WO1990013639A1 - Systeme de culture cellulaire - Google Patents

Systeme de culture cellulaire Download PDF

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Publication number
WO1990013639A1
WO1990013639A1 PCT/US1990/002490 US9002490W WO9013639A1 WO 1990013639 A1 WO1990013639 A1 WO 1990013639A1 US 9002490 W US9002490 W US 9002490W WO 9013639 A1 WO9013639 A1 WO 9013639A1
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WO
WIPO (PCT)
Prior art keywords
cartridge
medium
chamber
cell culture
product
Prior art date
Application number
PCT/US1990/002490
Other languages
English (en)
Inventor
William R. Tolbert
Mark F. Baumgartner
Original Assignee
Invitron Corporation
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 Invitron Corporation filed Critical Invitron Corporation
Priority to KR1019910701530A priority Critical patent/KR920701420A/ko
Publication of WO1990013639A1 publication Critical patent/WO1990013639A1/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
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus
    • 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
    • C12M29/10—Perfusion
    • 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
    • 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
    • C12M29/04—Filters; Permeable or porous membranes or plates, e.g. dialysis
    • 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

Definitions

  • the present invention relates to an apparatus and method for maintaining eucaryotic, especially animal, cells in culture and for continuous recovery of secreted products from these cells.
  • U.S. Patent No. 4,537,860 which describes a cell culture maintenance system developed by the inventor of the invention herein, provides a general background for the present invention.
  • Other perfusion cell culture systems have been described in U.S. Patent No. 4,661,458 and by Rainen, American Biotechnology Laboratory (1988) :20-24; and Kle ent et al, Develop Biol Standard (1987) 6:221-226.
  • Perfusion culture and maintenance systems for animal, and more specifically, mammalian cells have also been described in U.S.
  • U.S. Patent No. 4,201,845 and the references of Shuler and Hallsby, and Hallsby and Shuler, describe flat chambers with cells contained between membranes or porous plates. These apparatuses are essentially three- chambered devices with nutrient medium in the first chamber flowing through the middle or cell culture chamber into the third or product collection chamber.
  • porous hollow fibers are used within the cell chamber both for gas exchange and for attachment of anchorage dependent cells.
  • Such a system is severely limited by the amount of surface area available on the hollow fibers for cell attachment and by the inappropriateness of the device for cells that are anchorage independent.
  • the devices described by Hallsby and Shuler, and Shuler and Hallsby suffer from the same deficiency and in addition, do not provide a means for gas exchange. Disclosure of the Invention
  • the invention provides an improved apparatus and method for the culture of animal cells, especially mammalian cells.
  • the improved apparatus and method are particularly useful in culturing cells which -are not actively or normally proliferating but maintained in a "static" or greatly slowed condition with respect to growth, and actively secreting a desired biological product.
  • the invention method and apparatus provide a means of medium supply to such cells which resists the accumulation of gas bubbles, thus assuring an even and uninterrupted supply of medium.
  • the invention apparatus also provides means for release of any gas accumulation in the culture itself.
  • the method and apparatus are applicable both to anchorage independent and anchorage dependent cells.
  • the invention is directed to an apparatus which comprises a housing having, within it, a cell culture chamber flanked by a medium supply cartridge and a product removal cartridge.
  • the cell culture chamber has two vertical faces approximately opposite each other, one interfacing the medium supply cartridge and the other interfacing the product removal cartridge.
  • the vertical faces are porous surfaces of suitable pore size for delivery of the medium from the medium supply cartridge and for product removal into the product removal cartridge and are of appropriate relative size to assure flow from medium supply cartridge to product removal cartridge.
  • the cell culture chamber also contains an inlet or port for the introduction of matrix and suspended cells, and a number of generally tubular semi-per eable membranes for diffusion of oxygen into and removal of carbon dioxide from the body of the cell culture chamber. These membranes are disposed so that a finely divided or porous matrix and cells included within the cell culture chamber have no volumes which are too distant from the supply of oxygen or ability to remove carbon dioxide to prevent effective diffusion to and from the cells.
  • the cell culture chamber may also include, at its top, a gas outlet means to provide for release of any gas bubbles which may accumulate in the cell culture chamber.
  • the product removal cartridge has an outlet means for the medium containing secreted product which outlet means may optionally be in communication with a refrigerated reservoir for immediate cooling of the product.
  • the medium supply cartridge has an inlet and outlet means spaced preferably diagonally in the faces of the cartridge perpendicular to the porous face contiguous with the cell culture chamber.
  • the inlet means is disposed at the bottom of the medium supply cartridge; the outlet means is disposed proximal to the top of the cartridge in a manner which assures the medium will permeate the entire volume of the cartridge. This can be accomplished by having the outlet diagonally opposite the inlet at the top of the opposing face, or by providing a means for circulating the medium throughout the cartridge, in which case the outlet can be on the same vertical face as the inlet but at the to P-
  • the medium entering the apparatus may thus be partially removed at the outlet means along with any accumulated gas bubbles.
  • a percentage of the medium input flow between 0-75%, preferably 1-20%, is thus removed through the outlet means.
  • Temperature control means may also be utilized upstream of the inlet or downstream of the outlet means for this cartridge.
  • the housing may be provided with a multiplicity of cell culture chambers arranged in parallel and separated by alternating medium supply cartridges having inlet and outlet means as described, and product removal cartridges.
  • the medium supply cartridges and product removal cartridges will have two parallel vertical faces which are porous to serve the adjacent cell culture chambers, except for the medium supply cartridge or product removal cartridge at one end of the parallel array and the cartridge at the opposite end, which will have only one vertical porous face.
  • a medium supply cartridge having a single porous vertical face, and an opposite impermeable face, shares the porous face as a vertical face of a cell culture chamber whose opposite porous face is in common with a product removal cartridge having two porous vertical faces, one of which forms the vertical face of the next cell culture chamber which is in turn bounded at the opposite face by the porous face of an additional medium supply cartridge which has an impermeable opposite face.
  • this cartridge has a permeable opposite face contiguous with still another cell culture chamber which is, in turn, faced by a product removal cartridge again either having an opposite face which is impermeable or a porous face which forms the vertical face of still another cell culture chamber and so forth.
  • the inlet and outlet means of the medium supply cartridges may be connected through ports in the housing to manifolds for supply of the medium through the inlet means and removal of medium from the outlet means along with any accumulated gases.
  • the outlet means for the product removal chambers may be connected through ports in the housing to a manifold for collective removal of product.
  • Access ports at the base of the cell culture chambers for introduction of suspended cells and a finely divided or porous matrix may be similarly connected through a manifold.
  • the invention is directed to a method for culturing animal cells, especially mammalian cells using the apparatus of the invention.
  • fresh medium is supplied through the medium supply cartridge to the cell culture chambers which have been provided with suspensions of the subject cells along with a suspension of a finely divided or porous matrix having suitable interstices for cell growth.
  • Medium is supplied to the cartridge through the inlet means at the lower port and any accumulated gases, and part of the supplied medium, if desired, is removed from the outlet means at the top. About 0-75% of the supplied medium is removed through the outlet means, preferably 1-20%. The remainder of the medium passes through the porous face of the cartridge into the cell culture chamber.
  • oxygen is supplied through the permeable membranes disposed through the cell culture chamber and carbon dioxide is removed through these membranes.
  • Conditioned medium containing secreted product from the cells is removed through the porous face shared by the cell culture chamber and the product removal cartridge and through the outlet means of said cartridge.
  • the medium is stored and maintained at refrigerated temperatures of about 0-10°C and warmed before introduction into the medium supply cartridge to a suitable temperature of ambient-37°C, preferably 37°C.
  • the removed product stream is cooled after exit from the outlet means of the cartridge to refrigerated temperatures of 0-10°C.
  • the conditioned medium may also be subjected to dialysis or other means to concentrate the desired product.
  • Figure 1 is a top view of the cell culture apparatus of the invention with a single cell culture chamber.
  • Figure 2 is an end view along the line 1-1' of the cell culture apparatus of Figure 1.
  • Figure 3 is a side view of the medium supply cartridge.
  • Figure 4 is a side view of product removal cartridge.
  • Figure 5 is a top view of the apparatus of the invention with multiple cell culture chambers and alternating medium supply and product removal cartridges.
  • Figure 6 shows the apparatus of the invention in a product recovery system with a product flow-through configuration.
  • Figure 7 shows the apparatus of the invention in a product recovery system with a medium recycle configuration.
  • the apparatus may be constructed as a single cell culture chamber flanked by one medium supply cartridge having a single porous face and one product removal cartridge, also having a single porous face.
  • the porous surface of the medium supply cartridge has a pore size of 0.1-10 microns, preferably 0.5-5 microns;
  • the product removal cartridge has a porous surface having a pore size of 1-200 microns, preferably 10-100 microns, and, in any case, a pore size at least slightly greater than that of the face of the medium supply cartridge.
  • a top view of this embodiment having a single cell culture chamber is shown in Figure 1.
  • the apparatus comprises a housing 10, preferably rectangular, which contains a cell culture chamber 12 bounded on two vertical parallel opposing sides by the vertical faces 14 and 16 of a medium supply cartridge 18 and a product removal cartridge 20 which may be either removable or fixed in place, and which extend to the vertical walls of the housing 10.
  • At least one port (not shown) preferably disposed proximal to the bottom of the cell culture chamber 12 is provided for the introduction of a thick slurry of cells at high density, mixed with a non-toxic matrix material 26 in which the cells are held.
  • the cells are generally eucaryotic cells, preferably animal cells, and most preferably mammalian cells.
  • the cells may be cultured in suspension, or may be anchorage- dependent cells using the matrix as an anchor.
  • the matrix material 26 may be any non-toxic finely divided or porous substance which can be used for separation and retention of anchorage-independent cells or for the attachment of anchorage-dependent cells.
  • commercially available microcarriers such as Cytodex® 1, 2, or 3, or microcarriers marketed by Pharmacia Company, or collagen (gelatin) based micro ⁇ carriers from KC Biological or Ventrex Corp.
  • porous microcarriers such as those described by Nilsson, K. , et al, Nature (1983) 302:629-630 may be used.
  • Many other types of material including finely divided glass, stainless steel, or polymerics may also be used.
  • the matrix material itself may be solid, porous, or permeable to the medium.
  • the housing 10 may also contain a port 27 contiguous to an opening disposed in a side proximal to the top of the housing or on the top surfaces of the cell culture chamber for removal of gases which may otherwise become trapped.
  • the cell culture chamber 12 is also traversed by a number of selectively permeable generally tubular membranes 44 which provide for diffusion of oxygenated gases into, and carbon dioxide out of the cell-filled matrix 26.
  • the positioning of the membranes is spaced such that the majority of cells are located within an effective distance from the diffusion surface. Thus disposition is such that all volumes in the chamber are within about 3 mm, preferably 1 mm, of a diffusing surface of the permeable membrane.
  • This tubular membrane is attached to a gas inlet 46 and outlet 48 means disposed in one or more faces of the cell culture chamber and corresponding ports 50 in the housing 10.
  • the tubular membrane may be arranged horizontally along the length of the cell culture chamber as shown in Figure 1, or may be attached to a separate framework placed in the chamber, or may be wrapped around the medium or product cartridge, or both and in contact with the chamber if the chamber is sufficiently narrow.
  • the flanking cartridges are of two types, one 18 for the supply of a fresh nutrient medium to the cell chamber 12 and the other 20 for the removal of product containing medium.
  • the medium supply cartridge 18 is disposed generally vertical in the housing 10 with the side 14 which faces the cell chamber 12 consisting of a porous material such as a membrane filter, sintered plate, screen, or woven material with a pore size generally between 0.1-10 ⁇ , but in any case, smaller than the pore size of the opposite wall shared by the cell culture chamber with the product removal cartridge described below.
  • the medium supply cartridge 18 contains at least one inlet means 32 and at least one outlet means 34.
  • the inlet means 32 is located near the bottom of the cartridge for the introduction of fresh nutrient medium and is adjacent to a port 36 disposed in a wall proximal to the bottom of the housing 10.
  • the outlet means 34 is disposed near the top of the cartridge, and adjacent to a port 38 disposed in a wall proximal to the top of the housing, and is for removal of trapped gas bubbles and a percentage of the input nutrient medium of between 0 and 75% of the flow of input medium, preferably between 1 and 20%.
  • the remaining flow of medium exits the cartridge 18 through the porous face 14 into the cell chamber 12 containing the cells and matrix. As medium perfuses, generally horizontally, around and through the interstices of the matrix, the desired cell product is secreted into the medium.
  • the product-conditioned medium from the cell culture chamber 12 enters the product removal cartridge 20, disposed as shown generally vertically opposite the medium supply cartridge 18, through the face of the cartridge 16 common to the chamber 12.
  • the side of the cartridge 16 is composed of porous flat material such as a membrane filter, sintered plate, screen or woven material, with a pore size between 1-200 ⁇ , preferably 10-100 ⁇ and, in any case, larger than the pore size of the medium supply cartridge face.
  • the product removal cartridge has at least one outlet means 42 adjacent to a port 40 disposed in the wall of the housing which provides for removal of product containing conditioned medium.
  • Figures 2-4 show alternate views of the apparatus of the invention and of its parts.
  • Figure 2 shows a side view of the apparatus along the line 1-1'.
  • the cell culture chamber contains the inlet port for introduction of cells and matrix at 24 and an exit port for trapped gases 27.
  • the medium supply cartridge shown on the left shares the face 14 with the cell culture chamber and has an inlet means for medium 32 and an outlet means diagonally opposite (in this embodiment) at the top of the cartridge 34 for the trapped gases and a portion, if desired, of the medium.
  • the product removal cartridge 20 shares a face 16 with the cell culture chamber and contains an outlet means, 42 for the conditioned medium.
  • the position of the outlet means in the vertical face shown in Figure 2 is not critical.
  • FIGs 3 and 4 are side views of the medium supply cartridge and product removal cartridge, respectively, where the porous faces 14 and 16 are shown along with the inlet and outlet means 32 and 34 for the medium supply cartridge and the outlet means 42 for the product removal cartridge.
  • the housing 10 contains multiple cell culture chambers as shown in top view in Figure 5.
  • the horizontal dimension of the housing is increased along one axis 52 relative to the embodiment described in Figure 1.
  • the cell culture chambers 12 are defined by multiple alternating medium supply cartridges 18' and product removal cartridges 20' « These subdividing cartridges 18' and 20' differ from the medium supply cartridge 18 and the product recovery cartridge 20 as shown in Figure 1 and from those at opposite walls of the housing in that both parallel vertical walls are porous, so that medium flows out of each medium supply cartridge 18' into cell culture chambers 12 flanking it through vertical faces 14'.
  • Conditioned medium flows through the walls 16' of the product removal cartridges 20' .
  • the internal cartridges have two parallel porous sides and the end cartridges 18 and 20 have single porous faces as described in Figure 1. This provides for the flow of medium, in parallel, through the multiple cell chambers 12 and the concomitant increase in the volume and capacity of the cell culture chambers 12 without significantly changing the effective geometric relationship between the medium supply cartridges 18 and 18', the cell culture and the product removal cartridges 20 and 20' .
  • the cell culture chambers and the medium supply cartridges 18 and 18' and product removal cartridges 20 and 20' are constructed as described for the single cell culture chamber embodiment described in Figure 1.
  • the cell culture chambers optionally contain a gas outlet port proximal to the top of the chamber, as well as a means for introduction of the cells and matrix, as well as an internally disposed generally tubular gas diffusion membrane.
  • the product removal cartridge contains an outlet means for the conditioned medium containing product; the medium supply cartridges have an inlet means for medium at approx ⁇ imately the bottom of the cartridge and an outlet means for entrapped gas and, optionally, unperfused medium diagonally opposite and proximal to the top of the chamber.
  • FIG. 5 A typical such system is also shown in Figure 5.
  • medium is supplied to the medium supply cartridges 18 and 18' through a common manifold 90 exterior to the housing and in fluid communication with the inlet means 32.
  • the outlet means 34 of the medium supply cartridges are in fluid communication with a manifold 92.
  • the outlet means 42 of the product removal cartridges 20 and 20' are in fluid communication with a manifold 94 exterior to the housing.
  • the gas inlet means 46 are preferably supplied by an exterior manifold 96 and the gas outlet means 48 collect into a manifold 98.
  • the apparatus described in Figures 1 or 5 can be incorporated into an overall system that operates in a flow-through or recycling mode and provides for the culture of cells at high density for extended periods of time and for the continuous recovery of secreted cell products.
  • a flow-through configuration is shown in Figure 6.
  • Medium is pumped through the system by a series of sterile pumps 58, preferably peristaltic pumps.
  • the pump pressure is regulated such that the pressure differentials are maintained within the system; generally, the liquid pressure in the cell culture chambers is maintained at a level in relation to gas pressure in the diffusion membrane disposed in the chambers to optimize diffusion of gases through the wall of the tubular membrane with or without gas bubble formation, and to permit the diffusion back of carbon dioxide.
  • the nutrient medium is pumped from a reservoir 60 kept at 4°-10°C, through flexible tubing 61 through heat exchanger 62 to warm the medium to the desired temperature.
  • the warmed medium then passes through a gas removal vessel 64 which permits gas evolved from the medium due to the change in temperature to be dispelled, and into the invention apparatus 66, for example, into the medium supply manifold 90 of Figure 5.
  • the condi ⁇ tioned medium for example from the product recovery manifold 94 of Figure 5 passes out of the apparatus.
  • the product-conditioned medium is returned to a refrigerated environment via flexible tubing 61 and then to a product cooler 68 and finally to a product reservoir 70.
  • a small fraction of the medium is removed from the medium supply cartridges 18 (and 18') for example into the exhaust manifold 92.
  • This excess fresh medium may be alternatively combined with the product stream 72, reintroduced into the gas removal vessel 74 or discarded 76, as will be further described below.
  • a recycling form of the system described in Figure 6 is illustrated in Figure 7.
  • the product flow may be split, so that a portion is returned to the input means of the supply cartridges and the remainder harvested.
  • the product flow is split such that a portion 78 returns to the input side of the apparatus 66 and the remainder 79 is removed to the product vessel 70.
  • a filtration system 80 (consisting of prefilter and filter cartridges of appropriate size ranges) is used to remove any particles from the product flow to prevent clogging of the apparatus.
  • a pressure sensing and control device 88 may also optionally be employed.
  • a hollow fiber dialysis cartridge 84 or other means for concentrating larger proteins in the recycle circuit and for removal of water and low molecular weight components not containing the product may also be included.
  • the fraction of medium 78 returned to the supply side of the reactor is 0-100%, preferably 50-80%.
  • a means of pH monitoring and adjustment 82 is included in this recycle circuit, as well as automated or manual sampling systems 86. Such information could be used to adjust and/or supplement the incoming nutrient medium stream to replace those components that were being metabolized by the cells.

Abstract

Appareil (10) de culture cellulaire laissant passer un milieu par perfusion dans une chambre de culture cellulaire (12) pour produire des cellules en continu. Grâce à ce système (10), il n'y a plus de gaz pris dans le milieu (18) ou dans la chambre de culture cellulaire (12).
PCT/US1990/002490 1989-05-05 1990-05-04 Systeme de culture cellulaire WO1990013639A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019910701530A KR920701420A (ko) 1989-05-05 1990-05-04 개량된 세포배양 시스템

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34762789A 1989-05-05 1989-05-05
US347,627 1989-05-05

Publications (1)

Publication Number Publication Date
WO1990013639A1 true WO1990013639A1 (fr) 1990-11-15

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Application Number Title Priority Date Filing Date
PCT/US1990/002490 WO1990013639A1 (fr) 1989-05-05 1990-05-04 Systeme de culture cellulaire

Country Status (6)

Country Link
EP (1) EP0471747A4 (fr)
JP (1) JPH04506149A (fr)
KR (1) KR920701420A (fr)
AU (1) AU5639490A (fr)
CA (1) CA2054210A1 (fr)
WO (1) WO1990013639A1 (fr)

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WO1991015570A1 (fr) * 1990-03-30 1991-10-17 Bertin & Cie Dispositif de culture cellulaire
EP0537551A1 (fr) * 1991-10-18 1993-04-21 Integra Biosciences GmbH Système de contrôle de pression d'un dispositif pour la culture de cellules et la récupération des produits
WO1996034087A1 (fr) * 1995-04-28 1996-10-31 Baxter International Inc. Bioreacteur
US5622857A (en) * 1995-08-08 1997-04-22 Genespan Corporation High performance cell culture bioreactor and method
WO1997038777A1 (fr) * 1996-04-16 1997-10-23 Advanced Tissue Sciences, Inc. Appareil de conditionnement et de culture a grande echelle de suspensions cellulaires et de cultures tissulaires tridimensionnelles
US5728581A (en) * 1995-06-07 1998-03-17 Systemix, Inc. Method of expanding hematopoietic stem cells, reagents and bioreactors for use therein
US5792603A (en) * 1995-04-27 1998-08-11 Advanced Tissue Sciences, Inc. Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing tissue, synthetic or native, vascular grafts
US5827729A (en) * 1996-04-23 1998-10-27 Advanced Tissue Sciences Diffusion gradient bioreactor and extracorporeal liver device using a three-dimensional liver tissue
US5843766A (en) * 1995-06-07 1998-12-01 Advanced Tissue Sciences, Inc. Apparatus for the growth and packaging of three dimensional tissue cultures
US5846828A (en) * 1995-06-07 1998-12-08 Advanced Tissue Sciences Apparatus and method for sterilizing, seeding, culturing, storing, shipping, and testing tissue, synthetic, or mechanical heart valves orvalve segments
US5958763A (en) * 1994-02-09 1999-09-28 Genespan Corporation Cell culture incubator
US6060306A (en) * 1995-06-07 2000-05-09 Advanced Tissue Sciences, Inc. Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing replacement cartilage tissue constructs
US6121042A (en) * 1995-04-27 2000-09-19 Advanced Tissue Sciences, Inc. Apparatus and method for simulating in vivo conditions while seeding and culturing three-dimensional tissue constructs
DE102004032318A1 (de) * 2004-07-02 2006-01-19 Fachhochschule Gießen-Friedberg Herstellung einer konzentrierten Lösung aus biologischen Substanzen
WO2008028241A1 (fr) * 2006-09-06 2008-03-13 The University Of Queensland Microbioréacteur
US7923242B2 (en) 2005-02-03 2011-04-12 Sanyo Electric Co., Ltd. Microorganism detection apparatus and microorganism detection cassette
WO2017211750A1 (fr) * 2016-06-08 2017-12-14 Vito Nv (Vlaamse Instelling Voor Technologisch Onderzoek Nv) Contacteur à membrane de biomasse

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Cited By (30)

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US5290700A (en) * 1990-03-30 1994-03-01 Bertin & Cie. Cell culture device
WO1991015570A1 (fr) * 1990-03-30 1991-10-17 Bertin & Cie Dispositif de culture cellulaire
EP0537551A1 (fr) * 1991-10-18 1993-04-21 Integra Biosciences GmbH Système de contrôle de pression d'un dispositif pour la culture de cellules et la récupération des produits
WO1993008307A1 (fr) * 1991-10-18 1993-04-29 Endotronics, Inc. Systeme de regulation de pression pour bioreacteur
US5330915A (en) * 1991-10-18 1994-07-19 Endotronics, Inc. Pressure control system for a bioreactor
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EP0471747A1 (fr) 1992-02-26
KR920701420A (ko) 1992-08-11
CA2054210A1 (fr) 1990-11-06
JPH04506149A (ja) 1992-10-29
AU5639490A (en) 1990-11-29
EP0471747A4 (en) 1992-06-03

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