WO2001077284A2 - Vorrichtung zum stoffaustausch und kultivierung von zellen - Google Patents
Vorrichtung zum stoffaustausch und kultivierung von zellen Download PDFInfo
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- WO2001077284A2 WO2001077284A2 PCT/DE2001/001373 DE0101373W WO0177284A2 WO 2001077284 A2 WO2001077284 A2 WO 2001077284A2 DE 0101373 W DE0101373 W DE 0101373W WO 0177284 A2 WO0177284 A2 WO 0177284A2
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- cells
- wall
- blood
- elastic
- hollow fiber
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- 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
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/26—Constructional details, e.g. recesses, hinges flexible
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/1698—Blood oxygenators with or without heat-exchangers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
- A61M1/26—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes and internal elements which are moving
- A61M1/267—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes and internal elements which are moving used for pumping
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
- A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
- A61M1/3489—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents by biological cells, e.g. bioreactor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/10—Location thereof with respect to the patient's body
- A61M60/122—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/30—Medical purposes thereof other than the enhancement of the cardiac output
- A61M60/31—Medical purposes thereof other than the enhancement of the cardiac output for enhancement of in vivo organ perfusion, e.g. retroperfusion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/30—Medical purposes thereof other than the enhancement of the cardiac output
- A61M60/34—Medical purposes thereof other than the enhancement of the cardiac output for enhancement of circulation to the extremities, e.g. the feet
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/40—Details relating to driving
- A61M60/424—Details relating to driving for positive displacement blood pumps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/80—Constructional details other than related to driving
- A61M60/855—Constructional details other than related to driving of implantable pumps or pumping devices
- A61M60/871—Energy supply devices; Converters therefor
- A61M60/882—Devices powered by the patient, e.g. skeletal muscle powered devices
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/24—Dialysis ; Membrane extraction
- B01D61/30—Accessories; Auxiliary operation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/026—Wafer type modules or flat-surface type modules
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/06—Tubular membrane modules
- B01D63/068—Tubular membrane modules with flexible membrane tubes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/16—Rotary, reciprocated or vibrated modules
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D65/00—Accessories or auxiliary operations, in general, for separation processes or apparatus using semi-permeable membranes
- B01D65/08—Prevention of membrane fouling or of concentration polarisation
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
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- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F3/00—Biological treatment of water, waste water, or sewage
- C02F3/02—Aerobic processes
- C02F3/10—Packings; Fillings; Grids
- C02F3/102—Permeable membranes
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/10—Location thereof with respect to the patient's body
- A61M60/104—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body
- A61M60/109—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body incorporated within extracorporeal blood circuits or systems
- A61M60/113—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body incorporated within extracorporeal blood circuits or systems in other functional devices, e.g. dialysers or heart-lung machines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/80—Constructional details other than related to driving
- A61M60/855—Constructional details other than related to driving of implantable pumps or pumping devices
- A61M60/89—Valves
- A61M60/892—Active valves, i.e. actuated by an external force
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/80—Constructional details other than related to driving
- A61M60/855—Constructional details other than related to driving of implantable pumps or pumping devices
- A61M60/89—Valves
- A61M60/894—Passive valves, i.e. valves actuated by the blood
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2313/00—Details relating to membrane modules or apparatus
- B01D2313/20—Specific housing
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2313/00—Details relating to membrane modules or apparatus
- B01D2313/20—Specific housing
- B01D2313/203—Open housings
- B01D2313/2031—Frame or cage-like structures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2321/00—Details relating to membrane cleaning, regeneration, sterilization or to the prevention of fouling
- B01D2321/20—By influencing the flow
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- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F3/00—Biological treatment of water, waste water, or sewage
- C02F3/02—Aerobic processes
- C02F3/12—Activated sludge processes
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W10/00—Technologies for wastewater treatment
- Y02W10/10—Biological treatment of water, waste water, or sewage
Definitions
- the invention relates to a device for the exchange of gases or substances with liquids, solutions and suspensions or for the cultivation of cells or microorganisms by means of hollow fibers or flat material-permeable carrier systems.
- Patent EP0292445 Al for the oxygenation of blood describes a hollow fiber oxygenator in a rigid housing consisting of a hollow fiber bundle and two compartments in which the hollow fiber is arranged.
- Patent EP 0534386B1 describes a device for mass transfer with flexible properties characterized by hollow fibers which are arranged within a tube.
- the long construction is disadvantageous here. It generates high unphysiological see pressure differences and the poor flowability of the device damages cells or activates the naming system.
- Patent EP0590341A3 and WO12960 describes a module for growing cells with several hollow fiber membranes with different functions.
- Known according to patent (Bader WO 9318133) are plate oxygenators which are suitable for cell cultivation and for oxygenating blood.
- the use of hollow fibers in the field of dialysis is also part of the prior art.
- the known devices do not have a homogeneous and geometrically uniform arrangement of the hollow fiber structures, which is, however, essential for an optimal supply of material to the cells.
- the prior art generally includes cultivation containers, oxygenators and dialyzers which contain diffusely distributed permeable hollow fibers.
- the cells or media introduced here flow unidirectionally around the fibers.
- the above common technical state provides for the oxygenation of blood cells via semipermeable membrane structures or diffusion membranes, but the structure and separation of the compartments are not designed to ensure a gentle and optimal supply of material to the cells.
- the design is rigid and does not allow volume changes, which inevitably leads to a high pressure difference in the system.
- the fluids flowing through, such as blood are exposed to non-physiological pressure conditions without buffering.
- a particularly high stress load in the inflow area of the device acts on the cells introduced here.
- Pressure fluctuations have a particularly damaging effect on adherent cell systems that are supplied by nutrient medium.
- the known systems cannot be implanted in order to oxygenate internal organs or to cultivate large amounts of autologous cells within the body.
- the known methods for cell cultivation have serious deficiencies in handling, Long-term stability and are complex in process control, so that its use in medicine is questionable. Furthermore, all known devices have significant shortcomings such that blood cells and particularly suspended tissue cells are damaged by pumps. None of the known devices can independently pump blood or move in a directed manner. Additional pumps have to do this work.
- the object of the invention is therefore to develop a device which accomplishes the following tasks:
- It is intended to enable gentle oxygenation of body cells and microorganisms, in which the cells are exposed to buffered pressure conditions and ensure a continuous flow of blood or other liquids. It should form a surface for the cultivation of adherent cells and optimally supply them with substances.
- the invention achieves this object by means of a device for the mass and gas exchange of cells, microorganisms, suspensions, solutions or liquids which is characterized in that flexible walls and structures which can be linked to functions enable internal and / or external adaptation processes.
- the device consists of at least one flexible, preferably elastic, non-rigid wall made of biocompatible plastics, such as silicone or polyurethane, and that, on the inside, there is a geometrically preferably continuously homogeneous arrangement of hollow fiber mats or hollow fibers, eg. B. from polypropylene, polyethersulfone, polymethylpentene, native material such as collagen or alternatively from fabric permeabilities flat fabric supports made of sintered materials or flat membranes.
- the upper and / or the lower wall should have flexible or elastic properties.
- the side walls should preferably be rigid and should not allow any liquid to pass through the edges, so that the liquid can flow in a directed manner over the inner structures.
- the side walls could be flexible and the inner material / gas permeable structures could have flexible or elastic properties.
- the invention achieves the object in that, for example, the gas-carrying or material-carrying capillaries preferably consist of elastic material and are advantageously additionally connected via elastic knitting threads and enable a molecular diffusion of gases or substances.
- Heparin or hydrogel coatings are suitable for increasing biocompatibility.
- the inner surfaces can preferably be supplemented with proteins, in other words albumin and matrix proteins, such as, for. B. fibronectm, laminin, gelatin, collagen or ligand peptides can be coated.
- proteins in other words albumin and matrix proteins, such as, for. B. fibronectm, laminin, gelatin, collagen or ligand peptides can be coated.
- the interstices contain, for example, collagen structures that can arise from freeze drying. Endothelial cell sheathing of the hollow fibers improves the biocompatibility in the event of blood contact and reduces the harmful effects (coagulation and complement activation) on the blood cells. In this case, no collagen may be in direct blood contact.
- blood flows and the pressure differences occurring here are physiologically buffered via non-rigid, preferably elastic walls.
- An elastic wall in the inflow area reduces the stress load on the cells in this area.
- This buffering effect is essential for long-term cell-friendly operation with higher blood flows or for cell cultivation of adherent cells that are located within the device.
- blood could be pulsatilely printed by the device with the support of the patient's own cardiac output.
- Blood cells and changes in blood pressure in the system are lower than in known comparable rigid systems.
- the non-rigid walls of the device not only reduce the risk of high stress on the inserted cells, but also the associated coagulation activation in the case of blood.
- the outer flexible walls also consist of materials via which additional substances from the outside reach the interior of the device via diffusion.
- the internal structures of the device are surrounded by blood or liquid. The mass transfer takes place via the internal hollow fibers or flat material carriers.
- the geometric, preferably homogeneous arrangement provided in the invention with defined distances between the substance-permeable structures is essential for the cultivation and the mass exchange of cells, because identical conditions prevail in all areas of the device.
- Particularly adherent, sensitive tissue cells can thus colonize and be supplied to the outer walls of the substance-permeable supports because the substances reach the cell by diffusion through the hollow fiber in the shortest possible way.
- the solubility of oxygen which is only 6.5 mg / liter, contrasts. This amount is used up by the cells in less than a minute.
- the direct attachment of cells to the oxygen carrier increases the metabolic performance of the cells and guarantees that the cells can form a 3-D cell network with high cell densities on the hollow fiber surface.
- hollow fibers are used which are permeable to gases.
- the device can have a square or round shape.
- the gas exchange between the flowing cells, liquids, suspensions or solutions takes place due to the homogeneous arrangement of the hollow fibers under uniform conditions, whereby a build-up pressure in the system is buffered via the flexible outer wall and thus ensures that the cells in the system are protected ,
- the internal volume of the device changes. This state is preferably reversed to a defined degree via the restoring forces of the flexible wall.
- the outer wall can be guided in this way or delimited by an additional rigid outer shell.
- the expandable volume of the device is defined here.
- the restoring forces of the flexible wall also prevent the wall from resting on the preferably gas-permeable hollow fiber mats.
- a distributor plate between the outer wall and the hollow fiber system can prevent the fibers from being damaged mechanically or by an applied vacuum.
- This device is particularly suitable for the oxygenation of blood and thus as an artificial lung. Another area of application is dialysis, plasma separation and cell filtration.
- the high input of oxygen can also be used to fumigate large quantities of solutions or cell suspensions.
- the device can be tempered via an upstream heat exchanger.
- the square shape also enables the layered geometric arrangement of oxymerging fibers and dialysis fibers or hollow fiber mats.
- the properties of an oxygenator are combined with those of a dialyzer. Cells can thus be supplied with oxygen at the same time and synthetic substances from cells can be removed by dialysis.
- the homogeneity of the space between the hollow fibers improves the diffusion conditions for gaseous as well as for all other substances in this space.
- a mechanical drive device in connection with the flexible wall enables a gentle pumping of the liquid in such a way that the liquid is preferably propelled in a movement in the y-axis towards the device and in a movement away from the device Device is sucked again.
- Valves in the inlet and outlet area control and allow a directed flow.
- the substance-permeable carrier layers consist of flat, round structures and distribute blood or liquid in the center of the carrier layers via a supply channel.
- Another form of execution has a rigid outer shell and flexible, elastic material or gas exchange structures on the inside. Located between the rigid shell and the inner mass transfer structures, which are also encased by an elastic outer wall a work space in which liquids or gases are introduced via inlet and outlet valves. Flows z. B. liquid in this room, the inner elastic structures are compressed and z. B. gas, which is located within the capillaries, and at the same time liquid is pressed away from the extracorporeal space of the device. A directional pumping motion is created when valves control the inflow and outflow areas (for the extra and intracellular space) of the internal structures. If the liquid is actively removed from the work area by pumps, the internal structures can expand again and fill with liquid and gas.
- the cylinder has a rolled-up hollow fiber mat on the inside, which homogeneously fills the entire inner space. At least in the upper area there is an all-round elastic wall via which the blood or liquids are directed into the internal structures of the device.
- the upper part of the cylinder can have the shape of a balloon for better distribution and, in combination with valves and a mechanism, can pump liquid into the device in a directed manner.
- a hollow fiber bundle consisting of z. B. 4 - 12 fibers, from a flexible wall semi-variable elastic membrane z. B. from polyurethane, polypropylene, Teflon or silicone.
- sheathed fiber bundles together form a larger unit with the advantage that the internal fibers take over the oxygenation of medium and cells such as liver cells and substances and dissolved oxygen reach the blood cells in the space between the functional units via the semipermeable membrane.
- the membrane prevents mixing of the different cell systems.
- the round design is particularly suitable for dialysis. For example, blood can be dialyzed through a rolled up hollow fiber mat and through another rolled up hollow fiber mat
- the liquid can flow into the device from above.
- de is not rigid wall m the form of a balloon terminally sermatte to be rolling en Hohlfa ⁇ .
- the balloon structure can e.g. B. be firmly connected to the region of the polyurethane-bonded hollow fibers ", via a dialysis fluid which flows around the outside of the hollow fibers, a mass transfer takes place.
- the liquid can be oxygenated according to the patterns already described.
- the arrangement the devices allow a combination of different mass-exchanging processes, such as dialysis, blood filling or plasma operation with subsequent oxygenation.
- a further embodiment of the invention is that the device consists of a further non-rigid outer wall, in which liquid is brought to the temperature control.
- a defined volume flexibilization by the applied pressure is given by the fact that the expansion of the elastic wall is limited by a rigid housing and is accessible at least with one line.
- water-carrying hollow fibers can also be centrally contained in the device as a bundle. The advantage of this design is the large surface area and the direct contact with the surrounding medium.
- a thin plastic film or membrane preferably made of silicone, Teflon or polyurethane, is applied to a hollow fiber module or on a flat, flexible membrane support structure and this device is implanted in an organism for treatment.
- genetically modified cells in a permanent culture can exchange certain substances with the environment via the outer wall and thus supply hormones or active substances to the body.
- the wall should combine biocompatible and material-permeable properties.
- the device is supplied via lines and external peripheral devices and advantageously via implanted ports.
- the device serves as a cell reactor for the cultivation of Cells and at the same time as a medium reservoir. This device also provides an affordable alternative. It is also ideal scale for culturing cells in the lab ⁇ . Another advantage of this design is that gravity is sufficient to print the solution through the permeable module.
- An interesting alternative is when muscle cells in the abdominal cavity mechanically move the membrane and thus move fluid in the body in a directed manner.
- Fig. 2a Sectional view of a hollow fiber module with an elastic outer wall with low pressure conditions in the system.
- Fig. 2b Sectional view of a hollow fiber module with an elastic outer wall at high pressures in the system.
- Fig. 3a Sectional view (side view) of a construction with a reservoir function for the cultivation of cells with an internal flat gas-permeable hollow fiber mat module.
- Fig. 3b Sectional view (top view) of a construction with a reservoir function for cultivating cells with a flat, gas-permeable hollow fiber mat module.
- Fig. 4 Sectional view of an oxygenator device with an integrated pump function for blood in combination with flat, round, gas-permeable gas carriers.
- FIG. 5 Sectional view of a cylindrical device for oxygenation with a rolled-up hollow fiber mat.
- Fig. 6 Sectional view (looking at it) of a cylindrical device with integrated water-carrying and material-permeable hollow fibers.
- FIG. 1 shows a functional sectional view of the device according to the invention with an elastic outer wall in combination with an inner elastic material-exchanging hollow fiber arrangement.
- An arrangement A. is shown in the state of a low internal pressure load and an arrangement B. with an increased pressure load.
- Below an elastic wall (10) there are two hollow fibers (9), which are connected with an elastic knitting thread (8).
- the hollow fibers can in turn. B. present as a hollow fiber mat.
- the medium-carrying space (11) is located between the upper functional walls (10) and the adjacent functional hollow fiber wall (7) and this space is developed in a different geometric spatial arrangement (12) between the hollow fiber outer surfaces (7).
- the medium-carrying space (11, 12) can be flowed through for liquids, solutions or suspensions such as blood.
- the inner lumen of the hollow fiber (9) provides another separate medium-carrying space in this arrangement, for. B. for gaseous substances.
- the elasticity - shown here in a curvature of the entire arrangement B. - comes from an internal medium pressure (shown here as arrows A), which acts on the internal structures and continues over the liquid-carrying space and the outer wall (10) bulges.
- the elasticity of the arrangement changes the dimensions of the internal structures and, for example, enlarges the media-surrounding spaces 11 and 12.
- the thickness of the outer wall (10) also changes, since these takes up all the pressure and is stuck.
- the hollow fibers (9) themselves advantageously have elastic properties.
- the elasticity of the inner structures (9, 8) in combination with the outer elastic wall (10) increases the spatial distances in the device three-dimensionally.
- a positive factor for the capacitive mass transfer is if the elastic outer walls (7) of the hollow fibers reduce the wall thickness
- the rooms 11 and 12 can change unfavorably on the medium guide if the inner lumen of the hollow fiber increases via an elastic outer wall of the hollow fiber (7)
- Broaching the device changes the performance of the device in the area of volume flow and capacitive gas exchange via the hollow fiber membrane, so that the controllable adaptation of the inner structures (9, 8, 7) in combination with the outer wall (10) makes them optimal Conditions for the mass and gas exchange within the device created n.
- Fig. 2a shows a first exemplary embodiment of the invention m sectional view. It is an oxygenator for the oxygenation of blood. Alternatively, dialysis and oxygenation fiber mats can be layered in this module.
- the oxygenator consists of an oxygenation module consisting of hollow fibers (9) knitted to form hollow fiber mats (14) which are laid over one another in a crisscross pattern. The arrangement of the hollow fibers is strictly geometric and homogeneous. Between the hollow fibers is the space (12) for the flow of blood (here marked with arrows (A)). At the edges, the fiber mats are cast with polyurethane (16) and there is a gas-carrying space (13) in the connection.
- the gases are supplied via separate inlet (21) and outlet (22), which can be arranged laterally, for example.
- An elastic wall (10) is formed above and below the module, which preferably has an inlet (19) and outlet (20) at a central point.
- a cover frame (24) is welded above and below the device to the hollow fiber module .
- blood (arrows A) flows from un ⁇ m th the space (11) between the hollow fiber module and the ela ⁇ stica wall and displaces the air in the system.
- This device may additionally be a heat exchanger arranged upstream to the Fl LIQUID the apparatus m ⁇ warm to it.
- Fig. 2b shows a sectional view of the exemplary embodiment 1 a.
- the high bulge of the outer walls (10) indicates a high pressure in the system.
- the volume of space (11) above the hollow fiber module of the device is significantly increased and the wall is visibly curved outwards.
- the arrows A indicate the blood flow through the device and the pressure on the outer wall.
- Fig. 3a shows another exemplary embodiment (sectional view m side view) as a reservoir construction for the cultivation of cells with an internal flat gas-permeable hollow fiber mat module.
- the hollow fiber mat (14) has a thin-walled membrane or film (10) above and below.
- the flat device has lateral lines for the introduction and discharge of gases (21, 22) and liquids (19, 20).
- the hollow fiber mat is connected to a gas-carrying space (13) and to the membrane (10) via a frame construction (18).
- the side wall of the frame (18) is stable.
- the hollow fiber module consists of a long, homogeneously knitted fiber mat (14) which is folded over one another at defined intervals and has been potted at the ends with polyurethane (16).
- a defined space (12) is formed between the hollow fibers.
- Nutrient medium enters the interior (11) of the device via a feed line (19) and is discharged via a line (20).
- FIG. 3b shows a sectional illustration (top view of FIG. 3a) of a construction with a reservoir function for the cultivation of Cells.
- the inside fibers are potted at the ends (16) with polyurethane and form a flat gas-permeable hollow fiber mat module (14).
- the membrane (10) of the device is laterally connected to the frame (18) so that the liquid can only flow through the hollow fiber module.
- the top view shows with arrows B how the liquid is guided over the hollow fiber mat by means of a distributor pipe (25).
- FIG. 4 shows the sectional illustration of an oxygenator device with an integrated pump function for blood in combination with flat, round, gas-permeable gas carriers.
- the flat support structure consists of microporous support plates with a silicone membrane (15), which are stacked on top of each other.
- the blood (arrow A) passes through an inlet (19) with an integrated valve (26) into the space (11) between the oxygenation module (microporous support plates with a silicone membrane) and the elastic wall (10).
- a mechanical element (28) is fixedly attached to the elastic wall from outside, with which the wall (10) is moved up and down. In the upward movement, the liquid flows through the opened valve (26) m the device.
- a downward movement closes the above valve (26) via the liquid pressure and, in return, opens the lower valve (27) via the liquid pressure, so that the liquid can enter the oxygenation part.
- a center channel (29) guides the liquid evenly into the spaces (12) of the oxygenation plates.
- a plate (17) delimits the oxygenation space so that the liquid or blood can only be drained laterally and exits the device via an outlet (20). Air in the system can be eliminated via a ventilation valve (23).
- FIG. 5 shows a sectional view of a cylindrical device for oxygenation with a rolled-up hollow fiber mat.
- the cylindrical embodiment has an elastic wall (10) in the form of a balloon with an integrated inlet (19) and outlet (20) at the top and bottom. Between the balloon and the rolled up hollow sermatte (14) forms a small space (11) for receiving the liquid.
- the rigid structural part (18) is two-part ⁇ and has in the middle of the spaced balloons a jacket (30) in which water (31) flows for temperature control.
- the inlet (32) and outlet (33) for the tempered water is firmly integrated in the jacket.
- the rigid end pieces of the device are firmly connected to the final, polyurethane-stabilized hollow fiber mat (16) and preferably lead gas into the device via inlets (21) and outlets (22).
- Fig. 6. Shows a sectional view (top view) of a cylindrical device for dialysis with integrated water-carrying and permeable material hollow fibers (35) with a connector (34).
- a water-carrying hollow fiber bundle (35) in the center of the device.
- the water-carrying hollow fiber can be omitted and replaced by oxygenation fibers or oxygenation modules (comparable to structure 35) which are coated with a semipermeable membrane.
- Permeable hollow fibers (9) are located around this bundle of hollow fibers (35).
- the non-rigid wall (10) is designed like a balloon and is placed over the hollow fiber arrangement.
- the balloon with an inlet or outlet (21) is firmly connected to the rigid cylinder wall (18). Liquid can preferably flow in here and thus reaches the inner lumen of the hollow fiber.
- a dialysis fluid flows in the space between the fibers (12) to absorb substances.
- the device has a square oxygenation area consisting of superimposed hollow fiber mats with a total oxygenation area of approximately 1.8 m 2 and has a full volume of 250 ml (see FIG. 2).
- the device in the upper part consists of water-bearing mats for temperature control.
- Liver cells are isolated from a fresh pork liver by the action of collagenase and then centrifuged. After Resupenstechnik the cell in Krebs-Ringer solution or a comparable buffer, the cells with a defined cell count of 10 6 are - 10 7 cells / ml in the oxygenation e Nge introduced. The colonization of the outer hollow fiber is completed within two hours. To ensure a better distribution of the cells, the cell reactor is turned over when filling.
- the cells flow with a continuous flow of approx. 250-500 ml / day. supplied with nutrient medium. Temperature control of the medium is not necessary.
- the device is heated to 37 ° C. via the water-bearing mats and supplied with a defined gas composition via a water bath.
- the functionality of the cells takes place, for example, by analyzing the albumin secretion, lactate and urea production.
- the hepatocytes can be optimally cultivated for at least 3 weeks.
- the highest albumin synthesis rates were between the 5th and 20th achieved.
- the urea synthesis remained constant over a cultivation period of 21 days.
- Studies of the diazepane metabolism show that the phase I metabolism of the hepatocytes is intact.
- Studies with round cell reactors show comparable results.
- Example 2 In a similar device as in Example 1, several devices are combined in a modular design. Oxygenation areas of several m 2 can thus arise. High-performance microorganism strains are immobilized on the hollow fiber diffusion membrane in the device. Hardly degradable substances from wastewater with toxic substances such as heavy metals, surfactants etc. are carried in the same compartment where the microorganisms are located via the densely packed hollow fibers. The oxygen supply is via the hollow fibers.
- the reactors operate with flow rates of 0.2-0.6 liters / min and at temperatures between 20 - 40 ° C and can be operated for several months. Through direct and high oxygen input, the microorganisms can make optimal use of their high energy requirements. Alternatively, parts of microorganisms and fungi can also be used for plant cells or even multicellular organisms.
- Example of use 3 An extremity or an organ with damage is oxygenated separately. If the extremity is a leg with a thrombus, a bypass is placed over the leg vein in the upper main vessel, thus isolating the extremity from the central blood circulation system. Alternatively, blood flow through the leg can be stopped with a pressure cuff. Catheters are inserted into the vessels through a small surgical procedure to ensure an extracorporeal circulation. The leg is treated with an extracorporeal circuit, for example, during the treatment period Oxygenator supplied with an integrated pump, for example of the type described (Fig. 3). Here flows z. B. Blood with 1 - 2 liters / mm through the extremity.
- the oxygenation of the leg is coupled with therapy in such a way that very high doses of streptokinase or urokinase are administered to dissolve the clot.
- the pump can apply a high pressure of up to 1 bar to mechanically remove the thrombus.
- the advantage of this treatment is that it is possible to work with very high amounts of active ingredients for a short time without damaging the whole body.
- Another advantage is that the extremity can be optimally and controlled supplied with oxygen for the treatment period. The therapeutic agent or the pollutants formed are then removed from the extremity by means of an additional dialysis or a piasma replacement. The external supply of oxygen can take place over several hours without tissue damage.
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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EP01935954A EP1278822A2 (de) | 2000-04-08 | 2001-04-07 | Vorrichtung zum stoffaustausch und kultivierung von zellen |
Applications Claiming Priority (2)
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DE2000117690 DE10017690A1 (de) | 2000-04-08 | 2000-04-08 | Vorrichtung zum Stoffaustausch und Kultivierung von Zellen |
DE10017690.9 | 2000-04-08 |
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WO2001077284A2 true WO2001077284A2 (de) | 2001-10-18 |
WO2001077284A3 WO2001077284A3 (de) | 2002-09-19 |
WO2001077284B1 WO2001077284B1 (de) | 2003-01-09 |
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PCT/DE2001/001373 WO2001077284A2 (de) | 2000-04-08 | 2001-04-07 | Vorrichtung zum stoffaustausch und kultivierung von zellen |
Country Status (3)
Country | Link |
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EP (1) | EP1278822A2 (de) |
DE (1) | DE10017690A1 (de) |
WO (1) | WO2001077284A2 (de) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102004007564A1 (de) * | 2004-02-17 | 2005-09-01 | Cordes, Rudolf, Dipl.-Ing. | Vorrichtung zur Zucht und Massenproduktion von Algen |
WO2009098457A3 (en) * | 2008-02-06 | 2009-10-15 | Ecmo Associates Limited | Extracorporeal membrane oxygenation |
EP2322154A2 (de) * | 2002-07-09 | 2011-05-18 | Crossbeta Biosciences B.V. | Verfahren für den Nachweis und Beseitigung von Cross-Beta-Struktur- enthaltenden Proteinen mit Cross-Beta-Struktur-bindenden Verbindungen. |
WO2015075099A1 (de) * | 2013-11-21 | 2015-05-28 | Sartorius Stedim Biotech Gmbh | Filtermodul |
WO2021165277A1 (de) * | 2020-02-18 | 2021-08-26 | Universitaet Des Saarlandes | Vorrichtung zum entfernen eines gases aus einer wässrigen flüssigkeit |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1398047B1 (de) * | 2002-09-11 | 2005-11-16 | Gambro Lundia AB | Kappe für einen Dialysator, Dialysator und Verfahren zur Entfernung von Gasblasen |
ITFI20040025A1 (it) * | 2004-02-05 | 2004-05-05 | Angela Caramuta | Dispositivo per l'eliminazione dell'anidride carbonica dal sangue ed un'apparecchiatura equipaggiata con il dispositivo medesimo |
DE102007001665A1 (de) * | 2007-01-11 | 2008-07-17 | Raumedic Ag | Gasaustauschmembran insbesondere zum Einsatz in einer künstlichen Lunge sowie Verfahren zur Herstellung einer derartigen Gasaustauschmembran |
DE102009008601A1 (de) | 2009-02-12 | 2010-08-19 | Novalung Gmbh | Vorrichtung zur Behandlung einer biologischen Flüssigkeit |
DE102015000021A1 (de) * | 2015-01-07 | 2016-07-07 | Enmodes Gmbh | Vorrichtung für den Stoffaustausch zwischen Blut und einem Gas/Gasgemisch |
AU2017260221B2 (en) | 2016-05-05 | 2023-02-02 | The Regents Of The University Of California | Hemofiltration device and methods of use thereof |
CN115055770A (zh) * | 2022-06-25 | 2022-09-16 | 湖北欧米隆精密机械有限公司 | 一种电火花成型机油槽用放油机构 |
WO2024079290A1 (en) * | 2022-10-14 | 2024-04-18 | Sani Membranes A/S | Vibrating filtration device |
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US4308654A (en) * | 1979-09-24 | 1982-01-05 | Monsanto Company | Methods for assembling permeators |
US4647539A (en) * | 1985-05-24 | 1987-03-03 | Endotronics, Inc. | Method and apparatus for growing cells in vitro |
US4734106A (en) * | 1985-05-08 | 1988-03-29 | A/G Technology Corporation | Gas separating |
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- 2000-04-08 DE DE2000117690 patent/DE10017690A1/de not_active Withdrawn
-
2001
- 2001-04-07 WO PCT/DE2001/001373 patent/WO2001077284A2/de not_active Application Discontinuation
- 2001-04-07 EP EP01935954A patent/EP1278822A2/de not_active Withdrawn
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US4308654A (en) * | 1979-09-24 | 1982-01-05 | Monsanto Company | Methods for assembling permeators |
US4734106A (en) * | 1985-05-08 | 1988-03-29 | A/G Technology Corporation | Gas separating |
US4647539A (en) * | 1985-05-24 | 1987-03-03 | Endotronics, Inc. | Method and apparatus for growing cells in vitro |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2322154A2 (de) * | 2002-07-09 | 2011-05-18 | Crossbeta Biosciences B.V. | Verfahren für den Nachweis und Beseitigung von Cross-Beta-Struktur- enthaltenden Proteinen mit Cross-Beta-Struktur-bindenden Verbindungen. |
EP2322154A3 (de) * | 2002-07-09 | 2011-10-05 | Crossbeta Biosciences B.V. | Verfahren für den Nachweis und Beseitigung von Cross-Beta-Struktur- enthaltenden Proteinen mit Cross-Beta-Struktur-bindenden Verbindungen. |
DE102004007564A1 (de) * | 2004-02-17 | 2005-09-01 | Cordes, Rudolf, Dipl.-Ing. | Vorrichtung zur Zucht und Massenproduktion von Algen |
WO2009098457A3 (en) * | 2008-02-06 | 2009-10-15 | Ecmo Associates Limited | Extracorporeal membrane oxygenation |
WO2015075099A1 (de) * | 2013-11-21 | 2015-05-28 | Sartorius Stedim Biotech Gmbh | Filtermodul |
CN105848763A (zh) * | 2013-11-21 | 2016-08-10 | 赛多利斯司特蒂姆生物工艺公司 | 过滤器模块 |
US20160296890A1 (en) * | 2013-11-21 | 2016-10-13 | Sartorius Stedim Biotech Gmbh | Filter module |
KR101917876B1 (ko) * | 2013-11-21 | 2018-11-13 | 사토리우스 스테딤 바이오테크 게엠베하 | 필터 모듈 |
US10493406B2 (en) | 2013-11-21 | 2019-12-03 | Sartorius Stedim Biotech Gmbh | Filter module |
WO2021165277A1 (de) * | 2020-02-18 | 2021-08-26 | Universitaet Des Saarlandes | Vorrichtung zum entfernen eines gases aus einer wässrigen flüssigkeit |
CN115397546A (zh) * | 2020-02-18 | 2022-11-25 | 萨尔大学 | 从水性液体中除去气体的装置 |
Also Published As
Publication number | Publication date |
---|---|
WO2001077284B1 (de) | 2003-01-09 |
EP1278822A2 (de) | 2003-01-29 |
WO2001077284A3 (de) | 2002-09-19 |
DE10017690A1 (de) | 2001-10-25 |
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