Bioreactor and related methods

Abstract

An apparatus for culturing cells includes a bio reactor. The bioreactor may be modular and may include in a chamber a fixed bed, such as an unstructured or structured fixed bed (such as a spiral bed) for culturing cells, with a return column arranged centrally within the chamber. The modular bioreactor may include a plurality of structured fixed beds arranged in a stacked configuration. The modular bioreactor may include an outer casing forming a space for conditioning (e.g., insulating, heating, cooling) at least a chamber in which cells are cultured. The bioreactor may also include an impeller with radially curved blades, and may also suspend the impeller so that it may move from side-to-side and align with an external drive. Related methods are also disclosed.

What is claimed: 
     
         1 . An apparatus for culturing cells in connection with a fluid flow, comprising:
 a modular bioreactor including a fixed bed for culturing cells.   
     
     
         2 . The apparatus of  claim 1 , wherein the modular bioreactor comprises:
 a base portion having a first chamber;   an intermediate portion forming at least part of a second, outer chamber for receiving the fixed bed and at least part of a third inner chamber for returning fluid flow from the second outer chamber to the first chamber; and   a cover portion for positioning over the intermediate portion.   
     
     
         3 . The apparatus of  claim 1  or  2 , wherein the fixed bed comprises a structured fixed bed. 
     
     
         4 . The apparatus of  claim 2 , wherein the intermediate portion comprises a tubular part, the structured fixed bed extending spirally around the tubular part. 
     
     
         5 . The apparatus of  claim 2 , wherein the intermediate portion comprises a tubular part formed by an inner wall of the fixed bed. 
     
     
         6 . The apparatus of  claim 2 , wherein the intermediate portion comprises a plurality of intermediate parts, each associated with a structured fixed bed. 
     
     
         7 . The apparatus of  claim 6 , wherein at least one of the plurality of intermediate parts is perforated for allowing fluid to flow from a first structured fixed bed below the at least one intermediate part to a second structured fixed bed above the at least one intermediate part. 
     
     
         8 . The apparatus of  claim 6 , wherein each of the plurality of intermediate parts is tubular, and each structured fixed bed comprises a spiral bed wound around the tubular intermediate part. 
     
     
         9 . The apparatus of  claim 8 , further including a perforated support for the structured fixed bed. 
     
     
         10 . The apparatus of  claim 2 , wherein the intermediate portion further includes a tubular casing for forming a periphery of the modular bioreactor, the tubular casing forming a space for heating, cooling, or insulating the bioreactor. 
     
     
         11 . The apparatus of  claim 2 , wherein the intermediate portion comprises a plurality of intermediate parts, each adapted for connecting with each other. 
     
     
         12 . The apparatus of  claim 2 , wherein the intermediate portion includes a tube for engaging at least one intermediate part and forming an inner wall of the outer second chamber for receiving the fixed bed. 
     
     
         13 . The apparatus of  claim 12 , wherein the tube engages a first intermediate part below the tube and a second intermediate part above the tube. 
     
     
         14 . The apparatus of  claim 13 , wherein the second intermediate part includes openings for creating a fluid film along the third inner chamber. 
     
     
         15 . The apparatus of  claim 13 , further including supports for supporting the second intermediate part from the first intermediate part. 
     
     
         16 . The apparatus of  claim 15 , wherein the supports comprise vertical rods. 
     
     
         17 . The apparatus of  claim 2 , wherein the cover portion comprises a removable cap including a plurality of ports. 
     
     
         18 . The apparatus of  claim 17 , wherein the removable cap has an outer diameter that is less than an outer diameter of the intermediate portion. 
     
     
         19 . The apparatus of  claim 17 , wherein at least one of the ports includes a threaded metal insert. 
     
     
         20 . The apparatus of  claim 2 , wherein the cover portion has an outer diameter that is equal to or greater than an outer diameter of the intermediate portion. 
     
     
         21 . The apparatus of  claim 2 , wherein the intermediate portion comprises an intermediate part adapted for positioning at least partially within the base portion, the intermediate part further including a flow disruptor for disrupting fluid flow. 
     
     
         22 . The apparatus of  claim 2 , wherein the base portion includes a further chamber radially outward of the first chamber in fluid communication with the second outer chamber including the fixed bed, which is formed by an upstanding wall having a plurality of openings for transmitting fluid from the first chamber to the further chamber. 
     
     
         23 . The apparatus of  claim 2 , further including an agitator associated with the base portion. 
     
     
         24 . The apparatus of  claim 23 , wherein the intermediate portion is adapted for suspending the agitator in the first chamber in a manner that allows side-to-side movement for alignment with an external drive. 
     
     
         25 . The apparatus of  claim 24 , further including a container for containing the agitator, the container including a central inlet and a plurality of radially oriented outlets. 
     
     
         26 . The apparatus of  claim 25 , wherein a flow divider is associated with the central inlet. 
     
     
         27 . The apparatus of  claim 23 , wherein the agitator comprises a plurality of curved blades. 
     
     
         28 . The apparatus of  claim 2 , further including a plurality of flow disruptors for dividing the fluid flow entering the third inner chamber into a plurality of streams. 
     
     
         29 . The apparatus of  claim 28 , wherein the plurality of flow disruptors are associated with a ring. 
     
     
         30 . The apparatus of  claim 28 , further including one or more conduits for permitting gas to enter into a space behind one of the streams. 
     
     
         31 . The apparatus of  claim 30 , wherein the one or more conduits are connected to a structure including the plurality of flow disruptors. 
     
     
         32 . The apparatus of  claim 31 , wherein a first conduit is connected to the structure. 
     
     
         33 . The apparatus of  claim 31 , wherein first and second conduits are connected to the structure. 
     
     
         34 . The apparatus of  claim 31 , wherein first and second conduits are not connected to the structure. 
     
     
         35 . An apparatus for culturing cells, comprising:
 a modular bioreactor comprising a base portion connected to both a central column and an outer casing, the outer casing and central column together forming a compartment for culturing cells.   
     
     
         36 . The apparatus of  claim 35 , wherein the compartment includes at least one structured fixed bed. 
     
     
         37 . The apparatus of  claim 36 , wherein the compartment includes a plurality of structured fixed beds, arranged in a stacked configuration. 
     
     
         38 . The apparatus of  claim 37 , further including an intermediate part between at least two of the plurality of structured fixed beds. 
     
     
         39 . The apparatus of  claim 36 , wherein the at least one structured fixed bed comprises a spiral bed. 
     
     
         40 . The apparatus of  claim 37 , wherein each of the plurality of stacked, structured fixed beds is wrapped around the central column. 
     
     
         41 . The apparatus of  claim 40 , wherein the central column comprises first and second interconnected tubes, a first structured fixed bed of the plurality of structured fixed beds being wrapped around the first tube and a second structured fixed bed of the plurality of structured fixed beds being wrapped around the second tube. 
     
     
         42 . The apparatus of  claim 37 , wherein the central column comprises first and second tubes for engaging a perforated support extending between at least two of the plurality of structured fixed beds. 
     
     
         43 . The apparatus of  claim 3  or  claim 36 , wherein the structured fixed bed comprises a cartridge adapted for being inserted into and removed from the second, outer chamber or compartment. 
     
     
         44 . The apparatus of  claim 35 , wherein the base portion is removably connected to the central column. 
     
     
         45 . The apparatus of  claim 35  or  44 , wherein the base portion is removably connected to the outer casing. 
     
     
         46 . A bioreactor for culturing cells, comprising:
 a base part having a first chamber including an agitator for agitating a fluid; and   a first central column attached, preferably removably, to the base part, the first central column forming at least part of a second, outer chamber for culturing cells and a third inner chamber for returning fluid flow from the second outer chamber to the first chamber.   
     
     
         47 . The bioreactor of  claim 46 , wherein the second, outer chamber includes a first structured fixed bed. 
     
     
         48 . The bioreactor of  claim 46 , wherein the first structured fixed bed comprises a spiral bed. 
     
     
         49 . The bioreactor of  claim 48 , wherein the first structured fixed bed is wound around the first central column. 
     
     
         50 . The bioreactor of  claim 49 , further including a second central column forming at least part of the second outer chamber, and further including a second structured fixed bed spaced vertically from the first structured fixed bed. 
     
     
         51 . The bioreactor of  claim 50 , further including a perforated support between the first structured fixed bed and the second structured fixed bed. 
     
     
         52 . The bioreactor of  claim 46 , wherein the second, outer chamber includes an unstructured bed. 
     
     
         53 . A bioreactor for culturing cells in connection with a fluid, comprising:
 a first chamber including an agitator for agitating the fluid;   a second, outer chamber including a plurality of stacked beds for culturing cells; and   a third, inner chamber for returning fluid from the second outer chamber to the first chamber.   
     
     
         54 . The bioreactor of  claim 53 , comprising:
 a base portion having the first chamber;   an intermediate portion forming at least part of the second, outer chamber and at least part of the third inner chamber; and   a cover portion for positioning over the intermediate portion.   
     
     
         55 . The bioreactor of  claim 54 , wherein the intermediate portion comprises a first support for supporting a first bed of the plurality of stacked beds. 
     
     
         56 . The bioreactor of  claim 55 , wherein the intermediate portion comprises a second support for supporting a second bed of the plurality of stacked beds. 
     
     
         57 . The bioreactor of  claim 55 , wherein the intermediate portion is adapted for removably connecting with the base portion and the cover portion. 
     
     
         58 . The bioreactor of  claim 53 , wherein the second, outer chamber is bounded by an outer wall, and further including an outer casing forming a space with the outer wall, the space being for insulating, heating, or cooling the second, outer chamber. 
     
     
         59 . A bioreactor for culturing cells in connection with a fluid, comprising:
 a first chamber including an agitator for agitating the fluid;   a second, outer chamber including at least one bed for culturing cells; and   a third, inner chamber for returning fluid from the second outer chamber to the first chamber,   wherein the second, outer chamber is bounded by an outer wall, and further including an outer casing forming a space with the outer wall, the space being for insulating, heating, or cooling the second, outer chamber.   
     
     
         60 . The bioreactor of  claim 59 , wherein the at least one bed comprises a structured fixed bed. 
     
     
         61 . The bioreactor of  claim 59 , wherein the structured fixed bed comprises a spiral bed. 
     
     
         62 . The bioreactor of  claim 59 , wherein the inner chamber is formed by at least one tube. 
     
     
         63 . The bioreactor of  claim 62 , wherein the at least one tube is connected to first and second supports bounding the at least one bed. 
     
     
         64 . The bioreactor of  claim 63 , wherein the first and second supports are connected to the outer wall. 
     
     
         65 . The bioreactor of  claim 63  or  64 , wherein the first and second supports are at least partially perforated. 
     
     
         66 . An apparatus for culturing cells, comprising:
 a bioreactor including an agitator, the bioreactor adapted for maintaining the agitator in a suspended condition that allows side-to-side movement for alignment with an external drive.   
     
     
         67 . The apparatus of  claim 66 , wherein the bioreactor includes a base portion for receiving the agitator, and an intermediate portion for supporting a carrier for carrying the agitator in the suspended condition. 
     
     
         68 . The apparatus of  claim 67 , wherein the carrier comprises a clip for engaging the intermediate portion. 
     
     
         69 . An apparatus for culturing cells, comprising:
 a bioreactor including an agitator having a plurality of curved blades.   
     
     
         70 . The apparatus of  claim 69 , wherein the agitator includes a central open region radially inward of the plurality of curved blades. 
     
     
         71 . The apparatus of  claim 69  or  claim 70 , wherein the agitator includes one or more magnets. 
     
     
         72 . The apparatus of  claim 69 , wherein the blades are curved in a radial direction. 
     
     
         73 . A bioreactor comprising first and second stacked, structured beds. 
     
     
         74 . The bioreactor of  claim 73 , further including a screen engaging both the first and second stacked, structured beds. 
     
     
         75 . The bioreactor of  claim 73  or  claim 74 , wherein the first and second stacked, structured beds comprise spiral beds. 
     
     
         76 . A bioreactor including a structured fixed bed forming a central column of the bioreactor. 
     
     
         77 . The bioreactor of  claim 76 , wherein the structured fixed bed comprises a spiral bed. 
     
     
         78 . The bioreactor of  claim 76  or  claim 77 , wherein an inner surface of the structured fixed bed is fluid-impervious. 
     
     
         79 . A method of manufacturing a bioreactor, comprising:
 connecting a base portion including a first chamber with an agitator for agitating a fluid to at least one intermediate portion forming at least portion of a second, outer chamber for culturing cells in connection with fluid transferred from the second, outer chamber, and a third, inner chamber for returning fluid to the first chamber of the base portion.   
     
     
         80 . The method of  claim 79 , further including the step of connecting a cover portion over the at least one intermediate portion. 
     
     
         81 . The method of  claim 79 , further including the step of spirally wrapping a matrix material around the intermediate portion to form a structured fixed bed for culturing cells in the outer chamber. 
     
     
         82 . The method of  claim 79 , further including the step of inserting a structured fixed bed into the second, outer chamber. 
     
     
         83 . The method of  claim 79 , further including providing an outer casing to form a periphery of the second, outer chamber. 
     
     
         84 . The method of  claim 83 , further including the step of connecting the outer casing to the base portion. 
     
     
         85 . The method of  claim 79 , further including the step of stacking a plurality of structured fixed beds in the second, outer chamber. 
     
     
         86 . The method of  claim 85 , further including the step of providing a perforated support between the plurality of structured fixed beds. 
     
     
         87 . The method of any of  claims 79 - 86  further including the step of suspending the agitator above the base portion in a manner that permits side-to-side movement to align with an external drive. 
     
     
         88 . A method of manufacturing a bioreactor, comprising:
 providing a plurality of structured fixed beds in the bioreactor.   
     
     
         89 . The method of  claim 88 , further including the step of providing a perforated spacer between each of the plurality of structured fixed beds. 
     
     
         90 . The method of  claim 88  or  89 , further including the step of providing an inner tube along an inner side of each structured fixed bed and an outer tube along an outer side of each structured fixed bed. 
     
     
         91 . The method of  claim 88 , further including the step of providing a casing radially outward of the outer tube, the casing creating a space for insulating, heating, or cooling the bioreactor.