Cell expansion systems including biomass capacitance sensors and methods of integrating and using the same

Abstract

A cell expansion system includes a bioreactor including a first fluid circulation path and a second fluid circulation path, a control system configured to manage one or more first parameters in the first fluid circulation path and one or more second parameters in the second fluid circulation path, and one or more sensors configured to measure at least one of cell capacitance and cell impedance within the bioreactor and to communicate with the control system in communication with at least one of the first fluid circulation path and the second fluid circulation path.

Description

CELL EXPANSION SYSTEMS INCLUDING BIOMASS CAPACITANCE SENSORS AND METHODS OF INTEGRATING AND USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 448,871 filed on February 28, 2023. The entire disclosure of the above application is incorporated hereby by reference.FIELD

[0002] The present disclosure relates to biomass capacitance sensors for cell expansion systems and to methods of preparing and using the same, including methods for integrating the biomass capacitance sensor into the cell expansion systems.BACKGROUND

[0003] This section provides background information related to the present disclosure which is not necessarily prior art.

[0004] Cell expansion systems, also commonly referred to as hollow-fiber bioreactors, are cell culturing systems used to expand and differentiate cells, including both adherent and nonadherent cell types. The cell culturing systems may include one or more removable bioreactor cartridges. The bioreactor cartridges may include hollow-fiber membranes including a plurality of semi-permeable hollow fibers (also referred to as hollow columns and / or hollow matrixes). Spaces or voids within the hollow fibers define an intracapillary space, while a space outside of the hollow fibers defines an extracapillary space. It would be desirable to monitor materials (e.g., cells) held within the intracapillary space and / or extracapillary space and to modify one or more operating or material parameters as desired in real time in response to the measured values.SUMMARY

[0005] This section provides a general summary of the disclosure and is not a comprehensive disclosure of its full scope or all of its features.

[0006] In at least one example embodiment, the present disclosure provides a cell expansion system. The cell expansion system may include a bioreactor including a first fluid circulation path and a second fluid circulation path, a control system configured to manage one or more first parameters in the first fluid circulation path and one or more second parameters in the second fluid circulation path, and one or more sensors configured to measure at least one of cellcapacitance and cell impedance and to communicate with the control system that is in communication with at least one of the first fluid circulation path and the second fluid circulation path.

[0007] In at least one example embodiment, the bioreactor may include a housing that holds the first and second fluid circulation paths and having a first endcap and a second endcap opposing the first endcap. The one or more sensors may be disposed on or near at least one of the first endcap and the second endcap.

[0008] In at least one example embodiment, the one or more sensors may be disposed on or near an exterior-facing surface of the at least of the first endcap and the second endcap.

[0009] In at least one example embodiment, the one or more sensors may be disposed on an interior-facing surface of the at least one of the first endcap and the second endcap.

[0010] In at least one example embodiment, the one or more sensors may include a biomass sensor.

[0011] In at least one example embodiment, the one or more sensors may include a continuous strip that extends along a major length of the at least one of the first endcap and the second endcap.

[0012] In at least one example embodiment, the continuous strip extends along at least 25 % of a total length of the major length of the housing.

[0013] In at least one example embodiment, the one or more sensors includes a first sensor disposed on or near the at least one of the first endcap and the second endcap and a second sensor disposed on or near another of the at least one of the first endcap and the second endcap.

[0014] In at least one example embodiment, the one or more sensors may include a first sensor and a second sensor. The first sensor may be disposed on or near the at least one of the first endcap and the second endcap. The bioreactor may be defined by a housing having an exteriorfacing surface and an interior-facing surface, and the second sensor may be disposed on or near at least one of the exterior-facing surface and an interior-facing surface.

[0015] In at least one example embodiment, the second sensor may include a continuous strip that extends along a major length of the housing.

[0016] In at least one example embodiment, the second sensor may include a biomass sensor.

[0017] In at least one example embodiment, the bioreactor may be defined by a housing having an exterior-facing surface and an interior-facing surface. The one or more sensors may be disposed on or near at least one of the exterior-facing surface and an interior-facing surface.

[0018] In at least one example embodiment, the one or more sensors may include a continuous strip that extends along a major length of the housing.

[0019] In at least one example embodiment, the one or more sensors may include a biomass sensor.

[0020] In at least one example embodiment, the one or more sensors may be configured to convey the at least one of cell capacitance and cell impedance to the control system. The control system may be configured to correlate the at least one of cell capacitance and cell impedance and at least one of cell density, cell confluency, cell viability, and cell diameter in the respective first or second fluid circulation paths.

[0021] In at least one example embodiment, when the at least one of cell density, cell confluency, cell viability, and cell diameter is below a predetermined threshold, the control system may be configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

[0022] In at least one example embodiment, when the at least one of cell density, cell confluency, cell viability, and cell diameter is above a predetermined threshold, the control system may be configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

[0023] In at least one example embodiment, the one or more sensors may be configured to correlate the at least one of cell capacitance and cell impedance and at least one of cell density, cell confluency, cell viability, and cell diameter in the respective first or second fluid circulation paths and to convey the cell density to the control system.

[0024] In at least one example embodiment, when the at least one of cell density, cell confluency, cell viability, and cell diameter is below a predetermined threshold, the control system may be configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

[0025] In at least one example embodiment, when the at least one of cell density, cell confluency, cell viability, and cell diameter is above a predetermined threshold, the control system may be configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

[0026] Further areas of applicability will become apparent from the description provided herein. The description and specific examples in this summary are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.DRAWINGS

[0027] The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations and are not intended to limit the scope of the present disclosure.

[0028] FIG. 1 is an illustration of an example cell expansion system including a bioreactor in accordance with at least one example embodiment of the present disclosure;

[0029] FIG. 2 is an illustration of an example bioreactor that shows circulation paths through the bioreactor, and which may be incorporated into cell expansion systems like the cell expansion system illustrated in FIG. 1, in accordance with at least one example embodiment of the present disclosure;

[0030] FIG. 3 is an illustration of an example rocking device configured to move a bioreactor, like the bioreactor of FIG. 2, in accordance with at least one example embodiment of the present disclosure;

[0031] FIG. 4 is a schematic illustrating example flow paths of an example cell expansion system, like the cell expansion system illustrated in FIG. 1, in accordance with at least one example embodiment of the present disclosure;

[0032] FIG. 5A is an illustration of an example bioreactor having a first endcap and an opposing second endcap in accordance with at least one example embodiment of the present disclosure;

[0033] FIG. 5B is an illustration of a surface of the first endcap of the bioreactor of FIG. 5A, where the surface of the first endcap includes a plurality of sensors in accordance with at least one example embodiment of the present disclosure;

[0034] FIG. 5C is an illustration of a surface of the second endcap of the bioreactor of FIG. 5A, where the surface of the second endcap includes a plurality of sensors in accordance with at least one example embodiment of the present disclosure; and

[0035] FIG. 5D is an illustration of a surface of a housing defining the bioreactor of FIG. 5A, where the surface of the housing includes a plurality of sensors in accordance with at least one example embodiment of the present disclosure.

[0036] Corresponding reference numerals indicate corresponding parts throughout the several views of the drawings.DETAILED DESCRIPTION

[0037] Example embodiments will now be described more fully with reference to the accompanying drawings.

[0038] Example embodiments are provided so that this disclosure will be thorough and will fully convey the scope to those who are skilled in the art. Numerous specific details are set forth such as examples of specific components, devices, and methods, to provide a thorough understanding of embodiments of the present disclosure. It will be apparent to those skilled in the art that specific details need not be employed, that example embodiments may be embodied in many different forms and that neither should be construed to limit the scope of the disclosure. In some example embodiments, well-known processes, well-known device structures, and well- known technologies are not described in detail.

[0039] The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting. As used herein, the singular forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly indicates otherwise. The terms "comprises," "comprising," “including,” and “having” are inclusive and therefore specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. The method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated, unless specifically identified as an order of performance. It is also to be understood that additional or alternative steps may be employed.

[0040] When an element or layer is referred to as being "on," “engaged to,” "connected to," or "coupled to" another element or layer, it may be directly on, engaged, connected, or coupled to the other element or layer, or intervening elements or layers may be present. In contrast, when an element is referred to as being "directly on," “directly engaged to,” "directly connected to," or "directly coupled to" another element or layer, there may be no intervening elements or layers present. Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g., “between” versus “directly between,” “adjacent” versus “directly adjacent,” etc.). As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0041] Although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms may be only used to distinguish one element, component, region, layer or section from another region, layer, or section. Terms such as “first,” “second,” and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context. Thus, a first element, component, region,layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of the example embodiments.

[0042] Spatially relative terms, such as “inner,” “outer,” "beneath," "below," "lower," "above," "upper," and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. Spatially relative terms may be intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be oriented "above" the other elements or features. Thus, the example term "below" can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

[0043] Various components are referred to herein as “operably associated.” As used herein, “operably associated” refers to components that are linked together in operable fashion and encompasses embodiments in which components are linked directly, as well as embodiments in which additional components are placed between the linked components. “Operably associated” components can be “fluidly associated.” “Fluidly associated” refers to components that are linked together such that fluid can be transported between them. “Fluidly associated” encompasses embodiments in which additional components are disposed between the two fluidly associated components, as well as components that are directly connected. Fluidly associated components can include components that do not contact fluid but contact other components to manipulate the system (e.g., a peristaltic pump that pumps fluids through flexible tubing by compressing the exterior of the tube).

[0044] In the figures, the direction of an arrow, as indicated by the arrowhead, generally demonstrates the flow of information (such as data or instructions) that is of interest to the illustration. For example, when element A and element B exchange a variety of information, but information transmitted from element A to element B is relevant to the illustration, the arrow may point from element A to element B. This unidirectional arrow does not imply that no other information is transmitted from element B to element A. Further, for information sent from element A to element B, element B may send requests for, or receipt acknowledgements of, the information to element A.

[0045] In this application, including the definitions below, the term “module” or the term “controller” may be replaced with the term “circuit.” The term “module” may refer to, be part of, or include: an Application Specific Integrated Circuit (ASIC); a digital, analog, or mixedanalog / digital discrete circuit; a digital, analog, or mixed analog / digital integrated circuit; a combinational logic circuit; a field programmable gate array (FPGA); a processor circuit (shared, dedicated, or group) that executes code; a memory circuit (shared, dedicated, or group) that stores code executed by the processor circuit; other suitable hardware components that provide the described functionality; or a combination of some or all of the above, such as in a system-on-chip.

[0046] The module may include one or more interface circuits. In some examples, the interface circuits may include wired or wireless interfaces that are connected to a local area network (LAN), the Internet, a wide area network (WAN), or combinations thereof. The functionality of any given module of the present disclosure may be distributed among multiple modules that are connected via interface circuits. For example, multiple modules may allow load balancing. In a further example, a server (also known as remote, or cloud) module may accomplish some functionality on behalf of a client module.

[0047] The term code, as used above, may include software, firmware, and / or microcode, and may refer to programs, routines, functions, classes, data structures, and / or objects. The term shared processor circuit encompasses a single processor circuit that executes some or all code from multiple modules. The term group processor circuit encompasses a processor circuit that, in combination with additional processor circuits, executes some or all code from one or more modules. References to multiple processor circuits encompass multiple processor circuits on discrete dies, multiple processor circuits on a single die, multiple cores of a single processor circuit, multiple threads of a single processor circuit, or a combination of the above. The term shared memory circuit encompasses a single memory circuit that stores some or all code from multiple modules. The term group memory circuit encompasses a memory circuit that, in combination with additional memories, stores some or all code from one or more modules.

[0048] The term memory circuit is a subset of the term computer-readable medium. The term computer-readable medium, as used herein, does not encompass transitory electrical or electromagnetic signals propagating through a medium (such as on a carrier wave); the term computer-readable medium may therefore be considered tangible and non-transitory. Nonlimiting examples of a non-transitory, tangible computer-readable medium are nonvolatile memory circuits (such as a flash memory circuit, an erasable programmable read-only memory circuit, or a mask read-only memory circuit), volatile memory circuits (such as a static random access memory circuit or a dynamic random access memory circuit), magnetic storage media (such as an analog or digital magnetic tape or a hard disk drive), and optical storage media (such as a CD, a DVD, or a Blu-ray Disc).

[0049] The apparatuses and methods described in this application may be partially or fully implemented by a special purpose computer created by configuring a general-purpose computer to execute one or more particular functions embodied in computer programs. The functional blocks, flowchart components, and other elements described above serve as software specifications, which can be translated into the computer programs by the routine work of a skilled technician or programmer.

[0050] The computer programs include processor-executable instructions that are stored on at least one non-transitory, tangible computer-readable medium. The computer programs may also include or rely on stored data. The computer programs may encompass a basic input / output system (BIOS) that interacts with hardware of the special purpose computer, device drivers that interact with particular devices of the special purpose computer, one or more operating systems, user applications, background services, background applications, etc.

[0051] The computer programs may include: (i) descriptive text to be parsed, such as HTML (hypertext markup language), XML (extensible markup language), or JSON (JavaScript Object Notation) (ii) assembly code, (iii) object code generated from source code by a compiler, (iv) source code for execution by an interpreter, (v) source code for compilation and execution by a just-in-time compiler, etc. As examples only, source code may be written using syntax from languages including C, C++, C#, Objective-C, Swift, Haskell, Go, SQL, R, Lisp, Java®, Fortran, Perl, Pascal, Curl, OCaml, Javascript®, HTML5 (Hypertext Markup Language 5th revision), Ada, ASP (Active Server Pages), PHP (PHP: Hypertext Preprocessor), Scala, Eiffel, Smalltalk, Erlang, Ruby, Flash®, Visual Basic®, Lua, MATLAB, SIMULINK, and Python®.

[0052] None of the elements recited in the claims are intended to be a means-plus-function element within the meaning of 35 U.S.C. § 112(f) unless an element is expressly recited using the phrase “means for,” or in the case of a method claim using the phrases “operation for” or “step for.”

[0053] Example embodiments will now be described more fully with reference to the accompanying drawings.

[0054] The present disclosure relates to biomass capacitance sensors for cell expansion systems and methods of preparing and using the same, including methods for integrating the biomass capacitance sensor into the cell expansion systems, including into cell expansion systems like those described in U.S. Pat. No. 10,577,585, titled CELL EXPANSION, issued on March 3, 2020, the entire disclosure of which is hereby incorporated by reference. Cell expansion systems, also commonly referred to as hollow-fiber bioreactors, are cell culturing systems used to expand and differentiate cells, including both adherent and non-adherent cell types. For example, asillustrated in FIG. 1, an example cell expansion system 10 includes a first fluid circulation path 12 and a second fluid circulation path 14. The first fluid circulation path 12 includes, for example, a first fluid flow path 16 having opposing ends 18 and 20. The first fluid flow path 16 may be in fluid communication with a hollow fiber cell growth chamber 24 (which can also be referred to as a “bioreactor”). For example, the first opposing end 18 of the first fluid flow path 16 may be in fluid communication with a first inlet 22 of the cell growth chamber 24, and the second opposing end 20 may be in fluid communication with first outlet 28 of the cell growth chamber 24. Fluid in the first circulation path 12 may flow through an interior of a plurality of hollow fibers 116 of a hollow fiber membrane (“HFM”) 117 (see, e.g., FIG. 2) disposed in the cell growth chamber 24. In at least one example embodiment, a first fluid flow control device 30 may be operably coupled to the first fluid flow path 16 and may control the flow of fluid in first fluid circulation path 12.

[0055] The second fluid circulation path 14 includes, for example, a second fluid flow path 34 and a second fluid flow control device 32. Like the first fluid flow path 16, the second fluid flow path 34 may have opposing ends 36 and 38. The opposing ends 36 and 38 of second fluid flow path 34 may in fluid communication with an inlet port 40 and an outlet port 42 of the cell growth chamber 24. For example, a first opposing end 36 of the second fluid flow path 34 may be in fluid communication with the inlet port 40 of the cell growth chamber 24, and the second opposing end 38 of the second fluid flow path 38 may be in fluid communication with the outlet port 43. Fluid in the second circulation path 14 may be in contact with an outside of the hollow fiber membrane 117 (see, e.g., FIG. 2) disposed in the cell growth chamber 24. In at least one example embodiment, a second fluid flow control device 32 may be operably coupled to the second fluid flow path 34 and may control the flow of fluid in the second fluid circulation path 14.

[0056] The first and second fluid circulation paths 12, 13 may be maintained in the cell growth chamber 24 by way of the hollow fiber membrane 117, where fluid in first fluid circulation path 12 flows through an intracapillary (“IC”) space (which can also be referred to as an intraporous space) of the hollow fiber membrane 117 and fluid in the second circulation path 14 flows through the extracapillary (“EC”) space (which can also be referred to as an interporous space) of the cell growth chamber 24. The first circulation path 12 may be referred to as the “intracapillary loop” or “IC loop”. The second fluid circulation path 14 may be referred to as the “extracapillary loop” or “EC loop”. Fluid in first fluid circulation path 12 may flow in either a cocurrent or counter-current direction with respect to a fluid flow in second fluid circulation path 14.

[0057] In at least one example embodiment, a fluid inlet path 44 may be fluidly associated with the first fluid circulation path 12, and a fluid outlet path 46 may be fluidly associated with the second fluid circulation path 14. The fluid inlet path 44 permits fluid into first fluid circulation path 12, while the fluid outlet path 46 permits fluid to exit the cell expansion system 10. In at least one example embodiment, as illustrated, a third fluid flow control device 48 may be operably associated with the fluid inlet path 44. Although not illustrated, it should be recognized that, in other example embodiments, a fourth fluid flow control device may alternatively or additionally be associated operably associated with the first outlet path 46. In at least one example embodiment, the fluid flow control devices (including the first fluid flow control device 30, the second fluid flow control device 32, the third fluid flow control device 28, and / or the fourth fluid flow control device) may include a pump, valve, clamp, or any combination thereof. For example, multiple pumps, valves, and clamps can be arranged in any combination. In at least one example embodiment, the fluid flow control device may be, or include, a peristaltic pump. Fluid circulation paths (including the first fluid circulation path 12 and / or the second fluid circulation path 14), inlet ports (including the fluid inlet port 44), and / or the outlet port (including the fluid outlet port 46), may include any known tubing material, and any kind of fluid — including, for example, buffers, protein containing fluid, and cell-containing fluid — can flow through the various circulation paths (including the first fluid circulation path 12 and / or the second fluid circulation path 14), inlet paths (including the fluid inlet port 44), and outlet paths (including the fluid outlet port 46). It should be recognized that the terms “fluid,” “media,” and “fluid media” are used interchangeably.

[0058] An example hollow fiber cell growth chamber 100 (which can also be referred to as a “bioreactor”) is illustrated in FIG. 2. The hollow fiber cell growth chamber 100 may be used as the hollow fiber cell growth chamber 24 of the cell expansion system 10 illustrated in FIG. 1. The hollow fiber cell growth chamber 100 has a longitudinal axis (represented by the line LA- LA) and includes a cell growth chamber housing 104. The cell growth chamber housing 104 may have four openings or ports, including, for example, an intracapillary inlet port 108, an intracapillary outlet port 120, an extracapillary inlet port 128, and an extracapillary outlet port 132. A first fluid (which can also be referred to as an intracapillary fluid or media) in a first circulation path (like the first fluid circulation path 12) can enter the cell growth chamber 100 through the intracapillary inlet port 108 at a first longitudinal end 112 of the cell growth chamber 100 and into and through the intracapillary side of a plurality of hollow fibers 116 and out of cell growth chamber 100 through intracapillary outlet port 120, which is located at a second longitudinal end 124 of the cell growth chamber 100. The fluid path between the intracapillary inlet port 108 and the intracapillary outlet port 120 defines an intracapillary portion 126 of the cellgrowth chamber 100. A second fluid (which can also be referred to as an extracapillary media or fluid) in a second circulation path (like the second fluid circulation path 14) can enter the cell growth chamber 100 through the extracapillary inlet port 128, contacts with the extracapillary side or outside of the hollow fiber membrane 117 and exits the cell growth chamber 100 via the extracapillary outlet port 132. The fluid path between the extracapillary inlet port 128 and the extracapillary outlet port 132 defines an extracapillary portion 136 of the cell growth chamber 100.

[0059] As the second fluid comes into contact with the outside of the hollow fibers 116 small molecules (e.g., ions, water, oxygen, lactate, etc.) may diffuse and / or profuse through the hollow fibers 116 from the interior or intracapillary space of the hollow fibers 116 to the exterior or extracapillary space, or alternatively, or additionally, from the extracapillary space to the intracapillary space. For example, large molecular weight molecules (e.g., growth factors) are often too large to pass through the hollow fibers 116 and remain in the intracapillary space (or alternatively, or additionally, in the extracapillary space) of the hollow fibers 116. The mediums defining the first and second fluids may be replaced as needed and may alternatively, or additionally, be circulated through an oxygenator and / or gas transfer module to exchange gasses, as needed. As discussed below, cells for expansion may be contained within the first fluid circulation path 12 and / or the second fluid circulation path 14 and may enter the hollow fiber cell growth chamber 100 on one or both of the intracapillary side or the extracapillary side.

[0060] In at least one example embodiment, cells may be seeded (for example, for expansion, differentiation, and / or harvesting of cord blood derived CD34+ hematopoietic stem / progenitor cells, monocytes, macrophages, hepatocytes, and / or endothelial cells) in the intracapillary space of the hollow fibers 116, while a cell culture medium may be pumped through the extracapillary space of the hollow fibers 116 to deliver nutrients to the cells via hollow fiber membrane perfusion during expansion. However, in at least one other example embodiment, cells for expansion may be seeded in the extracapillary space, while the cell culture medium may be pumped through the intracapillary space to deliver nutrients to the cells via hollow fiber membrane perfusion during expansion. In at least one other example embodiment, cells for expansion may be seeded in the intracapillary space, while the cell culture medium may be pumped through both the extracapillary space and the intracapillary space. Movement of the cell culture medium through the intracapillary space and / or the extracapillary space can help to remove excess cells, for example, those not adhered to surfaces of the hollow-fiber membrane. In at least one example embodiment, the material used to form the hollow fiber membrane 117 may be any biocompatible polymeric material that is capable of being made into the hollow fibers 121. For example, syntheticpolysulfone-based materials (e.g., polyethersulfones (PES)) are often used to form the hollow fibers.

[0061] In at least one example embodiment, the cell expansion system 10 may also include a device that is configured to move or “rock” the cell growth chamber 100 relative to other components of the cell expansion system 10. The device may be a rotational and / or lateral rocking device. For example, as illustrated in FIG. 3, the cell growth chamber (also referred to as a bioreactor) 100 may be rotationally connected to one or more rotational rocking components 138 and to a lateral rocking component 140. A first rotational rocking component 138 may be rotationally associated with the bioreactor 100. For example, the first rotational rocking component 138 may be configured to rotate the bioreactor 100 around a first or central rotational axis 142. In at least one example embodiment, the bioreactor 100 may be rotated continuously in a single direction around the central axis 142 in a clockwise or counterclockwise direction. In at least one example embodiment, the bioreactor 100 may be rotated in alternating fashion, including, for example, in a first clockwise direction and then in a second counterclockwise direction around the central axis 142.

[0062] Although not illustrated, it should be recognized that, in other example embodiments, a second rotational rocking component may be configured to move the bioreactor 100 about a second rotational axis 144 that passes through a center point of the bioreactor 100 normal to the central axis 142. In at least one example embodiment, the bioreactor 100 may be rotated continuously in a single direction around the second axis 144 in a clockwise or counterclockwise direction. In at least one example embodiment, the bioreactor 100 may be rotated in alternating fashion, including, for example, in a first clockwise direction and then in a second counterclockwise direction around the second axis 144. In at least one example embodiment, the bioreactor 100 may also be rotated around the second axis 144 and positioned in a horizontal or vertical orientation relative to gravity. The lateral rocking component 140 may be laterally associated with the bioreactor 100. For example, a plane of the lateral rocking component 140 may move laterally in the x-direction and y-direction.

[0063] The rotational and / or lateral movement of the bioreactor 100 may reduce the settling of cells and the likelihood of cells becoming trapped within a portion of the bioreactor 100. In at least one example embodiment, the rate of cells settling in the cell growth chamber 100 may be proportional to the density difference between the cells and the suspension media, according to Stoke’s Faw. In at least one example embodiment, a 180-degree rotation (fast) with a pause (having, for example, a total combined time of 30 seconds) repeated as described above may help to keep non-adherent cells (for example, red blood cells) suspended. A minimumrotation of about 180-degrees may be preferred, however various degrees of rotation, including up to or greater than 360-degrees, may be used. Different rocking components may be used separately or may be combined in any combination. For example, a rocking component that rotates bioreactor 100 around central axis 142 may be combined with the rocking component that rotates bioreactor 100 around axis 144. Likewise, clockwise and counterclockwise rotation around different axes may be performed independently in any combination.

[0064] FIG. 4 is a schematic of an example cell expansion system 500, which may be like the cell expansion system 100 illustrated in FIG. 1, that illustrates example flow paths. In at least one example embodiment, the cells may be positioned in the intracapillary space, while a cell culture medium may be pumped through the extracapillary space to deliver nutrients to the cells via hollow fiber membrane perfusion during expansion. It should be recognized, however, in at least one other example embodiment, cells can be positioned in the extracapillary space, while the cell culture medium may be pumped through the intracapillary space to deliver nutrients to the cells via hollow fiber membrane perfusion during expansion. In at least one other example embodiment, cells may be positioned in the intracapillary space, while the cell culture medium may be pumped through both the extracapillary space and the intracapillary space.

[0065] As illustrated, the cell expansion system 500 may include a first fluid circulation path 502 (also referred to as the “intracapillary loop” or “IC loop”) and a second fluid circulation path 504 (also referred to as the “extracapillary loop” or “EC loop”). The first fluid flow path 506 may be fluidly associated with a cell growth chamber (also referred to as a “bioreactor”) 501 to form first fluid circulation path 502. The cell growth chamber 501 may be used as the hollow fiber cell growth chamber 24 illustrated in FIG. 1 and / or the hollow fiber cell growth chamber 100 illustrated in FIG. 1. A first fluid may flow into (e.g., profuse) cell growth chamber 501 through an intracapillary inlet port 501A. The first fluid may exit the cell growth chamber via an intracapillary outlet port 501B. In at least one example embodiment, the first fluid circulation path 502 may include a pressure gauge 510 configured to measure a pressure of the first fluid leaving the cell growth chamber 501. In at least one example embodiment, the first fluid circulation path 502 may include an intracapillary circulation pump 512 configured to control a first fluid flow rate. For example, the intracapillary circulation pump 512 may be configured to pump the first fluid in a first direction or a second direction that is opposite to the first direction. In the later instance, the intracapillary outlet port 501B may be used as an inlet, and the intracapillary inlet port 501A as an outlet. In at least one example embodiment, the first fluid circulation path 502 may include a sample port 516 and / or sample coil 518 configured for first fluid sample extraction. In at least one example embodiment, the first fluid circulation path 502 may include apressure / temperature gauge 520 configured to detect the pressure and / or temperature of the first fluid during operation. In at least one example embodiment, the first fluid may enter the intracapillary loop 502 via valve 514. In at least one example embodiment, a portion of the cells may be flushed from the intracapillary loop 502 into a harvest bag 599, for example, via valve 598. It should be recognized that, in at least one other example embodiment, the first fluid circulation path 502 may include additional or fewer valves, pressure gauges, pressure sensors, temperature sensors, ports, and / or other devices disposed to isolate and / or measure characteristics of the first fluid along portions of the intracapillary loop 502.

[0066] A second fluid may flow into (e.g., profuse) cell growth chamber 501 through an extracapillary inlet port 501C. The second fluid may leave the cell growth chamber 501 via an extracapillary outlet port 501D. In at least one example embodiment, the second fluid in the extracapillary loop 504 may contact an exterior facing surface of hollow fibers disposed in the cell growth chamber 501 thereby allowing diffusion of small molecules into and out of the hollow fibers. In at least one example embodiment, the extracapillary loop 504 may include a pressure / temperature gauge 524 configured to measure a pressure and / or temperature of the second fluid before the second fluid enters the cell growth chamber 501. In at least one example embodiment, the extracapillary loop 504 may include a pressure gauge 526 that is configured to measure a pressure of the second fluid, for example, as it leaves the cell growth chamber 501. In at least one example embodiment, the extracapillary loop 504 may include a sample port 530 configured for second fluid sample extraction.

[0067] In at least one example embodiment, the extracapillary loop 504 may include an extracapillary circulation pump 528 and an oxygenator or gas transfer module 532. For example, after leaving the cell growth chamber 501, the second fluid may pass through the extracapillary circulation pump 528 and to and through the oxygenator or gas transfer module 532. In at least one example embodiment, the extracapillary circulation pump 528 may be configured to control a second fluid flow rate. For example, like the intracapillary circulation pump 512, the extracapillary circulation pump 528 may be configured to pump the second fluid in a first direction or a second direction that is opposite to the first direction. In the later instance, the extracapillary outlet port 501D may be used as inlet, and the extracapillary inlet port 501C as an outlet.

[0068] In at least one example embodiment, the second fluid flow path 522 may be fluidly associated with the oxygenator or gas transfer module 532 via an oxygenator inlet port 534 and an oxygenator outlet port 536. For example, the second fluid may flow into the oxygenator or gas transfer module 532 via the oxygenator inlet port 534 and may leave or exit the oxygenator or gas transfer module 532 via the oxygenator outlet port 536. In at least one example embodiment, theoxygenator or gas transfer module 532 may be configured to add oxygen to and / or remove bubbles from the second fluid. For example, air and / or gas may flow into the oxygenator or gas transfer module 532 via a first filter 538 and may leave or exit (z.e., flow out of) the oxygenator or gas transfer device 532 through a second filter 540. The first and second filters 538, 540 may be configured to reduce or prevent contaminants from entering the oxygenator or gas transfer module 532. The second fluid in the second fluid circulation path 504 may be in equilibrium with gas entering the oxygenator or gas transfer module 532. In at least one example embodiment, air and / or gas may be purged from the cell expansion system 500, for example, during a priming sequence, air and / or gas may be vented to the atmosphere via the oxygenator or gas transfer module 532. It should be recognized that, in at least one other example embodiment, a second fluid circulation path 504 may include additional or fewer valves, pressure gauges, pressure sensors, temperature sensors, ports, and / or other devices disposed to isolate and / or measure characteristics of the second fluid along portions of the extracapillary loop 504.

[0069] In at least one example embodiment, an air removal chamber (ARC) 556 may be fluidly associated with the first circulation path 502. The air removal chamber 556 may include one or more ultrasonic sensors. For example, the air removal chamber 556 may include upper sensor and / or lower sensor which are configured to detect air and / or a lack of fluid and / or gasfluid interface at certain measuring positions within the air removal chamber 556. The upper sensor may be disposed near a first end (e.g., top) of the air removal chamber 556. The lower sensor may be disposed near a second end (e.g. , bottom) of the air removal chamber 556. Although ultrasonic sensors are discussed, it should be appreciated that, in other example embodiments, the air removal chamber 556 may include, additionally, or alternatively, one or more other sensors, including, for example, optical sensors. Air and / or gas purged from the cell expansion system 500 during portions of a priming sequence and / or other protocols may vent to the atmosphere out air valve 560 via line 558 that may be fluidly associated with air removal chamber 556.

[0070] In at least one example embodiment, the first fluid may include cells (for example, from a first fluid container (which can also be referred to as a first media bag or a first bag) 562 and also fluid media (e.g. , intracapillary media or fluid) from a second fluid container (which can also be referred to as a second media bag or a second bag) 546. Materials (i.e., cells and / or intracapillary media) form the first and second fluid containers 562, 546 may enter the first fluid circulation path 502 via a first fluid flow path 506. The first fluid container 562 may be fluidly associated with the first fluid flow path 506 and the first fluid circulation path 502 via valve 564. In at least one example embodiment, the second fluid container 546 and a third fluid container (which can also be referred to as a third media bag or third bag) 544 may be fluidly associatedwith the first fluid inlet path 542, for example, via valves 548 and 550, respectively, or with a second fluid inlet path 574, for example, via valves 570 and 576, respectively. In at least one example embodiment, the materials from the second fluid container 546 and / or the third fluid container 544 may be in fluid communication with a first sterile sealable input priming path 508 and / or a second sterile sealable input priming path 509.

[0071] In at least one example embodiment, a fourth fluid container (which can also be referred to as a fourth media bag or a fourth bag) 568 may include an extracapillary media, and a fifth fluid container (which can also be referred to a fifth media bag or a fifth bag) 566 may include a wash solution. Materials (z.e., extracapillary media and / or wash solution) from the fourth and fifth fluid containers 568, 566 may enter the first fluid circulation path 503 and / or the second fluid circulation path 504. For example, in at least one example embodiment, the fifth fluid container 566 may be fluidly associated with valve 570, where valve 570 is fluidly associated with first fluid circulation path 502, for example, via a distribution valve 572 and a first fluid inlet path 542. In at least one example embodiment, the fifth fluid container 566 may be fluidly associated with the second fluid circulation path 504 via the second fluid inlet path 574 and an extracapillary inlet path 584, for example, by opening valve 570 and closing distribution valve 572. The fourth fluid container 568 may be fluidly associated with valve 576, where valve 576 is fluidly associated with first fluid circulation path 502, for example, via the first fluid inlet path 542 and the distribution valve 572. In at least one example embodiment, the fourth fluid container 568 may be fluidly associated with the second fluid inlet path 574 by opening valve 576 and closing the distribution valve 572. In at least one example embodiment, the first fluid inlet path 542 and / or the second fluid inlet path 574 may be fluidly associated with an optional heat exchanger 552.

[0072] In at least one example embodiment, fluid may be advanced to the intracapillary loop 502 from the first fluid inlet path 542 and / or the second fluid inlet path 574 via an intracapillary inlet pump 554, and fluid may be advanced to the extracapillary loop 504 via an extracapillary inlet pump 578. In at least one example embodiment, an air detector 580 may also be associated with the extracapillary inlet path 584. The air detector 580 may include, for example, an ultrasonic sensor. In at least one example embodiment, the first and second fluid circulation paths 502, 504 may be fluidly associated with a water line 558. For example, when valve 590 is in an open state or position, the intracapillary media may flow through the waste line 588 to a waste bag (also referred to as an outlet bag) 586. When valve 582 is opened, extracapillary media may flow through the waste line 588 to the waste bag 586. In at least one example embodiment, cells may be harvested, for example, via a cell harvest path 596. For example, cells from the cellgrowth chamber 501 may be harvested by pumping the intracapillary media containing the cells through the cell harvest path 596 and also valve 598 to a cell harvest bag 599.

[0073] In at least one example embodiment, as illustrated, the fluid in the first fluid circulation path 502 and second fluid circulation path 504 flows through cell growth chamber 501 in the same direction (z.e., a co-current configuration). Although not illustrated, it should be recognized that, in other example embodiments, the cell expansion system 500 may also be configured to flow in a counter-current conformation. As illustrated in FIG. 4, fluid in the first fluid circulation path 502 may enter the bioreactor 501 at the intracapillary inlet port 501A and may leave or exit the bioreactor 501 at the intracapillary outlet port 501B. In at least one example embodiment, the first fluid flow path 506, for example, via connection 517. Connection 517 may be a point or location from which the fluid may flow in opposite directions, for example, based on the direction of the intracapillary inlet pump 554. Connection 517 may include any type of fitting, coupling, fusion, pathway, and / or tubing that allows the first fluid flow path to be fluidly associated with the first fluid circulation path 502. In at least one example embodiment, connection 517 may include a T-fitting or coupling and / or a Y- fitting or coupling.

[0074] In at least one example embodiment, one or more of the gauges (e.g., pressure gauge 510, pressure / temperature gauge 520, pressure / temperature gauge 524, and / or pressure gauge 526), one or more of the valves (e.g., valve 514, valves 548, valves 550, valve 560, valve 564, valve 570, valve 572, valve 576, valve 582, valve 590, valve 596, and / or valve 598), one or more of the ports (e.g., intracapillary inlet port 501 A, intracapillary outlet port 501B, extracapillary inlet port 501C, extracapillary outlet port 501D, sample port 516, sample port 530, oxygenator inlet port 534, and / or an oxygenator outlet port 536), one or more of the pumps (e.g., intracapillary circulation pump 512, extracapillary circulation pump 528, intracapillary inlet pump 554, and / or extracapillary inlet pump 578), one or more of the filters (e.g., first filter 538 and / or second filter 540), one or more coils (e.g. , sample coil 518), one or more modules (e.g. , oxygenator or gas transfer module 532), and / or one or more other components of the cell expansion system 500 may be in electrical communication with a control system (not shown). The control system may include a plurality of nodes, which can include various hardware, firmware, and / or software configured to control and / or communicate with the mechanical, electromechanical, and electrical components of the cell expansion system 500, including for example, a controller and a memory.

[0075] The controller (which can also be referred to as a processor), can be of any type of microcontroller, microprocessor, Field Programmable Gate Array (FPGA), Application Specific Integrated Circuit (ASIC), etc. An example controller may be the NK10DN512VOK10 microcontroller, made and sold by N9P USA, Incorporated, which is a microcontroller unit witha 32-bit architecture. Other examples controllers may include, for example, at least one of Qualcomm® Snapdragon® 800 and 801, Qualcomm® Snapdragon® 610 and 615 with 4G LTE Integration and 64-bit computing, Apple® A7 processor with 64-bit architecture, Apple® M7 motion coprocessors, Samsung® Exynos® series, the Intel® Core™ family of processors, the Intel® Xeon® family of processors, the Intel® Atom™ family of processors, the Intel Itanium® family of processors, Intel® Core® i5-4670K and i7-4770K 22nm Haswell, Intel® Core® i5- 3570K 22nm Ivy Bridge, the AMD® FX™ family of processors, AMD® FX-4300, FX-6300, and FX-8350 32nm Vishera, AMD® Kaveri processors, ARM® Cortex™-M processors, ARM® Cortex-A and ARM926EJ-S™ processors, other industry-equivalent processors, and may perform computational functions using any known or future-developed standard, instruction set, libraries, and / or architecture. The memory can be any type of memory including random access memory (RAM), read only memory (ROM), electrically erasable programmable ROM (EEPROM), a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, any suitable combination of the foregoing, or other type of storage or memory device that stores and provides instructions to program and control the controller.

[0076] As noted above, cells are seeded (for example, for expansion, differentiation, and / or harvesting of cord blood derived CD34+ hematopoietic stem / progenitor cells, monocytes, macrophages, hepatocytes, and / or endothelial cells) in an intracapillary space of a cell growth chamber (also referred to as a bioreactor) that includes a hollow fiber membrane while a cell culture medium may be pumped through the extracapillary space of the cell growth chamber to deliver nutrients to the cells via hollow fiber membrane perfusion during expansion. However, in at least one other example embodiment, cells for expansion may be seeded in the extracapillary space while the cell culture medium may be pumped through the intracapillary space to deliver nutrients to the cells via hollow fiber membrane perfusion during expansion. In at least one other example embodiment, cells for expansion may be seeded in the intracapillary space while the cell culture medium may be pumped through both the extracapillary space and the intracapillary space.

[0077] In each example embodiment, it may be desirable to gather information regarding materials (e.g., cells) held within the bioreactor (including, for example, the bioreactor 24 illustrated in FIG. 1 and / or the bioreactor 100 illustrated in FIG. 2 and / or the bioreactor 501 illustrated in FIG. 4) in real time. For example, in at least one example embodiment, the collection and processing of real time information may allow for primary cell expansion monitoring and / or controlling. The primary cell expansion monitoring and / or controlling may include the collection and processing of oxygen consumption data, acidity data, and / or cell density data. The oxygen consumption data may be used to monitor and / or control, for example, cellular respiration, cellviability, control of self-renewal. The acidity data may be used to monitor and / or control, for example, buffering capacity, cell membrane integrity, and / or metabolite transport. The cell density date may be used to monitor and / or control, for example, cell signaling, seeding, expansion, differentiation, and / or harvesting.

[0078] The primary cell expansion monitoring and / or controlling may be at least partially automated via one or more pre-configured feedback control loops. In at least one example embodiment, the collection and processing of real time information may allow for cell metabolite monitoring and / or controlling. The cell metabolite data may be used to monitor and / or control nutrient levels (e.g., glucose, lactate, glutamine, and / or ammonia) within the bioreactor. The cell metabolite expansion monitoring and / or controlling may be at least partially automated via one or more pre-configured feedback control loops.

[0079] In at least one example embodiment, the collection and processing of real time information may allow for cell product monitoring and / or controlling. The cell product data may include information regarding secreted proteins and / or nucleic acids and / or extracellular exosomes, microvesicles, and / or virions, which may be used to monitor and / or control cell signaling, diagnostics, and / or therapeutics. The cell product monitoring and / or controlling may be at least partially automated via one or more pre-configured feedback control loops. In at least one example embodiment, the collection and processing of real time information may allow for primary cell expansion monitoring and / or controlling and / or cell metabolite expansion monitoring and / or controlling and / or cell product monitoring and / or controlling.

[0080] The one or more sensors may be disposed within or on a bioreactor (like the bioreactor 24 illustrated in FIG. 1 and / or the bioreactor 100 illustrated in FIG. 2 and / or the bioreactor 501 illustrated in FIG. 4) and configured to collect and / or monitor real-time occurrences therewithin. For example, in at least one example embodiment, the one or more sensors may be disposed within or on at least one of the endcaps of a bioreactor. For example, as illustrated in FIGS. 5A and 5B, a plurality of sensors 610 may be disposed within or on at least one of a first header endcap 612 and a second header endcap 614 of a bioreactor 600. The first header endcap 612 may oppose the second header endcap 614, and as illustrated in FIG. 5A, and the first and second endcaps 612, 614 may together enclose the bioreactor 600.

[0081] The bioreactor may be like the bioreactor 24 illustrated in FIG. 1 and / or the bioreactor 100 illustrated in FIG. 2 and / or the bioreactor 501 illustrated in FIG. 4. The plurality of sensors 610 may include biomass sensors (for example, as provided by Aber Instruments Ltd.). In at least one example embodiment, as illustrated in FIG. 5B (which is an enlarged view of an exterior surface 616 of the first endcap 612) and in FIG. 5C (which is an enlarged view of anexterior surface 618 of the second endcap 614) the plurality of sensors 610 may be arrange radially on each surface. Although four sensors 610 are illustrated in FIGS. 5C and 5D, it should be appreciated that, in other example embodiments, one or more sensors 610 may be disposed on the first header endcap 612 and / or the second header endcap 614. Further although the exterior surfaces 616, 618 are illustrated in FIGS. 5C and 5D, it should be appreciated that, in other example embodiments, the plurality of sensors 610 may be disposed on or near an interior surface of the first endcap 612 and / or the second endcap 614. Further still, although the sensors 610 are illustrated in FIGS. 5B and 5C as distinct sensors, it should be appreciated that, in other example embodiments, a continuous sensor or a single sensor having one or more regions may be used. In each instance, the placement of the sensors 610 on at least one of the endcaps 613, 614 (interior or exterior) may allow the sensor array (z.e., the plurality of sensors 610) to determine both length and depth of cell distribution and concentration over the defined volume and surface area of the bioreactor 600.

[0082] In at least one other example embodiment, the one or more sensors 610 may be disposed on an exterior surface 652 of a housing 650 defining the bioreactor 600, where, by way of example, the housing 650 is shown in an unformed or flat state. As illustrated, the sensors 610 may be disposed longitudinally around the circumference of the bioreactor 600, such a placement may allow the sensor array (z.e., the plurality of sensors 610) to determine both length and depth of cell distribution and concentration over the defined volume and surface area of the bioreactor 600. Although nine sensors 610 are illustrated in FIG. 5D, it should be appreciated that, in other example embodiments, one or more sensors 610 may be disposed on the interior surface 652 of the housing 650. Further, although distinct sensors 610 are illustrated in FIG. 5D, it should be appreciated that, in other example embodiments, one or more continuous sensor (e.g., sensing strips) extending a substantial portion (e.g., greater than about 25 %) of a major length of the bioreactor 600 may be similarly used. Further still, although the exterior surface 652 is illustrated in FIG. 5D, it should be appreciated that, in other example embodiments, the one or more of sensors 610 may be disposed on or near an interior surface of the housing 650 defining the bioreactor 600 (e.g., the extracapillary space of the bioreactor 600).

[0083] Although not illustrated, it should be appreciated that, in other example embodiments, the one or more sensors may include a first plurality of sensors (for example, biomass sensors like those provided by Aber Instruments Ltd.) disposed within or on (exteriorly or interiorly) at least one of the endcaps of a bioreactor and a second plurality of sensors (for example, biomass sensors like those provided by Aber Instruments Ltd.) disposed an exteriorfacing surface of a housing of the bioreactor.

[0084] Although not illustrated, it should be appreciated that, in other example embodiments, the one or more sensors may include a sensor (for example, a biomass sensor like those provided by Aber Instruments Ltd.) disposed in an extracapillary space of the bioreactor.

[0085] Although not illustrated, it should be appreciated that, in other example embodiments, the one or more sensors may include a first plurality of sensors (for example, biomass sensors like those provided by Aber Instruments Ltd.) disposed within or on at least one of the endcaps (exteriorly or interiorly) of a bioreactor and a second plurality of sensors (for example, biomass sensors like those provided by Aber Instruments Ltd.) disposed within an extracapillary space of the bioreactor.

[0086] In each instance, the one or more sensors may each be configured to measure cell capacitance and / or cell impedance of intact cells, which hold charge, and to individually or collectively provide that information to a control system. The measured cell capacitance and / or cell impedance may be correlated with cell density and / or cell confluency and / or cell viability and / or cell diameter. For example, the cell density and / or cell confluency and / or cell viability and / or cell diameter can be determined by quantifying the cell capacitance and / or cell impedance.

[0087] In at least one example embodiment, the one or more sensors may be configured to quantify the cell capacitance and / or cell impedance and to optionally send the information to the control system. In at least one example embodiment, the one or more sensors may be configured to send the cell capacitance and / or cell impedance data to the control system and the control system may be configured to quantify the cell capacitance and / or cell impedance. In response to receiving the cell capacitance and / or cell impedance data and / or the quantified cell capacitance and / or cell impedance, the control system may be configured to initiate one or more actions.

[0088] For example, in at least one example embodiment, if the cell density is above or below a desired threshold, the control system may be configured to adjust (e.g., increase or decrease) inlet flow rate for the intracapillary space of the bioreactor, for example, to support cells in exponential growth phase. In at least one example embodiment, if the cell density is above or below a desired threshold, the control system may be configured to adjust (e.g., increase or decrease) a circulation rate in the extracapillary space, for example, to increase gas supply in order to maintain oxygen levels of high cell density. In at least one example embodiment, if the cell density is above or below a desired threshold, the control system may be configured to adjust (e.g. , increase or decrease) an inlet flow rate for the extracapillary space, for example, to provide for the control of metabolic waste products, such as lactic acid (lactate) or glutamate, by introducing appropriate buffer constituents.

[0089] The foregoing description of the embodiments has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but, where applicable, are interchangeable and can be used in a selected embodiment, even if not specifically shown or described. The same may also be varied in many ways. Such variations are not to be regarded as a departure from the disclosure, and all such modifications are intended to be included within the scope of the disclosure.

Claims

CLAIMSWhat is claimed is:

1. A cell expansion system comprising: a bioreactor including a first fluid circulation path and a second fluid circulation path; a control system configured to manage one or more first parameters in the first fluid circulation path and one or more second parameters in the second fluid circulation path; and one or more sensors configured to measure at least one of cell capacitance and cell impedance and to communicate with the control system in communication with at least one of the first fluid circulation path and the second fluid circulation path.

2. The cell expansion system of claim 1, wherein the bioreactor includes a housing that holds the first and second fluid circulation paths and has a first endcap and an opposing second endcap, the one or more sensors being disposed on or near at least one of the first endcap and the second endcap.

3. The cell expansion system of claim 2, wherein the one or more sensors are disposed on or near an exterior-facing surface of the at least of the first endcap and the second endcap.

4. The cell expansion system of claim 2, wherein the one or more sensors are disposed on an interior-facing surface of the at least one of the first endcap and the second endcap.

5. The cell expansion system of claim 2, wherein the one or more sensors includes a biomass sensor.

6. The cell expansion system of claim 2, wherein the one or more sensors includes a continuous strip that extends along a major length of the at least one of the first endcap and the second endcap.

7. The cell expansion system of claim 2, wherein the one or more sensors includes a first sensor disposed on or near the at least one of the first endcap and the second endcap and a second sensor disposed on or near another of the at least one of the first endcap and the second endcap.

8. The cell expansion system of claim 2, wherein the one or more sensors includes a first sensor and a second sensor, the first sensor is disposed on or near the at least one of the first endcap and the second endcap, the bioreactor is defined by a housing having an exterior-facing surface and an interior-facing surface, and the second sensor is disposed on or near the exteriorfacing surface.

9. The cell expansion system of claim 8, wherein the second sensor includes a continuous strip that extends along a major length of the housing.

10. The cell expansion system of claim 8, wherein the second sensor includes a biomass sensor.

11. The cell expansion system of claim 1, wherein the bioreactor is defined by a housing having an exterior-facing surface and an interior-facing surface, the one or more sensors being disposed on or near the exterior-facing surface.

12. The cell expansion system of claim 11, wherein the one or more sensors include a continuous strip that extends along a major length of the housing.

13. The cell expansion system of claim 12, wherein the continuous strip extends along at least 25 % of a total length of the major length of the housing.

14. The cell expansion system of claim 11, wherein the one or more sensors include a biomass sensor.

15. The cell expansion system of claim 1, wherein the one or more sensors are configured to convey the at least one of cell capacitance and cell impedance to the control system, and the control system is configured to correlate the at least one of cell capacitance and cell impedance and at least one of cell density, cell confluency, cell viability, and cell diameter in the at least one of the first fluid circulation path and the second fluid circulation path.

16. The cell expansion system of claim 15, wherein when the at least one of cell density, cell confluency, cell viability, and cell diameter is below a predetermined threshold, the control system is configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

17. The cell expansion system of claim 15, wherein when the at least one of cell density, cell confluency, cell viability, and cell diameter is above a predetermined threshold, the control system is configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

18. The cell expansion system of claim 1, wherein the one or more sensors are configured to correlate the at least one of cell capacitance and cell impedance and at least one of cell density, cell confluency, cell viability, and cell diameter in the respective first or second fluid circulation paths and to convey the cell density to the control system.

19. The cell expansion system of claim 18, wherein when the at least one of cell density, cell confluency, cell viability, and cell diameter is below a predetermined threshold, the control system is configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

20. The cell expansion system of claim 18, wherein when the at least one of cell density, cell confluency, cell viability, and cell diameter is above a predetermined threshold, the control system is configured to change at least one of the one or more first parameters in the first fluid circulation path and the one or more second parameters in the second fluid circulation path.

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