WO2019163304A1 - Culturing assisting device, observation device, and program - Google Patents

Abstract

This culturing assisting device is provided with: a first information acquisition unit for acquiring first information relating to the culture state of cells in a first period of a cell culture process; a second information acquisition unit for acquiring second information relating to the culture state of the cells in a second period which follows the first period; a parameter acquisition unit for acquiring a parameter for use in selecting a culture protocol indicating a condition for culturing the cells; and a culture protocol presentation unit for presenting the culture protocol on the basis of the parameter acquired by the parameter acquisition unit, the first information acquired by the first information acquisition unit, the second information acquired by the second information acquisition unit, and learning results that learned the association between the culture protocol and results of cell culturing based on the culture protocol.

Description

Culture support device, observation device, and program

The present invention relates to a culture support device, an observation device, and a program.
This application claims priority on February 22, 2018 based on Japanese Patent Application No. 2018-029336 for which it applied to Japan, and uses the content here.

In general, techniques for evaluating the culture state of cells are fundamental techniques in a wide range of fields including advanced medical fields such as regenerative medicine and drug screening. For example, in the field of regenerative medicine, there is a process for growing and differentiating cells in vitro. And in the above-mentioned process, it is required to accurately evaluate the culture state of the cells, such as the success or failure of the differentiation of the cells, the presence or absence of canceration or infection of the cells. As an example, a method for determining a culture state of a cell by performing image processing on an image obtained by imaging the cell (see Patent Document 1).

JP 2004-229619 A

One aspect of the present invention includes a first information acquisition unit that acquires first information related to a cell culture state in a first period of a cell culture process, and a cell in a second period after the first period. A second information acquisition unit for acquiring second information related to the culture state, a parameter acquisition unit for acquiring a parameter used for selection of a culture protocol indicating conditions for cell culture, the parameter acquired by the parameter acquisition unit, The relationship between the first information acquired by the first information acquisition unit, the second information acquired by the second information acquisition unit, the culture result of the cell by the culture protocol, and the culture protocol is learned. And a culture protocol presentation unit that presents the culture protocol based on the learning result obtained.

One embodiment of the present invention is capable of storing a culture vessel for culturing cells and capable of maintaining the interior in a predetermined environmental condition, and the cells stored in the culture container in the constant temperature chamber for a predetermined time. It is an observation apparatus provided with the imaging device imaged for every and the above-mentioned culture support device.

In one embodiment of the present invention, a first information acquisition step of acquiring, in a computer, first information related to a cell culture state at a first time of a cell culture process; and a second time after the first time Acquired in the second information acquisition step of acquiring second information relating to the culture state of the cell, the parameter acquisition step of acquiring a parameter used for selection of the culture protocol indicating the cell culture condition, and the parameter acquisition step The parameter, the first information acquired in the first information acquisition step, the second information acquired in the second information acquisition step, the culture result of the cell by the culture protocol, and the culture protocol Presenting the culture protocol based on the learning result of learning the relationship of Is a program for executing the steps, the.

It is a block diagram which shows the outline | summary of the incubator containing the culture assistance apparatus of embodiment of this invention. It is a figure which shows an example of the front view of the incubator of embodiment of this invention. It is a figure which shows an example of the top view of the incubator of embodiment of this invention. It is a figure which shows an example of the observation operation | movement with the incubator of embodiment of this invention. It is a figure which shows an example of a function structure of the control apparatus of embodiment of this invention. It is a figure which shows an example of the process of the learning stage of embodiment of this invention. It is an example of the information memorize | stored in the memory | storage part of embodiment of this invention. It is a figure which shows an example of the implementation event information of embodiment of this invention. It is a figure which shows an example of the process of the application stage of embodiment of this invention. It is a figure which shows an example of the image memorize | stored in the image memory | storage part of embodiment of this invention. It is a figure which shows an example of the initial stage information input screen of embodiment of this invention. It is a figure which shows an example of the completion | finish information input screen of embodiment of this invention. It is a figure which shows an example of the process of the culture process analysis of embodiment of this invention. It is a figure which shows an example of the process which estimates the image feature-value of the cell image of the final state of embodiment of this invention. It is a figure which shows an example of the culture mode selection screen of embodiment of this invention. It is a figure which shows an example of the analysis result screen of embodiment of this invention. It is a figure which shows an example of the event selection screen of embodiment of this invention.

[Embodiment]
Embodiments of the present invention will be described below with reference to the drawings. FIG. 1 is a block diagram illustrating an outline of an incubator 11 including a culture support apparatus according to an embodiment. Moreover, FIG.2 and FIG.3 is a figure which shows an example of the front view and top view of the incubator 11 of this embodiment.
This incubator 11 is an example of an observation apparatus.

The incubator 11 according to the embodiment includes an upper casing 12 and a lower casing 13. In the assembled state of the incubator 11, the upper casing 12 is placed on the lower casing 13. Note that the internal space between the upper casing 12 and the lower casing 13 is vertically divided by a base plate 14.

First, an outline of the configuration of the upper casing 12 will be described. A constant temperature chamber 15 for culturing cells is formed inside the upper casing 12. The temperature-controlled room 15 includes a temperature adjusting device 15a and a humidity adjusting device 15b, and the temperature-controlled room 15 is maintained in an environment suitable for cell culture (for example, an atmosphere having a temperature of 37 ° C. and a humidity of 90%) ( Note that illustration of the temperature adjusting device 15a and the humidity adjusting device 15b in FIGS. 2 and 3 is omitted). That is, the temperature-controlled room 15 can maintain the inside at a predetermined environmental condition.

A large door 16, a middle door 17, and a small door 18 are arranged in front of the temperature-controlled room 15. The large door 16 covers the front surfaces of the upper casing 12 and the lower casing 13. The middle door 17 covers the front surface of the upper casing 12 and isolates the environment between the temperature-controlled room 15 and the outside when the large door 16 is opened. The small door 18 is a door for carrying in and out a culture vessel 19 for culturing cells, and is attached to the middle door 17. It is possible to suppress environmental changes in the temperature-controlled room 15 by carrying the culture container 19 in and out of the small door 18. The large door 16, the middle door 17, and the small door 18 are kept airtight by the packing SL1, the packing SL2, and the packing SL3, respectively.

For example, when performing operations such as “medium exchange”, “passaging”, “cleaning”, and “transfer of incubator”, these doors are opened. The type of these operations is selected according to the culture state of the cells. In the following description, these operations are collectively referred to as “events”. The “event” includes work performed without opening the door, nothing to be done, and cell culture suspension.
Note that “medium exchange” refers to exchanging all or part of the medium in the culture container with a new medium. In addition, “passaging” refers to collecting the proliferated cells and reseeding them in another culture vessel. “Cleaning” means cleaning the inside of the incubator. Cleaning includes disinfection of the incubator surface and sterilization of water necessary for maintaining the humidity in the incubator. In addition, “transfer of the incubator” is to transfer the incubator to a different incubator when there are a plurality of incubators.

In the temperature-controlled room 15, a stocker 21, an observation unit 22, a container transport device 23, and a transport base 24 are arranged. Here, the conveyance stand 24 is disposed in front of the small door 18, and carries the culture container 19 in and out of the small door 18.

The stocker 21 is arranged on the left side of the temperature-controlled room 15 when viewed from the front surface of the upper casing 12 (the lower side in FIG. 3). The stocker 21 has a plurality of shelves, and each shelf of the stocker 21 can store a plurality of culture vessels 19. Each culture container 19 contains cells to be cultured together with a medium. Thus, the temperature-controlled room 15 accommodates a culture container for culturing cells.

The observation unit 22 is arranged on the right side of the temperature-controlled room 15 when viewed from the front of the upper casing 12. The observation unit 22 can execute time-lapse observation of cells in the culture vessel 19. Here, the time-lapse observation is a technique for observing a change in a time series of a sample by imaging the sample at a predetermined time based on a preset imaging schedule. The imaging of the sample may be performed at regular time intervals or at different time intervals.

Here, the observation unit 22 is fitted into the opening of the base plate 14 of the upper casing 12 and arranged. The observation unit 22 includes a sample stage 31, a stand arm 32 projecting above the sample stage 31, and a main body portion 33 containing a microscopic optical system for phase difference observation and an imaging device 34. The sample stage 31 and the stand arm 32 are disposed in the temperature-controlled room 15, while the main body portion 33 is accommodated in the lower casing 13.

The sample stage 31 is made of a translucent material, and the culture vessel 19 can be placed thereon. The sample stage 31 is configured to be movable in the horizontal direction, and the position of the culture vessel 19 placed on the upper surface can be adjusted. The stand arm 32 includes an LED light source 35. And the imaging device 34 can acquire the microscope image of a cell by imaging the cell of the culture container 19 permeate | transmitted and illuminated by the stand arm 32 from the upper side of the sample stand 31 via a microscopic optical system. The imaging device 34 images the cells accommodated in the culture container in the temperature-controlled room 15 every predetermined time.

The container transport device 23 is disposed in the center of the temperature-controlled room 15 when viewed from the front surface of the upper casing 12. The container transport device 23 delivers the culture container 19 between the stocker 21, the sample table 31 of the observation unit 22, and the transport table 24.

3, the container transport device 23 includes a vertical robot 38 having an articulated arm, a rotary stage 39, a mini stage 36, and an arm unit 37. The rotary stage 39 is attached to the tip of the vertical robot 38 so as to be able to rotate 180 ° in the horizontal direction via a rotary shaft 35a. Therefore, the rotary stage 39 can make the arm portion 37 face the stocker 21, the sample table 31, and the transport table 24.

Also, the mini stage 36 is attached to the rotary stage 39 so as to be slidable in the horizontal direction. An arm part 37 that holds the culture vessel 19 is attached to the mini stage 36.

Next, an outline of the configuration of the lower casing 13 will be described. Inside the lower casing 13, the main body portion 33 of the observation unit 22 and the control device 41 of the incubator 11 are accommodated.

The control device 41 is connected to the temperature adjustment device 15a, the humidity adjustment device 15b, the observation unit 22 and the container transport device 23, respectively. The control device 41 includes a calculation unit 42 and a storage unit 43, and comprehensively controls each unit of the incubator 11 according to a predetermined program. The control device 41 is an example of a culture support device.

As an example, the control device 41 controls the temperature adjustment device 15a and the humidity adjustment device 15b, respectively, to maintain the inside of the temperature-controlled room 15 at a predetermined environmental condition. The control device 41 controls the observation unit 22 and the container transport device 23 based on a predetermined observation schedule, and automatically executes the observation sequence of the culture vessel 19. Furthermore, the control device 41 executes a culture state evaluation process for evaluating the culture state of the cells based on the image acquired in the observation sequence.

[Example of observation operation]
Next, an example of the observation operation in the incubator 11 will be described with reference to the flowchart of FIG.
FIG. 4 is a diagram illustrating an example of an observation operation in the incubator 11 according to the present embodiment. The figure shows an operation example in which the culture vessel 19 carried into the temperature-controlled room 15 is time-lapse observed according to a registered observation schedule.

Step S101: The calculation unit 42 compares the observation schedule of the management data in the storage unit 43 with the current date and time to determine whether or not the observation start time of the culture vessel 19 has come. When it is the observation start time (step S101: YES), the calculation unit 42 shifts the process to S102. On the other hand, when it is not the observation time of the culture vessel 19 (step S101: NO), the calculation unit 42 waits until the time of the next observation schedule.

Step S102: The calculation unit 42 instructs the container transport device 23 to transport the culture container 19 corresponding to the observation schedule. Then, the container transport device 23 carries the instructed culture container 19 out of the stocker 21 and places it on the sample stage 31 of the observation unit 22. Note that, when the culture vessel 19 is placed on the sample stage 31, an entire observation image of the culture vessel 19 is captured by a bird view camera (not shown) built in the stand arm 32.

Step S103: The computing unit 42 instructs the observation unit 22 to take a microscopic image of the cell. The observation unit 22 turns on the LED light source 35 to illuminate the culture vessel 19 and drives the imaging device 34 to take a microscopic image of the cells in the culture vessel 19.

At this time, based on the management data stored in the storage unit 43, the imaging device 34 captures a microscope image based on the imaging conditions (magnification of the objective lens, observation point in the container) designated by the user. For example, when observing a plurality of points in the culture container 19, the observation unit 22 sequentially adjusts the position of the culture container 19 by driving the sample stage 31 and picks up a microscope image at each point. The microscopic image data acquired in S103 is read by the control device 41 and recorded in the storage unit 43 under the control of the calculation unit 42.

Step S104: The calculation unit 42 instructs the container transport device 23 to transport the culture container 19 after the observation schedule is completed. Then, the container transport device 23 transports the designated culture container 19 from the sample stage 31 of the observation unit 22 to a predetermined storage position of the stocker 21. Thereafter, the calculation unit 42 ends the observation sequence and returns the process to S101.

The time-series image data observed by the incubator 11 is stored in the storage unit 43 by the procedure described above. In the following description, obtaining time-series image data by the incubator 11 is also referred to as time-lapse imaging.

[Presentation function of culture protocol and final state prediction according to culture mode]
Next, with reference to FIG. 5 to FIG. 16, the culture protocol according to the culture mode and the final state prediction presentation function will be described. Here, the culture protocol is information indicating a procedure of an event to be performed and environmental conditions to be set. The final state is the state of cells obtained at the end of culture.

FIG. 5 is a diagram illustrating an example of a functional configuration of the control device 41 according to the present embodiment. As described above, the control device 41 includes the calculation unit 42 and the storage unit 43.
The calculation unit 42 includes an image acquisition unit 421, a display control unit 422, an operation detection unit 423, a storage control unit 424, a learning unit 425, an analysis information generation unit 426, a culture mode selection unit 427, and parameter acquisition. A unit 4285 and an analysis result presentation unit 428 are provided as functional units.
The storage unit 43 includes an image storage unit 431, an implementation event storage unit 432, an environment log storage unit 433, a learning result storage unit 434, a culture mode storage unit 435, and a prediction result storage unit 436.

The image acquisition unit 421 acquires the image P from the imaging device 34. The image P is an image in which cells in culture are imaged, for example, every predetermined time based on an imaging schedule. When the image acquisition unit 421 acquires the image P from the imaging device 34, the image acquisition unit 421 adds the imaging date / time information DT indicating the imaging date / time to be stored in the image storage unit 431.

The display control unit 422 controls the screen display of the display unit 44. Specifically, the display control unit 422 displays the image P stored in the image storage unit 431 and event candidates related to the image P on the display unit 44. The display control unit 422 includes an initial information input screen DI for inputting initial information IS, an end information input screen DF for inputting end information FS, a culture mode selection screen DM for selecting a culture mode, and a culture process. An analysis result screen DO indicating the analysis result and an event selection screen DE for selecting an event to be executed are displayed.

The operation unit 45 includes a touch panel, a mouse, a keyboard, or the like. When the operation unit 45 is a touch panel, the operation unit 45 and the display unit 44 may be configured integrally. Further, the operation unit 45 and the display unit 44 may be configured as a touch panel provided in the upper casing 12 or the lower casing 13.
The observer operates the operation unit 45 to select an implementation event. In the above example, when the medium replacement operation is performed, the observer operates the operation unit 45 to select “medium replacement” as an execution event.
The observer sets the environmental conditions of the temperature-controlled room 15 by operating the operation unit 45.
Moreover, although the above-mentioned example demonstrated the aspect in which the temperature and humidity of the temperature-controlled room 15 were set as an environmental condition of the temperature-controlled room 15, it is not restricted to this. The temperature-controlled room 15 may have a carbon dioxide concentration adjusting device that adjusts the carbon dioxide concentration, and this carbon dioxide concentration adjusting device may be controlled by the control device 41.

The operation detection unit 423 detects an operation on the operation unit 45. When the operation detection unit 423 detects an operation, the operation detection unit 423 generates implementation event information EV corresponding to the operation. When the observer performs an operation of selecting “medium replacement” on the operation unit 45, the operation detection unit 423 detects that “medium replacement” has been selected as an execution event.
Further, the operation detection unit 423 generates implementation event information EV indicating “medium replacement”. Moreover, if the operation detection part 423 detects operation which sets the environmental condition of the temperature-controlled room 15, it will produce | generate environmental log information EL according to this operation. When the observer performs an operation for setting the environmental condition of the temperature-controlled room 15 to an atmosphere of a temperature of 37 ° C. and a humidity of 90% on the operation unit 45, the operation detection unit 423 has an atmosphere of a temperature of 37 ° C. and a humidity of 90%. Detects that it was set as an environmental condition.

The storage control unit 424 controls the writing of information to the storage unit 43. Specifically, the storage control unit 424 associates the image acquired by the image acquisition unit 421 with the execution event information EV indicating an event related to cell culture at the timing when the image is captured, and performs the execution event storage unit 432. Remember me. The storage control unit 424 associates the image acquired by the image acquisition unit 421 with the environment log information EL indicating the environmental condition of the temperature-controlled room 15 at the timing when the image is captured, and causes the environment log storage unit 433 to store the image.

In addition, the storage control unit 424 may add and store information related to the date and time when the event is performed to the execution event information EV. In this case, the implementation event information EV includes information related to the date and time when the event was implemented.
Further, the storage control unit 424 may store the environment log information EL by adding information related to the date and time when the environment log was acquired. In this case, the environment log information EL includes information related to the date and time when the environment log was acquired.

The learning unit 425 learns the relationship between the image stored in the image storage unit 431, the implementation event information EV associated with the image, and the environment log information EL associated with the image. . The learning unit 425 learns the relevance between these pieces of information using various known methods. The learning unit 425 stores the learned result in the learning result storage unit 434 as the learning result LR.

The analysis information generation unit 426 generates information used by the analysis result presentation unit 428 for analysis. The analysis information generation unit 426 includes an initial information generation unit 4261, a current information generation unit 4262, an end information generation unit 4264, and an intermediate information generation unit 4263.

Of the images P stored in the image storage unit 431, the initial information generation unit 4261 acquires the images P acquired from the start of the culture process to the first medium exchange. The initial information generation unit 4261 acquires the execution event information EV for the execution event detected from the start of the culturing process to the first medium exchange among the execution event information EV stored in the execution event storage unit 432. The initial information generation unit 4261 acquires the environmental log information EL detected from the start of the culture process to the first medium exchange among the environmental log information EL stored in the environmental log storage unit 433. Here, the start of the culture process is, for example, immediately after seeding in the cell culture process.
The initial information generation unit 4261 supplies the acquired image P, implementation event information EV, and environment log information EL to the analysis result presentation unit 428 as initial information IS.

The current information generation unit 4262 acquires the images P acquired from immediately after sowing to the present among the images P stored in the image storage unit 431. The current information generation unit 4262 acquires the implementation event information EV for the implementation event detected from immediately after sowing to the present from the implementation event information EV stored in the implementation event storage unit 432. The current information generation unit 4262 acquires the environmental log information EL detected from immediately after sowing to the present among the environmental log information EL stored in the environmental log storage unit 433.
The current information generation unit 4262 supplies the acquired image P, implementation event information EV, and environment log information EL to the analysis result presentation unit 428 as current information PS.

The midway information generation unit 4263 acquires the midway information MS from the operation detection unit 423 and supplies it to the analysis result presentation unit 428. The midway information MS is input from the operation unit 45.
Note that the midway information generation unit 4263 may not be provided.

The end information generation unit 4264 acquires the end information FS from the operation detection unit 423 and supplies it to the analysis result presentation unit 428. Here, the end information FS is input from the operation unit 45.

The end information FS is information selected according to the purpose or target of the culture such as expansion culture, medicinal effect, transplantation, biological material production, cell experiment, and culture process improvement. The end information FS includes, for example, the amount of cells, the name of the cell / organ / organ, the sample image of the cell to be obtained by culturing, the name / article of differentiation induction, the drug / procedure / condition to be used, and the transplant operation for transplanting the cell. The name of the surgical method, the disease name / pathology or age / sex / height / weight / medical record of the patient to be transplanted, the name / component of the drug for which the pharmacological test is conducted, the name of the disease whose condition is to be elucidated, the biological material / protein to be obtained by culture This is the type of cell experiment that you want to make use of the cells obtained from the culture. In addition, the amount of cells is designated by the target increase amount of cells in expansion culture, the area, the number of passages after the culture, and the like.
A sample image of a cell desired to be obtained by culturing in the end information FS is referred to as an end image PF. The end information FS other than the end image PF is referred to as non-image end information CF.

The culture mode selection unit 427 selects a culture mode CM. The culture mode CM is information indicating a set of weights W indicating which set value is given priority over other set values among the set values V used when the analysis result presentation unit 428 analyzes the culture protocol. . Therefore, the culture mode CM is information indicating a predetermined set of weights W. The weight W is used to select a culture protocol that indicates cell culture conditions.

Here, the set value V is, for example, past culture results, predicted cell quantity, predicted cultured cell type, predicted accuracy (guaranteed accuracy), amount / period calculated from the culture set value, etc. Culture medium, consumption of medium / equipment calculated from the culture set value, process / degree of cell increase, culture work time, and the like. The set value V may be a value that specifies an upper limit value or a lower limit value of these amounts.
The weight W is a weight associated with each set value V. The weight W may be associated with a plurality of setting values V.

As an example, the culture mode CM includes a quality-oriented mode, a production-oriented mode, and a speed mode. The quality emphasis mode is a culture mode in which the prediction accuracy of the set value V is more important than other set values of the set value V. The production amount emphasis mode is a culture mode in which the predicted cell amount of the set value V is more important than other set values of the set value V. The speed mode is a culture mode in which the culture cost of the set value V is more important than other set values of the set value V.

The culture mode selection unit 427 selects the culture mode CM according to the operation from the operation unit 45. Here, the culture mode CM is stored in advance in the culture mode storage unit 435. That is, the culture mode selection unit 427 selects a culture mode CM from one or more culture mode CMs stored in advance in the culture mode storage unit 435.

In the above example, the weight W acquired by the culture mode selection unit 427 has been described based on the mode determined by the culture mode CM selected by the culture mode selection unit 427, but is not limited thereto. The culture mode selection unit 427 may acquire the weight W input from the operation unit 45. When the weight W is input from the operation unit 45, the observer inputs each of the weights W from the operation unit 45.

In addition, the culture mode CM may be information indicating one or more sets of set values V instead of the sets of weights W. Further, the culture mode CM may be information indicating a set of weights W and one or more set values V. The quality emphasis mode may include, for example, prediction accuracy as a predetermined value. The production amount emphasis mode may include, for example, a predicted amount of cells as a predetermined value. The speed mode may include, for example, the length of the culture period as a predetermined value.

The analysis result presentation unit 428 presents a culture protocol indicating cell culture conditions. The analysis result presentation unit 428 includes an initial information acquisition unit 4281, a current information acquisition unit 4282, an intermediate information acquisition unit 4283, an end information acquisition unit 4284, a parameter acquisition unit 4285, a feature amount extraction unit 4286, and a culture protocol. A presentation unit 4287 and a state prediction unit 4288 are provided.

The initial information acquisition unit 4281 acquires the initial information IS supplied by the initial information generation unit 4261. Here, the initial information IS is information on the cell culture state in the period from the start of the culture process to the first medium exchange. That is, the initial information generation unit 4261 obtains the initial information IS regarding the cell culture state in the period from the start of the culture process to the first medium exchange.

The current information acquisition unit 4282 acquires the current information PS supplied by the current information generation unit 4262. Here, the current information PS is information on the cell culture state in the period from immediately after seeding in the cell culture process to the present. That is, the current information acquisition unit 4282 acquires the current information PS regarding the cell culture state from the start of the culture process to the present.

The midway information acquisition unit 4283 acquires the midway information MS supplied by the midway information generation unit 4263. Here, the midway information MS is information about the culture state of the cells in the middle between the start of the culture process and the end of the culture process. That is, the midway information acquisition unit 4283 acquires midway information MS regarding the cell culture state at the time between the start of the culture process and the end of the culture process.

The end information acquisition unit 4284 acquires the end information FS supplied from the end information generation unit 4264. Here, the end information FS is information relating to the cell culture state at the end of the cell culture process. That is, the end information generation unit 4264 acquires the end information FS regarding the cell culture state at the end after the time from the start of the culture process to the first medium exchange.

The parameter acquisition unit 4285 acquires a parameter PM used for selection of a culture protocol indicating cell culture conditions. Here, the parameter PM is the weight W indicated by the culture mode CM selected by the culture mode selection unit 427 and the set value V supplied from the operation detection unit 423. The set value V is input from the operation unit 45 by the observer.

The feature amount extraction unit 4286 extracts an image feature amount FP from the image P included in the acquired initial information IS using a known machine learning technique. The feature amount extraction unit 4286 extracts an image feature amount FP from the image P included in the acquired current information PS using a known machine learning method.

Here, the image feature amount FP is, for example, the growth state (single, colony formation, sheet shape), the number of cells, the size of the cells, the characteristics of the outer shape of the cells (spherical shape, bubble shape, jagged shape), adhesion between cells. Sex, adjacent connectivity, number of nuclei, shape of nuclei, size of nuclei, number of nucleolus, size of nucleolus, concentration of nucleolus, amount of cytoplasmic granules, brightness of cytoplasmic granules, empty These include the size of the vesicles, the number of vacuoles, the shape (number, length, thickness) of the cytoplasm, the occupied area, and the density. Further, the image feature amount FP includes a feature amount with respect to the temporal change of the image P.

The feature amount extraction unit 4286 extracts the non-image feature amount F from the implementation event information EV and the environment log information EL included in the acquired initial information IS. The feature amount extraction unit 4286 extracts the non-image feature amount F from the implementation event information EV and the environment log information EL included in the acquired current information PS.

The non-image feature amount F is a feature amount other than the image feature amount FP immediately after seeding until the first medium exchange. Non-image feature amount F includes, for example, passage history (culture history of undifferentiated cells), coating agent, medium amount and type, cell line type, culture protocol name, seeding method, freezing method, Reference paper. Note that the non-image feature amount F may include cultivator information indicating the registered cultivator ID, the cultivator's years of culturing experience, and the like. Incubator information may be input from the operation unit 45.

The feature quantity extraction unit 4286 supplies the extracted image feature quantity FP and non-image feature quantity F to the culture protocol presentation unit 4287 and the state prediction unit 4288.
The culture protocol presentation unit 4287 calculates a culture protocol based on the image feature quantity FP and the non-image feature quantity F, the end information FS, the weight W and the set value V, and the learning result LR. Here, the culture protocol presentation unit 4287 acquires the learning result LR from the learning result storage unit 434.
The state predicting unit 4288 predicts the final state of culture based on the image feature quantity FP and the non-image feature quantity F, the end information FS, the weight W and the set value V, and the learning result LR. Here, the state prediction unit 4288 acquires the learning result LR from the learning result storage unit 434.

The analysis result presentation unit 428 supplies the culture protocol EVC indicating the culture protocol calculated by the culture protocol presentation unit 4287 and the final state prediction PFS indicating the final state of the culture predicted by the state prediction unit 4288 to the display control unit 422. Are displayed on the display unit 44. Further, the analysis result presentation unit 428 causes the learning result storage unit 434 to store the final state prediction PFS indicating the final state predicted by the state prediction unit 4288.

That is, the analysis result presentation unit 428 includes the parameters acquired by the parameter acquisition unit 4285, the initial information IS acquired by the initial information generation unit 4261, the end information FS acquired by the end information generation unit 4264, and the cell information based on the culture protocol. The culture protocol is presented based on the culture result and the learning result obtained by learning the relationship between the culture protocol.

Processing performed by the control device 41 will be described. The process performed by the control device 41 includes a learning stage process and an application stage process. The control device 41 performs an application stage process based on the result of the learning stage process.

[Learning stage]
Here, with reference to FIGS. 6 to 8, the learning stage process performed by the control device 41 will be described. FIG. 6 is a diagram illustrating an example of a learning stage process according to the present embodiment.

Step S200: The learning unit 425 acquires, from the storage unit 43, a plurality of pieces of data in which time-series cell images, implementation events, and environmental logs are associated throughout the culture process. Here, the learning unit 425 acquires the image P1 to the image Pn from the image storage unit 431 and the imaging date / time information DT1 to the imaging date / time information DTn added to each of the images P1 to Pn as time-series cell images. To do. The learning unit 425 obtains implementation event information EV1 to implementation event information EVn from the implementation event storage unit 432.
Here, a plurality of data that the learning unit 425 acquires from the storage unit 43 will be described with reference to FIG.
FIG. 7 is an example of information stored in the storage unit 43 of this embodiment. In the example shown in the figure, the storage unit 43 stores the culture progress in the culture sequence seq1. In the culture sequence seq1, images P are captured at time t1, time t2, and time t3. As described above, these images P are stored in time series in the image storage unit 431 in association with the imaging date / time information DT.
Further, each of the images P is associated with implementation event information EV. In this example, “change medium”, “immediately perform”, and “half amount exchange” are associated with the image P1 as the execution event information EV. As described above, the implementation event information EV is stored in the implementation event storage unit 432.
Also, each of these images P is associated with environment log information EL. In this example, a temperature “37 ° C.” and a humidity “90%” are associated with the image P1 as environment log information EL. As described above, the environment log information EL is stored in the environment log storage unit 433.

Here, the implementation event information EV will be described in more detail.
FIG. 8 is a diagram illustrating an example of the implementation event information EV of the present embodiment. In the implementation event information EV, events are divided into hierarchies. In this example, the events are divided into three layers.
As an example shown in the figure, the event (level 1) includes “medium replacement”, “passaging”, “cleaning”, and so on. Events (layer 2) for “medium replacement” include “Immediate execution”, “Execution after a predetermined time”,. In addition, although not shown in figure, the information of the observer who performs each event may also be displayed as event information.

Returning to FIG. 6, the description of the learning process of the learning unit 425 will be continued.
Step S201: The learning unit 425 divides a plurality of data acquired from the storage unit 43 for each predetermined period. Here, as an example, the learning unit 425 divides a plurality of pieces of data for each type of implementation event indicated by the implementation event information EV. The learning unit 425 may divide the plurality of data for each predetermined length of time. Each of the plurality of divided data includes one or more sets of an image capturing date / time, an image, an environment log, and an implementation event.

Step S202: The learning unit 425 extracts the feature amount of the cell image for each period. The learning unit 425 extracts the feature amount of the cell image for each piece of data divided in step S201. When the cell image in a certain period is the image Pi (i = 1, 2,..., N: N is the number of images included in the certain period), the learning unit 425 A feature quantity fi (i = 1, 2,..., N: N is the number of images included in a certain period) is extracted. In calculating the feature quantity fi, in addition to the corresponding image Pi, the preceding and succeeding images P- (i-1), P- (i + 1) and other images Pj (j = 1, 2, ..., N: N may be a combination of the number of images included in a certain period.

The learning unit 425 extracts a morphological feature quantity as a feature quantity fi using known image processing. Here, the morphological feature amount is, for example, the area of the cell imaged in the image Pi, the outer periphery, the seeding variation, and the like. The learning unit 425 may extract the feature quantity fi using a known machine learning method. Here, the machine learning is, for example, deep learning. The learning unit 425 uses learning data acquired in advance for learning of deep learning when using deep learning for extraction of the feature value fi. For this learning data, for example, an ideal cell area value is used. When deep learning is used to extract feature quantity fi, learning unit 425 may extract a value output from an intermediate layer of a neural network used for deep learning as feature quantity fi.
The learning unit 425 uses the representative value of each component of the extracted feature amount fi (i = 1, 2,..., N: N is the number of images included in a certain period) as the feature of the image in a certain period. Amount. Here, the representative value is an average value or a median value.

Step S203: The learning unit 425 learns a model that reproduces the feature value of the cell image of each period by regression analysis based on the feature value of the past cell image, the environment log, and the implementation event. Here, the feature amount of the past cell image is a feature amount extracted from an image of a period before each period. The model is a function that outputs one or more values when a feature value of a past cell image, an environment log, and an execution event are input. The number of one or more values is equal to the number of feature amount components of the cell image in each period. This model includes one or more model parameters that are values that characterize the model. When the learning unit 425 inputs the feature value of the past cell image, the environment log, and the implementation event to this model, one or more values output by the model are close to the feature value of the cell image in each period. Adjust the model parameters so that

Note that the learning unit 425 may extract a heuristic value from the environment log for each period before learning the model, and may learn the model after using the environment log for each period. Here, the heuristic value is an average, variance, maximum value, minimum value, or the like.
Further, the learning unit 425 may use a deep learning architecture that automatically performs feature extraction in the process of step S203.
The learning unit 425 supplies the learned model to the analysis result presentation unit 428 as a learning result LR. Here, when the learning unit 425 uses deep learning, the learning result LR is a result obtained by deep learning.

[Application stage]
With reference to FIGS. 9 to 17, the application stage processing performed by the control device 41 will be described.
FIG. 9 is a diagram illustrating an example of processing in an application stage of the present embodiment. The processing shown in FIG. 9 is performed after the learning stage processing shown in FIG. 6 is completed and the learning unit 425 supplies the learning result LR to the analysis result presentation unit 428.

Step S300: The initial information acquisition unit 4281 acquires the initial information IS. The initial information IS includes images P0 to Pn acquired from immediately after seeding to the first medium exchange, implementation event information EV, and environmental log information EL. The initial information acquisition unit 4281 supplies the acquired initial information IS to the culture protocol presentation unit 4287 and the state prediction unit 4288.

Here, with reference to FIG. 10, the images P0 to Pn acquired by the initial information acquisition unit 4281 from the image storage unit 431 will be described.
FIG. 10 is a diagram illustrating an example of the image P stored in the image storage unit 431 of the present embodiment. In this example, the imaging device 34 captures an image at each time of time t0, time t1,... Time tn-1, time tn, and time tn + 1. For example, the image P0 is an image captured at time t0. When the image acquisition unit 421 acquires the image P0 from the imaging device 34 at time t0, the image acquisition unit 421 adds the imaging date / time information DT indicating the time t0 and stores the image P0 in the image storage unit 431. Similarly, for the images P1 to Pn + 1, the image acquisition unit 421 adds the imaging date / time information DT to each image P and stores it in the image storage unit 431.

At time tE between time tn and time tn + 1, medium exchange is performed as an implementation event. Of the images P stored in the image storage unit 431, the initial information generation unit 4261 acquires images P0 to Pn acquired from time t0 immediately after seeding to time tE when the first medium replacement is performed. .

The display control unit 422 displays the initial information input screen DI on the display unit 44 when the initial information acquisition unit 4281 acquires the image Pn + 1. Here, the image Pn + 1 is a cell image picked up after the first medium exchange from immediately after seeding. The initial information input screen DI will be described with reference to FIG.

FIG. 11 is a diagram showing an example of the initial information input screen DI of the present embodiment. An initial information input screen DI is displayed on the display unit 44. In this example, the initial image PI is displayed in the area AR1 of the initial information input screen DI. This initial image PI is the image Pn + 1 in FIG. The implementation event information EV and the environment log information EL are displayed in the area AR2 of the initial information input screen DI. In this example, as the non-image feature amount F, passage history, amount and type of medium, cell line type, and procedure are displayed.

In addition, in this example, although the initial information acquisition part 4281 demonstrated the aspect which acquires the initial information IS from the initial information generation part 4261, it is not restricted to this. The initial information acquisition unit 4281 may acquire the initial information IS from the operation detection unit 423. The initial information acquisition unit 4281 may acquire the initial information IS from both the storage unit 43 and the operation detection unit 423.

Returning to FIG. 9, the description of the process in the application stage will be continued.
Step S301: The end information acquisition unit 4284 acquires the end information FS supplied by the operation detection unit 423. The end information acquisition unit 4284 supplies the acquired end information FS to the analysis result presentation unit 428. Here, the end information FS includes at least one of the end image PF and the non-image end information CF.

Here, the end information input screen DF will be described with reference to FIG.
FIG. 12 is a diagram illustrating an example of the end information input screen DF of the present embodiment. An end information input screen DF is displayed on the display unit 44. In this example, the end image PF is displayed in the area AR3 of the end information input screen DF. In the area AR4 of the end information input screen DF, an input form for inputting the non-image end information CF is displayed. The end image PF and the non-image end information CF are input from the operation unit 45 by the observer.

In addition, in this example, although the end information acquisition part 4284 demonstrated the aspect which acquires the end information FS from the present information generation part 4262, it is not restricted to this. The end information acquisition unit 4284 may acquire the end information FS from the image P stored in the storage unit 43. This image P is, for example, a cell image stored in the image storage unit 431 at the learning stage of the control device 41.

Returning to FIG. 9, the description of the process in the application stage will be continued.
Step S302: The analysis result presentation unit 428 analyzes the culture process. Here, the culture process analysis process will be described with reference to FIG. However, in the process of step S302, the present is the time immediately after the first medium exchange is performed immediately after seeding.

FIG. 13 is a diagram showing an example of the culture process analysis process of the present embodiment.
Step S400: The feature amount extraction unit 4286 extracts the image feature amount FP from the current image P. Here, the feature amount extraction unit 4286 extracts the image feature amount FP0 to the image feature amount FPn from the images P0 to Pn included in the initial information IS, respectively. The feature amount extraction unit 4286 extracts the image feature amount FP0 to the image feature amount FPn using a known machine learning method. The image feature quantity FP0 to image feature quantity FPn extracted by the feature quantity extraction unit 4286 may be selected according to the cell type. Also, the feature amount extraction unit 4286 extracts feature amounts with respect to temporal changes of the images P0 to Pn and includes them in the image feature amounts FP0 to FPn.
The feature quantity extraction unit 4286 supplies the extracted image feature quantity FP0 to image feature quantity FPn to the culture protocol presentation unit 4287 and the state prediction unit 4288.

Note that the feature amount extraction unit 4286 may extract the morphological feature amounts as the image feature amount FP0 to the image feature amount FPn from the images P0 to Pn using known image processing. Here, the morphological feature amount includes, for example, the area, outer periphery, and seeding variation of the cells captured in the images P0 to Pn. The feature quantity extraction unit 4286 replaces the image feature quantity FP0 to image feature quantity FPn extracted by using the machine learning technique with the morphological feature quantity extracted using image processing as the image feature quantity FP0 to image feature quantity. FPn may be used, and the feature quantity extracted using the machine learning technique and the morphological feature quantity extracted using the image processing may be combined into the image feature quantity FP0 to the image feature quantity FPn.

Step S401: The feature amount extraction unit 4286 sets a series of environment logs and implementation events based on the environment log information EL and the implementation event information EV. Here, the feature amount extraction unit 4286 sets a series of environmental logs and implementation events. The non-image feature amount F is extracted from the environmental logs and implementation events immediately after sowing until the present, and the culture protocol presentation unit 4287 and the state prediction unit 4288.

Step S402: The analysis result presentation unit 428 performs a process of predicting the image feature amount FP of the final cell image obtained by the culture. Here, the process of predicting the image feature quantity FP of the cell image in the final state will be described with reference to FIG.

FIG. 14 is a diagram illustrating an example of a process for predicting the image feature amount FP of the cell image in the final state according to the present embodiment.
Step S500: The state prediction unit 4288 acquires the image feature amount FP and the non-image feature amount F supplied by the feature amount extraction unit 4286. Here, the image feature quantity FP supplied by the feature quantity extraction unit 4286 is a feature quantity extracted from the current image P. The non-image feature amount F supplied by the feature amount extraction unit 4286 is a feature amount extracted from a set of environment logs and implementation events.

Step S501: The state prediction unit 4288 uses the image feature quantity FP extracted from the current image, the non-image feature quantity F extracted from the given environment log and event, and the learned model (learning result LR). It is used to predict the image feature quantity FP of the cell image in the next period. The state predicting unit 4288 sets the predicted image feature amount FP of the cell image and the non-image feature amount F as a set as a prediction result PR.

Step S502: The state prediction unit 4288 uses the non-image feature amount F extracted from the environment log and event of the next period, the prediction result PR, and the learned model (learning result LR) for the next period. The image feature amount FP of the cell image is predicted.
Each time the process of step S502 is performed, the state prediction unit 4288 includes the image feature amount FP of the cell image predicted in the prediction process of step S502, and the environment log and event of the next period used in the prediction process of step S502. Are combined with the non-image feature amount F extracted from the current prediction result PR.

Step S503: The state prediction unit 4288 determines whether or not the cell image has reached the final state. Here, as an example, the state prediction unit 4288 determines that the cell image has reached the final state when the culture sequence has a predetermined length or more. When the end information FS is included in the end information FS, the state prediction unit 4288 has a distance between the predicted image feature amount FP of the cell image and the image feature amount FP extracted from the end image PF equal to or less than a predetermined value. In this case, it may be determined that the cell image has reached the final state. Here, the distance between the image feature amounts FP is, for example, a distance between one or more values indicating the image feature amount FP. As this distance, the Euclidean distance or the like is used.

If the state prediction unit 4288 determines that the cell image has reached the final state (step S503: YES), the process ends. On the other hand, when determining that the cell image has not reached the final state (step S503: NO), the state prediction unit 4288 repeats the process shown in step S502.

Returning to FIG. 13, the description of the culture process analysis process will be continued.
Step S403: The state prediction unit 4288 stores the prediction result PR in the prediction result storage unit 436.

Returning to FIG. 9, the description of the process in the application stage will be continued.
Step S303: The parameter acquisition unit 4285 acquires the set value V from the operation detection unit 423. The parameter acquisition unit 4285 supplies the acquired set value V to the culture mode selection unit 427. Note that the parameter acquisition unit 4285 may set a predetermined value stored in advance as the set value V.

Step S304: The culture mode selection unit 427 presents the culture mode CM. Here, the culture mode selection unit 427 acquires the culture mode CM from the culture mode storage unit 435. The culture mode selection unit 427 acquires the prediction result PR from the prediction result storage unit 436. The culture mode selection unit 427 acquires the set value V from the parameter acquisition unit 4285.

The culture mode selection unit 427 selects an environment log and an event based on the prediction result PR and the set value V for each acquired culture mode CM. Here, the culture mode selection unit 427 predicts the culture mode selection unit 427 corresponding to the set value V when the final state is reached based on the environmental log and the event until the final state selected from the initial state is reached. Predict the value. The predicted value corresponding to the set value V is, for example, a predicted value of the period, cost, and success rate required for culture. The culture mode selection unit 427 selects an environmental log and an event that satisfy the condition that the predicted value predicted corresponds to the set value V. However, the culture mode selection unit 427 determines which of the conditions corresponding to the set value V has priority based on the culture mode CM.

The culture mode selection unit 427 supplies the culture mode CM and a predicted value corresponding to the culture mode CM to the display control unit 422. The display control unit 422 causes the display unit 44 to display the culture mode CM supplied by the culture mode selection unit 427 and the predicted value as the culture mode selection screen DM.

Here, the culture mode selection screen DM will be described with reference to FIG.
FIG. 15 is a diagram showing an example of the culture mode selection screen DM of the present embodiment. A culture mode selection screen DM is displayed on the display unit 44. In this example, quality-oriented mode information CM1, production-value-oriented mode information CM2, and speed mode information CM3 are displayed as the culture mode CM. In the area AR5 of the culture mode selection screen DM, quality-oriented mode information CM1 is displayed together with the predicted value. In the area AR6 of the culture mode selection screen DM, the production amount importance mode information CM2 is displayed together with the predicted value. In the area AR6 of the culture mode selection screen DM, speed mode information CM3 is displayed together with the predicted value.
The observer selects one of the culture modes CM displayed on the culture mode selection screen DM from the operation unit 45 according to the purpose of culture.

Returning to FIG. 9, the description of the process in the application stage will be continued.
Step S305: The culture mode selection unit 427 selects a culture mode CM. Here, the culture mode selection unit 427 acquires information indicating the selected culture mode CM supplied by the operation detection unit 423. The culture mode selection unit 427 selects a culture mode CM based on the acquired information indicating the selected culture mode CM. The culture mode selection unit 427 supplies the parameter acquisition unit 4285 with the set of weights W indicated by the selected culture mode CM. The parameter acquisition unit 4285 supplies the culture protocol presentation unit 4287 with the weight W supplied by the culture mode selection unit 427 and the set value V supplied by the operation detection unit 423.

Step S306: The analysis result presentation unit 428 presents the culture protocol EVC and the final state prediction PFS corresponding to the culture mode CM. Here, the analysis result presentation unit 428 acquires the prediction result PR from the prediction result storage unit 436.

The culture protocol presentation unit 4287 selects the culture protocol EVC based on the set value V, the weight W, the current information PS, the end information FS, and the prediction result PR. The culture protocol presentation unit 4287 predicts a predicted value corresponding to the set value V when the final state is reached, based on the environmental log and event until the final state selected from the current state is reached. The culture protocol presentation unit 4287 selects, as the culture protocol EVC, an environmental log and an event that satisfy the condition in which the predicted value predicted corresponds to the set value V.

However, the culture protocol presentation unit 4287 determines which of the conditions corresponding to the set value V has priority based on the weight W. That is, the culture protocol presentation unit 4287 selects the culture protocol EVC corresponding to the culture mode CM. The culture protocol presentation unit 4287 may select the culture protocol EVC without using the weight W.

The culture protocol presentation unit 4287 supplies the selected culture protocol EVC to the display control unit 422. The display control unit 422 causes the display unit 44 to display the culture protocol EVC supplied from the culture protocol presentation unit 4287 as the analysis result screen DO.

Note that the culture protocol presentation unit 4287 may select a plurality of culture protocols EVC. When the culture protocol presentation unit 4287 selects a plurality of culture protocols EVC, the display control unit 422 causes the display unit 44 to display an analysis result screen DO including the plurality of culture protocols EVC supplied by the culture protocol presentation unit 4287. The observer may select any one of the plurality of culture protocols EVC from the analysis result screen DO.

The state prediction unit 4288 predicts the final state based on the current information PS, the culture protocol EVC selected by the culture protocol presentation unit 4287, and the prediction result PR.
Here, the prediction result PR includes the non-image feature amount F extracted from the environment log and the event in a certain period, the prediction result PR, and the learned model (learning result LR) in steps S501 and S502 shown in FIG. ) And the result predicted by the state prediction unit 4288. That is, the prediction result PR is a result predicted based on the learning result LR. Therefore, the state prediction unit 4288 predicts the cell culture state based on the current information PS acquired by the current information acquisition unit 4282, the culture protocol EVC presented by the culture protocol presentation unit 4287, and the learning result LR.

The state prediction unit 4288 supplies the display control unit 422 with a final state prediction PFS indicating the predicted final state. The state prediction unit 4288 causes the display unit 44 to display the final state prediction PFS supplied by the state prediction unit 4288 as the analysis result screen DO.

Here, the analysis result screen DO will be described with reference to FIG.
FIG. 16 is a diagram illustrating an example of the analysis result screen DO of the present embodiment. The display unit 44 displays an analysis result screen DO. In this example, the speed mode information CM3 is displayed together with the predicted value in the area AR8 of the analysis result screen DO.
The culture protocol EVC is displayed in the area AR9 of the analysis result screen DO. In this example, the culture protocol EVC indicates instructions for replacing the medium, matters to be aware of, and conditions for stopping the culture.
The final state prediction PFS is displayed in the area AR10 of the analysis result screen DO. The final state prediction PFS includes the predicted end image PF. In this example, the final state prediction PFS indicates the number of cells, the quality, and the undifferentiated cell rate.

Returning to FIG. 9, the description of the process in the application stage will be continued.
Step S <b> 307: The operation detection unit 423 detects an observer's event selection operation on the operation unit 45. The observer selects an event to be executed from the event selection screen DE displayed on the display unit 44.

In the process shown in step S306 described above, the culture protocol presentation unit 4287 determines the culture protocol EVC based on the set value V, the weight W, the current information PS, the end information FS, and the prediction result PR. Although the aspect to select was demonstrated, it is not restricted to this. The culture protocol presentation unit 4287 selects the culture protocol EVC based on the set value V, the weight W, the current information PS, the end information FS, the prediction result PR, and the intermediate information MS. Also good.

That is, the culture protocol presentation unit 4287 includes the weight W acquired by the parameter acquisition unit 4285, the current information PS acquired by the current information acquisition unit 4282, the end information FS acquired by the end information generation unit 4264, and the midway information generation unit. The culture protocol EVC may be presented based on the midway information MS acquired by the 4263 and the learning result LR.

In this case, the culture protocol presentation unit 4287 selects the culture protocol EVC for passing through the intermediate state indicated by the intermediate information MS in the process of reaching the final state corresponding to the end image PF indicated by the end information FS.

Moreover, in the process shown in step S306 described above, the culture protocol presentation unit 4287 determines that the environment log and the event are based on the set value V, the weight W, the current information PS, the end information FS, and the prediction result PR. Although the aspect which selects as culture | cultivation protocol EVC was demonstrated, it is not restricted to this. The culture protocol presentation unit 4287 may generate an environment log and an event based on the set value V, the weight W, the current information PS, the end information FS, and the prediction result PR, and use it as the culture protocol EVC. That is, the culture protocol presentation unit 4287 may generate the culture protocol EVC based on the learning result LR.

Here, the event selection screen DE will be described with reference to FIG.
FIG. 17 is a diagram illustrating an example of the event selection screen DE according to the present embodiment. The display unit 44 displays an event selection screen DE. In this example, the current image Px is displayed together with the imaging date and time in the area AR11 of the event selection screen DE. The presentation event REV and the candidate event OEV are displayed in the area AR12 of the event selection screen DE. The presentation event REV is an event indicated by the culture protocol EVC presented by the culture protocol presentation unit 4287. A text “(recommended)” is added to the presentation event REV, which indicates that the event is indicated by the culture protocol EVC.
Note that the observer may select a candidate event OEV other than the presentation event REV indicated by the culture protocol EVC.

Returning to FIG. 9, the description of the process in the application stage will be continued.
Step S308: The current information acquisition unit 4282 acquires the current information PS. The current information PS includes an image P acquired from immediately after sowing to the present, implementation event information EV, and environmental log information EL. The current information acquisition unit 4282 supplies the acquired current information PS to the analysis result presentation unit 428.

Step S309: The state prediction unit 4288 determines whether or not the image P included in the current information PS has reached the final state. Here, for example, the state prediction unit 4288 determines that the cell image has reached the final state when the length of the culture sequence is equal to or longer than a predetermined length. Note that the state prediction unit 4288 determines that the cell image is displayed when the distance between the image feature amount FP of the image P included in the current information PS and the image feature amount FP extracted from the end image PF is equal to or less than a predetermined value. It may be determined that the final state has been reached.

Step S310: The analysis result presentation unit 428 analyzes the culture process. When the process of analyzing the culture process in step S310 is compared with the process of analyzing the culture process in step S302, the analysis result presenting unit 428 performs analysis based on the current information PS in step S310, whereas step 302 However, the analysis result presentation unit 428 is different in that the analysis result presentation unit 428 performs analysis based on the initial information IS. Since the other processing contents in step S310 are the same as those in step 302, description thereof will be omitted.

In the process shown in step S304 of FIG. 9, the culture mode selection unit 427 starts from the cell indicated by the initial image PI when the predicted log that satisfies the predicted value that satisfies the condition corresponding to the set value V cannot be selected. May supply the display control unit 422 with warning information AL0 indicating that it is predicted that a final state satisfying the set condition will not be obtained. The display control unit 422 may display the warning information AL supplied from the culture mode selection unit 427 on the display unit 44.

In addition, in the process shown in step S306 of FIG. 9, the culture protocol presentation unit 4287, when the predicted log predicted by the environment log and the event satisfying the condition corresponding to the set value V cannot be selected, the image P of the current information PS is displayed. Warning information AL1 indicating that it is predicted that the final state satisfying the set condition cannot be obtained may be supplied to the display control unit 422 from the indicated cell. The display control unit 422 may cause the display unit 44 to display the warning information AL1 supplied by the culture protocol presentation unit 4287.

In the above-described embodiment, the end information generating unit 4264 has acquired the end information FS from the operation detecting unit 423. That is, the end information FS is input from the operation unit 45. However, the present invention is not limited thereto. Absent. The end information generation unit 4264 may acquire one or more pieces of end information FSM-1 to end information FSM-n from the storage unit 43. When the end information generation unit 4264 acquires the end information FSM-1 to the end information FSM-n from the storage unit 43, the end information FSM-1 to the end information FSM-n are stored in the storage unit 43.

The end information generation unit 4264 acquires the end information FSM-1 to the end information FSM-n from the storage unit 43 and supplies them to the feature amount extraction unit 4286. The culture protocol presentation unit 4287 selects the culture protocol EVCM-1 to the culture protocol EVCM-n for each of the end information FSM-1 to the end information FSM-n supplied by the end information generation unit 4264. The display control unit 422 causes the display unit 44 to display an analysis result screen DO including the culture protocol EVCM-1 to the culture protocol EVCM-n selected by the culture protocol presentation unit 4287.

In this example, the control device 41 temporarily sets a plurality of culture purposes or targets even if the culture purpose or target is not input from the operation unit 45 as the end information FS. In response, culture protocol EVCM-1 to culture protocol EVCM-n can be presented. For example, when the end information FSM-1 to end information FSM-n stored in the storage unit 43 includes the amount of cells, the control device 41 changes the culture protocol EVCM-1 to culture protocol EVCM-n for each cell amount. Can be presented as a list of protocols.
In addition, the control apparatus 41 may perform the process of a learning stage using the information obtained in the process of the said application stage after completion | finish of the process of an application stage. In this way, the control device 41 can always obtain the best model by executing the learning stage process each time the application stage process information is obtained.

As described above, the culture support device (control device 41) according to the present embodiment includes the first information acquisition unit (initial information acquisition unit 4281 or current information acquisition unit 4282) and the second information acquisition unit (end information). An acquisition unit 4284), a parameter acquisition unit 4285, and a culture protocol presentation unit 4287.
The first information acquisition unit (initial information acquisition unit 4281 or current information acquisition unit 4282) acquires first information (initial information IS or current information PS) relating to the cell culture state in the first stage of the cell culture process. .
The second information acquisition unit (end information acquisition unit 4284) acquires second information (end information FS) related to the cell culture state in the second period after the first period.
The parameter acquisition unit 4285 acquires a parameter (set value V or weight W) used for selection of a culture protocol EVC indicating cell culture conditions.
The culture protocol presentation unit 4287 includes the parameters (set value V or weight W) acquired by the parameter acquisition unit 4285 and the first information (initial information acquisition unit 4281 or current information acquisition unit 4282) acquired by the first information acquisition unit (initial information acquisition unit 4281). Initial information IS or current information PS), second information (end information acquisition unit 4284) acquired by the second information acquisition unit (end information acquisition unit 4284), and the relationship between the culture result of the cell by the culture protocol EVC and the culture protocol EVC The culture protocol EVC is presented based on the learning result LR in which sex is learned.

With this configuration, the culture support device (control device 41) according to the present embodiment obtains the cell culture state indicated by the second information based on the learning result LR at the first stage of the cell culture process. Since the culture protocol EVC can be presented, the culture technique and environmental conditions can be finely adjusted successively while confirming the culture state according to the purpose and target of the culture.

In the culture support device (control device 41) according to the present embodiment, the learning result LR is a result obtained by deep learning.
With this configuration, the culture support device (control device 41) according to the present embodiment can present the culture protocol EVC based on a learning result with higher accuracy than when deep learning is not used.

Further, the culture support apparatus (control apparatus 41) according to the present embodiment further includes a state prediction unit 4288. The state prediction unit 4288 includes first information (initial information IS or current information PS), first information (initial information IS or current information PS) acquired by the second information acquisition unit (end information acquisition unit 4284), and culture. The cell culture state is predicted based on the culture protocol EVC presented by the protocol presenting unit 4287 and the learning result LR.

With this configuration, the culture support device (control device 41) according to the present embodiment predicts the cell culture state indicated by the second information based on the learning result LR at the first stage of the cell culture process. Therefore, the observer can make fine adjustments sequentially while confirming the prediction of the culture state.

In addition, the culture support apparatus (control apparatus 41) according to the present embodiment further includes a midway information acquisition unit 4283. The midway information acquisition unit 4283 acquires midway information MS related to the cell culture state in the period between the first period and the second period.
The culture protocol presentation unit 4287 includes the parameters (set value V or weight W) acquired by the parameter acquisition unit 4285 and the first information (initial information acquisition unit 4281 or current information acquisition unit 4282) acquired by the first information acquisition unit (initial information acquisition unit 4281). Initial information IS or current information PS), second information (end information FS) acquired by the second information acquisition unit (end information acquisition unit 4284), intermediate information MS acquired by the intermediate information acquisition unit 4283, and learning results The culture protocol EVC is presented based on LR.

With this configuration, in the culture support device (control device 41) according to the present embodiment, the first time and the second time indicated by the intermediate information MS based on the learning result LR in the first time of the cell culture process. Since the culture protocol EVC for obtaining the cell culture state indicated by the second information can be presented via the cell culture state in the period between the two periods, the state during the culture is designated and cultured. It can be performed.

In addition, the culture support device (control device 41) according to the present embodiment further includes a culture mode storage unit 435 and a culture mode selection unit 427. The culture mode storage unit 435 stores in advance one or more culture modes CM that are information indicating a predetermined set of parameters. The culture mode selection unit 427 selects a culture mode CM from one or more culture modes CM stored in the culture mode storage unit 435. The parameter acquisition unit 4285 acquires a parameter (set value V or weight W) indicated by the culture mode CM selected by the culture mode selection unit 427.
With this configuration, the culture support apparatus (control apparatus 41) according to the present embodiment does not need to sequentially specify parameters (setting value V or weight W) used for presentation of the culture protocol EVC. The parameters (setting value V or weight W) used for the can be easily specified.

In addition, the first time may be at the start of the culture process, and the second time may be at the end of the culture process.
With this configuration, in the culture support device (control device 41) according to the present embodiment, the culture for obtaining the cell culture state at the end of the culture process based on the learning result LR at the start of the cell culture process. Since the protocol EVC can be presented, the observer can successively fine-tune the culture technique and environmental conditions while confirming the culture state from the start to the end of the cell culture process. The first time is not limited to the start of the culture process, and may be a later time. In addition, the second time is not limited to the end of the culture process, and may be a timing before the end of the culture process.

The observation apparatus according to the present embodiment includes a temperature-controlled room 15, an imaging device 34, and a culture support device (control device 41). The temperature-controlled room 15 can store a culture vessel 19 for culturing cells, and can maintain the inside at a predetermined environmental condition. The imaging device 34 images the cells accommodated in the culture container 19 in the temperature-controlled room 15 every predetermined time.

[Modification]
As a modification of the above-described embodiment, a case where there are a plurality of incubators 11-1 to 11-n will be described. In this modification, even if it is predicted that a cell cultivated in one of the incubators 11-i cannot reach the target final state, the cells are cultured in other incubators 11-j. This is applicable to the case where the final state indicated by the end information FS can be reached in the cell to be processed.

The culture system S includes a management device AD and a plurality of incubators 11-1 to 11-n. The incubators 11-1 to 11-n include control devices 41-1 to 41-n, respectively.
The management device AD communicates with each of the control devices 41-1 to 41-n. The management device AD and the control devices 41-1 to 41-n are each provided with a communication module and communicate with each other by wired communication or wireless communication.

Among the control devices 41-1 to 41-n, the control device 41-i corresponds to the predicted value corresponding to the set value V in the process shown in step S304 of FIG. 9 or the process shown in step S306. When the environment log and the event satisfying the conditions cannot be selected, the warning information AL (warning information AL0 or warning information AL1) is supplied to the management device AD.

When the management device AD acquires the warning information AL supplied from the control device 41-i, the management device AD acquires the setting value V and the end information FS from the control device 41-i. Here, one of the control devices 41-1 to 41-n other than the control device 41-i is represented as a control device 41-j. The management device AD supplies the setting value Vi and the end information FS-i acquired from the control device 41-i to the control device 41-j.

The control device 41-j, based on the set value Vi acquired from the control device 41-i, the current information PS-j of the own device, and the end information FS-i acquired from the control device 41-i, It is determined whether the final state indicated by the end information FS-i can be reached from the state of the cell image indicated by the current information PS-j. When the control device 41-j determines that the final state indicated by the end information FS-i can be reached from the state of the cell image indicated by the current information PS-j, the cell cultured in the incubator 11-j reaches the final state. The culturable information PC indicating that it can be supplied is supplied to the management device AD.

The management device AD supplies the culturable information PC supplied from the control device 41-j to the control device 41-i. The control device 41-i displays the culturable information PC supplied from the management device AD on the display unit 44-i of the own device.
Note that the culture system S may directly communicate between the control devices 41-1 to 41-n instead of including the management device AD.

In this modified example, even if it is predicted that a cell cultured in one incubator 11-i cannot reach the final state indicated by the end information FS-i, the observer can It can be known that the cells cultured in the other incubator 11-j of S are predicted to reach the final state indicated by the end information FS-i.

Note that a part of the control device 41 in the above-described embodiment, for example, the image acquisition unit 421, the display control unit 422, the operation detection unit 423, the storage control unit 424, the learning unit 425, the analysis information generation unit 426, and the culture mode selection unit. 427 and the analysis result presentation unit 428 may be realized by a computer. In that case, the program for realizing the control function may be recorded on a computer-readable recording medium, and the program recorded on the recording medium may be read by the computer system and executed. Here, the “computer system” is a computer system built in the control device 41 and includes an OS and hardware such as peripheral devices. The “computer-readable recording medium” refers to a storage device such as a flexible medium, a magneto-optical disk, a portable medium such as a ROM or a CD-ROM, and a hard disk incorporated in a computer system. Furthermore, the “computer-readable recording medium” is a medium that dynamically holds a program for a short time, such as a communication line when transmitting a program via a network such as the Internet or a communication line such as a telephone line, In this case, a volatile memory inside a computer system that serves as a server or a client may be included that holds a program for a certain period of time. The program may be a program for realizing a part of the functions described above, and may be a program capable of realizing the functions described above in combination with a program already recorded in a computer system.
Moreover, you may implement | achieve part or all of the control apparatus 41 in embodiment mentioned above as integrated circuits, such as LSI (Large Scale Integration). Each functional block of the control device 41 may be individually made into a processor, or a part or all of them may be integrated into a processor. Further, the method of circuit integration is not limited to LSI, and may be realized by a dedicated circuit or a general-purpose processor. In addition, when an integrated circuit technology that replaces LSI appears due to the advancement of semiconductor technology, an integrated circuit based on the technology may be used.

As described above, the embodiment of the present invention has been described in detail with reference to the drawings. However, the specific configuration is not limited to the above, and various design changes and the like can be made without departing from the scope of the present invention. It is possible to

DESCRIPTION OF SYMBOLS 11 ... Incubator (observation apparatus), 41 ... Control apparatus (culture support apparatus), 43 ... Memory | storage part, 44 ... Display part, 45 ... Operation part, 421 ... Image acquisition part, 422 ... Display control part, 423 ... Operation detection part 424 ... Storage control unit, 425 ... Learning unit, 426 ... Analysis information generation unit, 427 ... Culture mode selection unit, 428 ... Analysis result presentation unit

Claims (9)

1. A first information acquisition unit for acquiring first information on a cell culture state in a first stage of the cell culture process;
   A second information acquisition unit for acquiring second information relating to the culture state of the cells in a second period after the first period;
   A parameter acquisition unit for acquiring parameters used for selection of a culture protocol indicating cell culture conditions;
   The parameter acquired by the parameter acquisition unit, the first information acquired by the first information acquisition unit, the second information acquired by the second information acquisition unit, and the culture result of the cells by the culture protocol And a culture protocol presenting unit for presenting the culture protocol based on a learning result in which a relationship between the culture protocol and the culture protocol is learned,
   A culture support apparatus comprising:
2. The culture support apparatus according to claim 1, wherein the learning result is a result obtained by deep learning.
3. The state prediction unit for predicting a culture state of a cell based on the first information acquired by the first information acquisition unit, the culture protocol presented by the culture protocol presentation unit, and the learning result. The culture support apparatus according to claim 1 or 2.
4. A midway information obtaining unit for obtaining midway information on a culture state of the cell in a period between the first period and the second period;
   The culture protocol presentation unit includes the parameter acquired by the parameter acquisition unit, the first information acquired by the first information acquisition unit, the second information acquired by the second information acquisition unit, and the midway The culture support apparatus according to any one of claims 1 to 3, wherein the culture protocol is presented based on the intermediate information acquired by the information acquisition unit and the learning result.
5. A culture mode storage unit that stores in advance one or more culture modes that are information indicating the predetermined set of parameters;
   A culture mode selection unit for selecting the culture mode from one or more culture modes stored in the culture mode storage unit;
   The culture support device according to any one of claims 1 to 4, wherein the parameter acquisition unit acquires the parameter indicated by the culture mode selected by the culture mode selection unit.
6. The culture support apparatus according to any one of claims 1 to 5, wherein the first time is a start time of the culture process.
7. The culture support apparatus according to any one of claims 1 to 6, wherein the second time is the end of the culture process.
8. A temperature-controlled room that can hold a culture vessel for culturing cells and maintain the inside at a predetermined environmental condition;
   An imaging device for imaging the cells contained in the culture vessel in the temperature-controlled room every predetermined time;
   The culture support apparatus according to any one of claims 1 to 7,
   An observation apparatus comprising:
9. On the computer,
   A first information acquisition step of acquiring first information relating to a cell culture state in a first stage of the cell culture process;
   A second information acquisition step of acquiring second information relating to the culture state of the cells in a second period after the first period;
   A parameter acquisition step for acquiring parameters used for selection of a culture protocol indicating cell culture conditions;
   The parameter acquired in the parameter acquisition step, the first information acquired in the first information acquisition step, the second information acquired in the second information acquisition step, and the cell according to the culture protocol A culture protocol presenting step for presenting the culture protocol on the basis of the culture result and the learning result obtained by learning the relevance of the culture protocol;
   A program for running

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