Abstract:
A bioreactor has a reactor bag ( 12 ) with a predominantly flexible bag wall ( 121 ) that has a rigid bearing area. A stirrer arrangement ( 14 ) is in the bearing area and includes rigid profile ring ( 16 ) made of a non-magnetic material and fixed in the bearing area. The stirrer arrangement ( 14 ) also includes a shaftless stirrer ( 18 ) rotatably engaged with the profile ring ( 16 ) and having parts that are permanently magnetic. An electric coil arrangement ( 20 ) is outside the reactor bag ( 12 ) and can produce a rotating magnetic field that interacts with the permanent-magnetic areas of the stirrer ( 18 ) to produce a torque that rotates the stirrer ( 18 ) and circulates the contents of the bag ( 12 ).

Description:
BACKGROUND 
     1. Field of the Invention 
     The invention relates to a bioreactor, comprising
         a reactor bag with a predominantly flexible bag wall which has a rigidly formed bearing area for housing a stirrer serving to circulate contents of the bag,   a shaftless stirrer, parts of which are permanently magnetic, housed inside the bag in the bearing area, and   a coil arrangement positioned outside the reactor bag with which coil arrangement a rotating magnetic field can be produced, which magnetic field interacts, in a manner exerting a torque on the stirrer, with the permanent-magnetic areas thereof.       

     2. Description of the Related Art 
     The invention further relates to a reactor bag for a bioreactor, comprising a predominantly flexible bag wall which has a rigidly formed bearing area for housing a shaftless stirrer serving to circulate the contents of the bag, at least parts of the stirrer being permanently magnetic. 
     Finally, the invention relates to a stirrer to circulate the contents of a bioreactor, parts of which stirrer being permanently magnetic and comprising a plurality of paddle-like circulation elements affixed to a holder. 
     Such bioreactors, reactor bags and stirrers for same are known from U.S. Pat. No. 8,123,199 B2. 
     As is known, bioreactors serve as containers for fluids in which biological processes, such as fermentation or cell growth, are intended to take place in a controlled manner. Due to the metabolic activity of the microorganisms involved, local changes arise in the concentration of various chemical components. To maintain the same, or at least controlled, concentration conditions in the entire container, the fluid in the reactor must be stirred occasionally; preferably, in a constant manner. To avoid contamination, the stirrers are generally arranged in the interior of the otherwise closed reactor container (except for specific inlets and outlets). One difficulty is causing the stirrers located in the interior of the reactor container to move in the desired stirring direction by means of drive mechanisms usually arranged outside of the reactor container. 
     For bioreactors with rigid walls, such as steel tanks, a familiar solution is to affix the actual circulation elements of the stirrer, such as impellers, on a shaft that penetrates the container wall in a sealed bearing such that the stirrer shaft can simply be coupled with the drive shaft of a motor of any desired configuration. 
     Recently there has been a steady increase in the use of bioreactors whose actual container is designed as a flexible bag for single use. Advantages include the cost-effective manufacture of the foil bags, straightforward and space-saving storage, ease of sterilization and contamination security, as well as dispensing with the need for laborious cleaning after use. However, the problem of appropriately circulating the contents of the bag has not been definitively solved. In particular, versions with stirrer shafts that penetrate the bag wall are regarded as disadvantageous as this increases the risk of contamination, considerably increases the amount of space required for storage and, because of the necessity of providing a sealed penetration point for the shaft, renders the manufacture of the bags more complicated and expensive. 
     The category-defining patent U.S. Pat. No. 8,123,199 B2 discloses a shaftless stirrer having a plurality of impellers around a flat, cylindrical holder, wherein the flat, cylindrical holder is housed in a correspondingly shaped rigid vessel forming the bottom of the reactor bag. At least part of the cylindrical holder is designed to be permanently magnetic and interacts with an external magnetic field that penetrates the vessel wall. The external magnetic field is designed as a rotational field, so that the stirrer holder, along with the paddle-like circulation elements, is caused to rotate in its bearing vessel. This known device has several disadvantages. On the one hand, it is limited in that the position of the stirrer is restricted to the bottom region of the reactor bag, which can be expected to result in insufficient mixing of the reactor contents in tall bioreactors. On the other hand, the stirrer is not axially fixed in its bearing vessel—rather, to the contrary, in order to reduce bearing friction, axial raising of the stirrer by the external magnetic field is described. This means that during transport, the stirrer can easily fall out of its bearing and damage the bag walls with its sharp-edged paddles. 
     It is the problem of the present invention to further develop category-defining bioreactors, reactor bags and stirrers so as to overcome the disadvantages of the prior art. In particular, bioreactors and/or reactor bags with significantly reduced space requirements during storage and/or transport are to be provided. Also improved mixing of the reactor contents and safer transport and storage options are intended to result. 
     SUMMARY OF THE INVENTION 
     This problem is solved in that a rigid profile ring made of non-magnetic material, e.g. plastic, is arranged in a segment of height of the reactor bag—however preferably not at the height of its top edge—as a bearing area in which the stirrer formed as the rotor spanning the cross-section of the bag is rotatably housed by means of a guide rail, the magnetic field of the electric coil arrangement interacting with at least one permanent magnet arranged in the radially outer area of the rotor. 
     The problem is further solved in that a rigid profile ring made of a non-magnetic material, e.g. plastic, is arranged as a bearing area at a segment of height of the reactor bag—however preferably not at the height of its top edge—in which the stirrer formed as the rotor spanning the cross-section of the bag is rotatably housed in an axial and radial manner by means of a guide rail. 
     The problem also is solved in that the stirrer is formed as a rotor having a central body and at least three spokes extending radially from the central body, the rotor having at least one permanent magnet arranged in its radially outer area and at least one guide element of an outer guide rail. 
     The essential subject of the invention is the special design of the bearing area and the corresponding design of the stirrer. The stirrer spans the entire cross-section of the bag and is housed in a profile ring which forms the rails of a guide rail at its radially outer area, the profile ring extending around the circumference of the reactor bag. The magnetic interaction to drive the stirrer in a motorized way also takes place in this radially outer mechanical interaction area between the rotor and its guide. The magnetic forces acting between the outer coil arrangement and the permanent magnet(s) arranged in the outer area of the stirrer penetrate the profile ring, which therefore must be made of a non-magnetic material, e.g. plastic. The entire stirrer arrangement can therefore be designed such that it occupies only very minimal axial space in the apparatus and moreover can be arranged at any desired axial position within the reactor bag. It is also conceivable that multiple such stirrer arrangements could be arranged at different axial positions within the reactor bag so as to ensure sufficient mixing of the entire reactor content in very tall bioreactors. Due to the minimal axial height of each stirrer arrangement, the walls of the reactor bag, which are inherently flexible, are only reinforced with “ribs”, flexible wall areas remaining between these profile rings forming the “ribs” such that the reactor bag can be compressed like a bellows for storage and transport, which significantly reduces the storage space required. With appropriate design of the guide rail, it will be impossible for any of the rotors to dislodge from their guides, which means that there is no risk of the bag walls being damaged in the compressed state and that in the expanded state, it is possible to begin stirring operation immediately without any prior assembly steps. 
     In a preferred embodiment, the profile ring penetrates the flexible bag wall and is bonded to it. The bonded connection, which can be implemented by means of welding or gluing, ensures the seal-tightness of the reactor bag, including in the area of the stirrer arrangement. Since the profile ring radially penetrates the bag wall, direct access to its external side is ensured from outside of the reactor bag. This feature takes on special importance in connection with the special designs of the motorized stirrer drive described below. However, it is generally also conceivable that the profile ring be bonded to the internal side of the otherwise flexible bag wall, the bag wall covering the radially external contours of the profile ring tightly. This version is generally reserved for devices with very thin, preferably elastic, bag wall material. 
     The profile ring preferably has a circumferential guide groove open to the bag interior in which at least one guide shoe arranged radially outside of the rotor is guided axially and radially. Special design versions of the guide shoe for rotors of different designs are discussed below. However, with respect to all such embodiments, the guide shoe is surrounded by the guide groove on at least three sides, such that both radial and axial support is ensured in this type of bearing. 
     Alternatively, it is also conceivable that the profile ring have a circumferential ridge oriented to the bag interior, which ridge projects into at least one groove element arranged at the radially outer side of the rotor such that the rotor is guided axially and radially. This version essentially represents the kinematic reverse of the preferred embodiment described above. One skilled in the art will easily be able to translate the embodiments of the groove-guided guide shoe described in detail below to the corresponding kinematically reversed embodiments with a ridge-guided groove element. 
     To reduce friction, a further development of the invention provides that at no fewer than three positions on the circumference of the profile ring, radially oriented roller bearings and/or axially oriented, opposing pairs of roller bearings project into the guide groove with spring action, or, in embodiments with a guide ridge, project out of it. 
     Alternatively or additionally to this, it is conceivable that at no fewer than three positions on the circumference of the profile ring, radially oriented slide bearing springs and/or axially oriented, opposing pairs of slide bearing springs project into the guide groove, or, in embodiments with a guide plane, project out of it. The surfaces of the slide bearing springs are preferably coated with friction-reducing material, such as polytetrafluoroethylene. 
     Of course, in principle, it is also conceivable that such or similar friction-reducing elements be provided on the rotor, especially on the guide shoe and/or on the groove element. The reason for the general preference for embodiments with a guide groove as opposed to embodiments with a guide ridge is the special suitability of the former for an especially advantageous further development of the invention. This provides that the guide groove on the exterior side of the profile ring form a projection having at least one axial mounting surface on which an electric coil arrangement designed as a separate unit or unit group is arranged and/or arrangeable, the coil arrangement being capable of generating the magnetic field. In this connection, an axial mounting surface is to be understood as a surface with surface normals oriented parallel to the axial direction on which a mounting element, in this case the electric coil arrangement in particular, is arrangeable such that a radial overlap occurs. In this way, a radial overlap of the guide shoe guided in the interior of the guide groove with the coil arrangement arranged on the exterior axial mounting surface can be realized, which serves to minimize the distance between the coil arrangement that generates the magnetic field and a permanent magnet arranged in the external region of the stirrer, or potentially even in the area of the guide shoe. This serves to maximize the interaction between the permanent magnet and the coil arrangement such that only small permanent magnets and/or low coil currents are required to achieve a predetermined drive power. It is advantageous if there is more than one axial mounting surface. 
     Rather, it is preferred that the guide groove on the exterior side of the profile ring be surrounded on three sides, by a form-fitting connection, by an electric coil arrangement designed as a separate unit or unit group, which coil arrangement is capable of generating the magnetic field. The interaction between the coils and permanent magnets can be yet further augmented by means of this measure. 
     One skilled in the art recognizes that the rearward accessibility of the profile ring has special importance in connection with this embodiment. In particular, this makes it conveniently possible to separate elements intended for single use (bag, rotor and profile ring) from reusable elements (coil inserts). 
     Regarding the design of the rotor, it is preferable that it have a central body and at least three spokes radially extending from the central body. This can be realized for example as a propeller-like rotor design in which the spokes are designed as paddles arranged in a hydrodynamically advantageous manner in order to effect the desired mixing of the reactor contents and to minimize shear forces affecting the cells in cell cultures within the bioreactor. 
     In another preferred embodiment, the spokes of the rotor are connected to one another by means of a ring-shaped rim. In this embodiment, the rotor has the form of a spoked wheel in which the actual circulation elements, i.e. the impellers, can also be realized by designing the spokes in a special way. 
     In both embodiments mentioned, i.e. the rotor designed in the form of a propeller and spoked-wheel, respectively, the circulation elements can also be arranged in the area of the central body. In this case, it would be necessary to design the spokes, to the extent possible, so that they would exert the lowest possible hydrodynamic resistance to the rotation of the rotor. 
     While with respect to the design of the rotor as a propeller the permanent magnets that interact with the coil arrangement are arranged together with the guide elements designed as sliding blocks or groove elements in the area of the propeller blade tips, it is preferred, in the case of the rotor being designed as a spoked-wheel, that a plurality of permanent magnets be arranged around the circumference of the rim. Depending on the embodiment, the rim itself can serve as a ring-shaped guide shoe. Alternatively, multiple isolated areas of the rim can be designed as sliding block-like guide shoes while the areas of the rim in between serve only to hold magnets. It is also conceivable that the spokes penetrate the rim radially such that a structure similar to a ship&#39;s helm results, where the magnets are located on the rim ring, and the sliding block-like guide shoes or groove elements are located in the area of the spoke tips. The inverse arrangement is also conceivable, in which the magnets are located in the area of the spoke tips while the sections of the rim in between serve as guide elements. This version renders radial guiding more difficult, however. 
     One skilled in the art will recognize that the motorized drive is preferably implemented in the form of a linear motor with a circular, curved long stator in which the sections of the rotor that bear the magnets or magnet groups can be regarded as sliders connected to one another. By controlling the coil arrangements to produce a rotating magnetic field, such as in the form of a three-phase alternating current, the armatures will move synchronously toward one another along the circular path provided by the guide rail of the profile ring. The mechanical connection of the sliders in the propeller- or spoked wheel-shaped rotor results in rotational motion of the rotor. Of course, it is also possible to create such rotational motion if only a single slider is provided, i.e. only one single rotor area bearing one or more magnets. 
     Further features and advantages of the invention result from the following specific description and the drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  a schematic cross-sectional view of a bioreactor in accordance with the invention. 
         FIG. 2  a perspective sectional view of the bioreactor in accordance with the invention. 
         FIG. 3  an enlarged view of a section of  FIG. 1 . 
         FIG. 4  a perspective view of a stirrer in accordance with the invention. 
         FIG. 5  a top view of the stirrer in  FIG. 4 . 
         FIG. 6  a lateral view of the stirrer in  FIG. 4 . 
         FIG. 7  a perspective view of a segment of a profile ring for housing the stirrer. 
         FIG. 8  a lateral view of the interior side of the profile ring segment in  FIG. 7 . 
         FIG. 9  a sectional view of the profile ring segment from  FIG. 7  along the cutting plane x-x in  FIG. 8 . 
         FIG. 10  a sectional view of the profile ring segment from  FIG. 7  along the cutting plane IX-IX in  FIG. 8 . 
         FIG. 11  a perspective view of a coil insert. 
         FIG. 12  a top view of the coil insert from  FIG. 11 . 
         FIG. 13  a lateral view of the exterior side of the coil insert from  FIG. 11 . 
         FIG. 14  a perspective view of a stirrer arrangement composed of a stirrer, profile ring and coil inserts. 
         FIG. 15  a schematic view of a possible coil/magnet configuration. 
         FIG. 16  a schematic view of an alternative coil/magnet configuration. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       FIGS. 1 to 14  illustrate as an example a preferred embodiment of the invention and will be discussed together, unless specific reference is made to a particular figure.  FIG. 15  and show, purely schematically and as an example, two possible coil/magnet configurations to implement the motorized drive of a stirrer arrangement in accordance with the invention, especially a stirrer arrangement in accordance with  FIGS. 1 to 14 . Identical reference numbers in the figures indicate identical or analogous elements. 
       FIGS. 1 to 3  show highly schematic views of a bioreactor that has a reactor bag  12  and a stirrer arrangement  14 . The reactor bag  12  has a predominantly flexible bag wall  121  that is made rigid only in the area of the stirrer arrangement  14  by the latter&#39;s profile ring  16 , which is made of a rigid, non-magnetic material, e.g. plastic. Preferably, the bag wall  121  is interrupted in the area of the stirrer arrangement  14  and is at least partially replaced by the profile ring  16 . The axial edge areas of the latter can be affixed to the bag wall by gluing or welding, for example. It is irrelevant whether the profile ring  16  is bonded to the interior or to the exterior side of the bag wall  121 . Ultimately, the bag wall  121  and the profile ring  16  together form a sealed container that is made rigid in rib-like fashion only in the area of the profile ring and is otherwise flexible. The exterior side of the profile ring  16  is accessible from the exterior of the bag. 
       FIGS. 1 to 3  do not show inlets and outlets usually provided on bioreactors; however, one skilled in the art would be able to include them depending on the requirements of a specific individual case. Also not shown is a bag holder serving as a bracket or support structure for hanging or supporting, respectively, the reactor bag  12 , which bag holder can be designed as a bracket frame to place the reactor bag  12  on or as an exoskeleton-like container to accommodate the reactor bag  12 . In the latter case in particular, it is possible to arrange the coil inserts, described in more detail below, in the wall of the exoskeleton container such that they are automatically introduced into the profile ring in their deployment position when the reactor bag  12  is inserted or when the exoskeleton container is closed, respectively. 
     In addition to the profile ring  16 , the stirrer arrangement comprises a rotor  18  rotatably housed in an axial and radial manner in the profile ring, as well as the coil inserts  20  which, although previously mentioned, are hardly visible in  FIGS. 1 to 3 . A stirrer arrangement  14  isolated from the reactor bag  12  is shown in  FIG. 14 . Its individual elements are described in more detail below in connection with the remaining figures. 
     One skilled in the art will easily recognize that the bioreactor  10  in accordance with the invention is not limited to versions with only one stirrer arrangement  14 . Rather, it is possible, especially for very tall bioreactors, to position multiple stirrer arrangements  14  at various axial heights. The flexibility of the bag wall  121  in the area between the stirrer arrangements  14  results in a bellows-like or accordion-like compressibility, which causes the storage space to be very small, even with multiple stirrer arrangements  14 . 
       FIGS. 4 to 6  show various views of a preferred embodiment of a rotor  18 . The actual stirring function is carried out by the elements in the central area of the rotor  18 . In the embodiment shown, these elements are a central body  181 , which is preferably designed in a flow-optimized form, as shown, which provides especially low hydrodynamic resistance to an axial flow. Propeller-like paddles  182 , which are to be regarded as the actual circulation elements, are molded to the central body  181 . The impellers  182  can be given a special design in accordance with standard hydrodynamic criteria, taking into account the requirements of the individual case, especially taking into account the viscosity of the fluid to be stirred as well as the desired rotations per minute. In the embodiment shown, the stirring structure consisting of the central body  181  and the impellers  182  is arranged in a cage  183  that serves, on the one hand, to stabilize the stirring structure and on the other, to effect the mechanical connection between it and the motorized drive described further below. For this purpose, multiple spokes  184  extending radially are molded onto the cage  183 . These spokes  184  preferably have a flow-optimized profile. What specifically is regarded as favourable depends on the requirements of the individual case. A profile form that offers as little resistance as possible can be chosen; on the other hand, it is also possible to design the spokes  184  similarly to the impellers  182  as effective circulation elements. The spokes  184  connect the cage  183  with a rim ring  185 , which, as described in more detail below, is rotatably housed in the profile ring  16 . The rim ring  185  therefore serves as the guide shoe that runs around the entire circumference. In the embodiment shown, the rim ring  185  also serves to bear a plurality of permanent magnets  186  which are inset within it. Preferably this is done such that the magnets  186  do not project axially above the rim ring. It is preferable for them to be molded inside the plastic material of which the rim ring  185  is made. 
     In an alternative embodiment that is not shown, a continuous rim ring  185  can be dispensed with. In this embodiment, only the radially outer tips of the spokes  184  are formed as isolated guide shoes; one or more of which can bear the magnets  186 . 
       FIGS. 7 to 10  show a segment  161  of the profile ring  16  in an especially preferred embodiment. Although in principle it is possible to design the basic structure of the profile ring  16  as a single piece, it has been shown to be advantageous, with regard to the assembly of a reactor bag in accordance with the invention and/or a bioreactor in accordance with the invention, to design the profile ring  16  in the form of multiple, preferably identical profile ring segments  161 . 
     The basic structure of the profile ring segment  161  consists of a curved plastic profile strip, the inner side of which has a guide groove  162 . The width of this groove correspond to the rim ring  185  of the rotor  18  such that the latter is housed axially and radially with little play in the guide groove  162 . Preferably, the appropriate amount of play is adapted to the intended contents of the reactor. In cell cultures in particular, provision of too little play can result in undesired crushing of cells that get between the rim ring  185  and guide groove  162 . It is therefore preferable that the amount of play be greater than the minimum required to maintain the rotational capacity of the rotor  18  and that groove formation on the rotor  18  be prevented by special rolling bearing elements or slide bearing elements  163 ,  164 . Multiple radial bearings  163  and axial bearings  164  are therefore distributed around the circumference of the profile ring in the embodiment shown. In the preferred embodiment, the radial bearings  163  each consist of two rollers housed in radial spring bearings, whose axis of rotation is oriented parallel to the axis of rotation of the rotor  18 . These pairs of rollers housed in spring bearings project radially from the exterior into the guide groove  162 . If at least (preferably exactly) three such radial bearings  163  are provided, the rim ring  185  of the rotor  18  is held elastically in a centered position. The axial bearings  164  are designed as spring-pretensioned roller pairs arranged axially opposite on either side of the guide groove  162 , with radially oriented axes of rotation that center the rim ring  185  of the rotor  18  axially and elastically in the guide groove  162 . 
     It is clearly apparent in  FIGS. 7 and 10  in particular that the profile ring segment  161  has a recess  165  on its outer side. This is flanked axially on both sides by the radial mounting surfaces  166  that serve to fasten the flexible bag wall  121  to the profile ring  16 . In particular, they can serve as contact surfaces for a bonded connection, especially by gluing or welding. In the area of a bearing  163 ,  164 , the recess  165 , as is especially evident in  FIGS. 9 and 10 , is less deep or is interrupted, respectively. However, the recess  165  is deep enough between the bearings that a radial overlap of the recess  165  and the guide groove  162  results. In other words, the radially outer wall of the guide groove  162  forms an axial mounting surface  167  on which the electric coils can be mounted and positioned there at a minimal distance to the permanent magnets  186  within the rim ring  185  that runs within the guide groove  162 . 
       FIGS. 11 to 13  show various views of a coil arrangement that is formed to correspond to the recess  165  in the outer side of the profile ring segments  161 . In the embodiment shown, the coil arrangement  20  has coil carrier strips  201  on its axial edges which, when the stirrer arrangement  14  is in the assembled state, abut the axial mounting surfaces  167  of the profile ring segment  161 . The coil carrier strips  201  are interrupted in certain areas to allow room for the axial bearings  164 . In the area of the radial bearings  163 , the coil inserts  20  have apertures  202  that provide the space necessary to accommodate the bearing elements. 
     The actual coils  203  are only indicated schematically in the figures. Their exact design, orientation and electrical contacting are not shown, however can be realized in detail by one skilled in the art, taking into account the requirements of the individual case.  FIGS. 15 and 16  show a highly schematized view of two possible designs for a coil. Of course, one skilled in the art will have to suitably coordinate the specific arrangement of the permanent magnets  186  in relation to the specific structure of the coils  203 . One skilled in the art can also design the coordinated controlling of the coils or coil groups in the manner of a circularly curved linear motor, taking into account known electrical engineering aspects. Purely as an example, the standard orientations of the permanent magnets  186  in radial magnetization, axial magnetization and arrangement in a Halbach array are mentioned, each of which requires corresponding coil arrangements and controls. 
     Of course, the embodiments discussed in the specific description and shown in the figures are merely illustrative exemplary embodiments of the present invention. In the light of the present disclosure one skilled in the art has a broad spectrum of optional variations available. 
     LIST OF REFERENCE NUMBERS 
     
         
           10  bioreactor 
           12  reactor bag 
           121  bag wall 
           14  stirrer arrangement 
           16  profile ring 
           161  profile ring segment 
           162  guide groove 
           163  radial bearing 
           164  axial bearing 
           165  recess 
           166  radial mounting area 
           167  axial mounting area 
           18  rotor/stirrer 
           181  central body 
           182  impeller 
           183  cage 
           184  spoke 
           185  rim ring 
           186  permanent magnet 
           20  coil arrangement 
           201  coil carrier strip 
           202  aperture 
           203  coil