WO2017187490A1 - Analytical device - Google Patents
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- WO2017187490A1 WO2017187490A1 PCT/JP2016/062956 JP2016062956W WO2017187490A1 WO 2017187490 A1 WO2017187490 A1 WO 2017187490A1 JP 2016062956 W JP2016062956 W JP 2016062956W WO 2017187490 A1 WO2017187490 A1 WO 2017187490A1
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- light
- illumination
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- 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
- G01N21/59—Transmissivity
Definitions
- the present invention relates to an analyzer.
- Patent Document 1 states that “when there is a relative movement between a measurement object and the measurement object, the imaging system is configured to determine one or more characteristics of the measurement object from the image of the measurement object, a) a condenser lens arranged to transmit light from the measurement object and travel along the condenser optical path, and (b) arranged to receive the light passing through the condenser lens, thereby At least one image lens for generating an image guided toward a predetermined position; and (c) arranged to receive light that has passed through the condenser lens so that the light from the measurement object passes only once.
- a plurality of light reflecting elements that reflect light having a predetermined characteristic along different reflection light paths and pass light having no predetermined characteristic; and (d) each of the light reflecting elements.
- the measurement object is positioned to receive an image of the measurement object from one of the light transmitted through the light reflecting element and the relative movement is occurring between the measurement object and the imaging system.
- a plurality of pixelated detectors configured to generate an output signal representative of at least one characteristic of and to generate the output signal by integrating light from at least a portion of the measurement object over time; (E) to determine at least one characteristic of the measurement object, 1) to determine which position on the measurement object to label, 2) to label the label at each different position to be labeled
- An imaging system comprising: a processor configured to analyze an output signal from the pixelated detector by performing matching There has been disclosed.
- Patent Document 1 uses a condenser lens as an essential component.
- this apparatus configuration has restrictions in layout such that the distance required for detection is restricted by the specifications of the condenser lens.
- the present invention adopts, for example, the configurations described in the claims.
- the present specification includes a plurality of means for solving the above-described problems. For example, the following description is given: “Supply the sample illumination channel and the first illumination light collimated to the first surface of the channel. And an illumination optical system that forms a linear first illumination region in the flow path, and a first detection unit that detects the first transmitted light generated from the flow path by the supply of the first illumination light. There is an “analyzer with”.
- FIG. 1 is a diagram illustrating a basic configuration of an analyzer according to Embodiment 1.
- FIG. 10 is a diagram illustrating a configuration example of an illumination system and a detection system used in the analyzer according to the second embodiment.
- FIG. 10 is a diagram illustrating a configuration example of a color separation unit used in an analyzer according to a third embodiment.
- FIG. 10 is a diagram illustrating a configuration example of an illumination system and a detection system used in the analyzer according to the fourth embodiment.
- FIG. 10 is a diagram for explaining a measurement operation in the analyzer according to the fifth embodiment.
- the figure which shows the example of application of an analyzer (Example 6).
- the figure which shows the other usage example of an analyzer (Example 6). (Example 7) explaining the sample flow path equipped with the cartridge type reaction cell.
- FIG. 1 shows a basic configuration of the analyzer 100 according to the embodiment.
- the analyzer 100 is used, for example, for cell observation, cell ecology observation, PET (Positron Emission Tomography) inspection, and water quality inspection.
- detection processing and analysis processing according to the purpose of inspection are executed. For example, it is used for counting and classification of particles (for example, dust) and cells contained in a fluid (including not only liquid but also gas) moved or conveyed along a flow path. If the fluid to be analyzed is blood, the analyzer 100 counts and classifies red blood cells, white blood cells, and platelets.
- a fluid including not only liquid but also gas
- Analyzing apparatus 100 includes a detection unit 101 and an analysis unit 102.
- the division between the detection unit 101 and the analysis unit 102 in FIG. 1 is convenient. Accordingly, the detection unit 101 may be configured including the analysis unit 102, or some of the components of the detection unit 101 may be provided as parts independent of the detection unit 101.
- the 1 includes a light source 103.
- the light source 103 is a light emitting element that outputs a single wavelength or white light, and is composed of, for example, an LED (light-emitting diode).
- the light source 103 is selected according to the measurement object and measurement items (number, shape, classification, etc.). Not only the type of the light source 103 but also the wavelength band output from the light source 103 is selected. For example, when only the counting of the measurement object is intended, the single wavelength light source 103 is selected. This is because it is sufficient to count the measurement target if it can be binarized by the density of the detected image. By employing the single wavelength light source 103, the apparatus price can be reduced.
- the light output from the light source 103 is branched into two by the optical path branching element 104.
- the optical path branching element 104 is composed of, for example, a half mirror.
- One of the branched lights is detected by the photodiode 105.
- the output signal S1 of the photodiode 105 is sent to the timing adjustment unit 106.
- the timing adjustment unit 106 outputs timing signals S2A and S2B for adjusting analog-digital conversion timing (light path difference of illumination light, difference in photoelectric conversion characteristics in the detection unit, delay in analog signal processing, etc.) synchronized with the illumination light. .
- the other of the branched lights is input to the collimator 107.
- the collimator 107 includes a first-stage lens that widens the diameter of incident light, a second-stage lens that converts incident light into parallel light, and a cylindrical lens that converts incident parallel light into a thin line shape.
- conversion of illumination light into parallel light is referred to as “collimation”, and parallel light is also referred to as “collimation light”.
- the thin linear illumination light (parallel light) output from the collimator 107 is divided into two by the half mirror 108.
- the split ratio of the half mirror 108 is 50:50.
- the first illumination light 109 that has passed through the half mirror 108 illuminates the sample channel 110 whose outer shape is a rectangular parallelepiped. At least the illumination region (illumination window portion) where the first illumination light 109 is incident and the detection region (detection window portion) on the opposite side of the sample channel 110 are made of a light transmitting member.
- the entire sample channel 110 may be made of a transparent material.
- the second illumination light 111 reflected by the half mirror 108 is sequentially reflected by the total reflection mirrors 112 and 113, and the surface (first surface) on which the first illumination light 109 enters the sample channel 110. Is incident on a different surface (second surface).
- the first surface and the second surface are surfaces orthogonal to each other.
- the sample channel 110 is a cylindrical member having a hollow inside.
- the sample (the above-described fluid) is moved in the sample channel 110 in the direction of the arrow M1, for example.
- the illumination light is incident on two orthogonal surfaces of the sample channel 110, but the illumination light may be incident on only one surface of the sample channel 110. In that case, the half mirror 108 and the total reflection mirrors 112 and 113 described above are unnecessary.
- the first illumination light 109 incident from the first surface and transmitted through the sample channel 110 enters the first detection unit 115 as the first projection light 114.
- the second illumination light 111 incident from the second surface and transmitted through the sample channel 110 enters the second detection unit 117 as the second projection light 116.
- the detection units 115 and 117 may be elements that convert photons into electric signals.
- a photodiode array including an avalanche photodiode array
- other photoelectric conversion element array is used.
- the array may be a plurality of elements arranged in a row (one-dimensional) or a plurality of elements arranged in a matrix (two-dimensional).
- the longitudinal direction of the array is parallel to the longitudinal direction of the transmitted light (projection light 114 and 116) which is a thin line.
- the light receiving surfaces of the detectors 115 and 117 have an area and shape that can receive at least all the projection lights 114 and 116. Accordingly, the length of the light receiving surfaces of the detection units 115 and 117 in the longitudinal direction is longer than the length of one side of the sample channel 110, and the length of the light receiving surfaces of the detection units 115 and 117 in the short side direction is the projection light 114 and 116. Longer than the line width.
- the measurement object that passes through the area (measurement area) surrounded by the illumination window and the detection window is basically projected onto the light receiving surface as a shadow.
- the illumination lights 109 and 111 and the projection lights 114 and 116 are both parallel lights. Accordingly, a ten-dimensional shadow of the substance to be measured is formed on the light receiving surface.
- the cross section of the sample channel 110 (measurement region) ) Can be measured all at once. That is, there is no oversight of the measurement object.
- the dimension projected on the light receiving surface does not change regardless of the position of the measurement object in the measurement region.
- the size of the measurement object detected varies depending on the position even in the spot corresponding to the measurement region, and the measurement object moving outside the spot cannot be detected.
- the light reception timing by the first detection unit 115 and the second detection unit 117 is also adjusted according to the timing signals S2A and S2B given from the timing adjustment unit 106. That is, the light reception timing is controlled to be synchronized with the incident timing of the projection lights 114 and 116.
- the first detection unit 115 and the second detection unit 117 output the reception intensities of the projection lights 114 and 116 received by the respective elements (pixels) at the respective light reception timings as output signals S3A and S3B.
- the timing signals S2A and S2B are adjusted so that the output signals S3A and S3B are maximized, that is, the SN ratio after digital conversion is maximized, and output to the analog-digital converters 118 and 119, respectively.
- the analog-digital converters 118 and 119 convert the output signals S3A and S3B output from each element constituting the array into digital values and output the digital values to the analysis unit 102.
- the analog-digital conversion timing in the analog-digital converters 118 and 119 is adjusted by the timing signals S2A and S2B as described above.
- the analysis unit 102 includes a so-called computer (RAM, ROM, CPU, hard disk, input / output unit, etc.).
- the analysis unit 102 performs analysis processing on data detected through execution of a program by the CPU, for example.
- the content of the analysis process varies depending on the application of the applied analyzer.
- the analysis unit 102 may be a module device in which a series of processing contents is packaged.
- a cylindrical member having a rectangular parallelepiped shape is used as the shape of the sample channel 110.
- the rectangular parallelepiped is used to reduce generation of unwanted light such as scattering and reflection.
- the region where the first and second illumination lights 109 and 111 enter the sample channel 110 uses a material that is substantially transparent to the illumination light, and other regions.
- the part may be opaque (for example, black).
- the first and second illumination lights 109 and 111 incident on the sample channel 110 are pulsed light.
- the first and second illumination lights 109 and 111 are pulsed light.
- the light source 103 may emit continuously oscillating light, and may be substantially pulsed by an optical element disposed on the optical path.
- a shutter is used for this type of optical element. Examples of the shutter include a mechanical shutter and an electrical shutter exemplified by a transparent ferroelectric substance.
- An avalanche photodiode array suitable for use in the detection units 115 and 117 will be described.
- An avalanche photodiode (hereinafter also referred to as “APD”), which is a basic unit of an avalanche photodiode array, is a type of photodiode (hereinafter also referred to as “PD”), and a photocurrent is increased by applying a reverse voltage. It is a high-speed and high-sensitivity PD that is doubled.
- An APD is a device that measures energy by counting energy (for example, the number of photons constituting light).
- magnification increase the internal electric field is increased is very high (e.g., 10 5 to 10 6 times).
- the operation of the APD with the doubling rate increased in this way is called Geiger mode.
- the pair of electrons and holes generated in the PN junction by the incidence of energy (for example, photons or charged particles) in the Geiger mode is accelerated by a high electric field.
- electrons generated by the incidence of energy are accelerated in the P layer and travel toward the N layer with increased kinetic energy.
- Electrons that have entered the N layer with kinetic energy sufficiently higher than the band cap energy of the N layer bounce off the N layer, and the electrons bounced from the N layer generate more electrons in a chain. To do. This is the principle of multiplication action.
- a very large pulse signal is generated by the above-described multiplication action, so that photons can be counted by the pulse signal.
- Light is a collection of photons (photons), and photons become discrete with weak light, but APD can be measured with high sensitivity by the above-described multiplication action even with weak light.
- the APD outputs a current having a magnitude corresponding to the number of photons and charged particles detected per time.
- APD has higher sensitivity to weak light than when general PD is applied.
- the APD array is a kind of device called a silicon photomultiplier (Si-PM), and is an aggregate of Geiger mode APDs that operate individually.
- the individual APDs constituting the pixels of the APD array output pulse signals when energy is detected as described above.
- the output of the APD array may be the sum of all pixels, or may be output in units of pixels.
- the output of the APD array is output from the output line.
- the usage mode of the analysis apparatus 100 varies depending on the measurement object and usage purpose. For example, there is a usage mode in which a fluid as a sample (gas or liquid) is supplied to the sample flow path 110 in the apparatus at every inspection, and there is a usage mode in which the apparatus is installed in the sample flow path 110 in which the sample always flows. There is also.
- the analyzer 100 applies the illumination light 109 and 111 converted into linear and pulsed parallel light to the first surface and the second surface of the sample channel 110 where the sample is moving. Irradiate.
- linear and pulsed parallel light that is, projection light 114 and 116 transmitted through the sample moving in the sample channel 110 is emitted. And is incident on the detection units 115 and 117.
- the electrical signals output from the detection units 115 and 117 are subjected to data analysis in the analysis unit 102.
- the analysis apparatus 100 irradiates the sample channel 110 with the parallel light, so that the shadow of the measurement object moving in the sample channel 110 can be obtained at a real size at a time. Moreover, since parallel light is used, a wide field of view of the measurement region can be easily realized. In addition, since parallel light is used, even if the measurement object passes through any position in the cross section of the sample channel 110, a shadow having an actual size is generated on the light receiving surface. That is, the depth of focus can be made infinite. By using this function, it is possible to accurately measure the number and dimensions of measurement objects (for example, micron-order dust and cells).
- the same region (measurement region) in the sample channel 110 is detected from two directions. For this reason, even when a plurality of measurement objects 201 appear to overlap in one detection direction (even when two measurement objects form one shadow in the shape of the light receiving surface of the detection unit 115), the detection units 115 and 117 By comparing the outputs, it is possible to reliably distinguish that there are a plurality of measurement objects 201.
- the analysis unit 102 when each signal intensity of the output data (corresponding to individual photoelectric conversion elements constituting the array) of the detection units 115 and 117 is lower than the threshold value, the analysis unit 102 outputs the shadow 202V of the measurement target 201 when the output data is lower than the threshold value. And 202H.
- the analysis unit 102 counts the number of measurement objects 201 that have passed through the measurement region by counting a single shadow as one. Further, by analyzing the output data of the detection units 115 and 117, the passing position, shape, and size (area and volume) of each measurement target 201 can be accurately specified. Further, the density can be calculated based on the measured number, and the weight of the sample can be analyzed from the density.
- the illumination energy can be minimized by irradiating the sample flow path 110 with pulsed illumination light 109 and 111, and damage to the measurement object can be reduced.
- the detection units 115 and 117 are formed of an avalanche photodiode array with high detection sensitivity.
- the use of the pulsed illumination lights 109 and 111 is effective for measuring a sample (for example, a cell or a photosensitive resist material) that needs to avoid a state change caused by energy irradiation, and the same sample is repeatedly used for the measurement. be able to. Therefore, the analyzer 100 can also be used for measuring changes over time of the same sample. Further, since it is possible to minimize the possibility of a change in character due to irradiation of the illumination lights 109 and 111, it is possible to perform 100% inspection instead of sample inspection performed by extracting a part of the sample.
- the analysis unit 102 if the transmitted light (that is, the projection light 114 and 116) is wavelength-resolved and the distribution and the change in the detection intensity of each wavelength are analyzed, the uniformity and the component change when a plurality of materials are mixed are obtained. Can be analyzed or evaluated. Further, the density change of the fluid moving through the sample channel 110 appears as a change in the refractive index of the fluid. This change in the refractive index appears as a change in the illuminance distribution of the transmitted light (that is, the projection lights 114 and 116). Therefore, if the analysis unit 102 compares the measured illuminance distribution with the template data, a change in the density of the fluid can be detected. The illuminance distribution has an inclination distribution within the imaging field.
- the transmitted light (that is, the projection light 114 and 116) transmitted through the sample channel 110 may change in spectrum (color) due to optical interference with the measurement target 201, and may decrease in luminance.
- the analysis unit 102 may execute the counting process of the measurement target 201 and the substance identification process based on the change in the spectrum and the decrease in luminance.
- the shadows 202V and 202H represent actual dimensions, the actual volume of the measurement object 201 can be calculated from these dimension information.
- the measurement object 201 here includes a transparent body other than cells (for example, a thin transparent body).
- the apparatus configuration of this embodiment that handles parallel light simplifies the configuration of the detection optical system and can reduce the manufacturing cost of the apparatus. Further, since the configuration is simple, assembly and adjustment are easy, and the detection optical system is stable. Furthermore, since the analyzing apparatus 100 of the present embodiment does not use a condensing lens, there is no layout restriction regarding the detection system, and the apparatus can be downsized.
- FIG. 3 shows another configuration example of the illumination system and the detection system of the analyzer 100.
- FIG. 3 is one example of an illumination system and a detection system of the analyzer 100 shown in FIG.
- the illumination system in FIG. 3 includes an illuminance adjustment unit 301, a wavelength band selection unit 302, and a polarization switching unit 303.
- the illuminance adjusting unit 301 adjusts and outputs the illuminance of the incident illumination light 109 and 111.
- the wavelength band selector 302 selectively extracts a wavelength component suitable for sample irradiation.
- the polarization switching unit 303 transmits a specific polarization component included in the illumination light.
- the illuminance adjusting unit 301, the wavelength band selecting unit 302, and the polarization switching unit 303 are not necessarily provided, and one or more of them may be used in combination as necessary.
- the 3 includes a magnifying optical system 304 and an analyzer 305.
- the magnifying optical system 304 is inserted according to the required optical resolution.
- the analyzer 305 selectively transmits a specific polarization component. It is not always necessary to provide all of the magnifying optical system 304 and the analyzer 305. Any one or a combination of both may be used as necessary. Note that any distance can be selected for L1 to L3 in the figure.
- FIG. 4 shows another configuration example of the detection system of the analyzer 100.
- the configuration of the detection system shown in FIG. 4 is suitable for use in detecting phenomena such as transmittance, transmission wavelength, and thin film interference as color information through transmitted light (projection lights 114 and 116).
- the analysis unit 102 uses the illuminance information of the illumination lights 109 and 111 given from the timing adjustment unit 106.
- Illuminance information of the illumination lights 109 and 111 is calculated in the timing adjustment unit 106 that receives the output signal S1 of the photodiode 105.
- the detection system shown in FIG. 4 is particularly effective when the measurement target is a transparent body (for example, a cell).
- the color separation unit 401 transmits the blue component of the transmitted light (projection light 114 and 116) and reflects the other color components in the direction of the color separation unit 402.
- the color separation unit 402 further separates the incident light into a red component and a green component and outputs them.
- three detectors 115R, 115G, and 115B (117R, 117G, and 117B) are arranged according to the separated red, green, and blue (RGB) components.
- Each of the detection units 115R, 115G, and 115B (117R, 117G, and 117B) outputs a corresponding color component intensity signal.
- the analysis unit 102 can be used even when the measurement target is a transparent body. Phenomena such as transmittance, transmission wavelength, and thin film interference can be detected as changes in color components. Further, by using the detection result, the analysis unit 102 can execute shape determination and classification of the measurement target.
- FIG. 5 shows another configuration example of the illumination system and the detection system of the analyzer 100.
- the case where the cross section of the sample flow path 110 is a quadrilateral or more polygonal (FIG. 5 shows a case where the cross section of the sample flow path 110 is a regular hexagon).
- the cross-sectional shape is a regular hexagon, three entrance surfaces and three transmission surfaces can be secured.
- the cross-sectional shape does not have to be a regular polygon.
- n is 5 or more
- FIG. 6 shows another measurement operation example for improving the measurement accuracy.
- each measurement object is basically measured only once in the measurement region.
- the same measurement object is obtained by adjusting the detection timing of the projection lights 114 and 116. Measure multiple times within the measurement area.
- T W / FV
- the timing adjustment unit 106 sets the sampling interval ST between the detection units 115 and 117 and the analog-digital converters 118 and 119 to less than T / 2. This means that the same measurement object can be detected twice or more.
- the timing adjustment unit 106 sets the sampling timing between the emission timings of the illumination lights 109 and 111. Are controlled synchronously.
- a measurement region (a space region through which illumination light is transmitted, the width in the direction in which the sample flows) is detected a plurality of times according to the time (that is, the flow velocity) through which the sample passes.
- the possibility that a plurality of measurement objects at positions that cannot be separated by measurement can be separated can be increased. For example, at a certain sampling timing, there is a higher possibility that a plurality of measurement objects may appear to be separated at another sampling timing even if they appear to be one because they are close by chance. For this reason, the measurement accuracy can be improved by employing the detection method of this embodiment.
- FIG. 7 shows a usage example suitable for real-time inspection (for example, foreign substance inspection, uniformity inspection, component inspection by mixing reaction reagents).
- an inspection unit 701 including the analyzer 100 is attached to a branch channel 703 branched from the main channel 702 for use.
- a flow rate control valve 711 provided on the upstream side of the branch channel 703 adjusts the flow rate of the sample flowing into one input port of the mixing unit 712 located on the downstream side.
- a reaction reagent tank 714 is connected to the other input port of the mixing unit 712 via a flow rate control valve 713.
- the flow control valve 713 adjusts the supply amount of the reagent.
- a reagent corresponding to the inspection purpose is stored.
- the reaction channel length switching unit 715 is connected to the output port of the mixing unit 712.
- the reaction channel length switching unit 715 is provided so that the path length from the mixing unit 712 to the analyzer 100 can be adjusted to a path length suitable for the reaction between the sample and the reagent.
- a plurality of channels having different lengths are prepared inside the reaction channel length switching unit 715.
- the installer selects a flow path having a length corresponding to the combination of the sample and the reagent.
- data processing corresponding to the inspection purpose (inspection item) is executed. For example, the detected data and template data registered in advance are compared, and the substance contained in the sample is specified and the concentration is determined.
- the number of branch channels 703 provided in the main channel 702 is not limited to one.
- the inspection unit 701 may be connected to each of the plurality of branch channels 703. In this case, the same inspection may be performed in each of the plurality of inspection units 701, or different types of inspections may be performed.
- one branch channel 703 may be further branched, and the inspection unit 701 may be connected to a plurality of branch channels 703 after branching. For example, as shown in FIG. 8, an inspection unit 701 may be connected to the sub-branch channels 704A and 704B further branched from the branch channel 703 branched from the main channel 702. If a plurality of inspection units 701 are connected in this way, a plurality of inspections can be executed simultaneously.
- FIG. 7 shows a configuration in which the analysis apparatus 100 is attached to the inspection unit 701, but a configuration part (that is, the detection unit 101) excluding the analysis unit 102 from the analysis apparatus 100 may be attached to the inspection unit 701.
- the output of the detection unit 101 (that is, the output of the analog-digital converters 118 and 119) is notified to the analysis unit 102 connected through a network or other communication path.
- the network may be a wireless network or a wired network.
- FIG. 9 shows an embodiment in which a cartridge-type reaction cell 901 is attached to the sample channel 110.
- the reaction cell 901 is mounted in the measurement region of the sample channel 110.
- the reaction cell 901 includes a container made of a material that transmits the illumination lights 109 and 111 and a reagent or a member containing the reagent (for example, a thin film sheet) filled therein.
- a container made of a material that transmits the illumination lights 109 and 111 and a reagent or a member containing the reagent (for example, a thin film sheet) filled therein.
- On the side surface of the container an opening for taking in the sample moving in the direction of the arrow M1 is provided.
- the reagent develops color by reacting with a specific component of the sample incorporated therein, emits fluorescence, or changes in concentration.
- the analysis unit 102 compares the assumed change with the template data, and performs identification and concentration determination of the substance contained in the sample.
- reaction cell 901 By using the reaction cell 901, various measurements can be realized by changing the type of reagent to be filled even in the case of a sample (measurement target) that is difficult to detect only by irradiation with the illumination light 109 and 111. For example, in the case of water quality inspection, a reagent that reacts with a specific substance (chlorine, heavy metal, etc.) to be detected is filled. If a plurality of reaction cells 901 with different reagents are prepared, various tests can be performed by simply replacing the reaction cell 901 or the sample channel 110 to which the reaction cell 901 is attached according to the purpose of the test.
- the present invention is not limited to the above-described embodiments, and includes various modifications.
- the above-described embodiments have been described in detail for easy understanding of the present invention, and it is not necessary to provide all the configurations described.
- a part of one embodiment can be replaced with the configuration of another embodiment.
- the structure of another Example can also be added to the structure of a certain Example.
- a part of the configuration of another embodiment can be added, deleted, or replaced.
- DESCRIPTION OF SYMBOLS 100 ... Analyzing apparatus 101 ... Detection unit 102 ... Analysis part 103 ... Light source 104 ... Optical path branching element 105 ... Photodiode 106 ... Timing adjustment part 107 ... Collimator 108 ... Half mirror 109, 111, 111A ... Illumination light 110 ... Sample flow path 112 , 113 ... Total reflection mirrors 114, 116 ... Projection light 115, 117, 117A ... Detection unit 118, 119 ... Analog-to-digital converter 201 ... Measurement object 202H, 202V ... Shadow 301 ... Illuminance adjustment unit 302 ...
- Wavelength band selection unit 303 DESCRIPTION OF SYMBOLS ... Polarization switching part 304 ... Magnification optical system 305 ... Analyzer 401, 402 ... Color separation unit 701 ... Inspection unit 702 ... Main flow path 703 ... Branch flow path 704A, 704B ... Child branch flow path 711, 713 ... Flow control valve 712 ... Mixing section 714 ... Reaction reagent tank 715 ... Anti Responding channel length switching unit 901 ... reaction cell
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Abstract
This analytical device is provided with: a sample flow channel; an illuminating optical system, which supplies collimated first illuminating light to a first surface of the flow channel, and which forms a linear first illuminating region in the flow channel; and a first detection unit that detects first transmitted light generated from the flow channel when the first illuminating light is supplied.
Description
本発明は、分析装置に関する。
The present invention relates to an analyzer.
既存の分析装置では、例えば特許文献1に記載の分析技術が用いられている。特許文献1には、「測定対象との間に相対移動がある場合、前記測定対象の画像から前記測定対象の1つまたは複数の特性を決定するようになされた画像化システムであって、(a)前記測定対象からの光を通過させ、集光光路に沿って進行するように配置された集光レンズと、(b)該集光レンズを通過した光を受光するべく配置され、それにより所定の位置に向けて導かれる画像を生成する少なくとも1つの画像レンズと、(c)前記集光レンズを通過した光を受光するべく配置され、前記測定対象からの光が、一度だけ通過するように、予め決められた特性の光を異なる反射光路に沿って反射し、かつ、該予め決められた特性を持たない光を通過させる複数の光反射素子と、(d)前記各光反射素子の各々に対して1つが、前記光反射素子で反射した光および前記光反射素子を透過した光のうちの1つから前記測定対象の画像を受け取るべく位置付けされ、前記測定対象と前記画像化システムとの間に前記相対移動が生じている間、前記測定対象の少なくとも1つの特性を表す出力信号を生成し、前記測定対象の少なくとも一部からの光を時間に対して積分することによって前記出力信号を生成するように配置される複数のピクセル化検出器と、(e)前記測定対象の少なくとも1つの特徴を決定するために、1)前記測定対象上のどの位置にラベル化するのかを決定すること、2)ラベル化される各々異なる位置にそのラベルを一致させること、を実行することによって、前記ピクセル化検出器からの出力信号を分析するように構成されたプロセッサとを備えることを特徴とする画像化システム」が開示されている。
In existing analyzers, for example, the analysis technique described in Patent Document 1 is used. Patent Document 1 states that “when there is a relative movement between a measurement object and the measurement object, the imaging system is configured to determine one or more characteristics of the measurement object from the image of the measurement object, a) a condenser lens arranged to transmit light from the measurement object and travel along the condenser optical path, and (b) arranged to receive the light passing through the condenser lens, thereby At least one image lens for generating an image guided toward a predetermined position; and (c) arranged to receive light that has passed through the condenser lens so that the light from the measurement object passes only once. A plurality of light reflecting elements that reflect light having a predetermined characteristic along different reflection light paths and pass light having no predetermined characteristic; and (d) each of the light reflecting elements. One for each light reflected by the light reflecting element And the measurement object is positioned to receive an image of the measurement object from one of the light transmitted through the light reflecting element and the relative movement is occurring between the measurement object and the imaging system. A plurality of pixelated detectors configured to generate an output signal representative of at least one characteristic of and to generate the output signal by integrating light from at least a portion of the measurement object over time; (E) to determine at least one characteristic of the measurement object, 1) to determine which position on the measurement object to label, 2) to label the label at each different position to be labeled An imaging system comprising: a processor configured to analyze an output signal from the pixelated detector by performing matching There has been disclosed.
特許文献1に記載の分析技術は、集光レンズを必須の構成要素として使用する。ところが、この装置構成は、検出に要する距離が集光レンズの仕様の制約を受ける等、レイアウト上の制約がある。
The analysis technique described in Patent Document 1 uses a condenser lens as an essential component. However, this apparatus configuration has restrictions in layout such that the distance required for detection is restricted by the specifications of the condenser lens.
上記課題を解決するために、本発明は、例えば特許請求の範囲に記載の構成を採用する。本明細書は上記課題を解決する手段を複数含んでいるが、その一例を挙げるならば、「試料の流路と、前記流路の第1の面にコリメートされた第1の照明光を供給し、前記流路に線状の第1の照明領域を形成する照明光学系と、前記第1の照明光の供給により前記流路から発生する第1の透過光を検出する第1の検出部とを有する分析装置」がある。
In order to solve the above-mentioned problems, the present invention adopts, for example, the configurations described in the claims. The present specification includes a plurality of means for solving the above-described problems. For example, the following description is given: “Supply the sample illumination channel and the first illumination light collimated to the first surface of the channel. And an illumination optical system that forms a linear first illumination region in the flow path, and a first detection unit that detects the first transmitted light generated from the flow path by the supply of the first illumination light. There is an "analyzer with".
本発明によれば、少なくとも検出系に関するレイアウト上の制約を低減することができる。前述した以外の課題、構成及び効果は、以下の実施の形態の説明により明らかにされる。
According to the present invention, at least restrictions on the layout relating to the detection system can be reduced. Problems, configurations, and effects other than those described above will become apparent from the following description of embodiments.
以下、図面に基づいて、本発明の実施の形態を説明する。なお、本発明の実施の形態は、後述する実施例に限定されるものではなく、その技術思想の範囲において、種々の変形が可能である。
Hereinafter, embodiments of the present invention will be described with reference to the drawings. The embodiment of the present invention is not limited to the examples described later, and various modifications are possible within the scope of the technical idea.
(1)実施例1
(1-1)装置構成
(1-1-1)概略構成
図1に、実施例に係る分析装置100の基本構成を示す。分析装置100は、例えば細胞観察、細胞生態観察、PET(Positron Emission Tomography)検査、水質検査に用いられる。分析装置100では、検査の目的に応じた検出処理と分析処理が実行される。例えば流路に沿って移動又は搬送される流体(液体だけでなく気体も含む)に含まれる粒子(例えばごみ)や細胞の計数と分類に用いられる。分析対象の流体が血液であれば、赤血球、白血球、血小板の計数や分類が分析装置100で行われる。 (1) Example 1
(1-1) Apparatus Configuration (1-1-1) Schematic Configuration FIG. 1 shows a basic configuration of theanalyzer 100 according to the embodiment. The analyzer 100 is used, for example, for cell observation, cell ecology observation, PET (Positron Emission Tomography) inspection, and water quality inspection. In the analysis apparatus 100, detection processing and analysis processing according to the purpose of inspection are executed. For example, it is used for counting and classification of particles (for example, dust) and cells contained in a fluid (including not only liquid but also gas) moved or conveyed along a flow path. If the fluid to be analyzed is blood, the analyzer 100 counts and classifies red blood cells, white blood cells, and platelets.
(1-1)装置構成
(1-1-1)概略構成
図1に、実施例に係る分析装置100の基本構成を示す。分析装置100は、例えば細胞観察、細胞生態観察、PET(Positron Emission Tomography)検査、水質検査に用いられる。分析装置100では、検査の目的に応じた検出処理と分析処理が実行される。例えば流路に沿って移動又は搬送される流体(液体だけでなく気体も含む)に含まれる粒子(例えばごみ)や細胞の計数と分類に用いられる。分析対象の流体が血液であれば、赤血球、白血球、血小板の計数や分類が分析装置100で行われる。 (1) Example 1
(1-1) Apparatus Configuration (1-1-1) Schematic Configuration FIG. 1 shows a basic configuration of the
分析装置100は、検出ユニット101と解析部102とで構成される。図1における検出ユニット101と解析部102の区分けは便宜的なものである。従って、解析部102も含めて検出ユニット101を構成することもあれば、検出ユニット101の構成要素の一部が検出ユニット101から独立した部品として設けられることもある。
Analyzing apparatus 100 includes a detection unit 101 and an analysis unit 102. The division between the detection unit 101 and the analysis unit 102 in FIG. 1 is convenient. Accordingly, the detection unit 101 may be configured including the analysis unit 102, or some of the components of the detection unit 101 may be provided as parts independent of the detection unit 101.
図1に示す検出ユニット101には、光源103が含まれる。光源103は、単波長又は白色光を出力する発光素子であり、例えばLED(light-emitting diode)で構成される。光源103は、測定対象や測定項目(個数、形状、分類等)に応じて選択される。光源103の種類だけでなく、光源103から出力される波長帯域も選択対象となる。例えば測定対象の計数のみを目的とする場合、単波長の光源103を選択する。測定対象の計数には、検出像の濃淡で2値化できれば十分なためである。単波長の光源103の採用により、装置価格を抑えることができる。
1 includes a light source 103. The detection unit 101 shown in FIG. The light source 103 is a light emitting element that outputs a single wavelength or white light, and is composed of, for example, an LED (light-emitting diode). The light source 103 is selected according to the measurement object and measurement items (number, shape, classification, etc.). Not only the type of the light source 103 but also the wavelength band output from the light source 103 is selected. For example, when only the counting of the measurement object is intended, the single wavelength light source 103 is selected. This is because it is sufficient to count the measurement target if it can be binarized by the density of the detected image. By employing the single wavelength light source 103, the apparatus price can be reduced.
光源103から出力された光は、光路分岐素子104で2つに分岐される。光路分岐素子104は、例えばハーフミラーで構成する。分岐された光の一方は、フォトダイオード105で検出される。フォトダイオード105の出力信号S1はタイミング調整部106へ送られる。タイミング調整部106は、照明光に同期したアナログ-デジタル変換タイミング(照明光の光路差、検出部における光電変換特性の差、アナログ信号処理の遅れ等)を調整するタイミング信号S2A及びS2Bを出力する。分岐された光の他方は、コリメータ107に入力される。コリメータ107は、入射した光の光束径を広げる1段目のレンズ、入射した光を平行光に変換する2段目のレンズ、入射した平行光を細線形状に変換する円柱レンズで構成される。本明細書では、照明光を平行光に変換することを「コリメートする」といい、平行光を「コリメート光」ともいう。
The light output from the light source 103 is branched into two by the optical path branching element 104. The optical path branching element 104 is composed of, for example, a half mirror. One of the branched lights is detected by the photodiode 105. The output signal S1 of the photodiode 105 is sent to the timing adjustment unit 106. The timing adjustment unit 106 outputs timing signals S2A and S2B for adjusting analog-digital conversion timing (light path difference of illumination light, difference in photoelectric conversion characteristics in the detection unit, delay in analog signal processing, etc.) synchronized with the illumination light. . The other of the branched lights is input to the collimator 107. The collimator 107 includes a first-stage lens that widens the diameter of incident light, a second-stage lens that converts incident light into parallel light, and a cylindrical lens that converts incident parallel light into a thin line shape. In this specification, conversion of illumination light into parallel light is referred to as “collimation”, and parallel light is also referred to as “collimation light”.
コリメータ107から出力される細い線状の照明光(平行光)は、ハーフミラー108によって2つに分割される。本実施例の場合、ハーフミラー108の分割比は50:50である。ハーフミラー108を通過した第1の照明光109は、外形が直方体形状の試料流路110を照明する。試料流路110のうち少なくとも第1の照明光109が入射する照明領域(照明窓の部分)とその反対側の検出領域(検出窓の部分)は、光を透過する部材で構成されている。試料流路110の全体が透明材料で構成されていても良い。ハーフミラー108で反射された第2の照明光111は、全反射ミラー112及び113で順番に反射され、試料流路110のうち第1の照明光109が入射する面(第1の面)とは異なる面(第2の面)に入射する。図1の場合、第1の面と第2の面は互いに直交する面である。
The thin linear illumination light (parallel light) output from the collimator 107 is divided into two by the half mirror 108. In this embodiment, the split ratio of the half mirror 108 is 50:50. The first illumination light 109 that has passed through the half mirror 108 illuminates the sample channel 110 whose outer shape is a rectangular parallelepiped. At least the illumination region (illumination window portion) where the first illumination light 109 is incident and the detection region (detection window portion) on the opposite side of the sample channel 110 are made of a light transmitting member. The entire sample channel 110 may be made of a transparent material. The second illumination light 111 reflected by the half mirror 108 is sequentially reflected by the total reflection mirrors 112 and 113, and the surface (first surface) on which the first illumination light 109 enters the sample channel 110. Is incident on a different surface (second surface). In the case of FIG. 1, the first surface and the second surface are surfaces orthogonal to each other.
試料流路110は、内部が空洞の筒状の部材である。試料(前述の流体)は、試料流路110の内部を、例えば矢印M1の方向に移動されている。図1では、試料流路110の直交する2面に対して照明光を入射しているが、試料流路110の1面にのみ照明光を入射しても良い。その場合は、前述したハーフミラー108や全反射ミラー112及び113は不要となる。
The sample channel 110 is a cylindrical member having a hollow inside. The sample (the above-described fluid) is moved in the sample channel 110 in the direction of the arrow M1, for example. In FIG. 1, the illumination light is incident on two orthogonal surfaces of the sample channel 110, but the illumination light may be incident on only one surface of the sample channel 110. In that case, the half mirror 108 and the total reflection mirrors 112 and 113 described above are unnecessary.
第1の面から入射して試料流路110を透過した第1の照明光109は、第1の投影光114として第1の検出部115に入射する。一方、第2の面から入射して試料流路110を透過した第2の照明光111は、第2の投影光116として第2の検出部117に入射する。
The first illumination light 109 incident from the first surface and transmitted through the sample channel 110 enters the first detection unit 115 as the first projection light 114. On the other hand, the second illumination light 111 incident from the second surface and transmitted through the sample channel 110 enters the second detection unit 117 as the second projection light 116.
検出部115及び117は、光量子を電気信号に変換する素子であれば良く、例えばフォトダイオードアレイ(アバランシェ・フォトダイオード・アレイを含む)その他の光電変換素子アレイを使用する。アレイは、複数個の素子を一列(一次元)に配列したものでも良いし、複数個の素子を行列(二次元)配置したものでも良い。勿論、アレイの長手方向は、細線状である透過光(投影光114及び116)の長手方向と平行である。
The detection units 115 and 117 may be elements that convert photons into electric signals. For example, a photodiode array (including an avalanche photodiode array) or other photoelectric conversion element array is used. The array may be a plurality of elements arranged in a row (one-dimensional) or a plurality of elements arranged in a matrix (two-dimensional). Of course, the longitudinal direction of the array is parallel to the longitudinal direction of the transmitted light (projection light 114 and 116) which is a thin line.
検出部115及び117の受光面は、少なくとも投影光114及び116を全て受光できる面積と形状を有する。従って、検出部115及び117の受光面の長手方向の長さは試料流路110の一辺の長さよりも長く、検出部115及び117の受光面の短辺方向の長さは投影光114及び116の線幅よりも長い。
The light receiving surfaces of the detectors 115 and 117 have an area and shape that can receive at least all the projection lights 114 and 116. Accordingly, the length of the light receiving surfaces of the detection units 115 and 117 in the longitudinal direction is longer than the length of one side of the sample channel 110, and the length of the light receiving surfaces of the detection units 115 and 117 in the short side direction is the projection light 114 and 116. Longer than the line width.
照明窓と検出窓で囲まれた領域部分(測定領域)を通過する測定対象は、基本的に影として受光面に投影される。本実施例の場合、照明光109及び111と投影光114及び116はいずれも平行光である。従って、受光面には、測定対象である物質の十寸法の影が形成される。しかも、特許文献1の装置では、集光レンズによる光の結像位置を通る測定対象だけを検出可能であるが、平行光を用いる本実施例の手法では、試料流路110の断面(測定領域)を通過する全ての測定対象を一度に測定することができる。すなわち、測定対象の見落としがない。更に、本実施例のように平行光を用いる手法では、測定対象が測定領域のどの位置を通過しても受光面に投影される寸法が変化することもない。因みに、集光レンズを用いる手法では、測定領域に相当するスポット内でも位置によって検出される測定対象の寸法が変化し、スポットの外側を移動する測定対象は検出することができない。
The measurement object that passes through the area (measurement area) surrounded by the illumination window and the detection window is basically projected onto the light receiving surface as a shadow. In the case of the present embodiment, the illumination lights 109 and 111 and the projection lights 114 and 116 are both parallel lights. Accordingly, a ten-dimensional shadow of the substance to be measured is formed on the light receiving surface. Moreover, in the apparatus of Patent Document 1, it is possible to detect only the measurement object passing through the light imaging position by the condensing lens. However, in the method of this embodiment using parallel light, the cross section of the sample channel 110 (measurement region) ) Can be measured all at once. That is, there is no oversight of the measurement object. Further, in the method using parallel light as in the present embodiment, the dimension projected on the light receiving surface does not change regardless of the position of the measurement object in the measurement region. Incidentally, in the method using the condensing lens, the size of the measurement object detected varies depending on the position even in the spot corresponding to the measurement region, and the measurement object moving outside the spot cannot be detected.
第1の検出部115及び第2の検出部117による受光タイミングも、タイミング調整部106から与えられるタイミング信号S2A及びS2Bに応じて調整される。すなわち、受光タイミングが、投影光114及び116の入射タイミングと同期するように制御される。第1の検出部115及び第2の検出部117は、個々の受光タイミングに各素子(画素)で受光した投影光114及び116の受信強度を出力信号S3A及びS3Bとして出力する。タイミング信号S2A及びS2Bは出力信号S3A及びS3Bが最大となるタイミング、つまりデジタル変換後のSN比が最大となるように調整され、それぞれアナログ-デジタル変換器118及び119に出力される。
The light reception timing by the first detection unit 115 and the second detection unit 117 is also adjusted according to the timing signals S2A and S2B given from the timing adjustment unit 106. That is, the light reception timing is controlled to be synchronized with the incident timing of the projection lights 114 and 116. The first detection unit 115 and the second detection unit 117 output the reception intensities of the projection lights 114 and 116 received by the respective elements (pixels) at the respective light reception timings as output signals S3A and S3B. The timing signals S2A and S2B are adjusted so that the output signals S3A and S3B are maximized, that is, the SN ratio after digital conversion is maximized, and output to the analog- digital converters 118 and 119, respectively.
アナログ-デジタル変換器118及び119は、アレイを構成する各素子から出力された出力信号S3A及びS3Bをそれぞれデジタル値に変換して解析部102へ出力する。アナログ-デジタル変換器118及び119におけるアナログ-デジタル変換タイミングは、前述したようにタイミング信号S2A及びS2Bによって調整される。解析部102は、いわゆるコンピュータ(RAM、ROM、CPU、ハードディスク、入出力部等)で構成される。解析部102は、例えばCPUによるプログラムの実行を通じて検出されたデータを解析処理する。解析処理の内容は適用する分析装置の用途等により異なる。なお、解析部102は、一連の処理内容がパッケージ化されたモジュールデバイスでも良い。
The analog- digital converters 118 and 119 convert the output signals S3A and S3B output from each element constituting the array into digital values and output the digital values to the analysis unit 102. The analog-digital conversion timing in the analog- digital converters 118 and 119 is adjusted by the timing signals S2A and S2B as described above. The analysis unit 102 includes a so-called computer (RAM, ROM, CPU, hard disk, input / output unit, etc.). The analysis unit 102 performs analysis processing on data detected through execution of a program by the CPU, for example. The content of the analysis process varies depending on the application of the applied analyzer. The analysis unit 102 may be a module device in which a series of processing contents is packaged.
(1-1-2)流路の構成
前述したように、図1では、試料流路110の形状として外形が直方体形状の筒状部材を使用する。直方体を用いるのは、散乱や反射といった望まない光の発生を低減するためである。また、前述したように、試料流路110のうち第1及び第2の照明光109及び111が入射する領域部分は照明光に対して実質的に透明な材料を使用するものとし、その他の領域部分は不透明(例えば黒色)であっても良い。 (1-1-2) Channel Configuration As described above, in FIG. 1, a cylindrical member having a rectangular parallelepiped shape is used as the shape of thesample channel 110. The rectangular parallelepiped is used to reduce generation of unwanted light such as scattering and reflection. Further, as described above, the region where the first and second illumination lights 109 and 111 enter the sample channel 110 uses a material that is substantially transparent to the illumination light, and other regions. The part may be opaque (for example, black).
前述したように、図1では、試料流路110の形状として外形が直方体形状の筒状部材を使用する。直方体を用いるのは、散乱や反射といった望まない光の発生を低減するためである。また、前述したように、試料流路110のうち第1及び第2の照明光109及び111が入射する領域部分は照明光に対して実質的に透明な材料を使用するものとし、その他の領域部分は不透明(例えば黒色)であっても良い。 (1-1-2) Channel Configuration As described above, in FIG. 1, a cylindrical member having a rectangular parallelepiped shape is used as the shape of the
(1-1-3)照明光
試料流路110に入射される第1及び第2の照明光109及び111はパルス光であることが望ましい。第1及び第2の照明光109及び111をパルス光とすることにより、瞬間的に高いエネルギーを供給できる一方、パルス間隔は短いため測定対象に加えられるトータルのエネルギー量を低くすることができる。第1及び第2の照明光109及び111のパルス化には様々な手法を適用することができる。例えば光源103としてパルス光源を採用する。また例えば、光源103は連続発振する光を射出するものとし、その光路上に配置した光学素子によって実質的にパルス化しても良い。この種の光学素子には、例えばシャッターを使用する。シャッターには、例えば機械式シャッター、透明強誘電体に例示される電気的なシャッターがある。 (1-1-3) Illumination Light It is desirable that the first and second illumination lights 109 and 111 incident on the sample channel 110 are pulsed light. By using the first and second illumination lights 109 and 111 as pulsed light, high energy can be instantaneously supplied. On the other hand, since the pulse interval is short, the total amount of energy applied to the measurement target can be reduced. Various methods can be applied to pulse the first and second illumination lights 109 and 111. For example, a pulse light source is employed as the light source 103. Further, for example, the light source 103 may emit continuously oscillating light, and may be substantially pulsed by an optical element disposed on the optical path. For example, a shutter is used for this type of optical element. Examples of the shutter include a mechanical shutter and an electrical shutter exemplified by a transparent ferroelectric substance.
試料流路110に入射される第1及び第2の照明光109及び111はパルス光であることが望ましい。第1及び第2の照明光109及び111をパルス光とすることにより、瞬間的に高いエネルギーを供給できる一方、パルス間隔は短いため測定対象に加えられるトータルのエネルギー量を低くすることができる。第1及び第2の照明光109及び111のパルス化には様々な手法を適用することができる。例えば光源103としてパルス光源を採用する。また例えば、光源103は連続発振する光を射出するものとし、その光路上に配置した光学素子によって実質的にパルス化しても良い。この種の光学素子には、例えばシャッターを使用する。シャッターには、例えば機械式シャッター、透明強誘電体に例示される電気的なシャッターがある。 (1-1-3) Illumination Light It is desirable that the first and
(1-1-4)アバランシェ・フォトダイオード・アレイ
ここでは、検出部115及び117に使用して好適なアバランシェ・フォトダイオード・アレイについて説明する。アバランシェ・フォトダイオード・アレイの基本単位であるアバランシェ・ホトダイオード(以下「APD」ともいう)は、ホトダイオード(以下、「PD」ともいう)の一種であり、逆電圧を印加することによって光電流が増倍される高速かつ高感度のPDである。APDは、エネルギー(例えば、光を構成するフォトンの数)を計数してエネルギー量を測定するデバイスである。 (1-1-4) Avalanche Photodiode Array Here, an avalanche photodiode array suitable for use in the detection units 115 and 117 will be described. An avalanche photodiode (hereinafter also referred to as “APD”), which is a basic unit of an avalanche photodiode array, is a type of photodiode (hereinafter also referred to as “PD”), and a photocurrent is increased by applying a reverse voltage. It is a high-speed and high-sensitivity PD that is doubled. An APD is a device that measures energy by counting energy (for example, the number of photons constituting light).
ここでは、検出部115及び117に使用して好適なアバランシェ・フォトダイオード・アレイについて説明する。アバランシェ・フォトダイオード・アレイの基本単位であるアバランシェ・ホトダイオード(以下「APD」ともいう)は、ホトダイオード(以下、「PD」ともいう)の一種であり、逆電圧を印加することによって光電流が増倍される高速かつ高感度のPDである。APDは、エネルギー(例えば、光を構成するフォトンの数)を計数してエネルギー量を測定するデバイスである。 (1-1-4) Avalanche Photodiode Array Here, an avalanche photodiode array suitable for use in the
APDの逆電圧を降伏電圧以上にすると、内部電界が上昇し増倍率が極めて高くなる(例えば105~106倍)。このように倍増率を高めた状態でAPDを動作させることをガイガーモードという。ガイガーモード時にエネルギー(例えばフォトンや荷電粒子)の入射によってPN接合に生じた電子と正孔の対は、高い電界によって加速される。このとき、エネルギーの入射によって発生した電子は、P層内で加速されることで運動エネルギーを高められた状態でN層に向かう。N層のバンドキャップエネルギーよりも十分に高い運動エネルギーを得てN層に突入した電子は、N層の電子を跳ね出し、さらにN層から跳ね出された電子が連鎖的により多くの電子を生成する。これが増倍作用の原理である。
When the reverse voltage of the APD is higher than the breakdown voltage, magnification increase the internal electric field is increased is very high (e.g., 10 5 to 10 6 times). The operation of the APD with the doubling rate increased in this way is called Geiger mode. The pair of electrons and holes generated in the PN junction by the incidence of energy (for example, photons or charged particles) in the Geiger mode is accelerated by a high electric field. At this time, electrons generated by the incidence of energy are accelerated in the P layer and travel toward the N layer with increased kinetic energy. Electrons that have entered the N layer with kinetic energy sufficiently higher than the band cap energy of the N layer bounce off the N layer, and the electrons bounced from the N layer generate more electrons in a chain. To do. This is the principle of multiplication action.
ガイガーモードのAPDに所定単位のエネルギー(例えば、1つのフォトンや荷電粒子)が入射すると、上記増倍作用によって非常に大きなパルス信号が生じるため、パルス信号でフォトンを計数することができる。光はフォトン(光子)の集まりであり、微弱な光ではフォトンは離散的になるが、APDは微弱な光であっても上記の増倍作用によって感度良く測定することができる。APDは、時間当たりに検出されたフォトンや荷電粒子の数に応じた大きさの電流を出力する。APDは、一般的なPDを適用した場合よりも微弱な光に対する感度が高い。
When a predetermined unit of energy (for example, one photon or charged particle) is incident on the Geiger mode APD, a very large pulse signal is generated by the above-described multiplication action, so that photons can be counted by the pulse signal. Light is a collection of photons (photons), and photons become discrete with weak light, but APD can be measured with high sensitivity by the above-described multiplication action even with weak light. The APD outputs a current having a magnitude corresponding to the number of photons and charged particles detected per time. APD has higher sensitivity to weak light than when general PD is applied.
APDアレイは、シリコンフォトマルチプライヤ(Silicon Photomultiplier:Si-PM)と呼ばれるデバイスの一種であり、個別に動作するガイガーモードのAPDの集合体である。APDアレイの画素を構成する個々のAPDは、上記のようにエネルギーを検出するとパルス信号を出力する。APDアレイの出力は全画素の総和であっても良いし、画素単位の出力でも良い。APDアレイの出力は、出力ラインから出力される。このようなAPDアレイを用いれば、より微弱なエネルギー(例えば、光や電子)であっても感度良く検出することができる。
The APD array is a kind of device called a silicon photomultiplier (Si-PM), and is an aggregate of Geiger mode APDs that operate individually. The individual APDs constituting the pixels of the APD array output pulse signals when energy is detected as described above. The output of the APD array may be the sum of all pixels, or may be output in units of pixels. The output of the APD array is output from the output line. By using such an APD array, even weaker energy (for example, light or electrons) can be detected with high sensitivity.
(1-2)分析動作及び効果
本実施例に係る分析装置100の使用態様は、測定対象や使用目的により様々である。例えば検査の度に装置内の試料流路110に試料(気体又は液体)としての流体が供給される使用態様もあれば、試料が常に流れている試料流路110に装置が設置される使用態様もある。いずれの場合も、分析装置100は、線状かつパルス状の平行光に変換された照明光109及び111を、試料が移動している試料流路110の第1の面及び第2の面に照射させる。第1の面及び第2の面に対して反対側の面からは、試料流路110内を移動する試料を透過した線状かつパルス状の平行光(すなわち、投影光114及び116)が射出され、検出部115及び117に入射される。検出部115及び117から出力された電気信号は、解析部102においてデータ解析される。 (1-2) Analysis Operation and Effect The usage mode of theanalysis apparatus 100 according to the present embodiment varies depending on the measurement object and usage purpose. For example, there is a usage mode in which a fluid as a sample (gas or liquid) is supplied to the sample flow path 110 in the apparatus at every inspection, and there is a usage mode in which the apparatus is installed in the sample flow path 110 in which the sample always flows. There is also. In any case, the analyzer 100 applies the illumination light 109 and 111 converted into linear and pulsed parallel light to the first surface and the second surface of the sample channel 110 where the sample is moving. Irradiate. From the surface opposite to the first surface and the second surface, linear and pulsed parallel light (that is, projection light 114 and 116) transmitted through the sample moving in the sample channel 110 is emitted. And is incident on the detection units 115 and 117. The electrical signals output from the detection units 115 and 117 are subjected to data analysis in the analysis unit 102.
本実施例に係る分析装置100の使用態様は、測定対象や使用目的により様々である。例えば検査の度に装置内の試料流路110に試料(気体又は液体)としての流体が供給される使用態様もあれば、試料が常に流れている試料流路110に装置が設置される使用態様もある。いずれの場合も、分析装置100は、線状かつパルス状の平行光に変換された照明光109及び111を、試料が移動している試料流路110の第1の面及び第2の面に照射させる。第1の面及び第2の面に対して反対側の面からは、試料流路110内を移動する試料を透過した線状かつパルス状の平行光(すなわち、投影光114及び116)が射出され、検出部115及び117に入射される。検出部115及び117から出力された電気信号は、解析部102においてデータ解析される。 (1-2) Analysis Operation and Effect The usage mode of the
このように分析装置100は、平行光を試料流路110に照射するため、試料流路110内を移動する測定物の影を実寸法で一度に取得することができる。また、平行光を用いているので、測定領域の広視野化を容易に実現できる。また、平行光を用いているので、測定対象が試料流路110の断面内のいずれの位置を通過しても実寸法の影が受光面に生成される。すなわち、焦点深度を無限大にできる。この機能を用いれば、測定対象(例えばミクロンオーダーの塵や細胞)の数や寸法を正確に測定することができる。
As described above, the analysis apparatus 100 irradiates the sample channel 110 with the parallel light, so that the shadow of the measurement object moving in the sample channel 110 can be obtained at a real size at a time. Moreover, since parallel light is used, a wide field of view of the measurement region can be easily realized. In addition, since parallel light is used, even if the measurement object passes through any position in the cross section of the sample channel 110, a shadow having an actual size is generated on the light receiving surface. That is, the depth of focus can be made infinite. By using this function, it is possible to accurately measure the number and dimensions of measurement objects (for example, micron-order dust and cells).
また、図2に示すように、本実施例の場合、試料流路110内の同一領域(測定領域)を2方向から検出する。このため、複数の測定対象201が一方の検出方向については重なって見える場合でも(検出部115の受光面状では2つの測定対象が1つの影を構成する場合でも)、検出部115及び117の出力を比較することにより、測定対象201が複数であること確実に分別することができる。
Further, as shown in FIG. 2, in the case of the present embodiment, the same region (measurement region) in the sample channel 110 is detected from two directions. For this reason, even when a plurality of measurement objects 201 appear to overlap in one detection direction (even when two measurement objects form one shadow in the shape of the light receiving surface of the detection unit 115), the detection units 115 and 117 By comparing the outputs, it is possible to reliably distinguish that there are a plurality of measurement objects 201.
ここで、解析部102は、検出部115及び117の出力データ(アレイを構成する個々の光電変換素子に対応する)の各信号強度が閾値より低いとき、当該出力データが測定対象201の影202V及び202Hを表していると判定する。解析部102は、一塊の影を1個と計数することにより、測定領域を通過した測定対象201の数を計数する。また、検出部115及び117の出力データを解析することにより、個々の測定対象201の通過位置、形状、サイズ(面積や体積)も正確に特定することができる。また、測定された個数に基づいて密度を計算し、当該密度から試料の重量を解析することもできる。
Here, when each signal intensity of the output data (corresponding to individual photoelectric conversion elements constituting the array) of the detection units 115 and 117 is lower than the threshold value, the analysis unit 102 outputs the shadow 202V of the measurement target 201 when the output data is lower than the threshold value. And 202H. The analysis unit 102 counts the number of measurement objects 201 that have passed through the measurement region by counting a single shadow as one. Further, by analyzing the output data of the detection units 115 and 117, the passing position, shape, and size (area and volume) of each measurement target 201 can be accurately specified. Further, the density can be calculated based on the measured number, and the weight of the sample can be analyzed from the density.
一般に測定対象201の検出を高速化するには、SN比を高めるために強い光を当てる必要がある。しかし、強度の高い光を用いると、測定対象がダメージを受ける心配がある。そこで、本実施例ではパルス状の照明光109及び111を試料流路110に照射することにより照明エネルギーを最小化し、測定対象へのダメージを低減させることができる。
Generally, in order to speed up the detection of the measurement target 201, it is necessary to shine strong light to increase the S / N ratio. However, when high intensity light is used, there is a concern that the measurement target is damaged. Therefore, in this embodiment, the illumination energy can be minimized by irradiating the sample flow path 110 with pulsed illumination light 109 and 111, and damage to the measurement object can be reduced.
なお、パルス状の照明光109及び111を用いる場合には、検出部115及び117を、検出感度の高いアバランシェ・フォトダイオード・アレイで構成することが好ましい。このパルス状の照明光109及び111の使用は、エネルギー照射による状態変化の回避が必要である試料(例えば細胞や感光性レジスト材料)の測定に効果的であり、同一の試料を繰り返し測定に用いることができる。従って、分析装置100は、同一の試料の経時変化の測定にも使用できる。また、照明光109及び111の照射による形質変化のおそれが無いか最小化できるため、試料の一部を抽出して行うサンプル検査ではなく、全数検査が可能となる。また、感光性レジスト材料などの反応する波長が既知の資料を測定対象とする場合には、反応する波長を含まない照明光109及び111を選択的に照射することで形質変化を回避することができる。
In addition, when using the pulsed illumination lights 109 and 111, it is preferable that the detection units 115 and 117 are formed of an avalanche photodiode array with high detection sensitivity. The use of the pulsed illumination lights 109 and 111 is effective for measuring a sample (for example, a cell or a photosensitive resist material) that needs to avoid a state change caused by energy irradiation, and the same sample is repeatedly used for the measurement. be able to. Therefore, the analyzer 100 can also be used for measuring changes over time of the same sample. Further, since it is possible to minimize the possibility of a change in character due to irradiation of the illumination lights 109 and 111, it is possible to perform 100% inspection instead of sample inspection performed by extracting a part of the sample. In addition, in the case where a material with a known reacting wavelength, such as a photosensitive resist material, is used as a measurement target, it is possible to avoid morphological changes by selectively irradiating illumination lights 109 and 111 that do not include the reacting wavelength. it can.
また、解析部102において、透過光(すなわち投影光114及び116)を波長分解し、その分布と各波長の検出強度の変化を解析すれば、複数材料を混合した場合の均一性や成分変化を分析又は評価できる。また、試料流路110を移動する流体の密度変化は、流体の屈折率の変化として現れる。この屈折率の変化は、透過光(すなわち投影光114及び116)の照度分布の変化として出現する。そこで、解析部102において、測定された照度分布とテンプレートデータとを比較すれば、流体の密度変化を検出することができる。なお、照度分布は、撮像視野内で傾斜分布を持つ。
Further, in the analysis unit 102, if the transmitted light (that is, the projection light 114 and 116) is wavelength-resolved and the distribution and the change in the detection intensity of each wavelength are analyzed, the uniformity and the component change when a plurality of materials are mixed are obtained. Can be analyzed or evaluated. Further, the density change of the fluid moving through the sample channel 110 appears as a change in the refractive index of the fluid. This change in the refractive index appears as a change in the illuminance distribution of the transmitted light (that is, the projection lights 114 and 116). Therefore, if the analysis unit 102 compares the measured illuminance distribution with the template data, a change in the density of the fluid can be detected. The illuminance distribution has an inclination distribution within the imaging field.
また、試料流路110を透過した透過光(すなわち投影光114及び116)は、測定対象201との光干渉によりスペクトル(色)が変化し、輝度も低下することがある。例えば測定対象201が透明な細胞であっても、透過光(すなわち投影光114及び116)には、スペクトル(色)の変化や輝度低下が現れる。そこで、解析部102は、このスペクトルの変化や輝度の低下に基づいて、測定対象201の計数処理や物質の同定処理を実行しても良い。また、影202V及び202Hはそれぞれ実寸法を表しているので、これらの寸法情報から測定対象201の実体積を計算することができる。ここでの測定対象201には、細胞以外の透明体(例えば薄膜状の透明体)がある。
In addition, the transmitted light (that is, the projection light 114 and 116) transmitted through the sample channel 110 may change in spectrum (color) due to optical interference with the measurement target 201, and may decrease in luminance. For example, even if the measurement object 201 is a transparent cell, a change in spectrum (color) or a decrease in luminance appears in the transmitted light (that is, the projection lights 114 and 116). Therefore, the analysis unit 102 may execute the counting process of the measurement target 201 and the substance identification process based on the change in the spectrum and the decrease in luminance. In addition, since the shadows 202V and 202H represent actual dimensions, the actual volume of the measurement object 201 can be calculated from these dimension information. The measurement object 201 here includes a transparent body other than cells (for example, a thin transparent body).
また、平行光を扱う本実施例の装置構成は、検出光学系の構成がシンプルとなり、装置の製造コストを低下できる。また、構成がシンプルであるため、組み立てや調整が容易になり、検出光学系も安定する。さらに、本実施例の分析装置100は、集光レンズを用いないため、検出系に関するレイアウト上の制約が無く、装置の小型化も実現できる。
Further, the apparatus configuration of this embodiment that handles parallel light simplifies the configuration of the detection optical system and can reduce the manufacturing cost of the apparatus. Further, since the configuration is simple, assembly and adjustment are easy, and the detection optical system is stable. Furthermore, since the analyzing apparatus 100 of the present embodiment does not use a condensing lens, there is no layout restriction regarding the detection system, and the apparatus can be downsized.
(2)実施例2
図3に、分析装置100の照明系及び検出系の他の構成例を示す。図3は、図1に示す分析装置100の照明系及び検出系の具体例の一つである。図3の照明系は、照度調節部301、波長帯域選択部302、偏光切換部303で構成される。照度調節部301は、入射された照明光109及び111の照度を調整して出力する。波長帯域選択部302は、試料の照射に適した波長成分を選択的に抽出する。偏光切換部303は、照明光に含まれる特定の偏光成分を透過する。なお、照度調節部301、波長帯域選択部302、偏光切換部303は全てを設ける必要は無く、必要に応じて、これらのうちの1つ又は複数を組み合わせて用いれば良い。 (2) Example 2
FIG. 3 shows another configuration example of the illumination system and the detection system of theanalyzer 100. FIG. 3 is one example of an illumination system and a detection system of the analyzer 100 shown in FIG. The illumination system in FIG. 3 includes an illuminance adjustment unit 301, a wavelength band selection unit 302, and a polarization switching unit 303. The illuminance adjusting unit 301 adjusts and outputs the illuminance of the incident illumination light 109 and 111. The wavelength band selector 302 selectively extracts a wavelength component suitable for sample irradiation. The polarization switching unit 303 transmits a specific polarization component included in the illumination light. The illuminance adjusting unit 301, the wavelength band selecting unit 302, and the polarization switching unit 303 are not necessarily provided, and one or more of them may be used in combination as necessary.
図3に、分析装置100の照明系及び検出系の他の構成例を示す。図3は、図1に示す分析装置100の照明系及び検出系の具体例の一つである。図3の照明系は、照度調節部301、波長帯域選択部302、偏光切換部303で構成される。照度調節部301は、入射された照明光109及び111の照度を調整して出力する。波長帯域選択部302は、試料の照射に適した波長成分を選択的に抽出する。偏光切換部303は、照明光に含まれる特定の偏光成分を透過する。なお、照度調節部301、波長帯域選択部302、偏光切換部303は全てを設ける必要は無く、必要に応じて、これらのうちの1つ又は複数を組み合わせて用いれば良い。 (2) Example 2
FIG. 3 shows another configuration example of the illumination system and the detection system of the
図3の検出系は、拡大光学系304、検光子305で構成される。拡大光学系304は、要求される光学上の分解能に応じて挿入される。検光子305は、特定の偏光成分を選択的に透過する。拡大光学系304と検光子305についても、必ずしも全てを設ける必要は無く、必要に応じて、いずれか一方又は両方を組み合わせて用いれば良い。なお、図中のL1~L3は、いずれも任意距離の選択が可能である。
3 includes a magnifying optical system 304 and an analyzer 305. The magnifying optical system 304 is inserted according to the required optical resolution. The analyzer 305 selectively transmits a specific polarization component. It is not always necessary to provide all of the magnifying optical system 304 and the analyzer 305. Any one or a combination of both may be used as necessary. Note that any distance can be selected for L1 to L3 in the figure.
(3)実施例3
図4に、分析装置100の検出系の他の構成例を示す。図4に示す検出系の構成は、透過光(投影光114及び116)を通じて、透過率、透過波長、薄膜干渉などの現象を色情報として検出する際に用いて好適である。透過率を計算する場合、解析部102は、タイミング調整部106から与えられた照明光109及び111の照度情報を使用する。照明光109及び111の照度情報は、フォトダイオード105の出力信号S1を入力するタイミング調整部106において計算される。なお、図4に示す検出系は、測定対象が透明体(例えば細胞)である場合に特に効果的である。 (3) Example 3
FIG. 4 shows another configuration example of the detection system of theanalyzer 100. The configuration of the detection system shown in FIG. 4 is suitable for use in detecting phenomena such as transmittance, transmission wavelength, and thin film interference as color information through transmitted light (projection lights 114 and 116). When calculating the transmittance, the analysis unit 102 uses the illuminance information of the illumination lights 109 and 111 given from the timing adjustment unit 106. Illuminance information of the illumination lights 109 and 111 is calculated in the timing adjustment unit 106 that receives the output signal S1 of the photodiode 105. Note that the detection system shown in FIG. 4 is particularly effective when the measurement target is a transparent body (for example, a cell).
図4に、分析装置100の検出系の他の構成例を示す。図4に示す検出系の構成は、透過光(投影光114及び116)を通じて、透過率、透過波長、薄膜干渉などの現象を色情報として検出する際に用いて好適である。透過率を計算する場合、解析部102は、タイミング調整部106から与えられた照明光109及び111の照度情報を使用する。照明光109及び111の照度情報は、フォトダイオード105の出力信号S1を入力するタイミング調整部106において計算される。なお、図4に示す検出系は、測定対象が透明体(例えば細胞)である場合に特に効果的である。 (3) Example 3
FIG. 4 shows another configuration example of the detection system of the
色分離ユニット401及び402には、例えば波長分離プリズムが用いられる。色分離ユニット401は、透過光(投影光114及び116)のうち青色成分を透過し、その他の色成分を色分離ユニット402の方向に反射する。色分離ユニット402は、入射光を更に赤色成分と緑色成分に分離して出力する。図4に示す構成の場合、分離された赤緑青(RGB)成分に応じて3つの検出部115R、115G、115B(117R、117G、117B)を配置する。各検出部115R、115G、115B(117R、117G、117B)は、対応する色成分の強度信号を出力する。
For the color separation units 401 and 402, for example, wavelength separation prisms are used. The color separation unit 401 transmits the blue component of the transmitted light (projection light 114 and 116) and reflects the other color components in the direction of the color separation unit 402. The color separation unit 402 further separates the incident light into a red component and a green component and outputs them. In the case of the configuration shown in FIG. 4, three detectors 115R, 115G, and 115B (117R, 117G, and 117B) are arranged according to the separated red, green, and blue (RGB) components. Each of the detection units 115R, 115G, and 115B (117R, 117G, and 117B) outputs a corresponding color component intensity signal.
このように、透過光(投影光114及び116)の光路上に検出部115R、115G、115B(117R、117G、117B)を配置することにより、測定対象が透明体の場合でも、解析部102は、透過率、透過波長、薄膜干渉などの現象を色成分の変化として検出することができる。また、当該検出結果を用いることにより、解析部102は、測定対象の形状判断や分類を実行することができる。
As described above, by arranging the detection units 115R, 115G, and 115B (117R, 117G, and 117B) on the optical path of the transmitted light (projection lights 114 and 116), the analysis unit 102 can be used even when the measurement target is a transparent body. Phenomena such as transmittance, transmission wavelength, and thin film interference can be detected as changes in color components. Further, by using the detection result, the analysis unit 102 can execute shape determination and classification of the measurement target.
(4)実施例4
図5に、分析装置100の照明系と検出系の他の構成例を示す。本実施例は、試料流路110の断面が4角形以上の多角形である場合(図5は、試料流路110の断面が正六角形である場合)について表している。断面形状が正六角形の場合、入射面と透過面をそれぞれ3つずつ確保できる。もっとも、断面形状が正多角形である必要はない。このように試料流路110の断面形状をn角形(nは5以上)として検出方向を増やすことにより、測定対象に関する検出情報を増やし、その検出精度を高めることができる。 (4) Example 4
FIG. 5 shows another configuration example of the illumination system and the detection system of theanalyzer 100. In the present embodiment, the case where the cross section of the sample flow path 110 is a quadrilateral or more polygonal (FIG. 5 shows a case where the cross section of the sample flow path 110 is a regular hexagon). When the cross-sectional shape is a regular hexagon, three entrance surfaces and three transmission surfaces can be secured. However, the cross-sectional shape does not have to be a regular polygon. Thus, by increasing the detection direction by setting the cross-sectional shape of the sample channel 110 to an n-gon (n is 5 or more), it is possible to increase detection information regarding the measurement target and increase the detection accuracy.
図5に、分析装置100の照明系と検出系の他の構成例を示す。本実施例は、試料流路110の断面が4角形以上の多角形である場合(図5は、試料流路110の断面が正六角形である場合)について表している。断面形状が正六角形の場合、入射面と透過面をそれぞれ3つずつ確保できる。もっとも、断面形状が正多角形である必要はない。このように試料流路110の断面形状をn角形(nは5以上)として検出方向を増やすことにより、測定対象に関する検出情報を増やし、その検出精度を高めることができる。 (4) Example 4
FIG. 5 shows another configuration example of the illumination system and the detection system of the
(5)実施例5
図6に、測定精度を向上させるための他の測定動作例を示す。前述の実施例では、基本的に、個々の測定対象は測定領域内で1回だけ測定されるが、本実施例では、投影光114及び116の検出タイミングを調整することにより、同じ測定対象を測定領域内で複数回測定する。 (5) Example 5
FIG. 6 shows another measurement operation example for improving the measurement accuracy. In the above-described embodiment, each measurement object is basically measured only once in the measurement region. However, in this embodiment, the same measurement object is obtained by adjusting the detection timing of the projection lights 114 and 116. Measure multiple times within the measurement area.
図6に、測定精度を向上させるための他の測定動作例を示す。前述の実施例では、基本的に、個々の測定対象は測定領域内で1回だけ測定されるが、本実施例では、投影光114及び116の検出タイミングを調整することにより、同じ測定対象を測定領域内で複数回測定する。 (5) Example 5
FIG. 6 shows another measurement operation example for improving the measurement accuracy. In the above-described embodiment, each measurement object is basically measured only once in the measurement region. However, in this embodiment, the same measurement object is obtained by adjusting the detection timing of the projection lights 114 and 116. Measure multiple times within the measurement area.
例えば検出幅をWとし、流速をFVとすると、試料(測定対象)が測定領域を通過するのに要する時間(通過時間)Tは、次式で与えられる。
T=W/FV For example, when the detection width is W and the flow velocity is FV, the time (passing time) T required for the sample (measurement target) to pass through the measurement region is given by the following equation.
T = W / FV
T=W/FV For example, when the detection width is W and the flow velocity is FV, the time (passing time) T required for the sample (measurement target) to pass through the measurement region is given by the following equation.
T = W / FV
この場合、タイミング調整部106は、検出部115及び117とアナログ-デジタル変換器118及び119のサンプリング間隔STをT/2未満に設定する。このことは、同一の測定対象を2回以上検出できることを意味する。勿論、サンプリングタイミングには、投影光114及び116が検出部115及び117の受光面に入射する必要があるので、サンプリングタイミングは、タイミング調整部106により、照明光109及び111の発光タイミングとの間で同期制御される。
In this case, the timing adjustment unit 106 sets the sampling interval ST between the detection units 115 and 117 and the analog- digital converters 118 and 119 to less than T / 2. This means that the same measurement object can be detected twice or more. Of course, since the projection lights 114 and 116 need to be incident on the light receiving surfaces of the detection units 115 and 117 at the sampling timing, the timing adjustment unit 106 sets the sampling timing between the emission timings of the illumination lights 109 and 111. Are controlled synchronously.
本実施例のように、測定領域(照明光が透過する空間領域であり、試料が流れる方向の幅)を試料が通過する時間(すなわち流速)に応じて複数回検出することにより、1回の測定では分別できない位置にある複数個の測定対象を分別できる可能性を高めることができる。例えばあるサンプリングタイミングでは、複数個の測定対象が偶然近接しているために1個に見える場合でも、別のサンプリングタイミングでは分離している見える可能性が高まる。このため、本実施例の検出方法の採用により、測定精度を向上させることができる。
As in this embodiment, a measurement region (a space region through which illumination light is transmitted, the width in the direction in which the sample flows) is detected a plurality of times according to the time (that is, the flow velocity) through which the sample passes. The possibility that a plurality of measurement objects at positions that cannot be separated by measurement can be separated can be increased. For example, at a certain sampling timing, there is a higher possibility that a plurality of measurement objects may appear to be separated at another sampling timing even if they appear to be one because they are close by chance. For this reason, the measurement accuracy can be improved by employing the detection method of this embodiment.
(6)実施例6
図7に、リアルタイム検査(例えば異物検査、均一性検査、反応試薬の混合による成分検査)に適した使用例を示す。この使用例の場合、一般的には、分析装置100を含む検査ユニット701を本流路702から分岐した支流路703に取り付けて使用する。支流路703の上流側に設けられる流量制御バルブ711は、下流側に位置する混合部712の一方の入力口に流入させる試料の流量を調整する。混合部712の他方の入力口には、流量制御バルブ713を介して反応試薬タンク714が接続されている。流量制御バルブ713は試薬の供給量を調整する。反応試薬タンク714には、検査目的(検査項目)に応じた試薬が格納される。 (6) Example 6
FIG. 7 shows a usage example suitable for real-time inspection (for example, foreign substance inspection, uniformity inspection, component inspection by mixing reaction reagents). In the case of this usage example, in general, aninspection unit 701 including the analyzer 100 is attached to a branch channel 703 branched from the main channel 702 for use. A flow rate control valve 711 provided on the upstream side of the branch channel 703 adjusts the flow rate of the sample flowing into one input port of the mixing unit 712 located on the downstream side. A reaction reagent tank 714 is connected to the other input port of the mixing unit 712 via a flow rate control valve 713. The flow control valve 713 adjusts the supply amount of the reagent. In the reagent reagent tank 714, a reagent corresponding to the inspection purpose (inspection item) is stored.
図7に、リアルタイム検査(例えば異物検査、均一性検査、反応試薬の混合による成分検査)に適した使用例を示す。この使用例の場合、一般的には、分析装置100を含む検査ユニット701を本流路702から分岐した支流路703に取り付けて使用する。支流路703の上流側に設けられる流量制御バルブ711は、下流側に位置する混合部712の一方の入力口に流入させる試料の流量を調整する。混合部712の他方の入力口には、流量制御バルブ713を介して反応試薬タンク714が接続されている。流量制御バルブ713は試薬の供給量を調整する。反応試薬タンク714には、検査目的(検査項目)に応じた試薬が格納される。 (6) Example 6
FIG. 7 shows a usage example suitable for real-time inspection (for example, foreign substance inspection, uniformity inspection, component inspection by mixing reaction reagents). In the case of this usage example, in general, an
混合部712の出力口には反応流路長切換部715が接続される。反応流路長切換部715は、混合部712から分析装置100までの経路長を、試料と試薬の反応に適した経路長に調整できるように設けられている。反応流路長切換部715の内部には長さの異なる複数の流路が用意されている。使用の際、例えば設置者が試料と試薬の組合せに応じた長さの流路を選択する。分析装置100の解析部102では、検査目的(検査項目)に応じたデータ処理が実行される。例えば検出されたデータと予め登録されているテンプレートデータとを比較し、試料に含まれる物質の特定と濃度判定を実行する。
The reaction channel length switching unit 715 is connected to the output port of the mixing unit 712. The reaction channel length switching unit 715 is provided so that the path length from the mixing unit 712 to the analyzer 100 can be adjusted to a path length suitable for the reaction between the sample and the reagent. A plurality of channels having different lengths are prepared inside the reaction channel length switching unit 715. In use, for example, the installer selects a flow path having a length corresponding to the combination of the sample and the reagent. In the analysis unit 102 of the analysis apparatus 100, data processing corresponding to the inspection purpose (inspection item) is executed. For example, the detected data and template data registered in advance are compared, and the substance contained in the sample is specified and the concentration is determined.
なお、本流路702に設ける支流路703の数は1つに限らない。また、複数の支流路703のそれぞれに対して検査ユニット701を接続しても良い。この場合、複数の検査ユニット701のそれぞれにおいて同じ検査を実行しても良いし、異なる種類の検査を実行しても良い。また、1つの支流路703を更に分岐し、分岐後の複数の支流路703に検査ユニット701を接続しても良い。例えば図8に示すように、本流路702から分岐した支流路703を更に分岐した子支流路704A、704Bに、検査ユニット701を接続しても良い。このように複数の検査ユニット701を接続すれば、同時に複数の検査を実行することができる。
Note that the number of branch channels 703 provided in the main channel 702 is not limited to one. In addition, the inspection unit 701 may be connected to each of the plurality of branch channels 703. In this case, the same inspection may be performed in each of the plurality of inspection units 701, or different types of inspections may be performed. Further, one branch channel 703 may be further branched, and the inspection unit 701 may be connected to a plurality of branch channels 703 after branching. For example, as shown in FIG. 8, an inspection unit 701 may be connected to the sub-branch channels 704A and 704B further branched from the branch channel 703 branched from the main channel 702. If a plurality of inspection units 701 are connected in this way, a plurality of inspections can be executed simultaneously.
図7では、検査ユニット701に分析装置100を取り付けた構成を示しているが、分析装置100から解析部102を除いた構成部分(すなわち、検出ユニット101)を検査ユニット701に取り付けても良い。この場合、検出ユニット101の出力(すなわち、アナログ-デジタル変換器118及び119の出力)は、ネットワークその他の通信経路を通じて接続された解析部102に通知される。ネットワークは、無線ネットワークでも良いし、有線ネットワークでも良い。
7 shows a configuration in which the analysis apparatus 100 is attached to the inspection unit 701, but a configuration part (that is, the detection unit 101) excluding the analysis unit 102 from the analysis apparatus 100 may be attached to the inspection unit 701. In this case, the output of the detection unit 101 (that is, the output of the analog-digital converters 118 and 119) is notified to the analysis unit 102 connected through a network or other communication path. The network may be a wireless network or a wired network.
(7)実施例7
図9に、カートリッジ型の反応セル901を試料流路110に装着する実施例を示す。反応セル901は、試料流路110のうち測定領域内に装着される。反応セル901は、照明光109及び111を透過する材質の容器と、その内部に充填された試薬又は試薬を含有する部材(例えば薄膜シート)で構成される。容器の側面には、矢印M1の方向に移動する試料を内部に取りこむための開口が設けられている。試薬は、内部に取りこまれた試料の特定の成分と反応することで発色し、又は、蛍光を発し、又は濃度が変化する。解析部102は、想定される変化とテンプレートデータとを比較し、試料に含まれる物質の特定と濃度判定を実行する。反応セル901は容器に対して着脱自在でも良いし、固定されていても良い。 (7) Example 7
FIG. 9 shows an embodiment in which a cartridge-type reaction cell 901 is attached to the sample channel 110. The reaction cell 901 is mounted in the measurement region of the sample channel 110. The reaction cell 901 includes a container made of a material that transmits the illumination lights 109 and 111 and a reagent or a member containing the reagent (for example, a thin film sheet) filled therein. On the side surface of the container, an opening for taking in the sample moving in the direction of the arrow M1 is provided. The reagent develops color by reacting with a specific component of the sample incorporated therein, emits fluorescence, or changes in concentration. The analysis unit 102 compares the assumed change with the template data, and performs identification and concentration determination of the substance contained in the sample. The reaction cell 901 may be detachable from the container, or may be fixed.
図9に、カートリッジ型の反応セル901を試料流路110に装着する実施例を示す。反応セル901は、試料流路110のうち測定領域内に装着される。反応セル901は、照明光109及び111を透過する材質の容器と、その内部に充填された試薬又は試薬を含有する部材(例えば薄膜シート)で構成される。容器の側面には、矢印M1の方向に移動する試料を内部に取りこむための開口が設けられている。試薬は、内部に取りこまれた試料の特定の成分と反応することで発色し、又は、蛍光を発し、又は濃度が変化する。解析部102は、想定される変化とテンプレートデータとを比較し、試料に含まれる物質の特定と濃度判定を実行する。反応セル901は容器に対して着脱自在でも良いし、固定されていても良い。 (7) Example 7
FIG. 9 shows an embodiment in which a cartridge-
反応セル901を用いることにより、照明光109及び111の照射だけによっては検出が難しい試料(測定対象)の場合でも、充填する試薬の種類を変えることで様々な測定を実現することができる。例えば水質検査であれば、検出したい特定の物質(塩素、重金属等)に反応する試薬を充填する。充填されている試薬が異なる反応セル901を複数用意すれば、検査目的に応じて反応セル901又は反応セル901を取り付けた試料流路110を交換するだけで様々な検査を実行することができる。
By using the reaction cell 901, various measurements can be realized by changing the type of reagent to be filled even in the case of a sample (measurement target) that is difficult to detect only by irradiation with the illumination light 109 and 111. For example, in the case of water quality inspection, a reagent that reacts with a specific substance (chlorine, heavy metal, etc.) to be detected is filled. If a plurality of reaction cells 901 with different reagents are prepared, various tests can be performed by simply replacing the reaction cell 901 or the sample channel 110 to which the reaction cell 901 is attached according to the purpose of the test.
(8)他の実施例
本発明は、上述した実施例に限定されるものでなく、様々な変形例を含んでいる。例えば、上述した実施例は、本発明を分かりやすく説明するために詳細に説明したものであり、必ずしも説明した全ての構成を備える必要はない。また、ある実施例の一部を他の実施例の構成に置換ることができる。また、ある実施例の構成に他の実施例の構成を加えることもできる。また、各実施例の構成の一部について、他の実施例の構成の一部を追加、削除又は置換ることもできる。 (8) Other Embodiments The present invention is not limited to the above-described embodiments, and includes various modifications. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and it is not necessary to provide all the configurations described. In addition, a part of one embodiment can be replaced with the configuration of another embodiment. Moreover, the structure of another Example can also be added to the structure of a certain Example. Further, with respect to a part of the configuration of each embodiment, a part of the configuration of another embodiment can be added, deleted, or replaced.
本発明は、上述した実施例に限定されるものでなく、様々な変形例を含んでいる。例えば、上述した実施例は、本発明を分かりやすく説明するために詳細に説明したものであり、必ずしも説明した全ての構成を備える必要はない。また、ある実施例の一部を他の実施例の構成に置換ることができる。また、ある実施例の構成に他の実施例の構成を加えることもできる。また、各実施例の構成の一部について、他の実施例の構成の一部を追加、削除又は置換ることもできる。 (8) Other Embodiments The present invention is not limited to the above-described embodiments, and includes various modifications. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and it is not necessary to provide all the configurations described. In addition, a part of one embodiment can be replaced with the configuration of another embodiment. Moreover, the structure of another Example can also be added to the structure of a certain Example. Further, with respect to a part of the configuration of each embodiment, a part of the configuration of another embodiment can be added, deleted, or replaced.
100…分析装置
101…検出ユニット
102…解析部
103…光源
104…光路分岐素子
105…フォトダイオード
106…タイミング調整部
107…コリメータ
108…ハーフミラー
109、111、111A…照明光
110…試料流路
112、113…全反射ミラー
114、116…投影光
115、117、117A…検出部
118、119…アナログ-デジタル変換器
201…測定対象
202H、202V…影
301…照度調節部
302…波長帯域選択部
303…偏光切換部
304…拡大光学系
305…検光子
401、402…色分離ユニット
701…検査ユニット
702…本流路
703…支流路
704A、704B…子支流路
711、713…流量制御バルブ
712…混合部
714…反応試薬タンク
715…反応流路長切換部
901…反応セル DESCRIPTION OFSYMBOLS 100 ... Analyzing apparatus 101 ... Detection unit 102 ... Analysis part 103 ... Light source 104 ... Optical path branching element 105 ... Photodiode 106 ... Timing adjustment part 107 ... Collimator 108 ... Half mirror 109, 111, 111A ... Illumination light 110 ... Sample flow path 112 , 113 ... Total reflection mirrors 114, 116 ... Projection light 115, 117, 117A ... Detection unit 118, 119 ... Analog-to-digital converter 201 ... Measurement object 202H, 202V ... Shadow 301 ... Illuminance adjustment unit 302 ... Wavelength band selection unit 303 DESCRIPTION OF SYMBOLS ... Polarization switching part 304 ... Magnification optical system 305 ... Analyzer 401, 402 ... Color separation unit 701 ... Inspection unit 702 ... Main flow path 703 ... Branch flow path 704A, 704B ... Child branch flow path 711, 713 ... Flow control valve 712 ... Mixing section 714 ... Reaction reagent tank 715 ... Anti Responding channel length switching unit 901 ... reaction cell
101…検出ユニット
102…解析部
103…光源
104…光路分岐素子
105…フォトダイオード
106…タイミング調整部
107…コリメータ
108…ハーフミラー
109、111、111A…照明光
110…試料流路
112、113…全反射ミラー
114、116…投影光
115、117、117A…検出部
118、119…アナログ-デジタル変換器
201…測定対象
202H、202V…影
301…照度調節部
302…波長帯域選択部
303…偏光切換部
304…拡大光学系
305…検光子
401、402…色分離ユニット
701…検査ユニット
702…本流路
703…支流路
704A、704B…子支流路
711、713…流量制御バルブ
712…混合部
714…反応試薬タンク
715…反応流路長切換部
901…反応セル DESCRIPTION OF
Claims (16)
- 試料の流路と、
前記流路の第1の面にコリメートされた第1の照明光を供給し、前記流路に線状の第1の照明領域を形成する照明光学系と、
前記第1の照明光の供給により前記流路から発生する第1の透過光を検出する第1の検出部と
を有する分析装置。 A sample flow path;
An illumination optical system that supplies collimated first illumination light to the first surface of the flow path and forms a linear first illumination area in the flow path;
And a first detector that detects first transmitted light generated from the flow path by the supply of the first illumination light. - 請求項1に記載の分析装置において、
前記第1の照明光は、パルス光であり、
前記第1の検出部は、ガイガーモードで動作する第1のアバランシェ・フォトダイオード・アレイである
分析装置。 The analyzer according to claim 1,
The first illumination light is pulsed light,
The first detection unit is a first avalanche photodiode array that operates in a Geiger mode. - 請求項2に記載の分析装置において、
前記第1の面と交差する第2の面にコリメートされたパルス状の第2の照明光を供給し、前記流路に線状の第2の照明領域を形成する第2の照明光学系と、
前記第2の照明光により発生した第2の透過光を検出する第2の検出部と、を更に有し、
前記第2の検出部は、ガイガーモードで動作する第2のアバランシェ・フォトダイオード・アレイである
分析装置。 The analyzer according to claim 2,
A second illumination optical system that supplies pulsed second illumination light collimated to a second surface intersecting the first surface and forms a linear second illumination region in the flow path; ,
A second detector for detecting second transmitted light generated by the second illumination light,
The second detection unit is a second avalanche photodiode array that operates in a Geiger mode. - 請求項3に記載の分析装置において、
前記第1の照明光及び前記第2の照明光の発光タイミングを検出するタイミング調整部と、
前記第1のアバランシェ・フォトダイオード・アレイの検出信号をデジタル値に変換する第1のアナログ-デジタル変換器と、
前記第2のアバランシェ・フォトダイオード・アレイの検出信号をデジタル値に変換する第2のアナログ-デジタル変換器と
を更に有し、
前記第1のアナログ-デジタル変換器及び前記第2のアナログ-デジタル変換器は、前記タイミング調整部から与えられるタイミング信号に基づいて前記検出信号を処理する
分析装置。 The analyzer according to claim 3, wherein
A timing adjustment unit for detecting a light emission timing of the first illumination light and the second illumination light;
A first analog-to-digital converter that converts a detection signal of the first avalanche photodiode array into a digital value;
A second analog-to-digital converter that converts a detection signal of the second avalanche photodiode array into a digital value;
The first analog-digital converter and the second analog-digital converter process the detection signal based on a timing signal provided from the timing adjustment unit. - 請求項4に記載の分析装置において、
前記第1のアバランシェ・フォトダイオード・アレイ及び前記第2のアバランシェ・フォトダイオード・アレイの検出結果を使用してデータ解析する解析部
を更に有する分析装置。 The analyzer according to claim 4, wherein
An analyzer further comprising: an analysis unit that analyzes data using detection results of the first avalanche photodiode array and the second avalanche photodiode array. - 請求項5に記載の分析装置において、
前記第1の透過光を、少なくとも第1の色成分と第2の色成分に分離する第1の色分離ユニットと、
前記第2の透過光を、少なくとも第1の色成分と第2の色成分に分離する第2の色分離ユニットと
を更に有する分析装置。 The analyzer according to claim 5, wherein
A first color separation unit that separates the first transmitted light into at least a first color component and a second color component;
An analyzer further comprising: a second color separation unit that separates the second transmitted light into at least a first color component and a second color component. - 請求項6に記載の分析装置において、
前記流路は、本流路から分岐された支流路である
分析装置。 The analyzer according to claim 6,
The analyzer is a branch channel branched from the main channel. - 請求項7に記載の分析装置において、
前記流路内に装着される反応セルを更に有し、
前記反応セルは、
前記第1の照明光及び前記第2の照明光の両方又は一方を透過する材質の容器と、
検出対象とする物質と反応する試薬と
を含む分析装置。 The analyzer according to claim 7,
A reaction cell mounted in the flow path;
The reaction cell is
A container made of a material that transmits both or one of the first illumination light and the second illumination light;
An analyzer comprising a reagent that reacts with a substance to be detected. - 請求項8に記載の分析装置において、
前記第1の検出部と前記第2の検出部は、それぞれ前記第1の照明領域及び前記第2の照明領域を試料が通過するのに要する時間内に、前記第1の透過光及び前記第2の透過光を複数回検出する
分析装置。 The analyzer according to claim 8, wherein
The first detection unit and the second detection unit are configured so that the first transmitted light and the second detection unit are within the time required for the sample to pass through the first illumination region and the second illumination region, respectively. An analyzer that detects the transmitted light of 2 multiple times. - 請求項1に記載の分析装置において、
前記第1の面と交差する第2の面にコリメートされた第2の照明光を供給し、前記流路に線状の照明領域を形成する第2の照明光学系と、
前記第2の照明光により発生した第2の透過光を検出する第2の検出部と
を更に有する分析装置。 The analyzer according to claim 1,
A second illumination optical system for supplying a second illumination light collimated to a second surface intersecting the first surface and forming a linear illumination region in the flow path;
An analyzer further comprising: a second detector that detects second transmitted light generated by the second illumination light. - 請求項1に記載の分析装置において、
前記第1の照明光の発光を検出するタイミング調整部と、
前記第1の検出部の検出信号をデジタル値に変換する第1のアナログ-デジタル変換器と
を更に有し、
前記第1のアナログ-デジタル変換器は、前記タイミング調整部から与えられるタイミング信号に基づいて前記検出信号を処理する
分析装置。 The analyzer according to claim 1,
A timing adjustment unit for detecting light emission of the first illumination light;
A first analog-to-digital converter that converts the detection signal of the first detection unit into a digital value;
The first analog-to-digital converter processes the detection signal based on a timing signal given from the timing adjustment unit. - 請求項1に記載の分析装置において、
前記第1の検出部の検出結果を使用してデータ解析する解析部
を更に有する分析装置。 The analyzer according to claim 1,
An analysis apparatus further comprising an analysis unit that analyzes data using a detection result of the first detection unit. - 請求項1に記載の分析装置において、
前記第1の透過光を、少なくとも第1の色成分と第2の色成分に分離する第1の色分離ユニット
を更に有する分析装置。 The analyzer according to claim 1,
An analyzer further comprising a first color separation unit that separates the first transmitted light into at least a first color component and a second color component. - 請求項1に記載の分析装置において、
前記流路は、本流路から分岐された支流路である
分析装置。 The analyzer according to claim 1,
The analyzer is a branch channel branched from the main channel. - 請求項1に記載の分析装置において、
前記流路内に装着される反応セルを更に有し、
前記反応セルは、前記第1の照明光を透過する容器と、検出対象とする物質と反応する試薬とを含む
分析装置。 The analyzer according to claim 1,
A reaction cell mounted in the flow path;
The reaction cell includes a container that transmits the first illumination light and a reagent that reacts with a substance to be detected. - 請求項1に記載の分析装置において、
前記第1の検出部は、前記第1の照明領域を試料が通過するのに要する時間内に、前記第1の透過光を複数回検出する
分析装置。 The analyzer according to claim 1,
The first detection unit detects the first transmitted light a plurality of times within a time required for the sample to pass through the first illumination region.
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