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WO2022195576A2 - Moyen de détection de cellules mobiles - Google Patents

Moyen de détection de cellules mobiles Download PDF

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Publication number
WO2022195576A2
WO2022195576A2 PCT/IL2022/050252 IL2022050252W WO2022195576A2 WO 2022195576 A2 WO2022195576 A2 WO 2022195576A2 IL 2022050252 W IL2022050252 W IL 2022050252W WO 2022195576 A2 WO2022195576 A2 WO 2022195576A2
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WIPO (PCT)
Prior art keywords
parameters
motility
imaging
spermatazoa
sperm
Prior art date
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Ceased
Application number
PCT/IL2022/050252
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English (en)
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WO2022195576A3 (fr
Inventor
Alon Shalev
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Qart Medical Ltd
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Qart Medical Ltd
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Publication date
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Publication of WO2022195576A2 publication Critical patent/WO2022195576A2/fr
Publication of WO2022195576A3 publication Critical patent/WO2022195576A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1434—Optical arrangements
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0608—Germ cells
    • C12N5/0612—Germ cells sorting of gametes, e.g. according to sex or motility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1429—Signal processing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1429—Signal processing
    • G01N15/1433—Signal processing using image recognition
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1027—Determining speed or velocity of a particle
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1434—Optical arrangements
    • G01N2015/1454—Optical arrangements using phase shift or interference, e.g. for improving contrast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N2015/1497—Particle shape

Definitions

  • the present invention relates generally to the field of automated detection of motile cells and specifically to analysis and detection of motile sperm cells.
  • the world health organization (WHO) manual for examination of human semen allows for a 20% variation in results for a given sample [2].
  • WHO world health organization
  • the sperm concentration, motility, and morphology are measured for instance by the SQA-V Spermalite.
  • US20040146848A1 measures total sperm concentration with a photodetector measuring absorbance in a certain wavelength range, and means for measuring average velocity (AV).
  • US4176953 discloses an automated method for determining sperm motility index (SMI) by means of detecting variations in optical density.
  • SI sperm motility index
  • TESE/TESA/micro-TEST a minimally invasive procedure
  • ICSI Intra cytoplasmic sperm injection
  • the invention comprises an apparatus and associated methods for detection, analysis, and extraction of individual, viable, biological cells over a large field of view, particularly useful for (a) sperm selection in backgrounds including blood and other particles making identification difficult for other systems, and (b) selecting sperm cells that have superior motion characteristics, among a large population of sperm cells (larger than is generally attainable in contemporary methods, due to the simultaneous particle motion analysis of a larger FOV).
  • the system comprises up to three major parts - an imaging system, analysis system, and optionally an immobilization system .
  • the imaging system detects motile biological cells, such as sperm cells, on a dish that is mountably attached to a camera having a large field of view (FOV) of the order of 2x2 mm 2 , 5x5 mm 2 , 10x10 mm 2 , 20x20 mm 2 or others.
  • FOV field of view
  • the system uses either lenseless, or low magnification, imaging, thereby allowing for a large field of view.
  • the imaging system may employ any of the standard microscopy and imaging techniques as are known in the art, including standard bright-field microscopy, dark-field microscopy, phase-contrast microscopy, DIC (difference interference contrast), or QPI (quantitative phase imaging).
  • the imaging system may be supplied with either motorized or manual focusing means used https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360083/ for example to scan various z planes to identify and localize individual sperm cells.
  • the analysis system may use motion detection means for the purpose of detection and characterization of sperm cells located over substantially most of the FOV (field of view) of the image sensor.
  • the analysis system may apply further pattern recognition mechanisms, computer vision, deep-learning based networks, GAN (generative adversarial networks) or other machine vision methodologies to the images or to the streaming video, obtained by the imaging system in order to characterize the quality of their morphology and/or motility, in order to eventually prioritize sperm selection for ICSI and/or verify that a sperm cell substantially comply with a desired morphology or has a desired set of motion characteristics.
  • GAN generative adversarial networks
  • An optional immobilization system is able to trap/immobilize the identified viable and/or motile sperm cells, so as to facilitate their removal by the operator, via, e.g. a micropipette.
  • Fig. 1 shows examples of reports produced by the invention indicating measures of motility and morphology.
  • Fig. 2 shows examples of trajectories of spermatazora.
  • Fig. 3 shows an example of a sample dish used with the invention.
  • Fig. 4 shows an example of a frame captured by the imaging system of the invention.
  • Fig. 5 shows an example of a frame captured by the imaging system, with overlays indicating motility and morphology measurements for each cell detected.
  • Fig. 6 shows an example of an overlay upon frames caputed by the imaging system adapted to guide a user to manually move a translation stage, such that an area larger than the imaging FOV may be analyzed.
  • the invention comprises an apparatus and associated methods for detection, analysis, and extraction of individual, viable, biological cells over a large field of view, particularly useful for sperm selection in backgrounds including blood and other particles making identification difficult for other systems, or in cases of numerous viable sperm cells swimming in the same FOV, where there is a desire to identify and highlight to an operator, only the very best of those sperm cells, in terms of motion and/or morphology characteristics.
  • the system comprises up to three parts - an imaging system , analysis system, and an optional immobilization system.
  • the imaging system detects motile biological cells, such as sperm cells, on a dish that is mountably attached to a camera having a large field of view (FOV) of the order of 10x10 mm 2 , 20x20 mm 2 , or more.
  • FOV field of view
  • the system uses either lenseless, or low magnification, imaging.
  • the system employs QPI (quantitative phase imaging) realized via an interferometer, such as a common path interferometer.
  • QPI quantitative phase imaging
  • the invention may employ focusing means and/or stage translation means, in order to scan various z planes to identify and localize individual sperm cells. Stage translation may also be used to increase the available analysis area.
  • the system is constructed such that a component of the imaging system is a regular microscope, preferably an inverted microscope, while the remainder of the imaging system comprises a digital image-sensor and supporting peripheral electronics (such as power supply) that are in communication with the analysis system to be described below.
  • the digital image sensor and supporting peripheral electronics are physically disposed in a separate enclosure relative to the analysis system, which, in turn, case be realized via a stand-alone computer or a cloud-based computer.
  • the digital image-sensor and supporting peripheral electronics are physically disposed in the same enclosure as the analysis sy stem and constitute a “plug-in” imaging and analysis extension assembly that may be fitted to an existing laboratory microscope, and is incorporated (for example) in an existing camera port of the laboratory microscope.
  • a separate output is often given for an external camera, which may be used in addition to or instead of the eyepiece.
  • the imaging system comprises means for speckle illumination, in which the sample is illuminated by a coherent light source.
  • the analysis system is adapted to correlate the speckle pattern on the image over time, to detect moving particles in the sample.
  • structured light may be used for detection and/or tracking of the stationary or moving spermatazoa.
  • the viable sperm cells are detected via polarization microscopy. Since viable sperm cells are birerefrigent, imaging via crossed polarizers can enable an imaging system to find their locations.
  • the sample is put on a thin flexible film, on which moving particles create ripples and mechanical tensions on the film, which are easier to detect with lenseless or low magnification imaging.
  • the analysis system includes a motion detection mechanism, which may utilize a temporal transformation such as time-domain Fourier transform or wavelet transform, to detect the locations of the cells wherein motion occurs.
  • the analysis system uses motion detection means, such as temporal derivative criteria or analogous methods, machine learning techniques, or other methods as will be familiar to those skilled in the art. Any other known technique of motion detection may he employed by the analysis system, for example frame differencing and use of the median image. These are employed for the purpose of detection and characterization of sperm cells located over substantially most of the FOV (field of view) of the image sensor.
  • the analysis system may apply further pattern recognition mechanisms to the images obtained by the imaging system in order to verify that they substantially comply with a desired shape, size, coloration, morphology, constitution, or behavior of a sperm cell, or a sperm cell element, such as a tail (flagellum) or head.
  • a desired shape, size, coloration, morphology, constitution, or behavior of a sperm cell, or a sperm cell element, such as a tail (flagellum) or head Such characteristics may be applied, for example, as a “screening” function, to distinguish between moving sperm cells and e.g. suspended debris within the semen sample.
  • morphology which may include a number of individual shape and size characteristics
  • motility which may include a number of individual motion characteristics
  • the analysis system acquires and presents a plurality of locations of suspected moving sperm cells to the operator, so that an operator can thereafter have access to such places and retrieve the live sperm ce!l(s) therefrom.
  • the analysis system acquires and presents an augmented-reality streaming video which overlays visual cues around, or adjacent to, at least one location of an identified sperm cell.
  • the shape, colour, line form or thickness of the overlay, or a dynamic change thereto may be used to indicate the quantitative or qualitative motility and/or morphology characteristics of detected cells or cued cells.
  • the shape of an icon overlaid onto the video captured by the imaging system represents the motion score of a sperm cell
  • the colour, or colour-intensity of an icon represents the morphological score of a tracked sperm cell.
  • the overlay shape may he used to indicate morphology and color motility; e.g. a circle around the sperm cell head may be used to represent fair morphology score, a square around the sperm cell head may be used to indicate an intermediate morphology score, while a triangle around a sperm cell head may represent a poor morphology score,.
  • a bright intensity colour represents fair motion score
  • intermediate intensity colour represents an intermediate motion score
  • a low intensity colour represents poor motion score.
  • a bright circle around a sperm cell head represents a fair motility-score and fair morphology-score sperm cell.
  • a bright triangle represents a poor morphology- score with a fair motion-score.
  • any parameters of the overlay may be changed to indicate measured quantities.
  • a text overlay may also be used near the top of a bounding box around the detected cell(s), where the text indicates numerical measures of motility and morphology score.
  • Fig. 5 An example of such an embodiment is shown in Fig. 5.
  • the shape of the overlay is used to indicate mobility (square for fair, circle for medium, and triangle for poor) and the color is used to indicate morphology (green for fair, yellow for medium, and orange for poor. )
  • all visual cues are circles, whose thickness indicates morphology and blinking rate of the circle indicates motion score.
  • a high blinking rate e.g. 3 times per second
  • a low' blinking rate e.g. once every 2 seconds
  • the immobilization system is able to trap/immobilize the identified viable and/or motile sperm cells, so as to facilitate their capturing/aspiration by the operator, via, e.g. a micropipette.
  • This may be achieved using optical means such as a pulsed laser, electronic means such as electrowetting manipulation, motorized positioning and micro- pipetting systems, or other means as will be known to those skilled in the art. Criteria for identification and prioritization of potentially viable sperm cells
  • the operator may define a plurality of criteria for motion and/or morphology to be applied by the system for identifying valid (or high-quality) sperm cells.
  • Valid cells will be highlighted for the operator to see, for instance by means of surrounding the valid cell by a bounding box in a live video feed of the sample.
  • Such criteria may include minimal linear or curvilinear velocity, self rotation frequency, radius of path curvature, SMI (sperm motility index), and other motion parameters; and morphological measurements such as size, shape parameters, and degree of match to an ideal shape.
  • the operator may optionally define one or more high-level quality criteria for the various parameters (e.g. on scales of 1-10) each of which is calculated by the system using the morphological and/or motion information from each identified sperm cell. Examples of such criteria and measurements are shown in Fig. 1, with analysis report 101 showing roughness, quality, width, length, and width/length, and analysis 102 showing width, length, length/width, and acrosome/head. Each of these is shown as a measured value on a line that also indicates the accepted, average, or nominal values, such that the operator can tell at a glance if a measured value is out of nominal range, and by how much.
  • the system will present to an operator a list of objects that are likely identified as sperm cells, with their respective values of (a) morphology and/or (b) motility parameters.
  • the system will present a filtered list of candidate cells to an operator, whose individual or collective criteria meet a certain set of threshold requirements. For instance, each candidate cell may be such that each criterion value are within desired tolerance values. Alternatively, candidate cells may be chosen such that more than 50% of the criteria parameters are within their respective desired tolerance values, or for another example, candidate cells may be chosen such that each criterion value will not exceed the desired tolerance values by more than 10% of the respective threshold value.
  • the system will have a default functionality measuring the velocity and radius of curvature of the path of a given cell. Those cells having a substantially non negligible linear component of motion may be selected and presented to the operator. Namely, the system will prioritize sperm cells that have a linear, or curvilinear trajectory, relative to those with a substantially circular, or ring-like trajectory , which are likely of lower fertilization potential.
  • the trajectory may for instance be characterized by the radius of curvature of the sperm cell path, with selected cells having a radius of curvature larger than some threshold.
  • Various trajectories may be seen in Fig. 2, with a largely linear trajectory 201, curvilinear trajectory 202, and roughly circular trajectory 203.
  • the system will present a sorted list of quality scores and/or direct measurements of identified sperm cells, in accordance with a predefined calculation of a quality score, so that an operator can prioritize collection of the higher quality score sperm cells.
  • highlighting of a potentially viable sperm cell can be done, for example, by “laser pointer”- like dots, rings, or “X” marks directed at the regions of suspected sperm cell motion, created by a dynamic phase mask projected onto spatial light modulator, or by a grid labelling engraved on a dish.
  • a dedicated disposable sample dish having dedicated markings, such as an alphanumeric grid, and having a layer of a hygroscopic polymer, or an otherwise sperm-immobilization material or a motion reduction medium such as Hyaluronic Acid, gelatine, PVP, provided thereupon.
  • a nonlimiting example of such a dish is shown in Fig. 3, having two matrices 301 and 302 each having nine sample cells.
  • the operator positions the sample dish in the ICSI workstation and sequentially positions the microscope stage at each of the plurality of locations on the dish, wherein motile sperm ceils were identified.
  • the operator may withdraw these sperm cells individually, to inject them into oocytes.
  • the system employs automated methods to withdraw the sperm cells, for example using a translation stage and automated micropipette.
  • the low- magnification/high-FOV imaging sensor is substantially transparent, such that it may be placed on the sample-stage in a so-called “host”, inverted microscope, while at the same time providing high-magnification/low-FOV imaging via the microscope objective lens and image sensor.
  • the operator may manually translate the microscope stage, so as to move each location identified by the device as potentially containing a viable sperm cell within the high-magnification/low-FOV area of the “host” inverted microscope. Such translation may be accomplished for instance by means of a manual translation stage.
  • the system includes an internal illumination source.
  • the system employs rear illumination, i.e., illumination that is generated from the imaging sensor’s side towards the sample.
  • illumination is of low coherence, and/or incorporates multiple wavelengths, so as to reduce the level of speckle noise in the obtained image.
  • speckle may be deliberately introduced e.g. for purposes of tracking.
  • Target location e.g., micronipette tip
  • an operator can effect a change between the relative location of a tip of a micromanipulator micropipette and the sample dish (or coordinate set of the camera’s FOV), so as to place the micropipette’s tip adjacent to an identified potentially viable sperm cell, and thereby allowing a user or automated system to aspirate the ceil into the micropipette.
  • This change in relative position may be accomplished by means of moving the micromanipulator with respect to the sample dish (e.g.
  • a motorized movement stage that moves either the micropipette, the sample stage, or both), by means of induced fluid flow, electrophoretic effects, or by any other means suitable to produce relative movement between sperm cell and micropippette, so as to bring a given sperm cell into proximity of the micromanipulator tip.
  • ⁇ As can be seen in Fig, 4, several identification areas 403 and 404 are indicated bv the analysis svstem of the invention bv means of bounding boxes, for instance bounding particular samples that have been measured in terms of their motility and morphology parameters.
  • the micropipette 402 is seen aspirating a sperm cell 401, which has been previously marked by the system as having favourable characteristics.
  • a “DR” (dead reckoning) tracking feature of the system on individual sperm cells so that in case an operator needs to transition from an objective lens of different (higher or lower) magnification, the system would have more information for registering images from before and after the transition, by “forward propagating” the expected trajectories of individual sperm cells that were tracked in the pre-switching FOV, to individual sperm-cells that are identifiable post-switching. This may be accomplished e.g. by some form of weighted cost function. This function is preferably carried out in addition to registering the before and after fields of view.
  • the system may track the curvilinear trajectory of the individually tracked sperm cells and forward- extrapolate this in case the objective lens has been switched.
  • the system may also use static patterns that are overlaid over the petri dish, to assist in registering the FOV before and after switching an objective lens.
  • the motion of the sperm cells may be largely removed in software by means of the calculation of the median image.
  • the median image is calculated from a series of images (e.g. frames of a video) by taking the median value over all frames for each pixel.
  • This method effectively removes all moving elements, leaving only the static background (which is largely unaffected by the moving elements, unlike the mean image), and this static background may be used both for movement detection (e.g. by means of subtraction of a given frame from the median image) and for registration (as in the situation above, where a first set of images is captured with a given magnification and FOV, and a second set of images is captured with a different magnification and FOV.
  • the registration itself may be accomplished by means known in the art, for example by use of homography and invariant features.
  • the system may include features to instruct the operator how to manually move the slideable microscope stage, so as to (a) span a large portion of the entire applicable viewable area over the slide, e.g. the semen sample droplet, and (b) to minimize overlapping areas in consecutive FOVs.
  • This may be accomplished by means of visual cues such as blinking arrows or the like, as is the case of hand-held cameras/cell phone camera apps; when the operator chooses “panorama” mode, an arrow indicates the direction in which to move the camera and tips are displayed indicating movement that is too fast or slow.
  • a schematic of such a system is shown in Fig. 6.
  • the sample dish 701 contains a sperm sample 710 that exceeds the size of the system FOV (individual squares 702).
  • the images of the FOV supplied by the system are overlaid with arrows 703 that indicate to the operator a direction in which to translate the translation stage holding the sample.
  • FOV field of view
  • QPI quantitative phase imaging
  • TESE/TESA/miero-TEST procedures for extraction of sperm cells from the testes, by direct aspiration or biopsy from the testicular tissue.
  • ICSI refers to intra cytoplasmic sperm injection.
  • AV refers to average velocity (of a population of sperm cells).
  • SMI refers to sperm motility index
  • DR refers to dead reckoning.

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Abstract

Un système d'identification automatisé. de spermatozoïdes est décrit. Le système comprend trois parties : un système d'imagerie, un système d'analyse et un système d'immobilisation. Le système d'imagerie détecte des cellules biologiques motiles, telles que des spermatozoïdes, au moyen d'une caméra possédant un grand champ de vision (FOV) et utilisant soit une imagerie sans lentille, soit à faible grossissement. Le système d'imagerie peut utiliser une QPI (imagerie en phase quantitative), avec des moyens de focalisation utilisés pour balayer divers plans z pour identifier et localiser des spermatozoïdes individuels. Le système d'analyse peut utiliser des moyens de détection de mouvement et de reconnaissance de motif dans le but de détecter et de caractériser des spermatozoïdes situés sur sensiblement la majeure partie du FOV (champ de vision) du capteur d'image. Le système d'immobilisation est apte à piéger/immobiliser les spermatozoïdes viables et/ou mobiles identifiés, de façon à faciliter leur retrait par l'opérateur, par l'intermédiaire, par exemple, d'une micropipette.
PCT/IL2022/050252 2021-03-15 2022-03-08 Moyen de détection de cellules mobiles Ceased WO2022195576A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9340762B2 (en) * 2010-08-20 2016-05-17 Yu Sun Method for automated sperm manipulation and device for holding sperm and oocytes
US20150031019A1 (en) * 2013-03-14 2015-01-29 Cellcura As Computer Assisted Sperm Profile Analysis and Recognition
WO2019197509A1 (fr) * 2018-04-13 2019-10-17 Ventana Medical Systems, Inc. Systèmes d'estimation de forme de cellule
GB201808312D0 (en) * 2018-05-21 2018-07-11 Governing Council Of The Univ Of Toronto A method for automated non-invasive measurement of sperm motility and morphology and automated selection of a sperm with high dna integrity

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