WO2021200911A1 - フローサイトメーター - Google Patents

フローサイトメーター Download PDF

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Publication number
WO2021200911A1
WO2021200911A1 PCT/JP2021/013478 JP2021013478W WO2021200911A1 WO 2021200911 A1 WO2021200911 A1 WO 2021200911A1 JP 2021013478 W JP2021013478 W JP 2021013478W WO 2021200911 A1 WO2021200911 A1 WO 2021200911A1
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WO
WIPO (PCT)
Prior art keywords
light
region
spatial filter
observation object
optical path
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2021/013478
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English (en)
French (fr)
Japanese (ja)
Inventor
亨 今井
圭亮 戸田
禎生 太田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thinkcyte Inc
University of Tokyo NUC
Original Assignee
Thinkcyte Inc
University of Tokyo NUC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thinkcyte Inc, University of Tokyo NUC filed Critical Thinkcyte Inc
Priority to CN202180025132.8A priority Critical patent/CN115349083B/zh
Priority to EP21779172.2A priority patent/EP4130714A4/en
Priority to JP2022512270A priority patent/JP7656837B2/ja
Priority to CN202511459345.8A priority patent/CN121476024A/zh
Publication of WO2021200911A1 publication Critical patent/WO2021200911A1/ja
Priority to US17/935,696 priority patent/US12339217B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • G01N15/1436—Optical arrangements the optical arrangement forming an integrated apparatus with the sample container, e.g. a flow cell
    • 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
    • G01N15/02—Investigating particle size or size distribution
    • G01N15/0205—Investigating particle size or size distribution by optical means
    • 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
    • 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
    • G01N15/1456—Optical investigation techniques, e.g. flow cytometry without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals
    • G01N15/1459—Optical investigation techniques, e.g. flow cytometry without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals the analysis being performed on a sample stream
    • 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
    • G01N15/1468—Optical investigation techniques, e.g. flow cytometry with spatial resolution of the texture or inner structure of the particle
    • G01N15/147—Optical investigation techniques, e.g. flow cytometry with spatial resolution of the texture or inner structure of the particle the analysis being performed on a sample stream
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
    • G01N21/53—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke
    • 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
    • G01N15/01—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials specially adapted for biological cells, e.g. blood cells
    • 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
    • G01N15/02—Investigating particle size or size distribution
    • G01N2015/0294—Particle shape
    • 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
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N2015/1497—Particle shape

Definitions

  • the present invention relates to a flow cytometer.
  • the present application claims priority based on Japanese Patent Application No. 2020-656940 filed in Japan on April 1, 2020, the contents of which are incorporated herein by reference.
  • the flow cytometry method has been proposed as a cell measurement technique in the case of performing such analysis by one cell (single cell).
  • This flow cytometry method is a technique for dispersing individual cells in a fluid and allowing the fluid to flow down finely for optical analysis, and an apparatus using this technique is called a flow cytometer (Patent Document 1). ).
  • excitation light is irradiated while fine particles such as cells to be observed flow down in the flow path at high speed, and the total amount of fluorescence brightness and scattered light emitted from each cell is obtained.
  • the observation object can be evaluated.
  • the scattered light emitted from the light-irradiated cell is related to the morphological information such as the shape and internal structure of the cell, and one of the morphological information is obtained depending on the direction in which the scattered light is scattered. It is known that it can be obtained. Therefore, also in flow cytometry, there is known a method of measuring scattered light by combining cells with fluorescence and identifying and sorting desired cells contained in a sample based on the measurement result (Patent Document 3). ).
  • the present invention has been made in view of the above points, and provides a means for detecting modulated light due to a measurement object such as scattered light by a mechanism simpler than the conventional one in flow cytometry using structured illumination. ..
  • a measurement object such as scattered light by a mechanism simpler than the conventional one in flow cytometry using structured illumination. ..
  • the present invention has been made to solve the above problems, and one aspect of the present invention is a flow path through which an object to be observed can flow together with a fluid, a light source, and a space that modulates the light emitted from the light source.
  • An illumination optical system including an optical modulation device, a first optical element that forms an image of light modulated by the spatial light modulation device in the flow path, and light formed by the first optical element.
  • a flow cytometer comprising a detection optical system including a first light detector that detects light modulated by the observation object flowing in the flow path, wherein the illumination optical system is the light source and the light source.
  • the detection optical system is in a second optical path between the first light detector and the imaging position in the flow path. It further comprises a second spatial filter having a second region that is installed and has a second region that directs the light modulated by the observation object towards the first light detector, the location of the first region and said. It is a flow cytometer that is installed in a substantially optically conjugate relationship with the position of the second region.
  • the light modulated by the spatial optical modulation device passes through the observation object and the second spatial filter is provided.
  • the region where the first spatial filter is irradiated by the light modulated by the spatial light modulation device and the first region overlap.
  • the image formed by the region on the second spatial filter is substantially the same as or included in the region occupied by the second spatial filter.
  • the light modulated by the observation object flowing in the flow path detected by the first photodetector is scattered light or diffracted light. ..
  • the first region transmits or blocks the light emitted from the light source to travel toward the observation object. Interfere with either diffraction or reflection.
  • a second light detector for detecting scattered light is further provided.
  • a second light detector for detecting the scattered light is further provided.
  • the first spatial filter and the spatial light modulation device are integrally provided in the flow cytometer.
  • the second spatial filter is also used by the first spatial filter.
  • the first photodetector is a region other than the second region of the second spatial filter in the light transmitted through the observation object.
  • the first photodetector is a region other than the second region of the second spatial filter in the light transmitted through the observation object.
  • one aspect of the present invention is a beam splitter that is arranged in the second optical path and takes out a part of the light modulated by the observation object in the flow cytometer, and is taken out by the beam splitter.
  • a third spatial filter having a third region for transmitting the modulated light and a second photodetector for detecting the modulated light transmitted through the third region are further provided.
  • modulated light due to an observation object can be detected by a simpler mechanism than in the past.
  • modulated light such as scattered light emitted from an observation object by illumination irradiation can be detected with a high signal-to-noise ratio, and detailed morphological information of the observation object can be acquired with a higher resolution than before. can.
  • label-free it becomes possible to separate an observation object such as a target cell at high speed based on morphological information in a non-invasive manner without labeling it with a fluorescent label or the like (hereinafter, also referred to as label-free).
  • FIG. 1 is a diagram showing an example of the configuration of the flow cytometer 1 according to the present embodiment.
  • the flow cytometer 1 includes a flow path (not shown), an illumination optical system 2, and a detection optical system 3.
  • the object 5 to be observed can flow together with the fluid in the flow path.
  • the observation object 5 is an object for which morphological information is acquired, and is, for example, a cell.
  • the observation object 5 may be fine particles such as bacteria.
  • FIG. 1 shows an xyz coordinate system as a three-dimensional Cartesian coordinate system.
  • the x-axis direction is the length direction of the flow path.
  • the y-axis direction is the width direction of the flow path.
  • the z-axis direction is a direction orthogonal to the flow path and is a height direction of the flow path.
  • the illumination optical system 2 is an optical system for irradiating the observation object 5 in the flow path by the structured illumination 4.
  • the structured illumination 4 detects the forward scattered light scattered by the observation object 5 by the detection optical system 3.
  • the forward scattered light is the light scattered in the positive direction of the z-axis among the scattered light by the observation object 5.
  • the flow cytometer 1 detects scattered light based on the principle of so-called dark field observation.
  • the optical path of the illumination light of the illumination optical system 2 is called the first optical path 24.
  • the first optical path 24 is parallel to the z-axis.
  • FIG. 1 as an example of the first optical path 24, the first optical path 24-1 and the first optical path 24-2 are shown.
  • the illumination optical system 2 includes a light source 20, a spatial light modulation device 21, a first spatial filter 22, and a first objective lens 23.
  • the light source 20, the spatial light modulation device 21, the first spatial filter 22, and the first objective lens 23 are in this order the first optical path 24 in the direction in which the illumination light is directed toward the observation object 5 flowing through the flow path. Be prepared on top.
  • the light source 20 is, for example, a laser light source.
  • the light source 20 emits illumination light, which is coherent light, as an example.
  • the light source 20 may be a light source that emits incoherent light.
  • Another example of the light source 20 is a semiconductor laser light source and an LED (LIGHT EMITTING DIODE) light source.
  • the spatial light modulation device 21 modulates the light emitted from the light source 20.
  • the spatial light modulation device 21 has a plurality of regions having different optical characteristics from each other.
  • the spatial light modulation device 21 performs different modulations on the optical characteristics of incident light in two or more regions among a plurality of regions having different optical characteristics.
  • the optical characteristic of incident light is, for example, a characteristic relating to any one or more of intensity, wavelength, phase, and polarization state.
  • the optical characteristics are not limited to these. Further, the modulation is to change the above-mentioned optical characteristics.
  • the spatial light modulation device 21 includes, for example, a diffractive optical element (DOE: Differential Optical Element), a spatial light modulator (SLM: Spatial Light Modulator), a digital mirror device (DMD: Digital Micromiror Device), and a plurality of digital mirror devices having different optical characteristics. Includes a film or the like in which the area is printed on the surface.
  • DOE diffractive optical element
  • SLM Spatial Light Modulator
  • DMD Digital Micromiror Device
  • a plurality of digital mirror devices having different optical characteristics Includes a film or the like in which the area is printed on the surface.
  • the spatial light modulation device 21 is a DMD.
  • the first spatial filter 22 has a blocking region that blocks the light emitted from the light source 20 and a transmission region that transmits the light emitted from the light source 20.
  • the first spatial filter 22 is installed on the first optical path 24, which is an optical path between the light source 20 and the imaging position 25 in the flow path.
  • the imaging position 25 is the position of an image of light imaged in the flow path by the first objective lens 23.
  • the position of the image of light imaged by the first objective lens 23 is the position where the structured illumination 4 is imaged.
  • the illumination pattern of the structured illumination light applied to the observation object is constant and does not change during the period of measuring one observation object.
  • the structured illumination 4 is a structured illumination pattern in which the illumination light modulated by the spatial light modulation device 21 is imaged by the first objective lens 23.
  • the first spatial filter 22 is provided, for example, between the spatial light modulation device 21 and the imaging position 25 in the first optical path 24.
  • the first spatial filter 22 is installed substantially perpendicular to the first optical path 24 (that is, in the z-axis direction).
  • the first spatial filter 22 is provided at any position between the spatial light modulation device 21 and the imaging position 25 in the first optical path 24, as long as it is at a position other than the imaging position 25. May be good.
  • the first spatial filter 22 is provided at the imaging position 25, the structured illumination 4 itself is missing, which is not preferable.
  • FIG. 2 is a diagram showing an example of the configuration of the first spatial filter 22 according to the present embodiment.
  • the shape of the first space filter 22 is, for example, a quadrangle and a plate shape.
  • FIG. 2 shows a plane 222 when the plate-shaped first space filter 22 is viewed from the side of the light source 20 in the z-axis direction.
  • the surface of the first spatial filter 22 on the light source 20 side is located on the plane 222.
  • the irradiation region R1 indicates a region in which the structured illumination light, which is the light from the light source 20 modulated by the spatial light modulation device 21, is irradiated on the plane 222.
  • the surface of the first spatial filter 22 located on the plane 222 is divided into a transmission region 220 and a blocking region 221.
  • the transmission region 220 of the first spatial filter 22 is separated by a blocking region 221 and consists of two regions in which the transmission region 220-1 and the transmission region 220-2 are not connected.
  • the transmission region 220 is configured by providing a gap in the first spatial filter 22.
  • the transmission region 220 is a region that transmits the light emitted from the light source 20.
  • the blocking region 221 is a mask that blocks the light emitted from the light source 20.
  • the shape of the blocking region 221 is rectangular as an example in this embodiment.
  • the shape of the blocking region 221 is not limited to a rectangle and may be any shape as long as it occupies a part of the irradiation region R1. That is, the shape and arrangement of the blocking region 221 in the first space filter 22 does not have to be the shape and arrangement as shown in FIG. 2 so as to divide the transmission region 220 into two or more regions. ..
  • the shape of the blocking region 221 may be a circle whose diameter is shorter than the diameter of the irradiation region R1 and may be arranged in the center of the first spatial filter 22.
  • the blocking region 221 is arranged at the end of the irradiation region R1, and a part of the light irradiated to the irradiation region R1 that is irradiated to the end is blocked by the blocking region 221. It may have been done.
  • the blocking region 221 is concentrically arranged at the end of the irradiation region R1, the shape of the transmission region 220 is a circle having a diameter shorter than the diameter of the irradiation region R1, and the transmission region 220 is the center. It may have a structure that is installed in a part.
  • the blocking region 221 is an example of a first region that prevents the light emitted from the light source 20 from traveling toward the observation object 5. Therefore, the first spatial filter 22 has a first region that prevents the light emitted from the light source 20 from traveling toward the observation object 5.
  • the first spatial filter 22 has the blocking region 221, a part of the frequencies of the light emitted as the structured illumination 4 may be lost.
  • the region of the irradiation region R1 where the irradiated light is blocked by the blocking region 221 is, in other words, a region where the irradiation region R1 and the blocking region 221 overlap.
  • the area of the area where the irradiation area R1 and the blocking area 221 overlap is determined in consideration of the structure of the observation object, the structure of the structured illumination light, and the like, and the ratio of the blocking region to the irradiation region R1. Is preferably in the range of 5% to 70%.
  • the first objective lens 23 forms an image of light modulated by the spatial light modulation device 21.
  • the first objective lens 23 forms an image of the light modulated by the spatial light modulation device 21 at the image formation position 25 of the flow path.
  • the light imaged by the first objective lens 23 irradiates the observation object 5 flowing through the flow path as the structured illumination 4.
  • the first objective lens 23 is an example of a first optical element that forms an image of light modulated by the spatial light modulation device 21 in the flow path.
  • the detection optical system 3 is an optical system that detects light modulated by the observation object 5 flowing in the flow path.
  • the detection optical system 3 includes a second objective lens 30, a second spatial filter 31, an imaging lens 32, and a first photodetector 33.
  • the optical path of scattered light is referred to as a second optical path 34.
  • the first photodetector 33 detects the forward scattered light, which is the light modulated by the object 5.
  • the second spatial filter 31 has a blocking region that blocks the light transmitted through the observation object 5 and a transmission region that transmits the light modulated by the observation object 5.
  • the light transmitted through the observation object 5 is direct light emitted from the light source 20 and transmitted through the observation object 5. That is, the second spatial filter 31 blocks the direct light transmitted through the observation object 5.
  • the light modulated by the observation object 5 is scattered light in which the light emitted from the light source 20 is scattered by the observation object 5. That is, the second spatial filter 31 transmits the scattered light scattered by the observation object 5.
  • the second space filter 31 is installed in the second optical path 34.
  • the position where the second space filter 31 is installed and the position where the first space filter 22 is installed have a substantially optically conjugate relationship.
  • the fact that the positions to be installed here have a substantially optically conjugate relationship means that they are installed at positions that are substantially optically conjugate.
  • the first spatial filter 22 and the second spatial filter 31 are arranged substantially in parallel.
  • FIG. 3 is a diagram showing an example of the configuration of the second spatial filter 31 according to the present embodiment.
  • the shape of the second space filter 31 is, for example, a quadrangle and a plate shape.
  • FIG. 3 shows a plane 312 when the plate-shaped second space filter 31 is viewed from the side of the light source 20 in the z-axis direction.
  • the surface of the second spatial filter 31 on the light source 20 side is located on the plane 312.
  • the irradiation region R2 when the first spatial filter 22 is not provided in the flow cytometer 1, the light irradiated to the observation object 5 as the structured illumination 4 is irradiated on the plane 312 through the second objective lens 30. Indicates the area to be used.
  • the surface of the second space filter 31 located on the plane 312 is divided into a blocking region 310 and a transmission region 311.
  • the blocking region 310 of the second spatial filter 31 is separated by a transmission region 311 and consists of two regions in which the blocking region 310-1 and the blocking region 310-2 are not connected.
  • the blocking area 310 is a mask that blocks the light transmitted through the observation object 5.
  • the light transmitted through the observation object 5 is direct light transmitted through the transmission region 220 included in the first spatial filter 22.
  • the transmission region 311 is configured by providing a gap in the second spatial filter 31 as an example. In the area where the transmission area 311 and the irradiation area R2 overlap on the plane 312, an image of the area where the blocking area 221 and the irradiation area R1 in the first space filter overlap is formed on the second space filter 31 and occupies the plane 312. It is almost the same as the area. As described above, since the shape of the blocking region 221 is rectangular in the present embodiment, the shape of the transmission region 311 is also rectangular.
  • the transmission region 311 is a region that transmits the scattered light scattered by the observation object 5.
  • the region where the irradiation region R2 and the transmission region 311 overlap on the plane 312 of the second space filter 31 and the region where the irradiation region R1 and the blocking region 221 overlap on the plane 222 of the first space filter 22 are imaged with each other. There is a relationship.
  • the shape and arrangement of the region where the irradiation region R2 and the transmission region 311 overlap may be such that the region where the irradiation region R1 and the blocking region 221 overlap is included in the image formed on the plane 312. good.
  • the transmission region 311 is an example of a second region that transmits light modulated by the observation object 5.
  • the first spatial filter 22 is not provided in the flow cytometer 1
  • the light radiated to the observation object 5 as the structured illumination 4 is radiated on the plane 312 through the second objective lens 30.
  • the region where the irradiation region R2 and the transmission region 311 overlap is the second spatial filter 31. It is substantially the same as or included in the region occupied by the imaged image in the second spatial filter 31.
  • the position where the second space filter 31 is installed and the position where the first space filter 22 is installed have a substantially optically conjugated relationship. Therefore, with respect to the positional relationship between the blocking region 221 of the first spatial filter 22 and the transmission region 311 of the second spatial filter 31, the position of the blocking region 221 and the position of the transmission region 311 are substantially optically conjugated. There is a relationship.
  • the transmission region 220 included in the first spatial filter 22 and the transmission region 311 included in the second spatial filter 31 are formed by gaps
  • the transmission region 220 and the transmission region 311 may be composed of a substance having a transmittance of a predetermined value or more.
  • the second objective lens 30 converts the light modulated by the observation object 5 into parallel light.
  • the second optical path 34 is an optical path for scattered light, which is an optical path between the first photodetector 33 and the imaging position 25.
  • the position where the second space filter 31 is installed and the position where the first space filter 22 is installed have a substantially optically conjugate relationship, and the second objective lens 30 is installed.
  • the position to be set is such that the structured illumination 4 is placed in the flow path in the second optical path 34 as long as it does not interfere with the substantially optically coupled relationship between the first spatial filter 22 and the second spatial filter 31. It may be arranged at any position between the imaging position 25 to be imaged and the second spatial filter 31.
  • the imaging lens 32 is arranged at a position between the second spatial filter 31 and the first photodetector 33 in the second optical path 34.
  • the imaging lens 32 images the light modulated by the observation object 5 that has passed through the second objective lens 30 on the detection surface of the first photodetector 33 by the imaging lens 32. It is placed in the position where it is.
  • the first photodetector 33 detects the scattered light imaged by the imaging lens 32.
  • the scattered light imaged by the imaging lens 32 is the forward scattered light generated by the observation object 5, and the structured illumination imaged in the flow path by the first objective lens 23 passes through the flow path.
  • the first photodetector 33 is an example of a first photodetector that detects light formed by an optical element and modulated by an observation object 5 flowing in a flow path.
  • the first photodetector 33 has, for example, an optical sensor such as a photomultiplier tube (PMT), a line-type PMT element, a photodiode, an APD (Avalanche Photo-deide), or a semiconductor optical sensor. ..
  • an optical sensor such as a photomultiplier tube (PMT), a line-type PMT element, a photodiode, an APD (Avalanche Photo-deide), or a semiconductor optical sensor. ..
  • the scattered light detected by the first photodetector 33 is imaged on the detection surface of the first photodetector 33 via the second objective lens 30 and the imaging lens 32.
  • the scattered light detected by the first photodetector 33 is preferably imaged on the detection surface of the first photodetector 33, but is predetermined on the detection surface of the first photodetector 33. As long as the amount of light or more is focused, it is not necessary to form an image on the detection surface of the first photodetector 33.
  • the scattered light detected by the photodetector may not be imaged on the detection surface as long as a predetermined amount of light or more is focused on the detection surface of the photodetector.
  • the first photodetector 33 converts the detected scattered light into a telegraph pulse and outputs it to a DAQ (Data Acquisition) device (not shown) or the like.
  • the DAQ device converts electrical signal pulses into electronic data on a pulse-by-pulse basis.
  • the DATA device outputs electronic data to an analyzer (not shown) or the like. The electronic data is analyzed by the analysis device, and the morphological information of the observation object 5 is acquired.
  • the flow cytometer 1 includes an illumination optical system 2, a flow path through which the observation object 5 can flow together with the fluid, and a detection optical system 3.
  • the illumination optical system 2 includes a light source 20, a spatial light modulation device 21, and a first optical element (first objective lens 23 in this embodiment).
  • the spatial light modulation device 21 modulates the light emitted from the light source 20.
  • the first optical element (first objective lens 23 in this embodiment) forms an image of light modulated by the spatial light modulation device 21 in the flow path.
  • the detection optical system 3 is a first light for detecting the light formed by the first optical element (the first objective lens 23 in the present embodiment) and modulated by the observation object 5 flowing in the flow path.
  • a detector 33 is provided.
  • the illumination optical system 2 further includes a first spatial filter 22.
  • the first spatial filter 22 is provided in the first optical path 24 between the light source 20 and the imaging position 25 in the flow path imaged by the first optical element (first objective lens 23 in this embodiment). It has a first region (blocking region 221 in the present embodiment) that is installed and prevents the light emitted from the light source 20 from traveling toward the observation object 5.
  • the detection optical system 3 further includes a second spatial filter 31.
  • the second spatial filter 31 is installed in the second optical path 34 between the first photodetector 33 and the imaging position 25 in the flow path, and the light modulated by the observation object 5 (the present embodiment). In the example, it has a second region (transmitted region 311 in the present embodiment) that transmits forward scattered light).
  • the position of the first region (blocking region 221 in the present embodiment) and the position of the second region (transmission region 311 in the present embodiment) are substantially optically conjugated.
  • the flow cytometer 1 has a simple configuration in which the first spatial filter 22 and the second spatial filter 31 are provided on the optical path in the flow cytometry using the structured illumination light. Therefore, the modulated light due to the observation object can be detected by a mechanism simpler than that of the conventional flow cytometer.
  • the conventional flow cytometer is, for example, a flow cytometer that evaluates the characteristics of cells by the total amount of fluorescence brightness and the total amount of scattered light using line-shaped illumination light.
  • the modulated light by the observation object includes scattered light and diffracted light.
  • the second region (the present embodiment) arranged at a position substantially optically conjugate with the position of the first region (the blocking region 221 in the present embodiment). Since the scattered light from the observation object 5 transmitted through the transmission region 311) can be detected in the form, the scattered light that realizes a higher signal noise ratio than the conventional one can be detected.
  • the signal-to-noise ratio is the ratio of scattered light to light other than scattered light among the lights detected by the first photodetector 33.
  • the light other than the scattered light is, for example, direct light.
  • the flow cytometer 1 can analyze the scattered light detected at a higher signal-to-noise ratio than the conventional one.
  • the illumination light is modulated by the modulation device, the structured illumination is applied to the measurement object, and higher resolution morphological information can be extracted based on the scattered light.
  • Detailed morphological information about the observation object 5 can be obtained (label-free) without labeling with a fluorescent substance, and the observation object 5 can be measured and classified non-invasively.
  • FIG. 4 is a diagram showing an example of a flow cytometer 1a according to a modified example of the present embodiment.
  • the flow cytometer 1a includes a flow path (not shown), an illumination optical system 2a, and a detection optical system 3a.
  • the same configurations and operations as those of the first embodiment described above are designated by the same reference numerals, and the description thereof will be omitted.
  • the illumination optical system 2a includes a light source 20a, a spatial light modulation device 21a, a first spatial filter 22a, and a first objective lens 23.
  • the optical path of the illumination light of the illumination optical system 2a is referred to as a first optical path 24a.
  • the first optical path 24a-1, the first optical path 24a-2, and the first optical path 24a-3 are shown.
  • the first optical path 24a is parallel to the x-axis in the section from the light source 20a to the first spatial filter 22a.
  • the first optical path 24a-1 and the first optical path 24a-3 are located at the positions of the first spatial filter 22a due to the illumination light being reflected by the first spatial filter 22a.
  • the first optical path 24a-1 and the first optical path 24a-3 are parallel to the z-axis in the section from the first spatial filter 22a to the observation object 5.
  • the light source 20a, the spatial light modulation device 21a, the first spatial filter 22a, and the first objective lens 23 are in this order the first optical path 24a in the direction in which the illumination light is directed toward the observation object 5 flowing through the flow path. Be prepared on top.
  • the configuration of the light source 20a and the spatial light modulation device 21a is the configuration of the light source 20 and the spatial light modulation device 21 of the first embodiment except that the direction of the first optical path 24a provided with them is parallel to the x-axis. Is the same as each.
  • the first spatial filter 22a has a reflection region that reflects the light emitted from the light source 20a and a transmission region that transmits the light emitted from the light source 20a.
  • the first spatial filter 22a is installed at an angle of a predetermined angle from a direction substantially perpendicular to the first optical path 24a (that is, the x-axis direction).
  • the predetermined angle is, for example, 45 degrees clockwise when viewed in the ⁇ y direction.
  • FIG. 5 is a diagram showing an example of the configuration of the first spatial filter 22a according to the present modification.
  • the flat surface of the plate-shaped first spatial filter 22a on the light source 20a side that is, the flat surface 222a of the first spatial filter 22a in FIG. 4 when viewed from the light source 20a side in the x-axis direction is It is shown.
  • the surface of the first spatial filter 22a on the light source 20 side is located on the plane 222a.
  • the surface of the first spatial filter 22a located on the plane 222a is divided into a reflection region 220a and a transmission region 221a.
  • the reflection region 220a of the first spatial filter 22a is separated by the transmission region 221a and consists of two regions in which the reflection region 220a-1 and the reflection region 220a-2 are not connected.
  • the reflection region 220a is a mirror that reflects the illumination light from the light source 20a.
  • the transmission region 221a transmits the illumination light from the light source 20a.
  • the transmission region 221a is an example of a first region that prevents the light emitted from the light source 20a from traveling toward the observation object 5.
  • the detection optical system 3a includes a second objective lens 30, a second spatial filter 31a, an imaging lens 32a, and a first photodetector 33a.
  • the optical path of the forward scattered light is referred to as a second optical path 34a.
  • the second optical path 34a is parallel to the z-axis in the section from the observation object 5 to the second spatial filter 31a.
  • the second optical path 34a bends at a substantially right angle at the position of the second spatial filter 31a due to the forward scattered light being reflected by the second spatial filter 31a.
  • the second optical path 34a becomes parallel to the x-axis in the section from the second spatial filter 31a to the first photodetector 33a.
  • the second objective lens 30, the second spatial filter 31a, the imaging lens 32a, and the first photodetector 33a are transferred from the observation object 5 flowing through the flow path to the first photodetector 33a in this order. It is provided on the second optical path 34a in the direction in which the forward scattered light is directed.
  • the second spatial filter 31a has a reflection region that reflects the light modulated by the observation object 5 and a blocking region that blocks the light that has passed through the observation object 5.
  • the light modulated by the observation object 5 is forward scattered light as described above.
  • the second spatial filter 31a is installed at an angle of a predetermined angle from a direction substantially perpendicular to the second optical path 34a (that is, the z-axis direction).
  • the predetermined angle is, for example, 45 degrees counterclockwise when viewed in the ⁇ y direction.
  • the position where the second spatial filter 31a is installed and the position where the first spatial filter 22a is installed have a substantially optically conjugate relationship.
  • FIG. 6 is a diagram showing an example of the configuration of the second spatial filter 31a according to the present modification.
  • the surface of the plate-shaped second space filter 31a on the observation object side that is, the plane 312a when the second space filter 31a in FIG. 4 is viewed from the observation object 5 side in the z-axis direction is It is shown.
  • the surface of the second spatial filter 31a on the observation object 5 side (light source 20 side) is located on the plane 312a.
  • the surface of the second spatial filter 31a located on the plane 312a is divided into a blocking region 310a and a reflection region 311a.
  • the blocking region 310a of the second spatial filter 31a is separated by the reflection region 311a and consists of two regions in which the blocking region 310a-1 and the blocking region 310a-2 are not connected.
  • the reflection region 311a is, for example, a mirror.
  • the configurations of the imaging lens 32a and the first photodetector 33a are the imaging lens 32 and the first photodetector 33a shown in FIG. 1, except that the orientation of the second optical path 34a provided with them is parallel to the x-axis.
  • the configuration is the same as that of the photodetector 33 of the above.
  • the flow cytometer 1a may be provided with the detection optical system 3 shown in FIG. 1 instead of the detection optical system 3a. Further, in the flow cytometer 1 of the first embodiment, the detection optical system 3a shown in FIG. 4 may be provided instead of the detection optical system 3.
  • FIG. 7 is a diagram showing an example of the configuration of the flow cytometer 1b according to the present embodiment.
  • the flow cytometer 1b includes a flow path (not shown), an illumination optical system 2b, and a detection optical system 3b.
  • the same configurations and operations as those of the first embodiment described above are designated by the same reference numerals, and the description thereof will be omitted.
  • the flow cytometer according to this embodiment is referred to as a flow cytometer 1b.
  • the flow cytometer 1b detects backscattered light as light modulated by the observation object.
  • the structured illumination 4 detects the backscattered light scattered by the observation object 5 by the detection optical system 3b.
  • the backscattered light is the light scattered in the negative direction of the z-axis among the scattered light by the observation object 5.
  • the illumination optical system 2b includes a light source 20, a spatial light modulation device 21, a first spatial filter 22b, and a first objective lens 23.
  • the optical path of the illumination light of the illumination optical system 2b is referred to as a first optical path 24b.
  • the first spatial filter 22b has a blocking region that blocks the light emitted from the light source 20 and a transmission region that transmits the light emitted from the light source 20. Further, the first spatial filter 22b has a reflection region for reflecting the backscattered light by the observation object 5 on the back side of the blocking region.
  • the first optical path 24b-1 and the first optical path 24b-3 are optical paths of light that passes through the transmission region of the first spatial filter 22b of the illumination light.
  • the first optical path 24b-2 is an optical path of light that is blocked by the blocking region of the first spatial filter 22b among the illumination lights.
  • the first spatial filter 22b is installed at an angle of a predetermined angle from a direction substantially perpendicular to the first optical path 24b (that is, the z-axis direction).
  • the predetermined angle is, for example, 45 degrees clockwise when viewed in the ⁇ y direction.
  • FIG. 8 is a diagram showing an example of the configuration of the first spatial filter 22b according to the present embodiment.
  • FIG. 8 shows a plane of the plate-shaped first space filter 22b on the light source 20 side, that is, a plane 222b which is a plane when the first space filter is viewed from the light source 20 side in the z-axis direction in FIG. 7. Has been done.
  • the surface of the first spatial filter 22b on the light source 20 side is located on the plane 222b.
  • the surface of the first spatial filter 22b located on the plane 222b is divided into a transmission region 220b and a blocking region 221b.
  • the transmission region 220b is separated by the blocking region 221b and consists of two regions in which the transmission region 220b-1 and the transmission region 220b-2 are not connected.
  • the first spatial filter 22b has a reflection region 223b in a region facing the blocking region 221b on the back surface of the first spatial filter 22b (the surface of the first spatial filter 22b on the imaging position 25 side).
  • the reflection region 223b is a mirror that reflects backscattered light from the observation object 5. This mirror is an example of a member that reflects scattered light emitted from the observation object 5.
  • the first region that prevents the light emitted from the light source 20 from traveling to the observation object 5 is a surface at the imaging position 25 among the surfaces constituting the first spatial filter 22b.
  • the light emitted from the light source 20 is composed of a member that reflects the scattered light scattered backward by the observation object 5.
  • the first spatial filter 22b has a blocking region 221b that blocks the light emitted from the light source 20 on the surface on the light source 20 side, and the observation object 5 is on the surface opposite to the light source 20. It has a reflection region 223b that reflects scattered light emitted from the light source.
  • the detection optical system 3b includes an imaging lens 32a and a first photodetector 33a.
  • the configurations of the imaging lens 32a and the first photodetector 33a are the same as the configurations of the imaging lens 32a and the first photodetector 33a shown in FIG. 4, respectively.
  • the second spatial filter is also used by the first spatial filter 22b.
  • the first spatial filter 22b has a first region (blocking region 221b in the present embodiment) that prevents the light source light from being irradiated to the observation object 5 on the surface on the light source 20 side, which is opposite to the light source 20.
  • It has a structure having a member (reflection region 223b in the present embodiment) that reflects the backward scattered light by the observation object 5 on the surface of the first region (blocking region 221b in the present embodiment) and the second.
  • the region (reflection region 223b in the present embodiment) is arranged at a position substantially optically conjugate.
  • the optical path of backscattered light is referred to as a second optical path 34b.
  • the second optical path 34b is parallel to the z-axis in the section from the observation object 5 to the first spatial filter 22b.
  • the second optical path 34b is substantially perpendicular to the position of the first spatial filter 22b because the backscattered light is reflected by the first spatial filter 22b (the side of the first spatial filter facing the imaging position 25). Turn to. As a result, the second optical path 34b becomes parallel to the x-axis in the section from the first spatial filter 22b to the first photodetector 33a.
  • the present invention is not limited to this.
  • the second spatial filter does not have to be combined with the first spatial filter 22b.
  • the position of the second optical path 34b is different from the position where the first spatial filter 22b is installed, and the position of the first region and the position of the second region are substantially optically conjugated.
  • a spatial filter different from the first spatial filter 22b is installed as a second spatial filter at a position having such a relationship.
  • FIG. 9 is a diagram showing an example of a flow cytometer 1c according to a modified example of the present embodiment.
  • the flow cytometer 1c includes a flow path (not shown), an illumination optical system 2c, and a detection optical system 3c.
  • the same configurations and operations as those of the second embodiment described above are designated by the same reference numerals, and the description thereof will be omitted.
  • the illumination optical system 2c includes a light source 20c, a spatial light modulation device 21c, a first spatial filter 22c, and a first objective lens 23.
  • the optical path of the illumination light of the illumination optical system 2c is referred to as a first optical path 24c.
  • the first optical path 24c-1 and the first optical path 24c-2 are shown.
  • the first optical path 24c is parallel to the x-axis in the section from the light source 20c to the first spatial filter.
  • the first optical path 24c-1 and the first optical path 24c-2 are bent at substantially right angles at the position of the first spatial filter 22c due to the illumination light being reflected by the first spatial filter 22c.
  • the first optical path 24c-1 and the first optical path 24c-2 are parallel to the z-axis in the section from the first spatial filter 22c to the observation object 5.
  • the light source 20c, the spatial light modulation device 21c, the first spatial filter 22c, and the first objective lens 23 are in this order the first optical path 24c in the direction in which the illumination light is directed toward the observation object 5 flowing through the flow path. Be prepared on top.
  • the configuration of the light source 20c and the spatial light modulation device 21c is the configuration of the light source 20 and the spatial light modulation device 21 of the first embodiment except that the direction of the first optical path 24c provided with them is parallel to the x-axis. Is the same as each.
  • the configuration of the first spatial filter 22c is the same as the configuration of the first spatial filter 22a shown in FIG.
  • the detection optical system 3c includes an imaging lens 32c and a first photodetector 33c.
  • the optical path of the backscattered light is referred to as a second optical path 34c.
  • the second optical path 34c is parallel to the z-axis.
  • the second optical path 34c is an optical path of light that passes through the first spatial filter 22c of the backscattered light.
  • the imaging lens 32c and the first photodetector 33c are provided on the second optical path 34c in the direction in which the scattered light is directed from the observation object 5 flowing through the flow path to the first photodetector 33c in this order. ..
  • the configurations of the imaging lens 32c and the first photodetector 33c are shown in FIG. 1, except that the orientation of the second optical path 34c and the orientation of the z-axis shown in the figure are opposite to each other.
  • the configuration is the same as that of the imaging lens 32 and the first photodetector 33, respectively.
  • FIG. 9 as a modification of the present embodiment, an example in which the second spatial filter is also used by the first spatial filter 22c is described, but the present invention is not limited thereto. Similar to the present embodiment, when the first space filter 22c also serves as the second space filter, the position in the second optical path 34c is different from the position where the first space filter 22c is installed. A spatial filter different from the first spatial filter 22c is installed as a second spatial filter at a position where the position of the first region and the position of the second region are substantially optically coupled. can do.
  • FIG. 10 is a diagram showing an example of the configuration of the flow cytometer 1d according to the present embodiment.
  • the flow cytometer 1d includes a flow path (not shown), an illumination optical system 2d, and a detection optical system 3d.
  • the same configurations and operations as those of the first embodiment described above are designated by the same reference numerals, and the description thereof will be omitted.
  • the structured illumination 4 detects the forward scattered light and the backscattered light scattered by the observation object 5 by the detection optical system 3d.
  • FIG. 10 describes, as an example, a case where the second spatial filter is also used by the first spatial filter 22d when detecting backscattered light, but the present invention is not limited to this.
  • the first spatial filter 22d also serves as the second spatial filter when detecting the backward scattered light
  • the position where the first spatial filter 22d is installed in the third optical path 37d Is a different position
  • a space filter different from the first space filter 22d is placed at a position where the position of the first region and the position of the second region are substantially optically coupled. It is installed as a space filter of 2.
  • the illumination optical system 2d includes a light source 20, a spatial light modulation device 21, a first spatial filter 22d, and a first objective lens 23.
  • the optical path of the illumination light of the illumination optical system 2d is referred to as a first optical path 24d.
  • the first optical path 24d-1 and the first optical path 24b-2 are shown.
  • the configuration of the first spatial filter 22d shown in FIG. 10 is the same as the configuration of the first spatial filter 22b shown in FIG. That is, the first spatial filter 22d has a blocking region 221d (corresponding to the blocking region 221b in FIG. 8) that blocks the light emitted from the light source 20 on the surface on the light source 20 side, and is on the side opposite to the light source 20.
  • the surface has a reflection region 223d (corresponding to the reflection region 223b in FIG. 8) that reflects the scattered light of the light emitted from the observation object 5.
  • the first optical path 24d-1 and the first optical path 24d-2 are optical paths of light that passes through the transmission region 220d of the first spatial filter 22d among the illumination lights.
  • the first spatial filter 22d is installed at an angle of a predetermined angle from a direction substantially perpendicular to the first optical path 24d (that is, the z-axis direction).
  • the predetermined angle is, for example, 45 degrees clockwise when viewed in the ⁇ y direction.
  • the second spatial filter 31d is installed as a second spatial filter.
  • the configuration of the second spatial filter 31d is the same as the configuration of the second spatial filter 31 shown in FIG. That is, the second spatial filter 31d has a transmission region 311d (corresponding to the transmission region 311 in FIG. 3) that transmits scattered light emitted from the observation object 5 on the surface on the light source 20 side and a direct emission from the light source 20. It has a blocking region 310d (corresponding to the blocking region 310 in FIG. 3) that blocks light.
  • the first space filter 22d is installed at a predetermined angle from a direction substantially perpendicular to the first optical path 24d (that is, a direction substantially perpendicular to the direction of the light emitted from the light source 20).
  • the images of the points included in the blocking region 221d are located at different locations in the direction of the optical axis.
  • the second spatial filter 31d is tilted, and the image of the region where the irradiation region R1 and the blocking region 221d overlap in the first spatial filter 22d is different from each other with respect to the direction of the optical axis of the second spatial filter 31d. An image is formed on the place.
  • the region where the irradiation region R1 of the first spatial filter 22d and the blocking region 221d overlap and the region where the irradiation region R2 and the transmission region 311d of the second spatial filter 31d overlap each other are optically substantially conjugated to each other. It is placed in a suitable position.
  • the first objective lens 23 forms an image of the light modulated by the spatial light modulation device 21 at the imaging position 25 on the flow path. Further, the first objective lens 23 makes the backscattered light from the observation object 5 parallel light. Here, the backscattered light by the observation object 5 is reflected by the reflection region 223d of the first spatial filter 22d, travels in the ⁇ X direction, passes through the second imaging lens 35d, and then the second light. Focuses on the detection surface of the detector 36d.
  • the detection optical system 3d includes a second objective lens 30, a second spatial filter 31d, an imaging lens 32, a first photodetector 33, a second imaging lens 35d, and a second photodetector. It is equipped with 36d.
  • the optical path of the forward scattered light is referred to as a second optical path 34d.
  • the second optical path 34d is parallel to the z-axis like the second optical path 34 shown in FIG.
  • the optical path of the backscattered light is referred to as a third optical path 37d.
  • the third optical path 37d is parallel to the z-axis in the section from the observation object 5 to the first spatial filter 22d.
  • the third optical path 37d bends at a substantially right angle at the position of the first spatial filter 22d due to the backscattered light being reflected by the first spatial filter 22d.
  • the third optical path 37d is parallel to the x-axis in the section from the first spatial filter 22d to the second photodetector 36d.
  • the second spatial filter 31d has a blocking region 310d that blocks the direct light transmitted through the observation object 5 and a transmission region 311d that transmits the forward scattered light transmitted by the observation object 5.
  • the second spatial filter 31d is installed at an angle of a predetermined angle from a direction substantially perpendicular to the second optical path 34d (that is, the z-axis direction).
  • the predetermined angle is, for example, 45 degrees counterclockwise when viewed in the ⁇ y direction.
  • the configuration of the second spatial filter 31d is the same as that of the second spatial filter 31 (FIG. 3), except that the second spatial filter 31d is installed at an angle of a predetermined angle from a direction substantially perpendicular to the second optical path 34d. Is.
  • the first spatial filter 22d and the second spatial filter 31d are tilted by a predetermined angle from a direction substantially perpendicular to the first optical path 24d (that is, the z-axis direction). is set up.
  • the position where the second spatial filter 31d is installed is arranged at a position conjugate with the first spatial filter 22d, and the shadow region (irradiation region) generated by the blocking region 221 of the first spatial filter 22d.
  • the image of the region of R1 blocked by the blocking region 221) is substantially the same as the region where the irradiation region R2 and the transmission region 311d overlap on the plane of the second space filter 31d.
  • the second imaging lens 35d forms an image of backscattered light reflected by the first spatial filter 22d.
  • the first spatial filter 22d also serves as a second spatial filter for backscattered light detection.
  • the first spatial filter 22d has a first region (blocking region 221d on the surface on the light source side) and a second region (reflection region 223d on the surface on the imaging position 25 side).
  • the second photodetector 36d detects the backscattered light imaged by the second imaging lens 35d.
  • the backscattered light imaged by the second imaging lens 35d is the light reflected by the reflection region 223d formed by the reflecting member of the first spatial filter 22d from the scattered light emitted from the observation object 5. Is. Therefore, the second photodetector 36d detects the scattered light emitted from the observation object 5 by being reflected by the reflecting member.
  • the flow cytometer 1d may detect only backscattered light.
  • the second objective lens 30, the second spatial filter 31d, the imaging lens 32, and the first photodetector 33 are omitted from the detection optical system 3d.
  • the side of the surfaces constituting the first spatial filter 22d facing the imaging position 25 is the first.
  • All or part of the region 1 is a member (in the present embodiment, the reflection region 223d) in which the light emitted from the light source 20 reflects the scattered light scattered by the observation object 5. It is composed of the constituent mirrors).
  • the light emitted from the light source 20 is reflected by a member (mirror constituting the reflection region 223d in the present embodiment) that reflects the scattered light by the observation object 5.
  • a second light detector 36d for detecting scattered light is provided.
  • the first spatial filter 22d prevents the light source light from being irradiated to the observation object 5 on the surface on the light source 20 side (the present embodiment).
  • the structure has a blocking region 221d) and a member (a mirror constituting the reflection region 223d in the present embodiment) that reflects the backward scattered light by the observation object 5 on the surface opposite to the light source 20.
  • the first region in the present embodiment, the blocking region 221d of the first spatial filter 22d
  • the first region that prevents the light source light from being irradiated to the observation object 5 is observed.
  • the illumination light is modulated by the modulation device, and the structured illumination is irradiated to the measurement object to be simultaneously acquired as scattered light in the front and the rear. Therefore, higher resolution morphological information regarding the observation object 5 can be obtained without labeling with a fluorescent substance (label-free), and the observation object 5 can be measured and classified non-invasively.
  • FIG. 11 is a diagram showing an example of the configuration of the flow cytometer 1e according to the present embodiment.
  • the flow cytometer 1e includes a flow path (not shown), an illumination optical system 2e, and a detection optical system 3e.
  • the same configurations and operations as those of the above-described embodiments and modifications thereof are designated by the same reference numerals, and the description thereof will be omitted.
  • the illumination optical system 2e includes a light source 20c, a spatial light modulation device 21c, a first spatial filter 22c, and a first objective lens 23.
  • the optical path of the illumination light of the illumination optical system 2e is referred to as a first optical path 24e.
  • the first optical path 24e-1, the first optical path 24e-2, and the first optical path 24e-3 are shown.
  • the first optical path 24e is parallel to the x-axis in the section from the light source 20c to the first spatial filter 22c.
  • the first optical path 24e-1 and the first optical path 24e-3 are bent at substantially right angles at the position of the first spatial filter 22c due to the illumination light being reflected by the first spatial filter 22c.
  • the first optical path 24e-1 and the first optical path 24e-3 are parallel to the z-axis in the section from the first spatial filter 22c to the observation object 5.
  • the illumination light passes through the first spatial filter 22c.
  • the light source 20c, the spatial light modulation device 21c, and the first spatial filter 22c are provided on the first optical path 24e in the + x direction in this order.
  • the first spatial filter 22c has a reflection region that reflects the light emitted from the light source 20c, and a transmission region that transmits the light emitted from the light source 20c and the backscattered light emitted by the observation object 5.
  • the first spatial filter 22c is installed at an angle of a predetermined angle from a direction substantially perpendicular to the z-axis direction, similarly to the first spatial filter 22c (FIG. 9) according to the modified example of the second embodiment. Will be done.
  • the configuration of the first spatial filter 22c is the same as the configuration of the first spatial filter 22a shown in FIG. 4, and includes a transmission region 221c as a transmission region in the central portion and a reflection region 220c as a reflection region at both ends. ..
  • the modulated illumination light is reflected by the reflection region 220c of the first spatial filter 22c, and the pattern of the structured illumination light is imaged at the imaging position 25 in the flow path. Further, the first objective lens 23 parallelizes the backscattered light from the observation object 5 and irradiates the first spatial filter 22c. The backscattered light irradiated to the first spatial filter 22c passes through the transmission region 221c of the first spatial filter 22b and travels in the ⁇ z direction.
  • the detection optical system 3e includes a second objective lens 30, a second spatial filter 31a, an imaging lens 32a, a first photodetector 33a, a second imaging lens 35c, and a second photodetector. It includes 36c.
  • the optical path of the forward scattered light is referred to as a second optical path 34e.
  • the second optical path 34e is parallel to the z-axis in the section from the observation object 5 to the second spatial filter 31a.
  • the second optical path 34e bends at a substantially right angle at the position of the second spatial filter 31a due to the forward scattered light being reflected by the second spatial filter 31a.
  • the second optical path 34e is parallel to the x-axis in the section from the second spatial filter 31a to the first photodetector 33a.
  • the optical path of the backscattered light is referred to as a third optical path 37e.
  • the third optical path 37e is parallel to the z-axis in the section from the observation object 5 through the first spatial filter 22c to the second photodetector 36c.
  • the configuration of the second spatial filter 31a, the imaging lens 32a, and the first photodetector 33a is that of the second spatial filter 31a, the imaging lens 32a, and the first photodetector 33a shown in FIG. It is the same as the configuration.
  • the configurations of the second imaging lens 35c and the second photodetector 36c are the same as the configurations of the imaging lens 32c and the first photodetector 33c shown in FIG. 9, respectively.
  • the configuration for detecting the forward scattered light in the detection optical system 3e may be replaced by the configuration for detecting the forward scattered light in the detection optical system 3d shown in FIG. good. That is, the second spatial filter 31a, the imaging lens 32a, and the first photodetector 33a of the detection optical system 3e are the second spatial filter 31d and the imaging of the detection optical system 3d shown in FIG. It may be replaced by a lens 32 and a first photodetector 33.
  • the configuration for detecting the forward scattered light in the detection optical system 3d is for detecting the forward scattered light in the detection optical system 3e shown in FIG. It may be replaced by the configuration. That is, the second spatial filter 31d of the detection optical system 3d, the imaging lens 32, and the first photodetector 33 have the second spatial filter 31a of the detection optical system 3e shown in FIG. 11 for imaging. It may be replaced by a lens 32a and a first photodetector 33a.
  • FIG. 11 as a modified example of the third embodiment, an example in which the second spatial filter is also used by the first spatial filter 22d in detecting backscattered light is described, but the present invention is limited to this. No. Similar to the previous example, when the first spatial filter 22c also serves as the second spatial filter when detecting the backward scattered light, the position where the first spatial filter 22c is installed in the third optical path 37e Is a different position, and a space filter different from the first space filter 22c is placed at a position where the position of the first region and the position of the second region are substantially optically coupled. It is installed as a space filter of 2.
  • the first objective lens 23 forms an image of the pattern of the structured illumination light at the imaging position 25 in the flow path, and observes the structured illumination 4. Irradiate the object 5.
  • the first spatial filter 22c is arranged in the first optical path 24e to prevent a part of the light emitted from the light source 20c from passing through the first spatial filter 22c and traveling toward the observation object 5. It functions as a first region (transmission region 221c in the present embodiment), and transmits backward scattered light from the observation object 5 in all or a part of the transmission region 221c of the first spatial filter 22c to transmit the second light. It is detected by the detector 36c.
  • the transmission region 221c arranged on the side of the first spatial filter 22c facing the imaging position 25 in the flow path constitutes a member that transmits light (the transmission region 221c in the present embodiment). It is formed by a gap) and prevents a part of the illumination light emitted from the light source 20c from passing through and traveling toward the observation object 5.
  • the backscattered light from the observation object 5 passes through the transmission region 221c arranged on the side facing the imaging position 25 in the flow path of the first spatial filter 22c again, and then passes through the transmission region 221c. It is detected by the second photodetector 36c.
  • the flow cytometer 1e includes a second imaging lens 35c and a second photodetector 36c as a detection optical system 3e related to the detection of backscattered light from the observation object 5.
  • the influence of the direct light emitted from the light source 20c when the backscattered light by the observation object 5 is detected by the second photodetector 36c can be reduced. can.
  • the backward scattered light by the observation object 5 is parallelized via the first objective lens 23 and transmitted through the transmission region 221c of the first spatial filter 22c. Only is detected by the second photodetector 36c.
  • the flow cytometer 1e according to the present embodiment can detect backscattered light in addition to forward scattered light as scattered light that realizes a higher signal noise ratio than the conventional one.
  • the illumination light is modulated by a modulation device, and the structured illumination light is irradiated to the measurement object to simultaneously acquire the scattered light in the front and the rear. Therefore, high-resolution morphological information regarding the observation object 5 can be obtained without labeling with a fluorescent substance (label-free), and the observation object 5 can be measured and classified non-invasively.
  • transmission or blocking of light is used as a method of preventing the light emitted from the light source in the first region of the first spatial filter from traveling toward the object to be observed.
  • An example of the case where the above is performed has been described, but the present invention is not limited to this.
  • the blocking region blocks the propagation of light that is not used as the light that irradiates the observation object.
  • the blocking region may block the propagation of light by utilizing the absorption or polarization of light.
  • the region other than the blocking region is composed of a transmission region that allows incident light to pass through as it is.
  • the first spatial filter spatially separates the light used as illumination light and the light not used as illumination light by changing the propagation direction between the light used as the light applied to the observation object and the light not used. Only the light to be used may be propagated toward the observation object.
  • the first spatial filter includes a single optical element (optical filter) having different optical characteristics in the first region and the other regions. The first spatial filter uses this optical element to propagate incident light incident on the first region and the other regions in different directions.
  • the different optical properties here include properties for reflection, properties for diffraction, properties for refraction, and the like.
  • the first spatial filter may prevent the illumination light emitted from the light source from traveling toward the observation object by utilizing diffraction.
  • the first spatial filter may prevent the illumination light emitted from the light source from traveling toward the observation object by utilizing the reflection.
  • FIG. 12 is a diagram showing an example of the first spatial filter 22f according to the modified example of each embodiment.
  • the first spatial filter 22f and the spatial light modulation device are integrally provided, and the first spatial filter 22f is included in the spatial light modulation device of each of the above-described embodiments. It has a function to generate the structured illumination light that was used. That is, the first spatial filter 22f is a single optical element having different optical characteristics in the non-modulation region and the other regions, and this configuration also functions as a modulation element similar to the spatial light modulation device at the same time. Be prepared.
  • FIG. 12 shows a flat surface 222f when the plate-shaped first spatial filter 22f is viewed from the light source side in the z-axis direction.
  • a plane viewed from the light source side is located on the plane 222f in the z-axis direction of the modulation element of the spatial light modulation device.
  • the surface of the first spatial filter 22f located on the plane 222f is divided into a structured illumination region 220f and a non-modulation region 221f.
  • the structured illumination region 220f of the first spatial filter 22f is separated by the non-modulation region 221f, and two regions in which the structured illumination region 220f-1 and the structured illumination region 220f-2 are not connected are connected. Consists of.
  • the structured illumination region 220f and the non-modulation region 221f are realized by a modulation element and have different optical characteristics from each other.
  • the structured illumination region 220f is realized, for example, by designing a diffraction pattern for generating structured illumination on the surface of the modulation element.
  • the first spatial filter 22f changes the light propagation direction by diffracting the modulated light that has passed through the structured illumination region 220f.
  • the light whose propagation direction is changed through the structured illumination region 220f is collected by, for example, the first objective lens 23f and used as structured illumination to irradiate the observation object.
  • the light that has passed through the unmodulated region 221f of the first spatial filter 22f goes straight from the light source (that is, is transmitted) without being modulated.
  • the image of the region where the non-modulation region 221f and the irradiation region R1 overlap creates a shadow in the second spatial filter provided in the subsequent stage.
  • the light used for irradiating the observation object and the light not used can be spatially separated.
  • the first spatial filter 22f has a function for generating the structured illumination possessed by the spatial light modulation device of each of the above-described embodiments.
  • the optical path 24f-1 is an optical path of the irradiation light to the observation object.
  • the first optical path 24f-2 is an optical path of light that is not used for irradiating the observation object.
  • the first spatial filter and the spatial light modulation device are provided as separate bodies. May be done. Even in that case, by using the diffraction element as the first spatial filter, it is possible to spatially separate the light used for irradiating the observation object and the light not used.
  • the diffractometer is used as the first spatial filter and the first spatial filter is provided separately from the spatial light modulation device, the first spatial filter is provided between the light source and the spatial light modulator. Is preferable. That is, in each embodiment when the first spatial filter uses light transmission, blocking, or reflection as a method of preventing the light emitted from the light source from traveling toward the object to be observed, the first.
  • a spatial filter is provided between the spatial light modulation device in the first optical path and the imaging position in the flow path irradiated with the structured illumination light, and these cases have been described as an example.
  • a first spatial filter is provided between the light source and the spatial light modulation device. In that case, it is desirable that the distance from the spatial light modulation device is short.
  • the diffraction element as the first spatial filter as another method in which the first spatial filter prevents the illumination light of the light source from traveling toward the object to be observed.
  • the first spatial filter is provided between the light source and the spatial light modulation device in the first optical path.
  • the configuration is preferable, and it is more desirable that the distance from the spatial light modulation device is short.
  • FIG. 14 is a diagram showing an example of a first spatial filter 22g according to a modified example of each embodiment.
  • FIG. 14 shows a flat surface 222 g of the plate-shaped first spatial filter 22 g when viewed from the light source in the z-axis direction.
  • the surface of the first spatial filter 22g on the light source side is located on a flat surface 222g.
  • the surface of the first spatial filter 22g on the flat surface 222g is divided into a transmission region 220g and a reflection region 221g.
  • the transmission region 220g of the first spatial filter 22g is separated by the reflection region 221g and consists of two regions in which the transmission region 220g-1 and the transmission region 220g-2 are not connected.
  • the reflection region 221g includes a protrusion 223g.
  • the protrusion 223g has a mirror on a surface inclined by a predetermined angle with respect to the plane 222g, and reflects the incident light to propagate the incident light in a direction that does not enter the subsequent optical system.
  • the 15 is an optical path of light that is not used for irradiating the observation object.
  • 23 g of the first objective lens in the subsequent optical system is shown.
  • the transmission region 220g transmits a part of the illumination light from the light source 20a.
  • the optical path 24g-1 is an optical path of the irradiation light to the observation object.
  • a mirror that reflects the incident light is installed so that the incident light does not enter the subsequent optical system. Propagate in the direction.
  • the illumination optical system 2 may further include one or more second optical elements in addition to the first optical element.
  • the second optical element forms an image of the light modulated by the spatial light modulation device in the first optical path.
  • the first spatial filter has a plurality of imaging positions of the structured illumination pattern by the first optical element and one or more imaging positions by one or more second optical elements in the first optical path. It is provided at a position other than the imaging position of.
  • the intensity and / or phase of the light transmitted through the observation object is modulated and passed through all or a part of the irradiation region R2 of the second spatial filter except the second region.
  • An example of acquiring phase difference information by interfering both of these lights on an optical detector will be described.
  • FIG. 16 is a diagram showing an example of the flow cytometer 1h according to the present embodiment.
  • the flow cytometer 1h includes a flow path (not shown), an illumination optical system 2h, and a detection optical system 3h.
  • the same configurations and operations as those of the above-described embodiments are designated by the same reference numerals, and the description thereof will be omitted.
  • the optical path of the illumination light of the illumination optical system 2h is called the first optical path 24h.
  • the first optical path 24h is parallel to the z-axis. In FIG. 16, as an example of the first optical path 24h, the first optical path 24h-1 and the first optical path 24h-2 are shown.
  • the illumination optical system 2h includes a light source 20, a spatial light modulation device 21, a first spatial filter 22, and a first objective lens 23.
  • the light source 20, the spatial light modulation device 21, the first spatial filter 22, and the first objective lens 23 are in this order the first optical path 24h in the direction in which the illumination light is directed toward the observation object 5 flowing through the flow path. Be prepared on top.
  • the first optical path 24h is an optical path of light that has passed through the transmission region of the first spatial filter 22 in the section between the first spatial filter 22 and the observation object 5.
  • the detection optical system 3h includes a second objective lens 30, a second spatial filter 31h, an imaging lens 32, and a first photodetector 33h.
  • the optical path of the forward scattered light or the diffracted light is referred to as a second optical path 34h.
  • the second optical path 34h is parallel to the z-axis.
  • the second spatial filter 31h has a transmission region for transmitting light modulated by the observation object 5 and a modulation region for modulating the intensity and / or phase of the light transmitted through the observation object 5.
  • the light transmitted through the observation object 5 is direct light.
  • the light modulated by the observation object 5 transmitted by the transmission region is, for example, the forward scattered light scattered by the observation object 5, but may be diffracted light generated by a structure that gives a phase change.
  • the forward scattered light or diffracted light transmitted by the second spatial filter 31h through the transmission region is referred to as the first light
  • the light transmitted by the second spatial filter 31h modulated by the modulation region is referred to as the first light.
  • the transmission region of the second spatial filter 31h is an example of the second region. The first light and the second light described above are detected by the first photodetector 33h.
  • the imaging lens 32 forms an image of the first light and the second light on the detection surface of the first photodetector 33h.
  • the imaging lens 32 may focus the first light and the second light on the detection surface of the first photodetector 33h, and may not be strictly imaged.
  • the first photodetector 33h the first light and the second light formed on the detection surface by the imaging lens 32 interfere with each other to obtain the first light and the second light. Detects the phase difference information of.
  • the light emitted to the observation object 5 is the light structured by the spatial light modulation device 21. Therefore, the first photodetector 33h detects the information on the phase difference between the direct light and the forward scattered light (or diffracted light) for the structured light.
  • the detection optical system 3h detects the phase difference of the structured light.
  • the first photodetector 33h is a region (the present embodiment) other than the second region (transmission region in the present embodiment) of the second spatial filter 31h among the light transmitted through the observation object 5.
  • the second region (in the present embodiment) of the light whose phase is modulated by modulating the intensity or phase of the light passing through all or a part of the modulation region) and the light modulated by the observation object 5.
  • the phase difference with the light that has passed through the transmission region) is detected. According to the flow cytometer 1h, the phase difference of light can be detected for structured light.
  • FIG. 17 is a diagram showing an example of a flow cytometer 1i according to a modified example of the present embodiment.
  • the flow cytometer 1i includes a flow path (not shown), an illumination optical system 2i, and a detection optical system 3i.
  • the same configurations and operations as those of the above-described embodiments are designated by the same reference numerals, and the description thereof will be omitted.
  • the optical path of the illumination light of the illumination optical system 2i is called the first optical path 24i.
  • the first optical path 24i is parallel to the z-axis. In FIG. 16, as an example of the first optical path 24i, the first optical path 24i-1 and the first optical path 24i-2 are shown.
  • the illumination optical system 2i includes a light source 20, a spatial light modulation device 21, a first spatial filter 22, and a first objective lens 23.
  • the light source 20, the spatial light modulation device 21, the first spatial filter 22, and the first objective lens 23 are in this order the first optical path 24i in the direction in which the illumination light is directed toward the observation object 5 flowing through the flow path. Be prepared on top.
  • the first optical path 24i is an optical path of light that has passed through the transmission region of the first spatial filter 22 in the section between the first spatial filter 22 and the observation object 5.
  • the detection optical system 3i includes a second objective lens 30, a half mirror 38i, a second spatial filter 31h, an imaging lens 32, a first photodetector 33h, a third spatial filter 39i, and a third. It includes a two imaging lens 35d and a second photodetector 36i.
  • the optical path toward the first photodetector in order for the forward scattered light or the diffracted light to detect the phase difference information is referred to as a second optical path 34i.
  • the second optical path 34i is parallel to the z-axis.
  • a second optical path 34i-1, a second optical path 34i-2, and a second optical path 34i-3 are shown.
  • the second optical path 34i-1 and the second optical path 34i-3 are optical paths of light transmitted through the observation object 5 and transmitted through the half mirror 38i.
  • the second optical path 34i-2 is an optical path of light in which the forward scattered light or diffracted light scattered by the observation object 5 has passed through the half mirror 38i.
  • the half mirror 38i extracts a part of the light modulated by the observation object 5.
  • the half mirror 38i transmits a part of the light incident on the half mirror 38i and reflects a part of the light to either the transmitted light or the reflected light. Is to propagate in a predetermined direction.
  • the half mirror 38i is arranged in the second optical path 34i.
  • the half mirror 38i is an example of a beam splitter which is an optical device arranged in a second optical path and extracting a part of light modulated by an observation object.
  • the configuration of the second spatial filter 31h, the imaging lens 32, and the first photodetector 33h is the configuration of the second spatial filter 31h, the imaging lens 32, and the first photodetector 33h shown in FIG. Is the same as each.
  • the optical path in which the forward scattered light or the diffracted light is detected by the second photodetector is referred to as a third optical path 37i.
  • the third optical path 37i is an optical path of light in which the forward scattered light or diffracted light scattered by the observation object 5 is reflected by the half mirror 38i.
  • the third optical path 37i is parallel to the x-axis.
  • the third spatial filter 39i, the second imaging lens 35d, and the second photodetector 36i have a third optical path in the direction in which the forward scattered light or diffracted light scattered by the observation object 5 travels in this order. It is provided on the 37i.
  • the third spatial filter 39i has a transmission region that transmits forward scattered light or diffracted light scattered by the observation object 5 and a blocking region that blocks the light transmitted through the observation object 5 (that is, direct light). Be prepared.
  • the direct light blocked by the blocking region of the third spatial filter 39i is the light reflected in the x-axis direction by the half mirror 38i among the direct light transmitted through the observation object 5.
  • the transmission region of the third spatial filter 39i is an example of the third region.
  • the second imaging lens 35d forms an image of the forward scattered light or diffracted light transmitted through the third spatial filter 39i on the imaging surface of the second imaging lens 35d.
  • the second imaging lens 35d may collect the forward scattered light or the diffracted light on the detection surface of the second imaging lens 35d, and may not form an image.
  • the second photodetector 36i detects forward scattered light or diffracted light imaged on the detection surface by the second imaging lens 35d.
  • the forward scattered light or diffracted light imaged on the detection surface by the second imaging lens 35d is a transmission region of the third spatial filter 39i in which the modulated light extracted by the half mirror 38i as described above has. It is the transmitted light. Therefore, the second photodetector 36i detects the light modulated by the observation object 5 that has passed through the third region.
  • forward scattered light or diffracted light scattered by the observation object 5 can be detected at the same time.
  • information including morphological information can be acquired at a higher resolution than the flow cytometer using conventional line-shaped illumination light for scattered light from cells, and thus an observation target. It is possible to separate an object (for example, a target cell) non-invasively (that is, label-free) at high speed based on morphological information without labeling with a fluorescent label or the like.

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12230023B2 (en) 2015-10-28 2025-02-18 The University Of Tokyo Analysis device
US12235202B2 (en) 2019-12-27 2025-02-25 Thinkcyte K.K. Flow cytometer performance evaluation method and standard particle suspension
US12259311B2 (en) 2018-06-13 2025-03-25 Thinkcyte K.K. Methods and systems for cytometry
US12298221B2 (en) 2020-04-01 2025-05-13 Thinkcyte K.K. Observation device
US12339217B2 (en) 2020-04-01 2025-06-24 Thinkcyte K.K. Flow cytometer

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024134240A1 (en) * 2022-12-20 2024-06-27 Bit Group France Optical flow cytometer for fluorescence and scattering measurements by segmentation of beam emitted by a single non-coherent light source
WO2024224366A1 (en) 2023-04-28 2024-10-31 Thinkcyte K.K. Systems and methods of machine learning-based sample classifiers for physical samples
US20240362454A1 (en) 2023-04-28 2024-10-31 Thinkcyte K.K. Systems and methods of machine learning-based physical sample classification with sample variation control

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011099848A (ja) 2009-10-05 2011-05-19 Bay Bioscience Kk フローサイトメータおよびフローサイトメトリ方法
JP2012500385A (ja) * 2008-08-06 2012-01-05 インビトロックス，インコーポレイテッド 生物学的応用における集束光散乱技術の使用
JP2014190748A (ja) * 2013-03-26 2014-10-06 Sysmex Corp 粒子分析装置、粒子分析装置用光学系および粒子分析装置用レンズ
JP2015512029A (ja) * 2011-12-29 2015-04-23 アボット・ラボラトリーズＡｂｂｏｔｔ Ｌａｂｏｒａｔｏｒｉｅｓ 回折パターンを遮断するためのフローサイトメトリーシステムおよび方法
JP2016073210A (ja) 2014-10-02 2016-05-12 国立大学法人山口大学 家畜下垂体細胞の集団からのゴナドトロフ細胞の分離方法
JP2016517526A (ja) * 2013-03-15 2016-06-16 ベックマン コールター， インコーポレイテッド フローサイトメーター用の放射光フィルター処理
WO2017073737A1 (ja) 2015-10-28 2017-05-04 国立大学法人東京大学 分析装置
JP2020065940A (ja) 2019-12-26 2020-04-30 株式会社サンセイアールアンドディ 遊技機

Family Cites Families (211)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4537861A (en) 1983-02-03 1985-08-27 Elings Virgil B Apparatus and method for homogeneous immunoassay
JPS613032A (ja) 1984-06-18 1986-01-09 Hitachi Ltd 水中懸濁物質監視装置
JPH068784B2 (ja) 1985-10-01 1994-02-02 株式会社日立製作所 フロツク監視装置
NL8601000A (nl) * 1986-04-21 1987-11-16 Jan Greve T H Twente Afdeling Het gebruik van gepolariseerd licht in stromingscytometrie.
JPH01118747A (ja) 1987-10-31 1989-05-11 Canon Inc 粒子解析装置
US5007737A (en) * 1988-11-01 1991-04-16 The United States Of America As Represented By The Secretary Of The Air Force Programmable detector configuration for Fraunhofer diffraction particle sizing instruments
JPH03216553A (ja) 1990-01-22 1991-09-24 Hitachi Ltd 粒子による免疫測定方法および装置
JPH06102152A (ja) 1992-09-18 1994-04-15 Hitachi Ltd フロー式粒子画像解析装置用標準液
US5483469A (en) 1993-08-02 1996-01-09 The Regents Of The University Of California Multiple sort flow cytometer
JPH07270314A (ja) 1994-03-29 1995-10-20 Kubota Corp 濁度検知方法及びその装置
JPH07270302A (ja) 1994-03-30 1995-10-20 Toa Medical Electronics Co Ltd イメージングフローサイトメータ
JP3444509B2 (ja) 1994-04-20 2003-09-08 株式会社リコー 画像読取装置
JP2827901B2 (ja) 1994-05-31 1998-11-25 株式会社島津製作所 粒度分布測定方法
JPH09311102A (ja) 1996-05-24 1997-12-02 Hitachi Ltd フロー式粒子画像解析方法および装置
US6525862B2 (en) 1996-10-30 2003-02-25 Photogen, Inc. Methods and apparatus for optical imaging
JP2941228B2 (ja) 1997-04-15 1999-08-25 日本カノマックス株式会社 粒子測定装置及びその校正方法
US6723290B1 (en) 1998-03-07 2004-04-20 Levine Robert A Container for holding biologic fluid for analysis
CA2341896A1 (en) 1998-08-28 2000-03-09 Febit Ferrarius Biotechnology Gmbh Support for a method for determining an analyte and a method for producing the support
US8005314B2 (en) 2005-12-09 2011-08-23 Amnis Corporation Extended depth of field imaging for high speed object analysis
US6249341B1 (en) 1999-01-25 2001-06-19 Amnis Corporation Imaging and analyzing parameters of small moving objects such as cells
US6956230B1 (en) * 1999-09-17 2005-10-18 California Institute Of Technology Integrated particles sensor formed on single substrate using fringes formed by diffractive elements
US7217573B1 (en) 1999-10-05 2007-05-15 Hitachi, Ltd. Method of inspecting a DNA chip
US7122330B2 (en) 2000-04-13 2006-10-17 Mark Aaron Emalfarb High-throughput screening of expressed DNA libraries in filamentous fungi
US7420659B1 (en) 2000-06-02 2008-09-02 Honeywell Interantional Inc. Flow control system of a cartridge
US6778263B2 (en) 2000-08-25 2004-08-17 Amnis Corporation Methods of calibrating an imaging system using calibration beads
JP3822785B2 (ja) 2000-10-11 2006-09-20 株式会社堀場製作所 散乱式粒子径分布測定装置
AU2001221481A1 (en) 2000-10-16 2002-04-29 Rudolf Schwarte Method and device for detecting and processing signal waves
CN1200111C (zh) 2001-06-20 2005-05-04 朱纪军 一种基于微流控技术的流式细胞仪
WO2003048345A1 (en) 2001-12-07 2003-06-12 Toolgen, Inc. Phenotypic screen of chimeric proteins
US7385694B2 (en) 2002-06-04 2008-06-10 Lockheed Martin Corporation Tribological debris analysis system
JP3731073B2 (ja) 2002-09-17 2006-01-05 独立行政法人理化学研究所 顕微鏡装置
JP3845053B2 (ja) 2002-10-28 2006-11-15 シスメックス株式会社 フローサイトメータ用標準粒子懸濁液
JP4240386B2 (ja) 2003-02-21 2009-03-18 エスケーエイ株式会社 被処理流体の変調電磁波処理方法
JP3842748B2 (ja) 2003-03-12 2006-11-08 株式会社日立ハイテクノロジーズ 液体試料中の粒子画像解析方法及び装置
FR2852700B1 (fr) 2003-03-19 2005-09-23 Centre Nat Rech Scient Procede et installation d'imagerie acousto-optique.
US7092078B2 (en) * 2003-03-31 2006-08-15 Nihon Kohden Corporation Flow cytometer for classifying leukocytes and method for determining detection angle range of the same
CA2527667C (en) 2003-07-02 2013-03-12 Gambro, Inc. Monitoring and control system for blood processing
US7812303B2 (en) 2007-12-06 2010-10-12 The United States Of America As Represented By The Secretary Of The Army Method and system for creating an image using quantum properties of light based upon spatial information from a second light beam which does not illuminate the subject
US7847234B2 (en) 2003-08-06 2010-12-07 The United States Of America As Represented By The Secretary Of The Army Method and system for observing a subject at a first location based upon quantum properties measured at a second location
JP4436091B2 (ja) 2003-08-22 2010-03-24 財団法人光科学技術研究振興財団 光反応制御装置
JP2007504445A (ja) 2003-08-26 2007-03-01 ブルーシフト・バイオテクノロジーズ・インコーポレーテッド 時間依存蛍光計測
US7477363B2 (en) * 2004-04-08 2009-01-13 Nihon Kohden Corporation Flow cytometer
NZ537147A (en) 2004-12-13 2007-06-29 Australo Ltd Method and apparatus for particle analysis
WO2006080314A1 (ja) 2005-01-26 2006-08-03 Osaka University 白血病浸潤精巣に由来する細胞集団から白血病細胞を除去する方法、及びそれに用いられる試薬キット
CN101151517A (zh) 2005-03-29 2008-03-26 希森美康株式会社 鉴别癌症/异型细胞和粒子团的方法及细胞分析仪
US20070057211A1 (en) 2005-05-25 2007-03-15 Karsten Bahlman Multifocal imaging systems and method
JP2007048172A (ja) 2005-08-12 2007-02-22 Fuji Xerox Co Ltd 情報分類装置
US7561274B2 (en) 2005-10-20 2009-07-14 Duke University Optical spectroscopy utilizing planar spectral filters
US9157066B2 (en) 2005-12-13 2015-10-13 The Trustees Of The University Of Pennsylvania Transcriptome transfer produces cellular phenotype conversion
JP4735375B2 (ja) 2006-04-04 2011-07-27 株式会社日立製作所 画像処理装置及び動画像符号化方法。
WO2008098179A1 (en) 2007-02-08 2008-08-14 Massachusetts Institute Of Technology In vitro microfluidic model of microcirculatory diseases, and methods of use thereof
JP4427074B2 (ja) 2007-06-07 2010-03-03 株式会社日立製作所 プラントの制御装置
US8165663B2 (en) 2007-10-03 2012-04-24 The Invention Science Fund I, Llc Vasculature and lymphatic system imaging and ablation
JP2010539516A (ja) 2007-09-17 2010-12-16 ルミネックス コーポレーション フロー内の粒子を識別するためのシステム、記憶媒体、及び方法
JP2009115672A (ja) 2007-11-08 2009-05-28 Sony Corp 微小粒子の光学的測定方法及び分取方法、並びに前記光学的測定方法及び分取方法に用いる流路、光学的測定装置及びフローサイトメータ
EP2232229B1 (en) 2007-12-04 2021-02-17 Particle Measuring Systems, Inc. Two-dimensional optical imaging methods for particle detection
JP4556996B2 (ja) 2007-12-13 2010-10-06 ソニー株式会社 光学的検出方法
US7817254B2 (en) 2008-01-30 2010-10-19 Palo Alto Research Center Incorporated Obtaining information from time variation of sensing results
JP5620642B2 (ja) 2008-01-30 2014-11-05 パロ・アルト・リサーチ・センター・インコーポレーテッドＰａｌｏＡｌｔｏ ＲｅｓｅａｒｃｈＣｅｎｔｅｒＩｎｃｏｒｐｏｒａｔｅｄ 符号器付センサを用いる方法、符号器付センサ及びシステム
KR101163197B1 (ko) 2008-02-07 2012-07-06 미쯔이 죠센 가부시키가이샤 형광 검출 장치 및 형광 검출 방법
JP2011513794A (ja) 2008-03-04 2011-04-28 カリフォルニア インスティテュート オブ テクノロジー フォトセンサーアレイを備える光学流体顕微鏡装置
JP4985480B2 (ja) 2008-03-05 2012-07-25 国立大学法人山口大学 がん細胞を分類する方法、がん細胞を分類するための装置及びがん細胞を分類するためのプログラム
US20090248318A1 (en) 2008-03-28 2009-10-01 Takaaki Nagai Sample analyzer, sample analyzing method and computer program product
US8184298B2 (en) * 2008-05-21 2012-05-22 The Board Of Trustees Of The University Of Illinois Spatial light interference microscopy and fourier transform light scattering for cell and tissue characterization
GB0814039D0 (en) 2008-07-31 2008-09-10 Imp Innovations Ltd Optical arrangement for oblique plane microscopy
WO2010032452A1 (ja) 2008-09-19 2010-03-25 三井造船株式会社 強度変調したレーザ光による蛍光検出装置および蛍光検出方法
JP2010092199A (ja) 2008-10-07 2010-04-22 Sony Corp 情報処理装置および方法、プログラム、並びに記録媒体
JP5321145B2 (ja) 2009-03-04 2013-10-23 日本電気株式会社 画像診断支援装置、画像診断支援方法、画像診断支援プログラム、及びその記憶媒体
US9134242B2 (en) 2009-04-27 2015-09-15 Ecole Polytechnique Federale De Lausanne (Epfl) Method and apparatus for retrieval of amplitude and phase of nonlinear electromagnetic waves
US8599383B2 (en) 2009-05-06 2013-12-03 The Regents Of The University Of California Optical cytometry
WO2011028109A1 (en) 2009-09-01 2011-03-10 Universiteit Leiden System and method for performing microscopy with light exhibiting an orbital angular momentum
ES2623375T3 (es) 2009-10-20 2017-07-11 The Regents Of The University Of California Holografía y microscopia celular incoherente sin lente en un chip
US20140152801A1 (en) 2009-10-28 2014-06-05 Alentic Microscience Inc. Detecting and Using Light Representative of a Sample
JP2011141444A (ja) 2010-01-07 2011-07-21 Nikon Corp 顕微鏡システム
JP5574407B2 (ja) 2010-01-14 2014-08-20 国立大学法人 筑波大学 顔面動作推定装置及び顔面動作推定方法
CN102272580B (zh) 2010-03-31 2014-07-30 古河电气工业株式会社 光信息解析装置及光信息解析方法
JP5418386B2 (ja) 2010-04-19 2014-02-19 ソニー株式会社 画像処理装置、画像処理方法及びプログラム
JP5740101B2 (ja) 2010-04-23 2015-06-24 国立大学法人名古屋大学 細胞評価装置、インキュベータ、細胞評価方法、細胞評価プログラムおよび細胞の培養方法
JP5816415B2 (ja) 2010-04-23 2015-11-18 国立大学法人名古屋大学 細胞評価装置、インキュベータ、プログラム、および、培養方法
US8384045B2 (en) * 2010-07-01 2013-02-26 Sony Corporation Minute particle analyzing device and method
US8913121B2 (en) 2010-07-11 2014-12-16 Spynsite, LLC System for image rendering or spectral recognition
JP5893564B2 (ja) 2010-09-10 2016-03-23 オリンパス株式会社 複数の波長帯域の光計測を用いた光分析方法
CN103168225B (zh) 2010-10-25 2015-11-25 阿库里赛托梅特斯公司 用于收集流式细胞仪中的数据集的系统和用户接口
SG10201912164UA (en) 2010-11-16 2020-02-27 1087 Systems Inc System for identifying and sorting living cells
US8941062B2 (en) 2010-11-16 2015-01-27 1087 Systems, Inc. System for identifying and sorting living cells
US9066657B2 (en) 2010-11-23 2015-06-30 General Electric Company Methods and systems of optical imaging for target detection in a scattering medium
JP2012132742A (ja) 2010-12-21 2012-07-12 Fujifilm Corp 時間分解蛍光測定装置、及び方法
US8896918B2 (en) 2010-12-24 2014-11-25 Huron Technologies International Inc. Pathology slide scanner
FR2971337B1 (fr) * 2011-02-04 2013-03-01 Horiba Abx Sas Dispositif et procede de mesures multiparametriques de microparticules dans un fluide
US8705031B2 (en) 2011-02-04 2014-04-22 Cytonome/St, Llc Particle sorting apparatus and method
NL2006600C2 (nl) 2011-02-11 2012-08-14 Dutch Water Technologies B V Inrichting en werkwijze voor het detecteren van sporen.
US9069175B2 (en) 2011-04-08 2015-06-30 Kairos Instruments, Llc Adaptive phase contrast microscope
EP2510958B2 (en) 2011-04-11 2023-02-15 Fresenius Medical Care Deutschland GmbH Method and apparatus for monitoring a treatment of a patient, preferably for monitoring hemodialysis, hemodiafiltration and/or peritoneal dialysis
JP5886838B2 (ja) 2011-04-25 2016-03-16 浜松ホトニクス株式会社 撮像装置
WO2012165400A1 (ja) 2011-06-03 2012-12-06 株式会社日立ハイテクノロジーズ 生体ポリマーの光学的解析装置及び方法
JP2013015357A (ja) 2011-07-01 2013-01-24 Shimadzu Corp フローサイトメータ
CN102331411A (zh) 2011-07-08 2012-01-25 无锡荣兴科技有限公司 一种具有蓝色半导体激光器的血液细胞分析仪
US9074978B2 (en) 2011-07-12 2015-07-07 The Regents Of The University Of California Optical space-time coding technique in microfluidic devices
JP2013024629A (ja) 2011-07-19 2013-02-04 Sysmex Corp フローサイトメータ
EP2757153B1 (en) 2011-08-02 2019-07-03 The University of Tokyo Method for assessing myelodysplastic syndrome or myeloid tumor predisposition, polypeptide and antibody therefor, and candidate screening method for therapeutic drug or prophylactic drug therefor
US8475739B2 (en) 2011-09-25 2013-07-02 Theranos, Inc. Systems and methods for fluid handling
US20160069919A1 (en) 2011-09-25 2016-03-10 Theranos, Inc. Systems and methods for multi-analysis
EP2769203B1 (en) 2011-10-21 2019-01-16 Acea Biosciences, Inc. System and method for detecting multiple-excitation-induced light in a flow channel
US9220415B2 (en) 2011-10-25 2015-12-29 Andreas Mandelis Systems and methods for frequency-domain photoacoustic phased array imaging
WO2013066896A1 (en) 2011-10-31 2013-05-10 Inview Technology Corporation High-speed event detection using a compressive sensing hyperspectral imaging architecture
WO2013067536A1 (en) 2011-11-04 2013-05-10 Massachusetts Institute Of Technology Multi-parameter thrombotic assay apparatus, systems, and methods
JP5941923B2 (ja) 2011-11-10 2016-06-29 オリンパス株式会社 単一発光粒子検出を用いた光分析装置、光分析方法及び光分析用コンピュータプログラム
CN102495467A (zh) 2011-11-11 2012-06-13 上海电机学院 一种利用混沌激光的时间关联特性进行成像的方法及装置
EP2602608B1 (en) 2011-12-07 2016-09-14 Imec Analysis and sorting of biological cells in flow
JP5333570B2 (ja) 2011-12-21 2013-11-06 富士ゼロックス株式会社 画像処理装置、プログラム及び画像処理システム
US8955973B2 (en) 2012-01-06 2015-02-17 Google Inc. Method and system for input detection using structured light projection
US10646160B2 (en) 2012-01-19 2020-05-12 Technion Research & Development Foundation Limited Vessel imaging system and method
JP6144915B2 (ja) 2012-01-30 2017-06-07 キヤノン株式会社 生体組織画像の再構成方法、取得方法及び装置
US9025881B2 (en) 2012-02-06 2015-05-05 Nanyang Technological University Methods and apparatus for recovering phase and amplitude from intensity images
JP5796509B2 (ja) 2012-02-16 2015-10-21 株式会社島津製作所 フローサイトメータ
JP5905317B2 (ja) 2012-03-30 2016-04-20 ソニー株式会社 微小粒子分取装置におけるキャリブレーション方法及び該装置
US20150177115A1 (en) 2012-04-06 2015-06-25 Slingshot Biosciences Hydrogel particles with tunable optical properties
US9360660B2 (en) 2012-05-24 2016-06-07 Northwestern University Methods and apparatus for laser scanning structured illumination microscopy and tomography
US9176054B2 (en) 2012-06-07 2015-11-03 Canon Kabushiki Kaisha System for tomographic imaging using coherent light that has a random phase distribution
JP5464244B2 (ja) 2012-08-24 2014-04-09 富士ゼロックス株式会社 画像処理装置、プログラム及び画像処理システム
US8723104B2 (en) 2012-09-13 2014-05-13 City University Of Hong Kong Methods and means for manipulating particles
CN105008895B (zh) 2012-10-15 2019-02-15 纳诺赛莱克特生物医药股份有限公司 颗粒分选的系统、设备和方法
EP2927666A4 (en) 2012-12-03 2016-08-03 Fuji Electric Co Ltd TEILCHENSTRAHLFORMUNGSVORRICHTUNG
US9357975B2 (en) 2013-12-30 2016-06-07 Carestream Health, Inc. Large FOV phase contrast imaging based on detuned configuration including acquisition and reconstruction techniques
WO2014121003A1 (en) 2013-02-04 2014-08-07 The General Hospital Corporation System and method for fluorescence detection
AU2014217893A1 (en) 2013-02-18 2015-07-30 Theranos Ip Company, Llc Systems and methods for multi-analysis
JP6822765B2 (ja) 2013-03-06 2021-01-27 オプティカル バイオシステムズ ホールディング インコーポレイテッド 分子イメージングおよび関連する方法
JP6196787B2 (ja) 2013-03-08 2017-09-13 キヤノン株式会社 画像形成装置、及びイメージングシステム
WO2014143235A1 (en) 2013-03-14 2014-09-18 Integrated Plasmonics Corporation Ambient light assisted spectroscopy
US9857361B2 (en) 2013-03-15 2018-01-02 Iris International, Inc. Flowcell, sheath fluid, and autofocus systems and methods for particle analysis in urine samples
JP6188400B2 (ja) 2013-04-26 2017-08-30 オリンパス株式会社 画像処理装置、プログラム及び画像処理方法
US9372143B2 (en) 2013-05-15 2016-06-21 Captl Llc Scanning image flow cytometer
CN103308440A (zh) 2013-05-28 2013-09-18 香港浸会大学深圳研究院 一种流式荧光显微成像装置及方法
WO2014191003A1 (en) 2013-05-28 2014-12-04 Chemometec A/S Image forming cytometer
EP3013983B1 (en) 2013-06-25 2023-02-15 Prognosys Biosciences, Inc. Spatially encoded biological assays using a microfluidic device
WO2015021332A1 (en) 2013-08-07 2015-02-12 The Regents Of The University Of California Real-time label-free high-throughput cell screening in flow
JP6230047B2 (ja) 2013-08-15 2017-11-15 国立大学法人北海道大学 複素振幅画像表示方法、散乱位相画像生成装置および散乱位相画像生成方法
JP2015052663A (ja) 2013-09-06 2015-03-19 キヤノン株式会社 画像処理方法、画像処理装置、撮像装置およびプログラム
CN105723280B (zh) 2013-09-24 2020-09-22 加利福尼亚大学董事会 使用灰度掩模生产分离介质
US9518916B1 (en) 2013-10-18 2016-12-13 Kla-Tencor Corporation Compressive sensing for metrology
FR3013169B1 (fr) 2013-11-08 2018-01-05 Valeo Systemes Thermiques Moteur synchrone sans balai a detection de position angulaire du rotor par action sur un faisceau de lumiere
JPWO2015068834A1 (ja) 2013-11-11 2017-03-09 国立大学法人北海道大学 複素振幅像生成装置および複素振幅像生成方法
CN103604737B (zh) 2013-12-10 2015-11-25 山东大学 一种自动化血细胞识别装置及工作方法
US20150170053A1 (en) 2013-12-13 2015-06-18 Microsoft Corporation Personalized machine learning models
US9823457B2 (en) 2014-01-08 2017-11-21 The Regents Of The University Of California Multiplane optical microscope
DK3094974T3 (da) 2014-01-14 2019-05-27 Asedasciences Ag Identifikation af funktionelle cellers tilstande
CN103837461B (zh) 2014-01-16 2016-08-24 麦克奥迪实业集团有限公司 一种灰度摄像头及具有高效率照明的细胞综合分析装置
US10061111B2 (en) 2014-01-17 2018-08-28 The Trustees Of Columbia University In The City Of New York Systems and methods for three dimensional imaging
US9952033B2 (en) 2014-02-14 2018-04-24 Palo Alto Research Center Incorporated Spatial modulation of light to determine object length
US9528925B2 (en) 2014-02-14 2016-12-27 Palo Alto Research Center Incorporated Spatial modulation of light to determine object position
US9778166B2 (en) 2014-02-24 2017-10-03 National University Corporation Kagawa University Microparticle measurement device
WO2015148560A1 (en) 2014-03-24 2015-10-01 Colorado State University Research Foundation Method and device for incoherent imaging with coherent diffractive reconstruction
CN103942415B (zh) 2014-03-31 2017-10-31 中国人民解放军军事医学科学院卫生装备研究所 一种流式细胞仪数据自动分析方法
US20170052106A1 (en) 2014-04-28 2017-02-23 The Broad Institute, Inc. Method for label-free image cytometry
CN106574925B (zh) 2014-05-23 2019-07-26 萤火虫生物股份有限公司 用于生物测定的底物介导的反应器
KR102167715B1 (ko) * 2014-07-04 2020-10-20 삼성디스플레이 주식회사 표시 장치
CN104154878B (zh) 2014-07-29 2016-09-28 暨南大学 一种使用单像素探测器的光学成像方法
CN104200114B (zh) 2014-09-10 2017-08-04 中国人民解放军军事医学科学院卫生装备研究所 流式细胞仪数据快速分析方法
JP2016057172A (ja) 2014-09-10 2016-04-21 キヤノン株式会社 波面演算装置、撮像システムおよび波面演算プログラム
EP3200917B1 (en) 2014-09-29 2020-02-19 Biosurfit, S.A. Cell counting
EP3202144A4 (en) 2014-09-30 2018-06-13 Washington University Compressed-sensing ultrafast photography (cup)
WO2016054293A1 (en) * 2014-09-30 2016-04-07 The Regents Of The University Of California Imaging flow cytometer using spatial-temporal transformation
JP6090286B2 (ja) 2014-10-31 2017-03-08 カシオ計算機株式会社 機械学習装置、機械学習方法、分類装置、分類方法、プログラム
JP6282969B2 (ja) 2014-10-31 2018-02-21 日本光電工業株式会社 フロー解析装置、フローサイトメータ、及びフロー解析方法
WO2016073985A1 (en) 2014-11-07 2016-05-12 The General Hospital Corporation Deep brain source imaging with m/eeg and anatomical mri
JP6321529B2 (ja) 2014-11-19 2018-05-09 日本電信電話株式会社 情報信憑性判定システム、情報信憑性判定方法、情報信憑性判定プログラム
US20160169786A1 (en) 2014-12-10 2016-06-16 Neogenomics Laboratories, Inc. Automated flow cytometry analysis method and system
US9645377B2 (en) 2015-02-06 2017-05-09 The Johns Hopkins University Compressive imaging systems and methods
EP3256850B1 (en) 2015-02-09 2025-07-09 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties and methods for using the same
CA2977481C (en) 2015-02-24 2021-02-02 The University Of Tokyo Dynamic high-speed high-sensitivity imaging device and imaging method
JP6492880B2 (ja) 2015-03-31 2019-04-03 日本電気株式会社 機械学習装置、機械学習方法、および機械学習プログラム
US10101250B2 (en) 2015-04-22 2018-10-16 Berkeley Lights, Inc. Manipulation of cell nuclei in a micro-fluidic device
CN106295251A (zh) 2015-05-25 2017-01-04 中国科学院青岛生物能源与过程研究所 基于单细胞表现型数据库的表型数据分析处理方法
CN104849874B (zh) 2015-06-02 2017-04-19 西安电子科技大学 基于稀疏表示的随机散射光学成像系统及成像方法
CN106267241B (zh) 2015-06-26 2019-10-22 重庆医科大学 一种多功能多模态肿瘤特异性靶向相变型纳米微球光声造影剂及其应用
CN105044897B (zh) 2015-07-07 2017-12-05 中国科学院上海高等研究院 基于稀疏约束的快速随机光学重构成像系统及方法
CN105005053B (zh) 2015-07-13 2017-11-21 西安电子科技大学 基于led照明的随机散射关联成像系统及成像方法
EP3335028A1 (en) 2015-08-11 2018-06-20 Scintillon Institute for Biomedical and Bioenergy Research Optical analyses of particles and vesicles
CN105223582B (zh) 2015-09-01 2018-01-16 西安交通大学 一种基于压缩感知的激光雷达成像装置及成像方法
JP6796917B2 (ja) 2015-09-18 2020-12-09 シスメックス株式会社 粒子撮像装置および粒子撮像方法
JP6790490B2 (ja) 2015-09-18 2020-11-25 ソニー株式会社 情報処理装置、情報処理方法及び情報処理システム
WO2017046988A1 (en) 2015-09-18 2017-03-23 Sony Corporation Information processing apparatus, information processing method, and information processing system
US11002655B2 (en) * 2015-09-23 2021-05-11 Malvern Panalytical Limited Cuvette carrier
CN105181649B (zh) 2015-10-09 2018-03-30 山东大学 一种新型免标记模式识别细胞仪方法
JP6882282B2 (ja) 2015-11-03 2021-06-02 プレジデント アンド フェローズ オブ ハーバード カレッジ 三次元核酸含有マトリックスの立体撮像のための方法と装置
CN108700500B (zh) * 2015-12-30 2021-10-29 生物辐射实验室股份有限公司 用于颗粒的光学检测系统
WO2017121896A1 (en) 2016-01-14 2017-07-20 Anton Bauer Method of producing a production cell line
US10346964B2 (en) 2016-02-02 2019-07-09 Steven M. Ebstein System for actinic inspection of semiconductor masks
US12060412B2 (en) 2016-03-21 2024-08-13 The Broad Institute, Inc. Methods for determining spatial and temporal gene expression dynamics in single cells
CN105651656B (zh) 2016-04-01 2018-09-11 黄恺 基于激光全息成像法分析颗粒形状的装置及其工作方法
US10337975B2 (en) 2016-05-06 2019-07-02 Deutsches Rheuma-Forschungszentrum Berlin Method and system for characterizing particles using a flow cytometer
CN109477784B (zh) 2016-05-12 2022-04-01 Bd生物科学公司 具有增强图像分辨率的荧光成像流式细胞术
CN106097437B (zh) 2016-06-14 2019-03-15 中国科学院自动化研究所 基于纯光学系统的生物自发光三维成像方法
JP6249049B2 (ja) * 2016-06-14 2017-12-20 ソニー株式会社 微小粒子測定装置
WO2017223386A1 (en) 2016-06-22 2017-12-28 Duke University Multiple-input-multiple-output (mimo) imaging systems and methods for performing massively parallel computation
EP3266877B1 (en) * 2016-07-08 2019-02-27 Biomérieux Flow cytometry data processing for antimicrobial agent sensibility prediction
EP3499201B1 (en) 2016-08-15 2022-12-07 Osaka University Electromagnetic wave phase/amplitude generation device, electromagnetic wave phase/amplitude generation method, and electromagnetic wave phase/amplitude generation program
US11225689B2 (en) 2016-08-17 2022-01-18 The Broad Institute, Inc. Method for determination and identification of cell signatures and cell markers
CN106520535B (zh) 2016-10-12 2019-01-01 山东大学 一种基于光片照明的免标记细胞检测装置及方法
CA3048645A1 (en) 2016-12-30 2018-07-05 The Regents Of The University Of California Methods for selection and generation of genome edited t cells
JP6781987B2 (ja) 2017-02-17 2020-11-11 国立大学法人大阪大学 電磁波検出装置、フローサイトメーター、電磁波検出方法及び電磁波検出プログラム
CN110520876B (zh) 2017-03-29 2024-05-14 新克赛特株式会社 学习结果输出装置及学习结果输出程序
JPWO2018199080A1 (ja) 2017-04-28 2020-03-12 シンクサイト株式会社 イメージングフローサイトメーター
WO2019217846A1 (en) * 2018-05-10 2019-11-14 Board Of Regents, The University Of Texas System Line excitation array detection microscopy
EP4306931B1 (en) 2018-06-13 2025-09-24 ThinkCyte K.K. Methods and systems for cytometry
CN109297888A (zh) * 2018-09-13 2019-02-01 福建师范大学 一种白光实时细胞体积精密测量仪
JP7626454B2 (ja) 2018-10-18 2025-02-04 シンクサイト株式会社 標的スクリーニングのための方法及びシステム
US11614398B2 (en) * 2019-09-17 2023-03-28 Robert Alfano Method for imaging biological tissue using polarized majorana vector and complex vortex photons from laser and supercontinuum light sources
EP4083603A4 (en) 2019-12-27 2024-04-03 ThinkCyte, Inc. FLOW CYTOMETER PERFORMANCE EVALUATION METHODS AND STANDARD PARTICLE SUSPENSION
WO2021200960A1 (ja) 2020-04-01 2021-10-07 シンクサイト株式会社 観察装置
JP7656837B2 (ja) 2020-04-01 2025-04-04 シンクサイト株式会社 フローサイトメーター

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012500385A (ja) * 2008-08-06 2012-01-05 インビトロックス，インコーポレイテッド 生物学的応用における集束光散乱技術の使用
JP2011099848A (ja) 2009-10-05 2011-05-19 Bay Bioscience Kk フローサイトメータおよびフローサイトメトリ方法
JP2015512029A (ja) * 2011-12-29 2015-04-23 アボット・ラボラトリーズＡｂｂｏｔｔ Ｌａｂｏｒａｔｏｒｉｅｓ 回折パターンを遮断するためのフローサイトメトリーシステムおよび方法
JP2016517526A (ja) * 2013-03-15 2016-06-16 ベックマン コールター， インコーポレイテッド フローサイトメーター用の放射光フィルター処理
JP2014190748A (ja) * 2013-03-26 2014-10-06 Sysmex Corp 粒子分析装置、粒子分析装置用光学系および粒子分析装置用レンズ
JP2016073210A (ja) 2014-10-02 2016-05-12 国立大学法人山口大学 家畜下垂体細胞の集団からのゴナドトロフ細胞の分離方法
WO2017073737A1 (ja) 2015-10-28 2017-05-04 国立大学法人東京大学 分析装置
JP2020065940A (ja) 2019-12-26 2020-04-30 株式会社サンセイアールアンドディ 遊技機

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4130714A4

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12230023B2 (en) 2015-10-28 2025-02-18 The University Of Tokyo Analysis device
US12259311B2 (en) 2018-06-13 2025-03-25 Thinkcyte K.K. Methods and systems for cytometry
US12235202B2 (en) 2019-12-27 2025-02-25 Thinkcyte K.K. Flow cytometer performance evaluation method and standard particle suspension
US12298221B2 (en) 2020-04-01 2025-05-13 Thinkcyte K.K. Observation device
US12339217B2 (en) 2020-04-01 2025-06-24 Thinkcyte K.K. Flow cytometer

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