Culture control device and culture control method

Abstract

A culture control device 8 includes: a calculation unit 18 that calculates a rate at which cells 10 in a culture medium 12 consume glucose, a rate at which the cells 10 produce lactic acid, and a glycolysis ratio, which is the ratio of the lactic acid production rate to the glucose consumption rate; and a selection unit 20 that selects either culture medium replacement or culture termination on the basis of the glucose consumption rate, the lactic acid production rate, and the glycolysis ratio.

Description

Technical Field

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[0001] The present disclosure relates to a culture control device and a culture control method.

Background Art

[0002] Patent Document 1 discloses a cell culture device including a cell state determination device and an operation control correction device. In this cell culture device, in order to create a database for classifying the state of cells into normal and abnormal, or to determine culture conditions for returning cells in an abnormal state to a normal state, culture experiments are carried out in various culture conditions in advance to obtain culture data.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] ​​​​​​​​​​​​To solve the above problems, one aspect of the present disclosure is a culture control device. This device comprises a calculation unit that calculates the rate at which cells in the culture medium consume glucose, the rate at which cells produce lactate, and the glycolysis ratio, which is the ratio of the lactate production rate to the glucose consumption rate, and a selection unit that selects either a culture medium change or termination of culture based on the glucose consumption rate, the lactate production rate, and the glycolysis ratio.

[0007] Another aspect of the present disclosure is a method for controlling culture. This method includes calculating the rate at which cells in the culture medium consume glucose, the rate at which cells produce lactate, and the glycolysis ratio, which is the ratio of the lactate production rate to the glucose consumption rate, and selecting either a medium change or termination of culture based on the glucose consumption rate, lactate production rate, and glycolysis ratio.

[0008] Any combination of the components described above, as well as any conversion of the expressions of this disclosure between methods, apparatus, systems, etc., are also valid as aspects of this disclosure. [Effects of the Invention]

[0009] According to this disclosure, culturing can be controlled more easily. [Brief explanation of the drawing]

[0010] [Figure 1] This is a schematic diagram of a culture system including a culture control device according to an embodiment. [Figure 2] Figure 2(A) shows the changes in glucose (Glc) consumption rate and lactate (Lac) production rate over time. Figure 2(B) shows the glycolysis ratio calculated from the glucose consumption rate and lactate production rate shown in Figure 2(A). [Figure 3] This flowchart shows an example of the control performed by the culture control system. [Modes for carrying out the invention]

[0011] The present disclosure will be described below with reference to the drawings, based on preferred embodiments. The embodiments are illustrative and not limiting, and not all features or combinations thereof described in the embodiments are necessarily essential to the present disclosure. The same or equivalent components, members, and processes shown in each drawing are denoted by the same reference numerals, and redundant descriptions are omitted where appropriate. The scale and shape of each part shown in each drawing are set for convenience to facilitate explanation and are not to be interpreted restrictively unless otherwise specified. Furthermore, where terms such as "first," "second," etc. are used in this specification or claims, unless otherwise specified, these terms do not indicate any order or importance, but are used to distinguish one configuration from another. In addition, some components that are not important for explaining the embodiments are omitted in each drawing.

[0012] Figure 1 is a schematic diagram of a culture system 1 including a culture control device 8 according to an embodiment. In Figure 1, a part of the configuration of the culture control device 8 is depicted as a functional block. This functional block is implemented as a hardware configuration using elements and circuits such as a computer's CPU and memory, and as a software configuration using a computer program, etc. Those skilled in the art will understand that these functional blocks can be implemented in various forms by combinations of hardware and software.

[0013] The culture system 1 comprises a culture vessel 2, a sensor 4, a culture medium exchange device 6, and a culture control device 8. The culture vessel 2 contains the cells 10 to be cultured and the culture medium 12. Examples of culture vessels 2 include well plates, culture bags, etc. The cells 10 are not particularly limited, but human iPS cells are an example. The culture medium 12 can be appropriately selected depending on the cells 10 to be cultured.

[0014] Sensor 4 measures the glucose and lactate concentrations in the culture medium 12. As an example, Sensor 4 is an electrochemical sensor with a working electrode, a counter electrode, and a reference electrode on a substrate. Sensor 4 has two working electrodes. One working electrode is provided with a reagent layer containing glucose oxidoreductase and a redox mediator. The other working electrode is provided with a reagent layer containing lactate oxidoreductase and a redox mediator. Sensor 4 is connected to a culture control device 8 and outputs currents to the culture control device 8 corresponding to the glucose concentration and lactate concentration in the culture medium 12. Note that the structure of Sensor 4 is not limited to the one described above. For example, the sensor for measuring glucose concentration and the sensor for measuring lactate concentration may be separate. Since the structure of Sensor 4 is well known, further detailed explanation is omitted.

[0015] The culture medium exchange device 6 exchanges the culture medium 12 contained in the culture vessel 2. The culture medium exchange device 6 has a discharge pipe 14 and a suction pipe 16. The culture medium exchange device 6 also has a culture medium tank (not shown) that contains new culture medium 12 to be supplied to the culture vessel 2, and a drainage tank (not shown) that contains old culture medium 12 recovered from the culture vessel 2. One end of the discharge pipe 14 is connected to the culture medium tank, and the other end is connected to the culture vessel 2. One end of the suction pipe 16 is connected to the drainage tank, and the other end is connected to the culture vessel 2. When the culture medium exchange device 6 receives a signal from the culture control device 8 to instruct it to exchange the culture medium, it performs the exchange. Specifically, the culture medium exchange device 6 drives a built-in pump (not shown) to supply new culture medium 12 from the culture medium tank to the culture vessel 2 via the discharge pipe 14, and recovers old culture medium 12 from the culture vessel 2 to the drainage tank via the suction pipe 16.

[0016] The cell culture control device 8 controls cell culture according to the state of the cells 10 and the culture environment. An example of the cell culture control device 8 includes a calculation unit 18 and a selection unit 20. The calculation unit 18 and the selection unit 20 operate by their respective integrated circuits executing programs stored in memory. The calculation unit 18 calculates the rate at which cells 10 in the culture medium 12 consume glucose (hereinafter referred to as the glucose consumption rate), the rate at which cells 10 in the culture medium 12 produce lactate (hereinafter referred to as the lactate production rate), and the glycolysis ratio. The glycolysis ratio is the ratio of the lactate production rate to the glucose consumption rate (lactate production rate / glucose consumption rate). In glycolysis, the main metabolic pathway of cells 10, one molecule of glucose is converted to two molecules of lactate. The glycolysis ratio is 100% when one molecule of glucose is consumed and two molecules of lactate are produced per unit time.

[0017] The selection unit 20 selects either changing the culture medium 12 or ending the cell culture of the cells 10 based on the glucose consumption rate, lactate production rate, and glycolysis ratio calculated by the calculation unit 18. If the state of the cells 10 or the culture environment of the cells 10 changes during the culture process, at least one of the glucose consumption rate and lactate production rate may change accordingly. The glycolysis ratio may also change in conjunction with such changes. Therefore, the glucose consumption rate, lactate production rate, and glycolysis ratio can be used as indicators to determine the timing of culture medium change or termination of culture. The glucose consumption rate, lactate production rate, and glycolysis ratio can be easily obtained during culture. Therefore, by monitoring these three parameters during cell culture, the culture can be easily controlled.

[0018] FIG. 2(A) is a diagram showing the change over time in the glucose (Glc) consumption rate and the lactic acid (Lac) production rate. FIG. 2(B) is a diagram showing the glycolysis ratio calculated from the glucose consumption rate and the lactic acid production rate shown in FIG. 2(A). The calculation unit 18 of the present embodiment repeatedly acquires the measurement results of the glucose concentration and the lactic acid concentration from the sensor 4. For example, the calculation unit 18 acquires each concentration every minute. Then, the calculation unit 18 repeatedly calculates the glucose consumption rate by differentiating the acquired glucose concentration with respect to time. Further, the calculation unit 18 repeatedly calculates the lactic acid production rate by differentiating the acquired lactic acid concentration with respect to time. The calculated glucose consumption rate and lactic acid production rate are held in a memory (not shown).

[0019] Generally, the cell 10 is placed in a normal culture medium 12 in substantially the same state as before the culture at the initial stage of the culture within a predetermined time from the start of the culture. As shown in FIG. 2(A), at the initial stage of the culture, the glucose consumption rate and the lactic acid production rate are below a predetermined value. Also, both rates are approximately constant with only a slight increase. Further, the glycolysis ratio is constant. The calculation unit 18 calculates the initial glycolysis ratio at this initial stage of the culture. The initial glycolysis ratio serves as a criterion when selecting medium replacement or culture termination. The “predetermined time” can be appropriately set based on experiments and simulations by the designer. As an example, the predetermined time is 2 hours.

[0020] As the culture time elapses, the number of cells gradually increases. As a result, the decrease in the glucose concentration and the increase in the lactic acid concentration in the culture medium 12 are accelerated. Therefore, as shown in FIG. 2(A), the glucose consumption rate and the lactic acid production rate gradually increase. In the example shown in FIG. 2(A), at time T1, both the glucose consumption rate and the lactic acid production rate reach a peak, and then turn to decrease. If the cell culture is being carried out normally, the glucose consumption rate and the lactic acid production rate should increase as the number of cells increases. Therefore, when at least one of the glucose consumption rate and the lactic acid production rate becomes constant or decreases, it can be inferred that the culture medium 12 has deteriorated or the state of the cell 10 has changed.

[0021] Therefore, when at least one of the following conditions is met: the calculated glucose consumption rate is less than or equal to the previously calculated glucose consumption rate, and the calculated lactic acid production rate is less than or equal to the previously calculated lactic acid production rate, the selection unit 20 executes the selection of medium replacement or culture termination.

[0022] In this selection, the selection unit 20 of the present embodiment selects culture termination when the difference between the glycolysis ratio calculated after the calculation of the initial glycolysis ratio and the initial glycolysis ratio is greater than or equal to a predetermined threshold. Also, when the difference is less than the threshold, the selection unit 20 selects medium replacement.

[0023] For example, the selection unit 20 converts the difference into a ratio to the initial glycolysis ratio, and selects culture termination or medium replacement based on whether the ratio is greater than or equal to the threshold. Note that the selection unit 20 may also execute the above selection based on the magnitude of the difference itself. The "threshold" can be appropriately set based on experiments and simulations by the designer. As an example, the threshold is 20% of the initial glycolysis ratio.

[0024] When the difference between the calculated glycolysis ratio and the initial glycolysis ratio is less than the threshold, that is, when the glycolysis ratio has not changed significantly, it is highly likely that the state of the cell 10 remains the same as in the initial stage of culture. In this case, the change in the glucose consumption rate and / or the change in the lactic acid production rate can be presumed to be caused by the deterioration of the culture environment due to, for example, the decrease in the pH of the medium 12. Therefore, the selection unit 20 selects medium replacement when the difference is less than the threshold. Also, when the difference is greater than or equal to the threshold, that is, when the glycolysis ratio has changed significantly, it is highly likely that the state of the cell 10 has changed from the initial stage of culture. For example, when the state of the cell 10 changes, the metabolic pathway of glucose can change from glycolysis to another pathway. In this case, components other than lactic acid are produced from one molecule of glucose. As a result, the glycolysis ratio changes significantly. Therefore, the selection unit 20 selects culture termination when the difference is greater than or equal to the threshold.

[0025] In Figure 2(B), the dashed-line region R1 represents the glycolysis ratio during the time period including time T1. In the example shown in Figure 2(B), a glycolysis ratio of 100% (i.e., Glc:Lac = 1:2) is defined as the initial glycolysis ratio, and ±20% of the initial glycolysis ratio is used as the threshold for judgment. The glycolysis ratio during the time period including time T1 is less than the threshold difference from the initial glycolysis ratio. Therefore, the selection unit 20 selects a medium change. When the selection unit 20 selects a medium change, it outputs a signal to the medium change device 6 instructing it to change the medium. This allows the cell culture of 10 to continue under a more suitable culture environment.

[0026] The culture control device 8 of this embodiment includes a display unit 22 that displays the selection result of the selection unit 20. When the selection unit 20 selects culture medium exchange, it may output a signal to the display unit 22 to notify the user that the culture medium exchange has been performed. This allows the user of the culture system 1 to be aware that the culture medium exchange has been performed. Furthermore, if the culture system 1 does not have a culture medium exchange device 6, the user can perform the culture medium exchange at an appropriate time.

[0027] In the example shown in Figure 2(A), the culture medium was not changed after time T1 in order to observe the changes in glucose consumption rate and lactate production rate, and the culture medium was changed at 144 hours from the start of culture. When cell culture was continued after the culture medium change, the glucose consumption rate and lactate production rate peaked again at time T2, and then began to decrease. In Figure 2(B), the dashed line region R2 represents the glycolysis ratio during the time period including time T2. The difference between the glycolysis ratio during the time period including time T2 and the initial glycolysis ratio is above the threshold. Therefore, the selection unit 20 selects termination of culture. The selection unit 20 outputs a signal to the display unit 22 to notify the termination of culture. This allows the user of the culture system 1 to perform the necessary processing at the appropriate timing. Examples of processing performed after the termination of culture include subculturing, differentiation induction, and disposal of cells 10.

[0028] The selection unit 20 preferably performs the selection described above when at least one of the following conditions is met: the calculated glucose consumption rate is less than the previous glucose consumption rate, and the calculated lactate production rate is less than the previous lactate production rate. As shown in Figure 2(A), for a predetermined time from the start of culture, especially up to about 60 hours of culture, the changes in glucose consumption rate and lactate production rate are substantially level off. During these periods, it is highly likely that the cells 10 maintain their initial state, and there is also a low probability of deterioration of the culture environment due to a decrease in the pH of the culture medium 12, etc. Therefore, it is preferable that the selection unit 20 does not perform selection during these periods. For this reason, the trigger for performing selection is limited to a decrease in glucose consumption rate and lactate production rate. This allows the selection unit 20 to perform selection at a more appropriate timing. Therefore, culture control according to the state of the cells 10 and the culture environment can be performed with higher precision.

[0029] Alternatively, the selection unit 20 may perform the selection described above when at least one of the following conditions is met: the calculated glucose consumption rate is greater than or equal to a predetermined value and less than or equal to the previous glucose consumption rate, and the calculated lactate production rate is greater than or equal to a predetermined value and less than or equal to the previous lactate production rate. As shown in Figure 2(A), around times T1 and T2, when the glucose consumption rate and lactate production rate change from rising to falling, the glucose consumption rate and lactate production rate take higher values ​​than in the initial stages of culture. Therefore, by including the condition that the glucose consumption rate and lactate production rate are greater than or equal to a predetermined value as a trigger for performing the selection, the selection unit 20 can perform the selection at a more appropriate timing. Thus, culture control according to the state of the cells 10 and the culture environment can be performed with higher precision. The "predetermined value" can be set as appropriate based on experiments and simulations by the designer. As an example, the predetermined value is 0.1 mM / h.

[0030] Figure 3 is a flowchart showing an example of the control performed by the culture control device 8. This flow is repeated at predetermined timings. First, the culture control device 8 obtains glucose concentration and lactate concentration from sensor 4 (S101). Then, it calculates the glucose consumption rate and lactate production rate by differentiating each obtained concentration with respect to time (S102). The culture control device 8 also calculates the glycolysis ratio from the calculated glucose consumption rate and lactate production rate (S103). Subsequently, the culture control device 8 determines whether the flag for generating the initial glycolysis ratio is turned on (S104).

[0031] If the generation flag is off (N in S104), the culture control device 8 determines whether the elapsed time since the start of culture has reached a predetermined time (S105). If the predetermined time has not been reached (N in S105), the culture control device 8 returns to the process in step S101. If the predetermined time has been reached (Y in S105), the culture control device 8 calculates the initial glycolysis ratio and sets the generation flag to on (S106). For example, the culture control device 8 sets the average value of the glycolysis ratios calculated from the start of culture until the predetermined time is reached as the initial glycolysis ratio. Note that the method for calculating the initial glycolysis ratio is not limited to the above. For example, the culture control device 8 may set the latest glycolysis ratio it holds at the time it is determined that the elapsed time since the start of culture has reached a predetermined time as the initial glycolysis ratio.

[0032] Next, the culture control device 8 determines whether the last calculated (i.e., most recent) glucose consumption rate is greater than or equal to a predetermined value and less than or equal to the previously calculated glucose consumption rate (S107). If the production flag is on (Y in S104), the culture control device 8 skips steps S105 and S106 and proceeds to step S107. If the glucose consumption rate is less than the predetermined value or greater than the previous value (N in S107), the culture control device 8 determines whether the last calculated lactate production rate is greater than or equal to a predetermined value and less than or equal to the previously calculated lactate production rate (S108).

[0033] If the lactate production rate is above a predetermined value and below the previous value (Y in S108), the culture control device 8 determines whether the difference between the last calculated glycolysis ratio and the initial glycolysis ratio is above a threshold (S109). If the glucose consumption rate is above a predetermined value and below the previous value (Y in S107), the culture control device 8 skips the process in step S108 and proceeds to the process in step S109. If the lactate production rate is below a predetermined value or above the previous value (N in S108), the culture control device 8 returns to the process in step S101.

[0034] If the difference between the glycolysis ratio and the initial glycolysis ratio is greater than or equal to a threshold (Y in S109), the culture control device 8 selects to terminate the culture. It then outputs a signal to the display unit 22 to notify the end of the culture (S110). Subsequently, the culture control device 8 sets the flag for generating the initial glycolysis ratio to off (S112) and terminates this routine. If the difference between the glycolysis ratio and the initial glycolysis ratio is less than a threshold (N in S109), the culture control device 8 selects to change the culture medium. It then outputs a signal to the culture medium change device 6 to perform the culture medium change (S111) and returns to the process in step S101.

[0035] If the process returns to step S101 after a medium change has been performed, the initial glycolysis ratio calculated previously is reused. In situations where a medium change is selected in step S109, it is highly likely that the state of cell 10 is maintained. Therefore, the initial glycolysis ratio can be reused. Note that the manner in which the initial glycolysis ratio is used is not limited to this configuration. For example, the initial glycolysis ratio may be updated each time a medium change is performed. This makes it possible to more reliably perform culture using the optimal initial glycolysis ratio for cell 10. Furthermore, the flowchart described above may be modified as follows: In step S107, it may be determined whether the lactate production rate is above a predetermined value and below the previous value, and in step S108, it may be determined whether the glucose consumption rate is above a predetermined value and below the previous value. In addition to the medium change performed according to the flowchart described above, medium changes may be performed periodically or irregularly.

[0036] As described above, the culture control device 8 according to this embodiment monitors the timing of culture exchange and culture termination based on the glucose consumption rate, lactate production rate, and glycolysis ratio. In other words, it uses the principles of cellular metabolism to determine changes in the state of the cells 10 and changes in the culture environment, and controls the culture accordingly. This makes it easier to control the culture. Furthermore, the culture control device 8 selects to terminate the culture when the difference between the glycolysis ratio and the initial glycolysis ratio is greater than or equal to a threshold, and selects to exchange the culture medium when the difference is less than the threshold. In addition, the culture control device 8 makes a selection between terminating the culture or exchanging the culture medium when the temporal change of at least one of the glucose consumption rate and lactate production rate levels off or decreases. These measures make it possible to more reliably carry out culture in response to changes in the state of the cells 10 and changes in the culture environment.

[0037] The embodiments of this disclosure have been described in detail above. The embodiments described above are merely examples of how to implement this disclosure. The content of the embodiments does not limit the technical scope of this disclosure, and many design changes, such as changes, additions, and deletions of components, are possible as long as they do not depart from the spirit of the invention as defined in the claims. A new embodiment with design changes will have the combined effects of the respective embodiments and modifications. In the embodiments described above, the content in which such design changes are possible is emphasized with notations such as "of this embodiment" or "in this embodiment," but design changes are also permitted even without such notations. Any combination of the above components is also valid as an embodiment of this disclosure. The hatching applied to the cross-section in the drawings does not limit the material of the object to which the hatching is applied.

[0038] The embodiments may be specified by the items described below. [1st item] A calculation unit (18) calculates the rate at which cells (10) in the culture medium (12) consume glucose, the rate at which cells (10) produce lactate, and the glycolysis ratio, which is the ratio of the lactate production rate to the glucose consumption rate. The apparatus includes a selection unit (20) that selects either a medium change or termination of culture based on the glucose consumption rate, lactate production rate, and glycolysis ratio. Culture control device (8). [Second item] The calculation unit (18) calculates the initial glycolysis ratio within a predetermined time from the start of cell (10) culture, The selection unit (20) selects termination of culture when the difference between the glycolysis ratio calculated after the calculation of the initial glycolysis ratio and the initial glycolysis ratio is greater than or equal to a predetermined threshold, and selects medium exchange when the difference is less than the threshold. The culture control device described in item 1 (8). [3rd item] The calculation unit (18) repeatedly acquires measurement results from the sensor (4) that measures the glucose concentration of the culture medium (12) and the sensor (4) that measures the lactic acid concentration of the culture medium (12), repeatedly calculates the glucose consumption rate from the acquired glucose concentration, and repeatedly calculates the lactic acid production rate from the acquired lactic acid concentration. The selection unit (20) performs a selection when at least one of the following conditions is met: the calculated glucose consumption rate is less than or equal to the previous glucose consumption rate, and the calculated lactate production rate is less than or equal to the previous lactate production rate. A culture control device as described in item 1 or item 2 (8). [4th item] The selection unit (20) performs a selection when at least one of the following conditions is met: the calculated glucose consumption rate is less than the previous glucose consumption rate, and the calculated lactate production rate is less than the previous lactate production rate. The culture control device described in item 3 (8). [Item 5] The selection unit (20) performs a selection when at least one of the following conditions is met: the calculated glucose consumption rate is greater than or equal to a predetermined value and less than or equal to the previous glucose consumption rate, and the calculated lactate production rate is greater than or equal to a predetermined value and less than or equal to the previous lactate production rate. The culture control device described in item 3 (8). [Item 6] It includes a display unit (22) that displays the selection result of the selection unit (20), A culture control device (8) as described in any of items 1 through 5. [Item 7] If the selection unit (20) selects a culture medium exchange, it outputs a signal to the culture medium exchange device (6) instructing it to exchange the culture medium. A culture control device as described in any of items 1 through 6. [Item 8] The rate at which cells (10) in the culture medium (12) consume glucose, the rate at which cells (10) produce lactate, and the glycolysis ratio, which is the ratio of the lactate production rate to the glucose consumption rate, are calculated. This includes selecting either a medium change or termination of the culture based on the glucose consumption rate, lactate production rate, and glycolysis ratio. Culture control method. [Industrial applicability]

[0039] This disclosure can be used in culture control devices and culture control methods. [Explanation of symbols]

[0040] 1 Culture system, 2 Culture vessel, 4 Sensor, 6 Medium exchange device, 8 Culture control device, 10 Cells, 12 Medium, 18 Calculation unit, 20 Selection unit, 22 Display unit.

Claims

1. A calculation unit that calculates the rate at which cells in the culture medium consume glucose, the rate at which the cells produce lactate, and the glycolysis ratio, which is the ratio of the lactate production rate to the glucose consumption rate. The system includes a selection unit that performs either a medium exchange or termination of culture based on the glucose consumption rate and the lactate production rate, and that selects whether to exchange the medium or terminate the culture based on the glycolysis ratio in the selection process. The calculation unit repeatedly acquires measurement results from sensors that measure the glucose concentration of the culture medium and sensors that measure the lactate concentration of the culture medium, repeatedly calculates the glucose consumption rate from the acquired glucose concentration, repeatedly calculates the lactate production rate from the acquired lactate concentration, and calculates the initial glycolysis ratio within a predetermined time from the start of cell culture. The selection unit performs the selection when at least one of the following conditions is met: the calculated glucose consumption rate is less than or equal to the previous glucose consumption rate, and the calculated lactate production rate is less than or equal to the previous lactate production rate. In the selection, if the difference between the glycolysis ratio calculated after the calculation of the initial glycolysis ratio and the initial glycolysis ratio is greater than or equal to a predetermined threshold, the unit selects to terminate the culture; and if the difference is less than the threshold, the unit selects to change the culture medium. Culture control device.

2. The selection unit performs the selection when at least one of the following conditions is met: the calculated glucose consumption rate is less than the previous glucose consumption rate, and the calculated lactate production rate is less than the previous lactate production rate. The culture control device according to claim 1.

3. The selection unit performs the selection when at least one of the following conditions is met: the calculated glucose consumption rate is greater than or equal to a predetermined value and less than or equal to the previous glucose consumption rate, and the calculated lactate production rate is greater than or equal to a predetermined value and less than or equal to the previous lactate production rate. The culture control device according to claim 1.

4. The system includes a display unit that displays the selection result of the selection unit. A culture control device according to any one of claims 1 to 3.

5. When the selection unit selects the medium exchange, it outputs a signal to the medium exchange device instructing it to exchange the medium. A culture control device according to any one of claims 1 to 3.

6. The rate at which cells in the culture medium consume glucose, the rate at which the cells produce lactate, and the glycolysis ratio, which is the ratio of the lactate production rate to the glucose consumption rate, are calculated. Based on the glucose consumption rate and the lactate production rate, the system performs either a medium change or termination of the culture, and in the selection, the system chooses between the medium change or termination of the culture based on the glycolysis ratio. The calculation includes repeatedly acquiring measurement results from a sensor that measures the glucose concentration of the culture medium and a sensor that measures the lactate concentration of the culture medium, repeatedly calculating the glucose consumption rate from the acquired glucose concentration, repeatedly calculating the lactate production rate from the acquired lactate concentration, and calculating the initial glycolysis ratio within a predetermined time from the start of cell culture. The selection is performed when at least one of the following conditions is met: the calculated glucose consumption rate is less than or equal to the previous glucose consumption rate, and the calculated lactate production rate is less than or equal to the previous lactate production rate. The selection also includes selecting to terminate the culture when the difference between the glycolysis ratio calculated after the calculation of the initial glycolysis ratio and the initial glycolysis ratio is greater than or equal to a predetermined threshold, and selecting to change the culture medium when the difference is less than the threshold. Culture control method.

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