Cell expansion systems including biomass capacitive sensors and methods of integration and use thereof

Abstract

A cell expansion system comprising: a bioreactor comprising 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 a cell capacitance and a cell impedance within the bioreactor and in communication with a control system in communication with at least one of the first fluid circulation path and the second fluid circulation path.

Description

Cross Reference to Related Applications

[0001] This disclosure claims priority to U.S. Provisional Application No. 63 / 448,871, filed February 28, 2023, the entire disclosure of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to biomass capacitance sensors for cell expansion systems and methods of making and using the same, including methods for integrating biomass capacitance sensors into 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 culture systems for cell expansion and differentiation, including adherent and non-adherent cell types. The cell culture system can include one or more detachable bioreactor culture cartridges. The bioreactor culture cartridges can include a hollow fiber membrane comprising a plurality of semi-permeable hollow fibers (also referred to as hollow columns and / or hollow matrices). The space or interstitial space within the hollow fibers defines an intracapillary space, while the space outside the hollow fibers defines an extracapillary space. It is desirable to be able to monitor the substances (e.g., cells) contained in the intracapillary and / or extracapillary spaces and modify one or more operational or substance parameters in real-time on demand based on the measurements. SUMMARY

[0005] This section provides a general summary of the disclosure and 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 can include a bioreactor comprising 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 in communication with the control system, the control system 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 can include a housing containing the first fluid circulation path and the second fluid circulation path and having a first end cap and a second end cap opposite the first end cap. The one or more sensors can be disposed on or proximate to at least one of the first end cap and the second end cap.

[0008] In at least one example embodiment, the one or more sensors can be disposed on or proximate to an outer surface of at least one of the first end cap and the second end cap.

[0009] In at least one example embodiment, the one or more sensors can be disposed on an inner surface of at least one of the first end cap and the second end cap.

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

[0011] In at least one example embodiment, the one or more sensors can include a continuous strip extending along a major length of at least one of the first end cap and the second end cap.

[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 include a first sensor disposed on or proximate to at least one of the first end cap and the second end cap, and a second sensor disposed on or proximate to the other of the first end cap and the second end cap.

[0014] In at least one example embodiment, the one or more sensors can include a first sensor and a second sensor. The first sensor can be disposed on or proximate to at least one of the first end cap and the second end cap. The bioreactor can be defined by a housing having an outer surface and an inner surface, and the second sensor can be disposed on or proximate to at least one of the outer surface and the inner surface.

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

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

[0017] In at least one example embodiment, the bioreactor can be defined by a housing having an outer surface and an inner surface. The one or more sensors can be disposed on or proximate to at least one of the outer surface and the inner surface.

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

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

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

[0021] In at least one example embodiment, the control system can 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 when the at least one of the cell density, the cell confluency, the cell viability, and the cell diameter is below a predetermined threshold.

[0022] In at least one example embodiment, the control system can 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 when the at least one of the cell density, the cell confluency, the cell viability, and the cell diameter is above a predetermined threshold.

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

[0024] In at least one example embodiment, the control system can 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 when the at least one of the cell density, the cell confluency, the cell viability, and the cell diameter is below a predetermined threshold.

[0025] In at least one example embodiment, the control system can 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 when the at least one of the cell density, the cell confluency, the cell viability, and the cell diameter is above a predetermined threshold.

[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. BRIEF DESCRIPTION OF DRAWINGS

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

[0028] Figure 1 is a diagram of an exemplary cell expansion system including a bioreactor according to at least one example embodiment of the present disclosure.

[0029] Figure 2 is a diagram of an exemplary bioreactor according to at least one example embodiment of the present disclosure, showing a circulation path through the bioreactor, and which can be incorporated into a cell expansion system (such as the cell expansion system shown in Figure 1 ).

[0030] Figure 3 is a diagram of an exemplary shaking device configured to move a bioreactor (such as the bioreactor shown in Figure 2 ).

[0031] Figure 4 is a diagram showing an exemplary flow path of an exemplary cell expansion system (such as the cell expansion system shown in Figure 1 ).

[0032] Figure 5A is a diagram of an exemplary bioreactor having a first end cap and an opposing second end cap according to at least one example embodiment of the present disclosure.

[0033] Figure 5B is a diagram of a surface of the first end cap of the bioreactor shown in Figure 5A , the surface of the first end cap including a plurality of sensors according to at least one example embodiment of the present disclosure.

[0034] Figure 5C is a diagram of a surface of the second end cap of the bioreactor shown in Figure 5A , the surface of the second end cap including a plurality of sensors according to at least one example embodiment of the present disclosure.

[0035] Figure 5D is a diagram defining a surface of a housing of the bioreactor shown in Figure 5A , the surface of the housing including a plurality of sensors according to at least one example embodiment of the present disclosure.

[0036] In the several views of the drawings, like reference numerals designate corresponding parts throughout the several views. DETAILED DESCRIPTION

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

[0038] The exemplary embodiments are provided so that the present disclosure will be thorough, and 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. Those skilled in the art recognize that embodiments of the present disclosure can be practiced without these specific details. In some instances, well-known processes, well-known device structures, and well-known technologies have not been described in detail so as not to obscure the disclosure.

[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" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The terms "comprises," "comprising," "includes," "including," and the like are to be construed to be inclusive (i.e., to mean "including but not limited to") unless otherwise indicated herein. The methods described herein are not limited to the order of the steps presented unless otherwise indicated herein. Additionally, the methods described herein are not limited to the steps presented unless otherwise indicated herein.

[0040] When an element or layer is referred to as being "on," "engaged to," "connected to" or "coupled to" another element or layer, it can be directly on, engaged, connected or coupled to the other element or layer, or intervening elements or layers can 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 are 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 terms.

[0041] Although the terms "first," "second," "third," etc. can 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 can 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 terminology as used herein, when used, are not intended to convey an ordering or sequence, unless specifically stated otherwise. Thus, a first element, first component, first region, first layer or first section discussed below could be termed a second element, second component, second region, second layer or second section without departing from the teachings of the example embodiments.

[0042] For ease of description, spatially relative terms, such as "internal," "external," "lower," "bottom," "bottom portion," "upper," "top," and the like, can be used herein for describing an element's or feature's relationship to another element or feature as illustrated in the figures. Spatially relative terms can 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 a 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 can be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

[0043] Various components can be referred to herein as being "operably associated." As used herein, "operably associated" refers to components that are connected together in an operable manner, and encompasses embodiments in which the components are directly connected, as well as embodiments in which additional components are placed between the connected components. Components that are "operably associated" can be "fluidly associated." "Fluidly associated" refers to components that are connected together such that a fluid can be transferred between them. "Fluidly associated" encompasses embodiments in which additional components are placed between two fluidly associated components, as well as embodiments in which the components are directly connected. Fluidly associated components can include components that do not contact the fluid but manipulate the system by contacting other components (e.g., a peristaltic pump, which pumps fluid through a flexible tube by compressing the outside of the flexible tube).

[0044] In the drawings, the direction of an arrow, as indicated by the arrowhead, is generally indicative of the flow of information (such as data or instructions) that is of interest to the illustration. For example, when elements A and B exchange a variety of information but the information passed from element A to element B is relevant to the illustration, an arrow can 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 can send requests for the information or receipt acknowledgements of the information to element A.

[0045] In this application, including the following definitions, the term "module" or the term "controller" can be replaced with the term "circuit." The term "module" can refer to, belong to, or include: an application specific integrated circuit (ASIC); a digital, analog, or mixed analog / digital discrete circuit; a digital, analog, or mixed analog / digital integrated circuit; a combination of combination logic circuits; a field programmable gate array (FPGA); a processor circuit that executes code (shared, dedicated, or group); a memory circuit (shared, dedicated, or group) that stores code executed by a 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-a-chip.

[0046] A module can include one or more interface circuits. In some examples, the interface circuits can 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 can be distributed among multiple modules that are connected via interface circuits. For example, a plurality of modules can implement load balancing. In another example, a server (also known as remote or cloud) module can implement some of the functionality of the client modules.

[0047] The term "code," as used above, can include software, firmware, and / or microcode, and can refer to programs, routines, functions, classes, data structures, and / or objects. The term "shared processor circuitry" includes a single processor circuitry that executes portions of code from multiple modules. The term "group processor circuitry" includes processor circuitry that combines with additional processor circuitry to execute portions of code from one or more modules. A reference to multiple processor circuitry includes multiple processor circuitries on discrete chips, multiple processor circuitries on a single chip, multiple cores of a single processor circuitry, multiple threads of a single processor circuitry, or combinations of the above. The term "shared memory circuitry" includes a single memory circuitry that stores portions of code from multiple modules. The term "group memory circuitry" includes memory circuitry that combines with additional memory to store portions of code from one or more modules.

[0048] The term“memory circuitry” is a subset of the term“computer-readable medium.” As used herein, the term“computer-readable medium” does not encompass transitory propagating signals or electromagnetic waves through a medium, such as on a carrier or the Internet. Thus, the term“computer-readable medium” can be considered tangible and non-transitory. Non-limiting examples of non-transitory, tangible computer-readable media are nonvolatile memory circuits (e.g., flash memory circuits, erasable programmable read-only memory circuits, or mask read-only memory circuits), volatile memory circuits (e.g., static or dynamic random- access memory circuits), magnetic storage media (e.g., analog or digital magnetic tapes or magnetic hard drives), and optical storage media (e.g., CD, DVD, or Blu-ray discs).

[0049] The apparatus and methods described in this application can be partially or entirely implemented by special-purpose computers created by configuring general-purpose computers to execute one or more particular functions embodied in computer programs. The foregoing blocks, flowchart components, and other elements herein can be used as software specifications to transform the general-purpose computers or special-purpose computers into a particular machine.

[0050] A computer program includes processor-executable instructions stored on at least one non-transitory computer-readable medium. A computer program can also include or rely on stored data. A computer program can include 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] A computer program can include: (i) descriptive text, such as hypertext markup language (HTML), extensible markup language (XML), or JavaScript Object Notation (JSON), to be parsed; (ii) assembly code; (iii) object code generated from source code by a compiler; (iv) source code, executed by an interpreter; (v) source code, compiled and executed by a just-in-time compiler, etc. By way of example only, source code can be written using the syntax of the following languages: C, C++, C#, Objective-C, Swift, Haskell, Go, SQL, R, Lisp, Java®, Fortran, Perl, Pascal, Curl, OCaml, JavaScript®, HTML, Ada®, ASP (Active Server Pages), SQL, R, Flash®, Visual Basic®, Visual Basic.NET, Haskell®, Delphi®, Python®, Halo®, Lua®, Scala®, F#, and Fortran, Perl, Pascal, Curl, OCaml, Hypertext Markup Language 5th Revision (HTML5), Ada, Active Server Pages (ASP), Hypertext Preprocessor (PHP), Scala, Eiffel, Smalltalk, Erlang, Ruby, Visual Lua, MATLAB, SIMULINK, and

[0052] No element recited in a claim is to be construed under the means-plus-function or step-plus-function doctrines of 35 U.S.C. § 112(f), unless the specification explicitly recites that the element is intended to be means-plus-function or step-plus-function.

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

[0054] The present disclosure relates to biomass capacitance sensors for cell expansion systems and methods of making and using the same, including methods for integrating biomass capacitance sensors into cell expansion systems, including those described in U.S. Patent No. 10,577,585, issued March 3, 2020, entitled “Cell Expansion,” the entire disclosure of which is incorporated herein by reference. Cell expansion systems, also commonly referred to as hollow fiber bioreactors, are cell culture systems for cell expansion and differentiation, including adherent and non-adherent cell types. For example, as shown in Figure 1 As shown, exemplary cell expansion system 10 includes a first fluid circulation path 12 and a second fluid circulation path 14. For example, first fluid circulation path 12 includes a first fluid flow path 16 having opposite ends 18 and 20. First fluid flow path 16 can be in fluid communication with a hollow fiber cell growth chamber 24 (which can also be referred to as a “bioreactor”). For example, first opposite end 18 of first fluid flow path 16 can be in fluid communication with a first inlet 22 of cell growth chamber 24, and second opposite end 20 can be in fluid communication with a first outlet 28 of cell growth chamber 24. Fluid in first circulation path 12 can flow through the interior of a plurality of hollow fibers 116 of a hollow fiber membrane (HFM) 117 disposed in cell growth chamber 24 (see, e.g., FIG. 1). Figure 2). In at least one example embodiment, the first fluid flow control device 30 can be operably coupled to the first fluid flow path 16 and can control fluid flow in the first fluid circulation path 12.

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

[0056] The first fluid circulation path 12 and the second fluid circulation path 13 can be maintained in the cell growth chamber 24 by the hollow fiber membrane 117, with fluid in the first fluid circulation path 12 flowing through an intracapillary (IC) space (also referred to as an intrapore space) of the hollow fiber membrane 117, and fluid in the second fluid circulation path 14 flowing through an extracapillary (EC) space (also referred to as an interpore space) of the cell growth chamber 24. The first fluid circulation path 12 can be referred to as an “intracapillary loop” or an “IC loop.” The second fluid circulation path 14 can be referred to as an “extracapillary loop” or an “EC loop.” Fluid in the first fluid circulation path 12 can flow in a co-current or counter-current direction relative to fluid flow in the second fluid circulation path 14.

[0057] In at least one example embodiment, the fluid inlet path 44 can be fluidly associated with the first fluid circulation path 12, and the fluid outlet path 46 can be fluidly associated with the second fluid circulation path 14. The fluid inlet path 44 allows fluid to enter the first fluid circulation path 12, while the fluid outlet path 46 allows fluid to exit the cell expansion system 10. In at least one example embodiment, as shown, a third fluid flow control device 48 can be operatively associated with the fluid inlet path 44. Although not shown, it should be recognized that in other example embodiments, a fourth fluid flow control device can alternatively or additionally be operatively 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) can include pumps, valves, clamps, 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 devices can be or include peristaltic pumps. The fluid circulation paths (including the first fluid circulation path 12 and / or the second fluid circulation path 14), the inlet ports (including the fluid inlet port 44), and / or the outlet ports (including the fluid outlet port 46) can include any known tubing material, and any kind of fluid (including, for example, buffers, protein-containing fluids, and cell-containing fluids) can flow through the various circulation paths (including the first fluid circulation path 12 and / or the second fluid circulation path 14), the inlet paths (including the fluid inlet port 44), and the outlet paths (including the fluid outlet port 46). It should be recognized that the terms "fluid," "medium," and "fluid medium" are used interchangeably.

[0058] In Figure 2 An example hollow fiber cell growth chamber 100 (which can also be referred to as a "bioreactor") is shown in Figure 1A hollow fiber cell growth chamber 24 of the illustrated cell expansion system 10 is shown. The hollow fiber cell growth chamber 100 has a longitudinal axis (indicated by line LA-LA) and includes a cell growth chamber housing 104. The cell growth chamber housing 104 can include four openings or ports, such as including 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 medium) in a first circulation path (similar to 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, enter and pass through the intracapillary side of a plurality of hollow fibers 116, and exit the cell growth chamber 100 through the intracapillary outlet port 120 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 cell growth chamber 100. A second fluid (which can also be referred to as an extracapillary medium or fluid) in a second circulation path (similar to the second fluid circulation path 14) can enter the cell growth chamber 100 through the extracapillary inlet port 128, contact the extracapillary side or exterior of the hollow fiber membranes 117, and exit the cell growth chamber 100 through 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] When the second fluid contacts the exterior of the hollow fibers 116, small molecules (e.g., ions, water, oxygen, lactate, etc.) can diffuse and / or permeate from the interior or intracapillary space of the hollow fibers 116 to the exterior or extracapillary space through the hollow fibers 116, or alternatively or additionally, from the extracapillary space to the intracapillary space. For example, large molecular weight molecules (e.g., growth factors) are typically too large to pass through the hollow fibers 116 and remain in the intracapillary space (or alternatively or additionally, the extracapillary space) of the hollow fibers 116. The media defining the first and second fluids can be replaced as desired, and alternatively or additionally, gases can be exchanged by an oxygenator and / or gas transfer module as desired. As described below, cells for expansion can be contained within the first fluid circulation path 12 and / or the second fluid circulation path 14 and can enter the hollow fiber cell growth chamber 100 from one or both of the intracapillary side or the extracapillary side.

[0060] In at least one exemplary embodiment, cells can be seeded (e.g., for expansion, differentiation, and / or collection of umbilical cord blood-derived CD34+ hematopoietic stem / progenitor cells, monocytes, macrophages, hepatocytes, and / or endothelial cells) into the intracapillary space of the hollow fiber 116, while cell culture medium can be pumped through the extracapillary space of the hollow fiber 116 to deliver nutrients to the cells through perfusion of the hollow fiber membrane during the expansion process. However, in at least one other exemplary embodiment, cells to be expanded can be seeded in the extracapillary space, while cell culture medium can be pumped through the intracapillary space to deliver nutrients to the cells through perfusion of the hollow fiber membrane during the expansion process. In at least one other exemplary embodiment, cells to be expanded can be seeded in the intracapillary space, while cell culture medium can be pumped through the extracapillary space and the intracapillary space simultaneously. The movement of cell culture medium in the intracapillary space and / or the extracapillary space helps to remove excess cells, such as cells that are not attached to the surface of the hollow fiber membrane. In at least one exemplary embodiment, the material used to form hollow fiber membranes 117 can be any biocompatible polymeric material that can be made into hollow fibers 121. For example, synthetic polysulfone-based materials, such as polyethersulfones (PES), are commonly used to form hollow fibers.

[0061] In at least one exemplary embodiment, cell expansion system 10 may further include a device configured to move or "shake" cell growth chamber 100 relative to the other components of cell expansion system 10. This device may be a rotating and / or lateral shaking device. For example, Figure 3 As shown, a cell growth chamber (also referred to as a bioreactor) 100 can be rotationally coupled to one or more rotary rocking assemblies 138 and lateral rocking assemblies 140. The first rotary rocking assembly 138 can be rotationally associated with the bioreactor 100. For example, the first rotary rocking assembly 138 can be configured to rotate the bioreactor 100 about a first, or central, axis of rotation 142. In at least one exemplary embodiment, the bioreactor 100 can be continuously rotated in a single direction, either clockwise or counterclockwise, about the central axis 142. In at least one exemplary embodiment, the bioreactor 100 can be rotated in an alternating manner, including, for example, first rotating in a first, clockwise direction and then rotating in a second, counterclockwise direction about the central axis 142.

[0062] Although not shown, it should be appreciated that in other example embodiments, the second rotational shaking assembly can be configured to move the bioreactor 100 about a second rotational axis 144 that is perpendicular to the central axis 142 and that passes through a center point of the bioreactor 100. In at least one example embodiment, the bioreactor 100 can be continuously rotated in a single direction about the second axis 144 in either a clockwise or counterclockwise direction. In at least one example embodiment, the bioreactor 100 can be rotated in an alternating fashion, including, for example, first in a first clockwise direction and then in a second counterclockwise direction about the second axis 144. In at least one example embodiment, the bioreactor 100 can also be rotated about the second axis 144 and positioned in a horizontal or vertical orientation with respect to gravity. The lateral shaking assembly 140 can be laterally associated with the bioreactor 100. For example, the plane in which the lateral shaking assembly 140 lies can be moved laterally in the x and y directions.

[0063] Rotation and / or lateral movement of the bioreactor 100 can 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 at which cells settle in the cell growth chamber 100 can be directly proportional to the difference in density between the cells and the suspension medium in accordance with Stokes' Law. In at least one example embodiment, repeated 180 degree (fast) rotations with pauses (e.g., for a total of 30 seconds) as described above can help to keep non-adherent cells (e.g., red blood cells) in suspension. Rotations of at least about 180 degrees are preferred, but rotations of varying degrees, including up to 360 degrees or more than 360 degrees, can also be employed. Different shaking assemblies can be used individually or in any combination. For example, a shaking assembly that rotates the bioreactor 100 about the central axis 142 can be combined with a shaking assembly that rotates the bioreactor 100 about the axis 144. Likewise, clockwise and counterclockwise rotations about different axes can be performed independently in any combination.

[0064] Figure 4 is a schematic diagram of an example cell expansion system 500 showing an example flow path of the system 500 in combination with Figure 1The illustrated cell expansion system 100 is similar. In at least one example embodiment, the cells can be located in the intracapillary space while the cell culture media can be pumped through the extracapillary space to deliver nutrients to the cells through hollow fiber membrane perfusion during expansion. However, it will be appreciated that in at least one other example embodiment, the cells can be located in the extracapillary space while the cell culture media can be pumped through the intracapillary space to deliver nutrients to the cells through hollow fiber membrane perfusion during expansion. In at least one other example embodiment, the cells can be located in the intracapillary space while the cell culture media can be pumped through both the extracapillary space and the intracapillary space.

[0065] As shown, the cell expansion system 500 can include a first fluid circulation path 502 (also referred to as an "intracapillary loop" or "IC loop") and a second fluid circulation path 504 (also referred to as an "extracapillary loop" or "EC loop"). A first fluid flow path 506 can be fluidly associated with a cell growth chamber (also referred to as a "bioreactor") 501 to form the first fluid circulation path 502. The cell growth chamber 501 can be used as Figure 1 The illustrated hollow fiber cell growth chamber 24 and / or Figure 1A hollow fiber cell growth chamber 100 is shown. A first fluid can flow into (e.g., permeate) the cell growth chamber 501 through an intracapillary inlet port 501 A. The first fluid can exit the cell growth chamber through an intracapillary outlet port 501B. In at least one example embodiment, a first fluid circulation path 502 can include a pressure gauge 510 configured to measure the pressure of the first fluid exiting the cell growth chamber 501. In at least one example embodiment, the first fluid circulation path 502 can include an intracapillary circulation pump 512 configured to control the flow rate of the first fluid. For example, the intracapillary circulation pump 512 can be configured to pump the first fluid in a first direction or a second direction opposite the first direction. In the second case, the intracapillary outlet port 501B can act as an inlet and the intracapillary inlet port 501A can act as an outlet. In at least one example embodiment, the first fluid circulation path 502 can include a sample port 516 and / or a sample coil 518 configured for first fluid sample withdrawal. In at least one example embodiment, the first fluid circulation path 502 can include a pressure / 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 can flow into the intracapillary circuit 502 through a valve 514. In at least one example embodiment, for example, a portion of cells can be flushed from the intracapillary circuit 502 through a valve 598 into a collection bag 599. It should be appreciated that in at least one other example embodiment, the first fluid circulation path 502 can include additional or fewer valves, pressure gauges, pressure sensors, temperature sensors, ports, and / or other devices for isolating and / or measuring characteristics of the first fluid along portions of the intracapillary circuit 502.

[0066] The second fluid can flow into (e.g., infiltrate) the cell growth chamber 501 through the extracapillary inlet port 501C. The second fluid can exit the cell growth chamber 501 through the extracapillary outlet port 501D. In at least one example embodiment, the second fluid in the extracapillary circuit 504 can be in contact with the outer surface of the hollow fibers disposed in the cell growth chamber 501, thereby allowing small molecules to diffuse into and out of the hollow fibers. In at least one example embodiment, the extracapillary circuit 504 can include a pressure / temperature gauge 524 configured to measure the pressure and / or temperature of the second fluid prior to the second fluid flowing into the cell growth chamber 501. In at least one example embodiment, the extracapillary circuit 504 can include a pressure gauge 526, e.g., configured to measure the pressure of the second fluid as it exits the cell growth chamber 501. In at least one example embodiment, the extracapillary circuit 504 can include a sample port 530 configured for sample extraction of the second fluid.

[0067] In at least one example embodiment, the extracapillary circuit 504 can include an extracapillary circulation pump 528 and an oxygenator or gas transfer module 532. For example, after exiting the cell growth chamber 501, the second fluid can 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 can be configured to control the flow rate of the second fluid. For example, similar to the intracapillary circulation pump 512, the extracapillary circulation pump 528 can be configured to pump the second fluid in a first direction or a second direction opposite the first direction. In the second case, the extracapillary outlet port 501D can serve as an inlet and the extracapillary inlet port 501C can serve as an outlet.

[0068] In at least one example embodiment, the second fluid flow path 522 can be in fluid association with an oxygenator or gas transfer module 532 through an oxygenator inlet port 534 and an oxygenator outlet port 536. For example, the second fluid can flow into the oxygenator or gas transfer module 532 through the oxygenator inlet port 534 and can exit or flow out of the oxygenator or gas transfer module 532 through the oxygenator outlet port 536. In at least one example embodiment, the oxygenator or gas transfer module 532 can be configured to add oxygen to the second fluid and / or remove gas bubbles from the second fluid. For example, air and / or gas can flow into the oxygenator or gas transfer module 532 through a first filter 538 and can exit (i.e., flow out of) the oxygenator or gas transfer device 532 through a second filter 540. The first filter 538 and the second filter 540 can 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 can equilibrate with the gas entering the oxygenator or gas transfer module 532. In at least one example embodiment, air and / or gas can be vented from the cell expansion system 500, for example, during a priming procedure, the air and / or gas can be vented to the atmosphere through the oxygenator or gas transfer module 532. It should be appreciated that in at least one other example embodiment, the second fluid circulation path 504 can include additional or fewer valves, pressure gauges, pressure sensors, temperature sensors, ports, and / or other devices for isolating and / or measuring 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 can be in fluid association with the first circulation path 502. The air removal chamber 556 can include one or more ultrasonic sensors. For example, the air removal chamber 556 can include an upper sensor and / or a lower sensor configured to detect air and / or a lack of fluid and / or a gas-liquid interface at a particular measurement location within the air removal chamber 556. The upper sensor can be disposed proximate a first end (e.g., a top) of the air removal chamber 556. The lower sensor can be disposed proximate a second end (e.g., a bottom) of the air removal chamber 556. While ultrasonic sensors are discussed, it should be appreciated that in other example embodiments, the air removal chamber 556 can additionally or alternatively include one or more other sensors, such as including optical sensors. During a portion of a priming procedure and / or other protocol, air and / or gas expelled from the cell expansion system 500 can be vented to the atmosphere through a line 558 from an air valve 560, which can be in fluid association with the air removal chamber 556.

[0070] In at least one example embodiment, the first fluid can include cells from a first fluid container (which can also be referred to as a first media bag or a first bag) 562 and 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. Material (i.e., cells and / or intracapillary media) from the first fluid container 562 and the second fluid container 546 can enter the first fluid circulation path 502 through the first fluid flow path 506. The first fluid container 562 can be in fluid association with the first fluid flow path 506 and the first fluid circulation path 502 through a 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 a third bag) 544 can be in fluid association with the first fluid inlet path 542, respectively, for example, through a valve 550 and a valve 548, or the second fluid container 546 and the third fluid container 544 can be in fluid association with the second fluid inlet path 574, respectively, for example, through a valve 570 and a valve 576. In at least one example embodiment, material from the third fluid container 544 and / or the second fluid container 546 can be in fluid communication with the first sterile sealable input priming path 508 and / or the 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 can include extracapillary media and a fifth fluid container (which can also be referred to as a fifth media bag or a fifth bag) 566 can include a wash solution. Material (i.e., extracapillary media and / or a wash solution) from the fourth fluid container 568 and the fifth fluid container 566 can 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 can be in fluid association with a valve 570, which is in fluid association with the first fluid circulation path 502, for example, through a distribution valve 572 and the first fluid inlet path 542. In at least one example embodiment, the fifth fluid container 566 can be in fluid association with the second fluid circulation path 504 through the second fluid inlet path 574 and the extracapillary inlet path 584, for example, by opening the valve 570 and closing the distribution valve 572. The fourth fluid container 568 can be in fluid association with a valve 576, which is in fluid association with the first fluid circulation path 502, for example, through the first fluid inlet path 542 and the distribution valve 572. In at least one example embodiment, the fourth fluid container 568 can be in fluid association with the second fluid inlet path 574 by opening the 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 can be in fluid association with an optional heat exchanger 552.

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

[0073] In at least one example embodiment, as shown, fluid in the first fluid circulation path 502 and the second fluid circulation path 504 flow in the same direction through the cell growth chamber 501 (i.e., a co-flow configuration). Although not shown, it should be recognized that in other example embodiments, the cell expansion system 500 can also be configured to flow in a counter-flow configuration. As shown, fluid in the first fluid circulation path 502 can enter the bioreactor 501 from the intracapillary inlet port 501 A, and can exit or flow out of the bioreactor 501 from the intracapillary outlet port 501B. In at least one example embodiment, for example, the first fluid flow path 506 passes through a junction 517. The junction 517 can be a point or location, for example, from which fluid can flow in opposite directions based on the direction of the intracapillary inlet pump 554. The junction 517 can include any type of fitting, coupling, fusion, channel, and / or tubing that fluidly associates the first fluid flow path with the first fluid circulation path 502. In at least one example embodiment, the junction 517 can include a T-shaped fitting or coupling, and / or a Y-shaped fitting or coupling. Figure 4

[0074] ​In at least one exemplary embodiment, the cell expansion system 500 includes one or more gauges (e.g., pressure gauge 510, pressure / temperature gauge 520, pressure / temperature gauge 524, and / or pressure gauge 526), ​​one or more valves (e.g., valve 514, valve 548, valve 550, valve 560, valve 564, valve 570, valve 572, valve 576, valve 582, valve 590, valve 596, and / or valve 598), one or more ports (e.g., capillary inlet port 501A, capillary outlet port 501B, extracapillary inlet port 501C, extracapillary The outlet port 501D, the sample port 516, the sample port 530, the oxygenator inlet port 534, and / or the oxygenator outlet port 536), one or more pumps (e.g., the intra-capillary circulation pump 512, the extra-capillary circulation pump 528, the intra-capillary inlet pump 554, and / or the extra-capillary inlet pump 578), one or more filters (e.g., the first filter 538 and / or the second filter 540), one or more coils (e.g., the sample coil 518), one or more modules (e.g., the oxygenator or gas delivery module 532), and / or one or more other components can be in electrical communication with a control system (not shown). The control system can include multiple nodes that 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, for example, the control system includes a controller and memory.

[0075] The controller (also referred to as a processor) may be any type of microcontroller, microprocessor, field programmable gate array (FPGA), application specific integrated circuit (ASIC), etc. An exemplary controller may be the NK10DN512VOK10 microcontroller manufactured and sold by N9PUSA, Incorporated, which is a microcontroller unit with a 32-bit architecture. Other exemplary controllers may include, for example, at least one of the following: Snapdragon 800 and 801, with integrated 4G LTE and 64-bit computing capabilities 610 and 615, Apple's 64-bit architecture A7 processor, M7 motion coprocessor, Samsung Orion series, Intel Core TMseries processors, Xeon Phi series processors, Atom TM series processors, Intel Itanium series processors, 22 nanometer, fourth generation i5-4670K and i7-4770K, 22 nanometer, third generation i5-3570K, FX TM series processors, FX-4300, FX-6300, and 32 nm FX-8350 Vishera processors, Kaveri processors, Cortex TM -M processors, Cortex-A and ARM926EJ-S TM processors, and other industry equivalent processors, which can use any known or future developed standard, instruction set, library, and / or architecture to perform computing functions. Memory can be any type of memory, including random access memory (RAM), read only memory (ROM), electrically erasable programmable ROM (EEPROM), compact disc ROM (CD-ROM), optical storage, magnetic storage, any suitable combination of the above, or other type of storage or memory device that stores and provides instructions to program and control the controller.

[0076] As described above, cells (e.g., for expanding, differentiating, and / or collecting umbilical cord blood-derived CD34+ hematopoietic stem / progenitor cells, monocytes, macrophages, hepatocytes, and / or endothelial cells) can be seeded into the intracapillary space of a cell growth chamber (also referred to as a bioreactor) comprising hollow fiber membranes, while cell culture medium can be pumped through the extracapillary space of the cell growth chamber during expansion to deliver nutrients to the cells via perfusion through the hollow fiber membranes. In at least one other exemplary embodiment, however, cells for expansion can be seeded in the extracapillary space, while cell culture medium can be pumped through the intracapillary space during expansion to deliver nutrients to the cells via perfusion through the hollow fiber membranes. In at least one other exemplary embodiment, cells for expansion can be seeded in the intracapillary space, while cell culture medium can be pumped through the extracapillary space and the intracapillary space.

[0077] In each example embodiment, real-time collection of information about the material (e.g., cells) contained in a bioreactor (e.g., bioreactor 24 and / or bioreactor 100 and / or bioreactor 501) can be desirable. For example, in at least one example embodiment, real-time collection and processing of information enables monitoring and / or control of nascent cell expansion. Monitoring and / or control of nascent cell expansion can include collection and processing of oxygen consumption data, acidity data, and / or cell density data. For example, oxygen consumption data can be used to monitor and / or control cell respiration, cell viability, self-renewal regulation. For example, acidity data can be used to monitor and / or control buffering capacity, cell membrane integrity, and / or metabolite transport. For example, cell density data can be used to monitor and / or control cell signaling, seeding, expansion, differentiation, and / or harvesting. Figure 1 Figure 2 Figure 4

[0078] Monitoring and / or control of nascent cell expansion can be at least partially automated through one or more preconfigured feedback control loops. In at least one example embodiment, real-time collection and processing of information enables monitoring and / or control of cell metabolites. Cell metabolite data can be used to monitor and / or control nutrient levels (e.g., glucose, lactate, glutamine, and / or ammonia) within a bioreactor. Monitoring and / or control of cell metabolite expansion can be at least partially automated through one or more preconfigured feedback control loops.

[0079] In at least one example embodiment, real-time collection and processing of information enables monitoring and / or control of cell products. Cell product data can include information about secreted proteins and / or nucleic acids and / or cellular exosomes, microvesicles, and / or virions, which can be used to monitor and / or control cell signaling, diagnostics, and / or therapeutics. Monitoring and / or control of cell products can be at least partially automated through one or more preconfigured feedback control loops. In at least one example embodiment, real-time collection and processing of information enables monitoring and / or control of nascent cell expansion, and / or monitoring and / or control of cell metabolite expansion, and / or monitoring and / or control of cell products.

[0080] One or more sensors can be disposed in a bioreactor (e.g., bioreactor 24 and / or bioreactor 100 and / or bioreactor 501). Figure 1 Figure 2 Figure 4 ​​​​​The illustrated bioreactor 501) interior or thereon, and is configured to collect and / or monitor real-time events within the reactor. For example, in at least one exemplary embodiment, one or more sensors can be disposed within or on at least one end cap of the bioreactor. For example, as Figure 5A and 5B illustrated, a plurality of sensors 610 can be disposed within or on at least one of a first head end cap 612 and a second head end cap 614 of a bioreactor 600. The first head end cap 612 can be opposite the second head end cap 614, and as Figure 5A illustrated, the first end cap 612 and the second end cap 614 can together enclose the bioreactor 600.

[0081] The bioreactor can be similar to the bioreactor 24 illustrated in Figure 1 and / or the bioreactor 100 illustrated in Figure 2 and / or the bioreactor 501 illustrated in Figure 4 . The plurality of sensors 610 can include biomass sensors (e.g., sensors provided by AberInstruments Ltd.). In at least one exemplary embodiment, as Figure 5B (being a close-up view of the outer surface 616 of the first end cap 612) and Figure 5C (being a close-up view of the outer surface 618 of the second end cap 614), the plurality of sensors 610 can be arranged radially on each surface. While four sensors 610 are illustrated in Figure 5C and Figure 5D , it should be understood that in other exemplary embodiments, one or more sensors 610 can be disposed on the first head end cap 612 and / or the second head end cap 614. Further, while the outer surface 616 and the outer surface 618 are illustrated in Figure 5C and Figure 5D , it should be understood that in other exemplary embodiments, the plurality of sensors 610 can be disposed on or near an inner surface of the first end cap 612 and / or the second end cap 614. Further, while the sensors 610 are illustrated as individual sensors in Figure 5B and Figure 5C , it should be understood that in other exemplary embodiments, a continuous sensor or a single sensor having one or more zones can be used. In each case, the placement of the sensors 610 on at least one of the end caps 613 and 614 (either internally or externally) enables the sensor array (i.e., the plurality of sensors 610) to determine the length and depth of cell distribution, as well as cell concentration, over a particular volume and surface area of the bioreactor 600.

[0082] In at least one other exemplary embodiment, one or more sensors 610 can be disposed on an outer surface 652 of a housing 650 defining the bioreactor 600, e.g., the housing 650 is shown in an unshaped or flat state. As shown, the sensors 610 can be arranged longitudinally along a circumference of the bioreactor 600, such an arrangement enables the sensor array (i.e., the plurality of sensors 610) to determine the length and depth of cell distribution, as well as cell concentration, over a particular volume and surface area of the bioreactor 600. Although nine sensors 610 are shown in Figure 5D at least one other exemplary embodiment, one or more sensors 610 can be disposed on an inner surface 652 of the housing 650. Further, although independent sensors 610 are shown in Figure 5D at least one other exemplary embodiment, one or more continuous sensors (e.g., a sensor strip) can be similarly used that cover a substantial portion (e.g., greater than about 25%) of the primary length of the bioreactor 600. Further, although an outer surface 652 is shown in Figure 5D at least one other exemplary embodiment, one or more sensors 610 can be disposed on or near an inner surface of the housing 650 defining the bioreactor 600 (e.g., the extracapillary space of the bioreactor 600).

[0083] Although not shown, it should be understood that in other exemplary embodiments, the one or more sensors can include a first set of sensors (e.g., biomass sensors as provided by Aber Instruments Ltd.) disposed on or within (external or internal) at least one end cap of the bioreactor and a second set of sensors (e.g., biomass sensors as provided by Aber Instruments Ltd.) disposed on an outer surface of the housing of the bioreactor.

[0084] Although not shown, it should be understood that in other exemplary embodiments, the one or more sensors can include sensors (e.g., biomass sensors as provided by Aber Instruments Ltd.) disposed in the extracapillary space of the bioreactor.

[0085] Although not shown, it should be understood that in other exemplary embodiments, the one or more sensors can include a first set of sensors (e.g., biomass sensors as provided by Aber Instruments Ltd.) disposed on or within (external or internal) at least one end cap of the bioreactor and a second set of sensors (e.g., biomass sensors as provided by Aber Instruments Ltd.) disposed in the extracapillary space of the bioreactor.

[0086] In each case, one or more sensors can be configured to measure cell capacitance and / or cell impedance of the intact cells (which are capable of storing electrical charge) and provide this information to the control system, individually or collectively. The measured cell capacitance and / or cell impedance can be related to cell density and / or cell confluency and / or cell viability and / or cell diameter. For example, cell density and / or cell confluency and / or cell viability and / or cell diameter can be determined by quantifying cell capacitance and / or cell impedance.

[0087] In at least one example embodiment, one or more sensors can be configured to quantify cell capacitance and / or cell impedance and optionally send information to the control system. In at least one example embodiment, one or more sensors can be configured to send cell capacitance and / or cell impedance data to the control system and the control system can be configured to quantify cell capacitance and / or cell impedance. Upon receiving the cell capacitance and / or cell impedance data and / or the quantified cell capacitance and / or cell impedance, the control system can 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 can be configured to adjust (e.g., increase or decrease) the inlet flow rate of the space within the capillary of the bioreactor, for example, to support cells in an exponential growth phase. In at least one example embodiment, if the cell density is above or below a desired threshold, the control system can be configured to adjust (e.g., increase or decrease) the circulation rate in the space outside the capillary, for example, to maintain oxygen levels at high cell densities by increasing gas supply. In at least one example embodiment, if the cell density is above or below a desired threshold, the control system can be configured to adjust (e.g., increase or decrease) the inlet flow rate of the space outside the capillary, for example, to control metabolic waste, such as lactic acid (lactate) or glutamate, by introducing appropriate buffering components.

[0089] The above description of examples is meant to be illustrative and not limiting of the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but are interchangeable with other embodiments, as appropriate, unless otherwise specifically noted. Such elements or features can be used with any other embodiment, even if not specifically stated herein. Such elements or features can be changed in various ways without departing from the scope of the disclosure, all such modifications being intended to be included within the scope of the disclosure.

Claims

1. A cell expansion system comprising: A bioreactor comprising 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; as well as One or more sensors are configured to measure at least one of cell capacitance and cell impedance and are in communication with the control system, the control system being in communication with at least one of the first fluid circulation path and the second fluid circulation path.

2. The cell expansion system according to claim 1, wherein The bioreactor includes a housing containing the first and second fluid circulation paths and having a first end cap and an opposing second end cap, wherein the one or more sensors are disposed on or near at least one of the first and second end caps.

3. The cell expansion system according to claim 2, wherein: The one or more sensors are disposed on or near an exterior surface of at least one of the first end cap and the second end cap.

4. The cell expansion system according to claim 2, wherein: The one or more sensors are disposed on an inner surface of at least one of the first end cap and the second end cap.

5. The cell expansion system according to claim 2, wherein: The one or more sensors include a biomass sensor.

6. The cell expansion system according to claim 2, wherein: The one or more sensors comprise a continuous strip extending along a major length of at least one of the first end cap and the second end cap.

7. The cell expansion system according to claim 2, wherein: The one or more sensors include a first sensor disposed on or near at least one of the first end cap and the second end cap, and a second sensor disposed on or near the other of the first end cap and the second end cap.

8. The cell expansion system according to claim 2, wherein: The one or more sensors include a first sensor and a second sensor, the first sensor being disposed on or near at least one of the first end cap and the second end cap, the bioreactor being defined by a housing having an outer surface and an inner surface, and the second sensor being disposed on or near the outer surface.

9. The cell expansion system according to claim 8, wherein: The second sensor comprises a continuous strip extending along a major length of the housing.

10. The cell expansion system according to claim 8, wherein: The second sensor includes a biomass sensor.

11. The cell expansion system according to claim 1, wherein: The bioreactor is defined by a housing having an outer surface and an inner surface, and the one or more sensors are disposed on or near the outer surface.

12. The cell expansion system according to claim 11, wherein The one or more sensors comprise a continuous strip extending along a major length of the housing.

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

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

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

16. The cell expansion system according to claim 15, wherein: When at least one of the cell density, the cell confluence, the cell viability, and the 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 according to claim 15, wherein: When at least one of the cell density, the cell confluence, the cell viability, and the 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 according to claim 1, wherein The one or more sensors are configured to correlate at least one of the cell capacitance and the cell impedance with at least one of cell density, cell confluence, cell viability, and cell diameter in the corresponding first fluid circulation path or the second fluid circulation path, and transmit the cell density to the control system.

19. The cell expansion system according to claim 18, wherein When at least one of the cell density, the cell confluence, the cell viability, and the 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 according to claim 18, wherein When at least one of the cell density, the cell confluence, the cell viability, and the 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.

Images