A cell proliferation system including a capacitive cell volume sensor, and a method for providing and using the same.

Abstract

The cell proliferation system comprises 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 in the bioreactor and to communicate with the control system which communicates with at least one of the first and second fluid circulation paths.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 448,871, filed Feb. 28, 2023. The entire disclosure of the above application is incorporated herein by reference.

[0002] This disclosure relates to methods of providing and using a capacitance - type cell mass sensor for a cell growth system, and a method of incorporating the capacitance - type cell mass sensor into a cell growth system.

Background Art

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

[0004] A cell growth system, commonly referred to as a hollow - fiber bioreactor, is a cell - culture system used to grow and differentiate cells, including both adherent and non - adherent cell types. The cell - culture system may include one or more removable bioreactor cartridges. The bioreactor cartridge includes a hollow - fiber membrane that includes a plurality of semi - permeable hollow fibers (also referred to as hollow columns and / or hollow matrices). The space or void inside the hollow fiber defines the capillary inner space, and the space outside the hollow fiber defines the capillary outer space.

Summary of the Invention

Problems to be Solved by the Invention

[0005] It is desirable to monitor substances (e.g., cells) held within the capillary inner space and / or capillary outer space and, in real - time, modify one or more operating parameters or substance parameters as desired, depending on the measured values.

Means for Solving the Problems

[0006] This section provides a general overview of the disclosure and does not constitute a comprehensive disclosure of its entire scope or all features.

[0007] In at least one exemplary embodiment, the present disclosure provides a cell proliferation system. The cell proliferation system comprises 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 which communicates with at least one of the first and second fluid circulation paths.

[0008] In at least one exemplary embodiment, the bioreactor includes a housing that holds the first fluid circulation path and the second fluid circulation path, and the bioreactor may have a first end cap and a second end cap opposite the first end cap. The one or more sensors may be positioned on or near at least one of the first and second end caps.

[0009] In at least one exemplary embodiment, the one or more sensors may be located on or near the outer surface of at least one of the first and second end caps.

[0010] In at least one exemplary embodiment, the one or more sensors may be positioned on the inner surface of at least one of the first and second end caps.

[0011] In at least one exemplary embodiment, the one or more sensors may include a cell volume sensor.

[0012] In at least one exemplary embodiment, the one or more sensors may include a sensor strip extending along the longitudinal length of at least one of the end caps, the first end cap and the second end cap.

[0013] In at least one exemplary embodiment, the sensor strip may extend over at least 25% of the total length of the longitudinal axis of the housing.

[0014] In at least one exemplary embodiment, the one or more sensors may include a first sensor disposed on or near at least one of the first and second end caps, and a second sensor disposed on or near another end cap, which is different from the at least one of the first and second end caps.

[0015] In at least one exemplary embodiment, the one or more sensors may include a first sensor and a second sensor. The first sensor may be located on or near at least one of the first and second end caps. The bioreactor may be defined by a housing having an outer surface and an inner surface, and the second sensor may be located on or near at least one of the outer and inner surfaces.

[0016] In at least one exemplary embodiment, the second sensor may include a sensor strip extending along the longitudinal axis length of the housing.

[0017] In at least one exemplary embodiment, the second sensor may include a cell volume sensor.

[0018] In at least one exemplary embodiment, the bioreactor may be defined by a housing having an outer surface and an inner surface. The one or more sensors may be located on or near at least one of the outer surface and the inner surface.

[0019] In at least one exemplary embodiment, the one or more sensors may include a sensor strip extending along the longitudinal axis length of the housing.

[0020] In at least one exemplary embodiment, the one or more sensors may include a cell volume sensor.

[0021] In at least one exemplary embodiment, the one or more sensors may be configured to transmit at least one of the cell capacitance and the cell impedance to the control system. The control system may be configured to correlate at least one of the cell capacitance and the cell impedance with at least one of the cell density, cell confluence, cell viability, and cell diameter in the first or second fluid circulation path.

[0022] In at least one exemplary embodiment, if at least one of the cell density, cell confluence, 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.

[0023] In at least one exemplary embodiment, when at least one of the cell density, the cell confluency, the cell viability, and the cell diameter exceeds a predetermined threshold, the control system may be configured to change at least one parameter among 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.

[0024] In at least one exemplary embodiment, the one or more sensors may be configured to correlate at least one of the cell capacitance and the cell impedance in the first fluid circulation path or the second fluid circulation path with at least one of the cell density, the cell confluency, the cell viability, and the cell diameter, and transmit the cell density to the control system.

[0025] In at least one exemplary embodiment, when at least one of the cell density, the cell confluency, the cell viability, and the cell diameter is less than a predetermined threshold, the control system may be configured to change at least one parameter among 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] In at least one exemplary embodiment, when at least one of the cell density, the cell confluency, the cell viability, and the cell diameter exceeds a predetermined threshold, the control system may be configured to change at least one parameter among 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.

[0027] <� Further applicable ranges will become apparent from the description provided herein. The description and specific examples in this summary are intended for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0028] The drawings in this specification are for the purpose of illustrating only selected embodiments and are not intended to limit the scope of the disclosure to all possible implementations.

Brief Description of the Drawings

[0029] [Figure 1] FIG. 1 is a diagram of an example of a cell growth system having a bioreactor according to at least one exemplary embodiment of the present disclosure. [Figure 2] FIG. 2 is a diagram of an example of a bioreactor showing a circulation path through the bioreactor incorporated into a cell growth system similar to the cell growth system illustrated in FIG. 1 according to at least one exemplary embodiment of the present disclosure. [Figure 3] FIG. 3 is a diagram of an example of a rocking device configured to move a bioreactor similar to the bioreactor of FIG. 2 according to at least one exemplary embodiment of the present disclosure. [Figure 4] FIG. 4 is a schematic diagram showing an example of a flow path of a cell growth system similar to the cell growth system shown in FIG. 1 according to at least one exemplary embodiment of the present disclosure. [Figure 5A] FIG. 5A is a diagram of an exemplary bioreactor having a first end cap and an opposite second end cap according to at least one exemplary embodiment of the present disclosure. [Figure 5B] FIG. 5B is a diagram of the surface of the first end cap of the bioreactor of FIG. 5A, the surface including a plurality of sensors according to at least one exemplary embodiment of the present disclosure. [Figure 5C] FIG. 5C is a diagram of the surface of the second end cap of the bioreactor of FIG. 5A, the surface including a plurality of sensors according to at least one exemplary embodiment of the present disclosure. [Figure 5D] FIG. 5D is a diagram of the surface of the housing constituting the bioreactor of FIG. 5A, the surface of the housing including a plurality of sensors according to at least one exemplary embodiment of the present disclosure.

Modes for Carrying Out the Invention

[0030] The corresponding reference numerals indicate the corresponding parts in the above diagram.

[0031] Exemplary embodiments will be described in more detail with reference to the accompanying drawings.

[0032] Exemplary embodiments are provided to those skilled in the art so that the disclosure may be complete and its scope fully conveyed. Numerous specific details, such as examples of specific components, apparatus, and methods, are described in order to provide a complete understanding of the embodiments of the disclosure. It will be apparent to those skilled in the art that specific details are not necessary, that the exemplary embodiments may be embodied in many different forms, and that none should be construed as limiting the scope of the disclosure. In some exemplary embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.

[0033] The terms used herein are for illustrative purposes only and are not intended to limit the use of any particular exemplary embodiment. Where used herein, the singular forms “a,” “an,” and “the” are intended to include the plural form unless the context clearly indicates otherwise. The terms “comprises,” “comprising,” “including,” and “having” are inclusive and thus specify the existence of the described features, entities, steps, actions, elements, and / or components, but do not exclude the existence or addition of one or more other features, integers, steps, actions, elements, components, and / or sets thereof. The steps, processes, and actions of the methods described herein should not necessarily be construed as requiring execution in a specific order described or illustrated unless specifically identified as the order of execution. It should also be understood that additional or alternative steps may be used.

[0034] When an element or layer is referred to as "on top of," "engaged to," "connected to," or "bonded to" another element or layer, it may be directly on, directly engaged to, directly connected to, or directly bonded to the other element or layer, or an intervening element or layer may exist. On the other hand, when an element is referred to as "directly on top of," "directly engaged to," "directly connected to," or "directly bonded to" another element or layer, there is no intervening element or layer. Other terms used to describe relationships between elements should be interpreted similarly (e.g., "between" vs. "directly between," "adjacent" vs. "directly adjacent," etc.). As used herein, the term "and / or" includes any and all combinations of one or more of the related enumerated items.

[0035] The terms "first," "second," "third," etc., may be used herein to describe various elements, components, regions, layers, and / or parts, but these elements, components, regions, layers, and / or parts should not be limited by these terms. These terms are used solely to distinguish one element, component, region, layer, or part from other regions, other layers, or other parts. The terms "first," "second," etc., and other numerical terms, when used herein, do not imply order or sequence unless explicitly indicated by the context. Accordingly, the first element, first component, first region, first layer, or first part described below may also be called the second element, second component, second region, second layer, or second part, without departing from the teaching of the exemplary embodiments.

[0036] Terms indicating spatial relationships, such as “inside,” “outside,” “directly below,” “downward,” “below,” “above,” and “up,” are used herein to facilitate explanation when describing the relationship between one element or feature part and other elements or feature parts, as shown in the figures. These terms indicating spatial relationships may be intended to include cases where the device is oriented in different directions during use or operation, in addition to the orientation shown in the figures. For example, if the device in the figures is inverted, an element described as being “below” or “directly below” another element or feature part will be changed accordingly to being “above” that other element or feature part. Therefore, for example, the term “below” may include both upward and downward orientations. The device may be oriented in other directions (by being rotated 90 degrees or in other directions), and the descriptions of spatial relationships used herein shall be interpreted accordingly.

[0037] Various components are referred to herein as “operably connected.” As used herein, “operably connected” refers to components that are connected to one another in an operable manner, and includes embodiments in which components are directly connected, as well as embodiments in which other components are arranged between connected components. “Operatively connected” components can be “fluidically connected.” “Fluidally connected” refers to components that are connected together so that fluid can be transported between them. The term “fluidically connected” includes embodiments in which one component is placed between two fluidly connected components, and embodiments in which components are directly connected, etc. Fluidly connected components may include components that control the system by contacting other components but not by contacting the fluid (for example, a peristaltic pump that pumps fluid through a flexible tube by compressing the outside of the tube).

[0038] In a diagram, the direction indicated by the tip of an arrow usually represents the flow of information (data, commands, etc.) related to the diagram. For example, when element A and element B exchange various types of information, if the information sent from element A to element B is associated with the diagram, the arrow will point from element A to element B. This one-way arrow does not mean that no other information is sent from element B to element A. Furthermore, with respect to the information sent from element A to element B, element B may send a request for that information or an acknowledgment of receipt of that information to element A.

[0039] In this application, which includes the following definitions, the terms “module” or “controller” may be replaced with the term “circuit.” The term “module” may mean, or be part of, or include: application-specific integrated circuits (ASICs); digital, analog, or mixed analog / digital discrete circuits; digital, analog, or mixed analog / digital integrated circuits; combinational logic circuits; field-programmable gate arrays (FPGAs); processor circuits (shared, dedicated, or grouped) that execute code; memory circuits (shared, dedicated, or grouped) that store code executed by the processor circuits; other suitable hardware components that provide the described function; or any combination of some or all of the above, such as a system on a chip.

[0040] A module may include one or more interface circuits. In some examples, the interface circuits include wired or wireless interfaces connected to a local area network (LAN), the internet, a wide area network (WAN), or a combination thereof. The functionality of any given module in this disclosure may be distributed among multiple modules connected via interface circuits. For example, multiple modules enable load balancing. In other examples, a server module (also known as a remote or cloud module) performs some functions on behalf of a client module.

[0041] 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 of the code from multiple modules. The term "group processor circuit" encompasses a processor circuit that, in combination with additional processor circuits, executes some or all of the code from one or more modules. References to multiple processor circuits include multiple processor circuits on separate dies, multiple processor circuits on a single die, multiple cores in a single processor circuit, multiple threads in 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 of the code from multiple modules. The term "group memory circuit" encompasses a memory circuit that, in combination with additional memory, stores some or all of the code from one or more modules.

[0042] The term "memory circuit" is included in what the term "computer-readable medium" refers to. As used herein, the term computer-readable medium does not include transient electrical or electromagnetic signals that propagate through a medium (like a carrier wave), and therefore the term computer-readable medium is considered tangible and non-transient. Non-limiting examples of non-transient tangible computer-readable medium include non-volatile memory circuits (such as flash memory circuits, erasable programmable read-only memory circuits, or mask read-only memory circuits), volatile memory circuits (such as static random-access memory circuits or dynamic random-access memory circuits), magnetic storage media (such as analog or digital magnetic tapes or hard disk drives), and optical storage media (such as CDs, DVDs, or Blu-ray discs).

[0043] The apparatus and methods described in this application may be partially or completely implemented by a dedicated computer created by configuring a general-purpose computer to perform one or more specific functions embodied in a computer program. The aforementioned functional blocks, flowchart components, and other elements function as software specifications, which can be converted into a computer program by the routine work of a skilled technician or programmer.

[0044] A computer program includes processor-executable instructions stored in at least one non-transient, tangible, computer-readable medium. A computer program may also include, or depend on, stored data. A computer program may encompass a basic input / output system (BIOS) that interacts with the hardware of a dedicated computer, device drivers that interact with specific devices of the dedicated computer, one or more operating systems, user applications, background services, background applications, and the like.

[0045] A computer program includes (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; and (v) source code for compilation and execution by a runtime compiler. For example, source code is written using the syntax of 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®.

[0046] The elements described in the claims are not intended to be means-plus-function elements within the meaning of 35 U.S.C. § 112(f), unless the element is expressly described using the expression “means for” or, in the case of a method claim using the expression “action for” or “step for.”

[0047] Exemplary embodiments will be described in more detail with reference to the accompanying drawings.

[0048] This disclosure relates to a capacitive cell mass sensor for a cell proliferation system, and a method for integrating the capacitive cell mass sensor into a cell proliferation system, as well as a method for providing and using the same. An example of such a cell proliferation system is described in U.S. Patent No. 10,577,585, issued March 3, 2020 (title “Cell Proliferation”). The entire disclosure of the above patent is incorporated herein by this reference. A cell proliferation system, also commonly referred to as a hollow fiber bioreactor, is a cell culture system used to grow and differentiate cells, including both adherent and non-adherent cell types. For example, as shown in Figure 1, an exemplary cell proliferation system 10 has a first fluid circulation channel 12 and a second fluid circulation channel 14. The first fluid circulation channel 12 includes, for example, a first fluid channel 16 having opposing ends 18, 20. The first fluid channel 16 may be in fluid communication with a hollow fiber cell growth chamber 24 (also called a “bioreactor”). For example, the first end 18 of the first fluid channel 16 is in fluid communication with the first inlet 22 of the cell growth chamber 24, and the second end 20 is in fluid communication with the first outlet 28 of the cell growth chamber 24. The fluid in the first fluid circulation channel 12 can flow through the interior of multiple hollow fibers 116 of a hollow fiber membrane ("HFM") 117 (see, for example, Figure 2) located inside the cell growth chamber 24. In at least one exemplary embodiment, a first flow control device 30 may be operably coupled to the first fluid channel 16 to control the flow of fluid in the first fluid circulation channel 12.

[0049] The second fluid circulation path 14 includes, for example, a second fluid passage 34 and a second flow control device 32. Similar to the first fluid passage 16, the second fluid passage 34 has opposing ends 36 and 38. The opposing ends 36 and 38 of the second fluid passage 34 may be in fluid communication with the inlet port 40 and outlet port 42 of the cell growth chamber 24. For example, the first end 36 of the second fluid passage 34 is in fluid communication with the inlet port 40 of the cell growth chamber 24, and the second end 38 of the second fluid passage 34 is in fluid communication with the outlet port 42. The fluid in the second fluid circulation path 14 is in contact with the outside of the hollow fiber membrane 117 (see, for example, Figure 2) located inside the cell growth chamber 24. In at least one exemplary embodiment, the second flow control device 32 may be operably coupled to the second fluid passage 34 to control the flow of fluid in the second fluid circulation path 14.

[0050] The first and second fluid circulation channels 12 and 14 are maintained within the cell growth chamber 24 by a hollow fiber membrane 117. In this case, the fluid in the first fluid circulation channel 12 flows through the capillary inner ("IC") space (also called the inner porous space) of the hollow fiber membrane 117, and the fluid in the second fluid circulation channel 14 flows through the capillary outer ("EC") space (interporous space) of the cell growth chamber 24. The first fluid circulation channel 12 is also called the "capillary inner loop" or "IC loop." The second fluid circulation channel 14 is also called the "capillary outer loop" or "EC loop." The fluid in the first fluid circulation channel 12 may flow in either a parallel or counter-flow direction relative to the fluid flow in the second fluid circulation channel 14.

[0051] In at least one exemplary embodiment, a fluid inlet passage 44 is fluidically associated with a first fluid circulation passage 12, and a fluid outlet passage 46 is fluidically associated with a second fluid circulation passage 14. The fluid inlet passage 44 allows fluid to enter the first fluid circulation passage 12, while the fluid outlet passage 46 allows fluid to exit the cell proliferation system 10. In at least one exemplary embodiment, a third flow control device 48 is operably associated with the fluid inlet passage 44, as shown. It should be noted that in other exemplary embodiments, a fourth flow control device may be operably associated with the first outlet passage 46, either alternatively or additionally, although not shown. In at least one exemplary embodiment, the flow control devices (including the first flow control device 30, the second flow control device 32, the third flow control device 48, and / or the fourth flow control device) include pumps, valves, clamps, or any combination thereof. For example, multiple pumps, multiple valves, and multiple clamps may be arranged in any combination. In at least one exemplary embodiment, the flow control device may be a peristaltic pump or may include a peristaltic pump. The fluid circulation pathways (including the first fluid circulation pathway 12 and / or the second fluid circulation pathway 14), the inlet port (including the fluid inlet port 44), and / or the outlet port (including the fluid outlet port 46) may include any known tubular material, and any type of fluid, such as buffer, protein-containing fluid, and cell-containing fluid, can flow through the various circulation pathways (including the first fluid circulation pathway 12 and / or the second fluid circulation pathway 14), the inlet pathway (including the fluid inlet port 44), and the outlet pathway (including the fluid outlet port 46). It should be noted that the terms “fluid,” “culture medium,” and “fluid culture medium” are used interchangeably.

[0052] An exemplary hollow fiber cell growth chamber 100 (also called a “bioreactor”) is shown in Figure 2. The hollow fiber cell growth chamber 100 may be used as the hollow fiber cell growth chamber 24 of the cell proliferation system 10 shown in Figure 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 has four openings or four ports, including, for example, an internal capillary inlet port 108, an internal capillary outlet port 120, an external capillary inlet port 128, and an external capillary outlet port 132. The first fluid (also called capillary fluid or capillary medium) in the first circulation path (such as the first fluid circulation path 12) enters the cell growth chamber 100 through the capillary inlet port 108 at the first longitudinal end 112 of the cell growth chamber 100, enters the capillary interior of a plurality of hollow fibers 116, passes through them, and exits the cell growth chamber 100 through the capillary outlet port 120 located at the second longitudinal end 124 of the cell growth chamber 100. The flow path between the capillary inlet port 108 and the capillary outlet port 120 constitutes the capillary interior portion 126 of the cell growth chamber 100. The second fluid (also called the capillary outer medium or capillary outer fluid) in the second circulation path (such as the second fluid circulation path 14) enters the cell growth chamber 100 through the capillary outer inlet port 128, comes into contact with the capillary outer or outer side of the hollow fiber membrane 117, and exits the cell growth chamber 100 through the capillary outer outlet port 132. The fluid path between the capillary outer inlet port 128 and the capillary outer outlet port 132 constitutes the capillary outer portion 136 of the cell growth chamber 100.

[0053] When the second fluid comes into contact with the outside of the hollow fiber 116, small molecules (e.g., ions, water, oxygen, lactate, etc.) can diffuse and / or flow in large quantities through the hollow fiber 116 from the inside of the hollow fiber 116, i.e., the capillary inner space, to the outside, i.e., the capillary outer space, or alternatively or additionally, from the capillary outer space to the capillary inner space. For example, molecules with large molecular weights (e.g., growth factors) are often too large to pass through the hollow fiber 116 and remain in the capillary inner space (or alternatively or additionally, the capillary outer space) of the hollow fiber 116. The culture media constituting the first and second fluids may be replaced as needed, and alternatively or in addition, gas may be exchanged by circulating them through an oxygen supplyer and / or gas transfer module as needed. As described below, cells for proliferation are housed in the first fluid circulation pathway 12 and / or the second fluid circulation pathway 14 and enter the hollow fiber cell growth chamber 100 either inside or outside the capillary tube, or both.

[0054] In at least one exemplary embodiment, cells are seeded in the capillary inner space of the hollow fiber 116 (for proliferation, differentiation, and / or harvesting, e.g., umbilical cord blood-derived CD34+ hematopoietic stem cells / progenitor cells, monocytes, macrophages, hepatocytes, and / or endothelial cells), while the cell culture medium is pumped through the capillary outer space of the hollow fiber 116, and nutrients are delivered to the cells via hollow fiber membrane perfusion during proliferation. However, in at least one other exemplary embodiment, cells for proliferation may be seeded in the capillary outer space, while the cell culture medium is pumped through the capillary inner space, and nutrients are delivered to the cells via hollow fiber membrane perfusion during proliferation. In at least one other exemplary embodiment, cells for proliferation may be seeded in the capillary inner space, while the cell culture medium may be pumped through both the capillary outer and inner spaces. The movement of the cell culture medium in the capillary inner space and / or capillary outer 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 prepare the hollow fiber membrane 117 may be any biocompatible polymer material, as long as it becomes a hollow fiber 121. For example, synthetic polysulfone materials (e.g., polyethersulfone (PES)) are often used to form the hollow fibers.

[0055] In at least one exemplary embodiment, the cell growth system 10 has a device configured to move, i.e., "rock" the cell growth chamber 100 relative to other parts of the cell growth system 10. The device may be a rotational and / or lateral rocking device. For example, as shown in Figure 3, the cell growth chamber (also called a bioreactor) 100 may be rotatably connected to one or more rotational rocking components 138 and lateral rocking components 140. The first rotational rocking component 138 may be rotatably associated with the bioreactor 100. For example, the first rotational rocking component 138 is configured to rotate the bioreactor 100 about a first axis or central axis of rotation (central axis) 142. In at least one exemplary embodiment, the bioreactor 100 can rotate continuously about the central axis 142 in a single direction (clockwise or counterclockwise). In at least one exemplary embodiment, the bioreactor 100 may be rotated alternately, for example, in a clockwise direction which is a first direction, and then in a counterclockwise direction which is a second direction, about a central axis 142.

[0056] It should be noted that, although not shown, in other exemplary embodiments, the second rotational oscillating component may be configured to move the bioreactor 100 about a second axis of rotation 144 that passes through the center point of the bioreactor 100 perpendicular to the central axis 142. In at least one exemplary embodiment, the bioreactor 100 can rotate continuously in a single direction (clockwise or counterclockwise) about the second axis of rotation 144. In at least one exemplary embodiment, the bioreactor 100 may rotate alternately, for example, in a first direction, which is clockwise, and then in a second direction, which is counterclockwise, about the second axis 144. In at least one exemplary embodiment, the bioreactor 100 may be rotated about the second axis 144 to be oriented horizontally or vertically to gravity. The lateral oscillating component 140 is associated with the bioreactor 100 laterally. For example, the plane of the lateral oscillating component 140 can move laterally in the x and y directions.

[0057] The rotation and / or lateral movement of the bioreactor 100 reduces cell sedimentation and also reduces the likelihood of cells becoming trapped in a portion of the bioreactor 100. In at least one exemplary embodiment, the cell sedimentation rate in the cell growth chamber 100 is proportional to the density difference between the cells and the suspension medium, according to Stokes' equation. In at least one exemplary embodiment, as described above, repeating 180-degree rotations with pauses (high speed) (e.g., operation with a total of 30 seconds of combined pause and rotation) helps maintain the suspension of non-adherent cells (e.g., erythrocytes). A minimum rotation of about 180 degrees is preferred, but various rotation angles including up to 360 degrees or more can be used. Different oscillating components may be used separately or in combination. For example, an oscillating component that rotates the bioreactor 100 around a central axis 142 can be combined with an oscillating component that rotates the bioreactor 100 around a second axis 144. Similarly, clockwise and counterclockwise rotations can be independently combined around different axes.

[0058] Figure 4 is a schematic diagram of an exemplary cell proliferation system 500, similar to the cell proliferation system 10 shown in Figure 1, showing exemplary flow paths. In at least one exemplary embodiment, cells are located in the inner capillary space, while the cell culture medium is pumped in the outer capillary space to deliver nutrients to the cells via hollow fiber membrane perfusion during proliferation. However, it should be noted that in at least one other exemplary embodiment, cells may be located in the outer capillary space, while the cell culture medium may be pumped in the inner capillary space to deliver nutrients to the cells via hollow fiber membrane perfusion during proliferation. In at least one other exemplary embodiment, cells are located in the inner capillary space, while the cell culture medium is pumped in both the outer and inner capillary spaces.

[0059] As illustrated, the cell growth system 500 includes a first fluid circulation channel 502 (also called the “inner capillary loop” or “IC loop”) and a second fluid circulation channel 504 (also called the “outer capillary loop” or “EC loop”). The first fluid channel 506 is fluidically associated with the cell growth chamber (also called the “bioreactor”) 501 to constitute the first fluid circulation channel 502. The cell growth chamber 501 may be used as the hollow fiber cell growth chamber 24 shown in Figure 1 and / or the hollow fiber cell growth chamber 100 shown in Figure 1. The first fluid flows into the cell growth chamber 501 (e.g., in large quantities (profuse)) through the inner capillary inlet port 501A. The first fluid exits the cell growth chamber through the inner capillary outlet port 501B. In at least one exemplary embodiment, the first fluid circulation path 502 is provided with a pressure gauge 510 configured to measure the pressure of the first fluid exiting the cell growth chamber 501. In at least one exemplary embodiment, the first fluid circulation path 502 is provided with an internal capillary circulation pump 512 configured to control the flow rate of the first fluid. For example, the internal capillary circulation pump 512 is configured to pump the fluid in a first direction or a second direction opposite to the first direction. In the latter case, the internal capillary outlet port 501B is used as an inlet and the internal capillary inlet port 501A is used as an outlet. In at least one exemplary embodiment, the first fluid circulation path 502 includes a sample port 516 and / or a sample coil 518 configured for extracting a sample of the first fluid. In at least one exemplary embodiment, the first fluid circulation path 502 is provided with a pressure / thermometer 520 configured to detect the pressure and / or temperature of the first fluid during operation. In at least one exemplary embodiment, a first fluid can enter the capillary inner loop 502 via valve 514. In at least one exemplary embodiment, a portion of the cells are flowed from the capillary inner loop 502 into a harvest bag 599, for example, via valve 598.It should be understood that in at least one other exemplary embodiment, several valves, pressure gauges, pressure sensors, temperature sensors, ports, and / or other devices may be added or removed in the first fluid circulation path 502 to isolate the first fluid along some portion of the capillary inner loop 502 and / or to measure the properties of the first fluid in some portion.

[0060] The second fluid can flow into the cell growth chamber 501 (e.g., in large quantities (profusely)) through the capillary outer inlet port 501C. The second fluid can exit the cell growth chamber 501 through the capillary outer outlet port 501D. In at least one exemplary embodiment, the second fluid in the capillary outer loop 504 comes into contact with the outer-facing surfaces of the hollow fibers placed in the cell growth chamber 501, thereby allowing the diffusion of small molecules into and out of the hollow fibers. In at least one exemplary embodiment, the capillary outer loop 504 is provided with a pressure / thermometer 524 configured to measure the pressure and / or temperature of the second fluid before it enters the cell growth chamber 501. In at least one exemplary embodiment, the capillary outer loop 504 is provided with a pressure gauge 526 configured to measure the pressure of the second fluid, for example, when the second fluid exits the cell growth chamber 501. In at least one exemplary embodiment, the capillary outer loop 504 is provided with a sample port 530 configured for a second fluid sample extraction.

[0061] In at least one exemplary embodiment, the capillary outer loop 504 is provided with an outer capillary circulation pump 528 and an oxygen supply or gas transfer module 532. For example, after leaving the cell growth chamber 501, the second fluid passes through the outer capillary circulation pump 528 to the oxygen supply or gas transfer module 532 and through it. In at least one exemplary embodiment, the outer capillary circulation pump 528 is configured to control the flow rate of the second fluid. For example, the outer capillary circulation pump 528 is configured to pump the second fluid in a first direction or in a second direction opposite to the first direction, similar to the inner capillary circulation pump 512. In the latter case, the outer capillary outlet port 501D is used as an inlet and the outer capillary inlet port 501C is used as an outlet.

[0062] In at least one exemplary embodiment, the second fluid passage 522 is fluidly associated with the oxygen supply or gas transfer module 532 via an oxygen supply inlet port 534 and an oxygen supply outlet port 536. For example, the second fluid flows into the oxygen supply or gas transfer module 532 via the oxygen supply inlet port 534 and flows out of or out of the oxygen supply or gas transfer module 532 via the oxygen supply outlet port 536. In at least one exemplary embodiment, the oxygen supply or gas transfer module 532 is configured to add oxygen to the second fluid and / or remove bubbles from the second fluid. For example, air and / or gas flows into the oxygen supply or gas transfer module 532 via a first filter 538 and flows out of or out of (i.e., out of) the oxygen supply or gas transfer module 532 through a second filter 540. The first and second filters 538, 540 are configured to reduce or prevent contaminants from entering the oxygen supply or gas transfer module 532. The second fluid in the second fluid circulation path 504 is in equilibrium with the gas entering the oxygen supply or gas transfer module 532. In at least one exemplary embodiment, air and / or gas is purged from the cell proliferation system 500, for example, during the priming sequence, and the air and / or gas is released into the atmosphere via the oxygen supply or gas transfer module 532. In at least one other exemplary embodiment, it should be understood that in the second fluid circulation path 504, several valves, pressure gauges, pressure sensors, temperature sensors, ports, and / or other devices may be added or removed to isolate the second fluid along several portions of the capillary outer loop 504 and / or to measure the properties of the second fluid in several portions.

[0063] In at least one exemplary embodiment, an air removal chamber (ARC) 556 is fluidically associated with a first fluid 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 and / or lower sensors configured to detect the absence of air and / or fluid and / or the gas-fluid interface at specific measurement locations within the air removal chamber 556. The upper sensor may be located near a first end (e.g., the top) of the air removal chamber 556. The lower sensor may be located near a second end (e.g., the bottom) of the air removal chamber 556. While ultrasonic sensors are described, it should be understood that in other embodiments, the air removal chamber 556 may additionally or alternatively include one or more other sensors, such as optical sensors. Air and / or gases purged from the cell proliferation system 500 during part of the priming process and / or other protocols can be vented to the atmosphere through an air valve 560 via a line 558 fluidically associated with the air removal chamber 556.

[0064] In at least one exemplary embodiment, the first fluid includes, for example, cells from a first fluid container (also called a first culture bag or first bag) 562 and a fluid culture medium (e.g., capillary culture medium or fluid) from a second fluid container (also called a second culture bag or second bag) 546. The material from the first and second fluid containers 562, 546 (i.e., cells and / or capillary culture medium) can enter a first fluid circulation path 502 via a first fluid channel 506. The first fluid container 562 is fluidically associated with the first fluid channel 506 and the first fluid circulation path 502 via a valve 564. In at least one exemplary embodiment, the second fluid container 546 and the third fluid container (also called the third culture bag or third bag) 544 are associated with the first fluid inlet passage 542, for example, via valves 548 and 550, respectively, or are fluidically associated with the second fluid inlet passage 574, for example, via valves 570 and 576, respectively. In at least one exemplary embodiment, material from the second fluid container 546 and / or the third fluid container 544 may be in fluid communication with the first sterile-sealable input priming passage 508 and / or the second sterile-sealable input priming passage 509.

[0065] In at least one exemplary embodiment, a fourth fluid container (also called a fourth culture bag or fourth bag) 568 contains capillary outer culture medium, and a fifth fluid container (also called a fifth culture bag or fifth bag) 566 contains a washing solution. Substances from the fourth and fifth fluid containers 568, 566 (i.e., capillary outer culture medium and / or washing solution) can enter a first fluid circulation path 502 and / or a second fluid circulation path 504. For example, in at least one exemplary embodiment, the fifth fluid container 566 is fluidically associated with a valve 570. The valve 570 is fluidically associated with the first fluid circulation path 502, for example, via a distribution valve 572 and a first fluid inlet path 542. In at least one exemplary embodiment, a fifth fluid vessel 566 can be fluidically associated with a second fluid circulation passage 504 via a second fluid inlet passage 574 and a capillary outer inlet passage 584, for example, by opening valve 570 and closing distribution valve 572. A fourth fluid vessel 568 is fluidically associated with valve 576. Valve 576 is fluidically associated with a first fluid circulation passage 502, for example, via a first fluid inlet passage 542 and distribution valve 572. In at least one exemplary embodiment, a fourth fluid vessel 568 can be fluidically associated with a second fluid inlet passage 574 by opening valve 576 and closing distribution valve 572. In at least one exemplary embodiment, the first fluid inlet passage 542 and / or the second fluid inlet passage 574 may optionally be fluidically associated with a heat exchanger 552.

[0066] In at least one exemplary embodiment, fluid is transferred from a first fluid inlet passage 542 and / or a second fluid inlet passage 574 to an inner capillary loop 502 via an inner capillary inlet pump 554, and fluid is also transferred to an outer capillary loop 504 via an outer capillary inlet pump 578. In at least one exemplary embodiment, an air detector 580 may also be associated with an outer capillary inlet passage 584. The air detector 580 may include, for example, an ultrasonic sensor. In at least one exemplary embodiment, the first fluid circulation passage 502 and the second fluid circulation passage 504 may be fluidically associated with a waste line 588. For example, when valve 590 is open or in the open position, the inner capillary culture medium flows through the waste line 588 to a waste bag (also called an outlet bag) 586. When valve 582 is opened, the outer capillary culture medium flows through the waste line 588 to the waste bag 586. In at least one exemplary embodiment, cells are harvested, for example, via a cell harvesting pathway 596. For example, cells can be harvested from the cell growth chamber 501 by pumping the capillary culture medium containing the cells into a cell harvesting bag 599 via the cell harvesting pathway 596 and valve 598.

[0067] In at least one exemplary embodiment, as shown, the fluids 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., parallel flow configuration). It should be understood that in other exemplary embodiments, though not shown, the cell growth system 500 may be configured to flow in a counterflow configuration. As shown in Figure 4, the fluid in the first fluid circulation path 502 enters the bioreactor 501 at the capillary inlet port 501A and leaves or exits the bioreactor 501 at the capillary inlet port 501B. In at least one exemplary embodiment, the first fluid passage 506 is via, for example, a connection 517. The connection 517 may be a point or position where the fluid flows in both opposing directions, based on, for example, the direction of the capillary inlet pump 554. The connection 517 may be any type of fitting, coupling, weld, path, and / or tube, etc., that allows the first fluid passage to be fluidically associated with the first fluid circulation path 502. In at least one exemplary embodiment, the connection 517 may include a T-joint or T-connection, and / or a Y-joint or Y-connection.

[0068] In at least one exemplary embodiment, one or more measuring instruments (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, and / or valve 598), one or more ports (e.g., capillary inner inlet port 501A, capillary inner outlet port 501B, capillary outer inlet port 501C, capillary outer outlet port 501D, sample port 516, sample port 530, acid The element supply inlet port 534 and / or oxygen supply outlet port 536), one or more pumps (e.g., capillary internal circulation pump 512, capillary external circulation pump 528, capillary internal inlet pump 554, and / or capillary external inlet pump 578), one or more filters (e.g., a first filter 538 and / or a second filter 540), one or more coils (e.g., a sample coil 518), one or more modules (e.g., an oxygen supply or gas transfer module 532), and / or one or more other components of the cell proliferation system 500 may communicate electrically with a control system (not shown). The control system may include a plurality of nodes, which may include various hardware, firmware, and / or software (e.g., controllers and memory) configured to control and / or communicate with the mechanical, electromechanical, and electrical components of the cell proliferation system 500.

[0069] The controller (also called a processor) may be any type of microcontroller, microprocessor, field-programmable gate array (FPGA), application-specific integrated circuit (ASIC), etc. An example of a controller may be the NK10DN512VOK10 microcontroller, manufactured and sold by N9P USA, Incorporated, which is a microcontroller unit with a 32-bit architecture. Other examples of controllers include 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 coprocessor, Samsung® Exynos® series, Intel® Core® processor family, Intel® Xeon® processor family, Intel® Atom® processor family, Intel Itanium® processor family, Intel® Core® i5-4670K and i7-4770K 22nm Haswell, Intel® Core® i5-3570K 22nm IvyBridge, AMD® FX® processor family, AMD® FX-4300, FX-6300, and FX-8350 32nm Vishera may include at least one of the following: AMD® Kaveri processors, ARM® Cortex®-M processors, ARM® Cortex-A and ARM926EJ-S® processors, or other equivalent processors, and may perform computer functions using any known or future-developed standard instruction sets, libraries, and / or architectures.The memory may be any type of memory, including random access memory (RAM), read-only memory (ROM), electrically erasable programmable ROM (EEPROM), portable compact disk read-only memory (CD-ROM), optical memory, magnetic memory, any suitable combination thereof, or any other type of memory or memory device that stores and provides instructions for programming and controlling the controller.

[0070] As described above, cells are seeded in the capillary inner space of a cell growth chamber (also called a bioreactor) having a hollow fiber membrane (for proliferation, differentiation, and / or harvesting, e.g., umbilical cord blood-derived CD34+ hematopoietic stem cells / progenitor cells, monocytes, macrophages, hepatocytes, and / or endothelial cells), while the cell culture medium is pumped through the capillary outer space of the cell growth chamber, and nutrients are delivered to the cells via hollow fiber membrane perfusion during proliferation. However, in at least one other exemplary embodiment, cells for proliferation may be seeded in the capillary outer space, while the cell culture medium is pumped through the capillary inner space, and nutrients are delivered to the cells via hollow fiber membrane perfusion during proliferation. In at least one other exemplary embodiment, cells for proliferation may be seeded in the capillary inner space, while the cell culture medium is pumped through both the capillary outer and inner spaces.

[0071] In each exemplary embodiment, it may be desirable to collect information in real time about the material (e.g., cells) held within the bioreactor (e.g., bioreactor 24 shown in Figure 1, bioreactor 100 shown in Figure 2, and bioreactor 501 shown in Figure 4). For example, in at least one exemplary embodiment, the collection and processing of real-time information enables monitoring and / or control of primary cell proliferation. Monitoring and / or control of primary cell proliferation may include the collection and processing of oxygen consumption data, acidity data, and / or cell density data. Oxygen consumption data may be used to monitor and / or control, for example, cellular respiration, cell viability, and self-renewal control. Acidity data may be used to monitor and / or control, for example, buffering capacity, cell membrane integrity, and / or metabolite transport. Cell density data may be used to monitor and / or control, for example, cell signaling, seeding, proliferation, differentiation, and / or harvesting.

[0072] Monitoring and / or control of primary cell proliferation can be at least partially automated via one or more pre-configured feedback control loops. In at least one exemplary embodiment, the collection and processing of real-time information enables monitoring and / or control of cellular metabolites. Cellular metabolite data can be used to monitor and / or control nutrient levels (e.g., glucose, lactate, glutamine, and / or ammonia) within the bioreactor. Monitoring and / or control of cellular metabolite proliferation can be at least partially automated via one or more pre-configured feedback control loops.

[0073] In at least one exemplary embodiment, the collection and processing of real-time information may enable monitoring and / or control of cell products. Cell product data may include information on 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, diagnosis, and / or therapy. Monitoring and / or control of cell products may be at least partially automated via one or more pre-configured feedback control loops. In at least one exemplary embodiment, the collection and processing of real-time information may enable monitoring and / or control of primary cell proliferation, and / or monitoring and / or control of cell metabolite proliferation, and / or monitoring and / or control of cell products.

[0074] One or more sensors are positioned inside or on a bioreactor (such as bioreactor 24 shown in Figure 1, bioreactor 100 shown in Figure 2, or bioreactor 501 shown in Figure 4) and are configured to collect and / or monitor events in the bioreactor in real time. For example, in at least one exemplary embodiment, one or more sensors are positioned inside or on at least one of the end caps of the bioreactor. For example, as shown in Figures 5A and 5B, a plurality of sensors 610 are positioned inside or on at least one of the first header end cap 612 and second header end cap 614 of the bioreactor 600. As shown in Figure 5A, the first header end cap 612 faces the second header end cap 614, and the first end cap 612 and the second end cap 614 cooperate to close the bioreactor 600.

[0075] The bioreactor may be such as bioreactor 24 shown in Figure 1, or such as bioreactor 100 shown in Figure 2, or such as bioreactor 501 shown in Figure 4. Examples of the multiple sensors 610 include cell volume sensors (such as those provided by Aber Instruments Ltd.). In at least one exemplary embodiment, the multiple sensors 610 are arranged radially on each surface, as shown in Figure 5B (enlarged view of the outer surface 616 of the first end cap 612) and Figure 5C (enlarged view of the outer surface 618 of the second end cap 614). While four sensors 610 are shown in Figures 5B and 5C, it should be understood that in other exemplary embodiments, one or more sensors 610 may be located on the first header end cap 612 and / or the second header end cap 614. Furthermore, although the outer surfaces 616, 618 are shown in Figures 5B and 5C, it should be understood that in other exemplary embodiments, multiple sensors 610 may be located on or near the inner surfaces of the first end cap 612 and / or the second end cap 614. Furthermore, although the sensors 610 are shown in Figures 5B and 5C as distinct individual sensors, it should be understood that in other exemplary embodiments, a single sensor having one or more regions, i.e., a series of sensors, may be used. In each case, by arranging the sensors 610 on at least one (inside or outside) of the end caps 612, 614, the sensor array (i.e., multiple sensors 610) can measure the length and depth, as well as the concentration, of the cell distribution over a specified volume and surface area in the bioreactor 600.

[0076] In at least one other exemplary embodiment, one or more sensors 610 may be arranged on the outer surface 652 of the housing 650 defining the bioreactor 600. Here, as an example, the housing 650 is shown in an unformed or flattened state. As shown, the sensors 610 may be arranged longitudinally along the perimeter of the bioreactor 600, such arrangement allowing the sensor array (i.e., multiple sensors 610) to measure both the length and depth and concentration of the cell distribution over a defined volume and surface area of ​​the bioreactor 600. Nine sensors 610 are shown in Figure 5D, but it should be understood that in other exemplary embodiments, one or more sensors 610 may be arranged on the inner surface of the housing 650. Furthermore, although Figure 5D shows a separate sensor 610, it should be understood that in other exemplary embodiments, one or more continuous sensors (e.g., a sensor strip) extending over a substantial portion of the longitudinal axis length of the bioreactor 600 (e.g., more than about 25%) may be used similarly. Also, although Figure 5D shows an outer surface 652, it should be understood that in other exemplary embodiments, one or more sensors 610 may be located on or near the inner surface of the housing 650 defining the bioreactor 600 (e.g., the capillary outer space of the bioreactor 600).

[0077] Although not shown, in other exemplary embodiments, it should be understood that one or more sensors include a first group of sensors (e.g., cell quantity sensors provided by Aber Instruments Ltd.) located inside or on (outside or inside) at least one of the end caps of the bioreactor, and a second group of sensors (e.g., cell quantity sensors provided by Aber Instruments Ltd.) located on the outer surface of the bioreactor housing.

[0078] Although not shown, in other exemplary embodiments, it should be understood that one or more sensors may include sensors located in the capillary space outside the bioreactor (e.g., cell volume sensors provided by Aber Instruments Ltd.).

[0079] Although not shown, in other exemplary embodiments, it should be understood that one or more sensors include a first group of sensors (e.g., cell mass sensors provided by Aber Instruments Ltd.) located inside or on (outside or inside) at least one end cap of the bioreactor's end caps, and a second group of sensors (e.g., cell mass sensors provided by Aber Instruments Ltd.) located in the capillary outer space of the bioreactor.

[0080] In each example, each of one or more sensors is configured to measure the cellular capacitance and / or cellular impedance of charge-retaining intact cells and provide this information to the control system individually or collectively. The measured cellular capacitance and / or cellular impedance can be correlated with cell density and / or cell confluence and / or cell viability and / or cell diameter. For example, cell density and / or cell confluence and / or cell viability and / or cell diameter can be determined by quantifying the cellular capacitance and / or cellular impedance.

[0081] In at least one exemplary embodiment, one or more sensors are configured to quantify cell capacitance and / or cell impedance and optionally transmit the information to a control system. In at least one exemplary embodiment, one or more sensors are configured to transmit cell capacitance data and / or cell impedance data to a control system, and the control system is configured to quantify cell capacitance and / or cell impedance. In response to receiving cell capacitance data and / or cell impedance data and / or quantified cell capacitance and / or cell impedance, the control system may be configured to initiate one or more actions.

[0082] For example, in at least one exemplary embodiment, if the cell density is above or below a desired threshold, the control system is configured to adjust (e.g., increase or decrease) the inlet flow rate in the capillary inner space of the bioreactor, for example, to support cells in the exponential growth phase. In at least one exemplary embodiment, if the cell density is above or below a desired threshold, the control system is configured to adjust (e.g., increase or decrease) the circulating flow rate in the capillary outer space, for example, to increase the gas supply for the purpose of maintaining oxygen levels at high cell densities. In at least one exemplary embodiment, if the cell density is above or below a desired threshold, the control system is configured to adjust (e.g., increase or decrease) the inlet flow rate in the capillary outer space to control metabolic waste products such as lactic acid (lactate) or glutamate by introducing appropriate buffering components.

[0083] The above description of embodiments is provided for illustrative and explanatory purposes only. 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 and, where applicable, may be used in selected embodiments, even if not specifically illustrated or described. The same may be modified in many ways. Such modifications should not be considered deviations from the disclosure, and all such variations are intended to be within the scope of the disclosure.

Claims

1. A cell proliferation system, wherein the cell proliferation system is 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, One or more sensors configured to measure at least one of cell capacitance and cell impedance, and configured to communicate with the control system which communicates with at least one of the first fluid circulation path and the second fluid circulation path, Equipped with, Cell proliferation system.

2. In the cell proliferation system according to claim 1, The bioreactor includes a housing that holds the first fluid circulation path and the second fluid circulation path, the bioreactor has a first end cap and a second end cap opposite to the first end cap, and the one or more sensors are positioned on or near at least one of the first end cap and the second end cap. Cell proliferation system.

3. In the cell proliferation system according to claim 2, The one or more sensors are arranged on or near the outer surface of at least one of the first and second end caps. Cell proliferation system.

4. In the cell proliferation system according to claim 2, The one or more sensors are arranged on the inner surface of at least one of the first and second end caps. Cell proliferation system.

5. In the cell proliferation system according to claim 2, The one or more sensors include a cell quantity sensor. Cell proliferation system.

6. In the cell proliferation system according to claim 2, The one or more sensors include a sensor strip extending along the length of the major axis of at least one of the first and second end caps. Cell proliferation system.

7. In the cell proliferation system according to claim 2, The one or more sensors include a first sensor disposed on or near at least one of the first and second end caps, and a second sensor disposed on or near another end cap, which is different from the at least one of the first and second end caps. Cell proliferation system.

8. In the cell proliferation system according to claim 2, The one or more sensors include a first sensor and a second sensor, the first sensor being positioned on or near at least one of the first and second end caps, the bioreactor being defined by a housing having an outer surface and an inner surface, and the second sensor being positioned on or near the outer surface. Cell proliferation system.

9. In the cell proliferation system according to claim 8, The second sensor includes a sensor strip extending along the longitudinal axis of the housing, Cell proliferation system.

10. In the cell proliferation system according to claim 8, The second sensor includes a cell quantity sensor. Cell proliferation system.

11. In the cell proliferation system according to claim 1, The bioreactor is defined by a housing having an outer surface and an inner surface, and the one or more sensors are arranged on or near the outer surface. Cell proliferation system.

12. In the cell proliferation system according to claim 11, The one or more sensors include a sensor strip extending along the longitudinal axis length of the housing. Cell proliferation system.

13. In the cell proliferation system according to claim 12, The sensor strip extends over at least 25% of the total length of the longitudinal axis of the housing. Cell proliferation system.

14. In the cell proliferation system according to claim 11, The one or more sensors include a cell quantity sensor. Cell proliferation system.

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

16. In the cell proliferation system according to claim 15, If at least one of the cell density, cell confluence, 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. Cell proliferation system.

17. In the cell proliferation system according to claim 15, If at least one of the cell density, cell confluence, cell viability, and cell diameter exceeds 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. Cell proliferation system.

18. In the cell proliferation system according to claim 1, The one or more sensors are configured to correlate at least one of the cell capacitance and cell impedance in the first or second fluid circulation path with at least one of the cell density, cell confluence, cell viability, and cell diameter, and to transmit the cell density to the control system. Cell proliferation system.

19. In the cell proliferation system according to claim 18, If at least one of the cell density, cell confluence, 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. Cell proliferation system.

20. In the cell proliferation system according to claim 18, If at least one of the cell density, cell confluence, cell viability, and cell diameter exceeds 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. Cell proliferation system.

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