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WO1986002379A1 - Dispositif de culture a fibres creuses pour ameliorer la perfusion de substances nutritives et la concentration des produits, et procede de fonctionnement - Google Patents

Dispositif de culture a fibres creuses pour ameliorer la perfusion de substances nutritives et la concentration des produits, et procede de fonctionnement Download PDF

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Publication number
WO1986002379A1
WO1986002379A1 PCT/US1985/001949 US8501949W WO8602379A1 WO 1986002379 A1 WO1986002379 A1 WO 1986002379A1 US 8501949 W US8501949 W US 8501949W WO 8602379 A1 WO8602379 A1 WO 8602379A1
Authority
WO
WIPO (PCT)
Prior art keywords
capillaries
medium
hollow fiber
cell unit
shell
Prior art date
Application number
PCT/US1985/001949
Other languages
English (en)
Inventor
Robert D. Walker
Michael L. Gruenberg
Ray F. Cracauer
Original Assignee
Endotronics, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Endotronics, Inc. filed Critical Endotronics, Inc.
Publication of WO1986002379A1 publication Critical patent/WO1986002379A1/fr

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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
    • 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
    • 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
    • C12M29/18—External loop; Means for reintroduction of fermented biomass or liquid percolate
    • 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
    • C12M47/00—Means for after-treatment of the produced biomass or of the fermentation or metabolic products, e.g. storage of biomass
    • C12M47/10—Separation or concentration of fermentation products

Definitions

  • the present invention relates to cell culturing devices, and in particular, it relates to cell culturing devices having a plurality of hollow fiber membran.es that efficiently transfer oxygen, nutrients and other chemical stimuli and remove waste products for the growth and maintenance of cells in vitro at high cell densities to provide high yields of product formation per unit reactor volume.
  • Hollow fiber culture devices have been proven to be ideal for the maintenance of many types of cells at high densities in vitro.
  • the mass transfer characteristics of hollow fiber culture devices provide an efficient means of delivering nutrients and removing waste products from a culture.
  • the semi-porous hollow fiber membranes can be selected with various pore sizes. With proper pore size selection, the cellular product can be maintained on the outside of the fibers, while waste products and contaminating proteins will pass through the membrane pores into the lumen of the hollow fibers where they can be subsequently removed from the culture.
  • Hollow fiber culture devices have many advantages over other culture technologies in economically producing cell-derived products. This is because the efficient mass transfer of nutrients and removal of waste products allows high cell densities to be achieved in a minimal space.
  • the molecular weight cut-offs of the fibers can be selected to maintain the cell product on the outside of the fibers, while lower molecular weight contaminates are removed by diffusing to the lumen of the fibers. In this manner, cell products concentrate in the fluid outside the fibers in a semi-pure state.
  • a major disadvantage of prior art hollow fiber culture devices is that the hollow fiber molecular weight cut-offs are generally specified under ultrafiltrative conditions and as a result, products of much larger molecular weights will pass through the lumen of the fibers. This problem becomes worse as the concentration of the product increases, the diffusion rates increase and a significant loss of product can occur.
  • the present invention includes a cell culturing device for growing and maintaining cells and collecting product.
  • the device includes first and second hollow fiber cartridges connected to each other such that the cells are grown and maintained in the first hollow fiber cartridge and product is conveyed to the second hollow fiber cartridge where it is concentrated.
  • Flow of medium from the lumen of the capillaries of the first hollow fiber cartridge to the capillaries of the second hollow fiber cartridge is restricted by a restriction that creates a back pressure in the flow of medium in the capillaries of the first hollow fiber cartridge.
  • the restriction permits medium to be delivered to the capillaries at a pressure that subjects the medium in the capillaries • to ultrafiltrative conditions.
  • the medium to ultrafiltrative conditions increases the mass transfer capability of the first hollow fiber cartridge and minimizes product loss by diffusion into the capillaries.
  • Product and metabolic waste are transferred from the first hollow fiber cartridge to the second hollow fiber cartridge.
  • the second hollow fiber cartridge has a molecular weight cut-off such that the product is selectively retained while the waste-containing medium is allowed to pass through. Due to the flow restriction between the first and second hollow fiber cartridges, the second hollow fiber cartridge is operated at a lower pressure than the first hollow fiber cartridge thereby aiding in the diffusion of waste contaminated medium.
  • the product in the second hollow fiber cartridge becomes concentrated over time and can be removed for further processing.
  • the device of the present invention has several advantages over prior art hollow fiber culture devices.
  • First, the first hollow fiber cartridge is operated under ultrafiltrative conditions using a larger molecular weight cut-off which permits better mass transfer.
  • Figure 1 is a diagrammatical view of the apparatus of the present invention.
  • Figure 2 is a diagrammatical view of an alternative embodiment containing an expansion chamber fluidly connected to and between the extracapillary units of the hollow fiber cartridges.
  • Figure 3 is a diagrammatical view of an alternative embodiment of the apparatus of Figure 2 further including a pump between the expansion chamber and the extracapillary space of the second hollow fiber cartridge.
  • Figure 4 is another alternative embodiment including sensors in the expansion chamber and a supply source for replenishing the medium in the expansion chamber.
  • Figure 5 is a diagrammatical view of still another alternative embodiment wherein the expansion chamber is fluidly connected to the capillaries of the second hollow fiber cartridge.
  • the apparatus of the present invention is generally indicated at 10 in Figure 1.
  • the apparatus 10 includes a first hollow fiber cartridge 12 and a second hollow fiber cartridge 14.
  • the first cartridge 12 includes a shell 16 and a plurality of capillaries 18 which are typically disposed in a bundle.
  • the capillaries 18 extend through the shell from an input end 20 to an output end 22.
  • the space between the shell 16 and the capillaries 18 is defined as a cell culturing space 24.
  • Cells such as mammalian cells, are maintained, grown and produce product in the cell culturing space 24.
  • the capillaries have selectively permeable wall membranes that allow oxygen, C ⁇ 2» nutrients and other chemical components to diffuse through the walls into the cell culturing space 24.
  • the molecular weight cut-off of the capillaries is preferably less than approximately 150,000 Daltons and more than 15,000 Daltons, although 5,000 Daltons has been found sufficient to effect ultrafiltrative conditions, as will be discussed subsequently.
  • the oxygen, co ' nutrients and other chemical components are carried within a medium that is transported through the lumen of the capillaries.
  • the second cartridge 14 is of a similar construction as the first cartridge 12.
  • the cartridge 14 includes a shell 26 and a plurality .of capillaries 28 disposed in a bundle extending from an input end 30 to an output end 32 of the shell.
  • the capillaries 28 also have selectively permeable wall membranes, preferably, less than 15,000 Daltons.
  • a product collection space 34 is defined by the space between the capillaries 28 and the shell 26.
  • a suitable hollow fiber cartridge is made by Amicon Corporation of Danvers, Massachusetts.
  • the capillaries of the cartridges 12 and 14 are fluidly connected in series such that the output end 22 of the cartridge 12 is fluidly connected to the input end 30 of the cartridge 14.
  • the cartridges 12 and 14 are fluidly connected by a fluid connection 36.
  • the fluid connection 36 is made of tubing and includes a restriction 38, such as produced by a pinch clamp, that restricts flow from the capillaries of the first cartridge 12 to the capillaries of the second cartridge 14.
  • the restriction 38 produces a pressure drop between the first cartridge 12 and the second cartridge 14.
  • the restriction 38 aids in presentation of medium within the capillaries 18 under ultrafiltrative conditions. In addition, the restriction 38 aids in removal of waste-containing medium from product, as will be discussed subsequently.
  • a delivery system 40 delivers a primary medium supply containing oxygen, nutrients or > other chemical stimuli through supply conduit 42 to the lumen of the capillaries 18.
  • the delivery system 40 delivers the primary medium supply at a selected rate and pressure.
  • Suitable delivery systems are well known in the art. Any suitable delivery system that is capable of pumping medium at a controlled rate and concentration to the capillaries 18 is includable within the present invention.
  • a suitable delivery system is sold by Endotronics, Inc. of Minnesota under the trademarks "ACUSYST” and "APS10" . Suitable delivery systems are also described in application Serial No. 350,135 filed on February 19, 1982, application Serial No. 388,136 filed on June 14, 1982, and application Serial No.
  • the medium is returned to the delivery system 40 by flow through the capillaries 18, through the fluid connection 36 with the restriction 38, into the capillaries 28, and through a recirculation line 44.
  • the shell 16 includes first and second ports 46 and 48 which fluidly connect tubing sections 50 and 52 with the extracapillary space 24.
  • the shell 26 of the cartridge 14 includes first and second ports 54 and 56.
  • Tubing 58 fluidly connects the tubing sections 50 and 52 with the port 54 such that the extracapillary space 24 is fluidly connected to the extracapillary space 26.
  • the port 56 fluidly connects an outlet conduit 60 with the extracapillary space 26.
  • the conduit 60 preferably includes a valve 62 that is positionable between an open and a closed position.
  • medium from delivery system 40 is delivered to the capillaries 18 at a pressure such that the medium is subjected to ultrafiltrative conditions which results in substantially even diffusion along the length of the capillaries within the cartridge 12.
  • the product and the waste materials and other components are forced to flow within the capillary space in the general direction of arrows 64 and 66 causing circulation within the extracapillary space 24.
  • the product and the waste materials flow out of the extracapillary space 24 into tubing 50 and 52, and then into tubing 58 and into the extracapillary space 34 of the cartridge 14.
  • the capillaries 28 generally have a molecular weight cut-off which is smaller than the molecular weight cut-off of the capillaries 24 to retain product in the extracapillary space 34.
  • the molecular weight cut-off is such that waste products and medium are allowed to diffuse into the capillaries 28 while product is retained.
  • the molecular weight cut-off of the capillaries 18 is approximately 50,000 Daltons and the molecular weight cut-off of the capillaries 28 is approximately 6,000 to 10,000 Daltons to minimize diffusion of the monoclonal antibody into the capillaries 28.
  • Diffusion of waste products and medium from the extracapillary space 34 into the capillaries 28 is enhanced by the flow restriction 38 since the pressure in the capillaries 28 is less than the pressure in the extracapillary space 34.
  • concentration of the product with respect to any medium in the extracapillary space increases.
  • the increase in the concentration or quantity of product results in a purer product for extraction.
  • the valve 62 is opened and the product is pumped out of the extracapillary space 34.
  • FIG 2 an alternative embodiment, generally indicated at 70, is diagrammatically illustrated.
  • the embodiment 70 is similar in many respects to the apparatus 10 illustrated in Figure 1 and like reference characters are used to indicate like elements.
  • An expansion chamber 72 is preferably fluidly connected to the ports 46 and 48 of the first cartridge 12 by tubing 74 and 76, respectively.
  • the expansion chamber 72 contains a supplementary supply of medium 78 that is pressurized by a gas pressurization system 80.
  • the gas pressurization system provides a substantially constant pressure level within the chamber 72.
  • the medium within the chamber 72 is fluidly connected by conduit 82 to the port 54 of the second cartridge 14.
  • First and second valves 84 and 86 are operably disposed with respect to the tubing 74 and 76, respectively, to selectively restrict flow between the extracapillary space 24 and the expansion chamber 72.
  • the tubing 74 and 76 was flexible tubing and the valves 84 and 86 were pinch-type valves which pinch the tubing to stop flow therethrough.
  • the valves 84 and 86 are operated in an alternating fashion, that is, one valve is kept open while the other valve is kept closed, to effect flow through the cell culturing space in • a predetermined direction.
  • valve 84 when valve 84 is closed and valve 86 is opened and the pressure within the capillaries 18 is at a level that is below the level of pressure within the chamber 72, medium flows from the chamber 72 through conduit 76 into the extracapillary space as indicated by arrow 85. Then valve 86 is closed and valve 84 is opened and the pressure within the capillaries 18 is increased to a level greater than the pressure in the chamber 72 so that medium flows from the extracapillary space, as indicated by arrow 87 through tubing 74 into the chamber 72. The cycle is repeated . causing a circulation effect within the extracapillary space.
  • Still another alternative embodiment 90 is diagrammatically illustrated in Figure 3.
  • the embodiment 90 is quite similar to the embodiment described with reference to Figure 2 and like elements are designated with like reference characters.
  • the embodiment 90 additionally includes a pump 92 operably disposed with respect to tubing 82 to provide motive force for transporting medium from the chamber 72 into the extracapillary space 34.
  • the pump 92 is preferably a peristaltic pump which provides a positive pressure pumping action and with which the medium does not come in contact with.
  • the pump 92 minimizes the need for balancing the pressures between the chamber 72 and the capillaries 18 to effect flow of product and waste-containing medium from the first cartridge 12 to the second cartridge 14.
  • Another alternative embodiment 100 of the present invention is diagrammatically illustrated in
  • the embodiment 100 includes a first hollow fiber cartridge 102, a second hollow fiber cartridge 104, an expansion chamber 106, a first medium delivery system 108 and a second medium delivery system 110.
  • the first cartridge 102 is similar to the cartridge 12 and has an exterior shell 112 and a plurality of capillaries 114 extending between an input end 116 and an output end 118 of the shell.
  • the capillaries 114 have selectively permeable membrane walls that permit diffusion of oxygen, C0 2 , nutrients and other chemical components through the membrane walls.
  • An extracapillary space 120 is defined between the shell 112 and the capillaries 114.
  • the capillaries 114 preferably have a pore size that permits medium to flow under ultrafiltrative conditions, such as 50,000 Daltons.
  • the second cartridge 104 is similar to the .
  • the cartridge 14 and also includes an exterior shell 122 and a plurality of capillaries 124 disposed in a bundle extending from an input end 126 to an output end 128 of the shell 122.
  • the capillaries 124 have selectively permeable membrane walls preferably having a molecular weight cut-off of 6,000 to 10,000 Daltons.
  • An extracapillary space 130 is defined between the shell 122 and the capillaries 124.
  • the capillaries 114 and the capillaries 124 are fluidly connected by a fluid connection 132, preferably a section of tubing, having a restriction 134.
  • the restriction 134 is similar to the restriction 38, as discussed with respect to Figures 1-3, and provides back pressure to the capillaries 114 so that an ultrafiltrative condition in the capillaries 114 is created.
  • the restriction 134 also produces a pressure drop between the capillaries 114 and the capillaries 124.
  • the delivery system 108 is similar to the delivery system 40 that was discussed previously with reference to Figures 1-3 and delivers a primary supply of medium, preferably containing oxygen, co 2' nutrients and other chemical components, to the capillaries 114 and 124.
  • a recirculation line 136 circulates the medium back to the delivery system 108 for replenishment.
  • the expansion chamber 106 is fluidly connected to the extracapillary space 120 by tubing 138 and 140, through ports 142 and 144, respectively.
  • First and second valves 146 and 148 are operably disposed to control flow within the tubing 142 and 144, respectively, so that flow can be selectively restricted in either tubing 138 and 140.
  • the tubing 138 and 140 is a medical grade flexible tubing and the valves 146 and 148 are pinch-type valves that pinch the tubing to stop flow therethroug .
  • the expansion chamber 106 contains a supply of medium 150.
  • the medium 150 preferably contains oxygen, co 2' nutrients and other chemical components for use by the cells in the extracapillary space 120.
  • the chamber 150 is pressurized by a pressure system 152 that provides a relatively constant level of pressure to the chamber 106.
  • the pressurizing system 152 is preferably a gas system similar to the gas pressurizing system 80 described with reference to Figures 2 and 3. - 14 -
  • the expansion chamber 106 is fluidly connected to the cartridge 104 by a product transport line 154 to a port 156 of the cartridge 104.
  • the port 156 fluidly connects the line 154 with the extracapillary space 130.
  • a pump 158 provides motive force to transport medium from the expansion chamber 106 to the extracapillary space 130.
  • a second port 160 is provided at a rearward position in the shell 122 as an outlet for the extracapillary space 130.
  • An outlet conduit 162 and a valve 164 provide a discharge exit from the extracapillary space 130.
  • Temperature,. pH and oxygen are monitored within the expansion chamber 106 by a temperature probe 166, a pH electrode 168, and an oxygen sensitive electrode 170.
  • the probe and electrodes 166, 168 and 170 provide signals to the second delivery system 110.
  • the second delivery system 110 adjusts the oxygen level and pH so that a preselected level is maintained by addition of further medium through a transport line 172 and a pump 174.
  • the pH and oxygen level within the expansion chamber 106 is reflective of the pH and oxygen level of the medium within the extracapillary space 120 since the medium is being circulated between the expansion chamber 106 and the extracapillary space 120.
  • the embodiment 200 includes a first hollow fiber cartridge 202, an expansion chamber 204, a second hollow fiber cartridge 206 and a medium delivery system 208.
  • the first hollow fiber cartridge 202 is similar to the cartridge 12 and has an outer shell
  • An extracapillary space 218 is defined as the space between the shell 210 and the capillaries 212.
  • Tubing 220 and 222 fluidly connect the expansion chamber 204 to the extracapillary space through ports 224 and 226, which are disposed proximate the forward end 214 and the rearward end 216 of the shell, all respectively.
  • Valves 228 and 230 are operably disposed with respect to tubing 220 and tubing 222, respectively, to selectively restrict flow between the expansion chamber and the extracapillary space 218 to effect circulation in the extracapillary space 218.
  • the second cartridge 206 is similar to cartridge 14 and includes an outer shell 232 and a plurality of capillaries 234, preferably disposed in a bundle, extending from a forward end 236 of the shell to a rearward end 238.
  • An extracapillary space 240 is defined as the space between the shell 232 and the capillaries 234.
  • the expansion chamber 204 is fluidly connected to the capillaries 234 of the cartridge 206 by a transport conduit 242.
  • a pump 244 preferably a peristaltic pump, is disposed operably with respect to the conduit 242 to provide motive force to transport liquid from the chamber 204 to the capillaries 234.
  • a medium delivery system 208 provides a first medium supply to the capillaries 212 of the cartridge 202 through a feed line 246.
  • a recirculation line 248 transports the medium back to the delivery system 208 for replenishment.
  • the extracapillary space 240 of the cartridge 206 is fluidly connected to the recirculation line 248 by conduit 250 and 252 which are fluidly connected to the recirculation conduit 248 by conduit 254.
  • Conduit 250 is fluidly connected to the extracapillary space 240 through port 256 and conduit 252 is fluidly connected to the extracapillary space 240 through port 258.
  • a section of flexible tubing 251 is fluidly disposed in the recirculation line 248 downstream of the capillaries 212 and upstream of the connection of conduit 254.
  • the tubing 251 includes a flow restriction 253 that provides back pressure to the capillaries 212.
  • a discharge conduit 260 is fluidly connected to the capillaries 234 of the cartridge 206 at the outlet end 238.
  • the discharge conduit is preferably a flexible piece of tubing and includes a restriction 262 which is preferably caused by a pinch-type clamp pinching the tubing.
  • the restriction 262 causes back pressure within the capillaries 234. in operation, medium from the delivery system
  • Circulation in the extracapillary space 218 is effected in the same manner as previously described.
  • the waste- and product-containing medium is pumped from the expansion chamber 204 through the line 242 into the capillaries 234.
  • the flow restriction 262 creates a back pressure within the capillaries 234 causing waste materials along with the medium to diffuse under ultrafiltrative conditions into the extracapillary space 240 for transport to the recirculation line 248.
  • Product in a concentrated and purified form exits the capillaries 234 past the flow restriction 262, as generally indicated by arrow 264. The result is a continuous stream of concentrated product that was produced by cells located in the extracapillary space 218 of the cartridge 202.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • General Engineering & Computer Science (AREA)
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  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Un dispositif de culture à fibres creuses comprend une première cartouche de fibres creuses (12) et une seconde cartouche de fibres creuses (14), dont les capillaires (18) sont connectés en série par une connexion fluide (36) ayant à l'intérieur un étranglement d'écoulement (38). L'étranglement d'écoulement (38) établit une chute de pression entre les capillaires de la première (18) et de la seconde (28) cartouches et établit une contre-pression sur les capillaires de la première cartouche de fibres creuses de sorte que le milieu est administré par perfusion dans des conditions d'ultrafiltration. L'espace extracapillaire (34) de la première cartouche de fibres creuses est connecté par des moyens fluides à l'espace extracapillaire de la seconde cartouche de fibres creuses (14) de sorte que le milieu contenant le déchet et le produit est acheminé vers l'espace extracapillaire (34) de la seconde cartouche de fibres creuses où le produit est concentré et le milieu contenant le déchet est diffusé dans le passage des capillaires.
PCT/US1985/001949 1984-10-09 1985-10-09 Dispositif de culture a fibres creuses pour ameliorer la perfusion de substances nutritives et la concentration des produits, et procede de fonctionnement WO1986002379A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US65855084A 1984-10-09 1984-10-09
US658,550 1984-10-09

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WO1986002379A1 true WO1986002379A1 (fr) 1986-04-24

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EP (1) EP0198033A4 (fr)
JP (1) JPS62500356A (fr)
WO (1) WO1986002379A1 (fr)

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EP0269444A2 (fr) * 1986-11-26 1988-06-01 Henry B. Kopf Appareil et procédé pour le transport de masse de millieux biologiques et pharmaceutiques
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US4894342A (en) * 1986-05-12 1990-01-16 C. D. Medical, Inc. Bioreactor system
US4918019A (en) * 1986-05-12 1990-04-17 C. D. Medical, Incorporated Bioreactor system with plasticizer removal
FR2640638A1 (fr) * 1988-12-20 1990-06-22 Commissariat Energie Atomique Bioreacteur et dispositif pour la culture de cellules animales
US4973558A (en) * 1988-04-28 1990-11-27 Endotronics, Inc. Method of culturing cells using highly gas saturated media
WO1993014186A1 (fr) * 1992-01-10 1993-07-22 Baxter International Inc. Dialyseur, membrane et procede de rectification
WO1994020603A1 (fr) * 1993-03-09 1994-09-15 Baxter International Inc. Dialyseur de rectification, bioreacteur et membrane
WO1997005233A1 (fr) * 1995-07-26 1997-02-13 Celltherapy, Inc. Dispositif de croissance cellulaire servant a augmenter une population de cellules in vitro
EP0765933A2 (fr) * 1995-09-29 1997-04-02 Becton, Dickinson and Company Dispositif de culture et méthode d'utilisation
EP0765935A2 (fr) * 1995-09-29 1997-04-02 Becton, Dickinson and Company Dispositif de culture et méthode d'utilisation
EP0765934A2 (fr) * 1995-09-29 1997-04-02 Becton, Dickinson and Company Dispositif de culture et méthode d'utilisation
EP0789072A2 (fr) * 1995-08-15 1997-08-13 Becton, Dickinson and Company Dispositif de culture et méthode d'utilisation
US5728581A (en) * 1995-06-07 1998-03-17 Systemix, Inc. Method of expanding hematopoietic stem cells, reagents and bioreactors for use therein
EP0894852A2 (fr) * 1997-07-31 1999-02-03 Roche Diagnostics GmbH Process and apparatus for performing biochemical reactions
WO2000012676A1 (fr) * 1998-09-02 2000-03-09 Cedars-Sinai Medical Center Bioreacteur et procedes associes
US6242248B1 (en) 2000-02-08 2001-06-05 Cedars-Sinai Medical Center Bioreactor and related method
US7160719B2 (en) 2002-06-07 2007-01-09 Mayo Foundation For Medical Education And Research Bioartificial liver system
WO2007116266A1 (fr) * 2006-04-12 2007-10-18 Synexa Life Sciences (Pty) Ltd Appareil de biotransformation à haute capacité
EP2441826A1 (fr) * 2010-10-15 2012-04-18 Melin, Thomas Procédé d'isolation de produit et alimentation en substrat dans un bioréacteur
US8309347B2 (en) 2007-03-05 2012-11-13 Terumo Bct, Inc. Cell expansion system and methods of use
US8691565B2 (en) 2008-03-05 2014-04-08 Terumo Bct, Inc. Method of reseeding adherent cells grown in a hollow fiber bioreactor system
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US9677042B2 (en) 2010-10-08 2017-06-13 Terumo Bct, Inc. Customizable methods and systems of growing and harvesting cells in a hollow fiber bioreactor system
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US10130748B2 (en) 2009-03-13 2018-11-20 Mayo Foundation For Medical Education And Research Bioartificial liver
US10577576B2 (en) 2012-08-20 2020-03-03 Terumo Bct, Inc. System for expanding cells
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US11608486B2 (en) 2015-07-02 2023-03-21 Terumo Bct, Inc. Cell growth with mechanical stimuli
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US11667881B2 (en) 2014-09-26 2023-06-06 Terumo Bct, Inc. Scheduled feed
US11685883B2 (en) 2016-06-07 2023-06-27 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
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JP6469287B1 (ja) * 2018-06-22 2019-02-13 株式会社 バイオミメティクスシンパシーズ 中空糸細胞培養装置，細胞培養方法，培養上清の製造方法
JP7325221B2 (ja) * 2019-05-22 2023-08-14 株式会社レゾナック・ガスプロダクツ 生物の育成装置

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Publication number Publication date
EP0198033A4 (fr) 1989-02-09
EP0198033A1 (fr) 1986-10-22
JPS62500356A (ja) 1987-02-19

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