Sampling device and cell culture system

Abstract

A cell culture system (10) (sampling device (60)) collects a liquid sample from a culture device (11) to a sampling path (64) via a sample introduction path (130). This sampling device (60) comprises a main mechanism side pump (92) in the sampling path (64) between a cleaning liquid accommodation part (70) and the sample introduction path (130), and distributes a cleaning liquid to a detection part (75). Furthermore, the sampling device (60) has an introductory mechanism side pump (142) that is provided in the sampling device (60) and sample introduction path (130), and distributes the sample from the sample introduction path (130) to the detection part (75).

Description

[Technical Field]

[0001] The present invention relates to a sampling device for collecting a sample of a liquid in a culture device for culturing cells, and a cell culture system. [Background technology]

[0002] For example, U.S. Patent No. 9,442,047 discloses a sampling device equipped with a sampling path for collecting a liquid sample from a culture device. The sampling device includes a pump that draws a sample from a sample introduction path connected to the culture device into the sampling path, and a detection unit provided downstream of the sampling path. The detection unit detects the components contained in the sample and the amount (concentration) of the components. Summary of the Invention

[0003] However, this type of sampling device must be sterilized when connected to a culture device. This is because the various cells cultured in the culture device must be cultured under sterile conditions, and the sampling device connected to the culture device must also be sterilized for continuity. However, some of the various sensors used in the detection unit provided in the sampling device are not suitable for sterilization, and such sensors are retrofitted to the circuit. In this case, there is a possibility that the sterility of the sampling device circuit cannot be maintained.

[0004] On the other hand, it is also possible to install a sterile filter between the sampling device and the culture device. However, if a sterile filter is installed, a pump installed downstream of the sampling flow path draws the sample from the sample introduction path into the sampling flow path through the sterile filter, creating negative pressure in the sample introduction path. If the sample introduction path is closed with a clamp for the cleaning process while the sample introduction path is still under negative pressure and the clamp is released after the cleaning process, cleaning fluid will flow (backflow) into the sample introduction path. If the negative pressure is too high, there is a risk that the cleaning fluid will flow all the way into the culture device. In this case, if the sterility of the sampling device cannot be guaranteed, the sterility of the culture device may also not be maintained.

[0005] The present invention is related to the above technology, and aims to provide a sampling device and a cell culture system that can maintain the sterility of the culture device with respect to the sample introduction path through which the sample is introduced, and can effectively suppress the inflow of cleaning liquid from the sampling path.

[0006] In order to achieve the above-mentioned object, a first aspect of the present invention is a sampling device for collecting a liquid sample from a culture device for culturing cells, comprising: a sampling path through which the sample flows; a detection unit provided in the sampling path so as to come into contact with the sample; a cleaning liquid storage unit connected upstream of the detection unit in the sampling path and storing a cleaning liquid; a sample introduction path connected to the culture device and to the sampling path between the detection unit and the cleaning liquid storage unit, and capable of introducing the sample from the culture device into the sampling path; and a first pump provided in the sampling path between the cleaning liquid storage unit and the sample introduction path for circulating the cleaning liquid to the detection unit; and a second pump provided in the sample introduction path for circulating the sample from the sample introduction path to the detection unit.

[0007] In addition, in order to achieve the above-mentioned object, a second aspect of the present invention is a cell culture system having a culture section for culturing cells, comprising: a sampling path through which a sample of liquid collected from the culture section flows; a detection section provided in the sampling path so as to come into contact with the sample; a washing liquid storage section connected upstream of the detection section in the sampling path and storing a washing liquid; a sample introduction path connected to the culture section and connected to the sampling path between the detection section and the washing liquid storage section, and capable of introducing the sample from the culture section to the sampling path; and a first pump provided in the sampling path between the washing liquid storage section and the sample introduction path for circulating the washing liquid to the detection section; and a second pump provided in the sample introduction path for circulating the sample from the sample introduction path to the detection section.

[0008] The above-described sampling device and cell culture system can effectively prevent the inflow of cleaning liquid from the sampling path into the sample introduction path through which the sample is introduced. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a perspective view schematically showing the overall configuration of a cell culture system to which a sampling device according to one embodiment of the present invention is applied. [Figure 2] FIG. 1 is an explanatory diagram schematically showing the path of a medium during cell culture. [Figure 3] FIG. 2 is an explanatory diagram illustrating a schematic path of a sampling device. [Figure 4] FIG. 2 is a perspective view showing each component of the sampling device. [Figure 5] FIG. 2 is a perspective view showing a first sensor unit and a second sensor unit. [Figure 6] 1 is a flowchart illustrating a sampling method of the sampling device. [Figure 7] 10A and 10B are explanatory diagrams showing the operations of a priming step and a cleaning step. [Figure 8]FIG. 10 is an explanatory diagram showing the operation of a sampling process. [Figure 9] FIG. 10 is an explanatory diagram showing the operation of a calibration process. [Figure 10] 10 is a flowchart showing a sampling method according to a first modified example. [Figure 11] FIG. 10 is an explanatory diagram showing the operation of the retraction process of the first modified example. [Figure 12] FIG. 10 is an explanatory diagram schematically showing a path of a sampling device according to a second modified example. [Figure 13] FIG. 11 is an explanatory diagram schematically showing a path of a sampling device according to a third modified example. [Figure 14] FIG. 10 is an explanatory diagram showing the connection between the culture device and the sampling device of the cell culture system according to the fourth modified example. DETAILED DESCRIPTION OF THE INVENTION

[0010] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will now be described in detail with reference to preferred embodiments thereof and the accompanying drawings.

[0011] As shown in Fig. 1, a sampling device 60 according to one embodiment of the present invention is applied to a cell culture system 10 that cultures living cells in regenerative medicine. The sampling device 60 samples the culture medium during cell culture in the cell culture system 10 to measure the state of the culture medium. For example, the cell culture system 10 continues cell culture for a long period of time by supplying culture medium and oxygen to a reactor 12, which is a cell culture container, while discharging lactic acid, carbon dioxide, and the like (including unused culture medium and oxygen) generated during cell culture from the reactor 12.

[0012] The biological cells are not particularly limited, but examples thereof include cells contained in blood (T cells, etc.) and stem cells (ES cells, iPS cells, mesenchymal stem cells, etc.). The medium may also be selected appropriately depending on the biological cells, and examples thereof include those prepared by adding various amino acids, vitamins, serum, etc. to a balanced salt solution (BSS) as a base solution.

[0013] The cell culture system 10 also includes a culture device 11 (culture unit) in which a reactor 12 is set and in which cells are actually cultured, and a sampling device 60 that collects liquid samples from the culture device 11 during culture. Although Fig. 1 illustrates the culture device 11 having one reactor 12, the culture device 11 may also be configured to have a plurality of reactors 12. Furthermore, although the present embodiment illustrates a cell culture system 10 in which the culture unit and the sampling unit are configured separately, the cell culture system 10 may also be an apparatus in which the culture unit and the sampling unit are integrated (united).

[0014] The culture device 11 has a culture medium storage section 14 that stores culture medium, a circulation path 16 that is provided between the reactor 12 and the culture medium storage section 14, a plurality of medical bags 18 that are connected to the circulation path 16, and a waste liquid section 20 that stores liquid discharged from the circulation path 16.

[0015] A hard tank capable of storing a large amount of culture medium is applied as the culture medium storage unit 14. The distribution path 16 is composed of a plurality of tubes 22, which are connected to the reactor 12, the culture medium storage unit 14, the plurality of medical bags 18, and the waste liquid unit 20, respectively.

[0016] The multiple medical bags 18 include, for example, a cell fluid bag 18A that stores a fluid containing cells (cell fluid), a cleaning fluid bag 18B that stores a cleaning fluid, a detachment fluid bag 18C that stores a detachment fluid, and a recovery bag (not shown) that recovers the cultured cells. The cleaning fluid is a liquid used when priming the reactor 12 and the distribution channel 16. Examples of this cleaning fluid include buffer solutions such as PBS (Phosphate Buffered Salts) and TBS (Tris-Buffered Saline), or physiological saline. The detachment fluid is a liquid that detaches cells cultured by a culture process. Examples of the detachment fluid that can be used include trypsin and EDTA solution.

[0017] When the cell culture system 10 is constructed, the flow path 16 is set to pass through a flow path control mechanism 24 of the culture device 11. The flow path control mechanism 24 includes a housing 26 that houses a part of the flow path 16. As shown in FIG. 2 , the flow path control mechanism 24 includes, in the housing 26, a clamp 28 that opens and closes a predetermined tube 22, a pump 30 that circulates the liquid in the tube 22, and a control circuit 32 that controls the operation of the clamp 28 and the pump 30.

[0018] The reactor 12 is housed in a housing 26 of the flow path control mechanism 24. The reactor 12 includes a plurality of hollow fibers 34 (e.g., 10,000 or more) and a case 36 that houses the plurality of hollow fibers 34. Each hollow fiber 34 has a lumen (not shown), and cells are seeded on the inner circumferential surface that constitutes the lumen. Each hollow fiber 34 also has a plurality of pores (not shown) that communicate between the outside and the lumen. Each pore is impermeable to cells and proteins but permeable to solutions and low-molecular-weight substances. A culture medium or the like is supplied to the cells seeded on the inner circumferential surface of the hollow fibers 34 via the lumen or the pores. Hereinafter, a configuration in which a liquid is circulated mainly through the lumen of the hollow fibers 34 is also referred to as an IC (intra capillary), and a configuration in which a liquid is circulated mainly outside the hollow fibers 34 is also referred to as an EC (extra capillary).

[0019] The case 36 is equipped with a first IC terminal 36a and a second IC terminal 36b that are connected to the multiple tubes 22 and communicate with the inner lumens of the hollow fibers 34, and a first EC terminal 36c and a second EC terminal 36d that are communicated with the space outside the hollow fibers 34 within the case 36.

[0020] 2, the flow path 16 has a culture medium delivery route 40 connected to the culture medium reservoir 14, and an IC route 42 (internal route) and an EC route 44 (external route) branching off from the culture medium delivery route 40. The IC route 42 is a route for supplying liquid to the lumen of the hollow fibers 34. The EC route 44 is a route for supplying liquid to the inside of the case 36 outside the hollow fibers 34.

[0021] The IC route 42 has an IC circulation circuit 42a capable of circulating liquid between the reactor 12 and the IC route 42, and an IC supply circuit 42b capable of distributing liquid from the culture medium delivery route 40 to the IC circulation circuit 42a. The IC circulation circuit 42a is connected to the first IC terminal 36a and the second IC terminal 36b of the reactor 12, and is equipped with an IC circulation pump 30a that circulates liquid through the lumen of the hollow fibers 34. An IC waste liquid circuit 46 that discharges the culture medium to the waste liquid section 20 is connected to the IC circulation circuit 42a downstream of the reactor 12. Meanwhile, the IC supply circuit 42b is equipped with an IC supply pump 30b that circulates liquid from the culture medium delivery route 40 to the IC circulation circuit 42a.

[0022] Meanwhile, the EC route 44 includes an EC circulation circuit 44a capable of circulating liquid between the reactor 12 and the EC route 44, and an EC supply circuit 44b capable of circulating liquid from the culture medium delivery route 40 to the EC circulation circuit 44a. The EC circulation circuit 44a is connected to the first EC terminal 36c and the second EC terminal 36d of the reactor 12, and includes an EC circulation pump 30c that circulates liquid around the outside of the hollow fibers 34. A gas exchanger 52 is provided upstream of the reactor 12 in the EC circulation circuit 44a. The gas exchanger 52 discharges carbon dioxide contained in the culture medium while mixing predetermined gas components (e.g., nitrogen (N2): 75%, oxygen (O2): 20%, carbon dioxide (CO2): 5%) into the culture medium. An EC waste liquid circuit 48 that discharges the culture medium to the waste liquid section 20 is connected downstream of the reactor 12 in the EC circulation circuit 44a. The EC supply circuit 44b is provided with an EC supply pump 30d that circulates the liquid from the culture medium delivery route 40 to the EC circulation circuit 44a.

[0023] Although not shown, in addition to the culture medium reservoir 14, a plurality of medical bags 18 (cell solution bag 18A, cleaning solution bag 18B, detachment solution bag 18C) are connected to the IC supply circuit 42b upstream of the IC supply pump 30b or the EC supply circuit 44b upstream of the EC supply pump 30d via a plurality of tubes 22. These medical bags 18 may be replaced with collection bags or the like using a sterile joining device that sterilizes and joins the bags depending on the application.

[0024] The sampling device 60 is connected to the EC circulation circuit 44a of the culture device 11 at a position near the downstream side (second EC terminal 36d) of the reactor 12 (between the reactor 12 and the EC waste liquid circuit 48). To this end, one end of a sample outflow path 54, through which a culture medium, which is a liquid sample, flows out, is connected to the EC circulation circuit 44a. A culture medium device-side connector 56 is provided at the other end of the sample outflow path 54. The culture medium device-side connector 56 is configured to be mutually connectable with a sampling device-side connector 132 of the sampling device 60. Note that the culture device 11 may be configured to have a plurality of sample outflow paths 54 (culture medium device-side connectors 56) according to the number of reactors 12 installed. In this case, a plurality of sample introduction paths 130 (sampling device-side connectors 132) of the sampling device 60 is also provided according to the number of sample outflow paths 54.

[0025] A sterile filter 58 is provided midway along the sample outflow path 54. The sterile filter 58 maintains the sterility of the culture medium flowing through the culture device 11 (EC circulation circuit 44a side). The sampling device 60 may be connected to the sample outflow path 54 on the downstream side (second IC terminal 36b) of the reactor 12 in the IC circulation circuit 42a.

[0026] Next, the configuration of the sampling device 60 will be described with reference to Figure 3. The sampling device 60 collects samples of culture medium from one or more culture devices 11 and detects the components contained in the sample and the amounts (concentrations) of the components. The sampling device 60 includes a sampling kit 62 having a sampling path 64 through which the sample is collected, multiple mechanical units 66 to which the sampling kit 62 is detachably set, and a controller 68 that controls the operation of the multiple mechanical units 66. The sampling kit 62 is a disposable item, and the multiple mechanical units 66 are reusable items.

[0027] In addition to the sampling path 64, the sampling kit 62 includes a cleaning liquid storage section 70, a standard liquid storage section 72, a waste liquid storage section 74, and a detection section 75 (first detection section 76, second detection section 80). The sampling path 64 is composed of a flexible tube of an appropriate diameter to allow the sample to flow through. The cleaning liquid storage section 70 is connected to a branch point 65 to which one end of the sampling path 64 is connected via a cleaning liquid branch path 71, and the standard liquid storage section 72 is connected to this branch point 65 via a standard liquid branch path 73. The other end of the sampling path 64 is connected to the waste liquid storage section 74.

[0028] The cleaning liquid storage section 70 and the standard liquid storage section 72 are formed in a bag shape (medical bag) from a soft resin material such as polyvinyl chloride or polyolefin. However, there are no particular limitations on the cleaning liquid storage section 70 and the standard liquid storage section 72 as long as they are capable of storing liquid. The waste liquid storage section 74 shares a tank with the waste liquid section 20 of the culture device 11, but is not limited to this and a medical bag or the like may be used.

[0029] A cleaning liquid is stored in the cleaning liquid storage section 70. The cleaning liquid is not particularly limited, and for example, a buffer solution, physiological saline, or the like, which are listed as cleaning liquids for the cleaning liquid bag 18B of the culture device 11, may be used as appropriate.

[0030] The standard solution storage section 72 stores a standard solution. The standard solution is a liquid for calibrating the first detection section 76 and the second detection section 80. The standard solution is a liquid whose pH value, glucose value (glucose concentration), and lactic acid value (lactic acid concentration) are set to specified values. The sampling device 60 may be provided with two or more standard solution storage sections 72, each containing a standard solution with a different specified value, and may perform two-point calibration for the first detection section 76 and the second detection section 80 by supplying two or more types of standard solution at different times.

[0031] The first detection unit 76 and the second detection unit 80 are provided in series and spaced apart from each other at a position along the sampling path 64. The detection unit 75 is not limited to a structure in which the first detection unit 76 and the second detection unit 80 are separated, but may be a structure in which the first detection unit 76 and the second detection unit 80 are integrated, or may be a structure in which the first detection unit 76 and the second detection unit 80 are separated into three or more units.

[0032] The first detection unit 76 is a cylindrical member having a plurality of first element units 78 that come into contact with the sample (wetted) in the flow path of the sampling path 64. For example, the plurality of first element units 78 include a pH tip 78a for measuring the pH of the sample, an O2 tip 78b for measuring the O2 concentration in the sample, and a CO2 tip 78c for measuring the CO2 concentration in the sample. The pH tip 78a is a tip for measuring H + , O.H. - The O2 tip 78b changes color in response to O2, and the CO2 tip 78c changes color in response to CO2.

[0033] The second detection unit 80 is a tubular member having a plurality of second element units 82 that come into contact with the sample (wetted) in the flow path of the sampling path 64, and is provided downstream (in the waste liquid storage unit 74) of the first detection unit 76. For example, the plurality of second element units 82 are biosensors that react an enzyme with the flowing sample and detect changes in current, etc. Examples of the plurality of second element units 82 include a glucose chip 82a that measures the glucose concentration in the sample and a lactic acid chip 82b that measures the lactic acid concentration in the sample.

[0034] The glucose tip 82a is electrically connected to a glucose terminal 83a that protrudes outside the tubular member. The lactic acid tip 82b is electrically connected to a lactic acid terminal 83b that protrudes outside the tubular member. The glucose terminal 83a and the lactic acid terminal 83b are preferably configured as an electrode terminal 83 that is integrated with each other via an insulating material.

[0035] The sampling kit 62 also includes a connection site 84 between the branch point 65 of the sampling path 64 and the first detection unit 76, to which one or more sample introduction paths 130 (described below) can be connected. The connection site 84 is, for example, a member formed by integrally molding multiple branch ports each having a valve (not shown) that closes when the sample introduction path 130 is not attached and opens when the sample introduction path 130 is attached (in FIG. 3, the connection site 84 is conveniently indicated by the area surrounded by a two-dot chain line). Alternatively, the connection site 84 can be a port to which the sample introduction path 130 can be connected while ensuring the sterility of the sampling path 64.

[0036] As shown in FIGS. 3 and 4, a portion of the sampling kit 62 described above is set in a main mechanism 90, which is one of the multiple mechanism units 66. The main mechanism 90 includes a housing 91 that houses a motor and an actuator (not shown). The housing 91 has grooves (not shown) on its surface that hold a portion of the cleaning liquid branch path 71, a portion of the standard liquid branch path 73, a predetermined range of the sampling path 64 from the branch point 65 to the connection site 84, and a predetermined range of the sampling path 64 from the second detection unit 80 to the waste liquid storage unit 74. The main mechanism 90 also includes a main mechanism pump 92 (first pump) and multiple clamps 94 that open and close the flow paths in each path (tube). Although not shown, a controller 68 that controls the sampling device 60 may also be provided in the main mechanism 90.

[0037] The main mechanism side pump 92 is provided with a sampling path 64 extending between the branch point 65 and the connection part 84. The main mechanism side pump 92 has a circular wrapped portion around which the sampling path 64 can be wrapped, and rotates to squeeze the wrapped sampling path 64 (tube), thereby circulating the internal fluid (liquid, air, etc.).

[0038] The multiple clamps 94 include a cleaning liquid clamp 94a in which the cleaning liquid branch path 71 is disposed, a standard liquid clamp 94b in which the standard liquid branch path 73 is disposed, and a waste liquid clamp 94c in which the sampling path 64 between the second detection unit 80 and the waste liquid storage unit 74 is disposed. The cleaning liquid clamp 94a opens and closes the cleaning liquid branch path 71 under the control of the controller 68, thereby switching between allowing and blocking the flow of cleaning liquid in the cleaning liquid storage unit 70. The standard liquid clamp 94b opens and closes the standard liquid branch path 73 under the control of the controller 68, thereby switching between allowing and blocking the flow of standard liquid in the standard liquid storage unit 72. The waste liquid clamp 94c opens and closes the sampling path 64 under the control of the controller 68, thereby switching between allowing and blocking the inflow of liquid into the waste liquid storage unit 74.

[0039] The sampling kit 62 is set in the main mechanism 90 to form a main unit 96 of the sampling device 60. The main unit 96 allows the sampling kit 62 (part of the sampling path 64 including the range from the cleaning liquid storage section 70 to the downstream side of the main mechanism pump 92), the main mechanism pump 92, and multiple clamps 94 to be handled together as a single unit.

[0040] As shown in FIG. 4 , the main unit 96 (main mechanism 90) includes a stand 98 on the top of the housing 91 for suspending the cleaning liquid storage section 70 and the standard liquid storage section 72, and a door-shaped monitor 100 on the front of the housing 91. The groove, the main mechanism pump 92, and the clamps 94 are provided on the housing surface on the rear side of the monitor 100. The user opens the monitor 100, sets the sampling kit 62, and then closes the monitor 100, preventing the sampling path 64 from falling off. A connection part 84 (sampling path 64) exposed from the main unit 96 is placed on the top surface of the housing 91. The cleaning liquid branch path 71 exposed from the housing 91 extends to the cleaning liquid storage section 70, and the standard liquid branch path 73 exposed from the housing 91 extends to the standard liquid storage section 72.

[0041] 3 and 5, the first detection unit 76 of the sampling kit 62 is set in a first measurement device 110, which is one of the multiple mechanism units 66. The first measurement device 110 has a rectangular cylindrical holder 112 that houses the multiple first element units 78, and a cylindrical measurement main body 114 to which the holder 112 is fixed and which optically measures the multiple first element units 78. The holder 112 is formed to be light-blocking, and has a recess 112a for storing and holding the first detection unit 76 from the side.

[0042] In the measurement main body 114, the optical detectors 116 are arranged so as to face the plurality of first element units 78 (PH tip 78a, O2 tip 78b, CO2 tip 78c) with the first detection unit 76 held in the holder 112. That is, the plurality of optical detectors 116 include a PH detector 116a, an O2 detector 116b, and a CO2 detector 116c. Under the control of the controller 68, each optical detector 116 emits measurement light of a wavelength corresponding to the characteristics of the corresponding first element unit 78 and receives excitation light resulting from excitation of the corresponding first element unit 78. As a result, each optical detector 116 transmits a detection signal based on the degree of coloration of the corresponding first element unit 78 to the controller 68.

[0043] The first measuring instrument 110 is housed in a calibration device 118 to perform calibration when the first detection unit 76 is not set. The calibration device 118 bubbles predetermined gas components into a standard liquid (not shown) and calibrates the relationship between the luminous intensity detected by each optical detector 116 of the set first measuring instrument 110 and the measurement values ​​(concentrations) of the detection targets, pH, O2, and CO2.

[0044] Furthermore, second detection unit 80 of sampling kit 62 is set in second measurement device 120, which is one of multiple mechanism units 66. Second measurement device 120 has a plate-shaped case 122 that can accommodate multiple electrode terminals 83 protruding from the multiple second detection units 80. Case 122 has a recess 122a for storing and holding second detection unit 80 from the side, and an opening (not shown) into which electrode terminal 83 is inserted.

[0045] The second measuring device 120 has an enzyme detector (not shown) electrically connected to the glucose terminal 83a and the lactic acid terminal 83b with the second detecting unit 80 held in the case 122. The enzyme detector detects the current values ​​from the glucose chip 82a and the lactic acid chip 82b, and transmits a detection signal based on the current values ​​to the controller 68.

[0046] In the sampling device 60, a first sensor unit 111 is constructed by setting the first detection section 76 described above in a first measuring device 110, and a second sensor unit 121 is constructed by setting the second detection section 80 described above in a second measuring device 120. By providing the first sensor unit 111 and the second sensor unit 121 at a distance from each other, different detection methods can be used while facilitating the setting of each.

[0047] 3, a sample introduction path 130 is connected to the connection site 84 of the sampling kit 62 (sampling path 64) in order to introduce a sample to be measured by the first sensor unit 111 and the second sensor unit 121. Similar to the sampling path 64, the sample introduction path 130 is made of a flexible tube having an appropriate thickness to allow the sample to flow through.

[0048] The sample introduction path 130 has at one end a sampling device side connector 132 for connection to the culture medium device side connector 56 (see also FIG. 2). At the other end of the sample introduction path 130, a detachable plug (not shown) is provided at the connection site 84. Hereinafter, the point where the sample introduction path 130 is connected to the sampling path 64 will be referred to as the connection point 134.

[0049] A portion of the sample introduction path 130 is detachably set in an introduction mechanism part 140, which is one of the multiple mechanism parts 66. The introduction mechanism part 140 includes a rectangular parallelepiped housing 141 that houses a motor (not shown) therein, and is configured so that the sample introduction path 130 passes through the housing 141 (see also FIG. 4). The housing 141 is disposed in the vicinity of the flow path control mechanism part 24 of the culture device 11. The introduction mechanism part 140 includes, in the housing 141, an introduction mechanism part-side pump 142 (second pump), a pressure sensor 144 that detects the pressure in the flow path of the sample introduction path 130, and an air bubble sensor 146 that detects air bubbles in the flow path of the sample introduction path 130.

[0050] The introduction mechanism part-side pump 142 has a circular wound part around which the sample introduction path 130 can be wound, and rotates to squeeze the wrapped-around sample introduction path 130 (tube), thereby circulating the internal fluid (liquid, air, etc.). The introduction mechanism part 140 including the introduction mechanism part-side pump 142 is preferably set near the connection point 134.

[0051] The pressure sensor 144 detects the internal pressure in the sample introduction path 130 between the sampling device side connector 132 and the introduction mechanism part side pump 142 (upstream of the introduction mechanism part side pump 142). The detection result detected by the pressure sensor 144 is wirelessly transmitted to the controller 68. In order to improve the pressure detection accuracy of the pressure sensor 144, the planned placement location of the pressure sensor 144 in the sample introduction path 130 may be formed into an appropriate shape (such as a cylinder or disk with a larger diameter than other locations).

[0052] The air bubble sensor 146 is provided in the sample introduction path 130 between the introduction mechanism part side pump 142 and the plug (connection point 134), and detects air bubbles in the sample introduction path 130. The detection result detected by the air bubble sensor 146 is wirelessly transmitted to the controller 68. The air bubble sensor 146 may be provided upstream of the introduction mechanism part side pump 142.

[0053] By setting the sample introduction path 130 in the introduction mechanism part 140, an introduction unit 148 of the sampling device 60 is constructed. The introduction unit 148 allows a part of the sample introduction path 130, the introduction mechanism part-side pump 142, the pressure sensor 144, and the air bubble sensor 146 to be handled as a single unit. The sample introduction path 130, which extends a short distance from the introduction unit 148, is connected to the connection part 84 on the main unit 96.

[0054] The arrangement of each component of this sampling device 60 can be summarized as follows: The main mechanism side pump 92 is arranged in the sampling path 64 between the branch point 65 (downstream of the cleaning liquid storage section 70 and the standard liquid storage section 72) and the connection point 134 of the sample introduction path 130. The cleaning liquid clamp 94a is arranged in the cleaning liquid branch path 71 between the cleaning liquid storage section 70 and the branch point 65. The standard liquid clamp 94b is arranged in the standard liquid branch path 73 between the standard liquid storage section 72 and the branch point 65.

[0055] The introduction mechanism side pump 142 is disposed in the sample introduction path 130 between the connection site 84 (connection point 134) of the sampling path 64 downstream of the main mechanism side pump 92 and the sampling device side connector 132. The extension length of the sampling path 64 from the connection site 84 to the main mechanism side pump 92 is shorter than the extension length of the sample introduction path 130 from the connection site 84 to the introduction mechanism side pump 142.

[0056] The controller 68 (controller) is a computer having one or more processors, memory, input / output interfaces, and electronic circuits (not shown). The controller 68 controls the entire sampling device 60 by having the processor execute a program stored in the memory. The controller 68 is communicatively connected to the main unit 96, the first sensor unit 111, the second sensor unit 121, and the introduction unit 148 via a wireless or wired communication module. The controller 68 controls the operation of the main mechanism pump 92, the multiple clamps 94, and the introduction mechanism pump 142, and also receives detection signals from the first measuring device 110, the second measuring device 120, the pressure sensor 144, and the air bubble sensor 146 to perform various processes. The controller 68 may be a control device integrated with the control circuit 32 of the culture device 11.

[0057] The sampling device 60 according to this embodiment is basically configured as described above, and the sampling method of the sampling device 60 will be described below with reference to Fig. 6. The sampling method sequentially performs a preparation step, a priming step, a sampling step, a cleaning step, and a calibration step.

[0058] First, in the preparation step (step S1), as shown in FIGS. 3 to 5 , the user of the cell culture system 10 sets (attaches) the sampling kit 62 on the main mechanism 90 to form the main unit 96. Thereafter, the user sets the first detection unit 76 exposed from the housing 91 on the first measurement device 110 to form the first sensor unit 111, and sets the second detection unit 80, also exposed, on the second measurement device 120 to form the second sensor unit 121. The first sensor unit 111 and the second sensor unit 121 are hung on a stand 98.

[0059] The user also sets the sample introduction path 130 in the introduction mechanism 140 to form the introduction unit 148. After that, the user connects the sampling device side connector 132 of the sample introduction path 130 exposed from the introduction unit 148 to the culture medium device side connector 56, and also connects the plug of the sample introduction path 130 to the connection site 84.

[0060] Subsequently, in the priming step (step S2 in FIG. 6 ), the controller 68 opens the cleaning liquid clamp 94a and the waste liquid clamp 94c, while closing the standard liquid clamp 94b, as shown in FIG. 7 . Then, the controller 68 rotates the main mechanism part-side pump 92. The rotation of the main mechanism part-side pump 92 applies negative pressure to the cleaning liquid branch path 71, causing the cleaning liquid to be supplied from the cleaning liquid storage section 70. The cleaning liquid that has passed through the cleaning liquid branch path 71 and the branch point 65 passes through the main mechanism part-side pump 92 in the sampling path 64. Furthermore, the main mechanism part-side pump 92 applies positive pressure to the cleaning liquid, causing it to flow sequentially through the connection part 84, the first detection section 76, and the second detection section 80, before being discharged into the waste liquid storage section 74. Furthermore, in the priming step, the introduction mechanism part-side pump 142 is stopped from rotating, preventing the cleaning liquid from flowing into the sample introduction path 130.

[0061] In the next sampling step (step S3 in FIG. 6), the sampling device 60 collects a sample from the culture device 11. As shown in FIG. 8, the controller 68 closes the cleaning solution clamp 94a and the standard solution clamp 94b, while opening the waste liquid clamp 94c. The controller 68 also stops the rotation of the main mechanism part side pump 92, while rotating the introduction mechanism part side pump 142. The rotation of the introduction mechanism part side pump 142 applies negative pressure to the sample introduction path 130 upstream of the introduction mechanism part side pump 142, and the sample is introduced from the culture device 11.

[0062] The sample drawn in from the culture device 11 passes through the sterile filter 58 in the sample outlet path 54 (see FIG. 2 ) and is led to the sample introduction path 130. When the sample flows through the sample introduction path 130 and passes through the introduction mechanism part side pump 142, positive pressure is applied from the introduction mechanism part side pump 142, causing the sample to flow sequentially through the connection part 84 (connection point 134), the first detection part 76, and the second detection part 80, and then be discharged into the waste liquid storage part 74.

[0063] As the sample passes through, the first element units 78 (pH tip 78a, O2 tip 78b, CO2 tip 78c) of the first detection unit 76 come into contact with the sample and change color according to the respective contents of pH, O2, and CO2. The first measuring device 110 performs optical measurement on each first element unit 78 and transmits the detection results to the controller 68. The controller 68 receives the detection results and performs appropriate processing to display the measured values ​​(pH value, O2 concentration, CO2 concentration) on the monitor 100.

[0064] Similarly, when the sample passes through, the multiple second element units 82 (glucose chip 82a, lactic acid chip 82b) of the second detection unit 80 come into contact with the sample, and the second measuring device 120 detects current values ​​corresponding to the glucose and lactic acid contents. The second measuring device 120 transmits each detection result to the controller 68. The controller 68 receives the detection results and performs appropriate processing to display the measured values ​​(glucose concentration, lactic acid concentration) on the monitor 100.

[0065] Here, during the sampling process, negative pressure is applied to the sample introduction path 130 upstream of the introduction mechanism part-side pump 142, while positive pressure is applied to the sample introduction path 130 downstream of the introduction mechanism part-side pump 142 and the sampling path 64. For this reason, when the sampling process is completed and the introduction mechanism part-side pump 142 is stopped, the pressure in the sample introduction path 130 acts to become uniform, and the pressure difference between the negative pressure and the positive pressure gradually disappears. Therefore, the negative pressure in the sample introduction path 130 is eliminated in a short time.

[0066] Furthermore, in the sampling process, the pressure sensor 144 of the introduction unit 148 detects the internal pressure of the sample introduction path 130 upstream of the introduction mechanism part-side pump 142 and transmits the detection result to the controller 68. The controller 68 recognizes the level of negative pressure based on the detection result of the pressure sensor 144. For example, when the internal pressure of the sample introduction path 130 is equal to or greater than a predetermined pressure threshold, the controller 68 reduces the rotation speed of the introduction mechanism part-side pump 142 or stops its rotation, and starts rotating the introduction mechanism part-side pump 142 after a certain amount of time has passed (after the negative pressure has decreased).

[0067] Furthermore, in the sampling process, the air bubble sensor 146 of the introduction unit 148 detects air bubbles in the sample introduction path 130 and transmits the detection result to the controller 68. Air bubbles are generated when gases (N2, O2, CO2) in the sample gather due to negative pressure or the like. Therefore, when the air bubble sensor 146 detects air bubbles, the controller 68 reduces the rotation speed of the introduction mechanism side pump 142 or stops its rotation, as described above.

[0068] After the sampling step, the controller 68 determines whether cell culture in the culture device 11 has been completed (step S4). If cell culture has not been completed (step S4: NO), a cleaning step (step S5) is performed. In the cleaning step, the controller 68 supplies the cleaning solution from the cleaning solution storage unit 70 to the sampling path 64, similar to the priming step shown in FIG. 7. As a result, the sample adhering to the plurality of first element units 78 (the pH tip 78a, the O2 tip 78b, and the CO2 tip 78c) and the plurality of second element units 82 (the glucose tip 82a and the lactic acid tip 82b) is removed by the cleaning solution.

[0069] As described above, at the start of the cleaning process, the introduction mechanism side pump 142 is stopped, and the sample introduction path 130 and the sampling path 64 are always blocked. Therefore, even if the sample introduction path 130 is under negative pressure, the cleaning liquid flowing through the sampling path 64 can be prevented from entering the sample introduction path 130.

[0070] Furthermore, the sampling device 60 performs a calibration process (step S6 in FIG. 6 ) as needed. In the calibration process, as shown in FIG. 9 , the controller 68 opens the standard solution clamp 94b and the waste solution clamp 94c and rotates the main mechanism pump 92 while keeping the cleaning solution clamp 94a closed. The standard solution in the standard solution storage section 72 is guided from the standard solution branch path 73 to the sampling path 64 by the action of the main mechanism pump 92. The standard solution passes through the main mechanism pump 92 in the sampling path 64, and then flows through the connection part 84, the first detection section 76, and the second detection section 80 in that order before being discharged into the waste solution storage section 74.

[0071] At this time, the second sensor unit 121 measures the glucose concentration and lactate concentration in the standard solution and transmits the measurement results to the controller 68 or the second measuring device 120. The controller 68 or the second measuring device 120 calibrates the second measuring device 120 based on the measurement results of the second sensor unit 121. Meanwhile, the first sensor unit 111 (first measuring device 110) is set in the calibration device 118, whereby it measures the standard solution, pH, O2 concentration, and CO2 concentration in the calibration device 118 and transmits the measurement results to the controller 68 or the first measuring device 110. The controller 68 or the first measuring device 110 calibrates the pH detector 116a, O2 detector 116b, and CO2 detector 116c based on the measurement results.

[0072] 6, when the cleaning step (or calibration step) is completed, the controller 68 returns to step S3 and sequentially performs the subsequent steps. On the other hand, in step S4, if the controller 68 determines that the cell culture is completed (step S4: YES), the operation flow of the sampling device 60 is terminated.

[0073] It should be noted that the sampling method of the sampling device 60 is not limited to the above, and various methods can be adopted. For example, as shown in Fig. 10, at the start of the sampling step, the sampling device 60 may perform a drawing step (step S3-1) in which, while the main mechanism side pump 92 is rotating, a small amount of sample is drawn upstream of the connection point 134 (toward the main mechanism side pump 92).

[0074] 11, during the retraction step, the controller 68 rotates the introduction mechanism side pump 142 to introduce the sample while rotating the main mechanism side pump 92 in the opposite direction to the rotation direction during the priming step. At this time, the controller 68 opens the cleaning liquid clamp 94a. This causes the sample introduced from the sample introduction path 130 to move from the connection point 134 to the sampling path 64 of the main mechanism side pump 92. The amount of sample movement is not particularly limited, but may be, for example, such that the sample stops just before the sampling path 64 wound around the main mechanism side pump 92.

[0075] After performing the retraction step for a short time, the controller 68 stops rotation of the main mechanism side pump 92 and closes the cleaning liquid clamp 94a. Thereafter, the controller 68 performs the normal step in Fig. 10 (step S3-2: the sampling step shown in Fig. 8). That is, the controller 68 rotates the introduction mechanism side pump 142 to introduce the sample from the sample introduction path 130 into the sampling path 64, and causes the sample to flow sequentially through the first detection unit 76 and the second detection unit 80.

[0076] After the drawing process is performed, the sample is present in the sampling path 64 upstream of the connection point 134 (on the main mechanism side pump 92 side). This prevents the sample from mixing with the cleaning liquid at the connection point 134 during the sampling process. Therefore, the sampling device 60 can further improve the detection accuracy of the pH, O2 concentration, CO2 concentration, glucose concentration, and lactic acid concentration of the sample.

[0077] The present invention is not limited to the above-described embodiment, and various modifications are possible within the spirit and scope of the invention. For example, the above-described sampling device 60 is configured such that the introduction unit 148 is provided with the pressure sensor 144 and the air bubble sensor 146, but the introduction unit 148 does not have to be provided with these sensors. Alternatively, the introduction unit 148 may be configured such that it is provided with only one of the pressure sensor 144 and the air bubble sensor 146.

[0078] 12, the sampling device 60 may connect the sample introduction paths 130 to a plurality of different culture devices 11 (culture device 11A, culture device 11B, culture device 11C, ...), and the plurality of sample introduction paths 130 may be connected to a connection portion 84. The sample introduction paths 130 are set in a plurality of introduction mechanism parts 140 (introduction mechanism part 140A, introduction mechanism part 140B, introduction mechanism part 140C, ...), and a plurality of introduction units 148 (introduction unit 148A, introduction unit 148B, introduction unit 148C, ...) are constructed. Each introduction unit 148 includes an introduction mechanism part-side pump 142, a pressure sensor 144, and an air bubble sensor 146.

[0079] In this case, in the sampling method, the controller 68 performs a sampling step for the culture device 11A (introduction unit 148A) and then a cleaning step, and then performs a sampling step for the culture device 11B (introduction unit 148B). Similarly, the cleaning step and sampling step may be repeated as many times as the number of introduction units 148 connected to the sampling path 64. In this way, even in a configuration in which samples are collected from each culture device 11, the sampling device 60 can sequentially measure the target components and the amounts (concentrations) of the components contained in each sample.

[0080] 13, the sampling device 60 may have an analytical path 152 connected to an analytical instrument 150 that analyzes the sample, connected to a connection portion 84 of the sampling path 64. This analytical instrument 150 is not particularly limited, but may be a high performance liquid chromatograph (HPLC) that separates target components (O2, CO2, glucose, lactic acid) from the sample and performs qualitative and quantitative analysis.

[0081] Furthermore, as shown in FIG. 14, the cell culture system 10A (culture device 11 and sampling device 60) may be configured without the sterile filter 58. For example, the cell culture system 10A may ensure the sterility of the culture device 11 by aseptically joining the joint 57 of the culture device 11 and the joint 133 of the sampling device 60 using a sterile joining device 160. The joints 57 and 133 are not particularly limited as long as they have a configuration that ensures sterility, and for example, a closed tube with a closed tip can be used. That is, the sample outlet path 54 of the culture device 11 includes a culture medium device-side connection end 57a as the joint 57, and the sample introduction path 130 of the sampling device 60 includes a sampling device-side connection end 133a as the joint 133.

[0082] The cell culture system 10A may be configured to include a plurality of joints 57, 133 depending on the number of reactors 12 installed. That is, the cell culture system 10A may be configured to include a plurality of sample outflow paths 54 (culture medium device side connection end portions 57a) and a plurality of sample introduction paths 130 (sampling device side connection end portions 133a), and the respective connection end portions may be joined together by a sterile joining device 160.

[0083] The technical ideas and effects that can be understood from the above-described embodiments will be described below.

[0084] A first aspect of the present invention is a sampling device 60 for collecting a liquid sample from a culture device 11 for culturing cells, comprising a sampling path 64 through which the sample flows, a detection section 75 provided in the sampling path 64 so as to come into contact with the sample, a cleaning liquid storage section 70 connected upstream of the detection section 75 on the sampling path 64 and storing a cleaning liquid, and a sample introduction path 130 connected to the culture device 11 and to the sampling path 64 between the detection section 75 and the cleaning liquid storage section 70, and capable of introducing a sample from the culture device 11 to the sampling path 64, and further comprising a first pump (main mechanism side pump 92) provided in the sampling path 64 between the cleaning liquid storage section 70 and the sample introduction path 130 for circulating the cleaning liquid to the detection section 75, and a second pump (introduction mechanism side pump 142) provided in the sample introduction path 130 for circulating the sample from the sample introduction path 130 to the detection section 75.

[0085] As described above, the sampling device 60 can effectively supply cleaning liquid using the first pump (main mechanism side pump 92) to clean the detection unit 75, and can effectively supply the sample to the detection unit 75 using the second pump (introduction mechanism side pump 142) to measure the sample. In other words, by blocking the sample introduction path 130 with the second pump, the sampling device 60 can effectively suppress the inflow of cleaning liquid from the sampling path 64 into the sample introduction path 130.

[0086] Furthermore, a sterile filter 58 that restricts the ingress of bacteria into the culture device 11 is provided between the culture device 11 and the second pump (the introduction mechanism side pump 142). Even if the amount of sample flowing decreases and negative pressure is generated in the sample introduction path 130, the sampling device 60 can always keep the sample introduction path 130 and the sampling path 64 in a blocked state by providing the second pump in the sample introduction path 130. Therefore, even if negative pressure is generated inside the sample introduction path 130, it is possible to prevent the cleaning liquid flowing through the sampling path 64 from entering the sample introduction path 130.

[0087] The sampling device 60 is also provided with a control section (controller 68) that controls the operation of the first pump (main mechanism section side pump 92) and the second pump (introduction mechanism section side pump 142), and the control section controls the circulation of the cleaning liquid by the first pump and the circulation of the sample by the second pump at mutually different times. This allows the sampling device 60 to repeat the cleaning step and the sampling step, and ensures the detection accuracy of the sample in the detection section 75.

[0088] The sampling device 60 is also connected upstream of the first pump (main mechanism pump 92) on the sampling path 64 and includes a standard liquid storage section 72 that stores a standard liquid for calibrating the detection section 75. The sampling path 64 is connected upstream of the first pump to a cleaning liquid branch path 71 that connects to the cleaning liquid storage section 70 and a standard liquid branch path 73 that connects to the standard liquid storage section 72, and includes a cleaning liquid clamp 94a that opens and closes the cleaning liquid branch path 71 and a standard liquid clamp 94b that opens and closes the standard liquid branch path 73. The control section (controller 68) opens one of the cleaning liquid clamp 94a and the standard liquid clamp 94b and closes the other in conjunction with the operation of the first pump. The sampling device 60 can effectively calibrate the detection section 75 by circulating a standard liquid as needed.

[0089] Furthermore, a portion of the sampling path 64, including the range from the cleaning liquid storage section 70 to the downstream side of the first pump (main mechanism side pump 92), and the first pump are configured as a main unit 96 that can be handled as an integrated unit, at least. This allows the user to handle the sampling device 60 easily.

[0090] Furthermore, a part of the sample introduction path 130 and the second pump (the introduction mechanism side pump 142) are configured as an introduction unit 148 that can be handled integrally with each other. This allows the user to easily handle the introduction unit 148 and to connect the sample introduction path 130 extending from the introduction unit 148 to the sampling path 64.

[0091] The introduction unit 148 also has at least one of a pressure sensor 144 that detects the internal pressure of the sample introduction path 130 upstream of the second pump (introduction mechanism part side pump 142) and an air bubble sensor 146 that detects air bubbles in the sample introduction path 130. This allows the sampling device 60 to monitor the negative pressure in the sample introduction path 130 and take appropriate measures. Furthermore, providing the sensor in the introduction unit 148 simplifies its handling.

[0092] Furthermore, the sampling path 64 has a connection portion 84 at a location downstream of the first pump (main mechanism side pump 92) and exposed from the main unit 96 for connecting the sample introduction paths 130 extending from each of the multiple introduction units 148 and / or the analysis path 152 communicating with an analytical instrument 150 that analyzes the sample. This allows the sampling device 60 to measure samples from multiple culture devices 11 with a single device.

[0093] Furthermore, detection unit 75 includes one or more element units (first element unit 78, second element unit 82) that are provided directly on sampling path 64, and the one or more element units can be set integrally with measuring devices (first measuring device 110, second measuring device 120) that are configured separately from main unit 96. This allows the user to set detection unit 75 (first sensor unit 111, second sensor unit 121) even more easily.

[0094] In addition, a second aspect of the present invention is a cell culture system 10 having a culture section (culture device 11) for culturing cells, comprising a sampling path 64 through which a sample of liquid collected from the culture section flows, a detection section 75 provided in the sampling path 64 so as to come into contact with the sample, a cleaning liquid storage section 70 connected upstream of the detection section 75 on the sampling path 64 and storing a cleaning liquid, and a sample introduction path 130 connected to the culture section and to the sampling path 64 between the detection section 75 and the cleaning liquid storage section 70, and capable of introducing a sample from the culture section to the sampling path 64, and further comprising a first pump (main mechanism side pump 92) provided in the sampling path 64 between the cleaning liquid storage section 70 and the sample introduction path 130 for circulating the cleaning liquid to the detection section 75, and a second pump (introduction mechanism side pump 142) provided in the sample introduction path 130 for circulating the sample from the sample introduction path 130 to the detection section 75.

Claims

1. A sampling device for collecting a liquid sample from a culture device for culturing cells, comprising: a sampling path through which the sample flows; a detection unit provided in the sampling path so as to come into contact with the sample; a cleaning liquid storage section connected to the sampling path upstream of the detection section and storing a cleaning liquid; a sample introduction path connected to the culture device and to the sampling path between the detection unit and the cleaning liquid storage unit, the sample introduction path being capable of introducing the sample from the culture device to the sampling path; a first pump provided in the sampling path between the cleaning liquid storage section and the sample introduction path, for circulating the cleaning liquid through the detection section; a second pump provided in the sample introduction path for circulating the sample from the sample introduction path to the detection unit; a control unit that controls the operation of each of the first pump and the second pump; a standard solution storage unit connected to the upstream side of the sampling path relative to the first pump and storing a standard solution for calibrating the detection unit, the sampling path is connected to a cleaning liquid branch path connected to the cleaning liquid storage section and a standard liquid branch path connected to the standard liquid storage section, on an upstream side of the first pump; The cleaning liquid clamp opens and closes the cleaning liquid branch path, and the standard liquid clamp opens and closes the standard liquid branch path, the control unit controls the first pump to distribute the cleaning liquid and the second pump to distribute the sample at different times; The control unit opens one of the cleaning liquid clamp and the standard liquid clamp and closes the other, in conjunction with the operation of the first pump. Sampling device.

2. 2. The sampling device according to claim 1, A sterile filter is provided between the culture device and the second pump to prevent bacteria from entering the culture device. Sampling device.

3. The sampling device according to claim 1 or 2, A part of the sampling path including a range from the cleaning liquid storage section to the downstream side of the first pump, and the first pump are configured as a main unit that can be handled integrally with each other. Sampling device.

4. 4. The sampling device according to claim 3, A part of the sample introduction path and the second pump are configured as an introduction unit that can be handled integrally with each other. Sampling device.

5. 5. The sampling device according to claim 4, The introduction unit a pressure sensor for detecting an internal pressure of the sample introduction path upstream of the second pump; and an air bubble sensor that detects air bubbles in the sample introduction path. Sampling device.

6. 6. The sampling device according to claim 4 or 5, The sampling path has a connection portion at a location downstream of the first pump and exposed from the main unit for connecting the sample introduction paths extending from each of the plurality of introduction units and / or an analysis path communicating with an analytical instrument that analyzes the sample. Sampling device.

7. The sampling device according to any one of claims 3 to 5, the detection unit includes one or more element units directly provided on the sampling path, The one or more element units can be set integrally in a measuring device configured separately from the main unit. Sampling device.

8. A cell culture system having a culture unit for culturing cells, a sampling path through which a liquid sample collected from the culture unit flows; a detection unit provided in the sampling path so as to come into contact with the sample; a cleaning liquid storage section connected to the sampling path upstream of the detection section and storing a cleaning liquid; a sample introduction path connected to the culture unit and to the sampling path between the detection unit and the cleaning liquid storage unit, the sample introduction path being capable of introducing the sample from the culture unit to the sampling path; a first pump provided in the sampling path between the cleaning liquid storage section and the sample introduction path, for circulating the cleaning liquid through the detection section; a second pump provided in the sample introduction path for circulating the sample from the sample introduction path to the detection unit; a control unit that controls the operation of each of the first pump and the second pump; a standard solution storage unit connected to the upstream side of the sampling path relative to the first pump and storing a standard solution for calibrating the detection unit, the sampling path is connected to a cleaning liquid branch path connected to the cleaning liquid storage section and a standard liquid branch path connected to the standard liquid storage section, on an upstream side of the first pump; The cleaning liquid clamp opens and closes the cleaning liquid branch path, and the standard liquid clamp opens and closes the standard liquid branch path, the control unit controls the first pump to distribute the cleaning liquid and the second pump to distribute the sample at different times; The control unit opens one of the cleaning liquid clamp and the standard liquid clamp and closes the other, in conjunction with the operation of the first pump. Cell culture system.

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