JP2020120618A - Manipulation system and driving method therefor - Google Patents

Abstract

To provide a manipulation system capable of stably and automatically collecting a minute object into a container and a driving method for the manipulation system.SOLUTION: A manipulation system comprises: a container in which a minute object is accommodated; a sample stage on which the container is mounted; a collection pipet for collecting the minute object; a drive control unit for controlling the sample stage and the collection pipet; a calculation unit for calculating an approximate expression of a plane which approximates a plurality of inspection points measured on a bottom surface of the container; and a storage unit for storing the approximate expression.SELECTED DRAWING: Figure 11

Description

The present invention relates to a manipulation system and a driving method for the manipulation system.

The cells that are the raw materials of biopharmaceuticals are required to be derived from single cells, and therefore it is required to select and recover specific cells from the culture solution. Patent Document 1 describes a manipulation system capable of collecting minute objects one by one.

JP, 2017-232065, A

By the way, as a container in which the cells to be collected are put, for example, a petri dish, a dish, a well plate and the like are known. Since such a container is generally manufactured by injection molding, it is difficult to make the bottom surface flat. For this reason, when automatically collecting cells, the height of the tip of the collecting instrument does not match the height of the cells on the bottom surface of the container, and stable automatic collection is difficult.

The present invention has been made in view of the above, and an object of the present invention is to provide a manipulation system and a driving method of the manipulation system capable of stably and automatically collecting a minute object in a container.

A manipulation system according to an aspect of the present invention includes a container for accommodating a microscopic object, a sample stage on which the container is mounted, a sampling pipette for sampling the microscopic object, the sample stage and the sampling. A drive control unit that controls the pipette, a calculation unit that calculates an approximate expression of a plane that approximates a plurality of inspection points measured on the bottom surface of the container, and a storage unit that stores the approximate expression.

According to this, since the approximated virtual plane is averaged from the bottom surface of the actual container, the error between the virtual surface and the actual bottom surface becomes small. Therefore, since it is not necessary to use an expensive container having a precise flatness of the bottom surface, it is possible to suppress the cost from being generated due to an additional grinding finishing step and the use of a custom-made product.

In the manipulation system according to the aspect of the present invention, the calculation unit calculates the position coordinates of the minute target object based on the approximate expression stored in the storage unit. According to this, the tip of the sampling pipette can be appropriately aligned with the height of the minute object existing on the bottom surface of the container, so that the minute object in the container can be stably and automatically sampled.

In the manipulation system according to the aspect of the present invention, the approximate expression is calculated based on coordinate information of the plurality of inspection points measured by bringing the tip of the sampling pipette into contact with the bottom surface of the container. According to this, since the approximate expression is calculated based on the position where the sampling pipette that actually collects the minute object contacts the bottom surface of the container, when collecting the minute object, the sampling pipette is more suitable. The tip can be aligned with the micro object.

In the manipulation system according to one aspect of the present invention, the drive control unit moves the sampling pipette in a direction normal to a mounting surface of the sample stage, and the storage unit stores the tip of the sampling pipette in the normal direction. The coordinates of the inspection point in the normal direction are stored based on the coordinate information of the position in contact with the bottom surface of the container. According to this, since the approximate expression is calculated based on the position where the sampling pipette that actually collects the minute object contacts the bottom surface of the container, when collecting the minute object, the sampling pipette is more suitable. The tip can be aligned with the micro object.

In the manipulation system according to one aspect of the present invention, the drive control unit moves the sampling pipette forward and backward in a state in which the sampling pipette is reciprocally moved within a predetermined range in one direction parallel to the mounting surface. Move it in the direction normal to the writing surface. According to this, the behavior of the tip of the sampling pipette changes when the sampling pipette contacts the bottom surface of the container. Therefore, the operator can confirm that the tip of the sampling pipette has come into contact with the bottom surface of the container.

In the manipulation system according to one aspect of the present invention, the storage unit performs a predetermined operation of inputting coordinates of a tip of the sampling pipette while the drive control unit is moving the sampling pipette. The coordinates of the tip of the sampling pipette at the time point are stored as the coordinates of the inspection point. According to this, since the approximate expression is calculated based on the position where the sampling pipette that actually collects the minute object contacts the bottom surface of the container, when collecting the minute object, the sampling pipette is more suitable. The tip can be aligned with the micro object.

In the manipulation system according to the aspect of the present invention, the sampling pipette includes a tip portion whose longitudinal direction is inclined at a predetermined inclination angle with respect to the mounting surface of the sample stage. According to this, when the collection pipette comes into contact with the bottom surface of the container, the tip of the collection pipette bends, and an error between the approximated virtual plane and the actual bottom surface can be allowed.

A driving method of a manipulation system according to an aspect of the present invention is a manipulation including a container in which a minute object is housed, a sample stage on which the container is placed, and a sampling pipette for sampling the minute object. A method of driving a system, comprising the steps of bringing the tip of the sampling pipette into contact with a plurality of preset inspection points on the bottom surface of the container, and the sampling pipette at the time of contacting each of the plurality of inspection points. Storing the coordinates of the tip of the as the coordinates of the inspection point, based on the coordinates of the plurality of inspection points, calculating an approximate expression of a plane that approximates the plurality of inspection points, based on the approximate expression Calculating the position coordinates of the minute object.

According to this, since the approximated virtual plane is averaged from the bottom surface of the actual container, the error between the virtual surface and the actual bottom surface becomes small. Therefore, the position of the tip of the pipette for collection can be preferably controlled so that the position of the minute object existing on the bottom surface of the container can be adjusted when the minute object is sampled. Therefore, it is possible to stably and automatically collect the minute object in the container. Further, since it is not necessary to use an expensive container having a precise flatness of the bottom surface, it is possible to suppress the cost generation due to the additional grinding finishing process and the use of a custom-made product.

According to the present invention, it is possible to provide a manipulation system and a driving method of the manipulation system that stably and automatically collect minute objects in a container.

FIG. 1 is a perspective view showing a configuration example of a manipulation system according to an embodiment. FIG. 2 is an enlarged perspective view showing a part of the manipulation system shown in FIG. FIG. 3 is a schematic diagram showing a configuration example of the manipulation system according to the embodiment. FIG. 4 is a block diagram showing a configuration example of the manipulation system according to the embodiment. FIG. 5 is a block diagram showing a configuration example of the detection unit. FIG. 6 is a block diagram showing a configuration example of the storage unit. FIG. 7 is a diagram showing an example of the screen of the display unit. FIG. 8 is a side view showing a configuration example of the sampling pipette according to the embodiment. FIG. 9: is a figure which expands and shows the front-end|tip part of the sampling pipette which concerns on embodiment. FIG. 10 is an enlarged view showing the tip portion of the sampling pipette according to the embodiment. FIG. 11 is a plan view showing an example of the container according to the embodiment. FIG. 12 is an explanatory diagram for explaining the operation of the sampling pipette of the embodiment. FIG. 13 is an explanatory diagram for explaining the operation of the sampling pipette of the embodiment. FIG. 14 is a flowchart showing an example of the operation of the embodiment. FIG. 15 is a flowchart showing an example of the operation of the embodiment. FIG. 16 is a schematic view showing an enlarged part of the shape of the bottom surface of the well of the embodiment.

Modes (embodiments) for carrying out the present invention will be described in detail with reference to the drawings. The present invention is not limited to the contents described in the embodiments below. Further, the components described below include those that can be easily conceived by those skilled in the art, those that are substantially the same, and those that are within the equivalent range. Furthermore, the components described below can be combined as appropriate.

(Embodiment)
FIG. 1 is a perspective view showing a configuration example of a manipulation system according to an embodiment. FIG. 2 is an enlarged perspective view showing a part of the manipulation system shown in FIG. FIG. 3 is a schematic diagram showing a configuration example of the manipulation system according to the embodiment. The manipulation system 100 shown in FIG. 1 to FIG. 3 is an apparatus that sorts out desired microscopic objects one by one from among a plurality of microscopic objects contained in a container 38. The minute object is, for example, a cell.

As shown in FIG. 1 to FIG. 3, the manipulation system 100 includes a base 1, a sampling pipette 10, a pipette holding section 15, a manipulator 20, a sample stage 30, and a first imaging device 45. The microscope unit 40, the controller 50, the second microscope unit 60 including the second imaging device 65, the third imaging device 75, the joystick 57, the input unit 58, and the display unit 80 are provided. In the embodiment, the X-axis direction is one direction parallel to the mounting surface 30a of the sample stage 30. In the embodiment, the Y-axis direction is a direction parallel to the mounting surface 30a and orthogonal to the X-axis direction. In the embodiment, the Z-axis direction is the normal line direction of the mounting surface 30a. The arrangement of the base 1 is adjusted, for example, so that the mounting surface 30a is a horizontal plane orthogonal to the vertical direction.

The collection pipette 10 is a tubular instrument for collecting cells. The sampling pipette 10 has, for example, a needle shape. The material of the sampling pipette 10 is, for example, glass. An opening 103a for collecting cells is provided at the tip of the collecting pipette 10. Details of the sampling pipette 10 will be described later with reference to FIGS. 8, 9 and 10.

The pipette holding portion 15 is a tubular instrument for holding the sampling pipette 10. The material of the pipette holding portion 15 is, for example, glass or metal. One end of the pipette holding portion 15 is connected to the sampling pipette 10. The other end of the pipette holder 15 is connected to the electric micropump 29 of the manipulator 20. The internal pressure of the pipette holding unit 15 and the sampling pipette 10 is reduced or increased by the pressure P supplied from the electric micropump 29. When the internal pressure of the collection pipette 10 is lower than the normal pressure, the collection pipette 10 can suction and collect cells from the opening 103a (see FIG. 9) at the tip. When the internal pressure of the collection pipette 10 is higher than normal pressure, the collection pipette 10 can discharge (release) the collected cells to the outside from the opening 103a at the tip of the collection pipette 10. The pipette holding portion 15 is connected to the manipulator 20 via a connecting portion 28 described below.

The manipulator 20 can operate the pipette holder 15 and the sampling pipette 10 by operating in the X-axis direction, the Y-axis direction, and the Z-axis direction. The manipulator 20 includes an X-axis table 21, a Y-axis table 22, a Z-axis table 23, drive devices 26 and 27 (for example, motors), connecting portions 28 and 71, and an electric micropump 29. The X-axis table 21 moves in the X-axis direction when driven by the drive device 26. The Y-axis table 22 moves in the Y-axis direction when driven by the drive device 26. The Z-axis table 23 moves in the Z-axis direction when driven by the drive device 27. The drive devices 26 and 27 and the electric micropump 29 are connected to the controller 50.

The connecting portion 28 connects the pipette holding portion 15 to the manipulator 20. The connecting portion 71 connects the lens barrel 411 of the first microscope unit 40 to the manipulator 20. The connecting portions 28 and 71 are made of metal, for example.

In the manipulator 20, the Z-axis table 23 is mounted on the Y-axis table 22. As a result, the pipette holding unit 15 and the sampling pipette 10 can move in the Y-axis direction by the same distance as the Y-axis table 22 as the Y-axis table 22 moves. Further, the Y-axis table 22 is mounted on the X-axis table 21. As a result, the pipette holding unit 15 and the sampling pipette 10 can move in the X-axis direction by the same distance as the X-axis table 21 as the X-axis table 21 moves. Further, the pipette holding unit 15 and the sampling pipette 10 can move in the Z-axis direction by the same distance as the Z-axis table 23 as the Z-axis table 23 moves.

The sample stage 30 supports the container 38. For example, the container 38 is mounted on the mounting surface 30a of the sample stage 30. The container 38 is a well plate in the embodiment. The sample stage 30 includes an X-axis stage 31, a Y-axis stage 32, and a driving device 36. The X-axis stage 31 moves in the X-axis direction when driven by the drive device 36. The Y-axis stage 32 moves in the Y-axis direction when driven by the driving device 36. The X-axis stage 31 is mounted on the Y-axis stage 32. The drive device 36 is connected to the controller 50.

Although the case where one container 38 is mounted on the sample stage 30 is shown in the embodiment, the number of containers 38 mounted on the sample stage 30 is not limited to one, and a plurality of containers 38 may be mounted. But it's okay. In the embodiment, the sample stage 30 has a rectangular shape in plan view (hereinafter referred to as a planar shape), but it may not be rectangular, and may be circular, for example. Although the container 38 has a rectangular planar shape in the embodiment, the container 38 may not be rectangular and may be circular, for example. The container 38 may be a petri dish or a dish.

The first microscope unit 40 is arranged above the sample stage 30. The first microscope unit 40 includes a first microscope 41, a first imaging device 45, and a light source that emits light toward the mounting surface 30a of the sample stage 30. The first microscope 41 includes a lens barrel 411, an objective lens 412, and a driving device 414. The first microscope 41 is a stereoscopic microscope in which the objective lens 412 is located above the container 38. The lens barrel 411 of the first microscope unit 40 moves in the Z-axis direction when driven by the driving device 414. Thereby, the first microscope 41 can adjust the focus position. A plurality of types of objective lenses 412 may be prepared according to a desired magnification. The first imaging device 45 includes, for example, a solid-state imaging device such as a CMOS image sensor or a CCD image sensor. The first imaging device 45 can image the tip of the sampling pipette 10 from the Z-axis direction via the first microscope 41. The first microscope unit 40 may include an eyepiece lens.

The first microscope unit 40 operates in the Z-axis direction by being driven by the driving device 414. The drive device 414 is driven by the drive control unit 55 described later. The lens barrel 411 is connected to the manipulator 20 by a connecting portion 71. As a result, the manipulator 20, the pipette holder 15, and the sampling pipette 10 move in the Z-axis direction in conjunction with the operation of the first microscope unit 40.

The second microscope unit 60 is arranged laterally of the sample stage 30. The second microscope unit 60 includes a second microscope 61 and a second image pickup device 65. The second microscope 61 includes a lens barrel 611, an objective lens 612, and a driving device 613. The objective lens 612 moves in the Y-axis direction when driven by the driving device 613. Thereby, the second microscope 61 can adjust the focus position. The second imaging device 65 includes a solid-state imaging device such as a CMOS image sensor or a CCD image sensor, for example. The second imaging device 65 can image the tip of the sampling pipette 10 from the Y-axis direction via the second microscope 61. The second microscope unit 60 is fixed to the base 1 via the fixture 3.

The third imaging device 75 is fixed to the base 1 via the fixture 4. The fixture 4 can move in the X-axis direction and the Y-axis direction, and can extend in the Z-axis direction. Accordingly, the third imaging device 75 can image the sample stage 30 side from the obliquely upper direction of the sample stage 30 that intersects the X-axis direction, the Y-axis direction, and the Z-axis direction, respectively.

The input unit 58 is a keyboard, a touch panel, or the like. The joystick 57 and the input unit 58 are connected to the controller 50. The operator can input a command to the controller 50 via the joystick 57 and the input unit 58. When the operator operates the joystick 57, the control signal Vsig1 is output from the joystick 57 to the controller 50. When the operator operates the input unit 58, the control signal Vsig2 is output from the input unit 58 to the controller 50.

Next, the function of the controller 50 will be described with reference to FIG. FIG. 4 is a block diagram showing a configuration example of the manipulation system according to the embodiment. The controller 50 includes hardware resources such as a CPU (central processing unit) as a calculation unit and a hard disk as a storage unit, a RAM (Random Access Memory), and a ROM (Read Only Memory).

As shown in FIG. 4, the controller 50 has, as its functions, an image input unit 51a, an image output unit 51b, an image processing unit 52, a detection unit 53, an image editing unit 54, a drive control unit 55, and The storage unit 56 and the calculation unit 59 are included. The image input unit 51a, the image output unit 51b, the image processing unit 52, the detection unit 53, the image editing unit 54, the drive control unit 55, and the calculation unit 59 are realized by the above calculation means. The storage unit 56 is realized by the storage unit described above. The controller 50 performs various calculations based on the programs stored in the storage unit 56, and outputs drive signals so that the drive control unit 55 performs various controls according to the calculation results.

The drive control unit 55 includes a drive unit 414 of the first microscope unit 40, drive units 26 and 27 of the manipulator 20, an electric micropump 29, a drive unit 36 of the sample stage 30, and a drive unit 613 of the second microscope unit 60. And control. The drive controller 55 supplies drive signals Vz1, Vxy2, Vz2, Vxy3, Vy4 (see FIG. 3) to the drive devices 414, 26, 27, 36, 613, respectively. The drive controller 55 supplies a drive signal Vmp (see FIG. 3) to the electric micropump 29. The drive control unit 55 may supply the drive signals Vz1, Vxy2, Vz2, Vxy3, Vy4, and Vmp via a driver, an amplifier, or the like provided as necessary.

The first image signal Vpix1 (see FIG. 3) output from the first imaging device 45, the second image signal Vpix2 (see FIG. 3) output from the second imaging device 65, and the third imaging device 75 are output. The third image signal Vpix3 (see FIG. 3) is input to the image input unit 51a. The image processing unit 52 receives the first image signal Vpix1, the second image signal Vpix2, and the third image signal Vpix3 from the image input unit 51a, and performs image processing. The image output unit 51b outputs the image information image-processed by the image processing unit 52 to the storage unit 56 and the display unit 80.

For example, the first image signal Vpix1 includes the first image captured by the first image capturing device 45 through the first microscope 41 and the capturing time thereof. The first image is a moving image. Similarly, the second image signal Vpix2 includes the second image captured by the second image capturing device 65 through the second microscope 61 and the capturing time thereof. The second image is also a moving image. The third image signal Vpix3 includes the third image captured by the third image capturing device 75 and the capturing time thereof. The third image is also a moving image.

The first image, the second image, and the third image are color images or gray images, respectively. The gray image is an image including white and black and gray which is an intermediate color between white and black. The gray image includes a plurality of gray levels in gray. The gradation means the number of gradations of color and brightness.

The image processing unit 52 performs image processing such as image enlargement and binarization on at least one of the first image and the second image in order to facilitate detection of cells. The binarization of an image is to convert a color image or a gray image (hereinafter referred to as an original image) into a binary image (binary image) that has no shading and has only white and black. The image processing unit 52 generates, for at least one of the first image and the second image, an enlarged image obtained by enlarging the original image and a binary image obtained by binarizing the original image. The image processing unit 52 may enlarge the original image and generate a binarized enlarged binary image. The image processing unit 52 outputs at least one kind of the enlarged image, the binary image, and the enlarged binary image to the detecting unit 53 and the image editing unit 54 as image information.

The detection unit 53 receives the image information from the image processing unit 52, and automatically detects the position and number of cells based on the received image information. Then, the detection unit 53 outputs the detection result to the image editing unit 54 and the storage unit 56.

FIG. 5 is a block diagram showing a configuration example of the detection unit. As shown in FIG. 5, the detection unit 53 includes a position detection unit 531, a distance detection unit 532, and a number detection unit 533 as its functions. The position detection unit 531 automatically detects the position of the cell ce (see FIG. 7, which will be described later) based on the first image or the second image image-processed by the image processing unit 52. The distance detection unit 532 automatically detects the separation distance between the cell ce detected by the position detection unit 531 and the opening 103a (see FIG. 9 described later) of the tip 103. The number detection unit 533 automatically detects the number of cells ce based on the first image or the second image processed by the image processing unit 52. Examples of the image processed by the image processing unit 52 include at least one kind of an enlarged image, a binary image, and an enlarged binary image. The detection results of the position detection unit 531, the distance detection unit 532, and the number detection unit 533 are output to the image editing unit 54 and the storage unit 56, respectively.

The image editing unit 54 associates the first image signal Vpix1, the second image signal Vpix2, and the third image signal Vpix3 with each other based on the image capturing time to generate the edited image signal Vpix4. The edited image signal Vpix4 includes an edited image. The edited image is a moving image in which the first image, the second image, and the third image captured at the same time are displayed side by side. In the edited image, each of the first image, the second image, and the third image may be an original image, or may be an enlarged image, a binary image, or an enlarged binary image obtained by performing image processing on the original image. The image output unit 51b outputs the first image signal Vpix1, the second image signal Vpix2, the third image signal Vpix3, and the edited image signal Vpix4 to the storage unit 56.

The image editing unit 54 receives the detection result of the cells ce from the detection unit 53. When the detection unit 53 detects the position of the cell, the image editing unit 54 may reflect the detection result on the edited image. For example, the image editing unit 54 may automatically indicate the position of the cell ce detected by the detecting unit 53 with an arrow in the enlarged image, the binary image, or the enlarged binary image received from the image processing unit 52, or the detecting unit 53 may The detected cell position may be automatically surrounded by a frame line.

FIG. 6 is a block diagram showing a configuration example of the storage unit. As shown in FIG. 6, the storage unit 56 has, as its functions, a program storage unit 56a that stores a program for operating the manipulation system 100, an image storage unit 56b that stores an image signal, and an inspection point SPn described later. (See FIG. 11) A coordinate storage unit 56c for storing coordinates is included. The image storage unit 56b includes a first image storage unit 561 that stores the first image signal Vpix1, a second image storage unit 562 that stores the second image signal Vpix2, and a third image storage that stores the third image signal Vpix3. A unit 563 and an edited image storage unit 564 that stores the edited image signal Vpix4 are included.

The image output unit 51b outputs at least one image signal of the first image signal Vpix1, the second image signal Vpix2, the third image signal Vpix3, and the edited image signal Vpix4 to the display unit 80 (see FIG. 3). .. The image output unit 51b selects an image signal to be output to the display unit 80 according to the control signal Vsig1 input to the controller 50, and outputs the image signal to the display unit 80. The image output unit 51b may select an image signal to be output to the display unit 80 and output it to the display unit 80 according to the control signal Vsig2 input to the controller 50.

The display unit 80 is, for example, a liquid crystal panel or the like. The display unit 80 is connected to the controller 50. The display unit 80 displays various character information, images, etc. on the screen. FIG. 7 is a diagram showing an example of the screen of the display unit. FIG. 7 illustrates a case where an edited image is displayed on the screen 81 of the display unit 80. In the edited image, the first image 811, the second image 812, and the third image 813 captured at the same timing are arranged side by side. The display unit 80 may display the edited image in real time or almost in real time, or may read the edited image stored in the edited image storage unit 564 and display it for reproduction.

The operator can operate the joystick 57 or the input section 58 to switch the image displayed on the screen 81. By operating the joystick 57 or the input unit 58 by the operator, the edited image (moving image) displayed on the screen 81 can be temporarily stopped. Based on the program stored in the program storage unit 56a (see FIG. 6), the controller 50 (see FIG. 4) automatically displays a predetermined image on the screen 81 or automatically displays the image displayed on the screen 81. You may switch.

The image displayed on the screen 81 is not limited to the edited image, and may be only the first image 811, the second image 812, or the third image 813. The image displayed on the screen is not limited to the original image and may be an image processed by the image processing unit 52 (for example, at least one of an enlarged image, a binary image, and an enlarged binary image). May be. For example, the images displayed on the screen 81 may be the first image 811, an enlarged image in which a part of the first image 811 is enlarged, and an enlarged binary image in which the enlarged image is binarized. Good.

FIG. 8 is a side view showing a configuration example of the sampling pipette according to the embodiment. 9 and 10 are enlarged views showing the tip of the sampling pipette according to the embodiment. As shown in FIG. 8, the sampling pipette 10 is a glass needle that is bent in two stages. Specifically, the collecting pipette 10 is, in plan view, a tubular central portion 101, a tubular rear portion 102 connected to one end of the central portion 101, and a tubular tip portion connected to the other end of the central portion 101. And 103. The rear part 102 is a part on the side held by the pipette holding part 15. The tip portion 103 is a portion on the side where a minute object such as a cell is collected. An opening 103a is provided at the tip of the tip 103.

A first bent portion 104 exists between the central portion 101 and the rear portion 102. A second bent portion 105 exists between the central portion 101 and the tip portion 103. The longitudinal direction of the central portion 101 and the longitudinal direction of the rear portion 102 intersect each other. The longitudinal direction of the central portion 101 and the longitudinal direction of the tip portion 103 intersect each other. The length L1 in the longitudinal direction of the central portion 101, the length L2 in the longitudinal direction of the rear portion 102, and the length L3 in the longitudinal direction of the tip portion 103 are L3<L1 and L3<L2. According to this, it is easy to dispose the tip portion 103, which is the tip portion of the sampling pipette 10, in the container 38.

The shape obtained by cutting the central portion 101 along a plane orthogonal to the longitudinal direction of the central portion 101 is circular. The shape obtained by cutting the rear portion 102 in a plane orthogonal to the longitudinal direction of the rear portion 102 is circular. The shape obtained by cutting the tip portion 103 along a plane orthogonal to the longitudinal direction of the tip portion 103 is circular. The outer diameter φ21 of the rear portion 102 and the outer diameter φ31 of the tip portion 103 are φ21>φ31. The outer diameter φ11 of the first pipe portion decreases from the first bent portion 104 side toward the second bent portion 105 side.

For example, the central portion 101 includes a narrowed portion 106 having a large change in outer diameter between the first bent portion 104 and the second bent portion 105. In the central portion 101, the second portion 101b located between the narrowed portion 106 and the second bent portion 105 is smaller than the first portion 101a located between the narrowed portion 106 and the first bent portion 104. The outer diameter φ11 is small. The length L4 in the longitudinal direction of the second portion 101b is longer than the length L3 in the longitudinal direction of the tip portion 103.

As shown in FIG. 9, the inner diameter φ32 of the tip portion 103 is substantially constant between the opening 103a and the second bent portion 105. The inner diameter φ32 of the tip portion 103 and the diameter φce of the cell ce that is the collection target of the collection pipette 10 are φ32>φce. The inner diameter φ32 of the tip portion 103 is preferably about several μm larger than the diameter φce of the cells ce. Thereby, the collection pipette 10 can introduce the cells ce into the inside of the tip portion 103.

The bending angle θ1 of the first bending portion 104 and the bending angle θ2 of the second bending portion 105 are θ1>θ2. The bending angle θ1 of the first bending portion 104 is an obtuse angle formed by the longitudinal direction of the central portion 101 and the longitudinal direction of the rear portion 102. The bending angle θ2 of the second bent portion 105 is an obtuse angle formed by the longitudinal direction of the central portion 101 and the longitudinal direction of the tip portion 103.

The tip portion 103 has a longitudinal direction inclined at an inclination angle θ3 with respect to the horizontal plane. The inclination angle θ3 is, for example, 2° or more and 3° or less. As shown in FIG. 10, when the tip of the tip 103 on the side of the opening 103a is in contact with the bottom surface 38b of the container 38, the distance H1 between the bottom surface 38b of the container 38 and the second bent portion 105 in the Z-axis direction is , For example, 30 μm. According to this, in the sampling pipette 10, the tip portion 103 can bend when the tip on the side of the opening 103a comes into contact with the bottom surface 38b of the well 38a of the container 38.

Next, a method of calculating the Z coordinate of the bottom surface 38b of the container 38 in which the collected cells ce are stored by the manipulation system 100 before performing the collection operation of the cells ce will be described. FIG. 11 is a plan view showing an example of the container according to the embodiment. As shown in FIG. 11, the container 38 is, in the embodiment, a well plate including six wells 38 a. The well 38a of the container 38 contains the liquid 39 (see FIG. 7) and the cells ce before collection. The cells ce before collection are placed on the bottom surface 38b of the well 38a.

The inspection region SZ is set on the bottom surface 38b of the well 38a in plan view. The inspection area SZ is a predetermined area including the cells ce. The inspection area SZ is determined by a plurality of inspection points SPn. The number ne of inspection points SPn is three in the present embodiment. The inspection point SPn includes a first inspection point SP1, a second inspection point SP2, and a third inspection point SP3. The inspection area SZ is determined by the first inspection point SP1, the second inspection point SP2, and the third inspection point SP3. The inspection area SZ has a rectangular shape including the first inspection point SP1, the second inspection point SP2, and the third inspection point SP3 at its apex. The inspection region SZ has a rectangular shape in the embodiment. The inspection area SZ may have a square shape.

The X coordinate X1 and Y coordinate Y1 of the first inspection point SP1, the X coordinate X2 and Y coordinate Y2 of the second inspection point SP2, and the X coordinate X3 and Y coordinate Y3 of the third inspection point SP3 will be described later with reference to FIG. In step ST14 shown in (4), the setting is made by the operator inputting through the input unit 58. The controller 50 inputs the XY coordinates (X1, Y1) of the first inspection point SP1, the XY coordinates (X2, Y2) of the second inspection point SP2, and the XY coordinates of the third inspection point SP3 (( The coordinate information of (X3, Y3) is stored in the coordinate storage unit 56c of the storage unit 56.

(First Method for Determining Z Coordinate of nth Inspection Point)
The Z coordinate Z1 of the first inspection point SP1 is the Z coordinate of the bottom surface 38b of the container 38 at the XY coordinates (X1, Y1) of the first inspection point SP1. First, the drive control unit 55 moves the sampling pipette 10 to the XY coordinates (X1, Y1) of the first inspection point SP1 stored in the coordinate storage unit 56c. Next, the drive control unit 55 moves the tip of the sampling pipette 10 downward in the Z-axis direction. The coordinate storage unit 56c stores the Z coordinate Z1 of the first inspection point SP1 based on the coordinates of the position where the tip of the sampling pipette 10 contacts the bottom surface 38b.

The Z coordinate Z2 of the second inspection point SP2 is the Z coordinate of the bottom surface 38b of the container 38 at the XY coordinates (X2, Y2) of the second inspection point SP2. Similar to the first inspection point SP, the drive control unit 55 moves the tip of the sampling pipette 10 downward in the Z-axis direction at the XY coordinates (X2, Y2) of the second inspection point SP2. The coordinate storage unit 56c stores the Z coordinate Z2 of the second inspection point SP2 based on the coordinates of the position where the tip of the sampling pipette 10 contacts the bottom surface 38b.

The Z coordinate Z3 of the third inspection point SP3 is the Z coordinate of the bottom surface 38b of the container 38 at the XY coordinates (X3, Y3) of the third inspection point SP3. Similar to the first inspection point SP, the drive control unit 55 moves the tip of the sampling pipette 10 downward in the Z-axis direction at the XY coordinates (X3, Y3) of the third inspection point SP3. The coordinate storage unit 56c stores the Z coordinate Z3 of the third inspection point SP3 based on the coordinates of the position where the tip of the sampling pipette 10 contacts the bottom surface 38b.

In the present embodiment, the number ne of inspection points SPn is three, but the Z coordinate Zn of the nth inspection point SPn can be similarly obtained even if the number ne is four or more. The drive control unit 55 moves the tip of the sampling pipette 10 downward in the Z-axis direction at the XY coordinates (Xn, Yn) of the nth inspection point SPn preset in the coordinate storage unit 56c via the input unit 58. Let The coordinate storage unit 56c stores the Z coordinate Zn of the nth inspection point SPn based on the coordinate information of the position where the tip of the sampling pipette 10 contacts the bottom surface 38b.

(Second Method of Determining Z Coordinate of nth Inspection Point)
12 and 13 are explanatory diagrams for explaining the operation of the sampling pipette of the embodiment. The Z coordinate Z1 of the first inspection point SP1 is the Z coordinate of the bottom surface 38b of the container 38 at the XY coordinates (X1, Y1) of the first inspection point SP1. First, the drive control unit 55 moves the sampling pipette 10 to the XY coordinates (X1, Y1) of the first inspection point SP1 stored in the coordinate storage unit 56c. Next, the drive controller 55 causes the sampling pipette 10 to reciprocate within a predetermined range in one direction parallel to the mounting surface 30 a of the sample stage 30. The one direction is a direction parallel to the Y-axis direction in the present embodiment. The predetermined range is, for example, 500 μm centering on Y1. The reciprocating movement of the sampling pipette 10 can be confirmed by the first imaging device 45 that images in the Z-axis direction via the first microscope 41. The distal end portion 103 of the sampling pipette 10 has a longitudinal direction parallel to the X-axis direction in a plan view, and thus reciprocates in a direction intersecting the longitudinal direction in a plan view, as shown in FIG. The drive control unit 55 moves the tip of the sampling pipette 10 downward in the Z-axis direction while the sampling pipette 10 is reciprocatingly moved. When the tip of the sampling pipette 10 comes into contact with the bottom surface 38b of the container 38, the tip portion 103 behaves as if it were dragged onto the bottom surface 38b, as shown in FIG. By changing the behavior of the tip portion 103 of the sampling pipette 10, the operator can confirm that the tip of the sampling pipette 10 has come into contact with the bottom surface 38b of the container 38. If the tip 103 behaves like being dragged by the bottom surface 38b, the operator determines that the tip of the sampling pipette 10 has contacted the bottom surface 38b of the container 38, and inputs the coordinates of the tip of the sampling pipette 10. A predetermined operation is performed. The predetermined operation is, for example, operation of a predetermined button of the input unit 58. The coordinate storage unit 56c stores the tip of the sampling pipette 10 at the time when a predetermined operation of inputting the coordinates of the tip of the sampling pipette 10 is started while the drive control unit 55 moves the sampling pipette 10 downward. Is stored as the Z coordinate Z1 of the first inspection point SP1.

The Z coordinate Z2 of the second inspection point SP2 is the Z coordinate of the bottom surface 38b of the container 38 at the XY coordinates (X2, Y2) of the second inspection point SP2. Similar to the first inspection point SP, the drive control unit 55 reciprocates the tip of the sampling pipette 10 in the Y-axis direction and moves downward in the Z-axis direction at the XY coordinates (X2, Y2) of the second inspection point SP2. Move to. If the tip portion 103 behaves like being dragged by the bottom surface 38b, the operator determines that the tip of the sampling pipette 10 has contacted the bottom surface 38b of the container 38, and inputs the coordinates of the tip of the sampling pipette 10. A predetermined operation is performed. The coordinate storage unit 56c stores the coordinates of the tip of the sampling pipette 10 when a predetermined operation of inputting the coordinates of the tip of the sampling pipette 10 is executed while the drive control unit 55 is moving the sampling pipette 10. Is stored as the Z coordinate Z2 of the second inspection point SP2.

The Z coordinate Z3 of the third inspection point SP3 is the Z coordinate of the bottom surface 38b of the container 38 at the XY coordinates (X3, Y3) of the third inspection point SP3. Similar to the first inspection point SP, the drive control unit 55 reciprocates the tip of the sampling pipette 10 in the Y-axis direction and moves downward in the Z-axis direction at the XY coordinates (X3, Y3) of the third inspection point SP3. Move to. If the tip 103 behaves like being dragged by the bottom surface 38b, the operator determines that the tip of the sampling pipette 10 has contacted the bottom surface 38b of the container 38, and inputs the coordinates of the tip of the sampling pipette 10. A predetermined operation is performed. The coordinate storage unit 56c stores the coordinates of the tip of the sampling pipette 10 when a predetermined operation for inputting the coordinates of the tip of the sampling pipette 10 is executed while the drive control unit 55 is moving the sampling pipette 10. Is stored as the Z coordinate Z3 of the third inspection point SP3.

In the present embodiment, the number ne of inspection points SPn is three, but the Z coordinate Zn of the nth inspection point SPn can be similarly obtained even if the number ne is four or more. The drive control unit 55 reciprocates the tip of the sampling pipette 10 in the Y-axis direction at the XY coordinates (Xn, Yn) of the n-th inspection point SPn preset in the coordinate storage unit 56c via the input unit 58. While moving in the Z-axis direction and downward. If the tip portion 103 behaves like being dragged by the bottom surface 38b, the operator determines that the tip of the sampling pipette 10 has contacted the bottom surface 38b of the container 38, and inputs the coordinates of the tip of the sampling pipette 10. A predetermined operation is performed. The coordinate storage unit 56c stores the coordinates of the tip of the sampling pipette 10 when a predetermined operation of inputting the coordinates of the tip of the sampling pipette 10 is executed while the drive control unit 55 is moving the sampling pipette 10. Is stored as the Z coordinate Zn of the nth inspection point SPn.

By measuring the Z coordinate Zn of each inspection point SPn by the above-mentioned first method or second method, the coordinate information of the coordinates (Xn, Yn, Zn) of each inspection point SPn can be obtained. In the present embodiment, the coordinates (X1, Y1, Z1) of the first inspection point SP1, the coordinates (X2, Y2, Z2) of the second inspection point SP2, and the coordinates (X3, Y3, Z3) of the third inspection point SP3. The coordinate information of is obtained. The calculator 59 calculates an approximate expression of the plane of the inspection area SZ based on the coordinate information of each inspection point SPn. Specifically, for example, the drive control unit 55 causes the coordinates (X1, Y1, Z1), (X2, Y2, Z2),..., (Xne, from the first inspection point SP1 to the nth inspection point SPn). An approximate expression of a plane that approximates Yne, Zne) is calculated. The approximate expression is represented by Z=aX+bY+c. a, b and c are constants. The calculation unit 59 calculates the approximate expression by, for example, the method of least squares. In the present embodiment, since the number ne of inspection points SPn is 3, the approximate plane is the coordinates (X1, Y1, Z1) of the first inspection point SP1, the coordinates (X2, Y2, Z2) of the second inspection point SP2, and It is a plane passing through the coordinates (X3, Y3, Z3) of the third inspection point SP3. When the number ne of inspection points SPn is 3, the calculation unit 59 may calculate the approximate expression by solving the simultaneous equations. The storage unit 56 stores the approximate expression calculated by the calculation unit 59.

As described above, the manipulation system 100 of this embodiment includes the container 38, the sample stage 30, the sampling pipette 10, the drive control unit 55, the calculation unit 59, and the storage unit 56. The container 38 stores cells ce (microscopic objects). A container 38 is placed on the sample stage 30. The collection pipette 10 collects the cells ce. The drive control unit 55 controls the sample stage 30 and the sampling pipette 10. The calculator 59 calculates a plane approximation formula that approximates the plurality of inspection points SPn measured on the bottom surface 38b of the container 38. The storage unit 56 stores the approximate expression.

According to this, since the approximated virtual plane is averaged from the bottom surface 38b of the actual container 38, the error between the virtual surface and the actual bottom surface 38b becomes small. Therefore, when collecting the cells ce, the position of the tip of the collecting pipette 10 can be suitably controlled so that the cells can be aligned with the height of the cells ce existing on the bottom surface 38b of the container 38. Therefore, the cells ce in the container 38 can be stably and automatically collected. Further, since it is not necessary to use an expensive container having a precise flatness of the bottom surface, it is possible to suppress the cost generation due to the additional grinding finishing process and the use of a custom-made product.

When collecting the cell ce, the controller 50 first detects the X coordinate Xce and the Y coordinate Yce of the cell ce. The calculation unit 59 calculates the Z coordinate Zce of the cell ce by substituting the X coordinate Xce for X of the approximate expression Z=aX+bY+c stored in the storage unit 56 and substituting the Y coordinate Yce for Y. Thereby, the movement distance of the manipulator 20 in the Z direction for obtaining an appropriate position of the collection pipette 10 when collecting the cells ce from the container 38 can be obtained.

Next, a method of acquiring the coordinates of the inspection point SPn and calculating the approximate expression of the plane of the inspection area SZ in the manipulation system 100 will be described. Before starting the operation of the manipulation system 100, the operator first arranges the sampling pipette 10 in the visual fields of the first microscope 41, the second microscope 61, and the third imaging device 75 shown in FIG. Here, the height of the tip of the sampling pipette 10 is at least higher than the height at which the container 38 is installed. The sampling pipette 10 is displayed on the screen 81 shown in FIG. 7. The operator operates the joystick 57 while checking the screen 81, and moves the sampling pipette 10 to the coordinates (X0, Y0, Z0) of the predetermined initial position set in advance. Next, the operator installs the container 38 containing the cells ce to be collected on the sample stage 30. Next, the operator moves the sample stage 30 so that the well 38a of the container 38 overlaps the visual fields of the first microscope 41, the second microscope 61, and the third imaging device 75. The operator then drives the driving device 414 to move the objective lens 412 of the first microscope 41 to focus the first microscope 41 on the cells ce existing on the bottom surface 38b of the well 38a. The operator moves the objective lens 612 of the second microscope 61 by driving the driving device 613 to focus the second microscope 61 on the cell ce.

FIG. 14 is a flowchart showing an example of the operation of the embodiment. The manipulation system 100 performs an operation on each of the inspection points SPn that determine the inspection area SZ, for each inspection point SPn, and repeatedly performs the operation of acquiring the Z coordinate Zn for each of the inspection points SPn. The number ne of inspection points SPn is three in the present embodiment. The controller 50 automatically executes the operation on the plurality of inspection points SPn. The automatic operation by the manipulation system 100 is started by pressing the start button of the input unit 58, for example.

First, in step ST10, the operator sets the operation end count ne, which is the number of times the operation is ended, after the manipulation system 100 has performed a plurality of inspection operations, to the controller 50 via the input unit 58 shown in FIG. It is set in the storage unit 56. After the start button is pressed, the controller 50 may cause the display unit 80 to display a notification prompting the operator to input the operation end count ne. Since the operation is performed for each one inspection point SPn, the operation end count ne is the number ne of the inspection points SPn to be operated. That is, in the present embodiment, the operation end count ne is 3. When the operation end count ne is stored in the storage unit 56, in step ST12, the controller 50 stores the operation execution count n, which is a counter value of the executed operation count, in the storage unit 56 as n=0.

Next, in step ST14, the operator sets the XY coordinates (Xn, Yn) of each inspection point SPn in the coordinate storage unit 56c of the storage unit 56 of the controller 50 via the input unit 58. After step ST12 is executed, the controller 50 sends a notification prompting the operator to input the XY coordinates (X1, Y1), (X2, Y2),..., (Xne, Yne) of each inspection point SPn. It may be displayed on the display unit 80. In the present embodiment, the operator operates the X coordinate X1 and the Y coordinate Y1 of the first inspection point SP1, the X coordinate X2 and the Y coordinate Y2 of the second inspection point SP2, and the X coordinates X3 and Y of the third inspection point SP3. The coordinate Y3 is set. When the coordinates (X1, Y1) of the first inspection point SP1, the coordinates (X2, Y2) of the second inspection point SP2, and the coordinates (X3, Y3) of the third inspection point SP3 are stored in the coordinate storage unit 56c, step In ST16, the controller 50 increments the counter value of the operation execution count n by 1, and stores it in the storage unit 56 as n=n+1.

Next, in step ST18, the drive control unit 55 drives the manipulator 20 to move the sampling pipette 10 to the nth inspection point SPn on the XY plane. That is, the drive control unit 55 moves the sampling pipette 10 to the coordinates (Xn, Yn, Z0) immediately above the nth inspection point SPn.

Next, in step ST20, the drive controller 55 drives the manipulator 20 to start the reciprocating movement of the sampling pipette 10 in one direction parallel to the mounting surface 30a of the sample stage 30 within a predetermined range. The one direction is a direction parallel to the Y-axis direction in the present embodiment. The predetermined range is, for example, 500 μm. The sampling pipette 10 repeatedly operates in the vertical direction within the field of view of the first microscope 41. The distal end portion 103 of the sampling pipette 10 has a longitudinal direction parallel to the X-axis direction in a plan view, and thus reciprocates in a direction intersecting the longitudinal direction in a plan view, as shown in FIG.

Next, in step ST22, the drive controller 55 drives the manipulator 20 to move the sampling pipette 10 downward in the Z-axis direction. That is, the drive control unit 55 moves the sampling pipette 10 in parallel with the Z-axis direction and downward while reciprocating in the Y-axis direction. When the sampling pipette 10 starts moving downward, in step ST24, the controller 50 waits for a predetermined operation to be executed. The controller 50 may display a notification indicating the standby state on the display unit 80. The predetermined operation is, for example, operation of a predetermined button of the input unit 58.

When the tip of the sampling pipette 10 comes into contact with the bottom surface 38b of the container 38, the tip portion 103 behaves as if it were dragged onto the bottom surface 38b, as shown in FIG. When the tip portion 103 behaves like being dragged by the bottom surface 38b, the operator determines that the tip of the sampling pipette 10 has come into contact with the bottom surface 38b of the container 38 and performs a predetermined operation. Based on the image data captured by the first image capturing device 45, the second image capturing device 65, and the third image capturing device 75, the behavior in which the tip portion 103 is dragged by the bottom surface 38b may be detected to determine the artificial intelligence. ..

In step ST26, the controller 50 determines whether or not a predetermined operation has been executed. When it is determined in step ST26 that the predetermined operation is not performed (step ST26; No), the process proceeds to step ST22. When it is determined in step ST26 that the predetermined operation has been performed (step ST26; Yes), the process proceeds to step ST28.

In step ST28, the controller 50 stores the Z coordinate of the tip of the sampling pipette 10 in the coordinate storage unit 56c as the Z coordinate Zn of the nth inspection point SPn. The calculator 59 may calculate the Z coordinate of the tip of the sampling pipette 10 based on, for example, the coordinates of the initial position of the sampling pipette 10 and the Z-axis movement distance of the sample stage 30 and the manipulator 20. In step ST30, the drive controller 55 drives the manipulator 20 to stop the reciprocating movement of the sampling pipette 10. Step ST30 may be executed before step ST28.

Next, in step ST32, the controller 50 determines whether the operation execution count n has reached the operation end count ne. When it is determined in step ST32 that the operation execution count n is smaller than the operation end count ne (step ST32; No), the process returns to step ST16 and the operation for another inspection point SPn is repeatedly executed. When it is determined in step ST32 that the operation execution count n is equal to or greater than the operation end count ne (step ST32; Yes), the operation of acquiring the Z coordinate Zn for the preset number ne of inspection points SPn is completed, and the process proceeds to step ST34. Transition.

In step ST34, the calculation unit 59 calculates a plane that approximates the inspection points SPn in the inspection area SZ based on the coordinates (Xn, Yn, Zn) of the inspection points SPn stored in the coordinate storage unit 56c. Calculate an approximate expression. In the present embodiment, the calculation unit 59 causes the coordinates (X1, Y1, Z1) of the first inspection point SP1, the coordinates (X2, Y2, Z2) of the second inspection point SP2, and the coordinates (X3, X3 of the third inspection point SP3. An approximate expression of a plane passing through Y3, Z3) is calculated. The controller 50 stores the calculated approximate expression in the storage unit 56. When the storage unit 56 stores the approximate expression, the manipulation system 100 ends the series of operations.

In the embodiment, the movement of the sampling pipette 10 to the initial position is performed by the operation of the joystick 57 by the operator before starting the automatic operation by the manipulation system 100, but the manipulation system 100 may be performed. For example, before step ST10 is executed, the image processing unit 52 of the controller 50 performs image processing of image data captured by the first imaging device 45, the second imaging device 65, and the third imaging device 75. The detection unit 53 of the controller 50 detects the position coordinates of the center of the tip of the sampling pipette 10 by image processing. The coordinate storage unit 56c stores the position coordinates of the center of the tip of the sampling pipette 10. Next, the drive control unit 55 drives the manipulator 20 to move the sampling pipette 10 to the coordinates (X0, Y0, Z0) of the preset predetermined initial position based on the detection result. Further, after step ST30, the drive control unit 55 may drive the manipulator 20 to move the sampling pipette 10 to the initial position.

Next, a method of collecting the cells ce in the container 38 in the manipulation system 100 will be described. It is assumed that the container 38 containing the collected cells ce is installed on the sample stage 30 in the above-described steps ST10 to ST34, and a plane approximation formula approximating the bottom surface 38b is calculated. FIG. 15 is a flowchart showing an example of the operation of the embodiment. The manipulation system 100 can perform an operation on a plurality of cells ce for each cell ce, and can repeatedly perform the operation on a plurality of cells ce. Here, the operation on one cell ce will be described. The controller 50 automatically executes the operation on the cell ce. The automatic operation by the manipulation system 100 is started by pressing the start button of the input unit 58, for example.

First, in step ST50, the image processing unit 52 of the controller 50 performs image processing of image data captured by the first imaging device 45, the second imaging device 65, and the third imaging device 75. The detection unit 53 of the controller 50 detects the XY coordinates (Xce, Yce) of the cell ce by image processing. The coordinate storage unit 56c stores the XY coordinates (Xce, Yce) of the cell ce.

In step ST52, the calculation unit 59 substitutes the X coordinate Xce into X of the approximate expression Z=aX+bY+c stored in the storage unit 56, substitutes the Y coordinate Yce into Y of the approximate expression, and calculates the Z coordinate of the cell ce. Calculate Zce. The coordinate storage unit 56c stores the Z coordinate Zce of the cell ce.

In step ST54, the drive control unit 55 drives the manipulator 20 to move the tip of the sampling pipette 10 to the cell ce based on the coordinates (Xce, Yce, Zce) of the cell ce stored in the coordinate storage unit 56c. Move to the sampling position for collecting. The sampling position is a position where the opening 103a (see FIG. 9) of the sampling pipette 10 faces the cell ce. Since the Z coordinate Zce of the cell ce has been calculated in step ST52, the sampling pipette 10 can be moved to an appropriate position.

In step ST56, the drive control unit 55 drives the electric micropump 29 (see FIG. 3) to make the internal pressure of the sampling pipette 10 lower than normal pressure. As a result, the collection pipette 10 sucks and collects the cells ce from the opening 103a at the tip.

FIG. 16 is a schematic view showing an enlarged part of the shape of the bottom surface of the well of the embodiment. As shown in FIG. 16, the bottom surface 38b of the actual well 38a has a shape including unevenness and inclination with respect to the horizontal plane. That is, the virtual plane represented by the approximate expression calculated in step ST34 shown in FIG. 14 includes an error with respect to the actual bottom surface 38b. As shown in FIG. 8, the longitudinal direction of the tip portion 103 of the sampling pipette 10 is inclined at an inclination angle θ3 with respect to the horizontal plane. As a result, in the sampling pipette 10, when the tip on the side of the opening 103a comes into contact with the bottom surface 38b of the well 38a of the container 38, the tip portion 103 bends, and the flat surface represented by the approximate expression and the actual bottom surface 38b. An error between can be tolerated. The sampling pipette 10 allows an error of not more than the distance H2 in the Z-axis direction between the plane represented by the approximate expression and the actual bottom surface 38b. When the distance H1 in the Z-axis direction between the bottom surface 38b of the container 38 and the second bent portion 105 is 30 μm, the distance H2 is, for example, 15 μm.

In the manipulation system 100 of the present embodiment, the calculation unit 59 calculates the position coordinates (Xce, Yce, Zce) of the cell ce (microscopic object) based on the approximate expression stored in the storage unit 56. According to this, the tip of the collection pipette 10 can be appropriately aligned with the height of the cell ce existing on the bottom surface 38b of the container 38, and thus the cell ce in the container 38 can be stably and automatically collected.

In the manipulation system 100 of the present embodiment, the approximate expression is calculated based on the coordinate information of the plurality of inspection points SPn measured by bringing the tip of the sampling pipette 10 into contact. According to this, since the approximate expression is calculated based on the position at which the collecting pipette 10 that actually collects the cells ce contacts the bottom surface 38b of the container 38, when collecting the cells ce, the collecting pipette is more suitable. The tip of 10 can be aligned with the cell ce.

In the manipulation system 100 of the present embodiment, the drive control unit 55 moves the sampling pipette 10 in the Z-axis direction (the normal direction of the mounting surface 30a of the sample stage 30). The storage unit 56 (coordinate storage unit 56c) stores the Z coordinate Zn (coordinates in the normal direction) of the inspection point SPn based on the coordinate information of the position where the tip of the sampling pipette 10 contacts the bottom surface 38b of the container 38. To do. According to this, since the approximate expression is calculated based on the position at which the collecting pipette 10 that actually collects the cells ce contacts the bottom surface 38b of the container 38, when collecting the cells ce, the collecting pipette is more suitable. The tip of 10 can be aligned with the cell ce.

In the manipulation system 100 according to the present embodiment, the drive control unit 55 causes the sampling pipette 10 to reciprocate in a predetermined range in the Y-axis direction (one direction parallel to the mounting surface 30a) while the sampling pipette 10 is reciprocating. 10 is moved in the Z-axis direction (direction normal to the mounting surface 30a). According to this, the behavior of the tip of the sampling pipette 10 changes when the sampling pipette 10 contacts the bottom surface 38b of the container 38. Therefore, the operator can confirm that the tip of the sampling pipette 10 has come into contact with the bottom surface 38b of the container 38.

In the manipulation system 100 of the present embodiment, the storage unit 56 (coordinate storage unit 56c) performs a predetermined operation of inputting the coordinates of the tip of the sampling pipette 10 while the drive control unit 55 moves the sampling pipette 10. The coordinates of the tip of the sampling pipette 10 at the time when is executed are stored as the Z coordinate Zn of the inspection point SPn. According to this, since the approximate expression is calculated based on the position at which the collecting pipette 10 that actually collects the cells ce contacts the bottom surface 38b of the container 38, when collecting the cells ce, the collecting pipette is more suitable. The tip of 10 can be aligned with the cell ce.

In the manipulation system 100 of the present embodiment, the sampling pipette 10 includes a tip portion 103 whose longitudinal direction is inclined with respect to the mounting surface 30a of the sample stage 30 by a predetermined inclination angle θ3. According to this, when the collection pipette 10 comes into contact with the bottom surface 38b of the container 38, the tip of the collection pipette 10 is bent, and an error between the approximated virtual plane and the actual bottom surface 38b can be allowed. it can.

The driving method of the manipulation system 100 according to the present embodiment includes a container 38 in which cells ce (microscopic objects) are housed, a sample stage 30 on which the containers 38 are mounted, a sampling pipette 10 for collecting cells ce, This is a driving method of the manipulation system 100 including. The manipulation method of the manipulation system 100 is step ST20 in which the tip of the sampling pipette 10 is brought into contact with a plurality of preset inspection points SPn on the bottom surface 38b of the container 38, and sampling when the plurality of inspection points SPn are brought into contact with each other. Step ST28 of storing the coordinates of the tip of the pipette 10 as coordinates of the inspection point SPn, and step ST34 of calculating an approximate expression of a plane that approximates the inspection points SPn based on the coordinates of the inspection points SPn, Step ST54 of calculating the position coordinates of the cell ce based on the approximate expression.

According to this, since the approximated virtual plane is averaged from the bottom surface 38b of the actual container 38, the error between the virtual surface and the actual bottom surface 38b becomes small. Therefore, when collecting the cells ce, the position of the tip of the collecting pipette 10 can be suitably controlled so that the cells can be aligned with the height of the cells ce existing on the bottom surface 38b of the container 38. Therefore, the cells ce in the container 38 can be stably and automatically collected. Further, since it is not necessary to use an expensive container having a precise flatness of the bottom surface, it is possible to suppress the cost generation due to the additional grinding finishing process and the use of a custom-made product.

The manipulation system 100 of the present embodiment and the driving method of the manipulation system 100 may be appropriately changed. For example, it is preferable to appropriately change the shape of the sampling pipette 10 and the like according to the type of the minute object and the operation on the minute object. The operation of calculating the approximate expression approximating the plane of the bottom surface 38b of the container 38 in the inspection region SZ may be omitted by omitting a part of the procedure as appropriate without departing from the spirit of the invention. You may execute.

DESCRIPTION OF SYMBOLS 1 Base 3 and 4 Fixture 10 Collecting pipette 101 Central part 101a 1st part 101b 2nd part 102 Rear part 103 Tip part 103a Opening part 104 1st bending part 105 2nd bending part 106 Narrow part 15 Pipette holding part 20 Manipulator 21 X-axis table 22 Y-axis table 23 Z-axis table 26, 27 Drive device 28, 71 Connection part 29 Electric micropump 30 Sample stage 30a Mounting surface 31 X-axis stage 32 Y-axis stage 36 Drive device 38 Container 38a Well 38b Bottom surface 39 Liquid 40 First microscope unit 41 First microscope 411 Lens barrel 412 Objective lens 414 Driving device 45 First imaging device 50 Controller 51a Image input unit 51b Image output unit 52 Image processing unit 53 Detection unit 531 Position detection unit 532 Distance detection Part 533 Number detection part 54 Image editing part 55 Drive control part 56 Storage part 56a Program storage part 56b Image storage part 561 First image storage part 562 Second image storage part 563 Third image storage part 564 Edited image storage part 56c Coordinate storage Part 59 Calculation part 57 Joystick 58 Input part 60 Second microscope unit 61 Second microscope 611 Lens barrel 612 Objective lens 613 Driving device 65 Second imaging device 75 Third imaging device 80 Display 81 Screen 811 First image 812 Second image 813 Third image 100 Manipulation system P pressure ce Cell L1, L2, L3, L4 Length H1, H2 Distance φ11, φ21, φ31 Outer diameter φ32 Inner diameter φce Diameter θ1, θ2 Bending angle θ3 Inclination angle SZ Inspection area SPn Inspection point SP1 1st inspection point SP2 2nd inspection point SP3 3rd inspection point

Claims (8)

A container for accommodating a minute object,
A sample stage on which the container is placed,
A pipette for collecting the minute object,
A drive control unit for controlling the sample stage and the sampling pipette,
A calculating unit that calculates an approximate expression of a plane that approximates a plurality of inspection points measured on the bottom surface of the container,
A storage unit that stores the approximate expression,
Manipulation system equipped with. The manipulation system according to claim 1, wherein the calculation unit calculates the position coordinates of the minute target object based on the approximate expression stored in the storage unit. The manipulation system according to claim 1, wherein the approximate expression is calculated based on coordinate information of the plurality of inspection points measured by bringing the tip of the sampling pipette into contact with the bottom surface of the container. The drive control unit moves the sampling pipette in a direction normal to a mounting surface of the sample stage,
4. The storage unit stores coordinates of a normal direction of the inspection point based on coordinate information of a position where the tip of the sampling pipette comes into contact with the bottom surface of the container. Manipulation system described. The drive control unit moves the sampling pipette in the normal direction of the mounting surface in a state where the sampling pipette is reciprocating in a predetermined range in one direction parallel to the mounting surface. Item 4. The manipulation system according to Item 4. The storage unit stores the coordinates of the tip of the sampling pipette when a predetermined operation of inputting the coordinates of the tip of the sampling pipette is executed while the drive control unit is moving the sampling pipette. The manipulation system according to claim 3, wherein the manipulation system stores the coordinate as the coordinate of the inspection point. The manipulation system according to claim 1, wherein the sampling pipette includes a tip portion whose longitudinal direction is inclined at a predetermined inclination angle with respect to a mounting surface of the sample stage. A container for accommodating a minute object,
A sample stage on which the container is placed,
A pipette for collecting the minute object,
A method of driving a manipulation system comprising:
Contacting the tip of the sampling pipette with a plurality of inspection points preset on the bottom surface of the container,
Storing the coordinates of the tip of the sampling pipette when each of the plurality of inspection points is contacted as the coordinates of the inspection point,
A step of calculating an approximate expression of a plane that approximates a plurality of inspection points based on the coordinates of the plurality of inspection points;
Calculating the position coordinates of the minute object based on the approximation formula,
Driving method for manipulating system including.

Images