CA2360664A1 - Method and apparatus for maintenance and expansion of hemopoietic stem cells and/or progenitor cells - Google Patents

Method and apparatus for maintenance and expansion of hemopoietic stem cells and/or progenitor cells Download PDF

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CA2360664A1
CA2360664A1 CA002360664A CA2360664A CA2360664A1 CA 2360664 A1 CA2360664 A1 CA 2360664A1 CA 002360664 A CA002360664 A CA 002360664A CA 2360664 A CA2360664 A CA 2360664A CA 2360664 A1 CA2360664 A1 CA 2360664A1
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cells
matrix
hemopoietic stem
fibers
stromal
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CA2360664C (en
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Shoshana Merchav
Shai Meretski
Dov Zipori
Avinoam Kadouri
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Pluri Biotech Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C12M25/14—Scaffolds; Matrices
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
    • C12N11/08—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer
    • C12N11/089—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C12N11/096—Polyesters; Polyamides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/125—Stem cell factor [SCF], c-kit ligand [KL]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/145—Thrombopoietin [TPO]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/26—Flt-3 ligand (CD135L, flk-2 ligand)
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    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
    • C12N2502/1394—Bone marrow stromal cells; whole marrow
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers

Abstract

A method of expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells by obtaining undifferentiated hemopoietic stem cells or progenitor cells; and either seeding the undifferentiated hemopoietic stem cells or progenitor cells into a stationary phase plug-flow bioreactor in which a three-dimensional stromal cell culture has been pre-established on a substrate in the form of a sheet, the substrate including a non-woven fibrou s matrix forming a physiologically acceptable three-dimensional network of fibers, thereby expanding/maintaining undifferentiated hemopoietic stem cell s or progenitor cells, or culturing the undifferentiated hemopoietic stem cell s or progenitor cells in conditioned medium obtained from such a reactor.</SDO AB>

Claims (99)

1. A method of expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells, the method comprising the steps of:
(a) obtaining undifferentiated hemopoietic stem cells or progenitor cells; and (b) seeding said undifferentiated hemopoietic stem cells or progenitor cells into a stationary phase plug-flow bioreactor in which a three dimensional stromal cell culture has been pre-established on a substrate in the form of a sheet, said substrate including a non-woven fibrous matrix forming a physiologically acceptable three-dimensional network of fibers, thereby expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells.
2. The method of claim 1, wherein said undifferentiated hemopoietic stem cells or progenitor cells are cells isolated from a tissue selected from the group consisting of cord blood, mobilized peripheral blood and bone-marrow.
3. The method of claim 1, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture share common HLA antigens.
4. The method of claim 1, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from a single individual.
5. The method of claim 1, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different individuals.
6. The method of claim 1, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from the same species.
7. The method of claim 1, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different species.
8. The method of claim 1, wherein stromal cells of said stromal cell culture are grown to a density of at least 5 x 10 6 cells per a cubic centimeter of said substrate.
9. The method of claim 1, wherein stromal cells of said stromal cell culture are grown to a density of at least 10 7 cells per a cubic centimeter of said substrate.
10. The method of claim 1, wherein said step of seeding said undifferentiated hemopoietic stem cells or progenitor cells into said stationary phase plug-flow bioreactor is effected while flow in said bioreactor is shut off for at least 10 hours following said seeding.
11. The method of claim 1, wherein said fibers form a pore volume as a percentage of total volume of from 40 to 95 % and a pore size of from 10 microns to 100 microns.
12. The method of claim 1, wherein said matrix is made of fiber selected from the group consisting of flat, non-round, and hollow fibers and mixtures thereof, said fibers being of from 0.5 microns to 50 microns in diameter or width.
13. The method of claim 1, wherein said matrix is composed of ribbon formed fibers having a width of from 2 microns to 20 microns, and wherein the ratio of width to thickness of the fibers is at least 2:1.
14. The method of claim 1, wherein said matrix having a pore volume as a percentage of total volume of from 60 to 95%.
15. The method of claim 1, wherein the matrix has a height of 50-1000 µm.
16. The method of claim 1, wherein the material of the matrix is selected from the group consisting of polyesters, polyalkylenes, polyfluorochloroethylenes, polyvinyl chloride, polystyrene, polysulfones, cellulose acetate, glass fibers, and inert metal fibers.
17. The method of claim 1, wherein the matrix is in a shape selected from the group consisting of squares, rings, discs, and cruciforms.
18. The method of claim 1, wherein the matrix is in the form of a disc.
19. The method of claim 1, wherein the matrix is coated with poly-D-lysine.
20. The method of claim 1, further comprising the step of isolating said undifferentiated hemopoietic stem cells or progenitor cells.
21. A method of expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells, the method comprising the steps of:
(a) obtaining undifferentiated hemopoietic stem cells or progenitor cells; and (b) culturing said undifferentiated hemopoietic stem cells or progenitor cells in a medium containing a stromal cell conditioned medium, said stromal cell conditioned medium being derived from a stationary phase plug-flow bioreactor in which a three dimensional stromal cell culture has been established on a substrate in the form of a sheet, said substrate including a non-woven fibrous matrix forming a physiologically acceptable three-dimensional network of fibers, thereby expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells.
22. The method of claim 21, wherein said undifferentiated hemopoietic stem cells or progenitor cells are cells isolated from a tissue selected from the group consisting of cord blood, mobilized peripheral blood and bone-marrow.
23. The method of claim 21, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture share common HLA antigens.
24. The method of claim 21, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from a single individual.
25. The method of claim 21, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different individuals.
26. The method of claim 21, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from the same species.
27. The method of claim 21, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different species.
28. The method of claim 21, wherein stromal cells of said stromal cell culture are grown to a density of at least 5 x 10 6 cells per a cubic centimeter of said substrate.
29. The method of claim 21, wherein stromal cells of said stromal cell culture are grown to a density of at least 10 7 cells per a cubic centimeter of said substrate.
30. The method of claim 21, wherein said fibers form a pore volume as a percentage of total volume of from 40 to 95 % and a pore size of from 10 microns to 100 microns.
31. The method of claim 21, wherein said matrix is made of fiber selected from the group consisting of flat, non-round, and hollow fibers and mixtures thereof, said fibers being of from 0.5 microns to 50 microns in diameter or width.
32. The method of claim 21, wherein said matrix is composed of ribbon formed fibers having a width of from 2 microns to 20 microns, and wherein the ratio of width to thickness of the fibers is at least 2:1.
33. The method of claim 21, wherein said matrix having a pore volume as a percentage of total volume of from 60 to 95%.
34. The method of claim 21, wherein the matrix has a height of 50-1000 µm.
35. The method of claim 21, wherein the material of the matrix is selected from the group consisting of polyesters, polyalkylenes, polyfluorochloroethylenes, polyvinyl chloride, polystyrene, polysulfones, cellulose acetate, glass fibers, and inert metal fibers.
36. The method of claim 21, wherein the matrix is in a shape selected from the group consisting of squares, rings, discs, and cruciforms.
37. The method of claim 21, wherein the matrix is in the form of a disc.
38. The method of claim 21, wherein the matrix is coated with poly-D-lysine.
39. A method of preparing a stromal cell conditioned medium useful in expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells, the method comprising the steps of:
(a) establishing a stromal cell culture in a stationary phase plug-flow bioreactor on a substrate in the form of a sheet, said substrate including a non-woven fibrous matrix forming a physiologically acceptable three-dimensional network of fibers, thereby expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells;
and (b) when a desired stromal cell density has been achieved, collecting medium from said stationary phase plug-flow bioreactor, thereby obtaining the stromal cell conditioned medium useful in expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells.
40. The method of claim 39, wherein stromal cells of said stromal cell culture are grown to a density of at least 5 x 10 6 cells per a cubic centimeter of said substrate.
41. The method of claim 39, wherein stromal cells of said stromal cell culture are grown to a density of at least 10 6 cells per a cubic centimeter of said substrate.
42. The method of claim 39, wherein said fibers form a pore volume as a percentage of total volume of from 40 to 95 % and a pore size of from 10 microns to 100 microns.
43. The method of claim 39, wherein said matrix is made of fiber selected from the group consisting of flat, non-round, and hollow fibers and mixtures thereof, said fibers being of from 0.5 microns to 50 microns in diameter or width.
44. The method of claim 39, wherein said matrix is composed of ribbon formed fibers having a width of from 2 microns to 20 microns, and wherein the ratio of width to thickness of the fibers is at least 2:1.
45. The method of claim 39, wherein said matrix having a pore volume as a percentage of total volume of from 60 to 95%.
46. The method of claim 39, wherein the matrix has a height of 50-1000 µm.
47. The method of claim 39, wherein the material of the matrix is selected from the group consisting of polyesters, polyalkylenes, polyfluorochloroethylenes, polyvinyl chloride, polystyrene, polysulfones, cellulose acetate, glass fibers, and inert metal fibers.
48. The method of claim 39, wherein the matrix is in a shape selected from the group consisting of squares, rings, discs, and cruciforms.
49. The method of claim 39, wherein the matrix is in the form of a disc.
50. The method of claim 39, wherein the matrix is coated with poly-D-lysine.
51. A method of transplanting undifferentiated hemopoietic stem cells or progenitor cells into a recipient, the method comprising the steps of:
(a) expanding/maintaining the undifferentiated hemopoietic stem cells or progenitor cells by:
(i) obtaining undifferentiated hemopoietic stem cells or progenitor cells; and (ii) seeding said undifferentiated hemopoietic stem cells or progenitor cells into a stationary phase plug-flow bioreactor in which a three dimensional stromal cell culture has been pre-established on a substrate in the form of a sheet, said substrate including a non-woven fibrous matrix forming a physiologically acceptable three-dimensional network of fibers, thereby expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells; and (b) transplanting said undifferentiated hemopoietic stem cells or progenitor cells resulting from step (a) in the recipient.
52. The method of claim 51, wherein said undifferentiated hemopoietic stem cells or progenitor cells are cells isolated from a tissue selected from the group consisting of cord blood, mobilized peripheral blood and bone-marrow.
53. The method of claim 51, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture share common HLA antigens.
54. The method of claim 51, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from a single individual.
55. The method of claim 51, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different individuals.
56. The method of claim 51, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from the same species.
57. The method of claim 51, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different species.
58. The method of claim 51, wherein stromal cells of said stromal cell culture are grown to a density of at least 5 x 10 6 cells per a cubic centimeter of said substrate.
59. The method of claim 5l, wherein stromal cells of said stromal cell culture are grown to a density of at least 10 7 cells per a cubic centimeter of said substrate.
60. The method of claim 51, wherein said step of seeding said undifferentiated hemopoietic stem cells or progenitor cells into said stationary phase plug-flow bioreactor is effected while flow in said bioreactor is shut off for at least 10 hours following said seeding.
61. The method of claim 51, wherein said fibers form a pore volume as a percentage of total volume of from 40 to 95 % and a pore size of from 10 microns to 100 microns.
62. The method of claim 51, wherein said matrix is made of fiber selected from the group consisting of flat, non-round, and hollow fibers and mixtures thereof, said fibers being of from 0.5 microns to 50 microns in diameter or width.
63. The method of claim 51, wherein said matrix is composed of ribbon formed fibers having a width of from 2 microns to 20 microns, and wherein the ratio of width to thickness of the fibers is at least 2:1.
64. The method of claim 51, wherein said matrix having a pore volume as a percentage of total volume of from 60 to 95%.
65. The method of claim 51, wherein the matrix has a height of 50-1000 µm.
66. The method of claim 51, wherein the material of the matrix is selected from the group consisting of polyesters, polyalkylenes, polyfluorochloroethylenes, polyvinyl chloride, polystyrene, polysulfones, cellulose acetate, glass fibers, and inert metal fibers.
67. The method of claim 51, wherein the matrix is in a shape selected from the group consisting of squares, rings, discs, and cruciforms.
68. The method of claim 51, wherein the matrix is in the form of a disc.
69. The method of claim 51, wherein the matrix is coated with poly-D-lysine.
70. The method of claim 51, further comprising the step of isolating said undifferentiated hemopoietic stem cells or progenitor cells prior to step (b).
71. A method of transplanting undifferentiated hemopoietic stem cells or progenitor cells into a recipient, the method comprising the steps of:
(a) expanding/maintaining the undifferentiated hemopoietic stem cells or progenitor cells by:
(i) obtaining undifferentiated hemopoietic stem cells or progenitor cells; and (ii) culturing said undifferentiated hemopoietic stem cells or progenitor cells in a medium containing a stromal cell conditioned medium, said stromal cell conditioned medium being derived from a stationary phase plug-flow bioreactor in which a three dimensional stromal cell culture has been established on a substrate in the form of a sheet, said substrate including a non-woven fibrous matrix forming a physiologically acceptable three-dimensional network of fibers, thereby expanding/maintaining undifferentiated hemopoietic stem cells or progenitor cells.
72. The method of claim 71, wherein said undifferentiated hemopoietic stem cells or progenitor cells are cells isolated from a tissue selected from the group consisting of cord blood, mobilized peripheral blood and bone-marrow.
73. The method of claim 71, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture share common HLA antigens.
74. The method of claim 71, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from a single individual.
75. The method of claim 71, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different individuals.
76. The method of claim 71, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from the same species.
77. The method of claim 71, wherein said undifferentiated hemopoietic stem cells or progenitor cells and stromal cells of said stromal cell culture are from different species.
78. The method of claim 71, wherein stromal cells of said stromal cell culture are grown to a density of at least 5 x 10 6 cells per a cubic centimeter of said substrate.
79. The method of claim 71, wherein stromal cells of said stromal cell culture are grown to a density of at least 10 7 cells per a cubic centimeter of said substrate.
80. The method of claim 71, wherein said fibers form a pore volume as a percentage of total volume of from 40 to 95 % and a pore size of from 10 microns to 100 microns.
81. The method of claim 71, wherein said matrix is made of fiber selected from the group consisting of flat, non-round, and hollow fibers and mixtures thereof, said fibers being of from 0.5 microns to 50 microns in diameter or width.
82. The method of claim 71, wherein said matrix is composed of ribbon formed fibers having a width of from 2 microns to 20 microns, and wherein the ratio of width to thickness of the fibers is at least 2:1.
83. The method of claim 71, wherein said matrix having a pore volume as a percentage of total volume of from 60 to 95%.
84. The method of claim 71, wherein the matrix has a height of 50-1000 µm.
85. The method of claim 71, wherein the material of the matrix is selected from the group consisting of polyesters, polyalkylenes, polyfluorochloroethylenes, polyvinyl chloride, polystyrene, polysulfones, cellulose acetate, glass fibers, and inert metal fibers.
86. The method of claim 71, wherein the matrix is in a shape selected from the group consisting of squares, rings, discs, and cruciforms.
87. The method of claim 71, wherein the matrix is in the form of a disc.
88. The method of claim 71, wherein the matrix is coated with poly-D-lysine.
89. A bioreactor plug comprising a container having an outlet and an inlet and containing therein a substrate in the form of a sheet, said substrate including a non-woven fibrous matrix forming a physiologically acceptable three-dimensional network of fibers, said substrate supporting at least 5 x 10 6 stromal cells per cubic centimeter of said substrate
90. The bioreactor of claim 89. wherein said fibers form a pore volume as a percentage of total volume of from 40 to 95% and a pore size of from 10 microns to 100 microns.
91. The bioreactor of claim 89, wherein said matrix is made of fiber selected from the group consisting of flat, non-round, and hollow fibers and mixtures thereof, said fibers being of from 0.5 microns to 50 microns in diameter or width.
92. The bioreactor of claim 89, wherein said matrix is composed of ribbon formed fibers having a width of from 2 microns to 20 microns, and wherein the ratio of width to thickness of the fibers is at least 2:1.
93. The bioreactor of claim 89, wherein said matrix having a pore volume as a percentage of total volume of from 60 to 95%.
94. The bioreactor of claim 89, wherein the matrix has a height of 50-1000 µm.
95. The bioreactor of claim 89, wherein the material of the matrix is selected from the group consisting of polyesters, polyalkylenes, polyfluorochloroethylenes, polyvinyl chloride, polystyrene, polysulfones, cellulose acetate, glass fibers, and inert metal fibers.
96. The bioreactor of claim 89, wherein the matrix is in a shape selected from the group consisting of squares, rings, discs, and cruciforms.
97. The bioreactor of claim 89, wherein the matrix is in the form of a disc.
98. The bioreactor of claim 89, wherein the matrix is coated with poly-D-lysine.
99. A plug-flow bioreactor comprising the bioreactor plug of claim 89.
CA2360664A 1999-02-04 2000-02-04 Method and apparatus for maintenance and expansion of hemopoietic stem cells and/or progenitor cells Expired - Fee Related CA2360664C (en)

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US11878999P 1999-02-04 1999-02-04
US60/118,789 1999-02-04
PCT/US2000/002688 WO2000046349A1 (en) 1999-02-04 2000-02-04 Method and apparatus for maintenance and expansion of hemopoietic stem cells and/or progenitor cells

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CA2360664C CA2360664C (en) 2012-04-17

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