DE102004062828A1 - 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 - Google Patents

Abstract

The hollow fiber bundles form a diaphragm separating the inner and outer chambers in the housing have an individual inner diameter of 100 mu m and the bundle has an optionally variable density along the length of the fibers of 1.2 to 10 (1 to 4) fibers/mm 2> . The fibers are embedded at either ends in sealing compound masses and are formed as bulgy or spiral hollow bundles. The diaphragm is formed from polytetrafluoroethylene gas exchange hollow fibers for the exchange of oxygen o. The fibers are arranged in the housing with an inlet and outlet and form a u-shaped flow channel. The housing is cylindrical and has connections for filling, emptying and/or sampling from the chamber. The hollow fibers forming the diaphragm have a hydraulic permeability of 500 ml/mm Hg*h*m 2>. The reactor units are rotatable and arranged in parallel. The housing is made from polypropylene and/or the sealing compound is made Polyurethane and/or the hollow fibers are made of from Polyarylethersulfone or Polytetrafluroethylene. Independent claims are also included for: (1) a procedure to the evaluation of a material exchange by hollow fibers; and (2) a system with a reactor unit.

Description

The The invention relates to a reactor with a rotatably arranged Reactor unit. Such reactors are in many different ways embodiments known and serve, for example, to human or animal cells of different origins or are used, for example, in artificial liver and pancreatic replacement therapy.

From US Pat. No. 5,437,998 a reactor is known 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.

Out WO 03/105663 A2 discloses a liver support system which has 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 through the interiors of hollow fibers of an in the housing recorded hollow fiber bundle is formed. The hepatocytes are in the first chamber. The Blood plasma is in one embodiment of the reactor described by the interiors of the hollow fibers, d. H. by led the second chamber. Of the Substance exchange takes place via the hollow fiber membranes. The hollow fibers are straight and running longitudinal of the housing. From WO 04/050864 A1 a bioreactor is known in which a the ones to be bred Cells containing chamber is provided, which by means of a membrane one of a nutrient medium leading Supply and discharge line is disconnected.

Of the present invention is based on the object, a reactor to provide with a rotatably arranged reactor unit, which has a high efficiency and a wide range of applications.

These The object is achieved by a reactor having the features of the claim 1 solved. Thereafter, it is provided that the reactor has a rotatably arranged Reactor unit having a first chamber and a second chamber comprises wherein the first chamber is formed by the interior of a housing and wherein the second chamber through the interior of one or a plurality of hollow fibers preferably formed of a hollow fiber bundle that is in the case are arranged and the over have an inlet and a drain, wherein the hollow fibers in such a way arranged that a flowing through the hollow fibers medium is guided in at least two directions. According to the invention undergoes by the hollow fibers flowing Medium thus at least one change of direction. For example, it is conceivable that the flow course of the flowing through the hollow fibers Medium substantially U-shaped is designed.

One Advantage of the reactor according to the invention results especially when the mass transfer between the two Chambers should at least be made by convection. The convective Mass transfer is directly proportional to the pressure difference across the Hollow fiber membranes. The pressure drop in the hollow fibers is direct proportional to length the fiber and inversely proportional to the diameter of the fiber in the fourth power. Thus, if the flow of the through Hollow fibers flowing medium at least once a change of direction, For example, a direction reversal is experienced by e.g. at least once back and forth, elevated the total path through the housing corresponding. This causes a correspondingly higher pressure in the hollow fiber membranes and leads to an increase the pressure difference over the Hollow fiber membranes and thus to an increase in the convective exchange.

Especially It is advantageous if the inlet and the outlet of the hollow fibers on the same side of the case are arranged. It is possible that the flow path of the guided through the hollow fibers Medium U-shaped is or several changes of direction having. It is possible, the pressure difference between the first chamber and the second To adjust the chamber or the media contained in these that it assumes the value zero at the reversal point of the hollow fibers. Before this reversal point takes place due to the pressure difference Convection of the hollow fibers in the first chamber and in the following the turning point flow a convection from the first to the second chamber instead, d. H. from inside the case located medium in the hollow fibers.

As stated above can the hollow fibers in the housing be arranged such that a medium flowing through the hollow fibers a substantially U-shaped flow pattern takes.

The Hollow fibers can essentially U-shaped accomplished be. It is also conceivable that the hollow fibers are straight and are embedded in potting compounds at their two end regions, the flow guide being such is configured that the medium first one or more hollow fibers flows through undergoes a change in direction in the end and then by other hollow fibers flowing back.

The casing can be rotationally symmetrical, preferably cylindrical.

In Another embodiment of the invention is provided that the hollow fibers starting from the inlet to an area where the direction the course of the hollow fibers changes, in a first direction and from the area of change of direction in a second, deviating from the first direction, wherein the hollow fiber sections extending in the first direction radially inward and extending in the second direction hollow fiber sections relative to it radially outside run. It is conceivable, for example, that the pressure difference between the first and second chamber is chosen so that a spatial Separation from feeding and laxative Hollow fibers is present. As a result, good mixing can be achieved become. It is conceivable, for example, the feeding fibers radially inside and the laxative Fibers parallel to it radially outside to arrange. Basically also deviating configurations conceivable, such as the reverse arrangement with outside lying feeding Fibers and internal laxative Fibers.

In a further embodiment of the invention, it is provided that the reactor is executed without slip ring seal. With at least one-time reversal of the flow direction through the hollow fibers, the inlet and the outlet of the hollow fibers can lie on the same side of the housing. In particular, in this case, it is possible to carry out the reactor unit without mechanical seal, as for example in the EP 1 270 079 A2 and DE 198 03 534 C2 is described using the example of a cell separator. In this regard, reference is made to these documents. There are significant advantages for the sterilizability as well as for the contamination safety when dispensing with a mechanical seal. In addition, the production costs for the reactor unit fall.

As stated above the pressure drop in the hollow fiber is inversely proportional to Diameter of the fiber in the fourth power. In the face of that is it cheap, one possible small fiber diameter to choose. It is preferably provided that the inner diameter of the hollow fibers at most 300 μm, preferably at most 200 μm and more preferably about 100 microns is.

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 × h × m ² , preferably at least 500 ml / mmHg × h × m ² .

In a further embodiment of the invention, it is provided that 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. Of course, deviating porosities or cutoffs are possible. Depending on the intended use, the use of hollow-fiber membranes with low porosity is also conceivable.

Especially It is advantageous if the reactor unit is designed as disposable.

Farther it is advantageous if the reactor unit constructed from materials is that are water vapor sterilizable. The materials used correspond prefers the materials that are also used in dialysis filters become. It is thus conceivable, the housing of PP and / or the potting compound of polyurethane and / or the hollow fibers of polyarylethersulfones, preferably from polysulfones and more preferably from PVP hydrophilized polysulfones perform. In a further embodiment all materials in a steam sterilization of the invention at 121 ° C dimensionally stable.

The The invention further relates to a method for effecting a mass transfer by means of one or more hollow fibers using a reactor according to one the claims 1 to 15, wherein the pressure in the formed by the hollow fibers second chamber and in the first chamber formed by the housing is set such that the mass transfer through the hollow fibers at least partially by convection. This convective Mass transfer can be superimposed on a mass transfer by diffusion be. The mass transfer by convection is preferably bidirectional and especially for medium and high molecular weight Synthesis products or nutrients with a lower diffusion rate into consideration.

In a further embodiment, it is provided that 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. In such an embodiment of the invention, a subdivision into feeding and laxative hollow fibers or hollow fiber sections takes place. For example, it is conceivable when using the method for cell cultivation that hollow fibers or hollow fiber sections are provided, by means of which nutrients are supplied to the medium located in the first chamber. Furthermore, hollow fibers or hollow fiber sections are provided, by means of which metabolic products from the medium located in the first chamber into the hollow fibers and then discharged who the.

The The invention further relates to a system with a reactor according to one the claims 1 to 15, with a reservoir connected to the reactor unit of the reactor communicates in such a way that from the reservoir medium in the second chamber of the reactor unit formed by the hollow fibers insertable or removable from this is, with a preferably designed as a peristaltic pump feed pump for advancement of the medium and with an oxygenator, by means of which the pumped medium can be enriched with oxygen. Preferably, the oxygenation takes place externally and is variably adjustable to the oxygen consumption. The oxygen supply takes place in this case, for example via the Blood plasma or the supplied Nutrient medium. The oxygenator is preferably in the flow direction of the medium Upstream reactor. Furthermore, a heating device for heating the funded Medium be provided.

Further Details and advantages of the invention will become apparent from a in the drawing illustrated embodiment. Show it:

1 FIG. 3: a perspective view of the reactor unit according to the invention, FIG.

2 FIG. 2: a perspective view of the inventive reactor with housing, FIG.

3 : a schematic representation of the reactor unit according to the invention,

4 FIG. 2: another schematic representation of the reactor unit according to the invention in another embodiment and FIG

5 : A schematic representation of the ertindungsgemäßen mass transfer system with reactor.

1 shows a perspective view of the invention designed as a disposable reactor unit 12 , This consists of a housing 20 in which hollow fibers are arranged in the form of a hollow fiber bundle. Furthermore, there is an inlet 40 and a process 50 provided, via which the hollow fibers flowing through the medium is supplied or removed.

Out 2 the reactor is apparent 10 without reactor unit. Visible is the rotatable receptacle for fixing the reactor unit according to 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.

• • Hepatozytenkultur für unterschiedliche Anwendungen
• • Künstliche Leber- und Pankreasersatztherapien
• • Züchtung von humanen und tierischen Zellen unterschiedlichen Ursprungs
• • Produktion von Antikörpern
• • Gewinnung von Substanzen aus transfizierte Hefen und Bakterien.

3 shows a schematic representation of a rotatably arranged reactor unit 12 , Conceivable applications are:

• • Hepatocyte culture for different applications
• • Artificial liver and pancreatic replacement therapies
• • Breeding of human and animal cells of different origin
• • production of antibodies
• • Obtaining substances from transfected yeasts and bacteria.

In the 3 The points shown represent the cells that are in the first through the housing 20 limited chamber of the reactor unit 12 are located. In the first chamber are hollow fibers 30 arranged, via an inlet 40 and a process 50 feature. If it is a cell culture, it will be over the inlet 40 fed to a nutrient medium. In the case of liver or pancreatic replacement therapy is about the inflow 40 Supplied with blood plasma. The spent nutrient medium or the treated blood plasma is on the process 50 deducted.

How out 3 further apparent, the housing has 20 two connections 22 which are used for filling, emptying or sampling from the first chamber. It is conceivable, the connections 22 after filling or sampling. In principle, it is also conceivable to allow a continuous operation to the effect that continuously medium over the terminals 22 is introduced into the first chamber or discharged from it. How out 3 further, are central in the area of the axis of rotation of the reactor unit 12 hollow fibers 30 provided a hollow fiber section 32c form, in which a comparatively high pressure is present, so that as indicated by arrows a convective mass transport from the section 32c the hollow fibers 30 in through the housing 20 limited first chamber of the reactor unit 12 he follows. In the end of the section 32c a change of direction takes place initially in the direction parallel to the end face of the housing 20 and then against the flow direction in the section 32c , In the hollow fiber sections 32d occurs due to the pressure loss caused by lower pressure in the hollow fibers 30 now a convective mass transport from the first chamber containing the cells in the hollow fibers 30 like this in the area of hollow fiber sections 32d indicated by arrows. Thus, a subdivision into feeding hollow fibers or hollow fiber sections takes place 32c and laxative hollow fibers or hollow fiber sections 32d instead of.

How out 3 finally further evident, is the inlet 40 and the flow of hollow fibers on the same side of the housing 20 , in the off as defined in 3 at the right end of the cylindrically designed Ge housing 20 , Such an embodiment makes it possible to provide a mechanical seal-free reactor available. The relative movement between stationary and moving parts can be determined by the EP 1 270 079 A2 and DE 198 03 534 C2 known system can be achieved.

The reactor unit 12 is preferably executed 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.

4 shows the reactor unit 12 in a further embodiment. In through the cylindrical rotationally symmetrical housing 20 limited first chamber are in a suitable medium human hepatocytes. In a radially central portion is made of individual hollow fibers hollow fiber bundle. The hollow fiber bundle has a multiplicity of hollow fibers arranged in the region of the axis of rotation 30a on, of which only a few are shown by way of example. Furthermore, a plurality of hollow fibers are offset radially outward 30b provided, which are arranged in the outer peripheral region of the hollow fiber bundle and of which also only one is shown. The hollow fibers 30a . 30b are arranged in parallel and in their two end areas in potting compounds 32 fixed in a suitable manner in the housing 20 are attached. About the inlet 40 medium flows into the hollow fibers 30a , flows through these and occurs at the end region of the hollow fibers shown on the left 30a out of these. The medium passes here into a flow space, the end portions of the hollow fibers 30a with the initial regions of the hollow fibers 30b combines. As indicated by the arrow in the end of the hollow fibers 30a indicated, the flow direction of the medium in the end region of the fibers 30a changed. It flows into the hollow fibers after passing through the flow space 30b and through them in the opposite direction than through the hollow fibers 30a , The hollow fibers 30b stand in the end area on the right with the drain 50 in connection, by means of which the appropriately treated medium from the reactor unit 12 is dissipated. The medium may be, for example, a nutrient medium or body fluids, such as blood or particularly preferably blood plasma.

In the 4 Of course, the illustrated reactor unit can also be used for other purposes, such as for cell cultures.

The through the housing 20 limited first chamber has two connections 22 on, which can serve for the supply or removal of medium from the first chamber or for sampling.

How out 4 further apparent and indicated by the arrow, the reactor unit 12 set in rotation during operation, wherein the axis of rotation is parallel to the hollow fibers. Preferably, the hollow fibers 30a arranged such that they lie in the region of the axis of rotation and the hollow fibers 30b are offset radially outwards. The pressure conditions may be selected such that the pressure in the hollow fibers 30a above the pressure of the case 20 limited first chamber and in the hollow fibers 30b below the pressure prevailing in the first chamber. At the reversal point marked by a curved arrow, it can be provided that there is no pressure difference between the first and second chambers. Even deviating designs of the pressure conditions are of course conceivable.

5 shows a schematic representation of an overall system for liver support therapy. This consists of a plasma reservoir 60 containing blood plasma taken from the patient to be treated. About the peristaltic pump 70 becomes the plasma reservoir 60 Plasma deprived and the gas exchanger 80 fed. In 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. 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. In a particularly preferred embodiment of the invention, the gas exchanger is designed as an oxygen generator for the exchange of oxygen.

After enrichment of the blood plasma with oxygen in the oxygenator 80 this passes through a heater 90 and then enters the reactor 10 , This has the rotatably arranged reactor unit 12 on, which is executed as a disposable. The reactor unit 12 is in a rotatable receptacle of the reactor 10 arranged and is set during operation of the system in a rotary motion. The axis of rotation coincides with the longitudinal axis of the reactor unit 12 together. The reactor is housed in a temperature controlled housing, like this 2 and 5 is apparent. The system is designed without mechanical seal.

Hereinafter, some advantageous embodiments of the invention are shown:
Polysulfone plasma fibers with a large available exchange surface, preferably in the range of 0-2 m ² with preferably variably adjustable porosity of up to 900,000 MW, are preferably usable as hollow fibers. As stated above, to increase the bidirectional exchange via the hollow-fiber membranes, the mass transfer preferably takes place primarily by means of convection.

In dependence of the properties of the cells or of the substances to be exchanged can hydrophilic and / or hydrophobic membranes used for the hollow fibers become.

As stated above can be a separation of the feeding Fibers from the laxative Fibers are made. This allows fiber bundles be variably assigned within the reactor. As an an example can feeding and laxatives Fibers be centrally located. It is also conceivable that feeding fibers central and laxative Fibers are arranged peripherally. Thus, a flow through the Reach cell culture in countercurrent.

Preferably are mechanical seals by using the above "tube feeding principle" of a standing avoided in a rotating part.

at the reactor unit can be a sterile disposable item act, which is separated from an unsterile turntable. Of the Sterile disposable articles are preferably water vapor sterilizable.

The Oxygenation is preferably external, it is variable on the Oxygen consumption adjustable. The oxygen supply is thus preferably over the blood plasma or over a nutrient medium.

The nutrition of cells is preferably over the blood plasma or nutrient medium.

It exists in a further embodiment of the invention, a simple way the filling, Addition and sampling. This allows a permanent control the functionality to reach. There is also the possibility the correction or adjustment.

Through the in 2 reproduced system can be carried out an integrated thermostating of the reactor unit.

As part of a therapy or culture, for example, cells of the following origin can be used:
Primary cells, stem cells differentiated cells, immortalized cells - each freshly isolated / cultured or cryopreserved.

It are in a further embodiment of the invention, cell quantities of very small quantities to about 1 kg cultivable.

• • Verwendung von Polysulfonhohlfasern mit großer Austauschoberfläche und variabel einstellbarer Porosität – besserer Stoffaustausch bei Einsatz von inerten Materialien
• • deutlich effizienterer bidirektionaler Stoffaustausch durch Konvektion, insbesondere für mittel- und höhermolekulare Syntheseprodukte mit geringer Diffusionsgeschwindigkeit
• • durch Einsatz hydrophiler und/oder hydrophober Membranen Stoffaustausch besser steuerbar/einstellbar
• • durch Trennung der Zuführfasern von den ableitenden Fasern und frei variierbare Anordnung der Fasern verbesserte Zellversorgung und damit Zellleistung
• • durch Gegenstrom und Rotation zusätzlich verbesserte Durchmischung und Stofftransport
• • Vermeidung von Gleitringdichtungen durch Verwendung des „Schlaucheinspeiseprinzipes" von einem stehenden in ein drehendes Teil- keine Schlauchverdrillung (störungsfreier Betrieb im klinischen Einsatz) und kein Abrieb in der Reaktoreinheit
• • durch die Möglichkeit des Einsatzes von humanen Körperflüssigkeiten Vermeidung des Einsatzes kommerzieller Ernährungslösungen (beispielsweise RPMI) und damit dem Kontakt unphysiologischer Substanzen beim Einsatz
• • Trennung von sterilem Einmalartikel und unsteriler Dreheinheit – einfaches Handling mit hoher Anwendersicherheit
• • Einmalartikel wasserdampfsterilisierbar – keine toxischen Abbauprodukte (ETO) und im Bezug auf mikrobiologische Kontamination höchstmögliche Anwendersicherheit
• • Oxygenierung und Ernährung der Leberzellen/Pankreaszellen außerhalb der rotierenden Einheit über das Blutplasma/Kulturmedium (nur ein Kreislauf im rotierenden Teil) und somit keine zusätzliche Membran im Zellmodul – damit höhere Anwendersicherheit
• • einfache Möglichkeit der Befüllung, Zugabe und Probennahme; durch Verfahren der Befüllung Kontamination minimiert und damit Anwendersicherheit erhöht
• • durch Probeentnahmemöglichkeit permanente Überwachung der Zellen möglich – höhere Sicherheit im Bezug auf Funktionalität und Unbedenklichkeit (Sterilität, PH, Bildung von toxischen Stoffwechselprodukten etc.)
• • durch Einsatz von kryokonservierten Zellen humanen Ursprungs unabhängig von Verfügbarkeit von Transplantaten
• • System schnell (Montage, Verfügbarkeit, Zellmaterial) und sicher funktionsbereit (Sterilität, Anwenderfreundlichkeit).

With appropriate design, the invention offers the following advantages:

• • Use of polysulfone hollow fibers with a large exchange surface and variably adjustable porosity - better mass transfer when using inert materials
• • significantly more efficient bidirectional mass transfer by convection, especially for medium and high molecular weight synthesis products with low diffusion rates
• • by using hydrophilic and / or hydrophobic membranes mass transfer more controllable / adjustable
• • By separating the supply fibers from the dissipative fibers and freely variable arrangement of the fibers improved cell supply and thus cell performance
• • by countercurrent and rotation additionally improved mixing and mass transfer
• • Prevention of mechanical seals by using the "tube feeding principle" from a stationary to a rotating part- no hose twisting (trouble-free operation in clinical use) and no abrasion in the reactor unit
• • by the possibility of using human body fluids avoiding the use of commercial nutritional solutions (eg RPMI) and thus the contact of unphysiological substances in use
• • Separation of sterile disposable and unsterile rotary unit - easy handling with high user safety
• • disposable water vapor sterilisable - no toxic decomposition products (ETO) and in terms of microbiological contamination highest possible user safety
• • Oxygenation and nutrition of the liver cells / pancreatic cells outside the rotating unit via the blood plasma / culture medium (only one cycle in the rotating part) and thus no additional membrane in the cell module - thus higher user safety
• • easy way of filling, adding and sampling; Contamination minimizes contamination and thus increases user safety
• • permanent monitoring of cells possible by sampling - higher safety in terms of functionality and safety (sterility, PH, formation of toxic metabolic products, etc.)
• • by using cryopreserved cells hu of many origin irrespective of the availability of transplants
• • System fast (assembly, availability, cell material) and safe to operate (sterility, ease of use).

Claims (21)

Reactor ( 10 ) with a rotatably arranged reactor unit ( 12 ), which has a first chamber and a second chamber, wherein the first chamber through the interior of a housing ( 20 ) and wherein the second chamber through the interior of one or more hollow fibers ( 30 ) is formed, which via an inlet ( 40 ) and a process ( 50 ), the hollow fibers ( 30 ) in the housing ( 20 ) are arranged such that a through the hollow fibers ( 30 ) flowing medium is guided in at least two different directions. Reactor ( 10 ) according to claim 1, characterized in that the feed ( 40 ) as well as the procedure ( 50 ) of the hollow fibers ( 30 ) in the same side of the housing ( 20 ) are arranged. Reactor ( 10 ) according to claim 1 or 2, characterized in that the hollow fibers ( 30 ) in the housing ( 20 ) are arranged such that a through the hollow fibers ( 30 ) flowing medium has a substantially U-shaped flow path. Reactor ( 10 ) according to one of the preceding claims, characterized in that the hollow fibers ( 30 ) Are U-shaped. Reactor ( 10 ) according to one of the preceding claims, characterized in that the hollow fibers ( 30 ) are executed straight and at its two end portions in casting compounds ( 32 ) are embedded. Reactor ( 10 ) according to one of the preceding claims, characterized in that the housing ( 20 ) is rotationally symmetrical, preferably cylindrical. Reactor ( 10 ) according to one of the preceding claims, characterized in that the hollow fibers ( 30 ) from the inlet ( 40 ) to a region in which the direction of the course of the hollow fibers ( 30 ), extend in a first direction and extend from the region of the direction change in a second, deviating from the first direction, wherein the running in the first direction hollow fibers ( 30a ) radially inward and in the second direction extending hollow fibers ( 30b ) run radially relative to the outside. Reactor ( 10 ) according to one of the preceding claims, characterized in that the reactor ( 10 ) is executed slip ring seal free. Reactor ( 10 ) according to one of the preceding claims, characterized in that the housing ( 20 ) via at least one connection ( 22 ) for filling, emptying or sampling from the first chamber. Reactor ( 10 ) according to one of the preceding claims, characterized in that the inner diameter of the hollow fibers ( 30 ) is at most 300 microns, preferably at most 200 microns and more preferably about 100 microns. Reactor ( 10 ) according to one of the preceding claims, characterized in that the hydraulic permeability of the membrane is at least 200 ml / mmHg × h × m ² , preferably at least 500 ml / mmHg × h × m ² . Reactor ( 10 ) according to one of the preceding claims, characterized in that the cutoff of the hollow fibers ( 30 ) forming membrane in the range between 10 ⁴ Da and 10 ⁷ Da, preferably in the range between 105 Da and 10 ⁶ Da, and more preferably between 700,000 and 900,000 Da. Reactor ( 10 ) according to one of the preceding claims, characterized in that the reactor unit ( 12 ) is a disposable. Reactor ( 10 ) according to one of the preceding claims, characterized in that the reactor unit ( 12 ) is constructed of materials that are water vapor sterilizable. Reactor ( 10 ) according to one of the preceding claims, characterized in that one of the ends of the hollow fibers ( 30 ) receiving potting compound ( 32 ) and that housing ( 20 ) made of PP and / or the potting compound of polyurethane and / or the hollow fibers ( 30 ) consist of polysulfones, preferably of polyarylethersulfones and more preferably of polysulfones hydrophilized with PVP. Method for effecting a substance exchange by means of one or more hollow fibers ( 30 ) using a reactor according to any one of claims 1 to 15, wherein the pressure in the second chamber formed by the hollow fiber inner spaces as well as in the through the housing ( 20 ) is set such that the mass transfer through the hollow fibers ( 30 ) at least partially by convection. A method according to claim 16, characterized in that the pressure conditions between the first and the second chamber are selected such that the convective mass transport in a section ( 32c ) of the hollow fibers ( 30 ) from the in the hollow fibers ( 30 ) in the in the housing ( 20 ) and in another section ( 32d ) of the hollow fibers ( 30 ) from the in the housing ( 20 ) into the hollow fibers ( 30 ) located medium takes place. System with a reactor ( 10 ) according to one of claims 1 to 15, with a reservoir ( 60 ) connected to the reactor unit ( 12 ) in such a way that from the reservoir ( 60 ) Medium into which through the hollow fibers ( 30 ) formed second chamber of the reactor unit ( 12 ) is insertable or can be discharged from it, with a delivery pump ( 70 ) for the delivery of the medium and with an oxygenator ( 80 ), by means of which the pumped medium can be enriched with oxygen. System according to claim 18, characterized in that the oxygenator ( 80 ) in the direction of flow of the medium to the reactor ( 10 ) is connected upstream. System according to claim 18 or 19, characterized in that in the flow direction in front of the reactor a heating device ( 90 ) is provided for heating the medium. System according to one of claims 18 to 20, characterized in that the feed pump ( 70 ) is a peristaltic pump.