CA2262812A1 - Hollow fiber bioreactor comprising a hydrogel flow restrictor - Google Patents
Hollow fiber bioreactor comprising a hydrogel flow restrictorInfo
- Publication number
- CA2262812A1 CA2262812A1 CA002262812A CA2262812A CA2262812A1 CA 2262812 A1 CA2262812 A1 CA 2262812A1 CA 002262812 A CA002262812 A CA 002262812A CA 2262812 A CA2262812 A CA 2262812A CA 2262812 A1 CA2262812 A1 CA 2262812A1
- Authority
- CA
- Canada
- Prior art keywords
- flow path
- housing
- filament
- cells
- bioreactor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
- C12M25/10—Hollow fibers or tubes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/16—Hollow fibers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
Abstract
A bioreactor containing living animal cells at density approaching that of normal animal tissue is described. High cell loading is achieved by providing a hydrogel plug which controls fluid flow through the bioreactor during cell loading. Methods for making and using the bioreactor are also described.
Claims (39)
1. A bioreactor which comprises:
a) an elongate housing defining a central axis;
b) a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough;
c) a cell population positioned within the housing, the cell population occupying the extrafilamentary space and comprising living cells;
d) a filament inlet port and a filament outlet port, said ports communicating through the hollow filaments to define a filament flow path;
e) a housing inlet port and a housing outlet port, said ports communicating through the cell population to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and f) a flow restrictor positioned in the extrafilament flow path to maintain a substantially uniform flow across the extrafilament flow path.
a) an elongate housing defining a central axis;
b) a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough;
c) a cell population positioned within the housing, the cell population occupying the extrafilamentary space and comprising living cells;
d) a filament inlet port and a filament outlet port, said ports communicating through the hollow filaments to define a filament flow path;
e) a housing inlet port and a housing outlet port, said ports communicating through the cell population to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and f) a flow restrictor positioned in the extrafilament flow path to maintain a substantially uniform flow across the extrafilament flow path.
2. A bioreactor of Claim 1 wherein the cells are mammalian cells.
3. A bioreactor of Claim 1 wherein the cells are present at a density of at least about 10 7 cells per milliliter.
4. A bioreactor of Claim 1 wherein the cells are present at a density of at least about 10 8 cells per milliliter.
5. A bioreactor of Claim 2 wherein the cells are hepatocytes.
6. A bioreactor of Claim 3 wherein the cells are hepatocytes.
7. A bioreactor of Claim 4 wherein the cells are hepatocytes.
8. A bioreactor of Claim 1 wherein the flow restrictor comprises a hydrogel.
9. A bioreactor of Claim 1 wherein the flow restrictor comprises a material selected from collagen, agarose, calcium alginate, chitosan acetate, a polyacrylamide, or a combination thereof.
10. A bioreactor of Claim 1 wherein the filaments are selected from filaments made of polysulfone, cellulose acetate, polyacrylonitrile, polymethylmethacrylate, or an ethylene polyvinyl alcohol copolymer.
11. A method for treating a biological fluid which comprises:
a) providing a bioreactor which comprises i) an elongate housing defining a central axis;
ii) a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough;
iii) a cell population positioned within the housing, the cell population occupying the extrafilamentary space and comprising living cells capable of treating the biological fluid;
iv) a filament inlet port and a filament outlet port, said ports communicating through the hollow filaments to define a filament flow path;
v) a housing inlet port and a housing outlet port, said ports communicating through the cell population to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and vi) a flow restrictor positioned in the extrafilament flow path to maintain a substantially uniform flow across the extrafilament flow path; and b) causing the biological fluid to travel along the filament flow path.
a) providing a bioreactor which comprises i) an elongate housing defining a central axis;
ii) a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough;
iii) a cell population positioned within the housing, the cell population occupying the extrafilamentary space and comprising living cells capable of treating the biological fluid;
iv) a filament inlet port and a filament outlet port, said ports communicating through the hollow filaments to define a filament flow path;
v) a housing inlet port and a housing outlet port, said ports communicating through the cell population to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and vi) a flow restrictor positioned in the extrafilament flow path to maintain a substantially uniform flow across the extrafilament flow path; and b) causing the biological fluid to travel along the filament flow path.
12. The method of Claim 11 which further comprises causing a fluid containing nutrients for the cells to travel along the extrafilament flow path.
13. The method of Claim 11 wherein the cells are mammalian cells.
14. The method of Claim 11 wherein the cells are present at a density of at least about 10 7 cells per milliliter.
15. The method of Claim 11 wherein the cells are present at a density of at least about 10 8 cells per milliliter.
16. The method of Claim 13 wherein the cells are hepatocytes.
17. The method of Claim 14 wherein the cells are hepatocytes.
18. The method of Claim 15 wherein the cells are hepatocytes.
19. The method of Claim 11 wherein the flow restrictor comprises a hydrogel.
20. The method of Claim 11 wherein the flow restrictor comprises a material selected from collagen, agarose, calcium alginate, chitosan acetate, a polyacrylamide, or a combination thereof.
21. The method of Claim 11 wherein the filaments are selected from filaments made of polysulfone, cellulose acetate, polyacrylonitrile, polymethylmethacrylate, or an ethylene polyvinyl alcohol copolymer.
22. The method of Claim 12 wherein the filament flow path and the matrix flow path have co-current flow.
23. The method of Claim 12 wherein the filament flow path and the matrix flow path have counter-current flow.
24. The method of Claim 11 wherein the biological fluid comprises blood.
25. The method of Claim 16 wherein the biological fluid comprises blood.
26. A method of fabricating a bioreactor having a flow restrictor, the method comprising:
a) providing a hollow filament bioreactor cartridge, the cartridge comprising a housing containing a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough, the housing further comprising a filament inlet port and a filament outlet port,said ports communicating through the hollow filaments to define a filament flow path, and a housing inlet port and a housing outlet port, said ports
a) providing a hollow filament bioreactor cartridge, the cartridge comprising a housing containing a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough, the housing further comprising a filament inlet port and a filament outlet port,said ports communicating through the hollow filaments to define a filament flow path, and a housing inlet port and a housing outlet port, said ports
27 communicating through the extrafilamentary space to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and b) introducing a volume of a gellable material into the housing in a manner such that it becomes positioned at least adjacent to the housing outlet port, the volume such that, upon gelling, the resulting gel will occupy a portion of the extrafilamentary space sufficient to restrict a fluid flowing through the housing outlet port.
27. The method of Claim 26 which further comprises gelling the gellable materialwhile flowing a sterile fluid through the filament flow path.
27. The method of Claim 26 which further comprises gelling the gellable materialwhile flowing a sterile fluid through the filament flow path.
28. The method of Claim 26 wherein the gelling is controlled by temperature variation.
29. The method of Claim 27 wherein the gelling is controlled by varying the temperature of the sterile fluid.
30. The method of Claim 26 wherein the gel becomes positioned at least adjacent to the housing outlet port by gravity.
31. The method of Claim 26 wherein the gel becomes positioned at least adjacent to the housing outlet port by centrifugation.
32. The method of Claim 26 wherein the gel comprises a material selected from collagen, agarose, calcium alginate, chitosan acetate, a polyacrylamide, or a combination thereof.
33. The method of Claim 26 wherein the resulting gel occupies a portion of the extrafilamentary space sufficient to maintain a substantially uniform flow across the extrafilament flow path.
34. A bioreactor which comprises:
a) an elongate housing defining a central axis;
b) a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough;
c) a filament inlet port and a filament outlet port, said ports communicating through the hollow filaments to define a filament flow path;
d) a housing inlet port and a housing outlet port, said ports communicating through the extrafilamentary space to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and e) a flow restrictor positioned in the extrafilament flow path to maintain a substantially uniform flow across the extrafilament flow path.
a) an elongate housing defining a central axis;
b) a plurality of elongate hollow filaments each positioned within the housing substantially parallel to the central axis and defining an extrafilamentary space within the housing, each of the hollow filaments formed of a material which allows molecular transport therethrough;
c) a filament inlet port and a filament outlet port, said ports communicating through the hollow filaments to define a filament flow path;
d) a housing inlet port and a housing outlet port, said ports communicating through the extrafilamentary space to define an extrafilament flow path, the extrafilament flow path being isolated from the filament flow path such that a material in one path may enter the other path only by molecular transport through the material comprising the hollow filaments; and e) a flow restrictor positioned in the extrafilament flow path to maintain a substantially uniform flow across the extrafilament flow path.
35. A bioreator of Claim 34 wherein the flow restrictor comprises a hydrogel.
36. A bioreactor of Claim 34 wherein the flow restrictor comprises a material selected from collagen, agarose, calcium alginate, chitosan acetate, a polyacrylamide, or a combination thereof.
37. A bioreactor of Claim 34 wherein the filaments are selected from filaments made of polysulfone, cellulose acetate, polyacrylonitrile, polymethylmethacrylate, or an ethylene polyvinyl alcohol copolymer.
38. An extracorporeal circuit comprising the bioreactor of Claim 1.
39. An extracorporeal circuit of Claim 38 wherein the cells are hepatocytes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/861,503 US5955353A (en) | 1997-05-22 | 1997-05-22 | Hollow fiber bioreactor with an extrafilament flow plug |
| US08/861,503 | 1997-05-22 | ||
| PCT/US1998/010111 WO1998053046A1 (en) | 1997-05-22 | 1998-05-13 | Bioreactor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2262812A1 true CA2262812A1 (en) | 1998-11-26 |
| CA2262812C CA2262812C (en) | 2011-02-08 |
Family
ID=25335987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2262812A Expired - Fee Related CA2262812C (en) | 1997-05-22 | 1998-05-13 | Hollow fiber bioreactor comprising a hydrogel flow restrictor |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5955353A (en) |
| EP (1) | EP0915965B1 (en) |
| JP (1) | JP2000515391A (en) |
| AT (1) | ATE231181T1 (en) |
| AU (1) | AU738641B2 (en) |
| CA (1) | CA2262812C (en) |
| DE (1) | DE69810740T2 (en) |
| NZ (1) | NZ333786A (en) |
| WO (1) | WO1998053046A1 (en) |
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| AU9031591A (en) * | 1990-10-29 | 1992-05-26 | Regents Of The University Of Minnesota | A bioartificial liver |
| US5270192A (en) * | 1991-02-07 | 1993-12-14 | Monsanto Company | Biological artificial liver |
| JP3026516B2 (en) * | 1991-05-15 | 2000-03-27 | 株式会社クラレ | Cell incubator |
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| DE4230194C2 (en) * | 1992-09-09 | 1995-07-27 | Joerg Dr Med Gerlach | Reactor for the cultivation and use of metabolic services and / or for the maintenance of microorganisms |
| US5368555A (en) * | 1992-12-29 | 1994-11-29 | Hepatix, Inc. | Organ support system |
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| JPH10512159A (en) * | 1995-10-30 | 1998-11-24 | セレックス バイオサイエンシズ，インコーポレイティド | Culture products for bioartificial liver |
-
1997
- 1997-05-22 US US08/861,503 patent/US5955353A/en not_active Expired - Fee Related
-
1998
- 1998-05-13 WO PCT/US1998/010111 patent/WO1998053046A1/en active IP Right Grant
- 1998-05-13 AU AU74947/98A patent/AU738641B2/en not_active Ceased
- 1998-05-13 JP JP10550484A patent/JP2000515391A/en not_active Ceased
- 1998-05-13 NZ NZ333786A patent/NZ333786A/en unknown
- 1998-05-13 CA CA2262812A patent/CA2262812C/en not_active Expired - Fee Related
- 1998-05-13 DE DE69810740T patent/DE69810740T2/en not_active Expired - Lifetime
- 1998-05-13 AT AT98922389T patent/ATE231181T1/en not_active IP Right Cessation
- 1998-05-13 EP EP98922389A patent/EP0915965B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000515391A (en) | 2000-11-21 |
| AU738641B2 (en) | 2001-09-20 |
| WO1998053046A1 (en) | 1998-11-26 |
| EP0915965B1 (en) | 2003-01-15 |
| NZ333786A (en) | 2000-07-28 |
| US5955353A (en) | 1999-09-21 |
| DE69810740D1 (en) | 2003-02-20 |
| ATE231181T1 (en) | 2003-02-15 |
| AU7494798A (en) | 1998-12-11 |
| DE69810740T2 (en) | 2003-10-16 |
| EP0915965A1 (en) | 1999-05-19 |
| CA2262812C (en) | 2011-02-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |