CN101087873A - Reactor and reactor unit with hollow fibers - Google Patents

Reactor and reactor unit with hollow fibers Download PDF

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Publication number
CN101087873A
CN101087873A CNA2005800448888A CN200580044888A CN101087873A CN 101087873 A CN101087873 A CN 101087873A CN A2005800448888 A CNA2005800448888 A CN A2005800448888A CN 200580044888 A CN200580044888 A CN 200580044888A CN 101087873 A CN101087873 A CN 101087873A
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CN
China
Prior art keywords
reactor unit
chamber
tubular fibre
reactor
fiber
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Granted
Application number
CNA2005800448888A
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Chinese (zh)
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CN101087873B (en
Inventor
F·库格尔曼
P·亨格斯特
R·马格雷特
B·内德洛夫
M·菲尼
C·特塔
T·维尔德
M·亚库博维克
M·保罗
M·卡罗纳
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Fresenius Medical Care Deutschland GmbH
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Fresenius Medical Care Deutschland GmbH
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Priority claimed from DE102005021305A external-priority patent/DE102005021305A1/en
Application filed by Fresenius Medical Care Deutschland GmbH filed Critical Fresenius Medical Care Deutschland GmbH
Priority claimed from PCT/EP2005/013906 external-priority patent/WO2006069737A1/en
Publication of CN101087873A publication Critical patent/CN101087873A/en
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Publication of CN101087873B publication Critical patent/CN101087873B/en
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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
    • C12M23/24—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

Abstract

The present invention relates to a reactor unit comprising a first chamber and a second chamber, wherein, the first chamber is formed by the inner side of the casing and the second chamber is formed by the inner side of a plurality of hollow fibers arranged in the casing. The hollow fibers are arranged in the casing to facilitate that the density of the hollow fibers in at least an area of the first chamber is no more than 10fibers/mm<2> on the base of the sectional area of the first chamber. According to the other aspect of the invention it is prescribed that two casting mixtures are arranged in the reactor unit, one part of the hollow fiber is inserted into the casting mixture and the other part of the hollow fiber extends between the casting mixtures, wherein, the length of at least some or total hollow fiber is longer than the distance of the casting mixtures for 0.5at least.

Description

Reactor unit and reactor with this reactor unit
The present invention relates to have the reactor of first chamber and second chamber, wherein, first chamber is formed by the inside of shell, and second chamber is formed by the inside that is arranged in a plurality of tubular fibres in the shell.
Dissimilar reactors is known and is used for as cultivating human or animal's cell of Different Origin, perhaps is used for as artificial liver or pancreas transplantation treatment.
Can be from US 5,437,998 know a kind of reactor, and this reactor comprises rotatably mounted reactor unit, and this rotatable reactor unit contains substratum (medium), and this substratum has the cultured cells of carrying out.Realize oxygen being provided and discharging formed CO by the permeable wall of reactor unit to substratum 2
Can know a kind of liver supporting system from WO 03/105663 A2, this system comprises reactor unit, this reactor unit has first chamber and second chamber, wherein, first chamber is formed by the inside of shell, and second chamber is formed by the inside of the tubular fibre that is contained in the hollow fiber bundle in the shell.Liver cell is contained in first chamber.In an embodiment of described reactor, blood plasma is passed the inside of tubular fibre, promptly pass second chamber.Mass transfer is finished by hollow-fibre membrane.Be designed to tubular fibre straight and extend with the longitudinal direction of shell.Can know a kind of bio-reactor from WO 04/050864 A1, be provided with chamber in this bio-reactor, this chamber contains and carries out cultured cells, by film this chamber is separated with vent pipe with the supply that is loaded with nutritional medium.
Such just as previously described, the mentioned reactor unit in front can be used for as culturing cell.Another kind of use field is treatment, as liver and pancreas transplantation treatment.Therefore, for example, reactor unit of the prior art has first chamber that is used for culturing cell, and the supply pipe that is formed by second chamber passes the extension of first chamber, and nutritional medium or blood or blood ingredient flow through this second chamber.Second chamber is formed by hollow fiber membrane bundle usually, and wherein, the film by tubular fibre in first chamber exchanges with material and substratum.Unit that general provision is bigger such as cell can not be through the films of tubular fibre.Can provide nutrition also meta-bolites can be discharged by the cell of this reactor unit in first chamber.That mentions in front is used as reactor unit in the situation of artificial liver, and the material and the chamber of autoblood exchange in the future, and then, these materials are by the liver cell metabolism.
First chamber of crossing the range request reactor unit that the front is mentioned and the good mass transfer between second chamber.The objective of the invention is to form such as previously mentioned a kind of reactor unit, have improved mass transfer characteristics so that this reactor unit is compared with known reactor unit.
This purpose is realized by the reactor unit with claim 1 and 14 described features.Therefore, regulation is arranged in tubular fibre in the shell, is no more than 10 fiber/mm with the density of the tubular fibre at least one zone that makes on the basis of the sectional area of first chamber at first chamber 2Have now found that, when the density of tubular fibre is no more than certain density on the basis of the sectional area of first chamber, can realize the mass transfer between first chamber and second chamber ideally.Now notice do not have the maximum value of possibility when the density of fiber but can realize good exchange during less than this value.In the artificial kidney the closeest filling benefit not in the present invention of the preferential fiber of selecting.When guaranteeing supplied capacity, realize least density, also depend on total exchange surface simultaneously.
In the tubular fibre of the external diameter with about 250 μ m, maximum fibre density is 12 fiber/mm 2Have now found that, when the density of tubular fibre is no more than 10 fiber/mm on the basis of the sectional area of first chamber 2Value the time can realize special ideal mass transfer.
Particularly advantageous is that the density of the tubular fibre of per unit area is at 0.2 to 10 fiber/mm at least one zone of first chamber 2Scope in, preferably at 0.5 to 6 fiber/mm 2Scope in, particularly preferably in 1 to 4 fiber/mm 2Scope in.These density can realize at least one point of first chamber.
Herein and hereinafter illustrated density be meant at 1cm 2Uniform fiber density on the basis.
Can realize on the one hand the creative density of the tubular fibre of per unit area reactor unit,, promptly fiber embedded in the cast mix in their terminal area because fiber is implanted among the corresponding density.And, can fiber be implanted with fiber the closeest possible filling, reduce in the chamber distance between two kinds of mixtures then, so that the distance of implant surface is less than the length of the pars fibrosa between these cast mix.In this case, not straight line extension between implant surface of fiber, but curved, for example be fusiform.
The fibre density that therefore can visualize on the basis of the sectional area of first chamber changes at the longitudinal direction with fiber.For example, that's how things stand when fiber is implanted its closeest filling, but mutually towards the surface of cast mix between distance less than the length of the pars fibrosa between these cast mix.Perhaps, the fibre density that also can be defined on the basis of sectional area of first chamber is a constant on the longitudinal direction of fiber.When these fibers were implanted desirable density, can visualize this embodiment was that desirable density is less than possible maximum density.
In principle, can be with a kind of or be arranged in the reactor unit more than a kind of cast mix, the part of tubular fibre normally end sections embeds in this cast mix.Can when flowing, U-shaped provide cast mix as having at fiber.
Certainly, reactor unit also can comprise two kinds of cast mix, these two kinds of cast mix mutually towards, the part of tubular fibre preferably end sections embed in the cast mix, and another part of tubular fibre is extended between these two kinds of cast mix.
Just as previously described, can stipulate that tubular fibre straight line between cast mix extends also can extend with curve, so just obtain as protrusion or the fusiform hollow fiber bundle.These fibers compare in the situation of the straight line fibre stream of elongation at the volume of filling first chamber to a greater extent.
Just as previously described, favourable aspect of the present invention comprise between the cast mix at least some or all the part of tubular fibres length than mutually towards the surface of cast mix between distance big at least 0.5%.The length of this part of preferred especially some or all tubular fibres is bigger at least by 1% than this distance between the implant surface, and preferably big at least 3%.
Available proper device restriction tubular fibre is with the fibre density on the basis of the sectional area that is increased in first chamber.In principle, for example, available O shape encircles tubular fibre or by the formed spindle of tubular fibre, so that density is adjusted upward once more.
In still another aspect of the invention, the regulation reactor unit comprises the 3rd chamber, and the 3rd chamber is formed by tubular fibre, and these tubular fibres are used for transmitting at least a gaseous medium by hollow-fibre membrane.Can realize a kind of circuit that is used for gas transfer.Except the tubular fibre that forms second chamber, also can therefore stipulate that other tubular fibre extends through the inside of shell or the inside of first chamber, preferred liquid is passed tubular fibre.The a plurality of this hollow gas transfer fiber that forms the 3rd chamber preferably is provided.
Can realize the layout of hollow gas transfer fiber to a great extent as desired.For example, can visualize the tubular fibre that will form second chamber is arranged in the centre portions of reactor unit, and with hollow gas transfer fibre placement in the outer peripheral areas of reactor unit, when operation, the preferred liquid substratum passes this tubular fibre, and preferred gaseous medium is passed hollow gas transfer fiber.
In another aspect of this invention, stipulate that hollow gas transfer fiber has internal diameter and or the external diameter greater than the tubular fibre that forms second chamber.
In a preferred embodiment of the invention, the regulation hollow gas transfer fiber design that will form the 3rd chamber becomes can carry out the transmission of oxygen by film.In this case, the hollow gas transfer fiber that forms the 3rd chamber can be used for oxidation and is contained in the substratum in first chamber or is contained in cell in first chamber.
Availablely make the hollow gas transfer fiber that forms the 3rd chamber, for example, can visualize hydrophobic gas transfer membrane is used for hollow gas transfer fiber as PTFE.
The invention still further relates to the reactor unit with first chamber and second chamber, wherein, first chamber is formed by the inside of shell, and second chamber is formed by the inside that is arranged in a plurality of tubular fibres in the shell.Regulation is arranged in two kinds of cast mix in the reactor unit at least, the part of tubular fibre preferably end sections embeds in this cast mix and another part of tubular fibre is extended between reactor unit, wherein, between the cast mix at least some or all the part of tubular fibres length than mutually towards the implant surface of cast mix between distance big at least 0.5%.Like this, obtain less than mutually towards implant surface distance corresponding to mutually towards implant surface between the fibre density of per unit area in the situation of length of part of the tubular fibre that extends.Particularly preferably be, design this reactor unit according to any one the characteristic in the claim 1 to 13.Tubular fibre stream in the shell to a great extent can be as desired.Can visualize tubular fibre is arranged to and will flows through the substratum of tubular fibre with a direction guiding or with at least two different direction guiding.Like this, in a kind of situation in back, the substratum that flows through tubular fibre stands the variation at least one direction.For example, the flow process that can visualize the substratum that flows through tubular fibre takes the shape of the letter U basically or uses the U-shaped tubular fibre.
If the variation at least a direction is arranged, just obtains favourable aspect of the present invention, when especially the mass transfer between two chambers at least also realizes by convection current.The convection current mass transfer is directly proportional with the pressure reduction that passes hollow-fibre membrane.Pressure drop in the tubular fibre is directly proportional with staple length and is inversely proportional to the biquadratic of Fibre diameter.Therefore, if the flow process that flows through the substratum of tubular fibre stands the variation that first power makes progress at least,, so, just correspondingly increase the total path that passes shell as substratum being guided back and forth the opposite direction as at least once.This just causes in the hollow-fibre membrane corresponding elevated pressures and causes passing the increase of the pressure reduction of hollow-fibre membrane, thereby causes the increase of convective exchange.
Particularly advantageous is that the entrance and exit of tubular fibre is arranged in the same side of shell.The flow process of passing the substratum of tubular fibre guiding can be U-shaped or also have several variations on the direction.Can regulate the pressure reduction between the substratum contained in the pressure reduction between first chamber and second chamber or first chamber and second chamber, so that be zero at this pressure reduction of the reversal point of tubular fibre.Before this reversal point, the convection current pressure reduction causes from tubular fibre to first chamber, and in the flow process of adjacency reversal point, cause convection current from first chamber to second chamber, promptly the substratum from be contained in shell is to the convection current of tubular fibre.
Just as previously described, tubular fibre can be arranged in the shell, so that the substratum that passes tubular fibre that flows is advanced along the flow process that takes the shape of the letter U basically.
Tubular fibre can take the shape of the letter U basically.Can visualize equally and be designed to tubular fibre straight and among two terminal area embeds cast mix, flow scheme design is become to make substratum at first pass one or more tubular fibres, in the terminal area of this tubular fibre, realize the change of direction, then, substratum passes other tubular fibre and flows back to.
Shell can have the symmetrical pref. cylindrical design of rotation.
In another aspect of the present invention, the regulation tubular fibre begins to extend with first direction to the zone that the direction of tubular fibre stream changes therein from inlet, and extend with the second direction that is different from first direction from the zone that direction changes therein, wherein, the part of the tubular fibre that extends with first direction is radially extended on inside, and the part of the tubular fibre that extends with second direction is radially extended on respect to the outside of inside.For example, when having embedded in the cast mix with less relatively density, tubular fibre considers this embodiment.For example, can visualize the pressure reduction of selecting between first and second chamber, with the separation on having living space between supply and the extraction tubular fibre.This can prepare for mixing fully.For example, can visualize the delivery of fibers radial arrangement on the inside and will extract the fiber radial arrangement out on the outside parallel with inside.In principle, can visualize different aspects, as delivery of fibers being arranged in upward outside and will extracting the reversed arrangement of fibre placement on inside out.
Just as previously described, the biquadratic of pressure drop in the tubular fibre and Fibre diameter is inversely proportional to.For this reason, it is favourable selecting very little Fibre diameter.The internal diameter of preferred regulation tubular fibre is not more than 300 μ m, preferably is not more than 200 μ m, preferred especially about 100 μ m.
The highly porous of hollow-fibre membrane is also prepared for good mass transfer equally.The Test Liquid Permeability of Core of film should be 200ml/mmHg * h * m at least 2, preferably be at least 500ml/mmHg * h * m 2
In another aspect of the present invention, the rejection of the film of regulation formation tubular fibre is 10 4Da to 10 7In the scope between the Da, preferably 10 5Da to 10 6In the scope between the Da.Particularly preferably be, rejection is 700,000 to 900, in the scope of 000Da.Certainly, different porositys or rejection can be arranged.According to designed purposes, also can visualize the use of hollow-fibre membrane with little porosity.
Particularly advantageous is that reactor unit is designed to disposable unit.
Further, advantageously, with constituting reactor unit with the material of steam sterilizing.Preferred employed material is corresponding to the material that also uses in dialysis filter.Therefore can visualize with PP make shell and or with urethane make cast mix and or with polyether sulphone preferably with polysulfones and preferred especially with the polysulfones manufacturing tubular fibre that utilizes the PVP hydrophilicity-imparting treatment to cross.In another aspect of this invention, when carrying out disinfection with 121 ℃ steam, these all materials are stable dimensionally.
The invention still further relates to reactor, wherein, reactor unit is rotatably installed with at least one creative reactor unit.When reactor unit is not to keep motionless but during rotation, obtain good especially mass transfer between first and second chambers.Therefore, favourable aspect of the present invention relates to the reactor with reactor unit of rotatably installing.Can be provided with corresponding drive unit, make reactor unit be rotated motion by drive unit.
In another aspect of the present invention, the regulation reactor not only comprises one but comprise a plurality of reactor units.These reactor units can be interconnected as required.For example, can visualize, so that the inlet that goes out another reactor unit of interruption-forming of a reactor unit these reactor unit series steps.Can visualize equally with the parallel layout of reactor unit and to reactor unit provides as identical tote, as accurate identical nutrient solution.
Can connected in seriesly be designed so that the flow process between the reactor unit extends with a direction with described above, promptly a reactor unit goes out the unitary inlet of another subsequent reaction device of interruption-forming.Also can visualize the inlet that forms this first reactor unit conversely that opens wide of this second reactor unit, like this, mass transfer takes place with both direction.
By reactor unit is arranged combination with serial with walking abreast, can realize purposes highly again.Particularly advantageous is that the reactor with a plurality of reactor units can be used for simulation " internal metabolism process ".
In another aspect of the present invention, being defined in does not have floating-ring seal when constituting reactor.When the flow direction that will pass tubular fibre was put upside down one time at least, the entrance and exit of tubular fibre can be positioned at the same side of shell.Especially in this case, reactor unit can be designed to do not have floating-ring seal, as the description of carrying out with regard to the example of cell separator among EP 1 270 079 A2 and DE 198 03 534 C2.At these these files of scope internal reference.When not using floating-ring seal, can and pollute secure context aspect sterilization and obtain substantial benefit.Also reduce the manufacturing cost of reactor unit in addition.
The invention still further relates to utilization according in the claim 1 to 29 any one reactor unit or realize the method for mass transfer by one or more tubular fibres according to any one the reactor in the claim 30 to 34, wherein, pressure in the pressure in second chamber that inside by these tubular fibres is formed and first chamber that formed by shell is regulated, and realizes by convection current at least in part so that pass the mass transfer of these tubular fibres.The mass transfer of being undertaken by diffusion can be superimposed upon on this convection current mass transfer.Preferably the mass transfer of being undertaken by convection current is two-way, and the special nutrition of considering to be used for substratum molecule and higher molecular synthetic products or having low diffusivity.
On the other hand, regulation is selected the pressure ratio between first and second chambers, so that the substratum of convection current mass transfer from be contained in tubular fibre in the part of tubular fibre realize in the substratum that is contained in the shell, and in another part of tubular fibre, realize in the opposite direction.In this respect of the present invention, supply arranged and extract the differentiation of tubular fibre out or the differentiation of tubular fibre part.For example, when adopting the method for culturing cell, can visualize provides tubular fibre or tubular fibre part, by these tubular fibres or tubular fibre part nutrition is offered the substratum that is contained in first chamber.And, tubular fibre or tubular fibre part are provided, by these tubular fibres or tubular fibre part the substratum of meta-bolites from be contained in first chamber is delivered to tubular fibre, then these meta-bolitess are discharged.
The invention still further relates to have according in the claim 1 to 29 any one reactor unit or according to any one the system of reactor in the claim 30 to 34, this system comprises holder, this holder is connected with reactor unit, so that substratum can be introduced second chamber of the reactor unit that is formed by tubular fibre or is discharged from second chamber from holder, holder comprises transferpump, preferably this transferpump is designed for carrying the peristaltic pump of substratum, this peristaltic pump comprises oxygenator, can be the substratum of being carried by this oxygenator and adds oxygen.For example, oxygenation externally realizes and can carry out variable adjustment according to the consumption of oxygen.The supply of oxygen is provided by blood plasma or the nutritional medium that provided in this case.Preferably oxygenator is located at upstream with the reactor of the flow direction of substratum.And, can be provided with heating unit, with the substratum heating of will be carried.In principle, also can realize oxygenation by the gas transfer hollow-fibre membrane that is arranged in the reactor unit.
Can know further details of the present invention and advantage from embodiment shown in the drawings, in the accompanying drawings:
Fig. 1 shows the skeleton view of the reactor unit among the present invention;
Fig. 2 shows the skeleton view of the creative reactor with shell;
Fig. 3 shows the synoptic diagram of the reactor unit among the present invention;
Fig. 4 shows another synoptic diagram of the reactor unit among the present invention among another embodiment;
Fig. 5 shows the synoptic diagram of the creative mass transfer system with reactor;
Fig. 6 shows the synoptic diagram of the different geometries of reactor unit of the prior art and creative reactor unit;
Base (time-based) concentration curve when urea when Fig. 7 shows use according to reactor unit of the present invention, protein and various ionic;
Base concentration curve when urea when Fig. 8 shows use according to the reactor unit of prior art, protein and various ionic;
Fig. 9 shows the synoptic diagram of creative reactor unit, this creative reactor unit has the tubular fibre that forms second chamber, liquid nutrient medium passes these tubular fibres, and these tubular fibres have the hollow gas transfer fiber that is used for oxygenation, and these hollow gas transfer fibers form the 3rd chamber; And
Figure 10 shows the synoptic diagram that the difference of several reactor units that serial or parallel connects is arranged.
Fig. 1 shows the skeleton view that is designed to disposable unitary creative reactor unit 12.Reactor unit 12 comprises shell 20, tubular fibre with the arranged in form of hollow fiber bundle in shell 20.And, being provided with inlet 40 and outlet 50, the substratum that passes tubular fibre provides by entrance and exit or extracts out.
Fig. 2 shows the unitary reactor 10 of reactionless device.There is shown the rotatable pedestal that is used for fixing the reactor unit that is shown among Fig. 1, electric motor is in pedestal and rotatablely moves.Pedestal or the reactor with reactor unit are contained in and heat in the shell.
Fig. 3 shows the synoptic diagram of rotatably mounted reactor unit 12.The use field that can visualize is as follows:
The liver cell culture that is used for different purposes
Artificial liver and transplantation of pancreas treatment
Cultivate human and animal's cell of Different Origin
The production of antibody
From transfection yeast and bacterium recover materials
Be shown in point among Fig. 3 and represent to be contained in cell in first chamber of reactor unit 12, first chamber is limited by shell 20.Tubular fibre 30 is arranged in first chamber, and first chamber has inlet 40 and outlet 50.If cell cultures 40 provides nutritional medium by entering the mouth.Treat for liver or pancreas transplantation, 40 provide blood plasma by entering the mouth.Extract nutritional medium or the treated blood plasma that is consumed out by exporting 50.
As Fig. 3 further illustrated, shell 20 comprised two ports 22, and these ports 22 are used to fill first chamber, first chamber or take a sample from first chamber of finding time.Can visualize and when filling or take a sample, close these ports 22.In principle, equally also can visualize the permission operate continuously, to reach the effect that substratum is introduced first chamber or discharged from first chamber continuously by port 22.As also can be as seen from Figure 3, tubular fibre 30 is located at the center and near the turning axle of reactor unit 12, these tubular fibres 30 form tubular fibre part 32c, in tubular fibre part 32c, there is quite high pressure to exist, so just realize the convection current mass transfer first chamber that is limited by shell 20 from the part 32c of tubular fibre 30 to reactor unit 12, as shown by arrows.The change of direction realizes in the terminal area of part 32c, and at first the direction with the end face that is parallel to shell 20 changes, and is relative with flow direction among the part 32c then.Reason owing to the lower pressure in the tubular fibre 30 that the pressure-losses caused, so in tubular fibre part 32d, realize now to the convection current mass transfer the tubular fibre 30 from first chamber that holds cell, shown near the arrow the tubular fibre part 32d.So just realize supply tubular fibre or tubular fibre part 32c and the separation of extracting tubular fibre or tubular fibre part 32d out.
At last, as also can be as seen from Figure 3, the same side that the inlet 40 and the outlet of tubular fibre is arranged on shell 20 be in being shown in the embodiment of Fig. 3, on its right end face of cylindrical outside shell 20.This design allows to provide the reactor of no floating-ring seal.Can realize the relative movement between static and the moving-member by the system of from EP 1 270 079 A2 and DE 198 03 534 C2, knowing.
Preferably reactor unit 12 is designed to disposable unit.This unit can be an injection-molded structure, and this structure comprises the similar basic method steps of the manufacturing of the artificial kidney made from usual manner, as implanting, cut and sterilization with PUR.
Fig. 4 shows the reactor unit 12 of another type.In first chamber that is limited by cylindrical rotational symmetric shell 20, human hepatocytes is contained in the suitable substratum.Hollow fiber bundle is arranged in the radial center part, and this hollow fiber bundle comprises independent tubular fibre.Hollow fiber bundle comprises near many tubular fibre 30a that are arranged on the turning axle, as example, wherein some only is shown in the drawings.And, also being provided with radial offset to many outside tubular fibre 30b, these tubular fibres 30b is arranged in the outer regions of hollow fiber bundle, and is same, and among the tubular fibre 30b only is shown in the drawings.For example, when having embedded in the cast mix with less relatively density, tubular fibre considers this embodiment.Tubular fibre 30a and 30b are arranged in parallel, and are fixed in the cast mix 32 in their two its zones of terminal, and these cast mix 32 are fixed in the shell 20 by rights.Substratum 40 flows into tubular fibre 30a by entering the mouth, passes tubular fibre 30a and leave tubular fibre 30a in the terminal area of tubular fibre 30a, and the terminal area illustrates in the left side.Substratum enters the fluid-space herein, and this fluid-space is connected the terminal area of tubular fibre 30a with the prime area of tubular fibre 30b.As the arrow in the terminal area of tubular fibre 30a was specified, the flow direction of substratum changed in the terminal area of tubular fibre 30a.When passing the fluid-space, substratum flows into tubular fibre 30b and to pass tubular fibre 30b in the opposite direction with the side of passing tubular fibre 30a.Tubular fibre 30b is connected with outlet 50 in their terminal area that is shown in the right side, and corresponding treated substratum is extracted out from reactor unit 12 by outlet 50.For example, substratum can be nutritional medium or body fluid, as blood, particularly preferably is blood plasma.
Certainly, the reactor unit that is shown among Fig. 4 also can be used for other purpose, as is used for cell cultures.
First chamber that is limited by shell 20 comprises two ports 22, and these ports can be used for substratum is provided or extracts substratum out or taking a sample from first chamber from first chamber to first chamber.
Just as further illustrated in Figure 4 and indicated like that by arrow, when operation, with reactor unit 12 rotations, and turning axle is parallel to tubular fibre and extends.Preferably tubular fibre 30a is arranged to make them to be positioned near the turning axle, and tubular fibre 30b from tubular fibre 30a radial offset to the outside.Can select pressure ratio, so that the pressure among the tubular fibre 30a is higher than the pressure of first chamber that is limited by shell 20, and the pressure in tubular fibre 30b is lower than the pressure that exists in first chamber.By the curved specified reversal point of arrow, can be fixed between first chamber and second chamber does not have pressure reduction.Certainly, also can visualize the different layouts of pressure ratio.
The present invention is different from according to prior art embodiments, arrange with possible maximum density because reactor unit is designed to will not to be arranged on the intrafascicular tubular fibre of tubular fibre, but be no more than 10 fiber/mm based on the fibre density of the sectional area of first chamber 2, the length that perhaps is contained in the tubular fibre part between the cast mix be no more than mutually towards the surface distance at least 0.5% of cast mix.
Fig. 6 a shows the synoptic diagram according to the reactor unit 12 of prior art design.Hollow-fibre membrane is enclosed in the plastic wire and forms the rigid cylindrical structure.The diameter of hollow fiber bundle is D=34mm.In the reactor unit that is shown in Fig. 6 a, the length between two cross sections of cast mix 32 is L=257mm.Therefore, when the quantity of tubular fibre is, be about 12 fiber/mm at 11,000 o'clock based on the fibre density of the sectional area of first chamber 2
Fig. 6 b shows the schematically illustrated embodiment according to reactor unit 12 of the present invention.As Fig. 6 b is schematically illustrated, be shown in Fig. 6 a in compare according to prior art embodiments, the distance L in the cross section of cast mix 32 reduces 10mm.In this case, spindle is put upside down and formed to tubular fibre between cast mix.According to implant surface promptly mutually towards the distance on surface of cast mix, obtain than the little fibre density of embodiment that is shown among Fig. 6 a.In the embodiment that is shown in Fig. 6 b, the maximum diameter of fibrous bundle is 95mm.Fibre density just in cast mix 32 corresponding in conjunction with the described fibre density of Fig. 6 a.For the reason of these sizes, be shown in fibre density in the reactor unit 12 among Fig. 6 b at 1.5 fiber/mm 2With 12 fiber/mm 2Between scope in.
Fig. 6 c shows a kind of embodiment, and in such an embodiment, the cross-sectional distance L of cast mix 32 is corresponding to the distance that is shown among Fig. 6 a.But, fibrous bundle is subjected to the compression of O shape ring, like this, compare with embodiment in being shown in Fig. 6 b, again with fibre density to adjusted.Near compression section, the diameter of fibrous bundle is 34mm.The maximum diameter of fibrous bundle is 60mm, so just obtains 3.9 fiber/mm of per unit area 2With 12 fiber/mm 2Between total fiber density.
Fig. 7 shows with reactor unit of the prior art with the contrast of Fig. 8 and compares and this creative reactor unit advantages associated.
Obtain concentration curve shown in Fig. 7 and 8 by following test setting or following experimentation:
When chamber was made up, (pressurized air) carried out the gentle bubble point inspection of stopping property to these chambers by exerting pressure.
In order to test the exchange substratum of preparation 400ml:
The buffer B ad 400ml of 1 plasma bags+0.5ml EDTA 100mM (test among Fig. 7 does not have)+50ml has the A.d. buffer B: urea 7.5mg/ml, NaCl22.5mg/ml (385mmol), KCl 1.25mg/ml (16.7mmol).
In all tests, tubular fibre is filled with the exchange substratum, and is connected to first chamber of reactor unit or reactor unit from " 0 " time decreased the time.
During exchange test, in the time of 25 ℃ with the flow velocity of 200ml/min to the reactor unit feed, and it is rotated with 15rpm, to check exchange by the sample of convection current and diffusion.
Sample in the following manner:
For each mensuration, point before entering chamber and the sample port in chamber 1 are by Monovette (Sarstedt 2ml LH; CE 0197) extract the sample of 2ml.Before each sampling, about liquid of 2 to 3ml is washed away from collection port, and extract at this moment and measure sample.The sample that is extracted is substituted by water by sample port 2 at chamber.The sample that is extracted is substituted by the damping fluid holder in the supply loop wire that is formed by tubular fibre.
In the test arrangement according to the test of Fig. 7, the volume of chamber is about 1.71.Hollow-fibre membrane is stable by 2 plastic optical fibres.Because the distance of cast mix reduces, so the short about 1cm of employed chamber in the test arrangement of chamber than the test result in obtaining Fig. 8.Therefore, filled chamber volumetrical fusiform structure is put upside down and formed to these films.
Be shown in the test arrangement of the test result among Fig. 8 in generation, chamber volume is about 1.81.These membrane closures are in plastic wire and form the rigid cylindrical structure.
As can finding out from the comparison of Fig. 7 and Fig. 8, boundling or hollow fiber bundle according to film have evident difference in the distribution speed of ion that passes the film with 60kd pore size and organic molecule.
Put upside down open film (fusiform) (fibre density: 1.5 fiber/mm 2) fill the tube chamber of first chamber to a great extent and therefore realize good mass transfer.As can from Fig. 7 a and 7b find out, the material transfer between the tubular fibre and first chamber realizes in first few minutes after starting loop.Under the situation of ion and urea, the transmission fully of concentration can detect after about 30 to 60 minutes.Owing to proteinic molecular weight height, so protein is slow and and incomplete when exchange.In Fig. 7 and Fig. 8, initialism " SC " and " chamber " represent that respectively supply loop wire (SC) promptly passes the concentration in first chamber of concentration in the substratum of tubular fibre and reactor unit.
Utilize common boundling film (cylindrical) (maximum fibre density) to obtain being shown in the test result among Fig. 8, this common boundling film forms the tight cylindrical thigh of the loop wire with less relatively transfer efficiency.As can from Fig. 8 a and 8b find out, the material transfer between the tubular fibre and first chamber is carried out to be considerably slower than the speed that is shown among Fig. 7.Under the situation of ion and urea, fully smoothly can after about 120 to 180 minutes, the measuring of concentration, and than in fusiform film according to the present invention slow 3 to 4 times.Equally, protein is slow and and incomplete when exchange.
Just as previously described, the reactor unit among the present invention can be used for treatment, as is used for liver transplantation or liver supportive treatment.
Fig. 5 shows the synoptic diagram of the total system that is used for the liver supportive treatment.This total system comprises blood plasma holder 60, and blood plasma holder 60 holds the blood plasma of taking from the patient who treats.Extract and offer blood plasma out gas exchanger 80 from blood plasma holder 60 by peristaltic pump 70.In gas exchanger 80,, so just be that blood plasma adds oxygen by the supply of oxygen source and sterilizing filter realization oxygen.Gas exchanger equally also comprises two chambers, and oxygen is mobile at a chamber, and blood plasma flows at another chamber.By permeable membrane these chambers are separated, these permeable membranes allow gas such as oxygen to be delivered in the blood plasma.By gas exchanger, not only can supply oxygen, and can supply or exchange other gas, as CO 2Or N 2Of the present invention preferred especially aspect, gas exchanger is designed for exchanging the oxygenator of oxygen.
When being the blood plasma oxygenation in oxygenator 80, blood plasma passes heating unit 90, and inflow reactor 10 then.Reactor 10 comprises the reactor unit 12 that the rotation among the present invention is installed, and this reactor unit 12 is designed to disposable unit.Reactor unit 12 is arranged in the rotatable pedestal of reactor 10, and is rotated motion at the operating period of system chien shih reactor unit 12.Turning axle overlaps with the longitudinal axis of reactor unit 12.Reactor is contained in the shell after the heating, as can be from finding out Fig. 2 and Fig. 5.This system is designed to not have floating-ring seal.
Compare with the structure in being shown in Fig. 5, also peristaltic pump 70 can be arranged on another point of loop.For example, also can visualize reactor 10 is the layout in the downstream of reactor 10 afterwards.
As another device, preferably be shown in layout among Fig. 5 and also can comprise and heating unit with the flow direction before the reactor 10 will offer the substratum heating of reactor 10 by this heating unit.
Several favourable aspect of the present invention is described below:
For tubular fibre, preferably can use polysulfones plasma fiber with big operational exchange surface, preferred this exchange surface 0 to 2m 2Scope, and preferably have and can reach 900, the variable adjustment porosity of 000MG.Just as previously described, preferably mainly realize mass transfer, the two-way exchange of passing hollow-fibre membrane with increase by convection current.
According to the characteristic of cell that exchanges or material, can with hydrophilic and or hydrophobic membrane be used for tubular fibre.
Just as previously described, can realize delivery of fibers and extract separating of fiber out.Therefore, can carry out variable allocation to fibrous bundle at inside reactor.As example, can and extract fibre placement out with supply at the center.Also can visualize delivery of fibers is arranged in the center and will extracts fibre placement out around.So just can realize passing the counter-current flow of cell cultures.
Preferably utilize front mentioned " pipe feed principle " from the stationary part to the rotating part to avoid floating-ring seal.
Reactor unit can be the disposable object of disinfectant, and separates with there not being the disinfectant rotary unit.Preferred used vapour is with the disposable object sterilization of disinfectant.
Preferably externally realize oxygenation, and big oxygen consumption is regulated in oxygenation changeably.Therefore, the supply of preferred oxygen realizes by blood plasma or by nutritional medium.But, also can visualize the inside oxygenation that is shown among Fig. 9 and being also included among the present invention.In this embodiment, reactor unit 12 comprises shell 20, and shell 20 forms first chamber.Tubular fibre 30 is arranged in first chamber, and liquid nutrient medium passes these tubular fibres 30.In addition, be provided with gas transfer fiber 130, realize being contained in the oxygenation of the substratum in first chamber of shell 20 by this gas transfer fiber 130.In principle, can visualize and also hollow gas transfer fiber is used to remove gaseous substance or also is used to provide and or extracts other gas outside the oxygen out.
Therefore, the present invention not only comprises extraneous gas transmission or external air source, but also comprises source of the gas or gas transfer in the reactor unit.
Preferably realize providing nutrition to cell by blood plasma or nutritional medium.
In another aspect of the present invention, can fill simply, add and take a sample.So just can realize functional permanent control.In addition, also can proofread and correct or regulate.
The top that the series of a plurality of reactor unit 1-n in identical reactor is arranged in Figure 10 illustrates.As the arrow indication, reactor unit is rotatably installed.The advantage that is produced is as follows like this:
In the various reactor units of identical reactor, cultivate the cell of various kinds;
Supply the cell of various kinds equably by identical loop;
Can clearly the cell category 1 of mesostate from reactor unit 1 be transported to the cell category 2 in the reactor unit 2.For example, the human liver cell is contained in the reactor unit 1, and human kidney's cell is contained in the reactor unit 2; As if the loop wire that medicine is added to reactor unit 1, the metabolite that is formed by the liver cell in the reactor unit 1 directly offers the kidney cell that is contained in the reactor unit 2, so just can distinguish further metabolism.
Can add material or extract mesostate out in any stage at any time;
Can extract the sample that has cell material out from the cell chamber at any time, to distinguish the cell condition;
Can determine the influence of chemistry, medicine and cosmetic material, also can in secular test, carry out different types of cell.
Show being arranged in parallel of rotatably mounted reactor unit in Figure 10 intermediary layout, therefore do not continued to pass through, but be parallel to each other.The advantage that is produced is as follows like this:
In the different reactor unit of identical reactor, cultivate different types of cell,
Accurately provide nutrient solutions such as identical chemical ingredients, oxygen level to each one reactor unit,
Be suitable for distinguishing as the difference between isocellular batch; Example: be connected in the identical reactor three reactor units are parallel.Reactor unit 1 contains the human hepatocytes of donor 1, and reactor unit 2 contains the human hepatocytes of donor 2, and reactor unit 3 contains the human hepatocytes of donor 3.Owing to being parallel layout and having identical supply, so can distinguish the progress of cell cultures separately.By corresponding sample from the cell chamber, can be in quality and quantitatively distinguish the progress behavior of each batch.If before entering reactor unit, medicine is added to as in the nutritional medium and if no longer the nutrient solution of extracting out from reactor unit is circulated once more, but separately batch liver cell to detecting from separately batch the metabolite that hepatocellular medicine produced, so just can with this system in quality with quantitatively determine to have different cell sources (batch) the individual difference of isocellular Metabolic activity aspect.
Returning stream and flowing between the reactor unit 1-n that equally rotatably installs illustrates in the bottom of Figure 10 respectively.As can be as seen from the figure, these reactor units comprise two inlets and two outlets, and interconnect, so that the inlet that goes out the next reactor unit of interruption-forming of previous reactor unit, and the inlet that goes out first reactor unit of interruption-forming of second reactor unit.This system also continues between other reactor unit.
Advantage in the layout shown in the bottom of Figure 10 is as follows:
In the different reactor unit of identical reactor, cultivate different types of cell,
Have the reactor unit of different cells batch (at cell category and or cell source/cell batch) by layout, can under conditions in vitro, simulate the internal metabolism process,
Opposite with the layout that is shown in Figure 10 top, will not be circulated again into reactor unit 1, but be circulated again into the upstream reactor unit from the nutrient solution that last reactor unit extracts; Example: reactor unit 1 contains skin cells, and reactor unit 2 contains liver cell, and reactor unit 3 contains virocyte.When being used in certain pharmaceutical chemicals on the skin cells, metabolite is formed by the liver cell in the reactor unit 2, and this metabolite can be by the kidney substance metabolism, but can not secrete.By being recycled to the liver cell reactor unit, can determine directly influences the liver cell active.
In principle, also can visualize these layouts is the connected in series and parallel combination that is connected.The advantage of this combination is as follows:
By the cell chamber is combined with different intermediate steps, can realize the highly application of innovation.
For example, when being used in medicine in the nutritional medium, can make the top of nutritional medium through the liver cell culture in first reactor unit, multiple metabolite produces in first reactor unit.After the generation of metabolite is the separation of metabolite, as the form with chromatographic process.Then different metabolites is transported to different cells, as with parallel form of arranging, to distinguish the influence of different metabolite to different cells.
This just means according to concrete test arrangement, and the various possible combination that is shown between three kinds of layouts of Figure 10 can visualize, and also is possible.
As can be as seen from Figure 10, shown reactor unit be arranged in the reactor.In principle, equally also can visualize and use a plurality of reactors, promptly all reactor units are not arranged in the reactor.
By being shown in the system among Fig. 2, but the unitary integrated constant temperature balance of realization response device.
With regard to treatment or cultivating, can use the cell of following Different Origin, for example:
Archeocyte, from the cell and the immortalized cells of differentiation of stem cells, every kind of cell is isolated recently/is cultivated and low temperature storage.
In another aspect of this invention, can cultivate quantity from trace to the cell more than the 1kg.
Utilize corresponding design, the invention provides following advantage:
Utilization has the polysulfone hollow fibre of big exchange surface and variable adjustment porosity-have preferable quality transmission when using inert material
By the effective more clearly two-way mass transfer of convection current, all the more so for substratum molecule with low diffusivity and higher molecular synthetic products
Because hydrophilic and or the use of hydrophobic membrane, can control better/the quality of regulation transmission
Since delivery of fibers with extract out fiber separate and fiber can freely change layout, the supply of cell is improved and so and causes the improvement of cell performance
Because adverse current and rotation mix with mass transfer also being improved
" pipe feed principle " of utilization from the stationary part to the rotating part avoided floating-ring seal-do not have tubulate reversing (the no problem operation when clinical use) and do not have wearing and tearing in reactor unit
Owing to can use human body fluid, avoided the use of coml nutrient solution (as RPMI), and the contact of the non-physiologically substance when therefore having avoided using
The disposable object of disinfectant with do not have the separating of disinfectant rotary unit-for the user, simple to operate and safe
Disposable object is with steam sterilizing-for the user, aspect microbial contamination, do not have poisonous degradation production (ETO) and possible security the highest
Inner or outside for liver cell/pancreatic cell oxygenation with nutrition is provided by blood plasma/substratum at rotary unit.Under the situation of externally oxygenation (loop wire is only arranged in rotating part), do not have other film in the cell module, this has higher security to the user
Be easy to fill, add and sampling; For the reason of this fill method,, reduced to pollute and also therefore improved security for the user
Owing to can sample, so but that pair cell carries out the security of nonvolatil monitoring-functional and innocuousness (the formation grade in an imperial examination of aseptic, pH, toxic metabolite product) is higher
Because the use of low temperature storage cell anthropogenous is so can independently use transplanting
Operation rapid (assembling, operability and cell material) is prepared and safety by system.

Claims (40)

1. reactor unit with first chamber and second chamber, wherein, described first chamber is formed by the inside of shell and described second chamber is formed by the inside that is arranged in a plurality of tubular fibres in the described shell, it is characterized in that: described tubular fibre is arranged in the described shell, is no more than 10 fiber/mm with the density of the described tubular fibre at least one zone that makes on the basis of the sectional area of described first chamber at described first chamber 2
2. reactor unit as claimed in claim 1 is characterized in that: the density of the described tubular fibre at least one zone of described first chamber on the basis of the sectional area of described first chamber is at 0.2 to 10 fiber/mm 2Scope in, preferably at 0.5 to 6 fiber/mm 2Scope in, particularly preferably in 1 to 4 fiber/mm 2Scope in.
3. reactor unit as claimed in claim 1 or 2 is characterized in that: change on the longitudinal direction of density at fiber of the described fiber on the basis of the sectional area of described first chamber.
4. reactor unit as claimed in claim 1 or 2 is characterized in that: constant on the longitudinal direction of density at fiber of the described fiber on the basis of the sectional area of described first chamber.
5. as any one the described reactor unit in the claim of front, it is characterized in that: one or more cast mix are arranged in the described reactor unit, and the part of described tubular fibre preferably terminal area embeds in the described cast mix.
6. as any one the described reactor unit in the claim of front, it is characterized in that: two kinds of cast mix are arranged in the described reactor unit, the part of described tubular fibre preferably terminal area embeds in the described cast mix, and another part of described tubular fibre is extended between described two kinds of cast mix.
7. reactor unit as claimed in claim 6 is characterized in that: described tubular fibre straight line or curve between described cast mix extend, with obtain especially protruding or the fusiform hollow fiber bundle.
8. as claim 6 or 7 described reactor units, it is characterized in that: several between the described cast mix or all the part of tubular fibres length than mutually towards the surface of described cast mix between distance big at least 0.5%.
9. reactor unit as claimed in claim 8 is characterized in that: the length of the part of the tubular fibre between the described cast mix than mutually towards the surface of described cast mix between distance big at least by 1%, preferably big at least 3%.
10. as any one the described reactor unit in the claim of front, it is characterized in that: be provided with device, described device surrounds described tubular fibre, so that compare with the density of not using described device, the density of the described fiber on the basis of the sectional area of described first chamber increases.
11. as any one the described reactor unit in the claim of front, it is characterized in that: described reactor unit comprises the 3rd chamber, and described the 3rd chamber is formed by the inside that is arranged in one or more hollow gas transfer fiber in described first chamber.
12. reactor unit as claimed in claim 11 is characterized in that: described hollow gas transfer fiber has external diameter and or the internal diameter bigger than the tubular fibre that forms described second chamber.
13., it is characterized in that: become to make them to be suitable for transmitting oxygen described hollow gas transfer fiber design, and preferred described hollow gas transfer fiber is made or comprised PTFE with PTFE by described film as claim 11 or 12 described reactor units.
14. reactor unit with first chamber and second chamber, wherein, described first chamber is formed by the inside of shell and described second chamber is formed by the inside that is arranged in a plurality of tubular fibres in the described shell, it is characterized in that: at least two kinds of cast mix are arranged in the described reactor unit, the part of described tubular fibre, the preferred terminal zone embeds in the described cast mix, and another part of described tubular fibre is extended between described cast mix, wherein, the length of the part of some or all tubular fibres between the described cast mix than mutually towards the surface of described cast mix between distance big at least 0.5%.
15. reactor unit as claimed in claim 14 is characterized in that: design described reactor unit according to one characteristic in the claim 1 to 13.
16. as any one the described reactor unit in the claim 1 to 15, it is characterized in that: described tubular fibre is arranged in the described shell, guides with a direction guiding or with at least two different directions with the substratum that will flow through described tubular fibre.
17. as any one the described reactor unit in the claim 1 to 16, it is characterized in that: described tubular fibre is provided with entrance and exit.
18. reactor unit as claimed in claim 17 is characterized in that: the entrance and exit of described tubular fibre is arranged on the same side of described shell.
19. any one the described reactor unit as in the claim 1 to 18 is characterized in that: described tubular fibre is arranged in the described shell, has the flow process that takes the shape of the letter U basically so that flow through the substratum of described tubular fibre.
20. any one the described reactor unit as in the claim 1 to 19 is characterized in that: described tubular fibre is designed to take the shape of the letter U basically.
21. any one the described reactor unit as in the claim 1 to 20 is characterized in that: described shell has the preferably columniform design of rotation symmetry.
22. as any one the described reactor unit in the claim 1 to 21, it is characterized in that: described tubular fibre has inlet, and begin to extend with first direction to the zone that the direction of described tubular fibre stream changes therein from described inlet, and extend with the second direction that is different from described first direction from the zone that direction changes therein, wherein, the described tubular fibre that extends with described first direction radially extends on inside, and radially extends on respect to the outside of described inside with the described tubular fibre that described second direction is extended.
23. as any one the described reactor unit in the claim 1 to 22, it is characterized in that: described shell has at least one port, described port is used to fill described first chamber, described first chamber of emptying or from described first chamber sampling.
24. any one the described reactor unit as in the claim 1 to 23 is characterized in that: the internal diameter of described tubular fibre is not more than 300 μ m, preferably is not more than 200 μ m, and is preferably about 100 μ m especially.
25. as any one the described reactor unit in the claim 1 to 24, it is characterized in that: the Test Liquid Permeability of Core of the film of described tubular fibre is at least 200ml/mmHg * h * m 2, preferably be at least 500ml/mmHg * h * m 2
26. any one the described reactor unit as in the claim 1 to 25 is characterized in that: the rejection of film that forms described tubular fibre is 10 4Da to 10 7In the scope between the Da, preferably 10 5Da to 10 6In the scope between the Da, particularly preferably in 700,000 to 900, in the scope of 000Da.
27. any one the described reactor unit as in the claim 1 to 26 is characterized in that: utilize used vapour disinfectant material to constitute described reactor unit.
28. any one the described reactor unit as in the claim 1 to 27 is characterized in that: described reactor unit is designed to disposable unit.
29. as any one the described reactor unit in the claim 1 to 28, it is characterized in that: be provided with the cast mix of the end that holds described tubular fibre, and make described shell and or make described cast mix and or preferably make described tubular fibre with the polysulfones that polysulfones and preferred especially usefulness utilize the PVP hydrophilicity-imparting treatment to cross with polyether sulphone with urethane with PP.
30. a reactor that has according to any one the described one or more reactor unit in the claim 1 to 29 is characterized in that: the described reactor unit of rotatable installation.
31. reactor as claimed in claim 30 is characterized in that: described reactor comprises according to any one the described a plurality of reactor unit in the claim 1 to 29.
32. reactor as claimed in claim 31 is characterized in that: described a plurality of reactor unit serial or parallels are arranged.
33. reactor as claimed in claim 32 is characterized in that: described a plurality of reactor unit serials arrange, so that the mass transfer between two adjacent reactors only may or be carried out with both direction with a direction simultaneously.
34. any one the described reactor as in the claim 30 to 33 is characterized in that: described reactor unit is designed to not have floating-ring seal.
35. a utilization according in the claim 1 to 29 any one reactor unit or realize the method for mass transfer by one or more tubular fibres according to any one the reactor in the claim 30 to 34, wherein, pressure in pressure in described second chamber that inside by described tubular fibre is formed and described first chamber that formed by described shell is regulated, and realizes by convection current at least in part so that pass the mass transfer of described tubular fibre.
36. method as claimed in claim 35, it is characterized in that: to described first and described second chamber between pressure ratio select, so that the substratum of convection current mass transfer from be contained in described tubular fibre in the part of described tubular fibre realize in the substratum that is contained in the described shell, and the substratum from be contained in described shell is realized to the substratum that is contained in the described tubular fibre in another part of described tubular fibre.
37. one kind have according in the claim 1 to 29 any one reactor unit or according to any one the system of reactor in the claim 30 to 34, described system comprises holder, described holder is connected with described reactor unit, so that substratum can be introduced described second chamber of the described reactor unit that is formed by described tubular fibre or from described second chamber discharge from described holder, described holder comprises transferpump, described transferpump is used to carry substratum, and comprise oxygenator, can be the substratum interpolation oxygen of being carried by described oxygenator.
38. system as claimed in claim 37 is characterized in that: described oxygenator is located at along the described reactor of the flow direction of described substratum or the upstream of described reactor unit.
39. as claim 37 or 38 described systems, it is characterized in that: the upstream at the described reactor of streamwise is provided with heating unit, and described heating unit is used for described substratum heating.
40. as any one the described system in the claim 37 to 39, it is characterized in that: described transferpump is a peristaltic pump.
CN2005800448888A 2004-12-27 2005-12-22 Reactor and reactor unit with hollow fibers Expired - Fee Related CN101087873B (en)

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DE200410062828 DE102004062828B4 (en) 2004-12-27 2004-12-27 Reactor with a rotatably arranged reactor unit
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DE102005021305A DE102005021305A1 (en) 2005-05-09 2005-05-09 Reactor unit comprises two of more chambers formed by the inner housing wall and a cylindrical layer of hollow fiber bundles embedded in sealing compound
PCT/EP2005/013906 WO2006069737A1 (en) 2004-12-27 2005-12-22 Reactor and reactor unit with hollow fibers

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CN101886032A (en) * 2010-02-24 2010-11-17 中国科学院过程工程研究所 Bioreactor for enhancing mass transfer and heat transfer by using microtubule system
CN102225222A (en) * 2011-05-13 2011-10-26 浙江大学 U-shaped hollow fiber pipe artificial liver bioreactor
CN105229139A (en) * 2012-12-11 2016-01-06 颇尔科技英国有限公司 For the vessel of cell cultures
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CN101787348A (en) * 2010-02-24 2010-07-28 中国科学院过程工程研究所 Biomimetic bioreactor for enhancing mass and heat transfer
CN101886032A (en) * 2010-02-24 2010-11-17 中国科学院过程工程研究所 Bioreactor for enhancing mass transfer and heat transfer by using microtubule system
CN101886032B (en) * 2010-02-24 2013-01-23 中国科学院过程工程研究所 Bioreactor for enhancing mass transfer and heat transfer by using microtubule system
CN101787348B (en) * 2010-02-24 2013-01-23 中国科学院过程工程研究所 Biomimetic bioreactor for enhancing mass and heat transfer
CN101837151A (en) * 2010-03-19 2010-09-22 南方医科大学珠江医院 Two-way filling type bioreactor control system and method
CN101837151B (en) * 2010-03-19 2012-07-04 南方医科大学珠江医院 Two-way filling type bioreactor control system and method
CN102225222A (en) * 2011-05-13 2011-10-26 浙江大学 U-shaped hollow fiber pipe artificial liver bioreactor
CN105229139A (en) * 2012-12-11 2016-01-06 颇尔科技英国有限公司 For the vessel of cell cultures
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