WO2015008682A1 - 細胞評価装置および方法、並びにプログラム - Google Patents
細胞評価装置および方法、並びにプログラム Download PDFInfo
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Definitions
- the present technology relates to a cell evaluation apparatus and method, and a program, and in particular, a cell evaluation apparatus and method capable of easily searching a region to be observed in a cardiomyocyte without requiring special preparation. , As well as programs.
- MEA multi-electrode array
- a visual field used for an experiment or the like is determined by a human visually confirming the pulsation of cardiomyocytes and qualitatively judging it. For this reason, for example, it was difficult to search for a region of cardiomyocytes to be compared before and after medication.
- cardiomyocyte morphology information For example, there was a method of searching for a target cell using simple motion information such as cardiomyocyte morphology information, luminance information, and interframe difference, but information such as the number of beats and contraction speed was considered. For example, it was not known whether cardiomyocytes were actively beating.
- the present technology is disclosed in view of such a situation, and does not require special preparation or the like, and can easily search a region to be observed in a cardiomyocyte.
- a motion detection unit that detects the motion of the cultured cardiomyocytes for each partial region of the plurality of observation fields on the cultured cardiomyocytes, and the motion amount of each detected motion
- a motion amount calculation unit to calculate, a pulsation information calculation unit to calculate pulsation information, which is information of a feature value of the pulsation of the cultured cardiomyocytes, based on the calculated motion amounts, and the pulsation information
- An evaluation value calculation unit that calculates an evaluation value corresponding to each of the plurality of observation visual fields calculated based on the visual field, and a visual field determination unit that determines an observation visual field to be observed on the cultured cardiomyocytes based on the evaluation value It is a cell evaluation apparatus provided with.
- the pulsation information may be a pulsation area of the cultured cardiomyocytes in the observation visual field.
- the motion detecting unit detects the motion for each partial region for each frame of the moving image in the observation region
- the pulsation information calculating unit is configured to detect the motion for each partial region of the plurality of frames of the moving image. Based on the quantity, waveform information representing the pulsation of the cultured cardiomyocytes in the partial region can be generated.
- the pulsation information may be the number of pulsations within a unit time of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the pulsation information may be a pulsation contraction time or a relaxation time of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the pulsation information may be a pulsation contraction rate or a relaxation rate of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the pulsation information may be a correlation coefficient of a pulsation waveform between the partial regions of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the pulsation information may be a propagation speed and a propagation direction of pulsation of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the evaluation unit calculates an evaluation value corresponding to the plurality of observation visual fields before and after a predetermined process applied to the cultured cardiomyocytes, and the observation visual field determination unit
- the observation visual field may be determined by selecting a predetermined number of observation visual fields from the plurality of observation visual fields based on the difference between the evaluation values before and after the predetermined processing performed in the above. it can.
- the motion detection unit detects the motion of the cultured cardiomyocytes for each partial region of the plurality of observation fields on the cultured cardiomyocytes
- the motion amount calculation unit detects the motion
- the pulsation information calculation unit calculates pulsation information, which is information of the pulsation feature amount of the cultured cardiomyocytes, based on the calculated movement amounts, and evaluates
- a value calculation unit calculates evaluation values corresponding to the plurality of observation visual fields calculated based on the pulsation information, and a visual field determination unit observes the cultured cardiomyocytes based on the evaluation values. It is a cell evaluation method including the step of determining the observation visual field.
- a computer detects a motion of a cultured cardiomyocyte for each partial region of a plurality of observation fields on the cultured cardiomyocyte, and the detected motion
- a motion amount calculation unit that calculates a motion amount
- a pulsation information calculation unit that calculates pulsation information that is information on the pulsation feature amount of the cultured cardiomyocytes, based on the calculated motion amounts
- An evaluation value calculation unit for calculating evaluation values corresponding to the plurality of observation visual fields calculated based on pulsation information, and an observation visual field to be observed on the cultured cardiomyocytes based on the evaluation values
- a program for causing a cell evaluation apparatus to function as a visual field determination unit.
- the motion of the cultured cardiomyocytes is detected for each partial region of the plurality of observation visual fields on the cultured cardiomyocytes, and the motion amount of each detected motion is calculated, Based on each calculated amount of motion, pulsation information, which is information on the pulsation feature amount of the cultured cardiomyocytes, is calculated, and corresponds to the plurality of observation visual fields calculated based on the pulsation information. An evaluation value is calculated, and an observation field to be observed on the cultured cardiomyocytes is determined based on the evaluation value.
- FIG. 16 is a block diagram illustrating a configuration example of a personal computer.
- cultured cells which are cell tissues produced by culturing cells collected from a living body.
- Cultured cardiomyocytes which are cultured cells obtained by culturing cardiomyocytes, may be used, for example, for the treatment of the heart. It is also used for evaluating toxicity to the heart in drug discovery.
- cardiomyocytes constantly beat and repeat contraction and relaxation. Accordingly, the cells of each part move in a predetermined direction so that the whole cardiomyocyte repeatedly contracts and relaxes.
- a cardiomyocyte has a part that beats autonomously and a part that beats depending on surrounding beats.
- FIG. 1 is a block diagram illustrating a configuration example of a drug evaluation device according to an embodiment of the present technology.
- the drug evaluation apparatus 100 shown in the figure is an apparatus that evaluates a drug administered to the cultured cardiomyocytes 110 by observing the movement of the cultured cardiomyocytes 110.
- the drug evaluation apparatus 100 includes an imaging unit 101, an evaluation target image data generation recording unit 102, an evaluation index data generation unit 103, an evaluation unit 104, a display unit 105, a control unit 106, and a stage 107.
- the imaging unit 101 images the cultured cardiomyocytes 110 to be observed.
- the imaging unit 101 may image the cultured cardiomyocytes 110 directly (without passing through other members), or may image the cultured cardiomyocytes 110 through other members such as a microscope.
- the cultured cardiomyocytes 110 are placed on the stage 107 and fixed to the imaging unit 101.
- the stage 107 is configured to move in the vertical and horizontal directions, for example, based on the control of the control unit 106.
- the imaging unit 101 images the cultured cardiomyocytes 110 for a predetermined period. That is, the imaging unit 101 obtains a moving image with the cultured cardiomyocytes 110 as a subject.
- the imaging unit 101 images the cultured cardiomyocytes 110 before and after drug administration. Note that the imaging unit 101 may image the cultured cardiomyocytes 110 a plurality of times after drug administration, for example, according to a predetermined condition such as every predetermined time.
- the imaging unit 101 is usually configured to image a part of the cultured cardiomyocytes 110, and the cultured cardiomyocytes 110 are moved by moving the stage 107 or moving the imaging unit 101.
- the area to be imaged moves within.
- An area imaged by the imaging unit 101 at a predetermined time is also referred to as an observation visual field.
- the imaging unit 101 supplies an image signal 111 (moving image) of an image of the cultured cardiomyocyte 110 obtained by imaging to the evaluation target image data generation recording unit 102.
- the evaluation target image data generation / recording unit 102 generates evaluation target image data based on the image signal supplied from the imaging unit 101, and records and stores the generated evaluation target image data in, for example, an internal recording medium.
- the evaluation target image data generated here is, for example, moving image data generated from an image signal obtained by imaging the cultured cardiomyocytes 110.
- the evaluation target image data generation / recording unit 102 may extract only a part of the frame images from a plurality of frame images supplied from the imaging unit 101 and use them as evaluation target image data. Good. Further, for example, the evaluation target image data generation / recording unit 102 extracts a partial region of each frame image supplied from the imaging unit 101 as a small frame image, and a moving image including the small frame image is determined as the evaluation target image data. You may make it.
- the evaluation target image data generation / recording unit 102 may perform arbitrary image processing on each frame image supplied from the imaging unit 101, and the image processing result may be used as evaluation target image data.
- image processing for example, image enlargement, reduction, rotation, deformation, brightness and chromaticity correction, sharpness, noise removal, intermediate frame image generation, and the like can be considered. Of course, any image processing other than these may be used.
- the evaluation target image data generation recording unit 102 supplies the stored evaluation target image data 112 to the evaluation index data generation unit 103 at a predetermined timing or based on a request from the evaluation index data generation unit 103.
- the evaluation index data generation unit 103 observes each block, which is a partial region obtained by dividing the entire region of the image of the observation target (cultured cardiomyocytes 110) into a plurality of frames between the frame images of the supplied evaluation target image data 112. The motion of the target (cultured cardiomyocytes 110) is detected.
- the evaluation index data generation unit 103 represents the detected motion of each block as a motion vector, and obtains the magnitude (motion amount) of the motion vector. In addition, the evaluation index data generation unit 103 calculates pulsation information that is information on the feature amount related to the pulsation of the cultured cardiomyocytes 110.
- Evaluation index data generation unit 103 supplies data including pulsation information to evaluation unit 104 as evaluation index data 113.
- Evaluation unit 104 calculates an evaluation value relating to each region in cultured cardiomyocytes 110 based on evaluation index data 113.
- the evaluation value calculated by the evaluation unit 104 is used, for example, to specify a region to be observed in the cultured cardiomyocytes 110.
- the display unit 105 visualizes and displays the evaluation index data 113 and information related to the evaluation value generated by the evaluation unit 104.
- the control unit 106 controls the movement of the stage 107 based on the information output from the evaluation unit 104, and also controls the imaging by the imaging unit 101. That is, the control unit 106 specifies the observation visual field in the cultured cardiomyocytes 110 based on the information output from the evaluation unit 104, and the stage 107 or the imaging so that the region corresponding to the observation visual field is imaged.
- the unit 101 is controlled.
- FIG. 2 is a block diagram illustrating a configuration example of the evaluation index data generation unit 103 in FIG. As illustrated in FIG. 2, the evaluation index data generation unit 103 includes a motion detection unit 121, a motion amount calculation unit 122, and a pulsation information calculation unit 123.
- the motion detection unit 121 receives the evaluation target image data 112 recorded from the evaluation target image data generation recording unit 102, performs motion detection for each block, and uses the detection result (motion vector) as motion detection data to be described later. And supplied to the motion amount calculation unit 122.
- the motion amount calculation unit 122 divides each supplied motion detection data into new blocks, and calculates an average motion amount in each block.
- the motion amount calculation unit 122 supplies the calculated average motion amount to the pulsation information calculation unit 123.
- the pulsation information calculation unit 123 calculates pulsation information to be described later at a predetermined timing or based on a request from the evaluation unit 104, and generates evaluation index data 113 including the pulsation information.
- the generated evaluation index data 113 is supplied to the evaluation unit 104.
- the motion detection unit 121 to the pulsation information calculation unit 123 perform this process for each frame image of the evaluation target image data.
- FIG. 3 shows an example of the structure of the evaluation target image data 112 supplied to the evaluation index data generation unit 103. Imaging is performed in an evaluation section having a predetermined length (for example, T + 1 frame (T is an arbitrary natural number)).
- the evaluation target image data 112 supplied to the evaluation index data generation unit 103 includes, for example, first to (T + 1) th frame image data 132-1 to 132- (T + 1) corresponding to the evaluation section.
- FIG. 4 is a block diagram illustrating a main configuration example of the motion detection unit 121.
- the motion detection unit 121 includes a frame memory 141 and a motion vector calculation unit 142.
- the frame memory 141 holds frame image data 132 that is sequentially input as the evaluation target image data 112 for each frame period.
- the motion vector calculation unit 142 obtains the frame image data input as the evaluation target image data 112 at the current time and the frame image data at the next time (previous in time) held in the frame memory 141. input. Then, a motion vector indicating the motion between these two frame image data is calculated for each block. The calculated motion vector is supplied to the motion amount calculation unit 122 as motion detection data 151.
- the motion vector calculation unit 142 receives the frame image data 132 at the current time and the frame image data 132 at the next (temporally previous) time.
- the motion vector calculation unit 142 divides these input frame image data 132 into M ⁇ N blocks 161 (M and N are arbitrary natural numbers) as shown in FIG.
- motion detection is performed by a technique such as block matching between frame images to generate a motion vector.
- the motion vector calculation unit 142 executes this motion detection processing by sequentially using the first to (T + 1) th frame image data 132. That is, the motion vector calculation unit 142 generates (M ⁇ N ⁇ T) motion detection data (motion vectors) using (T + 1) frame images. The motion vector calculation unit 142 supplies the motion vector calculated as described above to the motion amount calculation unit 122 as motion detection data.
- the motion amount calculation unit 122 sends T-frame unit motion detection data 171-1 as shown in FIG. Motion detection data consisting of 1 to 171-T is supplied.
- Each of the frame-unit motion detection data 171-1 to 171-T operates on the frame image data 132 at the current time obtained for each frame period and the frame image data 132 one time ahead (in time). It is obtained by performing the detection process.
- the third frame unit motion detection data 171-3 includes the fourth frame image data 132-4 and the third frame image data 132-3 as the frame image data at the current time and the next time, respectively. It can be obtained by inputting and performing motion detection.
- each of the frame unit motion detection data 171-1 to 171-T is formed by (M ⁇ N) block unit motion detection data 181.
- Each block unit motion detection data 181 corresponds to one block 161, and is data indicating a motion vector detected for the corresponding block 161.
- the motion detection data 151 of the present embodiment has a structure having (M ⁇ N) block unit motion detection data 181 for each frame unit motion detection data 171.
- FIG. 7 and 8 are diagrams for describing processing executed by the motion amount calculation unit 122.
- FIG. 7 and 8 are diagrams for describing processing executed by the motion amount calculation unit 122.
- the motion amount calculation unit 122 newly divides each of the frame unit motion detection data 171 including (M ⁇ N) blocks into (K ⁇ L) blocks. For example, as shown in FIG. 7, the frame unit motion detection data 171 is divided into (K ⁇ L) blocks 191.
- the values of K and L may vary depending on the pulsation information calculated by the pulsation information calculation unit 123.
- motion amount data 200 composed of T frame unit motion amount data 201-1 to 201-T is generated.
- each of the frame unit motion amount data 201-1 to 201-T is formed by (K ⁇ L) block unit motion amount data 211.
- Each block unit motion amount data 211 corresponds to one block 191 and is data indicating an average value of motion vectors in the corresponding block 191.
- the pulsation information calculation unit 123 calculates pulsation information that is information on the feature amount related to the pulsation of the cultured cardiomyocytes as follows.
- the pulsation information calculation unit 123 calculates the pulsation area within the observation visual field.
- the presence or absence of pulsation within a unit time is determined by adding a predetermined number of frames to each of the block unit motion amount data 211.
- the block unit motion amount data 211 of each block 191 of the frame unit motion amount data 201-1 to 201-J (J ⁇ T) is added.
- the addition value of the block unit motion amount data corresponding to each block 191 is compared with the threshold value, and it is determined that the block 191 having the addition value less than the threshold value has no pulsation within the unit time.
- the pulsation area calculated in this way is one of the pulsation information calculated by the pulsation information calculation unit 123.
- the pulsation information calculation unit 123 calculates the number of pulsations within the observation visual field.
- the pulsation information calculation unit 123 generates waveform information 220 representing a change in the amount of movement based on the amount of movement data 200. That is, the pulsation information calculation unit 123 calculates the change of the observation visual field with the passage of time by averaging the (K ⁇ L) block unit motion amount data 211 constituting the motion amount data 200 over the entire screen. To do.
- the average value of the block unit motion amount data in the frame unit motion amount data 201-1 to 201-T constituting the motion amount data 200 on the entire screen is plotted for each time. .
- the waveform information 220 about the observation visual field is generated.
- the horizontal axis represents time
- the vertical axis represents the amount of movement
- the change in the average value of the amount of movement in the observation field with the passage of time is shown as a waveform 221.
- a waveform 221 in FIG. 9 is a waveform in which a high peak and a low peak appear alternately and repeatedly. This is due to repeated contraction and relaxation in the pulsation of the cultured cardiomyocytes.
- the high peak corresponds to the time when the cultured cardiomyocytes are contracted, and the low peak is the time when the cultured cardiomyocytes are relaxed.
- the peak corresponding to the contraction of the cultured cardiomyocytes and the peak corresponding to the relaxation can be discriminated based on the following characteristics, for example.
- the peak of contraction is ahead of the peak of relaxation.
- the speed of shrinkage peak is higher.
- the peak of contraction has a steep rise.
- the speed of the starting point is smaller at the peak of contraction.
- the time from the rise of the contraction peak to the fall of the relaxation peak shown in the waveform 221 can be recognized as one beat of the cultured cardiomyocytes in the block. Then, from the waveform 221 of the waveform information 220, the number of beats within a unit time in the block can be calculated.
- the pulsation information calculation unit 123 calculates, for example, the average value of the number of pulsations of each block 191 in the observation visual field, and sets the average value as the number of pulsations in the observation visual field.
- the number of beats calculated in this way is one of the beat information calculated by the beat information calculation unit 123.
- the pulsation information calculation unit 123 calculates the pulsation contraction time and relaxation time within the observation visual field.
- the contraction time is calculated as the time from the rise of the contraction peak in the waveform 221 of the waveform information 220 to the fall of the contraction peak.
- the relaxation time is calculated as the time from the rise of the relaxation peak to the fall of the relaxation peak in the waveform 221 of the waveform information 220.
- the contraction time may be calculated by using the time from the rise of the contraction peak until the rise of the relaxation peak.
- the pulsation information calculation unit 123 sets, for example, the average value of the contraction time and relaxation time within a predetermined time as the contraction time and relaxation time within the observation visual field.
- the contraction time and relaxation time calculated in this way are one of the pulsation information calculated by the pulsation information calculation unit 123.
- the pulsation information calculation unit 123 calculates the contraction speed and relaxation speed of the pulsation within the observation visual field.
- the contraction speed is calculated from the time from the rise of the peak of contraction to the peak in the waveform 221 of the waveform information 220 and the amount of motion corresponding to the peak of contraction.
- the relaxation speed is calculated from the time from the rise of the relaxation peak to the peak in the waveform 221 of the waveform information 220 and the amount of motion corresponding to the relaxation peak.
- the pulsation information calculation unit 123 uses, for example, the average value of the contraction speed and the relaxation speed within a predetermined time as the contraction speed and the relaxation speed in the observation visual field.
- the contraction speed and the relaxation speed calculated in this way are set as one of the pulsation information calculated by the pulsation information calculation unit 123.
- the pulsation information calculation unit 123 calculates the pulsation duration in the observation visual field.
- the pulsation duration is calculated, for example, as the time from the rise of the contraction peak in the waveform 221 of the waveform information 220 to the fall of the relaxation peak.
- the pulsation information calculation unit 123 calculates a correlation coefficient between each block in the observation visual field.
- the pulsation information calculation unit 123 sets a block for which a correlation coefficient is to be calculated.
- block 191-A and block 191-B are set as blocks for which a correlation coefficient is to be calculated.
- the pulsation information calculation unit 123 acquires the waveform information 220 as described above with reference to FIG. 9 for each of the block 191 -A and the block 191 -B. For example, as shown in FIG. 10, the waveform information 220-A and the waveform information 220-B are acquired for each of the block 191-A and the block 191-B adjacent to each other.
- the pulsation information calculation unit 123 obtains the pulsation correlation coefficient of the block 191-A and the block 191-B.
- This correlation coefficient is a parameter indicating the cooperation of pulsation, and the value increases as the cooperation between blocks increases.
- the pulsation information calculation unit 123 calculates, for example, a correlation coefficient between the movement of the block 191-A and the movement of the block 191-B. That is, the motion amount of each of the block 191-1A and the block 191-B of the frame at a specific time, and the average value of the motion amounts of the block 191-A and the block 191-B in the time series direction in the evaluation section. Is used to calculate the correlation coefficient. That is, the degree of correlation between the two blocks and the change in the amount of motion within the evaluation section is calculated.
- the pulsation information calculation unit 123 obtains such a correlation coefficient in a brute force manner within an entire field of view or a predetermined neighborhood area between arbitrary blocks 191 within the observation field of view, and calculates an average value thereof.
- the correlation coefficient calculated in this way is one of the pulsation information calculated by the pulsation information calculation unit 123.
- the pulsation information calculation unit 123 calculates the pulsation propagation speed and propagation direction within the observation field as follows.
- FIG. 11 is an enlarged view of a part of the waveform 221 in FIG.
- the pulsation information calculation unit 123 sets the movement amount of the high peak (that is, the peak corresponding to the contraction of the cultured cardiomyocytes) PK1 to 100%, and the time when the waveform reaches the movement amount of 10% of the peak PK1. It is specified as the rise time Tup.
- FIG. 12 is an enlarged view of the vicinity of the rising edge of the waveform 221 in FIG. 11 (portion surrounded by a square in the drawing). In the figure, the waveform is interpolated based on the plot points PL1 and PL2.
- the rise time of the block 191-p corresponding to the block unit motion amount data 211-p is specified. Then, the rise times of the blocks around the block 191-p are also specified.
- the pulsation information calculation unit 123 sets a target block in each of (K ⁇ L) blocks 191 as illustrated in FIG. 13, for example.
- the block 191-p is set as the target block, and the rising time t0 of the first beat of the target block 191-p is specified.
- the rise time tx of the first beat of the block 191-q that is separated from the target block in the horizontal direction by a predetermined distance for example, two blocks
- a predetermined distance For example, the rising time ty of the first beat of the block 191-r separated by 2 blocks
- the pulsation information calculation unit 123 obtains each of the propagation velocity vx of the pulsation in the horizontal direction and the propagation velocity vy of the pulsation in the vertical direction by Expression (1).
- the pulsation information calculation unit 123 obtains the pulsation propagation speed
- the pulsation information calculation unit 123 obtains the pulsation propagation direction ⁇ by the equation (3) based on the horizontal pulsation propagation speed vx and the vertical pulsation propagation speed vy.
- the propagation speed and propagation direction of the block 191-p are calculated. Similarly, the propagation speed and propagation direction are calculated with the other blocks as the target block.
- the propagation speed and propagation direction obtained here are obtained for each pulsation for each block of the motion amount data 200.
- the propagation speed and propagation direction of the first beat in block 191-p, the propagation speed and propagation direction of the second beat, the propagation speed and propagation direction of the third beat,..., Propagation speed and propagation direction of the first beat, propagation speed and propagation direction of the second beat, propagation speed and propagation direction of the third beat, etc. Will be obtained.
- the propagation speed and propagation direction for each beat calculated in this way are set as one of the beat information calculated by the beat information calculation unit 123.
- information indicating the orientation of pulsation in the observation visual field may be calculated as one of the pulsation information.
- the data including the pulsation information about the observation visual field obtained in this way is output as the evaluation index data 113.
- the pulsation information calculation unit 123 calculates the pulsation information for the next observation visual field after calculating the pulsation information for one observation visual field.
- the stage 107 is moved based on a control signal output from the control unit 106, and is an area corresponding to the next observation visual field, which is a cultured myocardium. A part of the cell 110 is imaged by the imaging unit 101. Then, pulsation information about the next observation visual field is calculated.
- FIG. 14 is a diagram illustrating an aspect in which the observation field of view moves as the stage 107 moves based on the control of the control unit 106.
- Circles in the figure represent cultured cardiomyocytes 110 (actually, culture dishes, wells, etc. on which the cultured cardiomyocytes 110 are placed), and a rectangular region 110a in the circle can be an object of observation.
- cultured cardiomyocytes 110 actually, culture dishes, wells, etc. on which the cultured cardiomyocytes 110 are placed
- a rectangular region 110a in the circle can be an object of observation.
- each small rectangle in the region 110a is a region corresponding to one observation visual field, and the movement of the stage 107 is controlled so that the observation visual field moves as indicated by a line 241 in the drawing. .
- the evaluation unit 104 calculates an evaluation value related to each region in the cultured cardiomyocytes 110 based on the evaluation index data 113 including pulsation information.
- the evaluation unit 104 calculates an evaluation value E1 that evaluates that the number of pulsations within a unit time within the observation visual field is within a certain range.
- the evaluation value E1 is obtained as shown in FIG. 15, for example.
- the horizontal axis represents the number of beats
- the vertical axis represents the evaluation value.
- the evaluation value is 1, and when the number of beats is out of the certain range, the evaluation value decreases.
- the evaluation unit 104 calculates an evaluation value E2 that represents a small dispersion value (degree of dispersion) of the average value in the propagation direction related to a plurality of pulsations within the observation visual field.
- the evaluation value E2 is obtained, for example, as shown in FIG. In FIG. 16, the horizontal axis represents the dispersion value in the propagation direction, and the vertical axis represents the evaluation value. As shown in FIG. 16, when the value on the horizontal axis is smaller than the predetermined threshold value, the evaluation value is 1, and when the value on the horizontal axis is greater than or equal to the predetermined threshold value, the evaluation value decreases.
- the evaluation unit 104 calculates an evaluation value E3 for evaluating the magnitude of the contraction speed of pulsation within the observation visual field.
- the evaluation value E3 is obtained, for example, as shown in FIG. In FIG. 17, the horizontal axis represents the contraction speed and the vertical axis represents the evaluation value. As shown in FIG. 17, when the value on the horizontal axis is greater than or equal to a predetermined threshold, the value of the evaluation value is 1, and when the value on the horizontal axis is smaller than the predetermined threshold, the evaluation value decreases.
- evaluation unit 104 may calculate evaluation values E4, evaluation values E5,... Related to other pulsation information.
- the evaluation part 104 calculates the observation visual field evaluation value E which evaluates the importance as an area
- Equation (4) Note that ⁇ 1 to ⁇ 5 in Equation (4) are weighting factors set in advance.
- control unit 106 moves the stage 107, so that an area of high importance as an area to be observed in the cultured cardiomyocytes is automatically set as the observation visual field. Become.
- the stage 107 when calculation of the pulsation information for one observation visual field is completed, the stage 107 is moved based on the control signal output from the control unit 106 to correspond to the next observation visual field.
- the region has been described as being imaged by the imaging unit 101.
- the stage 107 when the calculation of the observation visual field evaluation value for one observation visual field is completed, the stage 107 is moved based on the control signal output from the control unit 106, and an area corresponding to the next observation visual field is captured by the imaging unit. 101 may be used for imaging.
- the display unit 105 visualizes and displays information related to the evaluation index data 113 and the evaluation value generated by the evaluation unit 104.
- FIG. 18 is a diagram illustrating an example of a screen displayed by the processing of the display unit 105.
- Waveform information is displayed in a region 271 in the upper left of FIG.
- the waveform information displayed in the region 271 is displayed based on the waveform information 220 generated by the pulsation information calculation unit 123, for example.
- the transition of the pulsation information with the passage of time is displayed as a graph.
- the transition of the pulsation information such as contraction time, contraction speed, correlation coefficient,.
- pulsation information is displayed in numerical values or characters.
- the pulsation information calculated by the pulsation information calculation unit 123 is displayed as a numerical value or a character.
- an image of the observation field is displayed. That is, in the region 274, an image of a partial region of the cultured cardiomyocyte 110 imaged by the imaging unit 101 is displayed. This image may be a moving image or a still image.
- FIG. 19 is a diagram illustrating another example of a screen displayed by the processing of the display unit 105.
- an evaluation value map 281 is displayed.
- each observation visual field described with reference to FIG. 14 is displayed in a color-coded manner based on the observation visual field evaluation value E.
- each of the rectangles corresponding to each observation field is displayed in a lighter color as the observation field evaluation value E of the observation field is larger, and the observation field evaluation value E of the observation field is smaller. It is displayed in a darker color.
- the evaluation value map 281 does not necessarily need to be color-coded based on only the observation visual field evaluation value E.
- the evaluation value map 281 may be color-coded based on any one of the evaluation values E1 to E5. Good.
- control unit 106 may select the observation field of view based on the evaluation value map 281 and move the stage 107. For example, an observation field where the observation field evaluation value E is maximum may be observed, or N observation fields whose observation field evaluation value E is the highest N are sequentially observed. As described above, the stage 107 may be moved.
- an observation visual field in which any one of the evaluation values E1 to E5 is maximized may be observed, or the evaluation value E1, the evaluation value E2, the evaluation value E3,.
- the stage 107 may be moved so that the N observation visual fields up to the top Nth of the various evaluation values are sequentially observed.
- the stage 107 may be moved so that an observation field where various evaluation values are maximized is observed among a plurality of observation fields selected in advance.
- the evaluation value map 281 displayed on the display may be used as a GUI (Graphical User Interface), and the stage 107 may be moved so that the observation visual field selected by the user is observed. .
- GUI Graphic User Interface
- cultured cardiomyocytes are placed in one culture dish, well, etc.
- culture placed in each of wells on a well plate in which a plurality of wells are arranged Cardiomyocytes may be observed.
- FIG. 20 is a diagram showing an example of an evaluation value map when a well plate in which six wells are arranged is used.
- six wells are arranged on a well plate 290 indicated by a rectangle, as indicated by a circle in the figure.
- evaluation value maps 282-1 to 282-6 are generated corresponding to each of the six wells.
- the stage 107 moves so that the observation visual field is selected from each of the six wells based on the evaluation value map 282-1 to the evaluation value map 282-6, as in the case described above. It may be allowed to be made.
- the observation visual field may be selected based on a difference between an evaluation value calculated in advance and an evaluation value calculated most recently.
- the calculation of the second evaluation value is performed after a predetermined time has elapsed since the evaluation value was calculated for the first time. Then, a difference between the first evaluation value and the second evaluation value may be calculated for each observation field, and for example, an observation field having a large difference may be selected. Further, for example, a difference in evaluation value may be calculated for each observation visual field before and after medication, and an observation visual field having a large difference in evaluation value may be selected.
- observation visual field may be selected based on, for example, the difference between the pulsation information calculated in advance and the pulsation information calculated most recently.
- step S21 the evaluation target image data generation recording unit 102 acquires image data obtained by capturing an image of cultured cardiomyocytes.
- step S22 the evaluation index data generation unit 103 executes an evaluation index data generation process to be described later with reference to the flowchart of FIG. Thereby, evaluation index data is generated.
- step S23 the evaluation unit 104 executes an evaluation value calculation process described later with reference to the flowchart of FIG. Thereby, an evaluation value is calculated and the above-described evaluation value map is generated.
- step S24 the display unit 105 displays information related to the observation visual field. Thereby, for example, a screen as described above with reference to FIG. 18 is displayed.
- step S25 the control unit 106 determines whether or not there is a next observation visual field. In step S25, when it is determined that there is a next observation visual field, the process proceeds to step S26.
- step S26 the control unit 106 moves the stage 107. Thereafter, the processing returns to step S21, and the subsequent processing is repeatedly executed. In this way, pulsation information and evaluation values for each observation visual field are calculated.
- step S25 determines whether there is no next observation visual field. If it is determined in step S25 that there is no next observation visual field, the process proceeds to step S27.
- step S27 the control unit 106 determines an observation field.
- the observation visual field is determined based on the evaluation value map.
- step S41 the motion detection unit 121 performs motion detection based on the image data acquired in step S21 of FIG. Thereby, as described above, motion detection data 151 having (M ⁇ N) block unit motion detection data 181 is obtained.
- step S42 the motion amount calculation unit 122 calculates a motion amount based on the motion detection data 151 obtained in the process of step S41.
- each frame unit motion detection data 171 composed of (M ⁇ N) blocks is divided into (K ⁇ L) blocks 191. Then, by calculating an average value of the block unit motion detection data 181 included in each of the (K ⁇ L) blocks 191, the average motion amount in each block is calculated.
- motion amount data 200 composed of T frame unit motion amount data 201-1 to 201-T is generated.
- step S43 the pulsation information calculation unit 123 calculates pulsation information.
- the number, pulsation propagation speed, propagation direction, and the like are calculated as pulsation information.
- step S44 the pulsation information calculation unit 123 outputs evaluation index data including the pulsation information calculated in the process of step S43.
- step S61 the evaluation unit 104 calculates an evaluation value related to the number of beats. At this time, for example, an evaluation value E1 for evaluating that the number of pulsations within a unit time within the observation visual field is within a certain range is calculated.
- step S62 the evaluation unit 104 calculates an evaluation value related to the propagation direction.
- an evaluation value E2 representing the small dispersion value (degree of dispersion) of the average value in the propagation direction related to a plurality of pulsations in the observation visual field is calculated.
- step S63 an evaluation value related to the contraction speed is calculated.
- an evaluation value E3 for evaluating the magnitude of the contraction speed of pulsation within the observation visual field is calculated.
- step S64 the evaluation unit 104 calculates an observation visual field evaluation value.
- step S65 the evaluation unit 104 generates an evaluation value map.
- the series of processes described above can be executed by hardware or can be executed by software.
- a program constituting the software executes various functions by installing a computer incorporated in dedicated hardware or various programs.
- a general-purpose personal computer 700 as shown in FIG. 24 is installed from a network or a recording medium.
- a CPU (Central Processing Unit) 701 executes various processes according to a program stored in a ROM (Read Only Memory) 702 or a program loaded from a storage unit 708 to a RAM (Random Access Memory) 703. To do.
- the RAM 703 also appropriately stores data necessary for the CPU 701 to execute various processes.
- the CPU 701, the ROM 702, and the RAM 703 are connected to each other via a bus 704.
- An input / output interface 705 is also connected to the bus 704.
- the input / output interface 705 includes an input unit 706 including a keyboard and a mouse, a display including an LCD (Liquid Crystal Display), an output unit 707 including a speaker, a storage unit 708 including a hard disk, a modem, a LAN, and the like.
- a communication unit 709 including a network interface card such as a card is connected. The communication unit 709 performs communication processing via a network including the Internet.
- a drive 710 is also connected to the input / output interface 705 as necessary, and a removable medium 711 such as a magnetic disk, an optical disk, a magneto-optical disk, or a semiconductor memory is appropriately mounted, and a computer program read from them is loaded. It is installed in the storage unit 708 as necessary.
- a program constituting the software is installed from a network such as the Internet or a recording medium such as a removable medium 711.
- this recording medium is a magnetic disk (including a floppy disk (registered trademark)) on which a program is recorded, which is distributed to distribute the program to the user separately from the apparatus main body shown in FIG.
- Removable media consisting of optical disc (including CD-ROM (compact disk-read only memory), DVD (digital versatile disk)), magneto-optical disk (including MD (mini-disk) (registered trademark)), or semiconductor memory It includes not only those configured by 711 but also those configured by a ROM 702 in which a program is recorded, a hard disk included in the storage unit 708, and the like distributed to the user in a state of being incorporated in the apparatus main body in advance.
- this technology can also take the following structures.
- a motion detector that detects the movement of the cultured cardiomyocytes for each partial region of the plurality of observation fields on the cultured cardiomyocytes;
- a motion amount calculating unit for calculating a motion amount of each detected motion;
- a pulsation information calculation unit that calculates pulsation information that is information of the characteristic amount of pulsation of the cultured cardiomyocytes;
- An evaluation value calculation unit for calculating an evaluation value corresponding to each of the plurality of observation visual fields calculated based on the pulsation information;
- a cell evaluation apparatus comprising: a visual field determination unit that determines an observation visual field to be observed on the cultured cardiomyocytes based on the evaluation value.
- the beat information is The cell evaluation apparatus according to (1), which is a pulsation area of the cultured cardiomyocytes in the observation visual field.
- the motion detector is Detecting the movement for each partial region for each frame of the moving image of the observation region;
- the pulsation information calculation unit The cell evaluation device according to (1), wherein waveform information representing pulsation of the cultured cardiomyocytes in the partial region is generated based on the amount of movement of each partial region of the plurality of frames of the moving image.
- the beat information is The cell evaluation device according to (3), which is the number of beats within a unit time of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the beat information is The cell evaluation apparatus according to (3), wherein the pulsation contraction time or relaxation time of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the beat information is The cell evaluation device according to (3), wherein the pulsation contraction rate or relaxation rate of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the beat information is The cell evaluation apparatus according to (3), wherein the correlation coefficient is a pulsation waveform between the partial regions of the cultured cardiomyocytes in the observation field of view calculated based on the waveform information.
- the beat information is The cell evaluation device according to (3), wherein the pulsation propagation speed and propagation direction of the cultured cardiomyocytes in the observation visual field calculated based on the waveform information.
- the evaluation unit is Before and after the predetermined treatment applied to the cultured cardiomyocytes, respectively, to calculate evaluation values corresponding to the plurality of observation fields,
- the observation visual field determination unit is The observation field is determined by selecting a predetermined number of observation fields from the plurality of observation fields based on a difference between the evaluation values before and after a predetermined process performed on the cultured cardiomyocytes.
- the cell evaluation device according to any one of (1) to (8).
- the motion detection unit detects the movement of the cultured cardiomyocytes for each partial region of the plurality of observation fields on the cultured cardiomyocytes,
- a motion amount calculator calculates a motion amount of each detected motion;
- a pulsation information calculation unit calculates pulsation information, which is information on the characteristic amount of pulsation of the cultured cardiomyocytes, based on each calculated amount of movement,
- the evaluation value calculation unit calculates an evaluation value corresponding to each of the plurality of observation visual fields calculated based on the pulsation information,
- a field evaluation method including a step of determining a field of view to be observed on the cultured cardiomyocytes based on the evaluation value.
- a motion detector that detects the movement of the cultured cardiomyocytes for each partial region of the plurality of observation fields on the cultured cardiomyocytes;
- a motion amount calculating unit for calculating a motion amount of each detected motion;
- a pulsation information calculation unit that calculates pulsation information that is information of the characteristic amount of pulsation of the cultured cardiomyocytes;
- An evaluation value calculation unit for calculating an evaluation value corresponding to each of the plurality of observation visual fields calculated based on the pulsation information;
- a program that functions as a cell evaluation device including a visual field determination unit that determines an observation visual field to be observed on the cultured cardiomyocytes based on the evaluation value.
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Abstract
Description
培養心筋細胞の動きを、前記培養心筋細胞上の複数の観察視野のそれぞれの部分領域毎に検出する動き検出部と、
前記検出された各動きの動き量を算出する動き量算出部と、
前記算出された各動き量に基づいて、前記培養心筋細胞の拍動の特徴量の情報である拍動情報を算出する拍動情報算出部と、
前記拍動情報に基づいて算出される前記複数の観察視野に対応する評価値をそれぞれ算出する評価値算出部と、
前記評価値に基づいて、前記培養心筋細胞上で観察すべき観察視野を決定する視野決定部と
を備える細胞評価装置。
(2)
前記拍動情報は、
前記観察視野内における前記培養心筋細胞の拍動面積である
(1)に記載の細胞評価装置。
(3)
前記動き検出部は、
前記観察領域の動画像の各フレームについて前記部分領域毎に前記動きを検出し、
前記拍動情報算出部は、
前記動画像の複数のフレームの前記部分領域毎の前記動き量に基づいて、前記部分領域の前記培養心筋細胞の拍動を表す波形情報を生成する
(1)に記載の細胞評価装置。
(4)
前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内における前記培養心筋細胞の単位時間内の拍動数である
(3)に記載の細胞評価装置。
(5)
前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の拍動の収縮時間または弛緩時間である
(3)に記載の細胞評価装置。
(6)
前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の拍動の収縮速度または弛緩速度である
(3)に記載の細胞評価装置。
(7)
前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の前記部分領域間の拍動の波形の相関係数である
(3)に記載の細胞評価装置。
(8)
前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の拍動の伝搬速度および伝搬方向である
(3)に記載の細胞評価装置。
(9)
前記評価部は、
前記培養心筋細胞に対して施される所定の処理の前後において、前記複数の観察視野に対応する評価値をそれぞれ算出し、
前記観察視野決定部は、
前記培養心筋細胞に対して施される所定の処理の前後での前記評価値の差分に基づいて、前記複数の観察視野の中から所定数の観察視野を選択することにより、前記観察視野を決定する
(1)乃至(8)のいずれかに記載の細胞評価装置。
(10)
動き検出部が、培養心筋細胞の動きを、前記培養心筋細胞上の複数の観察視野のそれぞれの部分領域毎に検出し、
動き量算出部が、前記検出された各動きの動き量を算出し、
拍動情報算出部が、前記算出された各動き量に基づいて、前記培養心筋細胞の拍動の特徴量の情報である拍動情報を算出し、
評価値算出部が、前記拍動情報に基づいて算出される前記複数の観察視野に対応する評価値をそれぞれ算出し、
視野決定部が、前記評価値に基づいて、前記培養心筋細胞上で観察すべき観察視野を決定するステップ
を含む細胞評価方法。
(11)
コンピュータを、
培養心筋細胞の動きを、前記培養心筋細胞上の複数の観察視野のそれぞれの部分領域毎に検出する動き検出部と、
前記検出された各動きの動き量を算出する動き量算出部と、
前記算出された各動き量に基づいて、前記培養心筋細胞の拍動の特徴量の情報である拍動情報を算出する拍動情報算出部と、
前記拍動情報に基づいて算出される前記複数の観察視野に対応する評価値をそれぞれ算出する評価値算出部と、
前記評価値に基づいて、前記培養心筋細胞上で観察すべき観察視野を決定する視野決定部とを備える細胞評価装置として機能させる
プログラム。
Claims (11)
- 培養心筋細胞の動きを、前記培養心筋細胞上の複数の観察視野のそれぞれの部分領域毎に検出する動き検出部と、
前記検出された各動きの動き量を算出する動き量算出部と、
前記算出された各動き量に基づいて、前記培養心筋細胞の拍動の特徴量の情報である拍動情報を算出する拍動情報算出部と、
前記拍動情報に基づいて算出される前記複数の観察視野に対応する評価値をそれぞれ算出する評価値算出部と、
前記評価値に基づいて、前記培養心筋細胞上で観察すべき観察視野を決定する視野決定部と
を備える細胞評価装置。 - 前記拍動情報は、
前記観察視野内における前記培養心筋細胞の拍動面積である
請求項1に記載の細胞評価装置。 - 前記動き検出部は、
前記観察領域の動画像の各フレームについて前記部分領域毎に前記動きを検出し、
前記拍動情報算出部は、
前記動画像の複数のフレームの前記部分領域毎の前記動き量に基づいて、前記部分領域の前記培養心筋細胞の拍動を表す波形情報を生成する
請求項1に記載の細胞評価装置。 - 前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内における前記培養心筋細胞の単位時間内の拍動数である
請求項3に記載の細胞評価装置。 - 前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の拍動の収縮時間または弛緩時間である
請求項3に記載の細胞評価装置。 - 前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の拍動の収縮速度または弛緩速度である
請求項3に記載の細胞評価装置。 - 前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の前記部分領域間の拍動の波形の相関係数である
請求項3に記載の細胞評価装置。 - 前記拍動情報は、
前記波形情報に基づいて算出される前記観察視野内の前記培養心筋細胞の拍動の伝搬速度および伝搬方向である
請求項3に記載の細胞評価装置。 - 前記評価部は、
前記培養心筋細胞に対して施される所定の処理の前後において、前記複数の観察視野に対応する評価値をそれぞれ算出し、
前記観察視野決定部は、
前記培養心筋細胞に対して施される所定の処理の前後での前記評価値の差分に基づいて、前記複数の観察視野の中から所定数の観察視野を選択することにより、前記観察視野を決定する
請求項1に記載の細胞評価装置。 - 動き検出部が、培養心筋細胞の動きを、前記培養心筋細胞上の複数の観察視野のそれぞれの部分領域毎に検出し、
動き量算出部が、前記検出された各動きの動き量を算出し、
拍動情報算出部が、前記算出された各動き量に基づいて、前記培養心筋細胞の拍動の特徴量の情報である拍動情報を算出し、
評価値算出部が、前記拍動情報に基づいて算出される前記複数の観察視野に対応する評価値をそれぞれ算出し、
視野決定部が、前記評価値に基づいて、前記培養心筋細胞上で観察すべき観察視野を決定するステップ
を含む細胞評価方法。 - コンピュータを、
培養心筋細胞の動きを、前記培養心筋細胞上の複数の観察視野のそれぞれの部分領域毎に検出する動き検出部と、
前記検出された各動きの動き量を算出する動き量算出部と、
前記算出された各動き量に基づいて、前記培養心筋細胞の拍動の特徴量の情報である拍動情報を算出する拍動情報算出部と、
前記拍動情報に基づいて算出される前記複数の観察視野に対応する評価値をそれぞれ算出する評価値算出部と、
前記評価値に基づいて、前記培養心筋細胞上で観察すべき観察視野を決定する視野決定部とを備える細胞評価装置として機能させる
プログラム。
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