Cell culture bioreactor with zone control

Abstract

A cell culture bioreactor has membranes divided into a plurality of zones. The membranes may include perfusion membranes carrying a liquid media and/or gas transfer membranes. The bioreactor has one or more sensors configured to collect data from one or more locations within the bioreactor. The supply of one or more of the gaseous and/or liquid media to a selected zone or zones may be controlled. In some examples, the supply includes a background supply and a selectable incremental supply. The bioreactor may be used to grow cells in suspension. Liquid media circulates within an extra-capillary space of the bioreactor. In some examples, a portion of cells is permitted for a period of time to be restrained within one or more zones of the membranes. Elements of a reactor may be made in a mold. A reactor may be operated in a fed-batch process.

We claim: 
     
         1 . A cell culture bioreactor comprising a plurality of zones wherein each of the zones has one or more membranes and wherein a flow of a fluid to each of the zones is separately controllable. 
     
     
         2 . The bioreactor of  claim 1  comprising a plurality of sensors associated with the plurality of zones. 
     
     
         3 . The bioreactor of  claim 1  comprising one or more fluid control modules in communication with the plurality of zones. 
     
     
         4 . The bioreactor of  claim 1  comprising a plurality of sensors configured to collect data through transparent windows of the bioreactor. 
     
     
         5 . The bioreactor of  claim 4  comprising a moving data collector. 
     
     
         6 . The bioreactor of  claim 1  having an aperture to hold an optical sensor body in a hole through a wall of the bioreactor. 
     
     
         7 . The bioreactor of  claim 1  having a mixer or a plurality of elements in a stack, each of the plurality of elements having associated membranes. 
     
     
         8 . The bioreactor of  claim 7  having ports to supply one or more gaseous and/or a liquid media separately to the membranes of an element. 
     
     
         9 . The bioreactor of  claim 1  having multiple mixers spaced along the height of the bioreactor. 
     
     
         10 . The bioreactor of  claim 1  having a magnetic base plate coupled to a motor for rotating the bioreactor. 
     
     
         11 . The bioreactor of  claim 1  having a based plate with a mixer, the mixer comprising a magnetic material. 
     
     
         12 . The bioreactor of  claim 1  wherein the membrane diameter is 0.5 mm or more, membranes are arranged in layers with spaces between adjacent layers, membranes are spaced apart by at least 0.2 mm in layers, membrane packing density in a zone or compound zone is 25% or less, the membranes are arranged in spaced apart zones, or the membranes are arranged in a pattern of zones, compound zones and open spaces. 
     
     
         13 . The bioreactor of  claim 1  having one or more elements, an element including membranes potted in a mold wherein portions of the mold remain with the element and define upper and lower surfaces of the element. 
     
     
         14 . The bioreactor of  claim 13  wherein upper or lower surface of a portion of the mold associated with an element are joined to a portion of a mold associated with another element, a base, a top plate, a harvest layer or a mixing layer. 
     
     
         15 . The bioreactor of  claim 13  wherein the mold is adapted to locate a membrane assembly inserted into the mold. 
     
     
         16 . The bioreactor of  claim 13  wherein surfaces of the mold generally parallel with the membranes comprise apertures. 
     
     
         17 . The bioreactor of  claim 13  comprising panels separating potting cavities of the mold. 
     
     
         18 . A method of making a bioreactor comprising,
 providing a plurality of membrane plates assembles comprising hollow fiber membranes having a controlled spacing;   inserting the plurality of membrane plate assemblies in a first part of a mold, wherein a portions of the ends of the membrane plate assemblies are located within portions of the mold;   attaching a second part of the mold to the first part of the mold to form potting cavities around the ends of the membrane plate assemblies;   adding liquid potting material to the potting cavities;   curing the potting material;   removing a portion of the mold and the potting material to expose lumens at the cut ends of the membranes; and,   placing caps over the ends of the membranes, thereby forming an element.   
     
     
         19 . The process of  claim 18  comprising attaching a portion of the mold of a first element to a portion of a mold of a second element, wherein the extra-capillary space of the first element is in communication with the extra capillary space of the second element. 
     
     
         20 . The process of  claim 18  wherein a portion of the mold generally parallel to the membranes comprises an aperture and the method comprising attaching a plate to the aperture.