Data processing device and data processing method

Abstract

A data processing device (14) comprises: an acquisition unit (34) that acquires first cell count data (42) and second cell count data (24); a calculation unit (36) that calculates a rate ratio, which is the ratio between a first change rate of the first cell count data (42) in a first prescribed period and a second change rate of the second cell count data (24) in a second prescribed period corresponding to the first prescribed period; and a prediction data generation unit (38) that generates, on the basis of the rate ratio and first partial data (42a) that is a part of the first cell count data (42) after the first prescribed period, prediction data (48) indicating a change in the cell count after the present under a second culture condition.

Description

Data processing device and data processing method

[0001] The present invention relates to a data processing device and a data processing method for processing data obtained by cell culture.

[0002] For example, Japanese Patent Application Laid-Open No. 2020-171241 discloses a cell culture device. A user sets culture conditions for the cell culture device so that a desired number of cells can be collected within a desired culture period. The cell culture device cultures cells under the set culture conditions.

[0003] Japanese Patent Application Laid-Open No. 2020-171241

[0004] In cell culture using hollow fiber membranes, it is difficult to directly observe the inside of the hollow fiber during cell culture, so there is a need to predict the progress of cell culture during culture.

[0005] The present invention aims to solve the above-mentioned problems.

[0006] (1) A data processing device of the first invention is a data processing device that processes data on cell culture performed in a cell culture device equipped with a hollow fiber membrane, and includes: an acquisition unit that acquires first cell count data that indicates the change in cell count from the start of culture under first culture conditions to the end of culture; and second cell count data that indicates the change in cell count from the start of culture under second culture conditions to the present; a calculation unit that calculates a rate ratio that is the ratio between a first change rate, which is the rate of change of the first cell count data in a first predetermined period, and a second change rate, which is the rate of change of the second cell count data in a second predetermined period corresponding to the first predetermined period; and a prediction data generation unit that generates prediction data that indicates the change in cell count from the present onwards under the second culture conditions based on first partial data, which is the portion of the first cell count data after the first predetermined period, and the rate ratio.

[0007] According to the configuration of the above item (1), predicted data reflecting the second cell count data, which is data during the culture, is generated, so that the progress of the culture can be predicted during the culture. As a result, the user can change the initial culture plan as needed during the culture. Therefore, it is possible to culture the cells in an optimal manner.

[0008] (2) The data processing device described in item (1) above may include a display control unit that controls the display of the number of cells calculated from third cell count data, which is data obtained by combining the second cell count data with the prediction data, on a display unit.

[0009] According to the configuration of the above item (2), the user can know the culture period during which the desired number of cells can be recovered, based on the number of cells displayed on the display unit.

[0010] (3) In the data processing device described in item (1) or (2) above, the predicted data generation unit may generate the predicted data when a deviation of the second change rate from the first change rate becomes equal to or greater than a predetermined amount.

[0011] According to the configuration of the above item (3), prediction data can be created only when the difference between the initial culture plan and the actual culture state becomes large.

[0012] (4) In the data processing device described in any one of items (1) to (3) above, the first cell count data may be data obtained by cell culture performed in the past or data obtained by a cell culture simulation.

[0013] (5) In the data processing device described in any one of items (1) to (4) above, the acquisition unit may acquire the first cell count data based on a plurality of cell count data.

[0014] (6) A data processing method of the second invention includes the steps of acquiring first cell count data indicating the change in cell count from the start of culture under first culture conditions to the end of culture and second cell count data indicating the change in cell count from the start of culture under second culture conditions to the present; calculating a rate ratio which is the ratio between a first change rate, which is the rate of change of the first cell count data in a first predetermined period, and a second change rate, which is the rate of change of the second cell count data in a second predetermined period corresponding to the first predetermined period; and generating prediction data indicating the change in cell count from the present onwards under the second culture conditions based on first partial data, which is the portion of the first cell count data after the first predetermined period, and the rate ratio.

[0015] According to the configuration of the above item (6), as with the configuration of the above item (1), predicted data reflecting the second cell count data, which is data during the culture, is generated, so that the progress of the culture can be predicted during the culture. As a result, the user can change the initial culture plan as needed during the culture. Therefore, it is possible to culture the cells in an optimal manner.

[0016] According to the present invention, the progress of cell culture can be predicted during culture.

[0017] FIG. 1 is a block diagram of a cell culture system. FIG. 2 is a circuit diagram of a cell culture circuit. FIG. 3 is a diagram showing the operation of the cell culture device when culturing cells in the first culture mode. FIG. 4 is a diagram showing the operation of the cell culture device when culturing cells in the second culture mode. FIG. 5 is a diagram showing the operation of the cell culture device when culturing cells in the third culture mode. FIG. 6 is a diagram showing the operation of the cell culture device when culturing cells in the fourth culture mode. FIG. 7 is a flowchart of a data display process. FIG. 8A is a graph showing the first cell count data and the second cell count data. FIG. 8B is a graph showing the first cell count data and the third cell count data. FIG. 9 is a diagram showing transition data displayed on the display unit. FIG. 10 is a table showing the evaluation results of an example. FIG. 11 is a table showing the culture conditions for each of three specimens. FIG. 12 is a graph showing cell count data (glucose) obtained by simulating specimen 2 (low) using specimen 1 (middle) of adherent cells as reference data. FIG. 13 is a graph showing cell count data (lactic acid) obtained by simulating specimen 2 (low) using specimen 1 (middle) of adhesive cells as reference data. FIG. 14 is a graph showing cell count data (oxygen) obtained by simulating specimen 2 (low) using specimen 1 (middle) of adhesive cells as reference data. FIG. 15 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 2 (low) using specimen 1 (middle) of adhesive cells as reference data. FIG. 16 is a graph showing cell count data (glucose) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adhesive cells as reference data. FIG. 17 is a graph showing cell count data (lactic acid) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adhesive cells as reference data. Fig. 18 is a graph showing cell count data (oxygen) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adherent cells as reference data. Fig. 19 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adherent cells as reference data. Fig. 20 is a table showing culture conditions. Fig. 21 is a table showing culture conditions. Fig. 22 is a table showing culture conditions.FIG. 23 is a graph showing cell count data (glucose) obtained by simulating sample 2 (low) using sample 1 (middle) of suspended cells as reference data. FIG. 24 is a graph showing cell count data (lactic acid) obtained by simulating sample 2 (low) using sample 1 (middle) of suspended cells as reference data. FIG. 25 is a graph showing cell count data (oxygen) obtained by simulating sample 2 (low) using sample 1 (middle) of suspended cells as reference data. FIG. 26 is a graph showing cell count data (carbon dioxide) obtained by simulating sample 2 (low) using sample 1 (middle) of suspended cells as reference data. FIG. 27 is a graph showing cell count data (glucose) obtained by simulating sample 3 (high) using sample 1 (middle) of suspended cells as reference data. Fig. 28 is a graph showing cell count data (lactic acid) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data. Fig. 29 is a graph showing cell count data (oxygen) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data. Fig. 30 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data.

[0018] Typically, before culturing cells, a user refers to past data to predict the change in cell number (metabolic state) during the upcoming cell culture, and creates a culture plan based on the prediction results. For example, the user creates a culture period during which a desired number of cells can be recovered, and then cultures the cells in a cell culture device during the created culture period.

[0019] However, when cells are actually cultured, the change in cell count over time may deviate from the predicted change. If the actual change in cell count over time is significantly lower than the predicted change, it may become impossible to recover the desired number of cells within the initially set culture period. The embodiment described below makes it possible to predict the change in cell count over time using data on the actual change in cell count during cell culture.

[0020] [1. Configuration of Cell Culture System 10] FIG. 1 is a block diagram of the cell culture system 10. The cell culture system 10 includes a cell culture device 12 and a data processing device 14. The data processing device 14 predicts the change in cell count over time and displays the change in cell count over time according to the prediction result. The cells used in the cell culture system 10 may be mammalian cells or mammal-derived cells. The cells used in the cell culture system 10 may also be adherent cells or suspension cells. Specific examples of the cells include HEK293 cells (human embryonic kidney cells), ES cells (embryonic stem cells), iPS cells (induced pluripotent stem cells), mesenchymal stem cells, fibroblasts, endothelial cells, and neural stem cells. Examples of floating cells include Jurkat cells (human myeloid leukemia-derived cells), T cells, regulatory T cells, tumor-infiltrating lymphocytes, CAR-T cells, CD34-positive cells, etc. The cells used in the cell culture system 10 are not limited to those mentioned above.

[0021] Basal media and complete media are used for cell culture. For example, MEM (Minimum Essential Media) is used as the basal media. For complete media, a basal media (e.g., MEM) containing nutritional components such as proteins is used. Proteins used include albumin, growth factors, cytokines, and the like. For example, bovine serum containing albumin, growth factors, and the like is added to the basal media.

[0022] [1-1 Cell Culture Device 12] The cell culture device 12 includes a cell culture circuit 16 and a detection unit 18. As shown in FIG. 2, the cell culture circuit 16 includes a bioreactor 160, a first supply unit 161, a first circuit 162, a second supply unit 163, a second circuit 164, a third circuit 165, a waste liquid storage unit 166, a first sampling unit 167, and a second sampling unit 168. The first sampling unit 167 and the second sampling unit 168 include various sensors (not shown) for detecting the concentrations of glucose, lactic acid, protein, and the like. The cell culture circuit 16 also includes various gas sensors for detecting the concentrations of gases (O2, CO2, etc.) in the liquid. The cell culture circuit 16 also includes multiple pumps (not shown) for applying flow force to the liquid and multiple valves 169 for opening and closing the flow paths.

[0023] The bioreactor 160 includes a housing 160a and a plurality of hollow fiber membranes 160b. The housing 160a accommodates the plurality of hollow fiber membranes 160b. Each hollow fiber membrane 160b is cylindrical. That is, each hollow fiber membrane 160b has a hole (inner hole) that penetrates from one end to the other. The bioreactor 160 includes a flow path defined by the inner circumferential surface of the hollow fiber membranes 160b and a flow path defined by the inner wall surface of the housing 160a and the outer circumferential surface of the hollow fiber membranes 160b. Within the housing 160a, fluid can flow from the inside to the outside of the hollow fiber membranes 160b and from the outside to the inside of the hollow fiber membranes 160b.

[0024] The first supply unit 161 includes a bag containing a liquid such as a cell solution, a complete medium, a basal medium, or a cleaning solution. The first circuit 162 includes a first supply flow path 162a and a first circulation flow path 162b. The first supply flow path 162a connects the first supply unit 161 to the first circulation flow path 162b. The first circulation flow path 162b includes a flow path defined by the inner circumferential surfaces of the hollow fiber membranes 160b of the bioreactor 160. The liquid supplied from the first supply unit 161 to the first circulation flow path 162b via the first supply flow path 162a can circulate through the first circulation flow path 162b. The first sampling unit 167 samples the culture medium from the first circulation flow path 162b.

[0025] The second supply unit 163 includes a bag containing a liquid such as a basal medium or a cleaning solution. The second circuit 164 includes a second supply flow path 164a and a second circulation flow path 164b. The second supply flow path 164a connects the second supply unit 163 to the second circulation flow path 164b. The second circulation flow path 164b includes a flow path defined by the inner wall surface of the housing 160a of the bioreactor 160 and the outer peripheral surface of the hollow fiber membrane 160b. The liquid supplied from the second supply unit 163 to the second circulation flow path 164b via the second supply flow path 164a can circulate through the second circulation flow path 164b. The second sampling unit 168 samples the culture medium from the second circulation flow path 164b.

[0026] The third circuit 165 connects the first circulation flow path 162b to the waste liquid storage section 166, and also connects the second circulation flow path 164b to the waste liquid storage section 166. The waste liquid storage section 166 includes a container for storing the waste liquid. The waste liquid discharged from the first circulation flow path 162b and the second circulation flow path 164b is collected in the waste liquid storage section 166.

[0027] One of the plurality of valves 169 is disposed in the first supply flow path 162a. One of the plurality of valves 169 is disposed in the second supply flow path 164a. One of the plurality of valves 169 is disposed in the flow path of the third circuit 165 that connects the first circulation flow path 162b and the waste liquid storage section 166. One of the plurality of valves 169 is disposed in the flow path of the third circuit 165 that connects the second circulation flow path 164b and the waste liquid storage section 166.

[0028] Returning to FIG. 1 , the description of the cell culture device 12 continues. The detection unit 18 detects second cell count data 24 from the culture medium sampled by at least one of the first sampling unit 167 and the second sampling unit 168. The detection unit 18 sends the second cell count data 24 to the data processing device 14 at predetermined time intervals. The second cell count data 24 is data indicating the change (increase or decrease) in the cell count under the second culture conditions. The second cell count data 24 is also data indicating the combined metabolic rates of all cells present in the bioreactor 160. The cell count data described herein (the second cell count data 24, the first cell count data 42 and the third cell count data 44 described below) corresponds to data indicating, for example, the concentrations of glucose, lactic acid, O2, CO2, etc. in the culture medium. The second culture conditions include, for example, information about substances contained in the culture medium, information about the gas supplied to the culture medium, information about the cell culture device 12 (volume information, operation information, culture mode, etc.), the number of days of culture, the number of seeds, various temperatures, etc. Details of the culture mode will be described in [2] below.

[0029] [1-2 Data Processing Device 14] The data processing device 14 includes an input unit 26, a calculation unit 28, a storage unit 30, and a display unit 32. The data processing device 14 may be configured as, for example, a computer (a personal computer, a tablet terminal, a smartphone, etc.). Note that, of the data processing device 14, the calculation unit 28 and the storage unit 30 may be provided in a server, and the display unit 32 may be provided in a terminal device.

[0030] The input unit 26 is a man-machine interface operated by a user. The input unit 26 may be, for example, a keyboard, a touch panel, a mouse, etc. The input unit 26 sends information input by the user to the calculation unit 28.

[0031] The calculation unit 28 may be configured by a processor such as a CPU (Central Processing Unit) or a GPU (Graphics Processing Unit), etc. In other words, the calculation unit 28 may be configured by a processing circuit.

[0032] The calculation unit 28 includes an acquisition unit 34, a calculation unit 36, a data generation unit 38 (prediction data generation unit), and a display control unit 40. Each of the acquisition unit 34, the calculation unit 36, the data generation unit 38, and the display control unit 40 can be realized by the calculation unit 28 executing a program stored in the storage unit 30.

[0033] At least a portion of the acquisition unit 34, the calculation unit 36, the data generation unit 38, and the display control unit 40 may be realized by an integrated circuit such as an ASIC (Application Specific Integrated Circuit) or an FPGA (Field-Programmable Gate Array). Also, at least a portion of the acquisition unit 34, the calculation unit 36, the data generation unit 38, and the display control unit 40 may be configured by an electronic circuit including a discrete device.

[0034] The acquisition unit 34 acquires data from devices external to the calculation unit 28 (such as the cell culture device 12, the input unit 26, the memory unit 30, and an external memory device). The calculation unit 36 ​​calculates a first change rate, a second change rate, and a rate ratio, which will be described later. The data generation unit 38 generates corrected data 46 and predicted data 48 ( FIG. 8B ) based on the first cell count data 42 and the rate ratio. Furthermore, the data generation unit 38 generates third cell count data 44 based on the second cell count data 24 and the predicted data 48. The display control unit 40 controls the display of the display unit 32.

[0035] The storage unit 30 may be composed of a volatile memory (not shown) and a non-volatile memory (not shown). Examples of the volatile memory include RAM (Random Access Memory). This volatile memory is used as a working memory for the processor and temporarily stores data necessary for processing or calculation. Examples of the non-volatile memory include ROM (Read Only Memory) and flash memory. This non-volatile memory is used as a storage memory and stores programs, tables, maps, etc. At least a portion of the storage unit 30 may be provided in the processor, integrated circuit, etc. described above.

[0036] The memory unit 30 stores first cell count data 42 in advance before cells are cultured in the cell culture device 12. The first cell count data 42 is data indicating a change (increase or decrease) in the cell count under the first culture conditions. The first cell count data 42 is data summing the metabolic rates of all cells present in the bioreactor 160. The first culture conditions include, for example, information about substances contained in the culture medium, information about the gas supplied to the culture medium, information about the cell culture device 12 (capacity information, operation information, culture form, etc.), number of culture days, number of seeds, various temperatures, etc.

[0037] The first cell count data 42 may be data obtained by previous cell culture. The first cell count data 42 may be data obtained by a cell culture simulation. The first cell count data 42 may be stored in an external storage device instead of the storage unit 30.

[0038] The display unit 32 may be, for example, a display. The display unit 32 displays various display objects (for example, the transition data 50) in accordance with the control of the display control unit 40.

[0039] [2 Culture Forms Using Cell Culture Circuit 16] In the cell culture circuit 16, a controller (not shown) controls multiple pumps (not shown) and multiple valves 169 to change the flow path through which the culture medium flows and the flow rate of the culture medium. This allows the cell culture circuit 16 to realize multiple culture forms. Below, first to eighth culture forms will be described as examples of the culture forms.

[0040] The first and second culture types are primarily performed in the early to middle stages of the cell culture process, the third and fourth culture types are primarily performed in the middle to late stages of the cell culture process, and the fifth culture type is appropriately performed during the culture period to harvest cells.

[0041] [2-1 First Culture Form] Figure 3 is a diagram showing the operation of the cell culture device 12 during cell culture in the first culture form. The first culture form is as follows: (a) Complete medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) No basal medium is supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the second circulation flow path 164b to the waste liquid storage unit 166 via the third circuit 165.

[0042] The first culture mode is primarily used in cell culture processes, but may also be used in cell collection processes. When the first culture mode is used in cell collection processes, for example, a basal medium is supplied from both ends of the hollow fiber membrane 160b. This allows cells present in the first circulation channel 162b to be collected within the hollow fiber membrane 160b.

[0043] [2-2 Second Culture Form] Figure 4 is a diagram showing the operation of the cell culture device 12 during cell culture in the second culture form. The second culture form is as follows: (a) Complete medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) Basal medium is not supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the first circulation flow path 162b to the waste liquid storage unit 166 via the third circuit 165.

[0044] [2-3 Third Culture Form] Figure 5 is a diagram showing the operation of the cell culture device 12 during cell culture in the third culture form. The third culture form is as follows: (a) Complete medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) Basal medium is supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the second circulation flow path 164b to the waste liquid storage unit 166 via the third circuit 165.

[0045] [2-4 Fourth Culture Form] Figure 6 is a diagram showing the operation of the cell culture device 12 during cell culture in the fourth culture form. The fourth culture form is as follows: (a) Complete medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) Basal medium is supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the first circulation flow path 162b to the waste liquid storage unit 166 via the third circuit 165.

[0046] [2-5 Fifth Culture Form] The fifth culture form is as follows. The operation of the cell culture device 12 during cell culture in the fifth culture form is the same as the operation of the cell culture device 12 during cell culture in the first culture form ( FIG. 3 ), except for the following (a): (a) The basal medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) The basal medium is not supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the second circulation flow path 164b to the waste liquid storage unit 166 via the third circuit 165.

[0047] In the fifth culture mode, similar to the first culture mode, the basal medium may be supplied from both ends of the hollow fiber membrane 160b. This allows the cells present in the first circulation channel 162b to be collected within the hollow fiber membrane 160b. The process in the fifth culture mode is referred to as the cell collection process.

[0048] [2-6 Sixth Culture Form] The sixth culture form is as follows. The operation of the cell culture device 12 during cell culture in the sixth culture form is the same as the operation of the cell culture device 12 during cell culture in the second culture form ( FIG. 4 ), except for the following (a): (a) The basal medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) The basal medium is not supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the first circulation flow path 162b to the waste liquid storage unit 166 via the third circuit 165.

[0049] [2-7 Seventh Culture Form] The seventh culture form is as follows. The operation of the cell culture device 12 during cell culture in the seventh culture form is the same as the operation of the cell culture device 12 during cell culture in the third culture form ( FIG. 5 ), except for the following (a): (a) A basal medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) A basal medium is supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the second circulation flow path 164b to the waste liquid storage unit 166 via the third circuit 165.

[0050] [2-8 Eighth Culture Form] The eighth culture form is as follows. The operation of the cell culture device 12 during cell culture in the eighth culture form is the same as the operation of the cell culture device 12 during cell culture in the fourth culture form ( FIG. 6 ), except for the following (a): (a) A basal medium is supplied from the first supply unit 161 to the first circuit 162 (first circulation flow path 162b). (b) A basal medium is supplied from the second supply unit 163 to the second circuit 164 (second circulation flow path 164b). (c) A portion of the medium is discarded from the first circulation flow path 162b to the waste liquid storage unit 166 via the third circuit 165.

[0051] The first, third, fifth, and seventh culture forms are implemented in a culture process for suspension cells. The second, fourth, sixth, and eighth culture forms are implemented in a culture process for adherent cells. In each of the culture processes for suspension cells and adherent cells, one of the above-mentioned culture forms may be implemented, or a combination of multiple culture forms may be implemented.

[0052] Each culture mode differs in the medium supplied, the method of supplying the medium, the method of disposing of the medium, etc. When generating third cell count data 44 ( FIG. 8B ) for an arbitrary period, data generation unit 38 can execute a simulation that combines multiple culture modes.

[0053] 7 is a flowchart of the data display process. The user causes the cell culture device 12 to perform cell culture, and also causes the data processing device 14 to perform data display process.

[0054] Before causing the data processing device 14 to execute the data display process, the user operates the input unit 26 to specify a target period (first predetermined period, second predetermined period). The target period is a period required to calculate the first change rate and second change rate (described below). The target period is a period selected by the user from within the cell culture period. As an example, if the cell culture period is seven days, the user can input "Day 1" as the start point of the target period and "Day 4" as the end point of the target period. Below, the target period will be described as "Day 1 to Day 4." The user can also input another period. The first predetermined period, which is the target period of the first cell count data 42, and the second predetermined period, which is the target period of the second cell count data 24, are the same period. In other words, the second predetermined period corresponds to the first predetermined period. After inputting the target period, the user operates the input unit 26 to cause the data processing device 14 to execute the data display process.

[0055] In step S1, the acquisition unit 34 acquires the second cell count data 24 from the detection unit 18 of the cell culture device 12. The storage unit 30 sequentially stores the acquired second cell count data 24.

[0056] In step S2, the calculation unit 36 ​​determines whether the fourth day (the end point of the target period) has arrived. If the fourth day has arrived (step S2: YES), the process proceeds to step S3. On the other hand, if the fourth day has not arrived (step S2: NO), the process returns to step S1.

[0057] When the process proceeds from step S2 to step S3, the acquisition unit 34 acquires the first cell count data 42 and the second cell count data 24 from the memory unit 30. The acquired first cell count data 42 is data indicating the change in cell count from the start of culture to the end of culture under the first culture conditions. The acquired second cell count data 24 is data indicating the change in cell count from the start of culture under the culture conditions (second culture conditions) of the currently performed cell culture to the present.

[0058] In step S4, the calculation unit 36 ​​calculates a first change rate and a second change rate for the target period specified by the user. The change rate is the ratio between the specified target period (days 1 to 4) and the amount of change in the cell count data during that target period. For example, the calculation unit 36 ​​calculates the first change rate by dividing the amount of change in the first cell count data 42 during the target period (first predetermined period) of the first cell count data 42 by the target period. Similarly, the calculation unit 36 ​​calculates the second change rate by dividing the amount of change in the second cell count data 24 during the target period (second predetermined period) of the second cell count data 24 by the target period.

[0059] In step S5, the calculation unit 36 ​​calculates the deviation amount of the second change rate from the first change rate. Furthermore, the calculation unit 36 ​​compares the deviation amount with a predetermined amount. The predetermined amount is a threshold for determining whether to execute the processes from step S6 onward. That is, the predetermined amount is a threshold for determining whether to display the trend data 50 on the display unit 32. The predetermined amount is pre-stored in the storage unit 30. If the deviation amount is equal to or greater than the predetermined amount (step S5: YES), the process proceeds to step S6. In this case, as shown in FIG. 8A , a deviation already occurs between the first cell count data 42 and the second cell count data 24 on the fourth day (the end of the target period). In this case, the trend of the second cell count data 24 from day 4 onward is likely to significantly deviate from the trend of the first cell count data 42. In other words, at the end of the cell culture period, the cell count is likely to be significantly lower than the initially predicted number. On the other hand, if the deviation is less than the predetermined amount (step S5: NO), the data display process ends. In this case, the trend of the second cell count data 24 from the fourth day onwards is likely to not deviate significantly from the trend of the first cell count data 42. In other words, at the end of the cell culture period, the cell count is likely to approximate the initially predicted number. Therefore, there is no need to display the trend data 50. Therefore, the data display process ends.

[0060] When the process proceeds from step S5 to step S6, a process is executed to predict the transition of the second cell count data 24 from the fourth day onwards. For example, the calculation unit 36 ​​calculates a rate ratio. The rate ratio is the ratio between the first change rate and the second change rate. For example, the calculation unit 36 ​​calculates the rate ratio by dividing the second change rate by the first change rate.

[0061] In step S7, data generator 38 corrects first cell count data 42 to generate corrected data 46. As shown in FIG. 8B , for example, data generator 38 generates corrected data 46 based on first partial data 42a of first cell count data 42 and the rate ratio. First partial data 42a is partial data of first cell count data 42 that comes after the target period. In this example, first partial data 42a is data from the fifth to seventh days of first cell count data 42. Data generator 38 generates corrected data 46 by multiplying first partial data 42a by the rate ratio.

[0062] In step S8, the data generation unit 38 brings the correction data 46 closer to the second cell count data 24. Specifically, the data generation unit 38 offsets the correction data 46 by the difference between the first cell count data 42 and the second cell count data 24 on the fourth day (the end of the target period). In this way, the data generation unit 38 generates predicted data 48. The corrected data 46 after the offset is referred to as predicted data 48. The predicted data 48 is data that indicates the change in the cell count from the present onwards under the second culture conditions.

[0063] In step S9, data generation unit 38 generates third cell count data 44 ( FIG. 8B ) by combining second cell count data 24 with predicted data 48. Data generation unit 38 then converts third cell count data 44 into a cell count using a predetermined method.

[0064] In step S10, data generation unit 38 performs fitting using the converted cell count data to generate transition data 50 that indicates the transition of cell count. Display control unit 40 controls display of transition data 50 on display unit 32. Display unit 32 then displays transition data 50 as shown in FIG. 9 . Note that display control unit 40 may control display of third cell count data 44 together with transition data 50 on display unit 32, or may control display of only the third cell count data 44 on display unit 32.

[0065] [4 Other Embodiments] There may be multiple pieces of cell count data before cell culture. For example, when there is cell count data obtained from multiple past cell cultures or when there is cell count data obtained from multiple simulations, the acquisition unit 34 may acquire the first cell count data 42 based on the multiple pieces of cell count data. For example, the acquisition unit 34 may calculate the average of the multiple pieces of cell count data to obtain the first cell count data 42.

[0066] The order of the multiplication by the rate ratio in step S7 and the offsetting in step S8 may be reversed. That is, the data generator 38 may offset the first partial data 42 a and use the offset first partial data 42 a as correction data. Furthermore, the data generator 38 may generate the prediction data 48 by multiplying the correction data by the rate ratio.

[0067] The display control unit 40 may display the allowable range of the cell number together with the transition data 50 on the display unit 32. In this case, the storage unit 30 stores the allowable range of the cell number in advance.

[0068] The data generating unit 38 may calculate the timing (date, time) when the number of cells specified by the user can be collected based on the transition data 50. In this case, the display control unit 40 may cause the display unit 32 to display the timing when the number of cells specified by the user can be collected.

[0069] When second cell count data 24 is acquired by acquisition unit 34, data generation unit 38 may calculate an acceptable range for the cell count data. For example, data generation unit 38 may calculate a value of ±5%×day for second cell count data 24. The value of −5%×day for second cell count data 24 is the lower limit of the acceptable range. The value of +5%×day for second cell count data 24 is the upper limit of the acceptable range. Display control unit 40 may cause display unit 32 to display the acceptable range for the cell count data calculated by data generation unit 38.

[0070] [5. Effects of Each Embodiment] According to each embodiment, predicted data 48 reflecting second cell count data 24, which is data during culture, is generated, making it possible to predict the progress of culture during culture. Since predicted data 48 reflecting second cell count data 24, which is data during culture, is generated, making it possible to predict the progress of culture during culture. As a result, the user can change the initial culture plan as needed during culture. Therefore, it becomes possible to culture cells in an optimal manner.

[0071] According to each embodiment, the user can understand the culture period during which the desired number of cells can be recovered based on the number of cells displayed on the display unit 32.

[0072] According to each embodiment, the prediction data 48 can be created only when the difference between the initial culture plan and the actual culture situation becomes large.

[0073] The present invention is not limited to the above disclosure, and various configurations can be adopted without departing from the gist of the present invention.

[0074] [6 Example of Process for Generating Third Cell Count Data 44] The inventors actually performed a process for generating third cell count data 44 based on the above-described embodiment. Furthermore, the inventors compared the generated third cell count data 44 with measurement results measured in actual cell culture to evaluate the accuracy of the third cell count data 44. As a result, the third cell count data 44 was close to the actual measurement results. From this, the inventors concluded that the third cell count data 44 is appropriate. Below, an example of the process for generating the third cell count data 44 will be described.

[0075] The cell culture device 12 used in the cell culture experiments was a Quantum cell expansion system (manufactured by Terumo BCT) or a Quantum Flex cell expansion system (manufactured by Terumo BCT). Hereinafter, the Quantum cell expansion system will be referred to as the "first culture device," and the Quantum Flex cell expansion system will be referred to as the "second culture device." The first and second culture devices differ in the size of the bioreactor 160. The size of the bioreactor 160 of the second culture device is 1 / 10 of the size of the bioreactor 160 of the first culture device. The size of the bioreactor 160 of at least one of the first and second culture devices may be adjustable.

[0076] FIG. 10 is a table showing the evaluation results of the examples. The "Cells" row in the table indicates the cultured cells. The "Bioreactor" row in the table indicates the culture device used. In the "Bioreactor" row, the notation "1x" indicates that the first culture device was used, and the notation "0.1x" indicates that the second culture device was used. The "Glucose" row in the table shows the evaluation results. In the "Glucose" row, the notation "A" indicates that the evaluation result was pass. In the examples, simulation values ​​that fell within a range of ±5% × day of the actual measured concentration were judged to be pass. Note that no examples were evaluated as failing (NA). The notation "N" in parentheses indicates the number of processes evaluated (processes that generate the third cell count data 44). The "TBD" in parentheses indicates the number of samples whose simulation values ​​did not fall within a range of ±5% × day of the actual measured concentration on the final day of culture. As with the "glucose" row, the evaluation results are also shown in the "lactic acid," "O2," and "CO2" rows.

[0077] As shown in Figure 10, for the simulation of culturing Jurkat cells in the first culture device (1x), some of the glucose and lactate evaluations were "TBD." However, the simulated values ​​for both up to day 6 of the 7-day simulation period were within the range of ±5% × day. Thus, for the simulation of culturing Jurkat cells in the first culture device (1x), it was possible to grasp the overall metabolic transition.

[0078] For the conditions resulting in "TBD," the simulation value can be improved by shifting the number of predicted days and performing the simulation again, increasing the frequency of data acquisition, increasing the number of reference data, etc. Below, a part of the evaluation results shown in FIG. 10 will be specifically described.

[0079] 6-1 Example of Cell Culture of Adherent Cells The present inventors conducted three cell culture experiments using the first culture device under different culture conditions to generate three specimens of adherent cells (specimen 1, specimen 2, and specimen 3). In each of the three cell culture experiments, cell culture was performed for seven days, and cell count data was measured periodically. Separately, the present inventors performed a process to generate third cell count data 44 under the culture conditions of specimen 2 and specimen 3 based on the cell count data (first cell count data 42) obtained by the cell culture of specimen 1. Furthermore, the third cell count data 44 was evaluated by comparing the third cell count data 44 obtained under the culture conditions of specimen 2 with the cell count data obtained in the cell culture experiment of specimen 2. Similarly, the third cell count data 44 was evaluated by comparing the third cell count data 44 obtained under the culture conditions of specimen 3 with the cell count data obtained in the cell culture experiment of specimen 3.

[0080] The conditions for the three cell culture experiments are as follows: HEK293 cells were used as the adherent cells to be cultured. A complete medium containing total protein was used as the protein. After priming the cell culture circuit 16 with PBS, the cell culture circuit 16 was precoated with a cellular adhesion factor (fibronectin), and a bag filled with the complete medium after precoating was connected to the first supply flow path 162a. Gas conditioning was performed, and cells were seeded in the first circulation flow path 162b. Cell culture was mainly performed using the second culture method. During the cell culture period, the flow rate of the first circulation flow path 162b was set to 20 mL / min, and the flow rate of the second circulation flow path 164b was set to 300 mL / min.

[0081] Fig. 11 is a table showing the culture conditions for each of the three specimens. Fig. 11 shows the flow rate of the complete medium supplied from the first supply unit 161 to the first circuit 162 (first supply flow path 162a) for each day.

[0082] Fig. 12 is a graph showing cell count data (glucose) obtained by simulating specimen 2 (low) using specimen 1 (middle) as reference data. Fig. 13 is a graph showing cell count data (lactic acid) obtained by simulating specimen 2 (low) using specimen 1 (middle) as reference data. Fig. 14 is a graph showing cell count data (oxygen) obtained by simulating specimen 2 (low) using specimen 1 (middle) as reference data. Fig. 15 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 2 (low) using specimen 1 (middle) as reference data.

[0083] In each of Figures 12 to 15, the graphs indicated by dashed lines are reference data. The reference data is cell count data obtained by cell culture of sample 1 (=first cell count data 42). In each of Figures 12 to 15, the graphs indicated by dashed lines are actual data. The actual data is cell count data obtained by cell culture of sample 2. In each of Figures 12 to 15, the graphs indicated by solid lines are data combining the actual data and predicted data 48 (=third cell count data 44).

[0084] 12 to 15, the solid line graphs generally fell within ±5% × day of the dashed line graphs. Therefore, the inventors concluded that the third cell count data 44 was appropriately generated for the adherent cell sample 2.

[0085] Fig. 16 is a graph showing cell count data (glucose) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adhesive cells as reference data. Fig. 17 is a graph showing cell count data (lactic acid) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adhesive cells as reference data. Fig. 18 is a graph showing cell count data (oxygen) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adhesive cells as reference data. Fig. 19 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 3 (high) using specimen 1 (middle) of adhesive cells as reference data.

[0086] In each of Figures 16 to 19, the graphs indicated by dashed lines are reference data. The reference data is cell count data obtained by cell culture of sample 1 (=first cell count data 42). In each of Figures 16 to 19, the graphs indicated by dashed lines are actual data. The actual data is cell count data obtained by cell culture of sample 3. In each of Figures 16 to 19, the graphs indicated by solid lines are data combining the actual data and predicted data 48 (=third cell count data 44).

[0087] 16 to 19, the solid line graphs generally fell within ±5% × day of the dashed line graphs. Therefore, the inventors concluded that the third cell count data 44 was appropriately generated for the adherent cell sample 3.

[0088] [6-2 Example of Cell Culture of Suspension Cells] The inventors conducted three cell culture experiments using the first culture device under different culture conditions to generate three suspension cell specimens (specimen 1, specimen 2, and specimen 3). In each of the three cell culture experiments, cell culture was performed for seven days, and cell count data was measured periodically. Separately, the inventors performed a process to generate third cell count data 44 under the culture conditions of specimens 2 and 3 based on the cell count data (first cell count data 42) obtained by the cell culture of specimen 1. Furthermore, the third cell count data 44 was evaluated by comparing the third cell count data 44 obtained under the culture conditions of specimen 2 with the cell count data obtained in the cell culture experiment of specimen 2. Similarly, the third cell count data 44 was evaluated by comparing the third cell count data 44 obtained under the culture conditions of specimen 3 with the cell count data obtained in the cell culture experiment of specimen 3.

[0089] The conditions for the three cell culture experiments are as follows: Jurkat cells were used as the suspension cells to be cultured. A complete medium containing total protein was used as the protein. After priming the cell culture circuit 16 with PBS, a bag filled with the complete medium after priming was connected to the first supply flow path 162a. Gas conditioning was performed, and cells were seeded into the first circulation flow path 162b. During the initial cell culture period (7 days), a series of processes consisting of a cell culture step using the first culture configuration, a cell dispersion step, and a cell collection step were repeatedly performed. In the cell dispersion step, the supply and discharge of the medium were stopped, and the medium was circulated within the first circulation flow path 162b. In the cell collection step, cells dispersed in the first circulation flow path 162b during the cell dispersion step were collected inside the bioreactor 160. Here, the cell collection step was performed using the fifth culture configuration. During the middle to late stages of the cell culture period (7 days), a series of processes consisting of a cell culture step using the third culture mode, a cell dispersion step, and a cell collection step were repeatedly performed. Here, the cell collection step was performed using the fifth culture mode.

[0090] 20 to 22 are tables showing culture conditions. FIG. 20 shows the culture conditions for specimen 1. FIG. 21 shows the culture conditions for specimen 2. FIG. 22 shows the culture conditions for specimen 3. The "IC supply flow rate" shown in each table is the flow rate of the complete medium supplied from the first supply unit 161 to the first circulation flow path 162b via the first supply flow path 162a. The "EC supply flow rate" shown in each table is the flow rate of the basal medium supplied from the second supply unit 163 to the second circulation flow path 164b via the second supply flow path 164a.

[0091] Fig. 23 is a graph showing cell count data (glucose) obtained by simulating specimen 2 (low) using specimen 1 (middle) of suspended cells as reference data. Fig. 24 is a graph showing cell count data (lactic acid) obtained by simulating specimen 2 (low) using specimen 1 (middle) of suspended cells as reference data. Fig. 25 is a graph showing cell count data (oxygen) obtained by simulating specimen 2 (low) using specimen 1 (middle) of suspended cells as reference data. Fig. 26 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 2 (low) using specimen 1 (middle) of suspended cells as reference data.

[0092] In each of Figures 23 to 26, the graphs indicated by dashed lines are reference data. The reference data is cell count data obtained by cell culture of sample 1 (=first cell count data 42). In each of Figures 23 to 26, the graphs indicated by dashed lines are actual data. The actual data is cell count data obtained by cell culture of sample 2. In each of Figures 23 to 26, the graphs indicated by solid lines are data combining the actual data and predicted data 48 (=third cell count data 44).

[0093] 23 to 26, the solid line graphs generally fell within ±5% × day of the dashed line graphs. Therefore, the inventors concluded that the third cell count data 44 was appropriately generated for the suspended cell specimen 2.

[0094] Fig. 27 is a graph showing cell count data (glucose) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data. Fig. 28 is a graph showing cell count data (lactic acid) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data. Fig. 29 is a graph showing cell count data (oxygen) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data. Fig. 30 is a graph showing cell count data (carbon dioxide) obtained by simulating specimen 3 (high) using specimen 1 (middle) of suspended cells as reference data.

[0095] In each of Figures 27 to 30, the graphs indicated by dashed lines are reference data. The reference data is cell count data obtained by cell culture of sample 1 (=first cell count data 42). In each of Figures 27 to 30, the graphs indicated by dashed lines are actual data. The actual data is cell count data obtained by cell culture of sample 3. In each of Figures 27 to 30, the graphs indicated by solid lines are data combining the actual data and predicted data 48 (=third cell count data 44).

[0096] 27 to 30, the solid line graphs generally fell within ±5% × day of the dashed line graphs. Therefore, the inventors concluded that the third cell count data 44 was appropriately generated for the suspended cell specimen 3.

Claims

1. A data processing device for processing data on cell culture performed in a cell culture device equipped with a hollow fiber membrane, comprising: an acquisition unit for acquiring first cell count data indicating a change in cell count from the start of culture under first culture conditions to the end of culture, and second cell count data indicating a change in cell count from the start of culture under second culture conditions to the present; a calculation unit for calculating a rate ratio which is a ratio between a first change rate which is a change rate of the first cell count data in a first predetermined period and a second change rate which is a change rate of the second cell count data in a second predetermined period corresponding to the first predetermined period; and a prediction data generation unit for generating prediction data indicating a change in cell count from the present onwards under the second culture conditions based on first partial data which is a portion of the first cell count data after the first predetermined period and the rate ratio.

2. A data processing device according to claim 1, further comprising a display control unit which controls the display of the number of cells calculated from third cell count data, which is data obtained by combining the second cell count data with the prediction data, on a display unit.

3. A data processing device according to claim 1, wherein the predicted data generating section generates the predicted data when the deviation of the second rate of change from the first rate of change becomes equal to or greater than a predetermined amount.

4. A data processing device according to claim 1, wherein the first cell count data is data obtained by a cell culture carried out in the past, or data obtained by a cell culture simulation.

5. A data processing device according to claim 1, wherein the acquisition section acquires the first cell count data based on a plurality of cell count data.

6. A data processing method comprising: a step of acquiring first cell count data indicating a change in cell count from the start of culture under first culture conditions to the end of culture, and second cell count data indicating a change in cell count from the start of culture under second culture conditions to the present; a step of calculating a rate ratio which is a ratio between a first change rate which is a change rate of the first cell count data in a first predetermined period and a second change rate which is a change rate of the second cell count data in a second predetermined period corresponding to the first predetermined period; and a step of generating prediction data indicating a change in cell count from the present onwards under the second culture conditions based on first partial data which is a portion of the first cell count data after the first predetermined period and the rate ratio.