EP1981963A1 - Reacteur et unite de reacteur comportant des fibres creuses - Google Patents

Reacteur et unite de reacteur comportant des fibres creuses

Info

Publication number
EP1981963A1
EP1981963A1 EP05819267A EP05819267A EP1981963A1 EP 1981963 A1 EP1981963 A1 EP 1981963A1 EP 05819267 A EP05819267 A EP 05819267A EP 05819267 A EP05819267 A EP 05819267A EP 1981963 A1 EP1981963 A1 EP 1981963A1
Authority
EP
European Patent Office
Prior art keywords
hollow fibers
reactor unit
reactor
chamber
unit according
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05819267A
Other languages
German (de)
English (en)
Inventor
Franz Kugelmann
Paul Hengster
Raimund Margreiter
Bernd Nederlof
Massimo Fini
Ciro Tetta
Thomas Wild
Micaela Yakubovich
Michael Paul
Marco Caronna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fresenius Medical Care Deutschland GmbH
Original Assignee
Fresenius Medical Care Deutschland GmbH
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
Priority claimed from DE200410062828 external-priority patent/DE102004062828B4/de
Priority claimed from DE102005021305A external-priority patent/DE102005021305A1/de
Application filed by Fresenius Medical Care Deutschland GmbH filed Critical Fresenius Medical Care Deutschland GmbH
Publication of EP1981963A1 publication Critical patent/EP1981963A1/fr
Withdrawn legal-status Critical Current

Links

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
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/24—Gas permeable parts
    • 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
    • C12M23/28—Constructional details, e.g. recesses, hinges disposable or single use
    • 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
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/10—Rotating vessel
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/14—Rotation or movement of the cells support, e.g. rotated hollow fibers

Definitions

  • the invention relates to a reactor unit having a first chamber and a second chamber, wherein the first chamber is formed by the interior of a housing and wherein the second chamber is formed by the interior of a plurality of arranged in the housing hollow fibers.
  • Such reactor units are known in different embodiments and serve, for example, to produce human or animal cells of different origin or are used, for example, in artificial liver and pancreatic replacement therapy.
  • a reactor which has a rotatably arranged reactor unit in which there is a medium with cells to be cultivated.
  • the supply of the cell medium with oxygen and the removal of the CO 2 formed is achieved by means of a permeable wall of the reactor unit.
  • a liver support system which comprises a reactor unit having a first chamber and a second chamber, wherein the first chamber through the interior of a housing and the second chamber is formed by the interiors of hollow fibers of a hollow fiber bundle accommodated in the housing.
  • the hepatocytes are in the first chamber.
  • the blood plasma is guided in one embodiment of the described reactor through the interiors of the hollow fibers, ie through the second chamber.
  • the mass transfer takes place via the hollow-fiber membranes.
  • the hollow fibers are straight and run in the longitudinal direction of the housing.
  • WO 04/050864 A1 discloses a bioreactor in which a chamber containing the cells to be cultivated is provided, which is separated by means of a membrane from a supply or discharge line leading to a nutrient medium.
  • reactor units of the type mentioned can be used, for example, to grow cells.
  • Another area of application is therapy, such as liver and pancreatic replacement therapy.
  • Previously known reactor units thus have, for example, a first chamber for culturing cells through which a supply circuit formed by the second chamber runs, through which a nutrient medium or blood or blood components flows.
  • the second chamber is formed by a hollow-fiber membrane bundle, wherein substances are exchanged with the medium in the first chamber via the membranes of the hollow fibers. It is usually provided that larger units, such. B. cells can not pass the membrane of the hollow fibers.
  • the cells in the first chamber can be supplied with nutrients and metabolic products can be removed.
  • substances from the blood are exchanged with the chamber, which are then metabolized by liver cells.
  • the maximum fiber density is 12 fibers / mm 2 . It has been found that a particularly favorable mass transfer is achieved when the density of the fibers, which is related to the cross-sectional area of the first chamber, does not exceed the value of 10 fibers / mm 2 .
  • the area-related density of the hollow fibers in at least one region of the first chamber in the range of 0.2 to 10 fibers / mm 2 , preferably in the range of 0.5 to 6 fibers / mm 2, and particularly preferably in the range of 1 to 4 fibers / mm 2 .
  • These densities can be realized at least in one point of the first chamber.
  • the fiber densities given here and below relate to a uniform fiber density based on 1 cm 2 .
  • the surface-related density of the hollow fibers of the reactor unit according to the invention can be realized, on the one hand, by casting the fibers already in the appropriate density, ie, or by embedding them in casting compounds in their end regions. Furthermore there is the possibility to use the fibers in the form of their To shed closest possible packing and then to reduce the distance between the two potting compounds in the chamber, so that the distance between the potting surfaces is less than the length of the potting compound located between the portion of the fibers. In this case, the fibers between the casting surfaces are not straight, but curved, for example spindle-shaped.
  • the relative to the cross-sectional area of the first chamber density of the fibers changes in the fiber longitudinal direction. This is z. Example, then the case when the fibers are cast in their closest packing, but the distance between the mutually facing surfaces of the potting compound is less than the length of the fiber sections located between the potting compounds.
  • the relative to the cross-sectional area of the first chamber density of the fibers in the fiber longitudinal direction is constant. Such an embodiment is conceivable when the fibers are cast in the desired density, which is below the maximum possible density.
  • one or more than one potting compound are arranged, in which a portion, usually the end portion, of the hollow fibers is embedded.
  • a potting compound can then be provided if the fibers have, for example, a U-shaped course.
  • the reactor unit has two potting compounds, which are opposite, in which a portion, preferably the end portion of the hollow fibers is embedded and between which extends another portion of the hollow fibers.
  • the hollow fibers extend straight or curved between the casting compounds, so that, for example, a bulbous or spindle-shaped hollow fiber bundle results.
  • the fibers fill the volume of the first chamber more than with a straight, straight grain.
  • an advantageous embodiment of the invention consists in the fact that the length of the section of at least some or all of the hollow fibers located between the casting compounds is at least 0.5% greater than the distance between the facing surfaces of the casting compounds. It is particularly preferred if the length of said sections of at least some or all of the hollow fibers is at least 1% and preferably at least 3% above the said spacing of the casting surfaces.
  • the hollow fibers or the spindles formed by them can be constricted, for example, by means of O-rings, so that the density can be regulated upwards again.
  • the reactor unit has a third chamber, which is formed by hollow fibers, which serve to transfer at least one gaseous medium via the hollow-fiber membrane. It can be realized a circuit for gas exchange.
  • the second chamber forming hollow fibers which are preferably flowed through by a liquid, it can thus be provided that further hollow fibers pass through the interior of the housing or the first chamber.
  • the third chamber forming gas exchange hollow fibers are provided.
  • the arrangement of the gas exchange hollow fibers is largely arbitrary. It is conceivable, for example, that the hollow fibers forming the second chamber and preferably flowed through by a liquid medium are arranged in a central section of the reactor unit and the gas exchange hollow fibers preferably flowed through by a gaseous medium in peripheral regions of the reactor unit. In a further embodiment of the invention, it is provided that the gas exchange hollow fibers have a larger inner and / or outer diameter than the hollow fibers forming the second chamber.
  • the third chamber forming gas exchange hollow fibers are designed such that a transfer of oxygen through the membrane is possible.
  • the gas exchange hollow fibers forming the third chamber can be used for oxygenating the medium or cells located in the first chamber.
  • the gas exchange hollow fibers forming the third chamber can be made of PTFE, for example. It is conceivable, for example, to use a hydrophobic gas exchange membrane for the gas exchange hollow fibers.
  • the invention further relates to a reactor unit having a first chamber and a second chamber, wherein the first chamber is formed by the interior of a housing and wherein the second chamber is formed by the interior of a plurality of arranged in the housing hollow fibers. It is provided that in the reactor unit at least two potting compounds are arranged in which a portion, preferably the end portion of the hollow fibers is embedded and between which another portion of the hollow fibers extends, wherein the length of the hollow fiber portion located between the potting masses at least some or of all hollow fibers at least 0.5% above the distance of the mutually facing casting surfaces.
  • an advantageous embodiment of the invention results, in particular, if the mass transfer between the two chambers is to take place at least also by convection.
  • the convective mass transport is directly proportional to the pressure difference across the hollow fiber membranes.
  • the pressure drop in the hollow fibers is directly proportional to the length of the fiber and inversely proportional to the diameter of the fiber in the fourth power.
  • the inlet and the outlet of the hollow fibers are arranged on the same side of the housing. It is possible that the flow path of the guided through the hollow fibers medium is U-shaped or has a plurality of changes in direction. It is possible to adjust the pressure difference between the first chamber and the second chamber or the media located in these so that it assumes the value zero at the reversal point of the hollow fibers. Prior to this reversal point is due to the pressure difference convection from the hollow fibers in the first chamber and in the adjoining the reversal point a convection of the first in the second chamber instead, ie from the medium located in the housing in the hollow fibers.
  • the hollow fibers can be arranged in the housing such that a medium flowing through the hollow fibers takes a substantially U-shaped flow path.
  • the hollow fibers may be made substantially U-shaped. It is also conceivable that the hollow fibers are straight and are embedded at their two end portions in potting compounds, wherein the flow guide is configured such that the medium first flows through one or more hollow fibers, undergoes a change in direction in the end region and then flows back through other hollow fibers.
  • the housing may be rotationally symmetrical, preferably cylindrical.
  • the hollow fibers starting from the inlet to a region in which the direction of the course of the hollow fibers changes, extend in a first direction and from the region of the direction change into a second, deviating from the first Direction, wherein extending in the first direction hollow fiber sections radially inward and extending in the second direction hollow fiber sections relative to radially outwardly.
  • Such an embodiment is considered, for example, when the hollow fibers are already embedded with relatively low density in the casting compounds. It is conceivable, for example, that the pressure difference between the first and second chamber is chosen so that there is a spatial separation of feeding and discharging hollow fibers. This allows a good mixing can be achieved.
  • the pressure drop in the hollow fiber is inversely proportional to the diameter of the fiber in the fourth power. In view of this, it is favorable to choose the smallest possible fiber diameter. It is preferably provided that the inner diameter of the hollow fibers is at most 300 ⁇ m, preferably at most 200 ⁇ m and particularly preferably approximately 100 ⁇ m.
  • a high porosity of the hollow fiber membranes also allows a good mass transfer.
  • the hydraulic permeability of the membrane should be at least 200 ml / mmHg xhxm 2 , preferably at least 500 ml / mmHg xhxm 2 .
  • the cutoff of the membrane forming the hollow fibers is in the range between 10 4 Da and 10 7 Da, preferably in the range between 10 5 Da and 10 6 Da.
  • a particularly preferred cutoff is in the range of 700,000 to 900,000 Da.
  • deviating porosities or cutoffs are possible.
  • the use of hollow-fiber membranes with low porosity is also conceivable.
  • the reactor unit is designed as a disposable.
  • the reactor unit is constructed from materials that are steam sterilizable.
  • the materials used preferably correspond to the materials which are also used in dialysis filters.
  • the housing made of PP and / or the potting compound of polyurethane and / or the hollow fibers of polyarylethersulfones, preferably from polysulfones and more preferably perform with PVP hydrophilized polysulfones.
  • all materials in a steam sterilization at 121 0 C dimensionally stable is further relates to a reactor having at least one reactor unit according to the invention, wherein the reactor unit is arranged to be rotatable.
  • an advantageous embodiment of the invention relates to a reactor with a rotatably arranged reactor unit. It can be provided corresponding drive means by which the reactor unit is placed in a rotational movement.
  • the reactor has not only one, but a plurality of reactor units.
  • the interconnection of these multiple reactor units is arbitrary. It is conceivable, for example, to arrange the reactor units in series, so that the outlet of one reactor unit forms the inlet of another reactor unit. It is also conceivable to arrange the reactor units in parallel and, for example, to supply them with an identical supply, for example exactly the same nutrient solution, etc.
  • Said series connection can be designed in such a way that a flow direction between the reactor units takes place in one direction, that is to say that the outlet of a first reactor unit forms the inlet of a second, subsequent reactor unit. It is also conceivable that the outlet of said second reactor unit in turn forms the inlet for the first reactor unit, so that a mass transfer takes place in two directions.
  • the reactor is executed without slip ring seal.
  • the inlet and the outlet of the hollow fibers can lie on the same side of the housing.
  • it is possible lent to carry out the reactor unit without mechanical seal as described for example in EP 1 270 079 A2 and DE 198 03 534 C2 using the example of a cell separator.
  • the invention further relates to a method for effecting a mass transfer by means of one or more hollow fibers using a reactor unit according to one of claims 1 to 29 or a reactor according to any one of claims 30 to 34, wherein the pressure in the second chamber formed by the hollow fiber inner spaces and in the first chamber formed by the housing is adjusted such that the mass transfer through the hollow fibers takes place at least partially by convection.
  • This convective mass transfer may be superimposed on a mass transfer by diffusion.
  • the mass transfer by convection is preferably bidirectional and is particularly for medium and high molecular weight synthesis products or nutrients with lower diffusion rate into consideration.
  • the pressure ratios between the first and the second chamber are selected such that the convective mass transport in a portion of the hollow fibers from the medium contained in the hollow fibers in the medium received in the housing and in another portion of the hollow fibers in the opposite direction.
  • a subdivision into feeding and laxative hollow fibers or hollow fiber sections takes place.
  • hollow fibers or hollow fiber sections are provided, by means of which nutrients are supplied to the medium located in the first chamber.
  • hollow fibers or hollow fiber sections are provided by means of which metabolic products from the medium in the first chamber are transferred into the hollow fiber and then removed.
  • the invention further relates to a system comprising a reactor unit according to one of claims 1 to 29 or a reactor according to one of claims 30 to 34 with a reservoir which communicates with the reactor unit in such a way that from the reservoir medium in the formed by the hollow fibers second chamber of the reactor unit can be introduced or discharged from this, with a preferably designed as a peristaltic pump feed pump for conveying the medium and with an oxygenator, by means of which the pumped medium can be enriched with oxygen.
  • the oxygenation takes place externally and can be variably adjusted to the oxygen consumption.
  • the oxygen supply takes place in this case, for example via the blood plasma or the nutrient medium supplied.
  • the oxygenator is preferably upstream of the reactor in the flow direction of the medium.
  • a heating device may be provided for heating the conveyed medium.
  • the oxygenation can also take place by means of gas exchange hollow-fiber membranes arranged in the reactor unit.
  • FIG. 2 shows a perspective view of the reactor according to the invention with housing
  • 5 shows a schematic representation of the mass transfer system according to the invention with reactor
  • 6 shows schematic representations of different geometries of a reactor unit according to the prior art and of reactor units according to the invention
  • FIG. 7 temporal concentration curves for urea, protein and various ions when using a reactor unit according to the invention
  • Fig. 9 a schematic representation of a reactor unit according to the invention with a flowing through a liquid medium, the second chamber forming hollow fibers and the third chamber forming gas exchange hollow fibers for oxygenation and
  • Fig. 10 schematic representations of different arrangements of several reactor units connected in series or in parallel.
  • FIG. 1 shows a perspective view of the reactor unit 12 according to the invention designed as a disposable. It consists of a housing 20 in which hollow fibers in the form of a hollow fiber bundle are arranged. Furthermore, an inlet 40 and a drain 50 are provided, via which the medium flowing through the hollow fibers is supplied or removed.
  • FIG. 2 From Fig. 2 it can be seen the reactor 10 without reactor unit. Visible is the rotatable receptacle for fixing the reactor unit of FIG. 1, which is rotated by an electric motor in rotational movements.
  • the recording or the reactor with reactor unit are housed in a temperature-controlled housing.
  • FIG. 3 shows a schematic representation of a rotatably arranged reactor unit 12. Conceivable fields of use are: • Hepatocyte culture for different applications
  • the points illustrated in FIG. 3 represent the cells which are located in the first chamber of the reactor unit 12 bounded by the housing 20.
  • hollow fibers 30 are arranged, which have an inlet 40 and a drain 50. If it is a cell culture, a nutrient medium is supplied via the inlet 40. In the case of liver or pancreatic replacement therapy, 40 blood plasma is supplied via the feed. The spent nutrient medium or the treated blood plasma is withdrawn via the drain 50.
  • the housing 20 has two ports 22 for filling, draining or sampling from the first chamber. It is conceivable to close the connections 22 after filling or sampling. In principle, it is also conceivable to allow continuous operation to the effect that medium is continuously introduced via the connections 22 into the first chamber or removed therefrom.
  • hollow fibers 30 are provided centrally in the region of the axis of rotation of the reactor unit 12, forming a hollow fiber section 32c in which a comparatively high pressure is present, so that convective mass transfer from section 32c of the hollow fibers is indicated by arrows 30 takes place in the limited by the housing 20 first chamber of the reactor unit 12.
  • the inlet 40 and the outlet of the hollow fibers are located on the same side of the housing 20, in the embodiment as in FIG. 3 on the right-hand end side of the cylindrically shaped housing 20.
  • Such an embodiment makes it possible to use a To provide mechanical seal-free reactor available.
  • the relative movement between stationary and moving parts can be achieved by the system known from EP 1 270 079 A2 and DE 198 03 534 C2.
  • the reactor unit 12 is preferably designed as a disposable. It can be carried out as an injection molding construction, which has the basic process steps analogous to the production of a conventionally manufactured hemodialyzer, such as casting with PUR, cutting and sterilization. The reactor unit can be produced efficiently in this way.
  • first chamber are located in a suitable medium human hepatocytes.
  • a radially central portion is made of individual hollow fibers hollow fiber bundle.
  • the hollow fiber bundle has a multiplicity of hollow fibers 30a arranged in the region of the axis of rotation, of which only a few are shown by way of example.
  • a plurality of hollow fibers 30b are provided for radially offset outward, which are arranged in the outer peripheral region of the hollow fiber bundle and of which also only one is shown.
  • Such an embodiment is considered, for example, when the hollow fibers are already embedded with relatively low density in the casting compounds.
  • the hollow fibers 30 a, 30 b are arranged in parallel and fixed in their two end regions in casting compounds 32, which are secured in the housing 20 in a suitable manner.
  • medium flows into the hollow fibers 30a, flows through them and exits at the end region of the hollow fibers 30a shown on the left.
  • the medium arrives here in a flow space connecting the end portions of the hollow fibers 30a with the initial portions of the hollow fibers 30b.
  • the flow direction of the medium in the end region of the fibers 30a is changed. It flows after passing through the flow space in the hollow fibers 30b and through this in the opposite direction than through the hollow fibers 30a.
  • the hollow fibers 30b are in their end region shown on the right with the sequence 50 in connection, by means of which the correspondingly treated medium is discharged from the reactor unit 12.
  • the medium may be, for example, a nutrient medium or body fluids, such as blood or particularly preferably blood plasma.
  • the reactor unit shown in Fig. 4 can of course be used for other purposes, such as for cell cultures.
  • the limited by the housing 20 first chamber has two ports 22, which can serve for the supply or removal of medium from the first chamber or for sampling.
  • the reactor unit 12 is set in rotation during operation, the axis of rotation being parallel to the hollow fibers.
  • the hollow fibers 30a are preferably arranged in such a way that they lie in the region of the axis of rotation, and the hollow fibers 30b are offset radially outward for this purpose.
  • the pressure ratios may be selected such that the pressure in the hollow fibers 30a is above the pressure of the first chamber bounded by the housing 20 and below the pressure prevailing in the first chamber in the hollow fibers 30b.
  • the present invention differs from prior art embodiments in that the reactor unit is designed such that the in this arranged hollow fibers of the hollow fiber bundle are not arranged in a maximum possible density, but that the relative to the cross-sectional area of the first chamber density of the fibers in at least a portion of the first chamber 10 fibers / mm 2 does not exceed or that the length of between two Casting compound recorded hollow fiber sections exceeds the distance between the mutually facing surfaces of the potting compounds by at least 0.5%.
  • FIG. 6 a shows a reactor unit 12 designed according to the prior art in a schematic view.
  • the hollow fiber membranes are enclosed in a plastic net and form a rigid, cylindrical structure.
  • the fiber density based on the cross-sectional area of the first chamber is thus about 12 fibers / mm 2 .
  • Fig. 6b shows an embodiment of the schematically illustrated reactor unit 12 according to the invention.
  • the distance L of the cut surfaces of the casting compounds 32 is shortened by 10 mm compared to the embodiment according to the prior art according to FIG. 6 a.
  • the hollow fibers between the potting compounds 32 are compressed and form a spindle.
  • the largest diameter of the fiber bundle is 95 mm.
  • the fiber density in the reactor unit 12 according to the invention as shown in FIG. 6b is in the range between 1.5 fibers / mm 2 and 12 fibers / mm 2 .
  • Fig. 6c shows an embodiment in which the distance L of the cut surfaces of the potting compound 32 corresponds to that of Fig. 6a.
  • the fiber bundle is constricted by an O-ring, so that the fiber density compared to the embodiment of FIG. 6b is again regulated upwards.
  • the diameter of the fiber bundle is 34 mm.
  • the maximum diameter of the fiber bundle is 60 mm, resulting in a total surface density of the fibers in the range between 3.9 fibers / mm 2 and 12 fibers / mm 2 .
  • the concentration curves according to FIGS. 7 and 8 are based on the following test setup or the following experimental procedure:
  • the hollow fibers were filled with exchange medium and connected after taking time "0" to the reactor unit or its first chamber.
  • the reactor unit was supplied at a flow rate of 200 ml / min at 25 ° C. during the exchange experiments and rotated at 15 rpm to examine the sample exchange by convection and diffusion.
  • sample Per ml, 2 ml of sample were administered by Monovette (Sarstedt 2 ml LH; CE 0197) at one point before entering the chamber and at sample port 1 in the chamber. removed. In the process, approx. 2 to 3 ml of liquid were rinsed out of the sampling ports before each sampling and only then the test sample was drawn. At the chamber sample port 2 was used to replace the sampled sample with water. In the supply circuit formed by the hollow fibers, the sampled sample was replaced by the buffer reservoir.
  • the volume of the chambers was about 1.7 I.
  • the hollow-fiber membranes are stabilized by 2 synthetic fibers. Due to the reduced spacing of the casting compounds, the chambers are about 1 cm shorter than in the test arrangement with which the test results according to FIG. 8 were obtained. As a result, the membranes are compressed and form a spindle-shaped, the chamber volume filling structure.
  • the chamber volume was about 1.8 I.
  • the membranes are enclosed in a plastic net and form a rigid, cylindrical structure.
  • the compressed open membrane (spindle shape) (fiber density: 1, 5 fibers / mm 2 ) fills the lumen of the first chamber for the most part and thereby causes a very good mass transfer.
  • the material exchange takes place between the hollow fibers and the first chamber within the first minutes after the circulation has been started.
  • the complete concentration exchange for ions and urea can after about 30 to 60 min. be determined.
  • the abbreviations "VKL” and "chamber” mean the concentrations in the supply circuit (VKL), ie in the medium flowing through the hollow fiber, or the concentrations in the first chamber of the reactor unit.
  • the material exchange between the hollow fibers and the first chamber takes place much slower than in accordance with FIG. 7.
  • the complete concentration compensation for ions and urea can be carried out after 120 to 180 min. be measured and thus 3-4 times slower than the spindle-shaped membranes according to the invention.
  • the protein is also exchanged slowly and incompletely.
  • the reactor unit according to the invention can be used for therapy, for example for liver replacement or liver support therapy.
  • FIG. 5 shows a schematic illustration of an overall system for liver support therapy.
  • This consists of a plasma reservoir 60 which contains blood plasma taken from the patient to be treated. Plasma is withdrawn from the plasma reservoir 60 via the peristaltic pump 70 and supplied to the gas exchanger 80.
  • the gas exchanger 80 via a source of oxygen and a sterile filter, the supply of oxygen, whereby the blood plasma is enriched with oxygen accordingly.
  • the gas exchanger also consists of two chambers, wherein in one chamber, the oxygen and in the other chamber, the blood plasma flows. The chambers are separated by permeable membranes, which prevent the passage of gases such. B. Allow oxygen into the blood plasma.
  • the gas exchanger By means of the gas exchanger not only oxygen can be supplied, but also other gases, such as CO 2 , N 2 can be supplied or exchanged.
  • the gas exchanger is designed as an oxygen generator for the exchange of oxygen. After the enrichment of the blood plasma with oxygen in the oxygenator 80, this passes through a heating device 90 and then enters the reactor 10.
  • This has the rotatably arranged inventive reactor unit 12, which is designed as disposable.
  • the reactor unit 12 is disposed in a rotatable receptacle of the reactor 10 and is rotated during operation of the system. The axis of rotation coincides with the longitudinal axis of the reactor unit 12.
  • the reactor is accommodated in a temperature-controlled housing, as can be seen from FIGS. 2 and 5.
  • the system is designed without mechanical seal.
  • Polysulfone plasma fibers having a large available exchange surface preferably in the range from 0 to 2 m 2 with preferably variably adjustable porosity up to 900,000 MW, are preferably usable as hollow fibers.
  • the mass transfer preferably takes place primarily by means of convection.
  • hydrophilic and / or hydrophobic membranes can be used for the hollow fibers.
  • separation of the feeding fibers from the laxative fibers can occur.
  • fiber bundles can be variably assigned within the reactor.
  • feeding and discharging fibers may be centrally located. It is also conceivable that feeding fibers are arranged centrally and laxative fibers peripherally. Thus, a flow through the cell culture can be achieved in countercurrent.
  • the reactor unit may be a sterile disposable article that is separate from an unsterile rotary unit.
  • the sterile disposable article is preferably water vapor sterilizable.
  • the oxygenation is preferably carried out externally, it is adjustable to the oxygen consumption adjustable.
  • the oxygen supply is thus preferably via the blood plasma or via a nutrient medium.
  • the reactor unit 12 includes a housing 20 that forms the first chamber.
  • hollow fibers 30 are arranged, which are flowed through by a liquid medium.
  • gas exchange fibers 130 are arranged, by means of which an oxygenation of the medium located in the first chamber of the housing 20 takes place.
  • the gas exchange hollow fibers also for the removal of gaseous substances or also for the supply and / or removal of gases other than oxygen.
  • the present invention thus comprises not only an external gas exchange or an external gas supply, but also a gas supply or a gas exchange within the reactor unit.
  • FIG. 10 shows a series arrangement of a plurality of reactor units 1 - n in the same reactor. As indicated by the arrow, the reactor units are rotatably arranged.
  • the resulting benefits are as follows:
  • the middle arrangement according to FIG. 10 shows a parallel arrangement of rotatably arranged reactor units, which are thus not flowed through sequentially but parallel to one another.
  • the resulting benefits are as follows:
  • bottom view shows a return or cross flow between the also rotatably arranged reactor units 1 - n.
  • the reactor units on two inlets and two processes and communicate with each other in such a way that the expiration of a first reactor unit forms the inlet of a second reactor unit and the outlet of this second reactor unit forms the inlet of the first reactor unit.
  • This system also continues between the other reactor units.
  • the nutrient solution from the last reactor unit is not recycled to the reactor unit 1 but to the previously connected reactor unit;
  • a metabolite is formed in the reactor unit 2 of the liver cells, which metabolizes but can not be excreted by the kidney substances.
  • a drug for example, after application of a drug into the nutrient medium, it can be passed over a liver cell culture in a first reactor unit, where several metabolites are generated. Immediately following the metabolite generation, a metabolite separation z. B. in the form of a chromatographic method. Subsequently, the transmission of the different metabolites, z. In parallel arrangement on different cells to characterize the effect of different metabolites on different cells.
  • the illustrated reactor units are arranged in a reactor.
  • cells of the following origin can be used:

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  • Separation Using Semi-Permeable Membranes (AREA)
  • External Artificial Organs (AREA)

Abstract

L'invention concerne une unité de réacteur comportant une première chambre et une deuxième chambre, la première chambre étant formée par l'intérieur d'un boîtier et la deuxième chambre étant formée par l'intérieur de plusieurs fibres creuses disposées dans le boîtier. Les fibres creuses sont disposées de telle manière dans le boîtier que leur densité par rapport à la section transversale de la première chambre ne dépasse pas 10 fibres/mm2 dans au moins une zone de la première chambre. Dans un autre mode de réalisation, l'unité de réacteur contient deux masses de scellement dans lesquelles une partie des fibres creuses est intégrée et entre lesquelles s'étend une autre section des fibres creuses, la longueur d'au moins quelques unes ou de toutes les fibres étant supérieure d'au moins 0,5 % à l'écart entre les masses de scellement.
EP05819267A 2004-12-27 2005-12-22 Reacteur et unite de reacteur comportant des fibres creuses Withdrawn EP1981963A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE200410062828 DE102004062828B4 (de) 2004-12-27 2004-12-27 Reaktor mit einer rotierbar angeordneten Reaktoreinheit
DE102005021305A DE102005021305A1 (de) 2005-05-09 2005-05-09 Reaktoreinheit und Reaktor mit einer derartigen Reaktoreinheit
PCT/EP2005/013906 WO2006069737A1 (fr) 2004-12-27 2005-12-22 Reacteur et unite de reacteur comportant des fibres creuses

Publications (1)

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EP1981963A1 true EP1981963A1 (fr) 2008-10-22

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US (1) US8557571B2 (fr)
EP (1) EP1981963A1 (fr)
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WO (1) WO2006069737A1 (fr)

Families Citing this family (5)

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DE102008010691A1 (de) * 2008-02-22 2009-08-27 Universität Rostock Bioäquivalenzdialyse
US20100112696A1 (en) * 2008-11-03 2010-05-06 Baxter International Inc. Apparatus And Methods For Processing Tissue To Release Cells
US8309343B2 (en) * 2008-12-01 2012-11-13 Baxter International Inc. Apparatus and method for processing biological material
DE102009022354B4 (de) * 2009-05-15 2015-05-07 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Bioreaktorsystem
US10179896B2 (en) 2015-05-12 2019-01-15 Baker Group, LLP Method and system for a bioartificial organ

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5882918A (en) * 1995-08-08 1999-03-16 Genespan Corporation Cell culture incubator

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US440853A (en) * 1890-11-18 Automatic wagon-gate
US4440853A (en) * 1980-08-21 1984-04-03 Board Of Trustees Of The Leland Stanford Junior University Microbiological methods using hollow fiber membrane reactor
US4647539A (en) * 1985-05-24 1987-03-03 Endotronics, Inc. Method and apparatus for growing cells in vitro
US4806246A (en) * 1986-04-11 1989-02-21 Applied Membrane Technology, Inc. Pore size control using plasma polymerization techniques
JPH0659206B2 (ja) 1988-03-01 1994-08-10 宇部興産株式会社 バイオリアクター
JPH02109966A (ja) * 1988-10-20 1990-04-23 Kirin Brewery Co Ltd ラジアルフロー式充填層型バイオリアクタ
JP2675408B2 (ja) * 1989-09-14 1997-11-12 宇部興産株式会社 中空糸膜型バイオリアクター
US5437998A (en) * 1993-09-09 1995-08-01 Synthecon, Inc. Gas permeable bioreactor and method of use
US5622857A (en) * 1995-08-08 1997-04-22 Genespan Corporation High performance cell culture bioreactor and method
US5955353A (en) * 1997-05-22 1999-09-21 Excorp Medical, Inc. Hollow fiber bioreactor with an extrafilament flow plug
US6001585A (en) * 1997-11-14 1999-12-14 Cellex Biosciences, Inc. Micro hollow fiber bioreactor
DE19803534C2 (de) 1998-01-30 1999-11-11 Fresenius Ag Zentrifuge und Leitung zum Zuführen und/oder Abführen mindestens eines Fluids von der Separationseinheit einer Zentrifuge zu einer ortsfesten Anschlußstelle
EP1098691B1 (fr) * 1998-06-29 2006-02-01 Microban Products Company Membranes antimicrobiennes semi-permeables
US20030129736A1 (en) * 1999-07-15 2003-07-10 Eduardo Mitrani Device and method for performing a biological modification of a fluid
JP3725147B2 (ja) * 1999-08-25 2005-12-07 東洋紡績株式会社 血管網類似構造体を有する細胞培養用モジュール
JP3553858B2 (ja) * 1999-08-25 2004-08-11 東洋紡績株式会社 血管網類似構造体を有する細胞培養用モジュール
DE10023505A1 (de) * 2000-05-13 2001-11-22 Fraunhofer Ges Forschung Reaktormodul mit Kapillarmembranen
JP2002112763A (ja) * 2000-10-10 2002-04-16 Nipro Corp 細胞培養容器
US6582955B2 (en) * 2001-05-11 2003-06-24 Spectrum Laboratories, Inc. Bioreactor with application as blood therapy device
DE10129769A1 (de) 2001-06-20 2003-01-09 Fresenius Hemocare Gmbh Schlauchanordnung und Verfahren zu ihrer Herstellung
US6566126B2 (en) * 2001-06-22 2003-05-20 Fibercell Systems, Inc. Apparatus and method for growing cells
WO2003105663A2 (fr) 2002-06-01 2003-12-24 Stelsys Llc Systeme d'assistance hepatique a base de cartouches de fibres creuses ou de bioreacteur rotatif
US7390653B2 (en) 2002-12-04 2008-06-24 Synthecon, Inc. Culture chamber for biologicals

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5882918A (en) * 1995-08-08 1999-03-16 Genespan Corporation Cell culture incubator

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JP2008524997A (ja) 2008-07-17
US8557571B2 (en) 2013-10-15
WO2006069737A1 (fr) 2006-07-06
JP5038149B2 (ja) 2012-10-03
US20080145926A1 (en) 2008-06-19

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