Cell culture management device, cell culture management system, cell culture management method, and computer program

Abstract

To provide a cell culture management device capable of managing culture of cells through non-invasive measurement of the cells.SOLUTION: A cell culture management device 15 comprises an analysis unit 211, an evaluation unit 213, an estimation unit 215, and a management unit 217. The analysis unit 211 acquires, in a time series, captured images indicating an imaging result of cells cultured in a container 13, analyzes a plurality of the captured images, and detects a cell image, which indicates a cell, for each captured image. The evaluation unit 213 evaluates the state of the cell for each captured image on the basis of the detection result of the cell image. The estimation unit 215 derives a cell state estimation model 231, which estimates temporal changes in the state of the cell, on the basis of the evaluation result of the state of the cell in the plurality of captured images. The management unit 217 manages culture of the cells on the basis of the estimation result by the cell state estimation model 231.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a cell culture management device, a cell culture management system, a cell culture management method, and a computer program. [Background technology]

[0002] In the method for estimating the number of viable cells described in Patent Document 1, in the first step, a culture medium containing cells is sampled from a culture vessel. In the second step, the total number of viable cells contained in the sampled sample is counted. In the trypan blue staining method, which is a method for counting the number of viable cells, live and dead cells are separated using trypan blue and the number of viable cells is counted. In the third step, the total ratio p(M+G2) of cells in the G2 phase to cells in the M phase is calculated. In the fourth step, the number of viable cells T(M+G2) hours after sampling is estimated. T(M+G2) is the total time of the M phase and the G2 phase. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-177063 Summary of the Invention [Problem to be solved by the invention]

[0004] However, the method for estimating the number of viable cells described in Patent Document 1 requires sampling and staining with trypan blue, and therefore does not allow for non-invasive measurement.

[0005] An object of the present invention is to provide a cell culture management device, a cell culture management system, a cell culture management method, and a computer program that are capable of managing cell culture by non-invasively measuring cells. [Means for solving the problem]

[0006] According to one aspect of the present invention, a cell culture management device includes an analysis unit, an evaluation unit, an estimation unit, and a management unit. The analysis unit acquires captured images showing the imaging results of cells cultured in a container in chronological order, analyzes the captured images, and detects a cell image showing the cell for each captured image. The evaluation unit 213 evaluates the state of the cell for each captured image based on the detection results of the cell image. The estimation unit 215 derives a cell state estimation model that estimates the time change in the state of the cell based on the evaluation results of the cell state in the multiple captured images. The management unit manages the culture of the cells based on the estimation results using the cell state estimation model.

[0007] In one aspect of the present invention, the evaluation unit preferably calculates a confluency value indicating the state of the cells for each captured image based on the detection result of the cell image. The confluency value preferably indicates the proportion of the cell image to a region of interest in the captured image. The estimation unit preferably derives an approximation curve approximating the time change of the confluency value based on the multiple confluency values ​​and multiple imaging times at which the multiple captured images were obtained. The approximation curve preferably represents the cell state estimation model.

[0008] In one aspect of the present invention, it is preferable that the estimation unit estimates the time when the state of the cell will reach a target state or the future state of the cell at the target time based on the cell state estimation model.

[0009] In one aspect of the present invention, the estimation unit preferably estimates a target time when the confluency value will reach a target value based on the cell state estimation model, and the management unit preferably sets the target time to a planned time when the cells will be passaged.

[0010] In one aspect of the present invention, the cell culture management apparatus preferably further includes a storage unit, and the management unit preferably controls the storage unit to store, on condition that the identification information of the container has been read by a reading device, the identification information read by the reading device, the captured image, and the image capturing time at which the captured image was obtained in association with each other, on condition that the identification information of the container has been read by the reading device.

[0011] In one aspect of the present invention, the cell culture management device preferably further includes a storage unit. The storage unit preferably stores the cell culture schedule information. The management unit preferably determines whether the cell culture operation is being performed in accordance with the culture schedule information based on the culture schedule information and the container identification information read by the reading device.

[0012] According to another aspect of the present invention, a cell culture management system includes the cell culture management device described above and an imaging device, wherein the imaging device images the cells cultured in the container and generates the captured image showing the imaging results of the cells.

[0013] According to yet another aspect of the present invention, a cell culture management system includes the above-described cell culture management device, an imaging device, an identifier creation device, and a reading device. The imaging device images the cells cultured in the container and generates the captured image showing the imaging results of the cells. The identifier creation device generates the identification information and creates an identifier including the identification information. The reading device reads the identification information from the identifier attached to the container.

[0014] According to yet another aspect of the present invention, a cell culture management method includes the steps of: acquiring captured images showing imaging results of cells cultured in a container in chronological order; analyzing a plurality of the captured images to detect a cell image showing the cell for each captured image; evaluating the state of the cell for each captured image based on the detection results of the cell image; deriving a cell state estimation model that estimates changes in the state of the cell over time based on the evaluation results of the state of the cell in the plurality of captured images; and managing the culture of the cells based on the estimation results obtained by the cell state estimation model.

[0015] According to yet another aspect of the present invention, a computer program causes a computer to execute the steps of: acquiring captured images showing imaging results of cells cultured in a container in chronological order; analyzing a plurality of the captured images to detect a cell image showing the cell for each captured image; evaluating the state of the cell for each captured image based on the detection results of the cell image; deriving a cell state estimation model that estimates changes in the state of the cell over time based on the evaluation results of the cell state in the plurality of captured images; and managing the culture of the cells based on the estimation results obtained by the cell state estimation model. [Effects of the Invention]

[0016] According to the present invention, cell culture can be managed by non-invasive measurement of cells. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a block diagram showing a cell culture management system according to an embodiment of the present invention. [Figure 2] FIG. 2 is a diagram showing an imaging device of the cell culture management system according to the present embodiment. [Figure 3] 1A and 1B are diagrams illustrating captured images generated by an imaging device according to the present embodiment. [Figure 4] 1A to 1C are diagrams showing captured images generated in time series by the imaging device according to the present embodiment. [Figure 5]FIG. 2 is a diagram showing a cell state estimation model of the cell culture management system according to the present embodiment. [Figure 6] FIG. 2 is a diagram showing record data stored in a storage unit of the cell culture management system according to the present embodiment. [Figure 7] FIG. 1 is a diagram for explaining subculture in a cell culture management system according to an embodiment of the present invention. [Figure 8] FIG. 2 is a diagram showing an example of culture schedule information of the cell culture management system according to the present embodiment. [Figure 9] 1 is a flowchart showing a cell culture management method according to the present embodiment. [Figure 10] 10 is a flowchart showing details of the first stage of the cell culture management method according to the present embodiment. [Figure 11] 10 is a flowchart showing details of the middle part of the cell culture management method according to the present embodiment. [Figure 12] 10 is a flowchart showing details of the latter stage of the cell culture management method according to the present embodiment. [Figure 13] 10 is a flowchart showing a part of the processing after subculture in the cell culture management method according to the present embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0018] Hereinafter, embodiments of the present invention will be described with reference to the drawings. In the drawings, identical or corresponding parts are designated by the same reference numerals, and description thereof will not be repeated. In addition, in this specification, mutually orthogonal X-axis, Y-axis, and Z-axis may be described to facilitate understanding of the invention. Typically, the X-axis and Y-axis are parallel to the horizontal direction, and the Z-axis is parallel to the vertical direction.

[0019] A cell culture management system 1 according to an embodiment of the present invention will be described with reference to FIGS. 1 to 13. FIG. 1 is a block diagram showing the cell culture management system 1. The cell culture management system 1 manages cell culture. For example, the cells are animal cells. The animal cells are, for example, human, mouse, or rat cells. The cells are not particularly limited and may be, for example, commercially available cell lines or cells collected from humans. Note that, in the case of cells with a slow proliferation rate, such as thawed cells, the proliferation rate of the cells may change depending on the passage, so it may be preferable to handle cells that are not immediately frozen. It may also be preferable to handle cells whose proliferation ability does not decrease with passage, such as iPS cells (induced pluripotent stem cells) and tumor cells.

[0020] As shown in FIG. 1 , the cell culture management system 1 includes an information processing system 3, an imaging device 5, a reading device 7, an identifier creation device 9, an incubator 11, and a container 13. The information processing system 3 includes an information processing device 15, a display unit 17, and an input unit 19. The information processing device 15 includes a processing unit 21 and a memory unit 23. The processing unit 21 includes an analysis unit 211, an evaluation unit 213, an estimation unit 215, and a management unit 217. The memory unit 23 stores at least one cell state estimation model 231, at least one set of record data 233, at least one culture schedule information 235, and a computer program 237. In the example of FIG. 1 , the memory unit 23 stores multiple cell state estimation models 231, multiple sets of record data 233, multiple culture schedule information 235, and a computer program 237. The culture schedule information 235 is cell culture schedule information.

[0021] The information processing device 15 corresponds to an example of the "cell culture management device" of the present invention.

[0022] Cells are placed in the container 13. Then, the cells are cultured in the container 13. For example, the cells are placed in the container 13 together with a culture medium, or a gel seeded with the cells is placed together with the culture medium. The gel is, for example, agarose, collagen, alginate, Matrigel (MATRIGEL: registered trademark), or Vitrigel (VITRIGEL: registered trademark). The gel is, for example, a hydrogel. The culture medium is, for example, a liquid culture medium. Furthermore, the culture method is not particularly limited, and for example, adhesion culture, suspension culture, or three-dimensional culture can be performed. Furthermore, for example, the culture surface may be coated, or the culture surface may not be coated.

[0023] The container 13 is, for example, a well plate, a dish, a petri dish, or a flask. The well plate has a size conforming to, for example, the ANSI / SBS standard. In this case, the number of wells is, for example, 6, 12, 24, or 96. The material of the container 13 is, for example, polystyrene, polyethylene terephthalate, or glass.

[0024] The container 13 containing the cells is stored in the incubator 11. The incubator 11 cultures the cells placed in the container 13 by maintaining constant temperature, humidity, and carbon dioxide concentration. In other words, the incubator 11 cultures the cells placed in the container 13 by setting the internal environment of the incubator 11 to a target environment for culturing the cells.

[0025] An identifier 25 is attached to the container 13. The identifier 25 includes identification information of the container 13. The identification information of the container 13 is not particularly limited as long as it is information that can identify the container 13. The identification information of the container 13 may include, for example, the date and time of registration of the container 13.

[0026] The identifier 25 is, for example, a one-dimensional code label, a two-dimensional code label, or an RFID (radio frequency identification) tag. The one-dimensional code label is a label on which a one-dimensional code such as a barcode is printed. The two-dimensional code label is a label on which a two-dimensional code such as a QR code (registered trademark) is printed.

[0027] The identification information of the container 13 is essentially the identification information of the cells cultured in the container 13 .

[0028] The identifier creation device 9 generates identification information for the container 13 and creates an identifier 25 that includes the identification information. For example, if the identifier 25 is a barcode label or a QR code label, the identification information is information indicated by the barcode or information indicated by the QR code, and the identifier creation device 9 is a label printer. In this case, for example, the identifier creation device 9 includes a printer that prints codes such as barcodes and QR codes on labels, and a microcomputer. The printer may employ, for example, a thermal transfer method or a thermal method. For example, if the identifier 25 is an RFID tag, the identifier creation device 9 is the reader portion of an RFID reader / writer. Furthermore, because the container 13 to which the identifier 25 is attached is stored in the incubator 11, it is preferable that the adhesive used to attach the identifier 25 to the container 13 be a material that does not peel off even at relatively high humidity.

[0029] The reader 7 reads the identification information of the container 13 from the identifier 25 attached to the container 13. The reader 7 then transmits the identification information of the container 13 to the information processing device 15. For example, if the identifier 25 is a barcode label or a QR code label, the identification information is information indicated by the barcode or information indicated by the QR code, and the reader 7 is a code reader or a code scanner. In this case, for example, the reader 7 includes an image sensor, a light source such as an LED, and a microcomputer. For example, if the identifier 25 is an RFID tag, the reader 7 is the writer portion of an RFID reader / writer.

[0030] The imaging device 5 captures images of the cells cultured in the container 13 and generates a captured image showing the imaging results of the cells. The imaging device 5 transmits the captured image to the information processing device 15. The imaging device 5 preferably has an autofocus mechanism.

[0031] FIG. 2 is a diagram showing the imaging device 5. As shown in FIG. 2, the container 13 includes a plurality of container bodies 131. The container 13 is transparent. When the container 13 is a well plate, the container bodies 131 are wells. As an example, cells 37 seeded in a gel 38 are placed in the container body 131, and a culture medium 39 is introduced into the container body 131. Hereinafter, the culture medium 39, the gel 38, and the cells 37 may be referred to as an imaging subject 36.

[0032] The imaging device 5 includes an imaging section 51, an illumination section 53, a drive mechanism 55, a control section 57, and a holder 59. The holder 59 holds the container 13 substantially horizontally.

[0033] The illumination unit 53 is disposed above the holder 59 and the container 13. The illumination unit 12 emits illumination light toward the container body 131. That is, the illumination unit 12 irradiates the imaging target 36 inside the container body 131 with the illumination light. The illumination unit 12 includes a light source and an illumination optical system. The light source is, for example, an LED (Light Emitting Diode). The illumination optical system includes, for example, a lens.

[0034] The imaging unit 51 is disposed below the holder 59 and the container 13. The imaging unit 51 captures an image of the imaging object 36 in the container body 131 and generates a captured image showing the imaging result of the imaging object 36. The imaging unit 51 includes an imaging optical system such as an image sensor and a lens, and a microcomputer. Specifically, the imaging unit 51 captures an image of the imaging object 36 illuminated with illumination light by the illumination unit 12.

[0035] The imaging unit 51 may, for example, image the entire surface of the container 13 (the imaging objects 36 in all of the container bodies 131), or may image a portion of the container 13 (the imaging objects 36 in some of the container bodies 131). For example, the imaging unit 51 may image the imaging object 36 in one container body 131, or may image the imaging objects 36 in multiple container bodies 131.

[0036] The drive mechanism 55 moves the imaging unit 51 in the horizontal direction, whereby the imaging unit 51 moves in the horizontal direction relative to the container body 131. The drive mechanism 55 also moves the imaging unit 51 in the vertical direction, whereby the focus of the imaging unit 51 is adjusted. When moving the imaging unit 51 in the horizontal direction, the drive mechanism 55 also moves the imaging unit 51 and the illumination unit 53 together. The drive mechanism 55 includes, for example, a motor and a ball screw mechanism. Note that the drive mechanism 55 may move the holder 59 in the horizontal direction instead of moving the imaging unit 51 and the illumination unit 53 in the horizontal direction.

[0037] The control unit 57 controls the imaging unit 51, the illumination unit 53, and the drive mechanism 55. The control unit 57 includes a processor and a storage device such as a memory. For example, the control unit 57 stores imaging conditions for the cell 37. The control unit 57 may then automatically image the cell 37 by controlling the drive mechanism 55, the imaging unit 51, and the illumination unit 53 in accordance with the imaging conditions. The imaging conditions include, for example, the illuminance of the illumination light from the illumination unit 53 and the focus conditions of the imaging unit 51. The focus conditions include, for example, the position of the imaging unit 51 when the imaging unit 51 focuses on the cell 37 and the settings of the imaging optical system of the imaging unit 51. Note that the control unit 57 may control the drive mechanism 55, the imaging unit 51, and the illumination unit 53 to perform focusing by pre-scanning.

[0038] Next, the information processing system 3 will be described with reference to Fig. 1 and Fig. 3 to Fig. 8. Fig. 3 is a diagram showing a captured image 500 generated by the imaging device 5. The captured image 500 includes a container body image 1310 showing the container body 131, a medium image 390 showing the medium 39, a gel image 380 showing the gel 38, and a cell image 370 showing the cells 37.

[0039] 1 and 2, the analysis unit 211 analyzes the captured image 500 to detect the cell image 370. Then, the analysis unit 211 calculates the area of ​​the cell image 370. The area may be indicated by, for example, the number of pixels that make up the cell image 370.

[0040] For example, in one detection algorithm, the analysis unit 211 detects the cell image 370 by detecting the contrast difference between the cell image 370 and the background image (gel image 380 and medium image 390). In this case, for example, the analysis unit 211 defines the contrast difference as the difference between the brightness of the cell image 370 and the brightness of the background image. Then, the analysis unit 211 sets a brightness threshold, distinguishes between the cell image 370 and the background image using the threshold, and detects the cell image 370.

[0041] For example, in another detection algorithm, the analysis unit 211 detects the cell image 370 pixel by pixel by semantic segmentation using AI (Artificial Intelligence).

[0042] Furthermore, the analysis unit 211 sets a region of interest (ROI) 133 in the captured image 500. The region of interest 133 indicates a specific region in the captured image 500. In the example of FIG. 3, the region surrounded by a circular dashed line indicates the region of interest 133. Furthermore, the region of interest 133 includes a cell image 370. The analysis unit 211 calculates the area of ​​the region of interest 133. The area may be indicated by, for example, the number of pixels that make up the region of interest 133.

[0043] In the example of FIG. 3, the analysis unit 211 detects a gel image 380 from the captured image 500 and sets a region including the gel image 380 as the region of interest 133. In the example of FIG. 3, the analysis unit 211 sets the region of interest 133 to a circular region. The shape of the region of interest 133 is not particularly limited and may be, for example, a rectangle. Also, for simplicity, in FIG. 3, the region of interest 133 and the gel image 380 are aligned, but in reality, the region of interest 133 does not need to completely match the gel image 380 and is set as any region including the gel image 380. Also, for example, the detection algorithm used in detecting the cell image 370 is used to detect the gel image 380.

[0044] Furthermore, for example, the analysis unit 211 may detect a peripheral image 1350 indicating the peripheral edge 135 of the container body 131 and set the region surrounded by the peripheral image 1350 as the region of interest 133.

[0045] The following image processing method can be applied as a detection algorithm for the cell image 370 and the gel image 380. The image processing method can be applied when determining the boundary position between the cell image 370 and the background image, and when determining the boundary position between the gel image 380 and the medium image 390.

[0046] Specifically, the image processing method includes the steps of: setting a plurality of search areas of a predetermined size near the peripheral image 1350 in the captured image 500, the search areas being at different circumferential positions along the peripheral image 1350 and extending radially from the center of the container body image 1310 toward the peripheral image 1350; detecting edges within the search areas and acquiring the detected edge positions and edge intensities for each search area; determining, for each search area, a relative shift amount that maximizes the similarity of the image patterns when other search areas adjacent to the search area in the circumferential direction are shifted radially relative to the search area; and identifying boundary positions within a search area based on the edge positions, edge intensities, and relative shift amounts of the search area and neighboring search areas in the circumferential direction. The image processing method then interpolates between the boundary positions of the plurality of search areas using approximate curves, thereby identifying boundary positions throughout the entire circumferential direction.

[0047] The evaluation unit 213 evaluates the state of the cell 37 based on the detection result of the cell image 370 by the analysis unit 211 .

[0048] Specifically, the evaluation unit 213 calculates a confluency value indicating the state of the cells 37 based on the detection result of the cell image 370. The confluency value indicates the progress of proliferation of the cells 37. As shown in FIG. 3, the confluency value indicates the proportion of the cell image 370 to the region of interest 133 in the captured image 500. Specifically, the confluency value is expressed by the following equation. In the following equation, "C" indicates the confluency value, "A" indicates the area of ​​the cell image 370, and "B" indicates the area of ​​the region of interest 133.

[0049] C=A / B

[0050] Next, the cell state estimation model 231 will be described with reference to Fig. 1, Fig. 4, and Fig. 5. Fig. 4 is a diagram showing captured images 500 generated in time series by the imaging device 5. As shown in Fig. 4, the area of ​​a cell image 370 showing a cell 37 expands with the passage of time T1 to Tn. In other words, the cell 37 proliferates with the passage of time T1 to Tn. Note that Fig. 4 shows a region of interest 133 in the captured image 500.

[0051] 1 and 4, the imaging device 5 captures images of the cells 37 in the container body 131 at time intervals, and generates captured images 500 in time series, each including a cell image 370. In the example of Fig. 4, images of the cells 37 are captured at times T1 to Tn, and n captured images 500, each including a cell image 370, are generated in time series, where "n" is an integer equal to or greater than 1.

[0052] In this embodiment, "time" may indicate, for example, the time of day, the date and time, the date, or the time elapsed from a reference time (relative time). The reference time may be set to, for example, "zero." The reference time can be set arbitrarily.

[0053] The analysis unit 211 acquires, in time series, captured images 500 showing the imaging results of cells 37 cultured in the container 13 from the imaging device 5. Then, the analysis unit 211 analyzes the multiple captured images 500 and detects cell images 370 showing cells 37 for each captured image 500. The analysis unit 211 also sets a region of interest 133 for each captured image 500. The area of ​​the region of interest 133 is the same for the multiple captured images 500.

[0054] The evaluation unit 213 evaluates the state of the cell image 370 for each captured image 500 based on the detection result of the cell image 370 for each captured image 500. Specifically, the evaluation unit 213 calculates a confluency value indicating the state of the cells 37 based on the detection result of the cell image 370 for each captured image 500. More specifically, the evaluation unit 213 calculates the confluency value for each captured image 500 based on the detection result of the cell image 370 and the region of interest 133.

[0055] The estimation unit 215 derives a cell state estimation model 231 based on the evaluation results of the states of the cells 37 in the multiple captured images 500. The cell state estimation model 231 estimates the change over time in the state of the cells 37. In this embodiment, the cell state estimation model 231 is a mathematical formula that estimates the change over time in the state of the cells 37.

[0056] 5 is a diagram showing the cell state estimation model 231. The vertical axis represents the confluency value (%), and the horizontal axis represents the imaging time. The imaging time represents the time when the cell 37 is imaged, that is, the time when the captured image 500 is generated.

[0057] 1 and 5, the estimation unit 215 calculates an approximation curve 232 that approximates the change in the confluency values ​​over time, based on a plurality of confluency values ​​calculated from a plurality of captured images 500 in time series and the times T1 to Tn (n=4 in the example of FIG. 5) at which the plurality of captured images 500 were obtained. In this embodiment, the approximation curve 232 is the cell state estimation model 231. The approximation curve 232 is expressed by a mathematical formula. For example, the estimation unit 215 calculates the approximation curve 232 by the least squares method, but the calculation method of the approximation curve 232 is not particularly limited.

[0058] When the estimation unit 215 inputs a confluency value to the cell state estimation model 231, the cell state estimation model 231 outputs a time corresponding to the confluency value. Therefore, the estimation unit 215 estimates the time when the state of the cell 37 will reach the target state based on the cell state estimation model 231. According to this embodiment, by using the cell state estimation model 231, it is possible to easily and accurately estimate the time when the state of the cell 37 will reach the target state.

[0059] For example, the target state is set to "a state in which the confluency value reaches 80%." In this case, when the estimation unit 215 inputs "80," which indicates the target state, into the cell state estimation model 231, the cell state estimation model 231 outputs the time Tt at which the state of the cell 37 will reach the target state. Also, for example, if the current state of the cell 37 is "a state in which the confluency value is 20%," when the estimation unit 215 inputs "20," which indicates the current state, into the cell state estimation model 231, the cell state estimation model 231 outputs the time T1 corresponding to the current state. As a result, the estimation unit 215 calculates the time at which the state of the cell 37 will reach the target state (a confluency value of 80%) from the period from time T1 to time Tt and the current time (for example, date and time).

[0060] Alternatively, when the estimation unit 215 inputs time to the cell state estimation model 231, a confluency value corresponding to the time is output from the cell state estimation model 231. Therefore, the estimation unit 215 estimates the future state of the cell 37 at the target time based on the cell state estimation model 231. According to this embodiment, by using the cell state estimation model 231, the future state of the cell 37 at the target time can be estimated easily and accurately.

[0061] For example, if the current state of cell 37 is "a state in which the confluency value is 20%," and the estimation unit 215 inputs "20," which indicates the current state, into the cell state estimation model 231, the cell state estimation model 231 outputs the time T1 corresponding to the current state. Furthermore, for example, when the estimation unit 215 inputs the time indicated by the sum of the period from the current time to the target time and the time T1 into the cell state estimation model 231, the cell state estimation model 231 outputs the confluency value corresponding to the input time. The confluency value in this case indicates the future confluency value at the target time. As a result, the estimation unit 215 obtains the future confluency value at the target time from the cell state estimation model 231.

[0062] As described above with reference to FIGS. 1 to 5 , according to this embodiment, the imaging device 5 captures an image of the cell 37, the analysis unit 211 detects the cell image 370 from the captured image 500, the evaluation unit 213 calculates a confluency value from the cell image 370, and the estimation unit 215 derives the cell state estimation model 231 based on the confluency value. Therefore, the cell state estimation model 231 is obtained based on non-invasive measurement of the cell 37. Then, the management unit 217 manages the culture of the cell 37 based on the estimation result of the state of the cell 37 by the cell state estimation model 231. In other words, in this embodiment, the management unit 217 can manage the culture of the cell 37 by non-invasive measurement of the cell 37.

[0063] In particular, according to this embodiment, the estimation unit 215 calculates an approximation curve 232 that approximates the change in the confluency value over time, thereby obtaining the cell state estimation model 231. Therefore, the cell state estimation model 231 can be easily derived. Furthermore, the state of the cell 37 can be accurately estimated based on the confluency value.

[0064] Furthermore, in this embodiment, the estimation unit 215 estimates the target time when the confluency value will reach the target value based on the cell state estimation model 231. Then, the management unit 217 sets the target time as the planned time to perform passaging of the cells 37. Therefore, according to this embodiment, by using the cell state estimation model 231, the planned time to perform passaging can be set easily and accurately. Note that, for example, an operator inputs the target confluency value into the information processing device 15 using the input unit 19.

[0065] Furthermore, in this embodiment, the operator can use the cell-state estimation model 231 as an index to create an appropriate culture plan according to the attributes of the cells 37 and the type of cell culture technique, without relying on the operator's experience and intuition. As a result, for example, the culture state of the cells 37 can be maintained in a good state.

[0066] For example, an operator creates a culture schedule based on the cell state estimation model 231. Then, the operator can register the culture schedule as culture schedule information 235 by inputting the culture schedule into the information processing device 15 using the input unit 19. The culture schedule includes, for example, the planned time for passage of the cells 37, passaging conditions such as the number of passages and the split rate, the time for replacing the medium 39, the time for capturing images using the imaging device 5, and the time for visually observing the cells 37.

[0067] Next, an example of the procedure for the culture work performed by an operator will be described with reference to Fig. 1. The culture work refers to work related to culture, and includes work prior to culture.

[0068] First, the operator creates an identifier 25 using the identifier creation device 9. Next, the operator attaches the identifier 25 to the container 13. Next, the operator introduces cells 37, a gel 38, and a culture medium 39 into the container 13. Next, the operator reads the identification information of the container 13 from the identifier 25 using the reading device 7. Next, the operator images the cells 37 using the imaging device 5 to obtain a captured image 500. The time from reading the identification information to imaging the cells 37 is short (e.g., 5 to 15 minutes), and therefore, in practice, in the culture management of the cells 37, reading the identification information and imaging the cells 37 can be considered to have been carried out simultaneously. Next, the operator stores the container 13 in the incubator 11 and starts culturing the cells 37. Specifically, primary culture is started.

[0069] The operator then continues the culture work in accordance with the culture schedule information 235. Specifically, the operator removes the container 13 from the incubator 11 to replace the culture medium 39 in accordance with the culture schedule information 235, and reads the identification information from the identifier 25 using the reader 7. After replacing the culture medium 39, the operator returns the container 13 to the incubator 11. The time from reading the identification information to replacing the culture medium 39 is short (for example, 5 to 15 minutes), and it can be considered that, in practice, the reading of the identification information and the replacement of the culture medium 39 are performed simultaneously in the culture management of the cells 37.

[0070] Furthermore, the operator removes the container 13 from the incubator 11 in order to capture an image of the cells 37 in accordance with the culture schedule information 235, and reads the identification information from the identifier 25 using the reading device 7. Then, the operator captures an image of the cells 37 using the imaging device 5 to obtain a captured image 500. After capturing the image of the cells 37, the operator returns the container 13 to the incubator 11.

[0071] The operator repeats replacing the culture medium 39 and photographing the cells 37 according to the culture schedule information 235 until the time for passage arrives. Then, when the time for passage arrives, the operator carries out passage of the cells 37. Furthermore, after passage of the cells 37, the operator starts the work of culturing the cells 37 after passage according to another culture schedule information 235 for the culture after passage. The procedure for the culture work after passage is the same as that for primary culture, for example.

[0072] In the procedure of the culture work, when the reading device 7 reads the identification information from the identifier 25, it transmits the identification information to the information processing device 15. In this case, the reading device 7 may transmit information about the time (e.g., time or date and time) when the identification information was read to the information processing device 15. Furthermore, when the imaging device 5 captures an image of the cell 37, it transmits the captured image and the time (e.g., time or date and time) to the information processing device 15. For example, when capturing an image for the first time after the start of the culture work, the imaging device 5 transmits information about the imaging conditions of the cell 37 to the information processing device 15.

[0073] Next, the storage unit 23 will be described with reference to Figures 1 and 6. As shown in Figure 1, the storage unit 23 stores a plurality of cell state estimation models 231 according to the attributes of cells 37 and the types of cell culture techniques, for example.

[0074] In other words, the estimation unit 215 creates multiple cell state estimation models 231 according to, for example, the attributes of the cells 37 and the type of cell culture technology. The attributes of the cells 37 are, for example, the type of the cells 37 and the source of collection of the cells 37. For example, even if the cells 37 are of the same type, the proliferation rate may differ if the source of collection is different. In other words, even if the cells 37 are of the same type, the proliferation rate may vary between individuals.

[0075] Moreover, types of cell culture techniques include, for example, two-dimensional culture and three-dimensional culture. In two-dimensional culture, for example, cells 37 are cultured in a state in which the cells 37 are adhered to the bottom surface of the container body 131. In three-dimensional culture, for example, cells 37 are cultured in a state in which the cells 37 are three-dimensionally aggregated on a U-shaped low-adhesion bottom surface.

[0076] For example, even if the same type and number of cells 37 are cultured at the same time, the proliferation rate of the cells 37 differs between two-dimensional culture and three-dimensional culture. For this reason, it is necessary to carry out the culture operation according to a culture schedule that is appropriate for the attributes of the cells 37 and the type of cell culture technique.

[0077] Therefore, in this embodiment, the analysis unit 211 analyzes the captured image 500 for each attribute of the cell 37 and each type of cell culture technique, and the evaluation unit 213 evaluates the state of the cell 37. As a result, the estimation unit 215 creates a cell state estimation model 231 for each attribute of the cell 37 and each type of cell culture technique. Therefore, the estimation unit 215 can estimate the state of the cell 37 using the cell state estimation model 231 according to the attribute of the cell 37 and each type of cell culture technique.

[0078] As a result, according to this embodiment, the appropriate growth phase of the cells 37 can be estimated based on the attributes of the cells 37 and the type of cell culture technique. Therefore, the culture of the cells 37 can be appropriately managed based on the attributes of the cells 37 and the type of cell culture technique. For example, because the state of the cells 37 can be estimated based on the attributes of the cells 37 and the type of cell culture technique, it is possible to determine an appropriate timing for replacing the culture medium 39 to prevent oxidation of the culture medium 39. As a result, for example, the culture state of the cells 37 can be maintained in good condition.

[0079] Furthermore, the storage unit 23 stores multiple sets of record data 233 according to the attributes of the cells 37 and the types of cell culture techniques, for example.

[0080] 6 is a diagram showing recorded data 233 stored in storage unit 23. As shown in FIG. 6, recorded data 233 includes identification information 31 of container 13, captured image 500, imaging time 33, and confluency value 34. Storage unit 23 stores captured image 500, imaging time 33, and confluency value 34 in association with identification information 31. In particular, for the first imaging after the start of the culture operation, storage unit 23 stores imaging conditions 35 for cells 37 in association with identification information 31.

[0081] 1 and 6, on the condition that the identification information 31 of the container 13 has been read by the reading device 7, the management unit 217 controls the storage unit 23 to store the identification information 31 read by the reading device 7, the captured image 500, and the imaging time 33 at which the captured image 500 was obtained in association with each other. Therefore, according to this embodiment, the captured image 500 and the imaging time 33 can be recorded in the storage unit 23 in association with the container 13 and the cell 37. Therefore, when the analysis unit 211 processes the captured image 500, it is possible to avoid a situation in which the captured image 500 does not correspond to the container 13 and the cell 37.

[0082] In particular, when the first image is taken after the start of the culture operation, the management unit 217 controls the memory unit 23 to store the identification information 31 read by the reading device 7 in association with the captured image 500, the imaging time 33, and the imaging conditions 35, provided that the identification information 31 of the container 13 has been read by the reading device 7.

[0083] Furthermore, the analysis unit 211 reads out the captured image 500 from the storage unit 23, detects the cell image 370 from the captured image 500, and further sets the region of interest 133 in the captured image 500. Furthermore, the evaluation unit 213 calculates the confluency value 34 based on the area of ​​the cell image 370 and the area of ​​the region of interest 133.

[0084] When the evaluation unit 213 calculates the confluency value 34 , the management unit 217 controls the storage unit 23 to store the confluency value 34 in association with the identification information 31 of the container 13 .

[0085] For example, when the primary culture is completed, the estimation unit 215 reads the recorded data 233 from the storage unit 23 and derives the cell state estimation model 231 based on the recorded data 233.

[0086] Next, subculture of cells 37 will be described with reference to Fig. 7. Fig. 7 is a diagram for explaining subculture according to this embodiment. Fig. 7 shows a primary culture P0, a first subculture P1, and a second subculture P2. That is, in the example of Fig. 7, the number of passages is "2." The number of passages is an example of a subculture condition.

[0087] In primary culture P0, container 13a is used. Cells 37, gel 38, and medium 39 are introduced into one container body 131. Cells 37 are cultured in one container body 131. When the time for subculture arrives in primary culture P0, subculture is carried out.

[0088] In the first subculture P1, container 13b is used. In the first subculture P1, cells 37 in one container body 131 in container 13a in primary culture P0 are transferred to two container bodies 131 in container 13b. Then, in container 13b, cells 37 are cultured in the two container bodies 131. When the time for subculture arrives in first subculture P1, subculture is carried out.

[0089] In the second subculture P2, container 13c is used. In the second subculture P2, cells 37 in one container body 131 in container 13b in the first subculture P1 are transferred to two container bodies 131 in container 13c. In addition, cells 37 in another container body 131 in container 13b in the first subculture P1 are transferred to the other two container bodies 131 in container 13c. Then, cells 37 are cultured in four container bodies 131 in container 13c.

[0090] Continuing to refer to FIG. 7, the split rate will be explained. The split rate is an example of a passaging condition. When passaging, the split rate indicates the ratio of the number of vessel bodies 131 in which cells 37 are cultured after passaging to the number of vessel bodies 131 in which cells 37 are cultured before passaging. Specifically, the split rate is expressed by the following formula. In the following formula, "C1" indicates the split rate. "A1" indicates the number of vessel bodies 131 in which cells 37 are cultured after passaging. "B1" indicates the number of vessel bodies 131 in which cells 37 are cultured before passaging.

[0091] C1=A1 / B1

[0092] In the example of Fig. 7, the split rate in the first subculture P1 and the second subculture P2 is "2." Note that the split rates in different subcultures may be the same or different.

[0093] In this embodiment, the information processing device 15 may calculate passaging conditions such as the split rate and the number of passages according to a predetermined algorithm based on the cell state estimation model 231. For example, as shown in FIGS. 1 and 5, the estimation unit 215 estimates a confluency value at the planned time of passaging based on the cell state estimation model 231. Then, the management unit 217 calculates the passaging conditions for the cells 37 based on the estimated confluency value according to the predetermined algorithm.

[0094] Next, the culture schedule information 235 will be described with reference to FIGS. 1 and 8. As shown in FIG. 1, the storage unit 23 stores multiple culture schedule information 235 corresponding to the attributes of the cells 37 and the type of cell culture technique. That is, the management unit 217 creates the culture schedule information 235 for each attribute of the cells 37 and each type of cell culture technique based on a cell state estimation model 231 corresponding to the attributes of the cells 37 and each type of cell culture technique. The culture schedule information 235 includes information on the work content and the planned time when the work is to be performed in the culture work. The work content indicates the work of capturing images of the cells 37. In addition, the work content may indicate the work of replacing the culture medium 39. The work content may also indicate passaging. Furthermore, the work content may indicate observation of the cells 37. In this embodiment, the work content is not particularly limited and may include any work necessary for culturing the cells 37.

[0095] The culture schedule information 235 may include a Gantt chart or a table. When the culture schedule information 235 includes a table, the culture schedule information 235 may include a culture schedule for each of a plurality of containers 13. In this case, the culture schedule information 235 may display a list of work to be performed for each container 13 on the day. Furthermore, the culture schedule information 235 may indicate a culture schedule for each container 13.

[0096] Fig. 8 is a diagram showing an example of the culture schedule information 235. As shown in Fig. 8, the culture schedule information 235 includes a table. The culture schedule information 235 includes operator information 61, identification information 31 of the container 13, split rate information 62, medium replacement information 63, passage number information 64, cell information 65, and a schedule 70.

[0097] The worker information 61 indicates the name of the worker. The identification information 31 indicates the identification information 31 read by the reading device 7. The split rate information 62 indicates the split rate calculated by the management unit 217. The culture medium replacement information 63 indicates the cycle for replacing the culture medium 39. In the example of FIG. 8, the culture medium replacement information 63 indicates that the culture medium 39 is replaced every day. The passage number information 64 indicates the passage number calculated by the management unit 217. The cell information 65 includes various information related to the cells 37. For example, the cell information 65 includes the attributes of the cells 37 and the type of cell culture technique.

[0098] The schedule 70 indicates a schedule for the culture work. Specifically, the schedule 70 includes scheduled time information 66 indicating the scheduled time for performing the work, work content 67, status 68, and alert information 69. The status 68 indicates whether the work has been performed. The alert information 69 is information notifying that the work will be performed. For example, the alert information 69 for the day of the scheduled time indicated by the scheduled time information 66 includes the text "Today is the deadline." For example, the alert information 69 for the case where the scheduled time indicated by the scheduled time information 66 has passed includes the text "The scheduled time has passed. Please perform the work immediately." Furthermore, the scheduled time information 66 for "passage" indicated by the work content 67 indicates, for example, the "scheduled time for performing passaging" set by the management unit 217.

[0099] 1 and 8, the display unit 17 displays the culture schedule information 235. The display unit 17 is, for example, a liquid crystal display or an organic electroluminescence display.

[0100] Furthermore, the operator inputs various pieces of information to the information processing device 15 via the input unit 19. For example, various pieces of information of the culture schedule information 235 are input from the input unit 19. The input unit 19 is, for example, a keyboard and pointing device, or a touch panel.

[0101] The management unit 217 determines whether the culture work of the cells 37 is being performed in accordance with the culture schedule information 235, based on the culture schedule information 235 and the identification information 31 of the container 13 read by the reading device 7. Therefore, according to this embodiment, the culture work of the cells 37 can be appropriately managed while preventing the container 13 from being mixed up.

[0102] Here, the processing unit 21 shown in FIG. 1 includes a processor such as a CPU (Central Processing Unit) and an MPU (Micro Processing Unit). The memory unit 23 includes a storage device. Specifically, the memory unit 23 includes a main storage device such as a semiconductor memory, and an auxiliary storage device such as a semiconductor memory, a solid-state drive, and / or a hard disk drive. The memory unit 23 may include removable media. The memory unit 23 corresponds to an example of a non-transitory computer-readable storage medium. The processing unit 21 functions as an analysis unit 211, an evaluation unit 213, an estimation unit 215, and a management unit 217 by executing a computer program 237 stored in the memory unit 23.

[0103] Next, a cell culture management method according to this embodiment will be described with reference to Figures 1 and 9. The cell culture management method is executed by an information processing device 15. Specifically, the processing unit 21 of the information processing device 15 executes a computer program 237 stored in the storage unit 23, thereby executing the cell culture management method. In other words, the computer program 237 causes the information processing device 15 (computer) to execute the cell culture management method.

[0104] 9 is a flowchart showing the cell culture management method according to this embodiment. As shown in FIG. 9, the cell culture management method includes steps S1 to S6.

[0105] First, in step S1, the management unit 217 controls the storage unit 23 to store the captured image 500 of the cell 37 and the image capturing time 33.

[0106] Next, in step S2, the analysis unit 211 analyzes the captured image 500 showing the image of the cells 37 cultured in the container 13, and detects the cell image 370 showing the cells 37.

[0107] Next, in step S3, the evaluation unit 213 evaluates the state of the cell 37 based on the detection result of the cell image 370.

[0108] Next, in step S4, it is determined whether the state of the cell 37 has reached the target state.

[0109] If it is determined in step S4 that the state of the cell 37 has not reached the target state (No), the process proceeds to step S1.

[0110] On the other hand, if it is determined in step S4 that the state of the cells 37 has reached the target state (Yes), the process proceeds to step S5. In this manner, steps S1 to S3 are repeated until the state of the cells 37 reaches the target state. As a result, the analysis unit 211 acquires captured images 500 showing the imaging results of the cells 37 cultured in the container 13 in chronological order, analyzes the multiple captured images 500, and detects cell images 370 showing the cells 37 for each captured image 500. Then, the evaluation unit 213 evaluates the state of the cells 37 for each captured image 500 based on the detection results of the cell images 370.

[0111] Next, in step S5, the estimation unit 215 derives a cell state estimation model 231 that estimates the change in the state of the cell 37 over time based on the evaluation results of the state of the cell 37 in the multiple captured images 500.

[0112] Next, in step S6, the management unit 217 manages the culture of the cells 37 based on the result of estimation of the state of the cells 37 by the cell-state estimation model 231. Specifically, in step S6, the management unit 217 manages the culture of a generation later than the generation used to create the cell-state estimation model 231. For example, the management unit 217 manages the culture for a subculture later than the primary culture.

[0113] In detail, step S6 includes steps S61 and S62.

[0114] First, in step S61, the management unit 217 creates culture schedule information 235 based on the result of estimation of the state of the cell 37 by the cell state estimation model 231. Specifically, in step S61, the management unit 217 creates culture schedule information 235 for culturing a generation later than the generation used to create the cell state estimation model 231. For example, the management unit 217 creates culture schedule information 235 for subculture later than primary culture.

[0115] For example, the management unit 217 sets split rate information 62 and passage number information 64 in the culture schedule information 235 shown in Fig. 8. Furthermore, the management unit 217 sets scheduled time information 66 for "passage" indicated by the work content 67 in the culture schedule information 235 shown in Fig. 8.

[0116] Next, in step S62, the culture of the cells 37 is monitored based on the culture schedule information 235. Then, when the subculture is completed, the cell culture management method ends.

[0117] 9 , according to the cell culture management method of this embodiment, the cell state estimation model 231 is obtained based on non-invasive measurement of the cells 37. Then, the management unit 217 manages the culture of the cells 37 based on the estimation result of the state of the cells 37 by the cell state estimation model 231. In other words, the management unit 217 can manage the culture of the cells 37 by non-invasive measurement of the cells 37.

[0118] In particular, in this embodiment, the management unit 217 creates a plurality of cell state estimation models 231 according to the attributes of the cells 37 and the type of cell culture technique. Therefore, a plurality of culture schedule information 235 is created according to the attributes of the cells 37 and the type of cell culture technique. As a result, culture management suitable for the attributes of the cells 37 and the type of cell culture technique can be performed. For example, a cell state estimation model 231 is created for each cell 37 with a different proliferation ability.

[0119] Next, an example of a cell culture method according to this embodiment will be described in detail with reference to Fig. 1 and Figs. 10 to 12. The cell culture management method is executed by the imaging device 5, the information processing device 15, and the reading device 7. As shown in Figs. 10 to 12, the cell culture management method includes steps S11 to S16, steps S21 to S47, and steps S51 to S55. Specifically, the imaging device 5 executes steps S11 to S16. The information processing device 15 executes steps S21 to S47. That is, the processing unit 21 of the information processing device 15 executes the computer program 237 stored in the storage unit 23, thereby executing steps S21 to S47. The reading device 7 executes steps S51 to S55.

[0120] 10, first, in step S51, the reading device 7 reads the identification information 31 of the container 13 from the identifier 25 of the container 13. Then, the reading device 7 transmits the identification information 31 to the information processing device 15.

[0121] Next, in step S21, the information processing device 15 receives the identification information 31 of the container 13 from the reading device 7.

[0122] On the other hand, in step S11, the imaging device 5 captures an image of the cell 37 in the container 13.

[0123] Next, in step S12, the imaging device 5 transmits the captured image 500 of the cell 37, the imaging time 33, and the imaging conditions 35 to the information processing device 15.

[0124] Next, in step S22, the information processing device 15 receives the captured image 500 of the cell 37, the imaging time 33, and the imaging conditions .

[0125] Next, in step S23, the management unit 217 controls the storage unit 23 to store the captured image 500 of the cell 37, the imaging time 33, and the imaging conditions 35 in association with the identification information 31 of the container 13.

[0126] Next, in step S24, the analysis unit 211 sets the region of interest 133 in the captured image 500. Furthermore, the analysis unit 211 calculates the area of ​​the region of interest 133.

[0127] Next, in step S25, the analysis unit 211 detects the cell image 370 in the captured image 500. Furthermore, the analysis unit 211 calculates the area of ​​the cell image 370.

[0128] Next, in step S26, the evaluation unit 213 calculates a confluency value based on the area of ​​the cell image 370 and the area of ​​the region of interest 133.

[0129] Next, in step S27, the management unit 217 controls the storage unit 23 to store the confluency value in association with the imaging time 33.

[0130] Next, as shown in FIG. 11, in step S28, the information processing device 15 determines whether or not the identification information 31 of the container 13 has been received from the reader 7.

[0131] If it is determined in step S28 that the identification information 31 has been received (Yes), the processing proceeds to step S29. In this case, in step S52, the reader 7 reads the identification information 31 of the container 13 and transmits the identification information 31 to the information processing device 15.

[0132] Next, in step S29, the management unit 217 refers to the culture schedule information 235 and determines whether the current time is the scheduled time for the work.

[0133] If it is determined in step S29 that the current time is the scheduled time for the work (Yes), the process proceeds to step S34.

[0134] On the other hand, if it is determined in step S29 that the current time is not the scheduled time for the work (No), the process proceeds to step S30.

[0135] Next, in step S30, the management unit 217 displays information indicating that it is not the scheduled time for work on the display unit 17. Then, the process proceeds to step S28.

[0136] On the other hand, if it is determined in step S28 that the identification information 31 has not been received (No), the process proceeds to step S31.

[0137] Next, in step S31, the management unit 217 refers to the culture schedule information 235 and determines whether the current time is a scheduled time for work.

[0138] If it is determined in step S31 that the current time is not the scheduled time for the work (No), the process proceeds to step S28.

[0139] On the other hand, if it is determined in step S31 that the current time is the scheduled time for the work (Yes), the process proceeds to step S32.

[0140] Next, in step S32, the management unit 217 notifies the display unit 17 of information indicating that the work will be performed at the scheduled time. For example, the management unit 217 sets information indicating that the work will be performed at the scheduled time in the culture schedule information 235, and causes the display unit 17 to display the culture schedule information 235.

[0141] Next, in step S33, the information processing device 15 determines whether or not the identification information 31 of the container 13 has been received from the reader 7.

[0142] If it is determined in step S33 that the identification information 31 has not been received (No), the process waits for step S33.

[0143] On the other hand, if it is determined in step S33 that the identification information 31 has been received (Yes), the processing proceeds to step S34. In this case, in step S53, the reader 7 reads the identification information 31 of the container 13 and transmits the identification information 31 to the information processing device 15.

[0144] After a positive judgment is made in step S29 or step S33, in step S34, the management unit 217 reads out the imaging conditions 35 of the cell 37 associated with the identification information 31 from the memory unit 23 and transmits the imaging conditions 35 to the imaging device 5.

[0145] Next, in step S13, the imaging device 5 receives the imaging conditions 35.

[0146] Next, in step S14, the imaging device 5 images the cells 37 in the container 13 in accordance with the imaging conditions 35 received from the information processing device 15. Therefore, according to this embodiment, when imaging the cells 37 in the same container body 131 in the container 13 every time, the cells 37 can be imaged under the same imaging conditions 35 every time. As a result, the reliability of the captured image 500 can be improved.

[0147] Next, in step S15, the imaging device 5 transmits the captured image 500 and the imaging time 33 to the information processing device 15.

[0148] Next, in step S35, the information processing device 15 receives the captured image 500 of the cell 37 and the image capturing time 33.

[0149] Next, in step S36, the management unit 217 controls the storage unit 23 to store the captured image 500 of the cell 37 and the image capturing time 33 in association with the identification information 31 of the container 13.

[0150] 12, in step S37, the analysis unit 211 sets the region of interest 133 in the captured image 500. In addition, the analysis unit 211 calculates the area of ​​the region of interest 133.

[0151] Next, in step S38, the analysis unit 211 detects the cell image 370 in the captured image 500. Furthermore, the analysis unit 211 calculates the area of ​​the cell image 370.

[0152] Next, in step S39, the evaluation unit 213 calculates a confluency value based on the area of ​​the cell image 370 and the area of ​​the region of interest 133.

[0153] Next, in step S40, the management unit 217 controls the storage unit 23 to store the confluency value in association with the imaging time 33.

[0154] Next, in step S41, the management unit 217 determines whether the confluency value is equal to or greater than a threshold value. The threshold value indicates a target value for the confluency value of the proliferated cells 37 and determines the timing of passaging.

[0155] If it is determined in step S41 that the confluency value is not equal to or greater than the threshold value (No), the process proceeds to step S28 in FIG.

[0156] On the other hand, if it is determined in step S41 that the confluency value is equal to or greater than the threshold value (Yes), the process proceeds to step S42. The confluency value being equal to or greater than the threshold value indicates that the time for passaging has arrived.

[0157] Next, in step S42, the management unit 217 causes the display unit 17 to display information indicating that passage is to be instructed.

[0158] Next, in step S43, the information processing device 15 determines whether or not the identification information 31 of the container 13 has been received from the reader 7.

[0159] If it is determined in step S43 that the identification information 31 has not been received (No), the process proceeds to step S42.

[0160] On the other hand, if it is determined in step S43 that the identification information 31 has been received (Yes), the process proceeds to step S44. In this case, in step S54, the reading device 7 reads the identification information 31 of the container 13 and transmits the identification information 31 to the information processing device 15. In addition, in response to receiving the identification information 31, the management unit 217 registers in the culture schedule information 235 that the culture of the current generation (e.g., primary culture) has been completed.

[0161] Next, in step S44, the estimation unit 215 derives a cell state estimation model 231 based on the multiple confluency values ​​and the multiple imaging times 33.

[0162] Next, in step S45, the management unit 217 determines the scheduled time for passaging based on the result of estimation of the state of the cells 37 by the cell state estimation model 231. Then, the management unit 217 sets the scheduled time for passaging in the culture schedule information 235.

[0163] Next, in step S46, the management unit 217 determines the passaging conditions based on the result of estimation of the state of the cells 37 by the cell state estimation model 231. Then, the management unit 217 sets the passaging conditions in the culture schedule information 235.

[0164] Next, in step S47, the management unit 217 monitors the culture of the cells 37 based on the identification information 31 of the container 13 and the culture schedule information 235. In this case, in step S55, the reading device 7 reads the identification information 31 of the container 13 and transmits the identification information 31 to the information processing device 15. Also, in step S16, the imaging device 5 captures an image of the cells 37 and transmits the captured image 500 to the information processing device 15. In this case, the imaging device 5 may transmit the imaging time 33 and imaging conditions 35 to the information processing device 15.

[0165] For example, step S47 includes steps similar to steps S21 to S36 shown in Figures 10 and 11. Furthermore, for example, step S16 includes steps similar to steps S11 to S15 shown in Figures 10 and 11. Furthermore, for example, step S55 includes steps similar to steps S51 to S53 shown in Figures 10 and 11.

[0166] Next, with reference to Fig. 13, the process after step S36 (Fig. 11) in step S47 of Fig. 12 (part of the process after passaging) will be described. Fig. 13 is a flowchart showing part of the process after passaging in the cell culture management method according to this embodiment. As shown in Fig. 13, after step S36 (Fig. 11) in step S47 of Fig. 12, the cell culture management method includes step S160, steps S370 to S460, and step S550.

[0167] As shown in Fig. 13, information processing device 15 executes steps S370 to S400. Steps S370 to S400 are similar to steps S37 to S40 in Fig. 12, respectively, and therefore description thereof will be omitted.

[0168] Next, in step S410, the management unit 217 refers to the culture schedule information 235 and determines whether the scheduled time for the next passage has arrived.

[0169] If it is determined in step S410 that the scheduled time for the next passage has not yet arrived (No), the process proceeds to step S28 in FIG.

[0170] On the other hand, if it is determined in step S410 that the scheduled time for the next passage has arrived (Yes), the process proceeds to step S420.

[0171] Next, in step S420, the management unit 217 causes the display unit 17 to notify information indicating that the next passage is to be carried out.

[0172] Next, in step S430, the information processing device 15 determines whether the identification information 31 of the container 13 has been received from the reader 7.

[0173] If it is determined in step S430 that the identification information 31 has not been received (No), the process proceeds to step S420.

[0174] On the other hand, if it is determined in step S430 that the identification information 31 has been received (Yes), the processing proceeds to step S440. In this case, in step S540, the reading device 7 reads the identification information 31 of the container 13 and transmits the identification information 31 to the information processing device 15. Furthermore, in response to receiving the identification information 31, the management unit 217 registers in the culture schedule information 235 that the culture of the current generation (for example, the first subculture) has been completed.

[0175] Next, information processing device 15 executes steps S440 to S460. Steps S440 to S460 are similar to steps S45 to S47 in Fig. 12, respectively, and therefore their explanations will be omitted. Step S550 is similar to step S55 in Fig. 12, and therefore its explanation will be omitted. Furthermore, step S160 is similar to step S16 in Fig. 12, and therefore its explanation will be omitted.

[0176] Next, the correspondence between the processing in FIG. 9 and the processing in FIGS. 10 to 12 will be described. Steps S1 to S4 in FIG. 9 correspond to steps S21 to S41 in FIGS. 10 to 12. Step S4 in FIG. 9 corresponds to step S41 in FIG. 12. Step S5 in FIG. 9 corresponds to step S44 in FIG. 12. Step S6 in FIG. 9 corresponds to step S45 to step S47 in FIG. 12. Step S61 in FIG. 9 corresponds to step S45 and step S46 in FIG. 12. Step S62 in FIG. 9 corresponds to step S47 in FIG. 12.

[0177] The embodiments of the present invention have been described above with reference to the drawings. However, the present invention is not limited to the above embodiments and can be implemented in various forms without departing from the spirit of the present invention. Furthermore, the components disclosed in the above embodiments can be modified as appropriate. For example, some of the components shown in one embodiment may be added to the components of another embodiment, or some of the components shown in one embodiment may be deleted from the embodiment.

[0178] Furthermore, the drawings mainly show each component in a schematic manner to facilitate understanding of the invention, and the thickness, length, number, spacing, etc. of each component shown in the drawings may differ from the actual ones due to the convenience of creating the drawings. Furthermore, the configuration of each component shown in the above embodiment is merely an example and is not particularly limited, and it goes without saying that various modifications are possible within a range that does not substantially deviate from the effects of the present invention.

[0179] (1) In the embodiment described with reference to FIGS. 9 to 13, the cell state estimation model 231 was created during primary culture. Then, in the subculture, the state of the cell 37 was estimated using the cell state estimation model 231 created during primary culture. The reason why the cell state estimation model 231 created during primary culture can be used in the subculture is that the culture characteristics of the cell 37 do not change as long as the attributes of the cell 37 and the type of cell culture technique are the same. The culture characteristics of the cell 37 are, for example, the proliferation rate of the cell 37. In this embodiment, the cell state estimation model 231 is not newly derived during the subculture, which prevents the process from becoming complicated. Note that the cell state estimation model 231 may be newly derived during the subculture.

[0180] (2) Furthermore, in the subculture, it is not necessary to calculate the confluency value. This is because the cell state estimation model 231 created in the primary culture can be used in the subculture. Furthermore, it is not necessary to image and detect the cells 37 and set the region of interest 133 in the subculture.

[0181] (3) Furthermore, the reading of the identification information 31 by the reading device 7 may be performed after the imaging device 5 has taken an image.

[0182] (4) In step S41 of Fig. 12, it may be determined whether the scheduled time for passaging has arrived. If the scheduled time for passaging has not arrived, proceed to step S28 of Fig. 11. On the other hand, if the scheduled time for passaging has arrived, proceed to step S42.

[0183] (5) Furthermore, the analysis unit 211, the evaluation unit 213, the estimation unit 215, and the management unit 217 may be installed in one computer or in different computers. In other words, the hardware arrangement of the analysis unit 211, the evaluation unit 213, the estimation unit 215, and the management unit 217 is not particularly limited. [Industrial Applicability]

[0184] The present invention relates to a cell culture management device, a cell culture management system, a cell culture management method, and a computer program, and has industrial applicability. [Explanation of symbols]

[0185] 1. Cell culture management system 3. Information Processing Systems 5. Imaging device 7 Reading device 9. Identifier Creation Device 11. Incubator 13 Container 15. Information processing device (cell culture management device) 25 Identifiers 37 cells 133 Areas of Interest 211 Analysis Department 213 Evaluation Department 215 Guessing Department 217 Management Department 231 Cell State Prediction Model 232 Approximate curve 235 Culture Schedule Information 370 Cell Images 500 captured images

Claims

1. an analysis unit that acquires captured images showing imaging results of cells cultured in a container in time series, analyzes the captured images, and detects a cell image showing the cells for each captured image; an evaluation unit that evaluates the state of the cells for each captured image based on the detection result of the cell image; an estimation unit that derives a cell state estimation model that estimates a time change in the state of the cell based on an evaluation result of the state of the cell in the plurality of captured images; a management unit that manages the culture of the cells based on the estimation result of the cell state estimation model; A cell culture management device comprising:

2. the evaluation unit calculates a confluency value indicating a state of the cells for each captured image based on a detection result of the cell image; the confluency value indicates a ratio of the cell image to a region of interest in the captured image; the estimation unit derives an approximation curve that approximates a change in the confluency value over time based on the plurality of confluency values ​​and a plurality of imaging times at which the plurality of captured images were respectively obtained; The cell culture management device according to claim 1 , wherein the approximation curve is the cell state estimation model.

3. The cell culture management device according to claim 1 or 2, wherein the estimation unit estimates a time when the state of the cell will reach a target state or a future state of the cell at the target time based on the cell state estimation model.

4. the prediction unit predicts a target time when the confluency value will reach a target value based on the cell state prediction model; The cell culture management apparatus according to claim 2 , wherein the management unit sets the target time to a planned time for subculture of the cells.

5. Further comprising a storage unit, The cell culture management device described in claim 1 or claim 2, wherein the management unit controls the memory unit to associate and store the identification information read by the reading device, the captured image, and the imaging time at which the captured image was obtained, provided that the identification information of the container has been read by the reading device.

6. Further comprising a storage unit storing the cell culture schedule information, The cell culture management device according to claim 1 or claim 2, wherein the management unit determines whether the cell culture work is being carried out in accordance with the culture schedule information based on the culture schedule information and the identification information of the container read by a reading device.

7. The cell culture management device according to claim 1 or 2; an imaging device that captures images of the cells cultured in the container and generates the captured image showing the imaging results of the cells; A cell culture management system comprising:

8. The cell culture management device according to claim 5 ; an imaging device that captures images of the cells cultured in the container and generates the captured image showing the imaging results of the cells; an identifier generation device that generates the identification information and creates an identifier including the identification information; a reader for reading the identification information from the identifier attached to the container; A cell culture management system comprising:

9. acquiring captured images in time series showing imaging results of cells cultured in a container, and analyzing the captured images to detect a cell image showing the cells for each captured image; evaluating the state of the cells for each captured image based on the detection result of the cell image; deriving a cell state estimation model that estimates a time change in the state of the cell based on the evaluation results of the state of the cell in the plurality of captured images; managing the culture of the cells based on the results of the prediction by the cell state prediction model; A cell culture management method comprising:

10. acquiring captured images in time series showing imaging results of cells cultured in a container, and analyzing the captured images to detect a cell image showing the cells for each captured image; evaluating the state of the cells for each captured image based on the detection result of the cell image; deriving a cell state estimation model that estimates a time change in the state of the cell based on the evaluation results of the state of the cell in the plurality of captured images; managing the culture of the cells based on the results of the prediction by the cell state prediction model; A computer program that causes a computer to execute the following.

Images