JP2018093749A - Cell quality evaluation system, program, and cell quality evaluation method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cell quality evaluation system, etc., that can automatically evaluate the quality of a cell being evaluated with high accuracy.SOLUTION: A server device 30 automatically captures images corresponding to each state stage of a fertilized egg E by imaging the fertilized egg E with a camera 10, applies different scoring reference information and algorithms to each state stage, calculates individual scores corresponding to each state stage, and evaluates the quality of the fertilized egg E on the basis of the overall score corresponding to the whole state stage.SELECTED DRAWING: Figure 1

Description

  The present invention relates to, for example, a cell quality evaluation system, a cell quality evaluation program, and a cell quality evaluation method used for superiority or inferiority evaluation of cultured cell quality.

  In recent years, in the medical field such as regenerative medicine and infertility treatment, it is necessary to prevent the use of cells other than cells that satisfy predetermined quality requirements in order to achieve the desired effect of cell therapy while ensuring safety. . For example, when creating, culturing, and transplanting fertilized eggs for in vitro fertilization, observe the state of the fertilized egg during culture at regular intervals and evaluate whether the fertilized egg is developing smoothly. In addition, excluding fertilized eggs that do not meet the predetermined developmental conditions and quality from the transplant target, or lowering the priority, specialists such as doctors take into account the patient's condition in addition to the quality of the fertilized eggs, It is necessary to make a final decision, such as transplanting a fertilized egg with a good growth state, in order to ensure safety.

  For this reason, in the conventional medical field, an operator such as a doctor takes a cell observation image using a microscope and confirms the image with the naked eye, and based on the experience and knowledge of each operator We evaluate the superiority or inferiority of the quality of cells and select cells suitable for transplantation.

  In recent years, in order to reduce the burden on the operator and to homogenize the determination of cell quality, an image showing the state of the chromosome in the cell is taken at predetermined time intervals, and based on the image, A state stage specifying method (for example, Patent Document 1) for automatically specifying a stage of an internal state of a cell (hereinafter referred to as a “state stage”) that changes every predetermined time and A cell quality evaluation system (for example, Patent Document 2) that extracts feature quantities in a cell image and determines the superiority or inferiority of cell quality from the extracted feature quantities or a combination of a plurality of feature quantities has been proposed. .

International Publication No. WO2006 / 061958 Japanese Patent No. 4852890

  However, in the method described in Patent Document 1, although it is possible to automatically specify the cell state stage, it is difficult to appropriately evaluate the cell quality.

  In the system described in Patent Document 2, it is difficult to evaluate the quality of cells reflecting the internal state of cells in each state stage at the time of cell quality evaluation, and it is difficult to improve the accuracy of quality evaluation.

  The present invention has been made in view of the above circumstances, and its purpose is to evaluate the quality automatically and with high accuracy by quantifying the quality of cells to be evaluated. It is to provide a cell quality evaluation system and the like that can be used.

  In order to solve the above-described problems, the cell quality evaluation system of the present invention is defined by a time axis in a cell quality evaluation system that evaluates the quality of cells in which a state stage indicating an internal state transitions in stages as time passes. An imaging control unit that controls an imaging unit that captures a cell corresponding to each state stage and generates image data of the cell image; and a quality of the cell in each state stage based on the cell image of the generated image data Recording control means for controlling recording means to be recorded in association with state stage identification information for identifying each state stage, wherein the scoring reference information used as a reference when evaluating the image by the score, and the imaging means Acquisition means for acquiring the image data output from, and for each of the state stages, a predetermined value for the acquired cell image While performing image processing, scoring means for scoring the quality of the corresponding cell based on the corresponding scoring reference information, and according to the scoring result indicating the scored result, the quality of the cell An evaluation means for evaluating superiority and inferiority, and a presentation means for presenting the evaluation result in the evaluation means so that the user can browse the structure are provided.

  With this configuration, the cell quality evaluation system of the present invention can automatically evaluate the quality of the target cell if the cell is imaged with the passage of time. (For example, doctors and operators) can reduce the work burden, and by scoring the cells that are in different states for each state stage, it is possible to evaluate the superiority or inferiority of the cell quality. Therefore, it is possible to accurately evaluate cells in which the growth process is important in quality evaluation.

  That is, since the internal structure of the cell changes according to the state stage, and the quality criterion also changes according to the state stage, the cell quality evaluation system of the present invention has different scoring reference information and algorithms for each state stage. As well as being able to perform scoring, appropriate scoring can be realized according to the state stage.

  Therefore, the cell quality evaluation system of the present invention can quantify the quality of cells to be evaluated, and can perform the evaluation automatically and with high accuracy.

  The cell quality evaluation system of the present invention can quantify the quality of cells to be evaluated, and can perform the evaluation automatically and with high accuracy.

It is a system configuration figure showing the composition of one embodiment of the cell quality evaluation system concerning the present invention. In the cell quality evaluation system of one embodiment, when cultivating a fertilized egg, it is a figure for explaining transition of a state stage which occurs in a fertilized egg with progress of time from insemination. It is a block diagram which shows the structure of the server apparatus of one Embodiment. It is a figure which shows an example of the data recorded on cultured cell management DB provided in the server apparatus of one Embodiment. It is a figure which shows an example of the data recorded on the state stage management DB provided in the server apparatus of one Embodiment. It is a figure which shows an example of the data recorded on scoring information DB provided in the server apparatus of one Embodiment. In the cell quality evaluation system of one Embodiment, it is a figure (the 1) explaining the outline | summary of the scoring process in the state stage (1st period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 2) explaining the outline | summary of the scoring process in the state stage (1st period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 1) explaining the outline | summary of the scoring process in the state stage (2nd period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 2) explaining the outline | summary of the scoring process in the state stage (2nd period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 1) explaining the outline | summary of the scoring process in the state stage (3rd period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 2) explaining the outline | summary of the scoring process in the state stage (3rd period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 3) explaining the outline | summary of the scoring process in the state stage (3rd period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 1) explaining the outline | summary of the scoring process in the state stage (4th period) of a fertilized egg. In the cell quality evaluation system of one Embodiment, it is a figure (the 2) explaining the outline | summary of the scoring process in the state stage (4th period) of a fertilized egg. It is a flowchart (the 1) which shows the process performed in the server apparatus of one Embodiment. It is a flowchart (the 2) which shows the process performed in the server apparatus of one Embodiment. It is a flowchart (the 3) which shows the process performed in the server apparatus of one Embodiment. It is a flowchart (the 4) which shows the process performed in the server apparatus of one Embodiment.

  Hereinafter, embodiments according to the present invention will be described with reference to the drawings.

  In the following embodiments, when a cell is cultured, the cell quality evaluation system, the cell quality evaluation program, and the cell quality evaluation method of the present invention are added to a system for imaging the cell and evaluating the quality of the cell. This is an embodiment when applied. However, the present invention is not limited to the following embodiments as long as the technical idea is included.

  In the following embodiments, in order to embody the explanation, in fertility treatment, fertilized eggs (embryos) fertilized with sperm and eggs collected from patients are cultured, and the superiority or inferiority of the quality of the fertilized eggs is evaluated. The case will be described as an example.

[1] Outline of Cell Quality Evaluation System First, the configuration and outline of the cell quality evaluation system 1 in the present embodiment will be described with reference to FIGS. 1 and 2.

  FIG. 1 is a system configuration diagram showing the configuration of the cell quality evaluation system 1 in the present embodiment, and FIG. 2 is a time after fertilization in a fertilized egg (embryo) fertilized with a sperm collected from a patient and an egg. It is a figure for demonstrating the development process of a fertilized egg with progress.

  As shown in FIG. 1, the cell quality evaluation system 1 of the present embodiment images a plurality of fertilized eggs E in culture and generates an image of the imaged cells (hereinafter referred to as “cell image”). In this system, the superiority or inferiority of the quality of the fertilized egg E is evaluated based on the generated cell image, and it is a system for evaluating whether or not the requirements for transplantation adaptation to the mother's fetus are satisfied by the score in each growth stage.

  In particular, the cell quality evaluation system 1 according to the present embodiment can be used as a system for supporting the determination when the quality of the cell is finally determined by an operator such as a doctor.

For example, as shown in FIG. 2, in the fertilized egg E, the state stage indicating the internal state of the cell with the lapse of time after completion of fertilization,
(1) The first stage in which at least the plasma membrane, zona pellucida and polar body occur during 0-8 hours after fertilization,
(2) The second period in which the pronucleus develop in the plasma membrane between 8 and 24 hours after fertilization,
(3) During the period of 20 to 100 hours after fertilization, the pronucleus disappear, the cleavage occurs sequentially inside the zona pellucida, and the third stage in which morulae develop, and
(4) The fourth stage in which a blastocyst in which the zona pellucida and the plasma membrane have disappeared and the cell trophoblast and the inner cell mass have developed after the elapse of 100 hours or more after fertilization,
Transitions are made in this order.

  Therefore, the cell quality evaluation system 1 according to the present embodiment uses the cell image of each state stage and the scoring as a reference when evaluating the cell quality in each state stage based on the score based on the cell image of each state stage. Using the reference information, the superiority or inferiority of the cell quality can be evaluated.

  In general, in each state stage of these stages, the fertilized egg E transitions to a state having a different internal structure, such as the number of cells changing. Therefore, the same evaluation standard and evaluation algorithm are used. It is difficult to accurately evaluate the quality of the fertilized egg E in each stage by applying.

  In the fertilized egg E, the initial stage after fertilization (that is, the first stage state stage (hereinafter simply referred to as “first stage”) and the second stage stage (hereinafter simply referred to as “second stage”). The quality of the fertilized egg in ())) is important for ensuring the safety after transplantation, and includes the first stage and the second stage, including the first stage and the second stage. Until the first and middle stages (also referred to as the “third stage”) (the first stage stage where 2 cleavage occurs and the middle stage where 4 cleavage occurs), the number of cells formed in the fertilized egg Greatly affects quality.

  On the other hand, if the cleavage progresses from the latter stage of the third stage to the state stage including the fourth stage, the difference in the number of several cells has less influence on the quality of the fertilized egg E. In particular, in the fourth stage, the number of cells contained in the inner cell mass is as large as about 200 to 400, so even if the number of cells is different, the effect on the quality of the fertilized egg E is small. Become.

  As described above, cells such as fertilized eggs change according to the state stage, and the quality criterion also changes according to the state stage. Therefore, it is difficult to uniformly evaluate the cells. In addition, the growth of cells is not uniform, and the degree of growth changes for each individual cell, so that quality control may not be performed accurately while following the growth of each cell.

  Therefore, as described above, the internal state of the fertilized egg E is characteristically indicated by the number of cells and other states for each state stage. The fertilized egg E to be evaluated is imaged as a cell image in accordance with the timing, and the quality evaluation in each period is performed while changing the quality evaluation standard and the quality evaluation algorithm according to each period to which the fertilized egg E belongs, And it has the structure which performs the cell evaluation as a whole by it, and while being able to quantify the quality of the cell used as evaluation object, the evaluation can be performed automatically and with high accuracy It is like that.

  The transition time of the state stage shown in FIG. 2 shows an example of the number of hours determined by general empirical rules. However, the transition time is not limited to the culture environment of the fertilized egg E (for example, medium components, temperature, humidity). Therefore, as a premise of the present embodiment, it is desirable to previously obtain the transition time in the actual culture environment by experiments. However, in this embodiment, it demonstrates based on said fiber time.

  Specifically, as shown in FIG. 1, the cell quality evaluation system 1 of the present embodiment is cultivated in each of a plurality of culture dishes (hereinafter referred to as “culture dishes”) 40-1 to 40-n. The camera 10 that images the fertilized eggs E1 to Ek (that is, the fertilized egg E) (k is, for example, 4) and generates a cell image, and controls the camera 10, and cell images based on each state stage And a server device 30 for evaluating the quality of the fertilized cells.

  The camera 10 is connected to the server device 30 directly or via a network (not shown), captures cells corresponding to each state stage defined by the time axis, and generates image data of cell images. .

  In particular, the camera 10 images the fertilized egg E cultured in the culture dish 40 at a predetermined timing based on control from the server device 30 to generate a still image or a moving image, and the generated cell image Is supplied to the server device 30 as image data.

  In order to realize this function, the camera 10 includes an objective lens, a flash, a shutter, and an optical system for adjusting the focus, zoom, and focus of the lens, and a CCDI sensor that converts an optical image input from the optical system into an electrical signal ( A Charge Coupled Device Image Sensor) unit, a generation unit that generates image data based on an electrical signal generated in the CCDI sensor unit, and a control signal from the server device 30 control each unit to display an image of the fertilized egg E. And a control unit for imaging.

  In addition, the camera 10 is good also as a structure which connects to the microscope which is not shown in figure using an adapter and an attachment, and images a microscope image.

  In this embodiment, the imaging timing of each state stage is, for example, “7 hours later”, “20 hours later”, “48 hours later”, “72” after insemination, as illustrated in FIG. It is set to “after time”, “after 90 hours”, “after 120 hours”, etc., and the camera 10 is controlled in accordance with the arrival of a predetermined timing under the control of the server device 30 (that is, a predetermined time from insemination). The fertilized egg E to be evaluated is imaged (based on the elapsed time).

  The server device 30 has various databases (hereinafter referred to as [DB]), and scores the cell quality in each state stage according to the information recorded in the DB, based on the cell image generated by the camera 10. Perform scoring to evaluate by.

In particular, the server device 30 includes:
(1) Control the camera 10 to obtain image data output from the camera 10;
(2) Scoring reference information serving as a reference when evaluating the quality of the fertilized egg E in each state stage based on the cell image of the image data corresponds to state stage identification information for identifying each state stage In addition, control the DB to be recorded,
(3) A scoring process for scoring the quality of the corresponding fertilized egg E based on the corresponding scoring reference information while performing predetermined image processing on the cell image for each state stage,
(4) According to the scoring result indicating the scored result, an evaluation process for evaluating superiority or inferiority of the fertilized egg E is performed.
(5) Present the evaluation result so that the user can view it,
It has a configuration.

  Then, the server device 30 causes the camera 10 to capture the fertilized egg E at different timings for each state stage to generate a cell image, and also applies the corresponding fertilized eggs based on a plurality of cell images having different timings for each state stage. It has a configuration for scoring the quality of E.

Specifically, the server device 30 performs the process (3) in conjunction with the control of the camera 10,
(3A) In order to evaluate the quality of the fertilized egg E in the first stage, the camera 10 is controlled about 7 hours after the insemination to image the fertilized egg E in the first stage, and the cell image is analyzed. Based on the state of the zona pellucida, plasma membrane and polar body, scoring the quality of the first stage fertilized egg E,
(3B) In order to evaluate the quality of the fertilized egg E in the second phase, the fertilized egg image in the second phase is captured by the camera 10 about 20 hours after fertilization, and the cell image is analyzed to determine the state of the pronucleus And scoring the quality of the fertilized egg E in the second phase,
(3C) In order to evaluate fertilized egg quality in the third stage, fertilized egg images of the third stage (early, middle and late) are obtained at each timing of about 48 hours, 72 hours and 90 hours after fertilization. The number of blastomeres (2 in principle, 4) indicating the number of cells (blastomeres) divided by the fertilized egg E in the third period (early period, middle period, and late period) while being imaged by the camera 10 and analyzing the cell image. Scoring the quality of the fertilized egg in the third stage based on
(3D) In order to evaluate the quality of the fertilized egg E in the 4th stage, the fertilized egg image in the 4th stage is captured by the camera 10 120 hours after insemination, and the cell image is analyzed to analyze the trophoblast cell Scoring the quality of the fertilized egg based on thickness and uniformity and the size or number of cells and clarity of the inner cell mass,
It has a configuration.

Further, the server device 30 performs the process (4) as follows:
(4A) Based on the sum of the scores scored for each state stage, it is determined whether or not a predetermined condition (first condition) is satisfied, and when the condition is not satisfied, As the superiority or inferiority of the cell quality, it is determined that the corresponding cell is unavailable, or
(4B) It is determined whether or not each score in each state stage has a predetermined condition (second condition) for each state stage, and if the condition is not satisfied, the corresponding cell Is determined to be unavailable,
It has a configuration.

  For example, the server device 30 determines whether or not the condition (4A) has a condition such as a predetermined threshold or more such as the sum, average, or mean square of the scores of all the state stages. . In this case, for example, only the scores in some state stages are high, and the overall score is low, so that cells that are not suitable for transplantation can be reliably excluded from the transplantation target.

  In addition, the server device 30 determines whether or not the condition (4B) includes a condition such that the score of each state stage is equal to or greater than a predetermined threshold value. In this case, for the fertilized egg E that is not highly evaluated in the most important initial state stage, even if the overall score is high and the transplantation requirement is satisfied, the cell is not suitable for transplantation from the transplant subject. It is possible to exclude it reliably.

  In addition, about the specific evaluation method of the fertilized egg E of this embodiment, it is arbitrary, for example, the said value is predetermined, taking the sum total of each score scored for every state stage, an average, a square mean, etc. May be evaluated as being usable for transplantation, and the final evaluation is performed by weighting the scores of each period according to the effect on the quality of the fertilized egg E You may do it.

  Moreover, when evaluating based on a one part score, for example, what is necessary is just to make final evaluation based on the score of the 1st period and 2nd period which have a big influence on the quality of the fertilized egg E. . However, in this embodiment, in order to make the description concrete, the description will be made assuming that the final evaluation is performed using the sum of scores in all the state stages.

[2] Server Device [2.1] Overall Configuration Next, the server device 30 according to the present embodiment will be described with reference to FIGS. FIG. 3 is a diagram illustrating the configuration of the server device 30 according to the present embodiment. FIGS. 4 to 6 illustrate the cultured cell management DB 301, the state stage management DB 302, and the scoring information provided in the server device 30, respectively. It is a figure which shows an example of the data recorded on DB303.

  As shown in FIG. 3, the server device 30 according to the present embodiment includes a recording device 300 provided with various DBs 301 to 303, an interface unit 310, a ROM (Read only Memory) / RAM (Random Access Memory) 320, Display unit 330, display control unit 340 for controlling image display on display unit 330, timer 360 for specifying the current time, server management control unit 370 for integrated control of the entire server device 30, and scoring processing And a data processing unit 380 that executes an evaluation process and the like, and an operation unit 390.

  These units are interconnected by a bus B, and data is transferred between the components via the bus B.

  The recording apparatus 300 is configured by an HDD (Hard Disc Drive) or an SSD (Solid State Drive). The recording apparatus 300 includes a cultured cell management DB 301, a state stage management DB 302, and a scoring information DB 303.

  For example, the scoring information DB 303 of this embodiment constitutes a recording unit of the present invention.

The cultured cell management DB 301 is a DB in which information (hereinafter referred to as “fertilized egg management information”) for managing the fertilized egg E being cultured in the culture dish 40 of the cell quality evaluation system 1 is recorded as data. It is. For example, in the cultured cell management DB 301, as shown in FIG.
(1) a culture petri dish ID for identifying each culture petri dish 40;
(2) a fertilized egg ID for identifying each fertilized egg E in culture;
(3) The date and time when each fertilized egg E was fertilized (hereinafter referred to as “fertilization date and time”);
(4) Each score calculated by scoring processing for each state stage of each fertilized egg E;
(5) an overall score showing scoring results in all state stages;
Are associated with each other.

  Note that each information of the culture petri dish ID, the fertilized egg ID, and the fertilization date recorded in the cultured cell management DB 301 is registered in advance by the user when the fertilized egg E is fertilized and the culture is started. Further, in the score of each state stage in (4), information indicating that an error (for example, a value indicating an error) is recorded when an error occurs because the score cannot be calculated as described later.

  For example, in FIG. 4, four fertilized eggs E corresponding to fertilized egg IDs “E001 to 004” are cultured in the culture petri dish 40 having the “D001” culture petri dish ID, and each state stage of each fertilized egg E is cultured. And the total score through all the state stages (in this embodiment, the sum of the scores) indicate the fertilized egg management information recorded in association with each other.

  In particular, in FIG. 4, the insemination date is “May 10, 2014, 13:00”, the first period score is “0 points”, the second period score is “10 points”, the third period The fertilized egg management information of the cell “E001” having a score of “12 points”, a fourth-phase score of “8 points”, and an overall score of “30 points” is recorded. An example is shown.

  FIG. 4 shows an example of recording information when four fertilized eggs E are cultured in each culture dish 40, but the number of cells cultured in one culture dish 40 is four. When the number of fertilized eggs is four or more, the data recording field may be added to the cultured cell management DB 301 as necessary.

  As for the score of the third period, comprehensive scores in a plurality of periods of the first period, the middle period and the latter period are recorded.

  The state stage management DB 302 is a DB for recording information (hereinafter referred to as “state stage management information”) for managing each state stage of the first to fourth periods generated in the fertilized egg E as data. It is.

For example, in the state stage management DB 302, as shown in FIG.
(1) a state stage ID for identifying each state stage of the fertilized egg E;
(2) a state stage name corresponding to the state stage ID;
(3) imaging timing for imaging the fertilized egg E in the state stage;
Are recorded in association with each other.

  In FIG. 5, state stage IDs “S001” to “S006” assigned to each of the first period to the fourth period and state stage names “first period” to “fourth” corresponding to each ID are shown. The period is recorded, and as an imaging timing of each state stage, an example is shown in which the time 1 hour before and 1 hour after the transition timing in the state stage is recorded as the imaging timing.

  In particular, FIG. 5 shows an example in which three timings “6, 7 and 8 hours later” are recorded as the imaging timing for “first period” of “S001”.

  The scoring information DB 303 is a DB in which scoring information used when executing the scoring process is recorded. For example, as shown in FIG. 6, the scoring information DB 303 is information necessary for scoring processing in each state stage in association with the state stage ID (that is, for each state stage). The scoring reference information indicating scoring criteria and scoring criteria for scoring in the process, and scoring information including an algorithm for performing the scoring process are recorded.

Specifically, the scoring information in the first period of this embodiment includes:
(1A) Determination to determine the presence or absence of a protoplasm, the presence or absence of a zona pellucida, the presence or absence of a zona pellucida and a plasma membrane, and the presence or absence of a polar body generated between the translucent body and the plasma membrane Standards and
(1B) a score value for each criterion,
(1C) Score correction values at a plurality of timings;
Is included.

In addition, as the score value included in the scoring information of this embodiment,
(1B-1) Score when there is no protoplasm (1B-2) Score when there is no zona pellucida (1B-3) There is a zona pellucida and a plasma membrane, and between the transparent body and the plasma membrane Score when there is no polar body (1B-4) When there is a zona pellucida and a plasma membrane, and there is a polar body generated between the transparent body and the plasma membrane, the number of polar bodies Score (1B-5) when there is one, and there is a zona pellucida and a plasma membrane, and there is a polar body generated between the transparent body and the plasma membrane, the number of polar bodies is 2 Score (1B-6) in the case of the individual When there is a zona pellucida and a plasma membrane, and there is a polar body generated between the transparent body and the plasma membrane, the number of polar bodies is 3 or more The score in the case of is used.

For example, in the scoring information of the present embodiment, as scoring reference information corresponding to the “first stage” state stage,
・ Score when there is no protoplasm: 0 point ・ Score when there is no zona pellucida: 0 point ・ There is zona pellucida and plasma membrane, and there is no polar body generated between the transparent body and the plasma membrane Case (case 3) score: 0 point, when there is a zona pellucida and a plasma membrane, and there is a polar body generated between the transparent body and the plasma membrane, the number of polar bodies is 1 Score in the case: 6 points-Score when the number of polar bodies is 2 when there is a zona pellucida and a plasma membrane and there is a polar body generated between the transparent body and the plasma membrane : 10 points / score when the zona pellucida and the plasma membrane are present, and there is a polar body generated between the transparent body and the plasma membrane, and the number of polar bodies is 3 or more: 0 Points are stored.

  In addition, as the score correction value at a plurality of timings in (1C), a value indicating the increase / decrease ratio of the score value is recorded. For example, when the standard timing of the first period is 7 hours later and the imaging timing is defined as 1 hour before and after the standard timing (that is, 6 hours and 8 hours later), correction of scores at a plurality of timings As the value, “0%” is recorded for each score after 7 hours, “20%” is recorded after 6 hours, and “−20%” is recorded after 8 hours.

  In the present embodiment, for example, when two polar bodies occur after 6 hours, the score value is corrected according to the imaging timing such as “12 points” and when 8 poles occur after 8 hours, “8 points” ( By increasing / decreasing), the score of the fertilized egg E having good growth can be set high, and the fertilized egg E having a high growth rate can be surely selected as the transplantation target.

In the scoring information in the second period of this embodiment,
(2A) criteria for determining the presence or absence of pronuclei inside the plasma membrane;
(2B) the score value for each criterion,
(2C) Score correction values at a plurality of timings;
Is included.

In addition, as the score value included in the scoring information of this embodiment,
(2B-1) Score when there is no pronucleus inside the plasma membrane (2B-2) Score when there is a pronucleus inside the plasma membrane and the number of the pronuclei is 1 (2B -3) Score when the pronucleus is present inside the plasma membrane and the number of the pronuclei is two (2B-4) When the pronucleus is present inside the plasma membrane and the previous The score when the number of nuclei is 3 or more is used.

For example, in the scoring information of the present embodiment, as scoring reference information corresponding to the “second stage” state stage,
・ Score when there is no pronucleus inside the plasma membrane: 0 point ・ Score when there is a pronucleus inside the plasma membrane and the number of the pronuclei is 1: 6 points ・ Plasma membrane Score when the pronucleus is present and the number of the pronuclei is 2: 10 points / when the pronucleus is present inside the plasma membrane and the number of the pronuclei is 3 or more Score in case of: -10 points are stored.

  Further, as the score correction values at a plurality of timings in (2C), a value indicating the increase / decrease ratio of the score value is recorded as in the first period. For example, when the standard timing of the second period is 20 hours later and 1 hour before and after the standard timing (that is, 19 hours and 21 hours later) is defined as the imaging timing, the correction of scores at a plurality of timings As the value, “0%” is recorded in each score after 20 hours, “20%” is recorded after 19 hours, and “−20%” is recorded after 21 hours.

  In the present embodiment, for example, when two pronuclei occur after 19 hours, “12 points” or when after 21 hours, “8 points”, the score value is determined according to the imaging timing. By correcting (increasing / decreasing), the score of the fertilized egg E having good growth can be set high, and the fertilized egg E having a high growth rate can be surely selected as the transplantation target.

In the scoring information in the first, middle and late period of the third period of this embodiment,
(3A) criteria for determining the presence or absence of a blast ball;
(3B) a score value with respect to the criterion,
(3C) Score correction values at a plurality of timings;
Is included.

In addition, as the score value included in the scoring information of this embodiment,
(3B-1) Score when there is no blast ball (3B-2) Score when there are fewer than the appropriate number (3B-3) Score when the number of blast balls is appropriate (3B-4) The score when is greater than the proper number is used.

For example, in the scoring information of the present embodiment, as scoring reference information corresponding to the “third stage” state stage,
-Score when there is no blast ball: -10 points-Score when the number of blast balls is a predetermined ratio (for example, 75%): 8 points-Number of blast balls is an appropriate number (for example, Score in the case of 2 in the first period, 4 in the middle period and 8 in the second period): 10 points.

  In addition, as the score correction values at a plurality of timings in (3C), values indicating the increase / decrease ratios of the score values are recorded as in the first and second periods. For example, the standard timing of the 3rd period is 1 hour before and after the standard timing of 48 hours, 72 hours and 90 hours after the standard timing (ie, 47 hours and 49 hours in the case of the first period). If the imaging timing is defined as 71 hours and 73 hours after the middle period, and 89 hours and 91 hours after the latter period, the correction of scores at a plurality of timings As the value, “0%” is recorded for each score after 48 hours in the previous term, “20%” is recorded after 47 hours, and “−20%” is recorded after 49 hours. Similar values are recorded in the middle and late periods.

  In the present embodiment, for example, in the case of the previous period, when two blast balls are generated after 47 hours, “12 points”, or when they are generated after 49 hours, “8 points”, the imaging timing is set. By correcting (increasing / decreasing) the score value, the score of the fertilized egg E having good growth can be set high, and the fertilized egg E having a high growth rate can be surely selected as a transplant target. It has become.

In the scoring information in the fourth period of this embodiment,
(4A) determination criteria for determining uniformity of trophoblast cell thickness, trophoblast cell thickness, inner cell mass size, inner cell mass clarity, and timing satisfying predetermined criteria;
(4B) a score value with respect to the criterion,
(4C) Score correction values at a plurality of timings;
Is included.

In addition, as the score value included in the scoring information of this embodiment,
(4B-1) Score of each grade of three grades (excellent, good, acceptable) in the thickness of trophoblast cells, and
(4B-2) Three grades (excellent, good, acceptable) in the size of the inner cell mass are used.

For example, in the scoring information of this embodiment, as scoring reference information corresponding to the state stage of “fourth period”,
-Score when the trophoblast cell thickness is assumed to be uniform and the number of cells is equal to or greater than a predetermined number: 5 points-The trophoblast cell thickness is assumed to be uniform and the cell count is a predetermined number Score less than 3 points: Score when out of the range where the trophoblast cell thickness is assumed to be uniform: 0 points. The size of the inner cell mass and the clarity on the image are each greater than or equal to a predetermined threshold Score in case: 5 points. When the size of the inner cell mass is less than a predetermined threshold and the clarity on the image is equal to or higher than the predetermined threshold: 5 points. The size of the inner cell mass is predetermined. The score when the clarity on the image is less than the predetermined threshold when the threshold is greater than or equal to the threshold: 3 points. The score when the size of the inner cell mass and the clarity on the image are each less than the predetermined threshold: 0 points Is memorized.

  Further, as the score correction values at a plurality of timings in (4C), as in the first period to the third period, a value indicating the increase / decrease ratio of the score value is recorded. For example, when the standard timing of the fourth period is 90 hours later and 1 hour before and after the standard timing (that is, 89 hours and 91 hours later) is defined as the imaging timing, the correction of scores at a plurality of timings As the value, “0%” is recorded in each score after 90 hours, “20%” is recorded after 89 hours, and “−20%” is recorded after 49 hours.

  In this embodiment, for example, after 90 hours, the trophoblast cell thickness is assumed to be uniform and the number of cells is a predetermined number or more, and the size of the inner cell mass and the image “12 points” is used as the score when the intelligibility is equal to or greater than a predetermined threshold value.

  The interface unit 310 is used for connecting to the camera 10 by wire or wireless using a communication standard such as USB (Universal Serial Bus), Ethernet (registered trademark), or IEEE802.11 wireless LAN (Local Area Network). It has a function.

  The interface unit 310 transmits a control signal for controlling the camera 10 by communicating with the connected camera 10 and receives image data output from the camera 10.

  For example, the interface unit 310 of the present embodiment constitutes an acquisition unit of the present invention together with the data processing unit 380.

  Various programs necessary for driving the server device 30 are recorded in the ROM / RAM 320. The ROM / RAM 320 is used as a work area when various processes are executed.

  The display unit 330 is configured by a panel of a liquid crystal element or an EL (Electro Luminescence) element, and displays a predetermined image based on display data generated by the display control unit 340. For example, the display unit 330 of the present embodiment constitutes the presenting unit of the present invention together with the display control unit 340.

  The display control unit 340 generates drawing data necessary for causing the display unit 330 to draw a predetermined image under the control of the server management control unit 370 and the data processing unit 380, and the generated drawing data is displayed on the display unit 330. Output to. For example, the display control unit 340 according to the present embodiment constitutes the presenting means of the present invention together with the display unit 330 in conjunction with the data processing unit 380.

  The timer 360 is used for managing the time necessary for managing each state stage.

  The server management control unit 370 is mainly configured by a central processing unit (CPU), and integrally controls each unit of the server device 30 by executing a program.

  The data processing unit 380 is configured by an independent central processing unit (CPU), or is configured using the central processing unit (CPU) of the server management control unit 370.

  In particular, the data processing unit 380 manages imaging of the fertilized egg E by the camera 10 by executing a program and an algorithm based on information recorded in each DB 301 to 303 under the control of the server management control unit 370. An imaging management unit 381, a cultured cell management unit 382 for managing each fertilized egg E cultured in the culture dish 40, and a first scoring process corresponding to each of the first to fourth periods A scoring processing unit 383, a second scoring processing unit 384, a third scoring processing unit 385, and a fourth scoring processing unit 386, and a fertilized egg evaluation unit 387 that executes an evaluation process of the fertilized egg E are realized. .

  Note that, for example, the imaging management unit 381 and the cultured cell management unit 382 of the present embodiment constitute the imaging control unit and the acquisition unit of the present invention in conjunction with the camera 10, and the first scoring processing units 383 to 4. The scoring processing unit 386 constitutes scoring means of the present invention. Further, for example, the fertilized egg evaluation unit 387 of the present embodiment constitutes the evaluation means of the present invention.

  The imaging management unit 381 outputs a control signal including setting values such as an imaging angle, a shutter speed, an exposure value, and an aperture to the camera 10 in order to cause the camera 10 to capture an image of the fertilized egg E to be evaluated. The image data of the cell image output from 10 is acquired. Then, the imaging management unit 381 records the acquired image data in the ROM / RAM 320 as data for scoring processing.

  Specifically, the imaging management unit 381 controls the camera 10 attached to the installation base having an angle changing function provided facing the culture dish 40 together with the installation base, and performs predetermined control. By outputting a signal to the camera 10, the shooting angle of the camera 10 is adjusted.

  The imaging management unit 381 determines the imaging timing according to the insemination date and time recorded in the cultured cell management DB 301, the imaging timing recorded in the state stage management DB 302 and the current date and time acquired by the timer 360. A predetermined control signal is output to the camera 10 at the imaging timing, and the fertilized egg E is imaged by the camera 10.

  Each of the first scoring processing unit 383 to the fourth scoring processing unit 386 performs scoring processing based on the cell image of the fertilized egg E in the corresponding state stage.

  In particular, the first scoring processing unit 383 to the fourth scoring processing unit 386 are applied to scoring of the corresponding state stage after the image data in the corresponding state stage is acquired by the camera 10 or at a predetermined timing. The scoring information to be read is read out from the scoring information DB 303, and scoring processing for performing scoring in each state stage is executed using the read scoring information.

  The details of each scoring process of the first scoring processing unit 383 to the fourth scoring processing unit 386 in the present embodiment will be described later.

  The fertilized egg evaluation unit 387 executes an evaluation process based on the score of each state stage recorded in the cultured cell management DB 301 or an evaluation process for evaluating the fertilized egg E based on the sum of the scores of all the state stages. Then, the result is recorded in the cultured cell management DB 301 and the cultured cell management DB 301 is updated.

  In addition, the fertilized egg evaluation unit 387 evaluates whether each fertilized egg is suitable for transplantation to the womb by comparing the total score with a predetermined first threshold value (first condition). The evaluation process is executed, and the evaluation result is displayed on the display unit 330 so as to be presented to the user. That is, the fertilized egg evaluation unit 387 evaluates that the fertilized egg is unusable for transplantation when the total score is lower than the first threshold, and evaluates that transplantation is possible when the total score is equal to or higher than the first threshold.

  In addition, for example, when a plurality of fertilized eggs E are cultured and the same processing is sequentially repeated for each fertilized egg E to perform scoring, the total score corresponding to each fertilized egg E is stored in the cultured cell management DB 301. Are stored, the fertilized egg evaluation unit 387 may sort the fertilized eggs E in descending order of the total score, and display them on the display unit 330 in the order of the high total score. In this case, a fertilized egg E that can be used for transplantation by the user can be freely selected and used for transplantation to the womb.

  The operation unit 390 includes various buttons, operation buttons for inputting operation commands, and a number of keys such as a numeric keypad. The operation unit 390 includes a touch sensor, a keyboard, and a mouse provided on the display unit 330, and performs each operation. When it comes to use.

[2.2] Scoring Processing Next, the first scoring processing unit 383, the second scoring processing unit 384, the third scoring processing unit 385, and the fourth score of the present embodiment will be described with reference to FIGS. Each scoring process executed in the ring processing unit 386 will be described.

[2.2.1] First Scoring Process First, the first scoring process executed by the first scoring processing unit 383 of the present embodiment will be described with reference to FIGS. 7 and 8. 7 and 8 are diagrams for explaining the scoring process in the first period executed by the first scoring processing unit 383. FIG.

  The first scoring processing unit 383 acquires scoring information (including scoring reference information and an algorithm) in the first period recorded in the scoring information DB 303 and the cell image acquired by the imaging management unit 381. Then, the state stage performs predetermined image processing on the first-stage cell image, and performs scoring of the fertilized egg E in the cell image.

  Specifically, the first scoring processing unit 383 uses, as the cell image, the cell image at the first stage state stage, that is, the cell image at the time when 6 hours, 7 hours, and 8 hours have passed since fertilization. .

  Then, the first scoring processing unit 383, as the predetermined image processing, detects an object imaged by detecting a pixel in which a color feature amount such as luminance is discontinuously changed in each cell image. An edge detection process for detecting an edge and a threshold process for generating a mask image of the plasma membrane by binarizing with a predetermined threshold, and performing plasma membrane in the fertilized egg E imaged in a cell image, transparent Detect body and polar body.

  In addition, the first scoring processing unit 383 performs scoring on each cell image according to the presence / absence, position and number of the plasma membrane, transparent body and polar body, and a plurality of cells such as an average or a sum total in each cell image The first period score using the image is determined.

  For example, in the case of the cell image of the fertilized egg E in the first stage state stage as shown in FIG. 7A, the first scoring processing unit 383 performs edge detection processing (FIG. 5) based on the preconditions. [1-1]) to generate an edge image (see FIG. 7B), and threshold processing ([1-2] in FIG. 5) to execute a mask image of the plasma membrane (see FIG. 5). 7 (C)).

Note that the preconditions include conditions for detecting the plasma membrane and polar body, that is,
(A) A parameter (hereinafter referred to as “parameter”) indicating a value from the minimum value to the maximum value (OR (min) to OR (max)) of the radius of the plasma membrane in advance OR,
(B) A parameter (hereinafter referred to as “parameter”) PR1 indicating a value from the minimum value to the maximum value of the polar body radius (PR1 (min) to PR1 (max)), and (C) a plasma image of the plasma membrane The condition that it exists near the center of
In the present embodiment, each numerical value and condition are defined in the algorithm.

  Further, since the edge detection process is the same as the conventional one, its details are omitted. In addition, the threshold processing may be performed by, for example, setting a threshold value in advance for the luminance value of a pixel and generating a binary image in which pixels whose luminance is equal to or lower than the threshold value are black.

  Furthermore, if the first scoring processing unit 383 cannot detect the plasma membrane, the polar body, and both based on the above preconditions, the first scoring processing unit 383 indicates an error with respect to the corresponding cell image as error processing. Information (for example, information indicating an error) is registered in the state stage management DB 302.

  On the other hand, when both the plasma membrane and the polar body can be detected, the first scoring processing unit 383 applies a mask image of the plasma membrane from the edge image obtained by the polar body edge detection process to perform edge processing. A removal process ([1-3] in FIGS. 7 and 8) for removing the edge portion of the zona pellucida from the image is executed, and an edge image as shown in FIG. 8A (hereinafter referred to as “plasma membrane edge image”) Is generated).

  In the present embodiment, if circle detection such as Hough transform is simply performed on the edge image, there is a possibility that a lot of noise is generated. Therefore, in order to limit the search range in circle detection in advance, the first score The ring processing unit 383 detects the plasma membrane, extracts edges around the boundary of the mask image, and generates a plasma membrane edge image excluding the zona pellucida.

  Then, the first scoring processing unit 383 performs Hough transform as circle detection on the plasma membrane edge image based on the parameter OR indicating the radius of the plasma membrane ([1-4] in FIG. 8), An edge image of a polar body (hereinafter referred to as “polar body edge image (FIG. 8)” is detected by detecting the edge of the plasma membrane included in the plasma membrane edge image and excluding the edge of the plasma membrane from the plasma membrane edge image. (See (B)) ”).

  Further, as shown in FIG. 8C, the first scoring processing unit 383 performs Hough transform as circle detection on the polar body edge image based on the polar body radius parameter PR1 (see FIG. 8). [1-5]), the polar body is extracted while removing noise.

  On the other hand, when the first scoring processing unit 383 extracts polar bodies, the first scoring processing unit 383 determines the score of the first period based on the number of extracted polar bodies.

In particular, the first scoring processing unit 383 has a normal state in which there are two polar bodies derived from an ovum and a polar body derived from a sperm,
(A) When there are two polar bodies, “10 points”,
(B) When there are three polar bodies, “0 point”,
(C) When there is only one polar body, “5 points” and
(D) When the number of polar bodies is zero, “0 point”,
And scoring.

  In the case of (B) above, it is determined that the sperm is fertilized with two sperm in one egg, which is not normal, and in the case of (C), the insemination fails. Since the polar bodies may appear to overlap each other depending on the imaging angle, the above-described score is given.

  In the case of (D), for example, an error occurs when generating an edge image or mask image of the plasma membrane.

[2.2.2] Second Scoring Process First, a second period scoring process executed in the second scoring processing unit 384 of the present embodiment will be described with reference to FIGS. 9 and 10. 9 and 10 are diagrams for explaining the scoring process in the second period that is executed in the second scoring processing unit 384. FIG.

  The second scoring processing unit 384 acquires scoring information (including scoring reference information and algorithm) in the second period recorded in the scoring information DB 303, and in the same way as in the first period, the imaging management unit 381, the state stage performs predetermined image processing on the second-stage cell image, and performs scoring of the fertilized egg E in the cell image.

  Specifically, the second scoring processing unit 384 uses an image of a fertilized egg E that has become a pronuclear stage embryo (or a fertilized egg E that is assumed to be the pronuclear stage embryo), and a cell As the image, a cell image at the state stage of the second phase, that is, a cell image at the time when 19 hours, 20 hours, and 21 hours have passed since fertilization is used.

  Then, as the predetermined image processing, the second scoring processing unit 384 detects the pixels imaged by detecting pixels in which the color feature amount such as luminance discontinuously changes in each cell image. An edge detection process for detecting an edge and a threshold process for binarizing with a predetermined threshold value to generate a mask image of the plasma membrane, and performing plasma membrane and pole in the fertilized egg E imaged in a cell image Detect body and pronucleus.

  The second scoring processing unit 384 performs scoring on each cell image based on the presence / absence, position and number of the plasma membrane, polar body, and pronucleus, and a plurality of cells such as an average or total sum in each cell image. A score for the second period using the image is determined.

  For example, in the case of the cell image of the fertilized egg E in the second stage state stage as shown in FIG. 9A, the second scoring processing unit 384, based on the preconditions, as in the first stage. Then, edge detection processing ([2-1] in FIG. 9) is executed to generate an edge image (see FIG. 9 (B)), and threshold processing ([2-2] in FIG. 9) is executed to perform original processing. A plasma membrane mask image is generated as a first mask image (see FIG. 9C).

  Then, unlike the first period, the second scoring processing unit 384 executes filter processing using a non-linear filter such as morphological processing on the first mask image due to the positional characteristics of the plasma membrane. The degeneration process is executed ([2-3] in FIG. 9) to generate a second mask image (see FIG. 9D).

  The preconditions for the second period include parameters (hereinafter referred to as “parameters”) indicating values (PR2 (min) to PR2 (max)) from the minimum value to the maximum value of the pronuclear radius in addition to the first preconditions. In this embodiment, each numerical value and condition are defined in the algorithm.

  Further, for example, since the plasma membrane is often present at the center of the cell and rarely touches the boundary, the second scoring processing unit 384 generates the second mask image by the above-described filtering process. doing.

  Furthermore, when the second scoring processing unit 384 cannot detect the plasma membrane, polar body, pronucleus, and any of them based on the above preconditions, the second scoring processing unit 384 performs error processing on the corresponding cell image. Then, information indicating an error (for example, information indicating an error) is registered in the state stage management DB 302.

  On the other hand, the second scoring processing unit 384 applies the second mask image of the plasma membrane from the edge image obtained by the edge detection processing when any of the plasma membrane, polar body, and pronucleus can be detected. Then, as in the first period, a removal process ([2-4] in FIGS. 9 and 10) for removing the edge portion of the zona pellucida from the edge image is executed, and the protoplasm as shown in FIG. A membrane edge image is generated.

  In the present embodiment, if circle detection such as Hough transform is simply performed on the edge image, there is a possibility that a lot of noise is generated. Therefore, a search range for detecting a pronucleus existing in the plasma membrane is set in advance. Therefore, the plasma membrane is detected, the inside of the pronuclear second mask image is extracted, and a plasma membrane edge image excluding the zona pellucida is generated.

  Then, the second scoring processing unit 384 performs Hough transformation (circle transformation) as circle detection on the plasma membrane edge image based on the parameter OR indicating the radius of the plasma membrane ([2- in FIG. 10). 5]), an edge image of only the pronucleus in which the edge of the plasma membrane included in the plasma membrane edge image is detected and the edge of the plasma membrane is excluded from the plasma membrane edge image (hereinafter referred to as “pronuclear edge”). An image (referred to as “FIG. 10B”) is generated.

  Further, the second scoring processing unit 384 performs Hough transform as circle detection on the previous edge image based on the polar body radius parameter PR1 and the anterior nucleus radius parameter PR2, and removes the anterior nucleus while removing noise. Extract ([2-6] in FIG. 10).

  On the other hand, when the second scoring processing unit 384 extracts the polar body and the pronucleus, the second scoring processing unit 384 determines the score of the second period based on the number of the extracted polar bodies and the pronuclei.

In particular, the second scoring processing unit 384 is normally fertilized and generates one each from an egg-derived pronucleus and polar body, and one each from a sperm-derived pronucleus and polar body (ie, polar body and pronucleus). Is a normal state in which there are two, two in total,
(A) If there are 2 polar bodies and 2 pronuclei (ie, 4), “10 points”
(B) If there are two polar bodies and one pronucleus, “5 points”
(C) When there is one polar body and three pronuclei, “−10 points”, and
(D) Otherwise, “0 point”,
And scoring.

  In the case of (B), not only fertilization has failed, but also when insemination has failed, there is a possibility that polar bodies overlap each other depending on the imaging angle. Therefore, the above score is given.

  In addition, if the number of polar bodies and pronuclei that are actually generated is only one, the score in the subsequent state stage will be low, so even if a score of about “5 points” is given as described above The quality of the fertilized egg E can be determined based on the scores throughout the whole period.

[2.2.3] Third Scoring Processing Next, the third scoring processing executed in the third scoring processing unit 385 of the present embodiment will be described with reference to FIGS. 11 to 13. . 11 to 13 are diagrams for explaining the scoring process in the third period executed by the third scoring processing unit 385.

  In the scoring process of the third period of the present embodiment, as will be described later, the third period is divided into three state stages. However, the third scoring processing unit 385 has a score in one state stage. The ring process may be executed, or the scoring process in four or more state stages may be executed, and the number of state stages is determined based on the type of cell for which quality evaluation is performed and other environmental conditions.

  The third scoring processing unit 385 acquires scoring information (including scoring reference information and algorithm) in the third period recorded in the scoring information DB 303, and similarly to the first period and the second period. The scoring of the fertilized egg E in the cell image, which is a cell image acquired by the imaging management unit 381, is performed on the cell image in the third stage in the state stage.

  In particular, the third scoring processing unit 385 divides the third period into a plurality of stages, and performs predetermined image processing for each divided stage (hereinafter referred to as “state division stage”), Scoring of the fertilized egg E in the cell image is executed.

  Specifically, the third scoring processing unit 385 is a fertilized egg E (or a fertilized egg assumed to be an embryo of these two-cell embryo, four-cell embryo and 8-cell follicle stage). As described above, the divided state stage is divided into three divided state stages as the first period, the middle period, and the second period, and the cell image is a cell image in each divided state stage in the third period. That is, in the case of the first period, cell images at the time when 47 hours, 48 hours and 49 hours have elapsed since fertilization, and in the case of the middle period, the cell images at the time when 71 hours, 72 hours and 73 hours have elapsed since fertilization In the later stage, cell images at the time when 89 hours, 90 hours, and 91 hours have passed since fertilization are used.

  Then, the third scoring processing unit 385 includes, as predetermined image processing, contour detection processing for detecting the contour in the zona pellucida in each cell image for each divided state stage of the first term, the middle term, and the latter term, The number of concave points detection process for detecting the number of concave points of the detected contour is executed, and the number of cells formed in the zona pellucida in the fertilized egg E imaged in the cell image is detected.

  In addition, the third scoring processing unit 385 performs scoring on each cell image according to the number of cells, that is, the number of blastomeres, and uses a plurality of cell images such as an average or a sum in each cell image. The score in each divided state stage is determined, and further, the score of the entire third period is calculated based on the average or sum of the scores in the first, middle, and late periods.

  In the scoring process in the third period of the present embodiment, the number of cells to be detected in the first period, the middle period, and the second period is only 2, 4, and 8, which are different from each other. The ring process will be described, and the description of the scoring process in the middle and late periods will be omitted.

For example, in the case of the cell image of the fertilized egg E in the third stage state stage as shown in FIG. 11 (A), the third scoring processing unit 385
(1) An edge extraction image (see FIG. 11B) is generated by performing edge detection processing ([3-1] in FIG. 11) as in the first period and the second period,
(2) A small edge having a predetermined length or less is deleted as noise from the edge extracted image ([3-2] in FIG. 11) to generate a small edge deleted image (see FIG. 11C).
(3) An unnecessary region edge is deleted from a small edge deletion image using a predetermined mask image (a mask image for detecting a region within a certain range from the center of the cell image) (see FIG. 11). [3-3]), generating a main edge image (see FIG. 11D) in which an edge having a length equal to or shorter than a predetermined length is deleted and a main edge is extracted;
(4) Binarization processing for determining a threshold value when binarizing with the main edge as a boundary and binarizing the edge extraction image based on the determined threshold value ([3-4] in FIGS. 11 and 12) To generate a binarized image (see FIG. 12A),
(5) Correction processing such as degeneration processing and expansion processing for forcibly binarizing the inner pixel and the outer pixel in contact with the main edge with respect to the generated binarized image ([[ 3-5]) to generate a corrected image (see FIG. 12B),
(6) The binarized boundary line of the generated corrected image is detected as an outline ([3-5] in FIG. 12).
Each process of the contour detection process is executed to generate a contour image (see FIG. 12C).

  On the other hand, when generating the contour image, the third scoring processing unit 385 calculates a curvature for each predetermined length with respect to the contour, and the value is negative as shown in FIGS. 13 (A) and 13 (B). Is detected as the number of cells. That is, in the fertilized egg E, the number of indentations is proportional to the number of blastomeres. If there are 2 indentations, the number of blastomeres is “2”, and if there are 3 indentations, the number of blastomeres is “4”. Therefore, the third scoring processing unit 385 can specify the number of blast balls generated according to the number of concave points.

  In FIGS. 13A and 13B, the horizontal axis indicates the distance from the starting point of curvature calculation, and the vertical axis indicates the curvature. Further, in the example of FIG. 13, since two concave points are shown, in this case, the number of cells is “2”.

  Further, when detecting the number of cells, the third scoring processing unit 385 divides the number of indentations assumed from the number of indentations in order to determine the size uniformity in the cell portion of the cell image based on the detected number of indentations. An ellipse that corrects the ellipticity of the divided area using an edge other than the main edge detected by the edge detection process (for example, an edge deleted near the main edge) while performing a segmentation process for determining the area The number of cells may be corrected while executing the fitting process to correct the contour image.

  On the other hand, when detecting the number of cells, the third scoring processing unit 385 determines the score of the third period based on the detected number of cells.

In particular, the third scoring processing unit 385 assumes that it is normal that there are two blastomeres in the previous period.
(A) If there is one identified number of blastomeres, 6 points (B) If there are two identified number of blastomeres, 10 points,
(C) If there are three identified blasts, 12 points,
(D) If there are four or more specified blastomeres, scoring is performed with 0 points.

  In the case of (A) above, there is a possibility that the growth is slow, and a score is given in consideration of that case, and in the case of (C), there is a possibility that the growth is fast, In the case of 4 or more, there is a high possibility that the size of the blast ball is uneven and there is a high possibility that the grade is low. It is attached.

  The case (D) includes, for example, a case where an error occurs during the edge detection process or the number of concave points detection process.

Furthermore, the third scoring processing unit 385 assumes that the number of blastomeres is 4 and 8 in each of the middle and late stages.
(A) When the specified number of blastomeres is 2 or less, or 6 and 7 or less, 6 points (B) When the specified number of blastomeres is 4 or 8, 10 points,
(C) If the specified number of blastomeres is 8 or 16, 12 points,
(D) If the specified number of blastomeres is 10 or more, or 20 or more, scoring is performed with 0 points.

[2.2.4] Fourth Scoring Processing Next, the fourth scoring processing executed in the fourth scoring processing unit 386 of the present embodiment will be described with reference to FIGS. 14 and 15. 14 and 15 are diagrams for explaining the scoring process in the fourth period executed by the fourth scoring processing unit 386. FIG.

  The fourth scoring processing unit 386 acquires scoring information (including scoring reference information and algorithm) in the fourth period recorded in the scoring information DB 303, and is similar to the first to third periods. The scoring of the fertilized egg E in the cell image, which is a cell image acquired by the imaging management unit 381, is performed on the cell image of the fourth stage in the state stage.

  Specifically, the fourth scoring processing unit 386 is a fertilized egg that is assumed to be a fertilized egg E (or a blastocyst stage embryo (transplanted embryo) that has become a blastocyst stage embryo (transplanted embryo). The image of the egg E) is used, and as the cell image, a cell image in the fourth stage state stage, that is, a cell image when 199 hours, 120 hours, and 121 hours have passed since fertilization is used.

  Then, the fourth scoring processing unit 386 performs image processing for determining trophoblast cells formed in the blastocyst shown in FIG. Trophoblast cell determination image processing ”) and image processing for determining the inner cell mass formed in the blastocyst stage embryo (hereinafter referred to as“ inner cell mass determination image processing ”). Then, the quality of trophoblast cells and inner cell mass in the fertilized egg E imaged in the cell image is detected.

  In addition, the fourth scoring processing unit 386 performs scoring based on the quality of the trophoblast cells and inner cell mass, and calculates a score of the fourth period using a plurality of cell images such as an average or a sum in each cell image. decide.

  For example, in the case of the cell image of the fertilized egg E in the fourth stage state stage as shown in FIG. 14 (A), the second scoring processing unit 384, based on the preconditions, as in the other stages. Then, the edge detection process is performed to detect the embryo (images [4-1] and (B) in FIG. 14), and the uniformity of the trophoblast cell thickness is evaluated ([4- in FIG. 14]). 2]), the evaluation result of the trophoblast cell is obtained.

  That is, the second scoring processing unit 384 detects the edge of the embryo part by executing the edge detection process, and based on the degree of coincidence with the ideal texture created in advance, or the edge of the embryo part While detecting the trophoblast cell part from the brightness value adjacent to the inside, the thickness is detected, and the thickness is compared with the thickness range (optimal range) determined by the precondition, Evaluate membrane cells.

  Specifically, when using an ideal texture created in advance, the second scoring processing unit 384 uses a brightness value filter created according to good, good, or bad, and the detected embryo part. The histograms of the luminance values of the respective pixels are compared with each other to calculate the degree of coincidence with the ideal texture, and the evaluation of the filter having the highest degree of coincidence is determined as the evaluation of the cell image.

  In addition, when the second scoring processing unit 384 evaluates from the brightness value adjacent to the inside of the edge of the embryo part, the average value of the total thickness of the trophoblast cells is within the optimum range, or And determining whether there is a thicker portion than the optimum range and, for example, executing the number-of-concaves detection process in the third period to detect the number of indentations in trophoblast cells, and whether the number is within a predetermined range The thickness of the trophoblast cell is evaluated in three stages: good, good, and bad.

  In particular, when the fourth scoring processing unit 386 evaluates from the luminance value adjacent to the inside of the edge, the range of luminance values regarded as trophoblast cells (ie, corresponding to the thickness of the trophoblast cells) is optimal. If it is uniform within the range, it is judged as “good”. If it is not within the optimum range but is within the predetermined range, it is judged as “good”, otherwise it is judged as “bad”. To do.

  The fourth scoring processing unit 386 may use other image processing as long as the trophoblast cell thickness can be detected to be uniform within a predetermined range.

  On the other hand, when the fourth scoring processing unit 386 detects the embryo by the edge detection process ([4-1] in FIG. 14), the fourth scoring processing unit 386 evaluates the clarity (concentration) of the inner cell mass (the clarity of FIG. 14). Evaluation [4-3]) to obtain the evaluation result of the inner cell mass.

  That is, when the fourth scoring processing unit 386 performs the edge detection process to detect the edge of the embryo part, as shown in FIG. 15, a predetermined condition is set for the luminance value of each pixel existing inside the edge. The detected pixels are detected as pixels constituting the inner cell mass, and the luminance values of the detected pixels are further histogrammed, and three levels of good, good, and bad hiss and gram that are converted into data as preconditions in advance. The inner cell mass is evaluated by comparing the data with the histogram data.

  Note that the three-stage hiss and gram data of good, good, and bad that have been converted into data as preconditions in advance are those generated by machine learning such as a support vector machine.

  Further, for example, in the present embodiment, the fourth scoring processing unit 386, when the internal cell mass hiss and gram data are within the range assumed to be the same or the same as the data determined to be “good”. If it is judged as “good” and the histogram and the gram data of the inner cell mass are within the range assumed to be the same or the same as the data judged as “good”, it is judged as “good” and the inner cell mass If the hiss and gram data are within the range assumed to be the same or the same as the data determined to be “bad”, it is determined to be “bad”.

  On the other hand, when the fourth scoring processing unit 386 detects the trophoblast cell and the inner cell mass, the fourth scoring processing unit 386 determines the score of the fourth period based on each evaluation of the detected trophoblast cell and the inner cell mass. In particular, the fourth scoring processing unit 386 determines a score according to the combination of each three-stage evaluation of the trophoblast cell and the inner cell mass.

  For example, the fourth scoring processing unit 386 determines the score by setting “good” as one “5 points”, “possible” as one “3 points”, and “bad” as one “0 points”.

[3] Operation of Cell Quality Evaluation System Next, the operation of the cell quality evaluation system 1 of the present embodiment will be described with reference to FIGS. 16 to 19 are flowcharts showing scoring processes executed in the first period to the fourth period, respectively.

  In this operation, it is assumed that the data shown in FIGS. 5 and 6 are already recorded in the state stage management DB 302 and the scoring information DB 303, and no information is registered in the cultured cell management DB 301. It shall be.

  In this operation, a plurality of cell images obtained by imaging the fertilized egg E three times in each state stage are used, and the average value is used as the score of each state stage.

[3.1] Operation start and scoring process in the first period First, after the sperm and eggs are collected from the patient by the user and the operation for insemination is completed, the cultured cell management unit 382 operates the operation unit 390. When an input operation for registering the fertilization date of the fertilized egg E, the culture petri dish ID, and the fertilized egg ID is detected (step Sa101), the input information is recorded in the ROM / RAM 320 and stored in the cultured cell management DB 301. The information is recorded (step Sa102).

  Next, the imaging management unit 381 reads the imaging timing from the state stage management DB 302 and records it in the ROM / RAM 320 (step Sa103), and outputs a control signal to the timer 360 to start measuring elapsed time (step Sa104). .

  Next, the imaging management unit 381 compares the elapsed time being measured by the timer 360 and the imaging timing recorded in the ROM / RAM 320, and determines whether or not the first period imaging timing has arrived (step Sa105). .

  At this time, when detecting the imaging timing, the imaging management unit 381 outputs a control signal to the camera 10, causes the fertilized egg E to be imaged, and acquires image data corresponding to the cell image from the camera 10 (step Sa106). Note that the imaging management unit 381 records the acquired image data in the ROM / RAM 320.

  Next, the imaging management unit 381 determines whether or not the first period imaging has been completed (step Sa107). At this time, the imaging management unit 381 proceeds to the process of step Sa105 when the first period imaging is not completed, and when it is determined that all the first period imaging is completed, the step Sa108 is performed. Move on to processing.

  The imaging management unit 381 repeats the processing of steps Sa105 to 107, so that images of the fertilized egg E are captured at each elapsed time of 6 hours, 7 hours, and 8 hours, and sequentially corresponds to the ROM / RAM 320. The image data to be recorded is recorded.

  Next, when it is determined that the imaging of the first period has been completed, the first scoring processing unit 383 reads the scoring reference information corresponding to the first period from the scoring information DB 303 (step Sa108).

  Next, the first scoring processing unit 383 executes the first period scoring process on the image data recorded in the ROM / RAM 320 according to the read scoring reference information and algorithm, and calculates the first period score. The determined first period score is recorded in the corresponding area of the cultured cell management DB 301 (step Sa109).

  Specifically, the first scoring processing unit 383 detects the number of polar bodies included in each cell image based on the algorithm of the first period, and based on the number of polar bodies in each cell image and the scoring reference information, The score of the first period is determined while determining the score of each cell image. Further, the first scoring processing unit 383 sets the score values according to the growth rate of the fertilized egg E, that is, according to the time reception when two polar bodies are generated, for example, “+ 20%”, “0%”. ”And“ −20% ”, the score of the first period is changed.

  Next, the first scoring processing unit 383 determines whether or not the calculated score of the first period exceeds the second threshold (step Sa110). At this time, if the first scoring processing unit 383 determines that the score of the first period is lower than the second threshold value, it determines that the fertilized egg E is not suitable for transplantation, and the second and subsequent periods The process is terminated without scoring. In addition, when the first scoring processing unit 383 determines that the score of the first period has exceeded the second threshold, the first scoring processing unit 383 proceeds to the process of step Sb101 in order to execute the scoring process of the second period. .

  In this operation, since the score of the first stage greatly affects the quality of the fertilized egg E, the second threshold is set to “10 points or more”, for example. In addition, by executing such a process, when the score of the first period, which has a large influence on the quality of the fertilized egg E, falls below the second threshold, the fertilized egg E is not usable for transplantation. By determining, it is possible to omit the processing after the second period and reduce the calculation burden of the scoring process.

[3.2] Second Period Scoring Process First, the imaging management unit 381 reads the imaging timing of the second period from the state stage management DB 302 and records it in the ROM / RAM 320 (step Sb101).

  Next, the imaging management unit 381 compares the elapsed time being measured by the timer 360 with the imaging timing recorded in the ROM / RAM 320, and determines whether or not the second period imaging timing has come (step Sb102). ).

  At this time, when detecting the imaging timing, the imaging management unit 381 outputs a control signal to the camera 10, causes the fertilized egg E to be imaged, and acquires image data corresponding to the cell image from the camera 10 (step Sb103). Note that the imaging management unit 381 records the acquired image data in the ROM / RAM 320.

  Next, the imaging management unit 381 determines whether or not the second period imaging has been completed (step Sb104). At this time, the imaging management unit 381 proceeds to the process of step Sb102 when the second period imaging is not completed, and when it is determined that the second period imaging is completed, the step Sb105 is performed. Move on to processing.

  Note that the imaging management unit 381 repeats the processes of steps Sb102 to S104, so that images of the fertilized egg E are captured at each elapsed time of 19 hours, 20 hours, and 21 hours, and sequentially stored in the ROM / RAM 320. Record the corresponding image data.

  Next, when the second scoring processing unit 384 determines that all imaging in the second period has been completed, the second scoring processing unit 384 reads the scoring reference information corresponding to the second period from the scoring information DB 303 (step Sb105).

  Next, the second scoring processing unit 384 executes the second period scoring process on the image data recorded in the ROM / RAM 320 according to the read scoring reference information and algorithm, and calculates the second period score. The determined second period score is recorded in the corresponding area of the cultured cell management DB 301 (step Sb106).

  Specifically, the second scoring processing unit 384 detects the number of polar bodies and pronuclei included in each cell image based on the second-phase algorithm, and the number of polar bodies and the number of pronuclei in each cell image And the score of a 2nd period is determined, determining the score of each cell image based on scoring reference | standard information. In addition, the second scoring processing unit 384 sets the score values according to the growth rate of the fertilized egg E, that is, according to the time when two polar bodies and pronuclei are generated, for example, “+ 20%”, “ The score of the second period is changed as “0%” and “−20%”.

  Next, the second scoring processing unit 384 determines whether or not the calculated second-term score exceeds a third threshold (step Sb107). At this time, if the second scoring processing unit 384 determines that the score of the second period is lower than the third threshold, it determines that the fertilized egg E is not suitable for transplantation, and the third and subsequent periods. The process is terminated without scoring. Further, when the second scoring processing unit 384 determines that the score of the second period has exceeded the third threshold value, the second scoring processing unit 384 proceeds to the process of step Sc101 in order to execute the scoring process of the third period. .

  In this operation, since the score of the second period greatly affects the quality of the fertilized egg E as in the first period, the third threshold is set to “10 points or more”, for example. In addition, by executing such processing, when the score of the second period, which has a large effect on the quality of the fertilized egg E, falls below the third threshold, the fertilized egg E is not usable for transplantation. By determining, it is possible to omit the processing after the third period and reduce the calculation burden of the scoring process.

[3.3] Scoring Process in Third Period First, the imaging management unit 381 reads out the imaging timing of the third period from the state stage management DB 302 and records it in the ROM / RAM 320 (step Sc101).

  Next, the imaging management unit 381 compares the elapsed time being measured by the timer 360 with the imaging timing recorded in the ROM / RAM 320 and determines whether or not the third imaging timing has come (step Sc102). ).

  At this time, when detecting the imaging timing, the imaging management unit 381 outputs a control signal to the camera 10, causes the fertilized egg E to be imaged, and obtains image data corresponding to the cell image from the camera 10 (step Sc103). Note that the imaging management unit 381 records the acquired image data in the ROM / RAM 320.

  Next, the imaging management unit 381 determines whether or not the third period imaging has been completed (step Sc104). At this time, if all of the third period imaging has not been completed, the imaging management unit 381 proceeds to the process of step Sc102, and if it is determined that all of the third period imaging has been completed, step Sc105. Move on to processing.

  The imaging management unit 381 repeats the processes of steps Sc102 to Sc104, so that an image of the fertilized egg E is captured at each elapsed timing in each divided state stage in the first, middle, and late stages, and is stored in the ROM / RAM 320. The corresponding image data is recorded sequentially.

  Next, if the third scoring processing unit 385 determines that all the imaging in the third period has been completed, the third scoring processing unit 385 reads out the scoring reference information corresponding to the third period from the scoring information DB 303 (step Sc105).

  Next, the third scoring processing unit 385 executes the third term scoring process on the image data recorded in the ROM / RAM 320 according to the read scoring reference information and algorithm, and calculates the third term score. The determined third stage score is recorded in the corresponding area of the cultured cell management DB 301 (step Sc106).

  Specifically, the third scoring processing unit 385 detects the number of blastomeres included in each cell image for each divided state stage, that is, in each of the first, middle, and second periods, based on the third period algorithm. Based on the number of blastomeres and scoring reference information, the score of each cell image is determined, and the respective scores of the first, middle, and latter periods are determined. In addition, the third scoring processing unit 385 corresponds to the growth rate of the fertilized egg E, that is, the prescribed number of blastomeres generated in each divided state stage (2 in the first period, 4 in the middle period, and 8 in the second period). The score of the third period is changed, for example, by setting the score value to “+ 20%”, “0%”, “−20%” in accordance with the time to reach the number of items. And the 3rd scoring process part 385 averages the score of each division | segmentation state stage, and determines the score of the whole 3rd period.

  Next, the third scoring processing unit 385 determines whether or not the calculated third-period score exceeds the fourth threshold value (step Sc107). At this time, if the third scoring processing unit 385 determines that the score of the third period is lower than the fourth threshold value, the third scoring processing unit 385 determines that the fertilized egg E is not suitable for transplantation, and the third and subsequent periods The process is terminated without scoring. In addition, when the third scoring processing unit 385 determines that the score of the third period has exceeded the fourth threshold value, the third scoring processing unit 385 proceeds to the process of step Sd101 in order to execute the scoring process of the fourth period. .

  In this operation, by performing such a process, when the score of the third period falls below the fourth threshold, it is determined that the fertilized egg E is not usable for transplantation. It is possible to omit the processing after the fourth period and reduce the calculation burden of the scoring process.

[3.4] Fourth Scoring Process and Comprehensive Evaluation of Fertilized Egg First, the imaging management unit 381 reads the imaging timing of the fourth period from the state stage management DB 302 and records it in the ROM / RAM 320 (step Sd101). .

  Next, the imaging management unit 381 compares the elapsed time being measured by the timer 360 with the imaging timing recorded in the ROM / RAM 320, and determines whether or not the fourth imaging timing has come (step Sd102). ).

  At this time, when detecting the imaging timing, the imaging management unit 381 outputs a control signal to the camera 10, causes the fertilized egg E to be imaged, and acquires image data corresponding to the cell image from the camera 10 (step Sd103). Note that the imaging management unit 381 records the acquired image data in the ROM / RAM 320.

  Next, the imaging management unit 381 determines whether or not the fourth period imaging has been completed (step Sd104). At this time, the imaging management unit 381 proceeds to the process of step Sd102 when all of the fourth period imaging is not completed, and when it is determined that all of the fourth period imaging is completed, the step Sd105. Move on to processing.

  Note that the imaging management unit 381 repeats the processing of steps Sd102 to S104, so that an image of the fertilized egg E is captured at each elapsed timing, and corresponding image data is sequentially recorded in the ROM / RAM 320.

  Next, if the fourth scoring processing unit 386 determines that all the imaging in the fourth period has been completed, the fourth scoring processing unit 386 reads the scoring reference information corresponding to the fourth period from the scoring information DB 303 (step Sd105).

  Next, the fourth scoring processing unit 386 performs the fourth period scoring process on the image data recorded in the ROM / RAM 320 according to the read scoring reference information and algorithm, and obtains the fourth period score. The determined fourth period score is recorded in the corresponding area of the cultured cell management DB 301 (step Sd106).

  Specifically, the fourth scoring processing unit 386 detects trophoblast cells and internal cell masses included in each cell image based on the fourth-phase algorithm, and the trophoblast cells and internal cell masses in each cell image And the score of a 4th period is determined, determining the score of each cell image based on scoring reference | standard information.

  In particular, the fourth scoring processing unit 386 calculates the thickness and uniformity of the trophoblast cells and the trophoblast cells in the trophoblast cells and inner cell mass detected in the cell image based on the fourth-phase algorithm, and the trophoblast cells Compared with the 4th stage scoring standard information (ideal state and bad state), evaluated trophoblast cells in three stages, good, good and bad, and the size and clarity of the inner cell mass The score (histogram based on the luminance value) is compared with the scoring reference information of the fourth period (histogram of ideal state and bad state), and trophoblast cells are evaluated in three stages: good, good and bad.

  In addition, the fourth scoring processing unit 386, according to the quality evaluation (specifically) of the trophoblast cell and the inner cell mass at each timing, for example, “+ 20%”, “0%”, The score of the fourth period is changed as “−20%”.

  Next, the fertilized egg evaluation unit 387 calculates the total score (final evaluation result) by calculating the sum of the scores in each state stage of the evaluation target fertilized egg (step Sd110), while recording it in the cultured cell management DB 301. Then, the total score is displayed on the display unit 330 in conjunction with the display control unit 340 (step Sd111), and this operation is terminated.

  In the process of step Sd111, if there is another fertilized egg E in the same patient, the fertilized egg evaluation unit 387 compares the total scores of the other fertilized eggs E recorded in the cultured cell management DB 301, The first score may be sorted and displayed, or when the total score is lower than the first threshold value compared to the first threshold value, the fertilized egg is evaluated as unusable for transplantation. If it is greater than or equal to the threshold value, it may be evaluated that transplantation is possible.

  As described above, the cell quality evaluation system 1 according to the present embodiment can automatically evaluate the quality of the target fertilized egg E by imaging the fertilized egg E over time. Therefore, the work burden of the user (for example, a doctor or an operator) at the time of quality evaluation of the fertilized egg E can be reduced, and cells that are in different states for each state stage can be scored on each state stage, thereby Therefore, it is possible to accurately evaluate the cells in which the growth process is important in the quality evaluation.

  That is, since the internal structure of the cell changes according to the state stage, and the quality criterion also changes according to the state stage, the cell quality evaluation system 1 of the present embodiment has different scoring reference information for each state stage. In addition, scoring can be performed while applying the algorithm, and appropriate scoring can be realized according to the state stage.

  Therefore, the cell quality evaluation system 1 of the present embodiment can automatically and accurately evaluate the quality of the cells to be evaluated.

  In addition, the cell quality evaluation system 1 of the present embodiment accurately identifies cells having a high growth rate by performing scoring on the basis of images of cells imaged at different timings in each state stage, Cell quality can be evaluated with high accuracy.

  Moreover, since the cell quality evaluation system 1 of this embodiment can evaluate that a cell whose score in any state stage falls below a predetermined threshold value cannot be used for transplantation, for example, The scoring at the stage can be omitted, and the processing burden at the time of evaluation can be reduced.

[4] Modification [4.1] Modification 1
In the above embodiment, the server apparatus 30 is provided with the DBs 301 to 303. However, these DBs 301 to 303 may be managed and operated by different computer systems.

[4.2] Modification 2
In the above embodiment, the case where the sum of the scores in each state stage is set as the total score has been described as an example. However, in step Sd110, the average or the square mean of the scores in all the state stages is calculated and set as the total score. A score may be used.

  In addition, weighting in each state stage (including the divided state stage) is performed at the time of calculating the total score, and for example, the weights in the first period and the second period that greatly affect the quality of the fertilized egg E are increased. Also good. Even in this case, the total score can be calculated using any of the sum, average, and root mean square.

  Furthermore, for example, the quality of the fertilized egg E is highly dependent on the quality of the first period to the third period (excluding the latter period) and the fourth period, so that a plurality of sums of scores corresponding to these specific state stages When the condition is not satisfied by calculating whether the average and the mean square, etc. are compared and comparing with a predetermined threshold, the fertilized egg E is used for transplantation. You may make it evaluate that it is impossible.

[4.3] Modification 3
The fertilized egg evaluation unit 387 of the above embodiment sorts in order of good overall score, presents it to the user, and uses it as a reference when the user selects a fertilized egg. A fertilized egg E having an extremely low value of “0 point” or less may be evaluated as being unsuitable for transplantation and may be displayed on the display unit 330 as being unusable.

  In this case, for example, when displaying a list of fertilized eggs E after sorting, by displaying a flag indicating that the fertilized eggs are unavailable in association with the unusable fertilized eggs, the fertilized eggs E are displayed to the user. It can be shown that it is not available.

[4.4] Modification 4
The imaging timing recorded in the state stage management DB 302 may be determined in advance by observing in advance according to the culture environment (type of medium, temperature, acidity, etc.).

  Even in this case, it is possible to specify whether the growth rate of the fertilized egg is fast or slow by performing imaging in 1 hour before and after the imaging timing.

[4.5] Modification 5
In the above embodiment, when the score corresponding to each state stage is lower than the second threshold value to the fourth threshold value, the scoring process in the subsequent state stage is not automatically performed. When the value falls below the threshold value, a message to that effect may be displayed on the display unit 330 to allow the user to determine whether to execute the subsequent process.

[4.6] Modification 6
In the above embodiment, the score is calculated using three cell images for each state stage, but a single cell image may be used, or four or more cell images may be used.

[4.7] Modification 7
Although the cell quality evaluation system of the above embodiment has been described for a case where it is applied to a fertilized egg, it can also be applied to other cells whose state inside the cell changes due to growth.

E ... Fertilized egg 10 ... Camera 30 ... Server device 300 ... Recording unit 301 ... Cultured cell management DB
302 ... State stage management DB
303 ... Scoring information DB
310 ... Interface unit 320 ... ROM / RAM
330 ... Display unit 340 ... Display control unit 360 ... Timer 370 ... Server management control unit 380 ... Data processing unit 381 ... Imaging management unit 382 ... Cultured cell management unit 383 ... First scoring processing unit 384 ... Second scoring processing unit 385 ... Third scoring processing unit 386 ... Fourth scoring processing unit 387 ... Fertilized egg evaluation unit 390 ... Operation unit

Claims (14)

In the cell quality evaluation system for evaluating the quality of cells in which a state stage indicating an internal state transitions in stages as time passes,
An imaging control unit that controls an imaging unit that captures a cell corresponding to each state stage defined by a time axis and generates image data of a cell image;
Scoring reference information used as a reference when evaluating the quality of cells in each state stage based on the cell image of the generated image data is associated with state stage identification information for identifying each state stage. Recording control means for controlling the recording means to be recorded,
Obtaining means for obtaining image data output from the imaging means;
Scoring means for scoring the quality of the corresponding cell based on the corresponding scoring reference information while performing predetermined image processing on the acquired cell image for each state stage;
An evaluation means for evaluating superiority or inferiority of the cell according to a scoring result indicating the scored result;
Presenting means for presenting an evaluation result in the evaluation means to a user so as to be viewable;
A cell quality evaluation system comprising: The cell quality evaluation system according to claim 1,
The imaging control means, for each state stage, causes the imaging means to image cells at different timings to generate the cell image,
The cell quality evaluation system, wherein the scoring means scores the quality of a corresponding cell based on a plurality of cell images having different timings for each state stage. In the cell quality evaluation system according to claim 2,
The scoring means scores the quality of cells corresponding to each state stage while weighting each cell image captured and generated at different timings for each state stage according to the elapsed time. Cell quality evaluation system. In the cell quality evaluation system according to claim 3,
The cell quality evaluation system which uses the average score obtained by averaging each score of the cell image in each timing from which the said elapsed time differs as a score of each said state stage. In the cell quality evaluation system according to claim 3,
The cell quality evaluation system using one representative score selected from each score of the cell image at each timing with different elapsed times as the score of each state stage. In the cell quality evaluation system according to any one of claims 1 to 5,
When the evaluation means determines whether or not the first condition set in advance is satisfied based on the sum of the scores scored for each state stage, and does not include the first condition In addition, the cell quality evaluation system that determines that the corresponding cell is unusable as superiority or inferiority of the cell quality. In the cell quality evaluation system according to any one of claims 1 to 6,
The evaluation means determines whether or not each score scored for each state stage has a second condition predetermined for each state stage, and does not have the second condition. A cell quality evaluation system that determines that the corresponding cell is not usable when it is detected. The cell quality evaluation system according to claim 7,
The evaluation means performs scoring in the scoring means of a state stage that arrives after the state stage when any of the scores in the state stages does not satisfy the second condition. Cell quality evaluation system to be discontinued. In the cell quality evaluation system according to any one of claims 1 to 8,
The cell quality evaluation system, wherein the evaluation means evaluates the superiority or inferiority of the corresponding cell while weighting the score of each scored state stage for each state stage. In the cell quality evaluation system according to any one of claims 1 to 9,
In the case where a cell image corresponding to each of the state stages is generated by the imaging means for each of a plurality of cells,
The scoring means calculates, for each cell, a score corresponding to each state stage using a corresponding cell image,
According to the scoring result for each cell, the evaluation means evaluates the superiority or inferiority of the quality of the cells, and ranks the values indicated by the scoring results of the cells in descending order,
The cell quality evaluation system in which the presenting means presents the evaluation result of each ranked cell so that the user can view it. In the cell quality evaluation system according to any one of claims 1 to 10,
The transition of the state stage starts by insemination of sperm cells to egg cells, and with the passage of time,
(1) a first state stage in which at least a plasma membrane, a zona pellucida, and a polar body are generated;
(2) a second state stage in which a pronucleus is generated in the plasma membrane;
(3) A third state stage in which the pronucleus disappear and cleavage occurs sequentially inside the zona pellucida,
(4) a fourth state stage in which the zona pellucida and the plasma membrane have disappeared and changed to blastocysts in which trophoblast cells and internal cell masses have developed,
In the order of
The imaging means is
The cell quality evaluation system which produces | generates the cell image corresponding to each of the said 1st-4th state stage by imaging the said oocyte at the timing which predetermined time passed after insemination. In a program for evaluating the quality of a cell in which a state stage showing an internal state gradually changes with the passage of time,
Computer
An imaging control unit that controls an imaging unit that generates a cell image by capturing an image of a corresponding cell for each state stage defined by a time axis,
Scoring reference information used as a reference when evaluating the quality of cells in each state stage based on the cell image of the generated image data is associated with state stage identification information for identifying each state stage. Recording control means for controlling the recording means to be recorded,
Obtaining means for obtaining image data output from the imaging means;
Scoring means for scoring the quality of the corresponding cell based on the corresponding scoring reference information while performing predetermined image processing on the acquired cell image for each state stage,
In accordance with the scoring result indicating the scored result, an evaluation means for evaluating superiority or inferiority of the cell, and
Presenting means for presenting the evaluation result in the evaluation means so that the user can view it,
A cell quality evaluation system comprising:
A program characterized by functioning as In the cell quality evaluation method for evaluating the quality of cells in which a state stage indicating an internal state transitions in stages as time passes,
Capture the corresponding cells for each state stage defined by the time axis, generate cell image image data,
Scoring reference information used as a reference when evaluating the quality of cells in each state stage based on the cell image of the generated image data is associated with state stage identification information for identifying each state stage. Control the recording means to be recorded,
For each state stage, while performing predetermined image processing on the generated cell image, scoring the quality of the corresponding cell based on the corresponding scoring reference information,
According to the scoring result indicating the scored result, the superiority or inferiority of the quality of the cell is evaluated,
Presenting the user with a view of the superiority or inferiority of the evaluated quality of the cells as an evaluation result,
A method for evaluating cell quality. An imaging unit that captures a corresponding cell for each state stage indicating an internal state that is defined in stages as time passes, and generates image data of a cell image;
A server device that controls the imaging means and evaluates the quality of the cell using the cell image based on each state stage;
Have
The server device is
Imaging control means for controlling the imaging means;
Scoring reference information used as a reference when evaluating the quality of cells in each state stage based on the cell image of the generated image data is associated with state stage identification information for identifying each state stage. Recording control means for controlling the recording means to be recorded,
Obtaining means for obtaining image data output from the imaging means;
Scoring means for scoring the quality of the corresponding cell based on the corresponding scoring reference information while performing predetermined image processing on the acquired cell image for each state stage;
An evaluation means for evaluating superiority or inferiority of the cell according to a scoring result indicating the scored result;
Presenting means for presenting the evaluation result in the evaluation means so that the user can browse;
A cell quality evaluation system comprising: