US3839155A - Cell and vaccine production - Google Patents

Cell and vaccine production Download PDF

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Publication number
US3839155A
US3839155A US00275642A US27564272A US3839155A US 3839155 A US3839155 A US 3839155A US 00275642 A US00275642 A US 00275642A US 27564272 A US27564272 A US 27564272A US 3839155 A US3839155 A US 3839155A
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Prior art keywords
propagator
cells
medium
cell
discs
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US00275642A
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English (en)
Inventor
Aleer W Mc
R Spier
K Posch
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Merck and Co Inc
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Merck and Co Inc
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Priority to US00275642A priority Critical patent/US3839155A/en
Priority to NL7309569A priority patent/NL7309569A/xx
Priority to JP48083707A priority patent/JPS4950180A/ja
Priority to BR5682/73A priority patent/BR7305682D0/pt
Priority to US474279A priority patent/US3905865A/en
Application granted granted Critical
Publication of US3839155A publication Critical patent/US3839155A/en
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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
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • C12M25/06—Plates; Walls; Drawers; Multilayer plates
    • 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
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/10—Rotating vessel
    • 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
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/14—Rotation or movement of the cells support, e.g. rotated hollow fibers
    • 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
    • C12N3/00—Spore forming or isolating processes
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18711—Rubulavirus, e.g. mumps virus, parainfluenza 2,4
    • C12N2760/18751—Methods of production or purification of viral material

Definitions

  • this invention relates to the use of tumbling in rotating disc machines in order to produce cells and vaccines in substantially increased yields, thereby greatly reducing production costs.
  • the present invention provides a method and device for overcoming the aforementioned disadvantages of the prior art procedures in which a cylindrical rotating disc apparatus is tumbled end over end at controlled speeds during the cell and vaccine production cycles, as for example during the cell plating, cell growth, cell washing, virus seeding, virus replication, and harvesting cycles of operation or during the addition of a chemical agent to the growth unit.
  • the nropagator can be tumbled at a speed of from about 1 rev./5 min. to about 1 rev./l5 min., preferably at a speed of about 1 rev./l min.
  • the propagator can be tumbled at a speed of from about 1 rev./3 min.
  • An advantage of the present invention is the ability to substantially increase the yield of cells and vaccines and thereby reduce the production costs.
  • a further advantage of the present invention is the ability to evenly distribute the cell slurry between the plates, thereby obtaining greater uniformity in the cell distribution and a higher yield of cells and vaccine.
  • a still further advantage of the present invention is the ability to obtain plating of cells on both sides of the plates from a single charge of cells without the necessity ofa two-step procedure which requires two separate charges of cells, thereby increasing the yield of cells and reducing the risk of contamination and the costs associated therewith.
  • Another advantage of the present invention is that extremely low volumes of fluid can be used to bathe the cell sheet, and to recover the cells from the tank,
  • FIG. 1 is a perspective view of a typical multiplate propagator and holding means for the propagator employed in the present invention
  • FIG. 2 is a cross sectional view of the propagator contained in the holding means
  • FIG. 3 is a sectional view taken along the line 33 of FIG. 2;
  • FIG. 4 is a front elevational view of the tumbling device of the present invention.
  • FIG. 5 is a side elevational view of the tumbling device of the present invention.
  • FIG. 6 is a sectional view of another propagator which is exemplary of those which can be utilized in accordance with the teachings of this invention.
  • FIG. 1 discloses the multiplate propagator (l) and the holding means (2).
  • the propagator (1) includes a cylindrical stainless steel vessel (3) having top and bottom flanges (4) and (5) and a top plate (6) and a bottom plate (7). Clamps (8) are used to seal plates (6) and (7) to flanges (4) and (5) respectively. Plates (6) and (7) also have fittings (9), (10), (11), and (12) which connect to various lines when the propagator is in use in order to cycle air and fluids through the propagator.
  • the holding means (2) also shown in FIG. 1 includes a cage like structure having two semi-tubular portions (13) and (14) which may be of an open or closed construction and are connected by hinges (l5).
  • Portions (13) and (14) each have flanges (16) and (17) which have holes (18) through which pins or clamps may be inserted to close and latch the holding means (2) around the propagator (l).
  • the holding means (2) also has two cylindrical arms (19) and (20) extending from opposite sides of the midpoint of the holding means.
  • the propagator (1) contains a series of titanium discs (21) mounted on a bar (22), which supports the plates (7) in a separated state due to the presence of cylindrical spacers between each plate.
  • One end of the bar is rotatably supported by a bearing (23) which is mounted in a recess (24) in the center of plate (7).
  • the other end of the bar (22) is rotatably supported by a bearing (25) which is mounted in a recess (26) in the center of plate (6).
  • a magnetic couple (25) which is fixedly mounted on the bar (20) is engaged by magnetic drive means (not shown) in order to rotate the plates.
  • the holding means (2) envelops the propagator and the edges of the semi-tubular members (13) and (14) about the edges of flanges (4) and (5) in order to hold the tank (1) in a fixed position.
  • FIG. 3 is a sectional view taken along line 33 of FIG. 2, and shows the two semi-tubular portions (13) and (14) in the closed position and a pin (28) inserted in the holes (18) in flanges (1 6) and (17) to lock the holding means in the closed position around the cylindrical portion (3) of the tank (1).
  • FIG. 4 is a front elevational view of the tumbling device of this invention and shows the propagator (1) contained in the holding means (2).
  • Arm (19) is surrounded by a bearing (29) rotatably mounted in hole (30) of supporting member (31) and arm (20) is fixedly mounted in sprocket wheel (32) which in turn is rotatably mounted on support member (33).
  • Wheel (32) is connected to sprocket wheel (34) of a motor (35) by a chain (36) in order to tumble the propagator (l).
  • the motor (35) has a variable speed transmission in order to tumble the propagator at the desired speed.
  • Support members (31) and (33) are positioned on stand (37).
  • FIG. is a side elevational view of the tumbling device of FIG. 4 and illustrates the manner in which the propagator is tumbled end over end while positioned in the tumbling device.
  • FIG. 6 there is disclosed another multiplate propagator (51) which can be used in conjunction with the tumbling device of this invention.
  • This propagator (51) comprises a cyclindrical stainless steel vessel (52) having a flange (53) at one end thereof. Plate (54) is sealed to the flange (53) by clamps (55).
  • An air-carbon dioxide mixture can be pumped into the vessel (52) from a reservoir (not shown) through a line (56) which extends along the length of the wall of the vessel (52) to the back of the vessel (52) where a portion of the line (56) extends along the back of the vessel.
  • This portion of the line (56) has openings (57) which permit the egress of the air-carbon dioxide mixture.
  • An outlet line (58) is also used to keep the air pressure within the vessel at a relatively constant level.
  • Another line (59) may be used to supply medium, serum and other nutrients and to withdraw the expended medium and product.
  • the plates (60) are mounted on a bar (61 which supports the plates (54) in a separated state due to the presence of cylindrical spacers between each plate.
  • One end of the bar (61) is rotatably supported by a bearing (62) which is mounted in recess (63) in the bottom of the vessel (52).
  • the other end of the bar (61) is also rotatably supported by a bearing (64) which is mounted in a recess (65) in plate (54).
  • a magnetic couple (66) which is fixedly mounted on bar (61) is engaged by a driven magnet (67) to rotate the plates (60) through the medium (58) during the cell growth and virus infection stages of the production cycle.
  • the process and device of this invention may be used to produce viral vaccines such as mumps, measles, rubella, parainfluenza, Mareks and cells such as WI-38, chick embryo and duck embryo cells.
  • Standard cells, sera and media may be used to produce the aforementioned vaccines.
  • primary cells such as chick embryo fibroblasts, green monkey kidney, bovine kidney, dog kidney or diploid cells such as WI-38 may be utilized as may standard sera such as fetal calf, calf, bovine, G-G-free newborn calf, a-gamma calf or a-gamma bovine and standard media such as Eagles Basel Medium, Medium EBME, Medium 199, and Eagles Minimum Essential Medium.
  • EXAMPLE 1 A rotating titanium disc propagator is charged with a mixture of 12 billion trypsinized chick embryo cells in Medium 199,45 ml. 2.8% NaHCO /L and fetal calf serum. The charged propagator is then locked into the tumbler and tumbled at 37C. end over end at a speed of l rev./l0 min. until two-side plating has occurred at which time the propagator is removed from the tumbler. The propagator is then positioned so that the plane of the discs is in the vertical axis and a portion of the medium and serum is discharged until the unit is about half full.
  • the discs are then rotated at a speed of l revolution/8 minutes and air or a mixture of air and 5% CO is passed through the unit at a rate of cc/minute until the cell growth cycle has been completed at which time the spent medium is discharged from the propagator, the propagator is washed with Hanks solution and charged with fresh Medium 199 containing 60 ml. 2.8% NaHCO;,/L 25% SPGA and 4 millilitres of a mumps virus suspension which has a log,., TClD /0.l ml. of 3.6.
  • the discs in the unit are again rotated at a speed of l revolution/8 minutes until there is no further increase in the concentration of virus in the supernatant fluids at which time the vaccine is harvested and frozen.
  • the yield of mumps vaccine when prepared by the above process is substantially higher than the yield obtained by using conventional procedures.
  • EXAMPLE 2 A rotating titanium disc propagator is charged with a mixture of 12 billion trypsinized duck embryo cells in Medium 199 containing 45 ml. NaHCO /L and 10% fetal calf serum. The charged propagator is then locked into the tumbler and tumbled at 37C. end over end at a speed of l revolution/l0 minutes until two side plating has occurred at which time the propagator is removed from the tumbler. The propagator is then positioned so that the plane of the discs is in the vertical axis and a portion of the medium and serum is discharged until the unit is about half full.
  • the discs are then rotated at a speed of l revolution/8 minutes and air or a mixture of 95% air and 5% CO is passed through the unit at a rate of 100 cc/minute until the cell growth cycle has been completed at which time the spent medium is discharged from the propagator.
  • the propagator is then recharged with 2 litres of Medium 199 containing 60 ml. 2.8% NaHCO /L, 2% cit-gamma.
  • calf serum and ml. of a rubella virus suspension which has log, IND /0.l ml. of 3.5.
  • the propagator and contents are then locked into the tumbler and tumbled end over end at a speed of l revolution/ 1 5 minutes for 2 hours after which the propagator is removed from the tumbler and a further 6 litres of Medium 199 containing 60 ml. 2.8% NaHCO /L and 2% a-gamma calf serum is added to the propagator.
  • the unit is then set so that the discs rotate at one revolution in 8 minutes with air or a mixture of air or 95% air and 5% CO passing through it at 100 cc/minute at 37C.
  • the spent medium is disharged and fresh Medium 199 containing 60 ml. 2.8% NaHCO /L 10% SPGA is added to the propagator. This medium in turn is discharged when the concentration of rubella virus has reached a maximum concentration.
  • EXAMPLE 3 A rotating titanium disc propagator is charged with a mixture of Medium 199, F 10 and tryptose phosphate broth with 5% fetal calf serum and 12 X 10 cells from trypsinized 12 day duck embryos and 14.4 X 10' PFU Marek THV. The charged propagator is then locked into the tumbler and tumbled at 37C. end over end at a speed of l revolution/20 minutes until two side plating has occurred at which time the propagator is removed from the tumbler. The propagator is then positioned so that the plane of the discs is in the vertical axis and a portion of the medium and serum is discharged until the unit is about half full.
  • the discs are then rotated at a speed of 1 revolution/8 minutes and air or a mixure of 95% air and 5% CO is passed through the propagator at a flow rate of 100 cc/minute.
  • the pH is adjusted from time to time with 7.5% NaHCO 3 so that it remains within the limits of pH 6.8-7.4.
  • glucose is added to the system periodically so that at no time should the glucose concentration to outside the limits of 15-100 mg/lOO ml.
  • the spent medium is discharged and 6 litres of KCl-citrate/Trypsin is transferred into the propagator.
  • the discs are rotated two complete revolutions and then the KCl-citrate/Trypsin solution is voided.
  • the propagator is then looked into the tumbler and held with the plane of the discs in the horizontal axis for 5 minutes after which it is rotated about its long axis 90 so that the plane of the discs is in the vertical axis. While in this position 1.5 L of Eagles Basel Medium containing 15% fetal calf serum is pumped into the propagator. The propagator and its contents are then rotated end over end at a speed of l revolution/- second for minutes. Following this tumbling the contents are discharged and assayed for Marek THV.
  • the yield of Mareks vaccine when prepared by the above process is substantially higher than the yield obtained by using conventional procedures.
  • EXAMPLE 4 A rotating titanium disc propagator is charged with a mixture of 300 X 10 Wl-38 cells in Medium EBME containing 10% fetal calf serum and 10 ml. of glutamine/L. The propagator and its contents are then held with the plane of the plates in the horizontal axis at 37C until plating has been achieved. The propagator is then positioned so that the plane of the discs is in the vertical axis and a portion of the medium and serum is discharged until the unit is about half full. The discs are then rotated at a speed of l revolution/5 minutes and air or a mixture of 5% CO and 95% air is passed through the unit at a rate of 100 cc/minute.
  • the medium is discharged from the machine and the unit is refilled with an equal volume of fresh Medium EBME containing 5% fetal calf serum and 10 ml. glutamine/L.
  • the cell suspension is harvested from the unit.
  • the unit is voided of spent medium and is then half filled with a solution containing trypsin.
  • the plates are rotated through the trypsin solution so that all parts of. each plate contact the solution.
  • the trypsin is then voided.
  • 1 L of Medium EBME containing fetal calf serum is pumped into the propagator and the whole unit is then tumbled end over end at a speed of l rev./sec. for 10 minutes, after which the cell suspension is discharged and collected.
  • EXAMPLE 5 A rotating disc propagator is charged with a mixture 6 of 3.0 billion trypsinized chick embryo cells, Medium 199, 45 ml. 2.8% NaHCQ-JL and 5% fetal calf serum. The propagator is held in the vertical position at a temperature of 37C and plating is effected. After 3 hours the fluid in the propagator is discharged and a further 3.0 billion trypsinized chick embryo cells are added to the fluid. After mixing the fresh suspension is transferred back into the propagator which is held in the 0pposite vertical position to the first plating at a temperature of 37C in order to effect plating on the second side of the discs.
  • the propagator is positioned so that the plane of the discs is in the vertical axis and a portion of the medium and serum is discharged until the unit is about half full.
  • the discs are then rotated at a speed of l revolution in 5 minutes and air or a mixture of 5% CO and air is passed through the propagator ata rate of cc/min.
  • the cells may be harvested.
  • the medium in the propagator is discharged and the propagator is filled up to the halfway mark with a solution containing trypsin.
  • the discs are rotated twice so that all parts of the disc become wetted with the tryp-.
  • the trypsin solution is then discharged and the unit is held with the plane of the plates in the horizontal axis for 5 minutes.
  • the propagator is then charged with l L of fresh Medium 199 and 45 ml. 2.8% NaHCO /L and is tumbled end over end at a speed of 1 rev./min. for 10 minutes after which the cell suspension is discharged.
  • EXAMPLE 6 A rotating disc propagator is charged with a mixture of 3.0 billion trypsinized duck embryo cells, Medium 199, F 10 5% fetal calf serum and 30 ml. 2.8% NaH- CO /L. The propagator is held in the vertical position at a temperature of 37C and plating is effected. After three hours the fluid in the propagator is discharged and a further 3.0 billion trypsinized duck embryo cells are added to the fluid. After mixing the fresh suspension is transferred back into the propagator which is held in the opposite vertical position to the first plating at a temperature of 37C in order to effect plating on the second side of the discs.
  • the propagator is positioned so that the plane of the discs is in the vertical axis and a portion of the medium and serum is discharged until the unit is about half full.
  • the discs are then rotated at a speed of 1 revolution in 5 minutes and air or a mixture of 5% CO and 95% air is passed through the propagator at a rate of 100 cc/min.
  • the cells may be harvested.
  • the medium in the propagator is discharged and the propagator is filled up to the halfway mark with a solution containing trypsin.
  • the discs are rotated twice so that all parts of the disc become wetted with the trypsin.
  • the trypsin solution is then discharged and the unit is held with the plane of the plates in the horizontal axis for 5 minutes.
  • the propagator is then charged with l L of fresh Medium 199, E10 5% fetal calf serum, 30 ml. 2.8% NaHCO lL and is tumbled end over end at a speed of l rev./sec. for 10 minutes after which the cell within the said propagator and are positioned in suspension is discharged. planes parallel to the end plates of said propagator In this way it was possible to prepare with great effiand are rotatively mounted on a shaft that is posiciency and economy large quantities of duck embryo tioned in the center of each of said end plates; cells. 5 means for holding the propagator; and means for What is claimed is: tumbling said propagator end over end.
  • a device for use in the production of at least one 2.
  • a device as in claim 1 which further comprises member selected from the group consisting of cells and means to control the tumbling speed of the propagator. vaccines which comprises;
  • a multiplate propagator comprising a substantially n 3.

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US00275642A 1972-07-27 1972-07-27 Cell and vaccine production Expired - Lifetime US3839155A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US00275642A US3839155A (en) 1972-07-27 1972-07-27 Cell and vaccine production
NL7309569A NL7309569A (enrdf_load_stackoverflow) 1972-07-27 1973-07-09
JP48083707A JPS4950180A (enrdf_load_stackoverflow) 1972-07-27 1973-07-26
BR5682/73A BR7305682D0 (pt) 1972-07-27 1973-07-26 Dispositivo aperfeicoado para a producao de celulas e vacio
US474279A US3905865A (en) 1972-07-27 1974-05-29 Cell and vaccine production

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JP (1) JPS4950180A (enrdf_load_stackoverflow)
BR (1) BR7305682D0 (enrdf_load_stackoverflow)
NL (1) NL7309569A (enrdf_load_stackoverflow)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925165A (en) * 1972-08-18 1975-12-09 Mueller Hans Apparatus for culturing of tissue cells and micro-organisms
US4080258A (en) * 1973-01-04 1978-03-21 Merck & Co., Inc. Cell and vaccine production
US4172013A (en) * 1976-05-28 1979-10-23 Dr. Rentschler Arzneimittel Gmbh & Co. Process for the mass growth of cells and system of chambers for the carrying out thereof
US4208483A (en) * 1978-09-21 1980-06-17 The University Of Toledo Tissue culture system
US4339537A (en) * 1978-11-10 1982-07-13 Olympus Optical Company Limited Method of culturing biological substances
US4377639A (en) * 1982-01-18 1983-03-22 University Of Toledo Tissue culture device for mass cell culture
US5190878A (en) * 1989-07-14 1993-03-02 Minuth Wilhelm Apparatus for cultivating cells
US5270205A (en) * 1990-03-19 1993-12-14 Alena Rogalsky Device for growing cells
US5316945A (en) * 1991-12-14 1994-05-31 Will Minuth Cell carrier arrangement
US5427948A (en) * 1993-07-29 1995-06-27 Michigan State University Apparatus for conducting hybridization
US5432087A (en) * 1990-11-29 1995-07-11 Spielmann; Richard Apparatus having rotatable planar trays for culturing microorganisms
US5534423A (en) * 1993-10-08 1996-07-09 Regents Of The University Of Michigan Methods of increasing rates of infection by directing motion of vectors
US5650325A (en) * 1990-11-29 1997-07-22 Spielmann; Richard Apparatus having a rotatable stack of parallel trays with culturing surfaces on opposite sides for liquid/gas exchange
US5654185A (en) * 1994-12-09 1997-08-05 The Regents Of The University Of Michigan Methods, compositions and apparatus for cell transfection
US5728576A (en) * 1995-08-08 1998-03-17 The Board Of Governors For Higher Education, State Of Rhode Island In vitro cover slip suspension module
US20050106717A1 (en) * 2003-10-08 2005-05-19 Wilson John R. Cell culture methods and devices utilizing gas permeable materials
US20080176318A1 (en) * 2006-12-07 2008-07-24 Wilson John R Highly efficient devices and methods for culturing cells
US20100055774A1 (en) * 2008-07-08 2010-03-04 Wilson John R Gas permeable cell culture device and method of use
US20110003366A1 (en) * 2005-10-26 2011-01-06 Pbs Biotech, Inc. Methods of using pneumatic bioreactors
US9290730B2 (en) 2005-07-26 2016-03-22 Corning Incorporated Multilayered cell culture apparatus
EP4294919A4 (en) * 2021-02-22 2025-04-16 The Board Of Regents Of The University Of Texas System MAGNETIC SHEAR BIOREACTOR DEVICE AND METHOD

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2996429A (en) * 1959-02-12 1961-08-15 Nat Toxicological Lab Inc Method and apparatus for growing living tissue
US3407120A (en) * 1965-12-23 1968-10-22 Abbott Lab Tissue culture propagator and method
US3732149A (en) * 1970-09-16 1973-05-08 Farmitalla Soc Apparatus for the large scale growth of living cells

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2996429A (en) * 1959-02-12 1961-08-15 Nat Toxicological Lab Inc Method and apparatus for growing living tissue
US3407120A (en) * 1965-12-23 1968-10-22 Abbott Lab Tissue culture propagator and method
US3732149A (en) * 1970-09-16 1973-05-08 Farmitalla Soc Apparatus for the large scale growth of living cells

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925165A (en) * 1972-08-18 1975-12-09 Mueller Hans Apparatus for culturing of tissue cells and micro-organisms
US4080258A (en) * 1973-01-04 1978-03-21 Merck & Co., Inc. Cell and vaccine production
US4172013A (en) * 1976-05-28 1979-10-23 Dr. Rentschler Arzneimittel Gmbh & Co. Process for the mass growth of cells and system of chambers for the carrying out thereof
US4208483A (en) * 1978-09-21 1980-06-17 The University Of Toledo Tissue culture system
US4339537A (en) * 1978-11-10 1982-07-13 Olympus Optical Company Limited Method of culturing biological substances
US4377639A (en) * 1982-01-18 1983-03-22 University Of Toledo Tissue culture device for mass cell culture
US5190878A (en) * 1989-07-14 1993-03-02 Minuth Wilhelm Apparatus for cultivating cells
US5270205A (en) * 1990-03-19 1993-12-14 Alena Rogalsky Device for growing cells
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JPS4950180A (enrdf_load_stackoverflow) 1974-05-15
NL7309569A (enrdf_load_stackoverflow) 1974-01-29
BR7305682D0 (pt) 1974-09-24

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