chamber containing lung cells with the gas-liquid exchange device and with one or more of said plurality of cell culture chambers each containing different types of cells.

4. An in vitro system according to claim 3, wherein one of said plurality of cell culture chambers contains liver cells.

5. An in vitro system according to claim 3, wherein the one or more of said plurality of cell culture chambers each containing different types of cells are arranged in parallel with respect to one another.

6. An in vitro system according to claim 2, wherein the lung cells are pulmonary Clara cells, pulmonary macrophages, or Type II cells.

7. An in vitro system according to claim 1, wherein one of said plurality of cell culture chambers contains liver cells.

8. An in vitro system according to claim 1, wherein one of said plurality of cell culture chambers contains cells transfected with a human gene.

9. An in vitro system according to claim 1, wherein said circulation mechanism includes one or more pumps to withdraw culture medium from said plurality of cell culture chambers.

10. An in vitro system according to claim 9, wherein said circulation mechanism further includes means to pressurize said gas-liquid exchange device to a level sufficient for culture medium to flow through said conduit system to said plurality of cell culture chambers without aid of a pump.

11. A method for physiological and metabolic evaluation of a substance comprising:

providing an in vitro system for physiological and metabolic evaluation of substances, said system comprising;

a plurality of cell culture chambers each containing different types of cells in a culture medium;

a gas-liquid exchange device;

a conduit system to conduct culture medium between said gas-liquid exchange device and said plurality of cell culture chambers;

a circulation mechanism for circulating culture medium through said conduit system; and

a microprocessor to control operation of said gas-liquid exchange device and said circulation mechanism;

adding a substance to be evaluated to the culture medium of said in vitro system;

circulating the culture medium containing the substance through said plurality of cell culture chambers, said gas-liquid exchange device, and said conduit system with said circulation mechanism, wherein the substance to be evaluated contacts the different types of cells, thereby producing either metabolites of the substance to be evaluated or metabolites of the different types of cells and the metabolites of the different types of cells or the metabolites of the substance to be evaluated are exchanged between said plurality of cell culture chambers; and

evaluating the cells in each of said plurality of cell culture chambers or the culture medium for physiological and metabolic changes resulting from the presence of the substance in the culture medium.

12. A method according to claim 11, wherein said evaluating comprises determining the efficacy of the substance which is a biologically active compound.

13. A method according to claim 11, wherein said evaluating comprises determining the toxicity of the substance which is a biologically active compound.

14. A method according to claim 11, wherein said evaluating comprises determining the sensitivity of cells in said plurality of cell culture chambers to the substance which is a biologically active compound.

15. A method according to claim 11, wherein said evaluating comprises determining the efficacy of a multiple dose regimen of the substance.

16. A method according to claim 11, wherein one of said plurality of cell culture chambers contains lung cells.

17. A method according to claim 16, wherein said conduit system connects the cell culture chamber containing lung cells with the gas-liquid exchange device and with one or more of said plurality of cell culture chambers each containing different types of cells.

18. A method according to claim 17, wherein one of said plurality of cell culture chambers contains liver cells.

19. A method according to claim 17, wherein the one or more of said plurality of cell culture chambers each containing different types of cells are arranged in parallel with respect to one another.

20. A method according to claim 16, wherein the lung cells are pulmonary Clara cells, pulmonary macrophages, or Type II cells.

21. A method according to claim 11, wherein one of said plurality of cell culture chambers contains cells transfected with a human gene.

22. An in vitro system which maintains different cell types in a viable state comprising:

a plurality of cell culture chambers each suitable for containing the different cell types in a culture medium containing a substance to be evaluated;

a gas-liquid exchange device;

a conduit system suitable for conducting culture medium between said gas-liquid exchange device and said plurality of cell culture chambers;

a circulation mechanism for circulating culture medium through said conduit system, said plurality of cell culture chambers, and said gas-liquid exchange device, including circulating culture medium between said plurality of cell culture chambers, wherein the circulation mechanism is capable of selectively providing a flow of culture medium directly between at least two of said plurality of culture chambers or from one culture chamber through the gas-liquid exchange device and through another culture chamber and wherein the substance to be evaluated contacts the different cell types, thereby producing either metabolites of the substance to be evaluated or metabolites of the different cell types; and

a microprocessor to control operation of said gas-liquid exchange device and said circulation mechanism, wherein said plurality of cell culture chambers, said conduit system, and said circulation mechanism are configured such that the metabolites of the different cell types or the metabolites of the substance to be evaluated are exchanged between said plurality of cell culture chambers.

23. An in vitro system according to claim 22 further comprising:

a cabinet surrounding elements of said system to maintain sterile conditions in said system.

24. An in vitro system comprising:

a plurality of cell culture chambers each containing different cells in a culture medium containing a substance to be evaluated;

a reservoir for contacting the culture medium with a gas and from which by-product gases are removed;

a conduit system to conduct culture medium between said reservoir and said plurality of cell culture chambers;

a circulation mechanism for circulating culture medium through said conduit system, said plurality of cell culture chambers, and said reservoir, including circulating culture medium between said plurality of cell culture chambers, wherein the substance to be evaluated contacts the different cells, thereby producing either metabolites of the substance to be evaluated or metabolites of the different cells; and

a microprocessor to control operation of said reservoir and said circulation mechanism, wherein said plurality of cell culture chambers, said conduit system, and said circulation mechanism are configured such that the metabolites of the different cells or the metabolites of the substance to be evaluated are exchanged between said plurality of cell culture chambers.

25. A method for physiological and metabolic evaluation of a substance comprising:

providing an in vitro system for physiological and metabolic evaluation of substances, said system comprising;

a plurality of cell culture chambers each containing cells in a culture medium;

a reservoir for contacting the culture medium with a gas and from which by-product gases are removed;

a conduit system to conduct culture medium between said reservoir and said plurality of cell culture chambers;

a circulation mechanism for circulating culture medium through said conduit system; and

a microprocessor to control operation of said reservoir and said circulation mechanism;

adding a substance to be evaluated to the culture medium of said in vitro system;

circulating the culture medium containing the substance through said plurality of cell culture chambers, said reservoir, and said conduit system with said circulation mechanism, wherein the substance to be evaluated contacts the cells, thereby producing either metabolites of the substance to be evaluated or metabolites of the cells and the metabolites of the cells or the metabolites of the substance to be evaluated are exchanged between said plurality of cell culture chambers; and

evaluating the cells in each of said plurality of cell culture chambers or the culture medium for physiological and metabolic changes resulting from the presence of the substance in the culture medium.

26. An in vitro system comprising:

a plurality of cell culture chambers each suitable for containing different cell types in a culture medium containing a substance to be evaluated;

a reservoir suitable for contacting the culture medium with a gas and from which by-product gases are removed;

a conduit system suitable for conducting culture medium between said reservoir and said plurality of cell culture chambers;

a circulation mechanism for circulating culture medium through said conduit system, said plurality of cell culture chambers, and said reservoir, including circulating culture medium between said plurality of cell culture chambers, wherein the circulation mechanism is capable of selectively providing a flow of culture medium directly between at least two of said plurality of culture chambers or from one culture chamber through the gas-liquid exchange device and through another culture chamber and wherein the substance to be evaluated contacts the different cell types, thereby producing either metabolites of the substance to be evaluated or metabolites of the different cell types; and

a microprocessor to control operation of said reservoir and said circulation mechanism, wherein said plurality of cell culture chambers, said conduit system, and said circulation mechanism are configured such that the metabolites of the different cell types or the metabolites of the substance to be evaluated are exchanged between said plurality of cell culture chambers.