DE102005021305A1 - 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 unit with a first chamber and a second chamber, wherein the first chamber through the interior a housing is formed and wherein the second chamber through the interior of several arranged in the housing Hollow fibers is formed.

such Reactor units are known in different embodiments and serve for example, human or animal cells different Origin to breed 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 described reactor through 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.

As stated above can Reactor units of the type mentioned above, for example, used to grow cells. Another area of application is therapy, for example the Liver and pancreatic replacement therapy. Previously known reactor units thus have, for example, a first chamber for cultivation of cells through which a supply circuit formed by the second chamber runs, through which a nutrient medium or Blood or blood components flow. The second chamber is usually formed by a hollow fiber membrane bundle, being over the membranes of the hollow fibers substances with the medium in the first chamber be replaced. It is usually provided that larger units, such as B. cells can not pass the membrane of the hollow fibers. through In such a reactor unit, the cells in the first Chamber supplied with nutrients and metabolites dissipated become. In the case of the above-mentioned use of the reactor unit as artificial Liver substances are exchanged from the blood with the chamber, which then be metabolized by liver cells.

For the above mentioned operations is a good mass transfer between the first chamber and the second chamber of the reactor unit required. It is the task of the present invention, a reactor unit of the aforementioned Further develop type in that the reactor unit compared to previously known Reactor units has improved mass transfer properties.

This object is achieved by a reactor unit having the features of claims 1 and 11. Thereafter, it is provided that the hollow fibers are arranged in the housing such that their relative to the cross-sectional area of the first chamber density in at least a portion of the first chamber 10 fibers / mm ² does not exceed. It has been found that the mass transfer between the first and the second chamber can take place optimally if the hollow fibers do not exceed a certain density relative to the cross section of the first chamber. It was found that a good exchange occurs when the density of the fibers does not have the maximum possible value, but lies below. A preferred as in hemodialysis densest packing of the fibers is not advantageous here. A minimum density results from ensuring the supply capacity, which also depends on the total exchange area.

For a hollow fiber having an outer diameter of about 250 microns, the maximum fiber density is 12 fibers / mm ² . It has been found that a particularly favorable mass transfer is achieved when the density of the fibers, which is related to the cross-sectional area of the first chamber, does not exceed the value of 10 fibers / mm ² .

It is particularly advantageous if the area-related density of the hollow fibers in at least one region of the first chamber in the range of 0.2 to 10 fibers / mm ² , preferably in the range of 0.5 to 6 fibers / mm ^2, and particularly preferably in the range of 1 to 4 fibers / mm ² . These densities can be realized at least in one point of the first chamber.

The fiber densities given here and below refer to a uniform Fa serdichte related to 1 cm ² .

The surface density according to the invention the hollow fibers of the reactor unit can be realized on the one hand be that the fibers already shed in the appropriate density, d. H. or embedded in encapsulants in their end regions. Furthermore, there is the possibility of the Fibers in the form of their densest possible Shed pack and then the distance between the two potting compounds in the Decrease chamber, so that the distance of the casting surfaces lower is as the length the between the potting compounds located portion of the fibers. In this case, the fibers do not run straight between the potting surfaces, but curved, for example, spindle-shaped.

Consequently It is conceivable that the on the cross sectional area of the first chamber related density of the fibers in the fiber longitudinal direction changes. This is z. As is the case when the fibers are in their densest packing be shed, but the distance between the facing each other Surfaces of the Potting compounds is less than the length of the between the potting compounds located fiber sections. Alternatively, it may also be provided be that related to the cross-sectional area of the first chamber Density of the fibers in the fiber longitudinal direction is constant. Such an embodiment is then conceivable if the fibers are in the desired Density below the maximum possible Density lies, shed.

Basically it is possible that in the reactor unit one or more than one potting compound are arranged, in which a section, usually the end section, embedded in the hollow fibers. A potting compound can then be provided For example, if the fibers have a U-shaped course.

Of course it is it also possible that the reactor unit has two potting compounds which face each other, in which a portion, preferably the end portion of the hollow fibers is embedded and between which another section of the Hollow fibers extends.

As stated above can be provided that the hollow fibers between the potting compounds straight or curved run, so that, for example, results in a bulbous or spindle-shaped hollow fiber bundle. Fill it Fibers the volume of the first chamber more largely than at a straight, straight grain.

As stated above There is an advantageous embodiment of the invention is that the length of the between the potting masses section of at least some or all hollow fibers at least 0.5% above the distance of the facing each other surfaces the Vergussmassen lies. It is particularly preferred if the length of said sections of at least some or all hollow fibers at least 1% and preferably at least 3% above said distance of potting lies.

It it is possible, to constrict the hollow fibers by suitable means such that the on the cross-sectional area the density increased in the first chamber is increased. Basically, the Hollow fibers or the spindles formed by them, for example constricted by O-rings so that the density can be regulated upwards again.

The The invention further relates to a reactor unit having a first chamber and a second chamber, wherein the first chamber through the interior of a housing is formed and wherein the second chamber through the interior of several in the case arranged hollow fibers is formed. It is envisaged that at least two potting compounds are arranged in the reactor unit, in which a portion, preferably the end portion of the hollow fibers is embedded and between which another section of the Hollow fibers extends, the length of which is located between the potting compounds Hollow fiber portion of at least some or all hollow fibers at least 0.5% over the distance of the mutually facing Vergussflächen lies. In this way results in a lower area related Fiber density than for the case that the distance between the facing casting surfaces of the Length of the Section of the hollow fibers corresponds between them extends. It is particularly advantageous if such a reactor unit according to the characterizing one Part of one of claims 1 to 10 executed is.

Of the Course of the hollow fibers in the housing is largely arbitrary. It is conceivable that the hollow fibers are arranged such that the flowing through it Medium in one direction or in at least two different ones Directions is guided. In the last case learns the flowing through the hollow fibers 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 is designed substantially U-shaped or the U-fönnig executed Hollow fibers are used.

If there is at least one change of direction, an advantageous embodiment of the invention results, in particular, if the mass transfer between the two chambers at least also to be done by convection. The convective mass transport is directly proportional to the pressure difference across the hollow fiber membranes. The pressure drop in the hollow fibers is directly proportional to the length of the fiber and inversely proportional to the diameter of the fiber in the fourth power. Thus, if the flow of the flowing through the hollow fibers medium at least once undergoes a change in direction, for example, a reversal in direction, in which he z. B. is at least once back and returned, the total path through the housing increases accordingly. This causes a correspondingly higher pressure in the hollow-fiber membranes and leads to an increase in the pressure difference across 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. Such an embodiment For example, comes into consideration when the hollow fibers already embedded with relatively low density in the casting compounds. Conceivable For example, that is the pressure difference between the first and second chamber chosen will that be a spatial Separation from feeding and laxative hollow fibers is present. This allows a good mixing can be achieved. It is conceivable, for example, the feeding fibers radially inside and the laxative Fibers parallel to it radially outside to arrange. in principle are also deviating embodiments conceivable, such as the reverse arrangement with outside lying feeding Fasem and internal laxative Fibers.

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.

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

The Invention further relates to a reactor having a reactor unit according to the invention, wherein the reactor unit is arranged rotatably. A special good mass transfer between the first and second chamber results when the reactor unit does not rest but rotates. Accordingly, an advantageous embodiment of the invention relates a reactor with a rotatably arranged reactor unit. It can be provided corresponding drive means through which the reactor unit is set in a rotational movement.

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.

The The invention further relates to a method for effecting a mass transfer by means of one or more hollow fibers using a reactor unit according to one of the claims 1 to 26 or a reactor according to claim 27 or 28, wherein the pressure in through the hollow fiber interiors formed second chamber and in the formed by the housing first chamber is set so that the mass transfer the hollow fibers are at least partially convected. 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 Another embodiment provides that the pressure conditions between the first and the second chamber are chosen such that the convective fabric is transporting in a section of the hollow fibers from the medium contained in the hollow fibers in the accommodated in the housing Medium and in another section of the hollow fibers in reverse Direction takes place. In such an embodiment of the invention there is a subdivision into feeding and laxatives Hollow fibers or hollow fiber sections. For example, it is in use the method of cell culture conceivable that hollow fibers or hollow fiber sections are provided, by means of which nutrients 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 that in the first chamber located medium in the hollow fibers and then removed.

The The invention further relates to a system with a reactor unit according to one of the claims 1 to 26 or a reactor according to one of claims 27 to 28 with a reservoir, which is in communication with the reactor unit such that the reservoir medium in the second fibers formed by the hollow fibers Chamber of the reactor unit insertable or from this deductible is, with a preferably designed as a peristaltic pump feed pump to promote 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 direction of flow of the medium to the reactor upstream. 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 : a perspective view of the reactor unit according to the invention,

2 FIG. 2: a perspective view of the reactor according to the invention with housing, FIG.

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

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

5 : a schematic representation of the mass transfer system according to the invention with reactor,

6 FIG. 2: schematic representations of different geometries of a reactor unit according to the prior art and of reactor units according to the invention, FIG.

7 : temporal concentration curves for urea, protein and various ions at Ein set of a reactor unit according to the invention and

8th : Time-course concentration curves for urea, protein and various ions when using a reactor unit according to the prior art.

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 execution area as per 3 on the right side of the cylindrical 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. Such an embodiment is considered, for example, when the hollow fibers are already embedded with relatively low density in the casting compounds. The hollow fibers 30a . 30b are arranged in parallel and in their two end areas in potting compounds 32 fixed in an appropriate 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 ratios can 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.

The present invention differs from prior art embodiments in that the reactor unit is configured such that the hollow fibers of the hollow fiber bundle arranged therein are not arranged in a maximum possible density, but rather that the density related to the cross-sectional area of the first chamber Fibers in at least a region of the first chamber 10 fibers / mm ² does not exceed or that the length of the recorded between two potting hollow fiber sections exceeds the distance of the mutually facing surfaces of the potting compounds by at least 0.5%.

6a shows a running according to the prior art reactor unit 12 in a schematic view. The hollow fiber membranes are enclosed in a plastic net and form a rigid, cylindrical structure. The diameter of the hollow fiber bundle is D = 34 mm. The length between the two cut surfaces of the casting compounds 32 is in the reactor unit according to 6a L = 257 mm. With a number of 11,000 hollow fibers, the fiber density based on the cross-sectional area of the first chamber is thus about 12 fibers / mm 2.

6b shows an embodiment of the reactor unit shown schematically 12 according to the invention. Like this in 6b is schematically indicated, is compared to the embodiment according to the prior art after 6a the distance L of the cut surfaces of the casting compounds 32 shortened by 10 mm. In this case, the hollow fibers are between the potting compounds 32 upset and form a spindle. Depending on the distance of the casting surfaces, ie the facing surfaces of the casting compounds, lower fiber densities are obtained, as in the embodiment according to 6a , In the embodiment according to 6b the largest diameter of the fiber bundle is 95 mm. Immediately to the potting compounds 32 the fiber density corresponds to 6a explained. Due to these dimensions, the fiber density is in the reactor unit according to the invention 12 according to 6b in the range between 1.5 fibers / mm ² and 12 fibers / mm ² .

6c shows an embodiment in which the distance L of the cut surfaces of the casting compounds 32 to the 6a equivalent. However, the fiber bundle is constricted by an O-ring, so that the fiber density compared to the embodiment according to 6b is regulated back up. In the area of the constriction, the diameter of the fiber bundle is 34 mm. The maximum diameter of the fiber bundle is 60 mm, resulting in a total surface density of the fibers in the range between 3.9 fibers / mm ² and 12 fibers / mm ² .

From a comparison of 7 and 8th It is clear what advantage with respect to the mass transfer brings the reactor unit according to the invention over a reactor unit according to the prior art with it.

The concentration gradients according to the 7 and 8th the following experimental setup or the following test procedure is based on:
After assembly of the chambers they were checked by applying pressure (compressed air) for tightness and "bubble points".

For the experiments, 400 ml of exchange medium were prepared:
1 plasma bag + 0.5 ml EDTA 100 mM (not in the experiments according to 7 + 50 ml buffer B ad 400 ml with Ad buffer B: urea 7.5 mg / ml, NaCl 22.5 mg / ml (385 mmol), KCl 1.25 mm / ml (16.7 mmol).

at In all experiments, the hollow fibers were filled with exchange medium and after taking time "0" to the reactor unit or their first chamber connected.

The Reactor unit was during the replacement tests at 25 ° C supplied at a flow rate of 200 ml / min and rotated at 15 rpm, to study the sample exchange by convection and diffusion.

The sampling took place as follows:
For each determination, 2 ml of sample were taken by Monovette (Sarstedt 2 ml LH; CE 0197) at one point before entering the chamber and at the sample port 1 in the chamber. In the process, approx. 2 to 3 ml of liquid were rinsed out of the sampling ports before each sampling and only then the test sample was drawn. At the chamber sample port 2 was used to replace the sampled sample with water. In the supply circuit formed by the hollow fibers, the sampled sample was replaced by the buffer reservoir.

In the experimental arrangement according to the experiments to 7 the volume of the chambers was about 1.7 l. The hollow fiber membranes are stabilized by 2 plastic fibers. The chambers are due to the reduced distance of the potting compounds about 1 cm shorter than in the experimental arrangement, with the experimental results according to 8th were obtained. As a result, the membranes are compressed and form a spindle-shaped, the chamber volume filling structure.

In the test results according to 8th leading experimental arrangement, the chamber volume was about 1.8 l. The membranes are enclosed in a plastic net and form a rigid, cylindrical structure.

As if from a comparison of 7 and 8th As can be seen, there is a significant difference in the speed of the distribution of ions and organic molecules through the membranes with 60 kd pore size as a function of the bundling of the membrane or of the hollow fiber bundle.

The compressed open membrane (spindle shape) (fiber density: 1.5 fibers / mm ² ) fills the lumen of the first chamber for the most part and thereby causes a very good mass transfer. As shown in the pictures 7a . 7b becomes apparent, the material exchange between the hollow fibers and the first chamber within the first minutes after the start of the cycle. The complete concentration exchange for ions and urea can after about 30 to 60 min. be determined. The protein exchanges more slowly and incompletely due to its high molecular weight. In 7 and 8th the abbreviations "VKL" and "chamber" mean the concentrations in the supply circuit (VKL), ie in the medium flowing through the hollow fiber, or the concentrations in the first chamber of the reactor unit.

The normal, bundled membrane (cylindrical shape) (maximum fiber density), with which the test results according to 8th are obtained forms a compact cylindrical wiring harness with relatively small exchange efficiency. As shown in the pictures 8a . 8b becomes apparent, the material exchange between the hollow fibers and the first chamber is much slower than in accordance 7 , The complete concentration compensation for ions and urea can after 120 to 180 min. be measured and thus 3-4 times slower than the spindle-shaped membranes according to the invention. The protein is also exchanged slowly and incompletely.

As initially stated, can the reactor unit according to the invention for therapy, for example for liver replacement or liver support therapy be used.

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 reaction gate 10 , This has the rotatably arranged reactor unit according to the invention 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.

The peristaltic pump 70 may deviate from the design according to 5 be arranged elsewhere in the cycle. It is also conceivable, for example, an arrangement behind, ie downstream of the reactor 10 ,

As a further component, the arrangement according to 5 preferably in the flow direction in front of the reactor 10 optionally have a heating device, by means of which the the reactor 10 supplied medium is heated.

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 Fasem done. 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 Fasem 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 höhenmolekulare 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 of human origin regardless of the availability of transplants
• • System fast (assembly, availability, cell material) and safe to operate (sterility, ease of use).

Claims (34)

Reactor unit having a first chamber and a second chamber, wherein the first chamber is formed by the interior of a housing and wherein the second chamber is formed by the interior of a plurality of arranged in the housing hollow fibers, characterized in that the hollow fibers are arranged in the housing such in that its density, which is related to the cross-sectional area of the first chamber, does not exceed 10 fibers / mm ² in at least one region of the first chamber. Reactor unit according to claim 1, characterized in that the relative to the cross-sectional area of the first chamber density of the hollow fibers in at least a region of the first chamber in the range of 0.2 to 10 Fa fibers / mm ² , preferably in the range of 0.5 to 6 Fibers / mm ² and more preferably in the range of 1 to 4 fibers / mm ² . Reactor unit according to claim 1 or 2, characterized that's on the cross-sectional area the density of the fibers in the fiber longitudinal direction relative to the first chamber varied. Reactor unit according to claim 1 or 2, characterized that's on the cross-sectional area the density of the fibers in the fiber longitudinal direction relative to the first chamber is constant. Reactor unit according to one of the preceding claims, characterized characterized in that in the reactor unit one or more than one Potting compound is arranged, in which a section, preferably the End region of the hollow fibers is embedded. Reactor unit according to one of the preceding claims, characterized characterized in that two potting compounds are arranged in the reactor unit, in which a portion, preferably the end portion of the hollow fibers is embedded and between which another section of the Hollow fibers extends. Reactor unit according to claim 6, characterized in that that the hollow fibers between the potting compounds are straight or curved, so that in particular results in a bulged or spindle-shaped hollow fiber bundle. Reactor unit according to claim 6 or 7, characterized that the length of the potting mass located portion of several or all hollow fibers at least 0.5% above the distance of each other facing surfaces the Vergussmassen lies. Reactor unit according to claim 8, characterized in that that the length located between the potting compound portion of the hollow fibers minde least 1% and preferably at least 3% above the distance from each other facing surfaces the Vergussmassen lies. Reactor unit according to one of the preceding claims, characterized characterized in that means are provided, which are the hollow fibers surrounded so that the related to the cross-sectional area of the first chamber Density of fibers opposite the density is increased without the use of funds. Reactor unit with a first chamber and a second chamber, wherein the first chamber through the interior of a housing is formed and wherein the second chamber through the interior of several in the case arranged hollow fibers is formed, characterized in that at least two potting compounds are arranged in the reactor unit, in which a portion, preferably the end portion of the hollow fibers is embedded and between which another section of the Hollow fibers extending, the length of the between the potting compounds located portion of at least some or all hollow fibers at least 0.5% above that Distance between the facing surfaces of the potting compounds is. Reactor unit according to claim 11, characterized in that the reactor unit according to the characterizing part of one of claims 1 to 10 is executed. Reactor unit according to one of the preceding claims, characterized characterized in that the hollow fibers are arranged in the housing such that a flowing through the hollow fibers Medium in one direction or in at least two different ones Guided directions becomes. Reactor unit according to one of the preceding claims, characterized characterized in that the hollow fibers via an inlet and a Destroy the process. Reactor unit according to claim 14, characterized in that that the inlet and the outlet of the hollow fibers on the same side of the housing are arranged. Reactor unit according to one of the preceding claims, characterized characterized in that the hollow fibers are arranged in the housing such that a flowing through the hollow fibers Medium a substantially U-shaped Has flow course. Reactor unit according to one of the preceding claims, characterized characterized in that the hollow fibers are U-shaped. Reactor unit according to one of the preceding claims, characterized characterized in that the housing is rotationally symmetrical, preferably cylindrical. Reactor unit according to one of the preceding claims, characterized characterized in that the hollow fibers have an inlet and starting from the inflow to an area where the direction of the course the hollow fibers changes, in a first direction and from the area of change of direction in a second direction deviating from the first direction, wherein the hollow fibers extending in the first direction are radial inside and in the second direction extending hollow fibers relative to radially outside run. Reactor unit according to one of the preceding claims, characterized characterized in that the housing over at least a connection to filling, Emptying or sampling from the first chamber has. Reactor unit according to one of the preceding claims, characterized characterized in that the inner diameter of the hollow fibers at most 300 μm, preferably at most 200 μm and more preferably about 100 microns. Reactor unit according to one of the preceding claims, characterized in that the hydraulic permeability of the membrane of the hollow fibers is at least 200 ml / mm Hg × h × m ² , preferably at least 500 ml / mm Hg × h × m ² . Reactor unit according to one of the preceding claims, characterized in that the cutoff of the membrane forming the hollow fibers is in the range between 10 ⁴ and 10 ⁷ Da, preferably in the range between 10 ⁵ and 10 ⁶ Da and particularly preferably between 700,000 and 900,000 Da. Reactor unit according to one of the preceding claims, characterized characterized in that the reactor unit is constructed of materials is that are water vapor sterilizable. Reactor unit according to one of the preceding claims, characterized characterized in that the reactor unit is designed as disposable. Reactor unit according to one of the preceding claims, characterized in that a potting compound which receives the ends of the hollow fibers is provided and that the housing made of PP and / or the potting compound of polyurethane and / or the hollow fibers from polysulfones, preferably from polyarylethersulfones and especially preferably consist of polysulfones hydrophilized with PVP. Reactor with a reactor unit according to one of claims 1 to 26, characterized in that the reactor unit rotatable is arranged. Reactor according to claim 27, characterized in that that the reactor is executed without mechanical seal. Method for effecting a substance exchange by means of one or more hollow fibers using a reactor unit according to one of the claims 1 to 26 or a reactor according to claim 27 or 28, wherein the Pressure in the second chamber formed by the hollow fiber inner spaces as well in through the housing formed first chamber is set such that the mass transfer at least partially by convection through the hollow fibers. Method according to claim 29, characterized that the pressure conditions between the first and the second chamber are chosen such that the convective mass transport in a section of the hollow fibers from the medium contained in the hollow fibers in the housing located in the housing Medium takes place and in another section of the hollow fibers in the case absorbed medium in the medium contained in the hollow fibers he follows. System with a reactor unit according to one of claims 1 to 26 or a reactor according to one of claims 27 to 28, with a reservoir, the is in communication with the reactor unit in such a way that from the Reservoir medium in the second chamber formed by the hollow fibers the reactor unit inserted or deductible from this is, with a delivery pump to promote of the medium and with an oxygenator, by means of which the pumped medium can be enriched with oxygen. System according to claim 31, characterized that the oxygenator in the flow direction of Medium upstream of the reactor or the reactor unit. System according to claim 31 or 32, characterized that in the flow direction provided in front of the reactor, a heater for heating the medium is. System according to one of Claims 31 to 33, characterized that the feed pump a is peristaltic pump.