WO2019042198A1 - 镜像显微成像装置、显微操作针姿态校准系统及方法 - Google Patents

镜像显微成像装置、显微操作针姿态校准系统及方法 Download PDF

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WO2019042198A1
WO2019042198A1 PCT/CN2018/101669 CN2018101669W WO2019042198A1 WO 2019042198 A1 WO2019042198 A1 WO 2019042198A1 CN 2018101669 W CN2018101669 W CN 2018101669W WO 2019042198 A1 WO2019042198 A1 WO 2019042198A1
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Prior art keywords
mirror
needle
angle
former
needle holder
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PCT/CN2018/101669
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English (en)
French (fr)
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彭建军
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长沙傲图生物科技有限公司
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Priority to JP2019546967A priority Critical patent/JP6944532B2/ja
Priority to EP18850693.5A priority patent/EP3534199B1/en
Priority to RU2019118977A priority patent/RU2713074C1/ru
Priority to US16/467,034 priority patent/US11372225B2/en
Priority to AU2018325048A priority patent/AU2018325048B2/en
Publication of WO2019042198A1 publication Critical patent/WO2019042198A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
    • C12M21/06—Bioreactors or fermenters specially adapted for specific uses for in vitro fertilization
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0004—Microscopes specially adapted for specific applications
    • G02B21/0088—Inverse microscopes
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/24—Base structure
    • G02B21/26—Stages; Adjusting means therefor
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/32—Micromanipulators structurally combined with microscopes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D19/00—Instruments or methods for reproduction or fertilisation
    • A61D19/02—Instruments or methods for reproduction or fertilisation for artificial insemination
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/42—Integrated assemblies, e.g. cassettes or cartridges

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  • the present disclosure relates to the field of microscopic instrumentation devices, and more particularly to a mirror image microscopic imaging device, a micromanipulation needle attitude calibration system, and a method.
  • Inverted microscopes are important instruments in biological laboratories and are indispensable tools in the field of microscopy.
  • Single sperm intracytoplasmic injection (ICSI) as a treatment for male infertility, has become the preferred method of insemination and is widely used throughout the world.
  • the traditional ICSI method performs the ICSI process by manually operating the micromanipulator.
  • Lu et al. describe a scheme for selecting sperm and performing robotic ICSI on oocytes by an operator (Lu et al. IEEE Trans Biomed Eng. 2011 Jul; 58(7): 2102-8.doi: 10.1109/TBME .2011.2146781.Epub 2011Apr 25.).
  • the patent "Automated Intracytoplasmic Sperm Injection Auxiliary Insemination System” (Application No.: CN201380021578.9) describes a complete ICSI automation system. Due to the complexity of ICSI technology, there are still many details to be solved in the robotic ICSI and ICSI automation systems, and there is still a long way to go from clinical applications. At present, the traditional ICSI method is still the only method for clinical application as a relatively reliable method.
  • an inverted microscope includes basic functional components such as a light source 11, a stage 12, and an eyepiece 13.
  • the microinjection system includes basic functional components such as a microneedle 14, a needle holder 15, a needle holder level adjuster 16, and a needle holder coronal angle adjuster 17.
  • the microscopic operating system includes basic functional components such as a needle holder stereo position adjuster 18.
  • the microneedle 14 has a special structure including an elongated body and a functional portion 141 at an angle to the body. The relationship between the micromanipulation needle in the conventional ICSI method and the related device after assembly is shown in Fig. 1.
  • the stage 12 is set to have a square shape, and has four sides of a left side 121, a right side 122, a front side 123, and a rear side 124, as shown in FIG.
  • the X-axis of the reference coordinate system is set to be parallel to the front edge 123 or the rear edge 124 of the stage 12, and the Y-axis is parallel to the left side 121 or the right side 122 of the stage 12, and the Z-axis is perpendicular to the stage 12.
  • XY constitutes a horizontal plane
  • XZ constitutes a coronal plane
  • YZ constitutes a sagittal plane.
  • Parallel to the Y-axis, the near and far angle of view is a head-view view, and the view from the top to the bottom parallel to the Z-axis is a top view.
  • the installation requirements of the microneedle 14 are very strict.
  • the posture of the ideal micromanipulation needle 14 has the following two characteristics: 1. In a plan view, the central section of the functional portion 141 of the micromanipulation needle 14 is parallel to the coronal plane, as shown in FIG. 2; The lower edge of the functional portion 141 of the micro-needle 14 is parallel to the horizontal plane, as shown in FIG.
  • the overhead view is a conventional viewing angle of the microscope, and it is possible to directly observe whether the central section of the functional portion 141 of the microneedle 14 is parallel to the coronal plane. Due to limitations of the existing optical microscopy technique, the microscopic image of the pan-view angle shown in Fig. 3 is not actually observed, so that it is impossible to judge whether the posture of the micromanipulation needle 14 after installation is in the ideal state of the second feature.
  • the stringency of the microneedle 14 mounting effect is required to achieve an ideal micromanipulation outcome.
  • the angle between the central section of the functional portion 141 of the microneedle 14 and the coronal plane is larger, or the angle between the lower edge of the functional portion 141 of the microneedle 14 and the horizontal plane is larger, and the microscopic object is the oocyte.
  • the greater the damage to the cells the more difficult the operation, resulting in poor microstructural outcomes.
  • the operator observes through the eyepiece in a bird's eye view, and adjusts the needle holder level angle adjuster 16, the needle holder crown angle adjuster 17, and the needle holder stereo position adjuster 18 and the like.
  • the first feature the state shown in Figure 2, can be implemented.
  • the microscopic image of the functional portion 141 of the micromanipulation needle 14 is not observed from a normal viewing angle, it is naturally impossible to judge the angle between the lower edge of the functional portion 141 of the microneedle 14 and the horizontal plane.
  • the functional portions 141 of the different micromanipulation needles 14 are different in thickness.
  • the outer diameters of the commonly used egg-holding needles, injection needles, and biopsy needle functional portions are 120 ⁇ m, 10 ⁇ m, and 40 ⁇ m, respectively.
  • the functional portions 141 of the different micromanipulation needles 14 have different lengths, for example, about 300 to 1000 ⁇ m.
  • the functional portions 141 of the different micromanipulation needles 14 have different angles, because the angles of the main body portion of the micromanipulation needle 14 and the functional portion 141 are artificially calcined, and the angles of different models of each model and the same model are There is an angular difference between them.
  • the distance between the functional portion 141 of the micromanipulation needle 14 and the table top of the microscope stage 12 after mounting is very short, about 500 ⁇ m. Obviously, it is very difficult to judge whether the level is very difficult by the naked eye, and it is also difficult to design a super close-range imaging device to observe the micromanipulation tube function from a horizontal perspective.
  • the current state of the art is to judge the angle between the lower edge of the functional portion 141 of the micromanipulation needle 14 and the horizontal plane based on the operator's experience. It is still possible for the same operator to install different types of microneedle 14 or the same operator to install the same type of microneedle 14 at different times. The importance and technical status of the microneedle 14 installation is discussed in more detail in pages 332-334 of the "Practical Manual of In Vitro Fertilization", and will not be repeated here.
  • the embodiments of the present disclosure provide an automated micromanipulation needle attitude calibration system and a calibration method, which can realize precise installation of the micromanipulation needle.
  • a mirror microscopic imaging apparatus comprising:
  • a mirror former holder having one end coupled to the motion actuator
  • the mirror image former has a mirror mirror having an angle of 45° with respect to the horizontal plane of the microscope stage and an angle of 45° with the coronal plane, and is mounted on the other end of the mirror former holder.
  • the mirror area of the mirror former is rectangular.
  • the mirror former bracket is a rigid physical structure that connects the mirror former to the motion actuator.
  • the motion actuator is configured to effect movement of the mirror former bracket from an original position to a predetermined position corresponding to forming a mirror image in an automated manner, either manually or with a drive.
  • the motion actuator is a displacement structure that cooperates with a linear guide rail, and the linear guide is parallel to a sagittal plane of the microscope stage, the mirror image holder being opposite to the The linear guide is set vertically.
  • the motion actuator is a displacement structure employing an axial joint that connects one arm of the mirror former as the mirror former bracket, configured to be manually or by a drive
  • the mirroring of the mirror former bracket from the original angle to a predetermined angle corresponding to the mirror image is achieved in an automated manner.
  • the motion actuator further includes a reset structure for effecting a return movement of the mirror former holder from the preset position to the home position.
  • a light source disposed on a mirror side of the plane mirror for enhancing light intensity at a head-view perspective.
  • a microneedle attitude calibration system comprising:
  • Inverted microscope system including video image capture unit and manual focus unit or auto focus unit;
  • Microscopic operating system including needle holder, needle holder anchor and needle holder front/rear/left/right/up and down displacement actuators;
  • a needle holder rotary drive mechanically coupled to the needle holder
  • a coronal angle driver mechanically coupled to the needle holder anchor
  • a sagittal angle driver mechanically coupled to the needle holder anchor
  • processing software is for automatically monitoring and controlling the in-position of the mirror imager, autofocusing of the autofocus unit, image acquisition and analysis of the video image collector, and implementing the needle holding Front/rear/left/right/up and down displacement drive, needle holder rotary drive, coronal angle drive and sagittal angle drive drive.
  • a calibration method based on the aforementioned automated microneedle attitude calibration system comprising the steps of:
  • a video image of the functional portion of the micromanipulation needle on the coronal plane is obtained by a combination of the autofocus unit and the front/rear/left/right/upper and lower displacement drivers of the needle holder;
  • the automatic calibration mode includes performing automatic calibration on the postures of the left and right micromanipulators, or simultaneously performing the postures of the left and right micromanipulators. calibration.
  • step S8 the distance between the preset position and the functional portion of the microneedle is 0.5 mm.
  • the embodiment of the present disclosure can calibrate the posture of the functional portion of the microneedle to a desired state by a simple structure and scheme, that is, the positional relationship between the lower edge of the functional portion of the microneedle and the horizontal plane. .
  • Figure 1 is a schematic view showing the relationship between the micromanipulation needle in the conventional ICSI method and the related device after assembly.
  • Figure 2 is one of the ideal micromanipulator postures: a schematic view of the central section of the functional portion of the microneedle parallel to the coronal plane in a top view.
  • Figure 3 is a schematic diagram of the ideal micromanipulation needle posture: in the head-view perspective, the lower edge of the functional portion of the micromanipulation needle is parallel to the horizontal plane.
  • Figure 4 is a schematic diagram showing the basic imaging principle of a conventional optical microscope.
  • FIG. 5 is a schematic block diagram of some embodiments of a microneedle attitude calibration system of the present disclosure.
  • Figure 6 is a schematic view showing the structure of some embodiments of the mirror image microscopic imaging device of the present disclosure.
  • FIG. 7 is a schematic diagram of the principle of mirror microscopic imaging of the embodiment of the mirror image microscopic imaging device of the present disclosure.
  • Figure 8 is a mirror image of the microscopic operation of the mirror image microscopic imaging device of the present invention.
  • the microscopic needle portion mirrored by the mirror imager can be observed from the eyepiece in a plan view. image.
  • Figure 9 is a micrograph of the functional portion of the microneedle prior to calibration obtained from a top view perspective of the microneedle attitude calibration system embodiment of the present disclosure.
  • Figure 10 is a microscopic image of the functional portion of the calibrated microneedle obtained in a top view view of the microneedle attitude calibration system embodiment of the present disclosure.
  • Figure 11 is a mirror image of a functional portion of a microneedle obtained from an eyepiece prior to calibration, in a plan view, of the embodiment of the microneedle attitude calibration system of the present disclosure.
  • Figure 12 is a mirror image of a functional portion of a microneedle obtained from an eyepiece after calibration, in a plan view, of the embodiment of the microneedle attitude calibration system of the present disclosure.
  • Micromanipulation tube attitude calibration is to calibrate the attitude of the functional part of the microneedle to the ideal state from a top view and a side view. As described in the background art, microscopic images of a head-up viewing angle have not been obtained. Therefore, in order to achieve automated micromanipulation needle posture calibration, the first technical problem to be solved is to obtain a microscopic image of the functional portion 141 of the micromanipulation needle at a horizontal viewing angle in real time.
  • the basic imaging principle of a conventional optical microscope is that the light of the light source 11 passes through the functional portion 141 of the transparent microneedle and directly enters the optical imaging system starting from the objective lens 13, as shown in FIG.
  • the angle of view of the image is a view of the Z axis that is parallel to the ray. This angle of view is unitary, that is, it can only be viewed from a top view.
  • the intersection with the coronal plane of the microscope stage is the X-axis
  • the intersection of the horizontal plane of the microscope stage and the sagittal plane of the microscope stage is the Y-axis
  • the sagittal plane of the microscope stage and the microscope stage The intersection of the coronal plane is the Z axis.
  • the embodiment of the present disclosure designs a mirror image microscopic imaging device 19 including a mirror image former 191 and a mirror image former bracket. 192 and exercise actuator 193.
  • the motion actuator 193 is fixedly mounted on the microscope stage.
  • One end of the mirror former holder 192 is coupled to the motion actuator 193.
  • the mirror former 191 is mounted to the other end of the mirror former holder 192.
  • the mirror surface of the mirror imager 191 is at an angle of 45° to the horizontal plane of the microscope stage and at an angle of 45° to the coronal plane.
  • the motion actuator is fixedly mounted on the microscope stage in a Y-axis direction, and the mirror-former bracket is disposed along an X-axis direction.
  • the mirror image forming structure of the mirror imager 191 is a plane mirror for capturing a mirror image of an object to be observed and a specific angle of view.
  • the mirror image forming device 191 can be processed by a plane mirror process using materials such as glass and metal.
  • the plane mirror area is rectangular.
  • the mirror former holder 192 is preferably a rigid physical structure that connects the mirror former 191 to the motion actuator 193.
  • the motion actuator 193 can be configured to effect movement of the mirror former bracket 192 from an original position to a predetermined position corresponding to a mirror image by manual means or with a drive.
  • the motion actuator 193 is a displacement structure that uses a slider and a linear guide, and the linear guide is parallel to a sagittal plane of the microscope stage, and the mirror former bracket is opposite to the linear guide.
  • Vertical setting is a displacement structure employing an axial joint that connects one arm of the mirror former as the mirror former bracket.
  • the shaft joint can be configured to effect the swinging of the mirror former bracket from an original angle to a predetermined angle corresponding to a mirror image by manual means or by means of a drive.
  • the object can be accurately moved from the original position to another preset position by the motion actuator 193 described above, and the reset movement of the mirror former holder from the preset position to the original position can also be achieved by a reset mechanism.
  • the motion actuator can also be selectively driven by the drive, ie to implement an automatic control function.
  • the embodiment of the present disclosure may further include a light source 194 disposed on one side of the plane mirror of the mirror imager 191 for enhancing the light intensity of the viewing angle, which effectively increases the brightness of the image formed by the observed object on the mirror imager. .
  • the principle of the mirror image microscopic imaging device is that the light is passed through the object from a specific viewing angle (the head-viewing angle in the embodiment of the present disclosure) by the flat mirror imaging characteristic (the functional portion 141 of the microneedle in the embodiment of the present disclosure) ) is shot on a plane mirror and reflected into an optical imaging system starting from the objective lens to obtain a microscopic image of the object.
  • the image is a microscopic image of the image formed on the plane mirror at an particular viewing angle.
  • the plane mirror MN is at an angle of 45 with the plane of the stage (i.e., the horizontal plane) OS, and is at an angle of 45 to the coronal plane.
  • the incident light A passing through the transparent object S is incident on the plane mirror MN at the incident point O at an incident angle ⁇ i .
  • the reflected light B is reflected at the reflection angle ⁇ r to enter the objective lens, and the obtained image is a mirror image S′. Microscopically magnified image.
  • the mirror former holder 192 and the motion actuator 193 coupled to the mirror former holder 192 serve as a participating component of the mirror former 191 in place and reset such that the in-position/reset trajectory of the mirror former 191 is subjected to the motion actuator 193 Limit to be parallel to the Y axis of the stage.
  • the mirror image of the microscope is shown in Figure 8.
  • the microscopic image of the microneedle portion mirrored in the plan view from the mirror imager was observed from the eyepiece, and the image was not observed in the portion where the mirror imager was mirrored. Because of the characteristics of the mirror image, the image observed in the eyepiece is mirror-symmetric with the actual direction of the micro-needle function, and is displayed as an inverted feature. In the schematic, the mirror image shows that the lower edge of the microneedle function portion 141 is in a non-horizontal posture.
  • the present disclosure can obtain a microscopically magnified image of the microscopic operation needle function portion 141 of a horizontal viewing angle by adding a mirror image microscopic imaging device to an existing inverted microscope, thereby laying a foundation for judging and adjusting the horizontal posture of the microneedle function portion. technical foundation.
  • the embodiment further provides a micromanipulation posture calibration system, including
  • the mirror microscopic imaging device 19 of the foregoing embodiment is the mirror microscopic imaging device 19 of the foregoing embodiment.
  • Inverted microscope system including video image collector and manual focus unit or auto focus unit 21;
  • Microscopic operating system including a needle holder 23, a needle holder anchor 24 and a needle holder front and rear / left and right / up and down displacement drive 25;
  • a needle holder rotary driver 28 mechanically coupled to the needle holder
  • a coronal angle driver 27 mechanically coupled to the needle holder anchor, in place of the needle holder crown angle adjuster 17;
  • a horizontal angle driver 26 mechanically coupled to the needle holder anchor in place of the needle holder level adjuster 16;
  • the processing software is used for automatically monitoring and controlling the mirror imager in position, autofocusing of an autofocus single cloud, video image acquisition and analysis of a video image collector, and realizing front/rear/left/right/up and down displacement of the needle holder Drive, needle holder rotary drive, coronal angle drive and sagittal angle drive drive.
  • the microscopic image obtained in a bird's-eye view wherein the projection of the microneedle function at the horizontal plane and the angle of the coronal plane, that is, the angle with the X-axis ⁇ 1 ⁇ 0, ⁇ 2 ⁇ 0.
  • the mirror image obtained from the head-view angle the angle of the projection of the lower edge of the micro-needle function portion on the coronal plane and the horizontal plane, that is, the angle ⁇ 1' ⁇ 0 with the X-axis, 22' ⁇ 0.
  • the calibration method of the micromanipulation needle attitude calibration system specifically includes the following steps:
  • the automatic calibration mode may include performing automatic calibration on the postures of the left and right micromanipulators, or simultaneously performing automatic calibration on the postures of the left and right micromanipulators.
  • the distance between the preset position and the functional portion of the microneedle can be 0.5 mm.
  • the present disclosure can calibrate the posture of the functional portion of the calibration microneedle to a desired state by a simple structure and scheme, that is, a positional relationship in which the lower edge of the functional portion of the microneedle is parallel to the horizontal plane.

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Abstract

一种镜像显微成像装置、显微操作针姿态校准系统和方法。镜像显微成像装置包括：运动执行机构（193），固定安装于显微镜载物台上；镜像形成器支架（192），一端与运动执行机构连接；和镜像形成器（191），具有镜面与显微镜载物台的水平面呈45°夹角且与冠状面呈45°夹角的平面镜，并安装于镜像形成器支架的另一端。可采用简单的结构和方案校准显微操作针的功能部姿态至理想状态，即显微操作针的功能部的下缘与水平面平行的位置关系。

Description

镜像显微成像装置、显微操作针姿态校准系统及方法 技术领域
本公开涉及显微仪器设备技术领域，更具体地说，特别涉及一种镜像显微成像装置、显微操作针姿态校准系统及方法。
背景技术
倒置显微镜是生物学实验室重要的仪器设备，在显微操作领域是不可或缺的工具。单精子胞浆内注射(ICSI)作为男性不育症的治疗手段，已成为优选的授精方法，在全世界得到广泛应用。传统ICSI方法由人工操作显微操作装置完成ICSI过程。Lu等人描述了一种选择精子并且由操作人员实行对卵母细胞执行机器人化ICSI的方案(Lu等人.IEEE Trans Biomed Eng.2011Jul；58(7)：2102-8.doi：10.1109/TBME.2011.2146781.Epub 2011Apr 25.)。专利“自动化胞浆内精子注射辅助授精系统”(申请号：CN201380021578.9)描述了一种完整的ICSI自动化系统。限于ICSI技术的复杂性，机器人化ICSI和ICSI自动化系统还有许多细节问题有待解决，离临床应用还有很长的距离。目前，传统的ICSI方法作为一种比较可靠的方法，仍旧是临床应用的唯一方法。
传统ICSI方法涉及到的倒置显微镜与显微注射系统、显微操作系统共同组成执行显微操作的装置。参考图1，倒置显微镜包含了光源11、载物台12和目镜13等基本功能部件。显微注射系统包含了显微操作针14、持针器15、持针器水平面角度调节器16和持针器冠状面角度调节器17等基本功能部件。显微操作系统包含了持针器立体位置调节器18等基本功能部件。其中，显微操作针14具有特殊结构，包括细长状的主体及与主体呈夹角的功能部141。传统ICSI方法中的显微操作针在组装后与相关装置的关系如图1所示。
为了便于说明，现在将涉及到的方向予以限定。设定载物台12为方形，具有左边121、右边122、前边123、后边124四个边，如图1所示。设定参考坐标系的X轴与载物台12的前边123或后边124平行，Y轴与载物台12的左边121或右边122平行，Z轴与载物台12垂直。XY构成水平面、XZ构成冠状面、YZ构成矢状面。与Y轴平行由近及远的视角为平视视角，与Z轴平行由上往下的视角为俯视视角。
显微操作针14的安装要求非常严格。理想的显微操作针14的姿态具有以下两个 特征：一、在俯视视角，显微操作针14的功能部141中心剖面与冠状面平行，如图2所示；二、在平视视角，显微操作针14的功能部141下缘与水平面平行，如图3所示。
俯视视角是显微镜的常规视角，可以直接观察显微操作针14的功能部141中心剖面与冠状面是否平行。由于现有光学显微镜技术的限制，实际上观察不到图3所示的平视视角的显微图像，从而无法判断安装后的显微操作针14的姿态是否处在第二个特征的理想状态。
显微操作针14安装效果的严格性是获得理想显微操作结局所要求的。显微操作针14的功能部141的中心剖面与冠状面的夹角越大，或显微操作针14的功能部141的下缘与水平面的夹角越大，对显微操作对象即卵母细胞的损伤越大，同时操作越困难，导致显微操作结局变差。为了达到显微操作针的理想姿态，操作者在俯视视角通过目镜观察，并调整持针器水平面角度调节器16、持针器冠状面角度调节器17和持针器立体位置调节器18等部件可以实现第一个特征，即图2所示状态。但是，因为在平视视角观察不到显微操作针14的功能部141的显微图像，自然也就无法判断显微操作针14的功能部141下缘与水平面之间的夹角大小。
不同显微操作针14的功能部141粗细不同，例如常用的持卵针、注射针、活检针功能部的外径分别是120μm、10μm、40μm。不同显微操作针14的功能部141长度不同，例如300～1000μm左右。不同显微操作针14的功能部141角度不同，这是由于显微操作针14的主体部与功能部141的弯角为人工煅烧而成，每种型号及同一型号的不同个体的弯角之间存在角度差异。另外，显微操作针14在安装后其功能部141距离显微镜载物台12的台面距离非常短，约500μm。显然，通过裸眼判断其是否水平非常困难，而设计一种超近距的摄像装置从水平视角观察显微操作管功能部也存在较大难度。
目前的现状是，判断显微操作针14的功能部141下缘与水平面之间的夹角全凭操作者经验。同一个操作者安装不同型号的显微操作针14或者同一个操作者在不同时间安装相同型号的显微操作针14仍然可能会发生较大的主观差异。对于显微操作针14安装的重要性及技术现状在专著《Practical Manual of In Vitro Fertilization》的332～334页有更详细的论述，这里不再赘述。
发明内容
有鉴于此，本公开实施例提供一种自动化显微操作针姿态校准系统及校准方法，能够实现显微操作针的精密安装。
在本公开的一个方面，提供了一种镜像显微成像装置，包括：
运动执行机构，固定安装于显微镜载物台上；
镜像形成器支架，一端与所述运动执行机构连接；和
镜像形成器，具有镜面与所述显微镜载物台的水平面呈45°夹角且与冠状面呈45°夹角的平面镜，并安装于所述镜像形成器支架的另一端。
在一些实施例中，所述镜像形成器的平面镜区域为矩形。
在一些实施例中，所述镜像形成器支架是连接所述镜像形成器与运动执行机构的刚性物理结构。
在一些实施例中，所述运动执行机构被配置为通过手动方式或利用驱动器以自动方式，实现所述镜像形成器支架从原始位置到对应于形成镜像的预设位置的运动。
在一些实施例中，所述运动执行机构为采用滑块与直线导轨配合的位移结构，且所述直线导轨与所述显微镜载物台的矢状面平行，所述镜像形成器支架相对于所述直线导轨垂直设置。
在一些实施例中，所述运动执行机构为采用轴关节的位移结构，所述轴关节连接所述镜像形成器的一个臂作为所述镜像形成器支架，被配置为通过手动方式或利用驱动器以自动方式实现所述镜像形成器支架从原始角度到对应于形成镜像的预设角度的摆动。
在一些实施例中，所述运动执行机构还包括复位结构，用于实现所述镜像形成器支架从所述预设位置返回所述原始位置的复位运动。
在一些实施例中，还包括设于所述平面镜的镜面一侧的光源，该光源用于增强平视视角的光线强度。
在本公开的一个方面，提供一种显微操作针姿态校准系统，包括：
前述的镜像显微成像装置；
倒置显微镜系统，包括视频图像采集器和手动对焦单元或自动对焦单元；
显微操作系统，包括持针器、持针器锚定器和持针器前后/左右/上下位移驱动器；
与所述持针器机械耦合的持针器旋转驱动器；
与所述持针器锚定器机械耦合的冠状面角度驱动器；
与所述持针器锚定器机械耦合的矢状面角度驱动器；和
集成有处理软件的中央处理单元，
其中，所述处理软件用于自动化监视和控制所述镜像形成器的就位、所述自动对焦单元的自动对焦、对所述视频图像采集器的图像采集及分析、以及实现对所述持针器前后/左右/上下位移驱动器、持针器旋转驱动器、冠状面角度驱动器和矢状面角度驱动器的驱动。
在本公开的一个方面，提供一种基于前述自动化显微操作针姿态校准系统的校准方法，包括以下步骤：
S1、手动将左、右两支显微操作针组装在相应的持针器上；
S2、手动将持针器固定在持针器锚定器上；
S3、手动调整显微操作针的功能部至目镜的视野中央区域；
S4、启动自动校准模式；
S5、通过自动对焦单元和持针器前后/左右/上下位移驱动器的联合作用，得到显微操作针的功能部在水平面的视频图像；
S6、通过视频图像采集器采集所述水平面的视频图像；
S7、通过处理软件分析所述水平面的视频图像中显微操作针的功能部在水平面上的投影与冠状面的角度α，并启动持针器旋转驱动器和矢状面角度驱动器，将α校准到α＝0，从而完成所述显微操作针的功能部在水平面的校准；
S8、将镜像形成器定位到对应于形成镜像的预设位置；
S9、通过所述自动对焦单元和所述持针器前后/左右/上下位移驱动器的联合作用，得到显微操作针的功能部在冠状面的视频图像；
S10、通过所述视频图像采集器采集所述冠状面的视频图像；
S11、通过处理软件分析所述冠状面的视频图像中显微操作针的功能部在冠状面与水平面的角度α’，并启动冠状面角度驱动器，将α’校准到α’＝0，从而完成所述显微操作针的功能部在冠状面的校准；
S12、使所述镜像形成器复位，并使所述显微操作系统整体处于ICSI操作准备就绪状态。
在一些实施例中，在步骤S4中，所述自动校准模式包括先后对左、右两支显微操作针的姿态执行自动校准，或者同时对左、右两支显微操作针的姿态执行自动校准。
在一些实施例中，在步骤S8中，所述预设位置与所述显微操作针的功能部的距离为0.5mm。
与现有技术相比，本公开实施例可采用简单的结构和方案将显微操作针的功能部的姿态校准至理想状态，即显微操作针的功能部的下缘与水平面平行的位置关系。
附图说明
为了更清楚地说明本公开实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本公开的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为传统ICSI方法中的显微操作针在组装后与相关装置关系的结构示意图。
图2为理想的显微操作针姿态之一：在俯视视角，显微操作针的功能部中心剖面与冠状面平行的示意图。
图3为理想的显微操作针姿态之二：在平视视角，显微操作针的功能部下缘与水平面平行的示意图。
图4为普通光学显微镜的基本成像原理示意图。
图5为本公开显微操作针姿态校准系统的一些实施例的结构示意图。
图6为本公开镜像显微成像装置的一些实施例的结构示意图。
图7为本公开镜像显微成像装置实施例的镜像显微成像原理示意图。
图8为本公开镜像显微成像装置的显微操作针功能部的镜像显微成像效果图，在平视视角下镜像形成器所成镜像的显微操作针部分从目镜中可以观察到其显微图像。
图9为本公开显微操作针姿态校准系统实施例在俯视视角获得的校准前的显微操作针的功能部的显微图像。
图10为本公开显微操作针姿态校准系统实施例在俯视视角获得的校准后的显微操作针的功能部的显微图像。
图11为本公开显微操作针姿态校准系统实施例在校准前从目镜获得的显微操作针的功能部在平视视角的镜像显微图像。
图12为本公开显微操作针姿态校准系统实施例在校准后从目镜获得的显微操作针的功能部在平视视角的镜像显微图像。
具体实施方式
下面结合附图对本公开的优选实施例进行详细阐述，以使本公开的优点和特征能 更易于被本领域技术人员理解，从而对本公开的保护范围做出更为清楚明确的界定。
显微操作管姿态校准就是在俯视视角和平视视角将显微操作针的功能部的姿态校准至理想状态。如背景技术所述，平视视角的显微图像尚不能获得。因此，要实现自动化的显微操作针姿态校准，首先要解决的技术问题是：实时获得显微操作针的功能部141在水平视角的显微图像。
普通光学显微镜的基本成像原理是：光源11的光线穿过透明的显微操作针的功能部141，并直接进入以物镜13为起始的光学成像系统，如图4所示。显然，成像的视角为与光线平行的Z轴俯视视角。这种视角是单一的，即只能从俯视视角观察。
参考背景技术中对参考坐标系的三条正交轴线(X轴、Y轴和Z轴)和三个正交的参考面(水平面、冠状面和矢状面)的定义，显微镜载物台的水平面与显微镜载物台的冠状面的交线为X轴，显微镜载物台的水平面与显微镜载物台的矢状面的交线为Y轴，显微镜载物台的矢状面与显微镜载物台的冠状面的交线为Z轴。
为了实现平视视角的显微操作针功能部141的显微图像，如图5和6所示，本公开实施例设计了一种镜像显微成像装置19，包括镜像形成器191、镜像形成器支架192和运动执行机构193。所述运动执行机构193固定安装于显微镜载物台上。所述镜像形成器支架192的一端与运动执行机构193连接。所述镜像形成器191安装于镜像形成器支架192的另一端。所述镜像形成器191的平面镜的镜面与显微镜载物台的水平面呈45°夹角且与冠状面呈45°夹角。可选地，所述运动执行机构沿Y轴方向固定安装于所述显微镜载物台上，所述镜像形成器支架沿X轴方向设置。
所述镜像形成器191的镜像形成结构为平面镜，用于捕获被观察物体与特定视角的镜像。所述镜像形成器191可采用玻璃、金属等材质经平面镜工艺加工而成。优选的，平面镜区域为矩形。
所述镜像形成器支架192优选为连接所述镜像形成器191与运动执行机构193的刚性物理结构。
所述运动执行机构193可被配置为通过手动方式或利用驱动器以自动方式实现所述镜像形成器支架192从原始位置到对应于形成镜像的预设位置的运动。例如，所述运动执行机构193为采用滑块与直线导轨配合的位移结构，且所述直线导轨与所述显微镜载物台的矢状面平行，所述镜像形成器支架相对于所述直线导轨垂直设置。又例如，运动执行机构193为采用轴关节的位移结构，所述轴关节连接所述镜像形成器的一个臂作为所述镜像形成器支架。所述轴关节可被配置为通过手动方式或利用驱动器 以自动方式实现所述镜像形成器支架从原始角度到对应于形成镜像的预设角度的摆动。
通过上述运动执行机构193可以将物体精确的从原始位置移到另一个预设位置，并且还可以通过复位机构实现所述镜像形成器支架从所述预设位置返回所述原始位置的复位运动。
所述运动执行机构还可选择性地由驱动器驱动，即实现自动控制功能。
本公开实施例还可以包括设于镜像形成器191的平面镜一侧的光源194，该光源194用于增强平视视角的光线强度，这样可有效增加被观察物体在镜像形成器上形成的镜像的亮度。
所述的镜像显微成像装置的原理是：利用平镜面成像特性，光线从特定视角(本公开实施例中为平视视角)穿过物体(本公开实施例中为显微操作针的功能部141)射在平面镜上，经过反射进入以物镜为起始的光学成像系统，从而获得物体的显微图像。该图像是物体在特定视角条件下在平面镜上形成的镜像的显微图像。如图7所示，平面镜MN与载物台平面(即水平面)OS呈45°夹角，与冠状面呈45°夹角。穿过透明物体S的入射光A以入射角θ i在入射点O射在平面镜MN上，基于法线N’，以反射角θ r反射形成反射光B进入物镜，获得的图像为镜像S’的显微放大图像。
镜像形成器支架192和与所述镜像形成器支架192连接的运动执行机构193作为镜像形成器191就位与复位的参与组件，使得镜像形成器191的就位/复位轨迹受到运动执行机构193的限制而与载物台的Y轴平行。
镜像显微成像效果图如图8所示。在平视视角于镜像形成器成镜像的显微操作针部分从目镜中可以观察到其显微图像，没在有镜像形成器成镜像的部分不能观察其图像。又因为镜像的特点，在目镜中观察到的图像与显微操作针功能部的实际方向呈镜像对称，显示为倒立的特征。在示意图中，镜像显微图像显示显微操作针功能部141下缘处于非水平姿态。
本公开通过在现有倒置显微镜上加装镜像显微成像装置就可以得到水平视角的显微操作针功能部141的显微放大图像，从而为判断并调整显微操作针功能部的水平姿态奠定技术基础。
在前述镜像显微成像装置的实施例的基础上，本实施例还提供一种显微操作针姿态校准系统，包括，
前述实施例的镜像显微成像装置19；
倒置显微镜系统，包括视频图像采集器和手动对焦单元或自动对焦单元21；
显微操作系统，包括持针器23、持针器锚定器24和持针器前后/左右/上下位移驱动器25；
与所述持针器机械耦合的持针器旋转驱动器28；
与所述持针器锚定器机械耦合的冠状面角度驱动器27，取代持针器冠状面角度调节器17；
与所述持针器锚定器机械耦合的水平面角度驱动器26，取代持针器水平面角度调节器16；和
集成有处理软件的中央处理单元，
其中，所述处理软件用于自动化监视和控制镜像形成器就位、自动对焦单云的自动对焦、对视频图像采集器的视频图像采集及分析、以及实现对持针器前后/左右/上下位移驱动器、持针器旋转驱动器、冠状面角度驱动器和矢状面角度驱动器的驱动。
如图9所示，在校准前，于俯视视角获得的显微图像，其中显微操作针功能部在水平面的投影与冠状面的角度，也即是与X轴的角度α1≠0、α2≠0。
如图11所示，在校准前，于平视视角获得的镜像显微图像：显微操作针功能部下缘在冠状面的投影与水平面的角度，也即是与X轴的角度α1’≠0、α2’≠0。
显微操作针姿态校准系统的校准方法具体包括以下步骤：
S1、手动将左、右两支显微操作针组装在相应的持针器上；
S2、手动将持针器固定在持针器锚定器上；
S3、手动调整显微操作针的功能部至目镜的视野中央区域；
S4、启动自动校准模式；
S5、通过自动对焦单元和持针器前后/左右/上下位移驱动器的联合作用，得到显微操作针的功能部在水平面的视频图像；
S6、通过视频图像采集器采集水平面的视频图像；
S7、通过处理软件分析水平面的视频图像中显微操作针的功能部在水平面的投影与冠状面的角度，也即是与X轴的角度α，并启动持针器旋转驱动器和矢状面角度驱动器，将α校准到α＝0，从而完成所述显微操作针的功能部在冠状面的校准；
S8、将镜像形成器定位到对应于形成镜像的预设位置；
S9、通过自动对焦单元和持针器前后/左右/上下位移驱动器的联合作用，得到显微操作针的功能部在冠状面的视频图像；
S10、通过视频图像采集器采集冠状面的视频图像；
S11、通过处理软件分析冠状面的视频图像中显微操作针的功能部在冠状面与水平面的角度，也即是与X轴的角度α’，并启动冠状面角度驱动器，将α’校准到α’＝0，从而完成所述显微操作针的功能部在水平面的校准；
S12、将镜像形成器复位，并使所述显微操作系统整体处于ICSI操作准备就绪状态。
在上述步骤S4中，所述自动校准模式可包括先后对左、右两支显微操作针的姿态执行自动校准，或者同时对左、右两支显微操作针的姿态执行自动校准。
在上述步骤S8中，所述预设位置与所述显微操作针的功能部的距离可为0.5mm。
通过以上调整，如图10所示，显微操作针姿态校准后在俯视视角获得显微操作针的功能部的显微图像：显微操作针的功能部中心剖面在水平面的投影与冠状面的角度，也即是与X轴的角度α1＝0、α2＝0。
如图12所示，显微操作针姿态校准后从目镜获得的显微操作针功能部在平视视角的镜像显微图像：显微操作针的功能部下缘在冠状面的投影与水平面的角度，也即是与X轴的角度α1’＝0、α2’＝0。
即本公开可采用简单的结构和方案将校准显微操作针的功能部的姿态校准至理想状态，即显微操作针的功能部的下缘与水平面平行的位置关系。
虽然结合附图描述了本公开的实施方式，但是专利所有者可以在所附权利要求的范围之内做出各种变形或修改，只要不超过本公开的权利要求所描述的保护范围，都应当在本公开的保护范围之内。

Claims (13)

  1. 一种镜像显微成像装置，包括：
    运动执行机构，固定安装于显微镜载物台上；
    镜像形成器支架，一端与所述运动执行机构连接；和
    镜像形成器，具有镜面与所述显微镜载物台的水平面呈45°夹角且与冠状面呈45°夹角的平面镜，并安装于所述镜像形成器支架的另一端。
  2. 根据权利要求1所述的镜像显微成像装置，其中，所述镜像形成器的平面镜区域为矩形。
  3. 根据权利要求1所述的镜像显微成像装置，其中，所述镜像形成器支架是连接所述镜像形成器与运动执行机构的刚性物理结构。
  4. 根据权利要求1所述的镜像显微成像装置，其中，所述运动执行机构被配置为通过手动方式或利用驱动器以自动方式实现所述镜像形成器支架从原始位置到对应于形成镜像的预设位置的运动。
  5. 根据权利要求4所述的镜像显微成像装置，其中，所述运动执行机构为采用滑块与直线导轨配合的位移结构，且所述直线导轨与所述显微镜载物台的矢状面平行，所述镜像形成器支架相对于所述直线导轨垂直设置。
  6. 根据权利要求4所述的镜像显微成像装置，其中，所述运动执行机构为采用轴关节的位移结构，所述轴关节连接所述镜像形成器的一个臂作为所述镜像形成器支架，被配置为通过手动方式或利用驱动器以自动方式实现所述镜像形成器支架从原始角度到对应于形成镜像的预设角度的摆动。
  7. 根据权利要求4所述的镜像显微成像装置，其中，所述运动执行机构还包括复位结构，用于实现所述镜像形成器支架从所述预设位置返回所述原始位置的复位运 动。
  8. 根据权利要求1所述的镜像显微成像装置，还包括设于所述平面镜的镜面一侧的光源，该光源用于增强平视视角的光线强度。
  9. 根据权利要求1所述的镜像显微成像装置，其中，所述运动执行机构沿Y轴方向固定安装于所述显微镜载物台上，所述镜像形成器支架沿X轴方向设置。
  10. 一种显微操作针姿态校准系统，包括：
    权利要求1-9任意一项所述的镜像显微成像装置；
    倒置显微镜系统，包括视频图像采集器和手动对焦单元或自动对焦单元；
    显微操作系统，包括持针器、持针器锚定器和持针器前后/左右/上下位移驱动器；
    与所述持针器机械耦合的持针器旋转驱动器；
    与所述持针器锚定器机械耦合的冠状面角度驱动器；
    与所述持针器锚定器机械耦合的矢状面角度驱动器；和
    集成有处理软件的中央处理单元，
    其中，所述处理软件用于自动化监视和控制所述镜像形成器的就位、所述自动对焦单元的自动对焦、对所述视频图像采集器的图像采集及分析、以及实现对所述持针器前后/左右/上下位移驱动器、持针器旋转驱动器、冠状面角度驱动器和矢状面角度驱动器的驱动。
  11. 一种基于根据权利要求10所述的显微操作针姿态校准系统的校准方法，包括以下步骤：
    S1、手动将左、右两支显微操作针组装在相应的持针器上；
    S2、手动将持针器固定在持针器锚定器上；
    S3、手动调整显微操作针的功能部至目镜的视野中央区域；
    S4、启动自动校准模式；
    S5、通过自动对焦单元和持针器前后/左右/上下位移驱动器的联合作用，得到显微操作针的功能部在水平面的视频图像；
    S6、通过视频图像采集器采集所述水平面的视频图像；
    S7、通过处理软件分析所述水平面的视频图像中显微操作针的功能部在水平面上的投影与冠状面的角度α，并启动持针器旋转驱动器和矢状面角度驱动器，将α校准到α＝0，从而完成所述显微操作针的功能部在水平面的校准；
    S8、将镜像形成器定位到对应于形成镜像的预设位置；
    S9、通过所述自动对焦单元和所述持针器前后/左右/上下位移驱动器的联合作用，得到显微操作针的功能部在冠状面的视频图像；
    S10、通过所述视频图像采集器采集所述冠状面的视频图像；
    S11、通过处理软件分析所述冠状面的视频图像中显微操作针的功能部在冠状面与水平面的角度α’，并启动冠状面角度驱动器，将α’校准到α’＝0，从而完成所述显微操作针的功能部在冠状面的校准；
    S12、使所述镜像形成器复位，并使所述显微操作系统整体处于ICSI操作准备就绪状态。
  12. 根据权利要求11所述的校准方法，其中，在步骤S4中，所述自动校准模式包括先后对左、右两支显微操作针的姿态执行自动校准，或者同时对左、右两支显微操作针的姿态执行自动校准。
  13. 根据权利要求11所述的校准方法，其中，在步骤S8中，所述预设位置与所述显微操作针的功能部的距离为0.5mm。
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