ABSTRACT
Abstract
A microchip-type optical measuring apparatus includes an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a division of and claims the benefit under 35 U.S.C. § 120 of U.S. patent application Ser. No. 15/875,846, titled âMICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF,â filed on Jan. 19, 2018, which is a continuation of and claims the benefit under 35 U.S.C. § 120 of U.S. patent application Ser. No. 14/386,499, titled âMICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF,â filed on Sep. 19, 2014, now U.S. Pat. No. 9,915,935, which is a U.S. National Stage Entry under 35 U.S.C. § 371 of International Application No. PCT/JP2013/051800, filed in the Japanese Patent Office as a Receiving Office on Jan. 28, 2013, which claims priority to Japanese Patent Application Number JP2012-080472, filed in the Japanese Patent Office on Mar. 30, 2012, each of which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The present technology relates to a microchip-type optical measuring apparatus and an optical position adjusting method thereof. More specifically, the present technology relates to a microchip-type optical measuring apparatus or the like which allows an optical position of a microchip to be automatically optimized and to be measured with high accuracy.
BACKGROUND ART
A microparticle measuring apparatus (for example, a flow cytometer) which optically measures characteristics of a microparticle such as a cell is known.
In the flow cytometer, sample liquid including the cell flows through a flow passage formed in a flow cell or a microchip, and a detector detects fluorescence or scattering light generated from the cell by irradiating the cell which through-flows inside the flow passage with laser, so that an optical characteristic of the cell is measured. In addition, in the flow cytometer, as a measurement result of the optical characteristic, a population (a group) which is determined to satisfy a predetermined condition is separately collected from the cell.
For example, in PTL 1, as a microchip-type flow cytometer, âa microparticle splitting device including a microchip provided with a flow passage through which liquid including a microparticle flows, and an orifice which ejects the liquid flowing through the flow passage into a space outside the chip, an oscillating element for discharging the liquid to be liquid droplets in the orifice, a charging unit for applying an electric charge to the discharged liquid droplets, an optical detection unit which detects optical characteristic of the microparticle flowing through the flow passage, counter electrodes which are disposed to face each other and to interpose the liquid droplets moved along a movement direction of the liquid droplets which are discharged into the space outside the chip, and two or more containers which collect the liquid droplets passed between the counter electrodesâ is disclosed.
CITATION LIST
Patent Literature
PTL 1: Japanese Unexamined Patent Application Publication No. 2010-190680
SUMMARY OF INVENTION
Technical Problem
The microparticle measuring apparatus is required to perform position adjustment of a through-flow position of the microparticle inside the flow passage formed in the flow cell or the microchip and an optical axis of the laser with high accuracy, in order to accurately measure the optical characteristic of the microparticle. In the related art, since the position adjustment is manually performed by a user with particles for calibration (calibration beads), the position adjustment requires proficiency, and thus has a problem in reliability or stability. Particularly, in the microchip-type microparticle measuring apparatus, the optical position adjustment is required whenever the microchip is exchanged or is analyzed, and thus the position adjustment is considerably cumbersome and complicated.
Therefore, an object of the present invention is to provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.
Solution to Problem
In order to solve the problem described above, the present invention provides a microchip-type optical measuring apparatus including an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.
In this microchip-type optical measuring apparatus, the control unit may assume that a relationship between a detected position and the integrated value or the average value of the detected intensity of the light follows pre-stored probability distribution, may estimate a distribution parameter of the probability distribution on the basis of a stochastic method, and thus may create the movement signal for the position in which the integrated value or the average value of the detected intensity of the light becomes maximum according to the estimation. The control unit may select the probability distribution according to an irradiation profile of the laser.
In addition, the control unit may output the movement signal for a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum to the position adjustment unit.
In addition, the control unit may output the movement signal for an area in which an area average of the integrated value of the detected intensity in a plurality of preset areas becomes maximum to the position adjustment unit.
In addition, the control unit may output the movement signal for a position in which the integrated value of the detected intensity in the plurality of preset points becomes maximum to the position adjustment unit.
In addition, the control unit may output the movement signal for a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum, or for a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum to the position adjustment unit.
In addition, the control unit may output the movement signal for the second optimal position to the position adjustment unit when the first optimal position and the second optimal position are different from each other.
This microchip-type optical measuring apparatus may be configured as a microchip-type microparticle measuring apparatus.
In addition, the present invention provides an optical position adjusting method including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, and a procedure for specifying a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes maximum.
In the procedure for specifying the position, a relationship between a detected position and the integrated value or the average value of the detected intensity of the light may be assumed to follow a pre-stored probability distribution, a distribution parameter of the probability distribution may be estimated on the basis of a stochastic method, and thus the position in which the integrated value or the average value of the detected intensity of the light becomes maximum may be specified by the estimation.
In addition, this optical position adjusting method may further include a procedure for assuming that the integrated value or the average value of the detected intensity of the light from the position in which the integrated value or the average value of the detected intensity of the light is estimated to be maximum by the probability distribution to a predetermined position is in a one-dimensional distribution, and thus for specifying a position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the one-dimensional distribution.
In addition, in the procedure for specifying the position, the position may be set to a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum.
In addition, this optical position adjusting method may further include a procedure for specifying a position in which an area average of the integrated value of the detected intensity of the light in a plurality of preset areas becomes maximum.
In addition, this optical position adjusting method may further include a procedure for specifying a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum.
In addition, the procedure for specifying the position in which the variation coefficient becomes minimum may be a procedure for specifying a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum.
In addition, this optical position adjusting method may include a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.
Further, the present invention provides an optical position adjusting method of a microchip-type optical measuring apparatus, including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, a procedure for specifying a position in which an area average of an integrated value of a detected intensity of the light becomes high, a procedure for specifying a first optimal position in which the integrated value or an average value of the detected intensity in an area where the area average becomes higher, becomes higher, a procedure for specifying a second optimal position in which a variation coefficient of the integrated value or the average value of the detected intensity in the area where the area average becomes higher, becomes smaller, and a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.
In the present technology, a cell or a microbe, a biologically-relevant microparticle such as a liposome, or a latex particle or a gel particle, a synthetic particle such as an industrial particle, and the like are broadly included in the âmicroparticleâ.
In the biologically-relevant microparticle, a chromosome, a liposome, a mitochondria, an organelle (a cell organelle), and the like which configure various cells are included. In the cell, an animal cell (a blood cell or the like) and a plant cell are included. In the microbe, a bacteria such as a bacteria coliform, a virus such as a tobacco mosaic virus, a fungus such as a Yeast fungus, and the like are included. Further, in the biologically-relevant microparticle, a biologically-relevant polymer such as a nucleic acid or a protein, or a complex thereof is also able to be included. In addition, the industrial particle may be, for example, an organic or inorganic polymeric material, a metal, and the like. In the organic polymeric material, polystyrene, styrene â divinylbenzene, polymethylmethacrylate, and the like are included. In the inorganic polymeric material, glass, silica, a magnetic body material, and the like are included. In the metal, a gold colloid, aluminum, and the like are included. Generally, it is ordinary that the shape of the microparticle is spherical, but the shape may also be non-spherical, and the size, mass, or the like is not particularly limited.
Advantageous Effects of Invention
According to the present invention, a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy is provided.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (a flow cytometer 1 ) according to the present invention which is configured as a microchip-type flow cytometer.
FIG. 2 is a diagram for describing a configuration of an example of a microchip 2 which is mountable on the flow cytometer 1 .
FIG. 3 is a diagram for describing a configuration of an orifice 21 of the microchip 2 .
FIG. 4 is a flowchart for describing a control step according to a first embodiment in order to optimize an optical position of the flow cytometer 1 .
FIG. 5 is a diagram for describing control of an original point â reference point movement step S 1 to an area average value maximum position determination step S 3 according to the first embodiment.
FIG. 6 is a diagram for describing control of an area average maximum position movement step S 4 to an integrated value maximum position determination step S 6 according to the first embodiment.
FIG. 7 is a diagram for describing control of a variation coefficient determination step S 7 according to the first embodiment.
FIG. 8 is a flowchart for describing a control step according to a second embodiment in order to optimize the optical position of the flow cytometer 1 .
FIG. 9 is a diagram for describing control of a coarse adjustment step S 21 according to the second embodiment.
FIG. 10 is a diagram for describing a fixed distribution assumed in the coarse adjustment step S 21 according to the second embodiment.
FIG. 11 is a diagram for describing control of a first fine adjustment step S 22 according to the second embodiment.
FIG. 12 is a diagram for describing control of a second fine adjustment step S 23 according to the second embodiment.
FIG. 13 is a diagram for describing control of a finer adjustment step S 24 according to the second embodiment.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a division of and claims the benefit under 35 U.S.C. § 120 of U.S. patent application Ser. No. 15/875,846, titled âMICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF,â filed on Jan. 19, 2018, which is a continuation of and claims the benefit under 35 U.S.C. § 120 of U.S. patent application Ser. No. 14/386,499, titled âMICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF,â filed on Sep. 19, 2014, now U.S. Pat. No. 9,915,935, which is a U.S. National Stage Entry under 35 U.S.C. § 371 of International Application No. PCT/JP2013/051800, filed in the Japanese Patent Office as a Receiving Office on Jan. 28, 2013, which claims priority to Japanese Patent Application Number JP2012-080472, filed in the Japanese Patent Office on Mar. 30, 2012, each of which is hereby incorporated by reference in its entirety.
TECHNICAL FIELD
The present technology relates to a microchip-type optical measuring apparatus and an optical position adjusting method thereof. More specifically, the present technology relates to a microchip-type optical measuring apparatus or the like which allows an optical position of a microchip to be automatically optimized and to be measured with high accuracy.
BACKGROUND ART
A microparticle measuring apparatus (for example, a flow cytometer) which optically measures characteristics of a microparticle such as a cell is known.
In the flow cytometer, sample liquid including the cell flows through a flow passage formed in a flow cell or a microchip, and a detector detects fluorescence or scattering light generated from the cell by irradiating the cell which through-flows inside the flow passage with laser, so that an optical characteristic of the cell is measured. In addition, in the flow cytometer, as a measurement result of the optical characteristic, a population (a group) which is determined to satisfy a predetermined condition is separately collected from the cell.
For example, in PTL 1, as a microchip-type flow cytometer, âa microparticle splitting device including a microchip provided with a flow passage through which liquid including a microparticle flows, and an orifice which ejects the liquid flowing through the flow passage into a space outside the chip, an oscillating element for discharging the liquid to be liquid droplets in the orifice, a charging unit for applying an electric charge to the discharged liquid droplets, an optical detection unit which detects optical characteristic of the microparticle flowing through the flow passage, counter electrodes which are disposed to face each other and to interpose the liquid droplets moved along a movement direction of the liquid droplets which are discharged into the space outside the chip, and two or more containers which collect the liquid droplets passed between the counter electrodesâ is disclosed.
CITATION LIST
Patent Literature
PTL 1: Japanese Unexamined Patent Application Publication No. 2010-190680
SUMMARY OF INVENTION
Technical Problem
The microparticle measuring apparatus is required to perform position adjustment of a through-flow position of the microparticle inside the flow passage formed in the flow cell or the microchip and an optical axis of the laser with high accuracy, in order to accurately measure the optical characteristic of the microparticle. In the related art, since the position adjustment is manually performed by a user with particles for calibration (calibration beads), the position adjustment requires proficiency, and thus has a problem in reliability or stability. Particularly, in the microchip-type microparticle measuring apparatus, the optical position adjustment is required whenever the microchip is exchanged or is analyzed, and thus the position adjustment is considerably cumbersome and complicated.
Therefore, an object of the present invention is to provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.
Solution to Problem
In order to solve the problem described above, the present invention provides a microchip-type optical measuring apparatus including an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.
In this microchip-type optical measuring apparatus, the control unit may assume that a relationship between a detected position and the integrated value or the average value of the detected intensity of the light follows pre-stored probability distribution, may estimate a distribution parameter of the probability distribution on the basis of a stochastic method, and thus may create the movement signal for the position in which the integrated value or the average value of the detected intensity of the light becomes maximum according to the estimation. The control unit may select the probability distribution according to an irradiation profile of the laser.
In addition, the control unit may output the movement signal for a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum to the position adjustment unit.
In addition, the control unit may output the movement signal for an area in which an area average of the integrated value of the detected intensity in a plurality of preset areas becomes maximum to the position adjustment unit.
In addition, the control unit may output the movement signal for a position in which the integrated value of the detected intensity in the plurality of preset points becomes maximum to the position adjustment unit.
In addition, the control unit may output the movement signal for a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum, or for a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum to the position adjustment unit.
In addition, the control unit may output the movement signal for the second optimal position to the position adjustment unit when the first optimal position and the second optimal position are different from each other.
This microchip-type optical measuring apparatus may be configured as a microchip-type microparticle measuring apparatus.
In addition, the present invention provides an optical position adjusting method including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, and a procedure for specifying a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes maximum.
In the procedure for specifying the position, a relationship between a detected position and the integrated value or the average value of the detected intensity of the light may be assumed to follow a pre-stored probability distribution, a distribution parameter of the probability distribution may be estimated on the basis of a stochastic method, and thus the position in which the integrated value or the average value of the detected intensity of the light becomes maximum may be specified by the estimation.
In addition, this optical position adjusting method may further include a procedure for assuming that the integrated value or the average value of the detected intensity of the light from the position in which the integrated value or the average value of the detected intensity of the light is estimated to be maximum by the probability distribution to a predetermined position is in a one-dimensional distribution, and thus for specifying a position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the one-dimensional distribution.
In addition, in the procedure for specifying the position, the position may be set to a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum.
In addition, this optical position adjusting method may further include a procedure for specifying a position in which an area average of the integrated value of the detected intensity of the light in a plurality of preset areas becomes maximum.
In addition, this optical position adjusting method may further include a procedure for specifying a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum.
In addition, the procedure for specifying the position in which the variation coefficient becomes minimum may be a procedure for specifying a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum.
In addition, this optical position adjusting method may include a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.
Further, the present invention provides an optical position adjusting method of a microchip-type optical measuring apparatus, including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, a procedure for specifying a position in which an area average of an integrated value of a detected intensity of the light becomes high, a procedure for specifying a first optimal position in which the integrated value or an average value of the detected intensity in an area where the area average becomes higher, becomes higher, a procedure for specifying a second optimal position in which a variation coefficient of the integrated value or the average value of the detected intensity in the area where the area average becomes higher, becomes smaller, and a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.
In the present technology, a cell or a microbe, a biologically-relevant microparticle such as a liposome, or a latex particle or a gel particle, a synthetic particle such as an industrial particle, and the like are broadly included in the âmicroparticleâ.
In the biologically-relevant microparticle, a chromosome, a liposome, a mitochondria, an organelle (a cell organelle), and the like which configure various cells are included. In the cell, an animal cell (a blood cell or the like) and a plant cell are included. In the microbe, a bacteria such as a bacteria coliform, a virus such as a tobacco mosaic virus, a fungus such as a Yeast fungus, and the like are included. Further, in the biologically-relevant microparticle, a biologically-relevant polymer such as a nucleic acid or a protein, or a complex thereof is also able to be included. In addition, the industrial particle may be, for example, an organic or inorganic polymeric material, a metal, and the like. In the organic polymeric material, polystyrene, styrene â divinylbenzene, polymethylmethacrylate, and the like are included. In the inorganic polymeric material, glass, silica, a magnetic body material, and the like are included. In the metal, a gold colloid, aluminum, and the like are included. Generally, it is ordinary that the shape of the microparticle is spherical, but the shape may also be non-spherical, and the size, mass, or the like is not particularly limited.
Advantageous Effects of Invention
According to the present invention, a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy is provided.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (a flow cytometer 1 ) according to the present invention which is configured as a microchip-type flow cytometer.
FIG. 2 is a diagram for describing a configuration of an example of a microchip 2 which is mountable on the flow cytometer 1 .
FIG. 3 is a diagram for describing a configuration of an orifice 21 of the microchip 2 .
FIG. 4 is a flowchart for describing a control step according to a first embodiment in order to optimize an optical position of the flow cytometer 1 .
FIG. 5 is a diagram for describing control of an original point â reference point movement step S 1 to an area average value maximum position determination step S 3 according to the first embodiment.
FIG. 6 is a diagram for describing control of an area average maximum position movement step S 4 to an integrated value maximum position determination step S 6 according to the first embodiment.
FIG. 7 is a diagram for describing control of a variation coefficient determination step S 7 according to the first embodiment.
FIG. 8 is a flowchart for describing a control step according to a second embodiment in order to optimize the optical position of the flow cytometer 1 .
FIG. 9 is a diagram for describing control of a coarse adjustment step S 21 according to the second embodiment.
FIG. 10 is a diagram for describing a fixed distribution assumed in the coarse adjustment step S 21 according to the second embodiment.
FIG. 11 is a diagram for describing control of a first fine adjustment step S 22 according to the second embodiment.
FIG. 12 is a diagram for describing control of a second fine adjustment step S 23 according to the second embodiment.
FIG. 13 is a diagram for describing control of a finer adjustment step S 24 according to the second embodiment.
DESCRIPTION OF EMBODIMENTS
Hereinafter, best modes for carrying out the present invention will be described with reference to the drawings. Furthermore, embodiments described below indicate an example of a representative embodiment of the present invention, and it is not construed as narrowing the range of the present invention by the embodiments. The description will be provided according to the following order.
1. Microchip-type Optical Measuring Apparatus
(1) Irradiation Detection Unit
(2) Position Adjustment Unit
(3) Oscillating Element
(4) Charging Unit
(5) Deflection Plate
(6) Collection Container
(7) Control Unit or the like
(8) Microchip
2. Optimization Control of Optical Position of Microchip-Type Optical Measuring Apparatus According to First Embodiment of the Present Invention
(1) Original Point â Reference Point Movement Step S 1
(2) Signal Acquisition Step S 2
(3) Area Average Value Maximum Position Determination Step S 3
(4) Area Average Maximum Position Movement Step S 4
(5) Signal Acquisition Step S 5
(6) Integrated Value Maximum Position Determination Step S 6
(7) Variation Coefficient Determination Step S 7
(8) Position Optimization Step S 8
3. Optimization Control of Optical Position of Microchip-Type Optical Measuring Apparatus According to Second Embodiment of the Present Invention
(1) Coarse Adjustment Step S 21
(1-1) Grid-like Signal Acquisition Step S 211
(1-2) Two-dimensional Distribution Parameter Estimation Step S 212
(1-3) Maximum Position Movement Step S 213
(2) First Fine Adjustment Step S 22
(2-1) Linear Signal Acquisition Step S 221
(2-2) One-dimensional Distribution Parameter Estimation Step S 222
(2-3) Maximum Position Movement Step S 223
(3) Second Fine Adjustment Step S 23
(3-1) Linear Signal Acquisition Step S 231
(3-2) One-dimensional Distribution Parameter Estimation Step S 232
(3-3) Maximum Position Movement Step S 233
(4) Finer Adjustment Step S 24
1. Microchip-Type Optical Measuring Apparatus
FIG. 1 is a schematic diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (hereinafter, referred to as a â flow cytometer 1 â) according to the present technology which is configured as a microchip-type flow cytometer. In addition, FIG. 2 and FIG. 3 illustrate an example of a microchip 2 which is mountable on the flow cytometer 1 . FIG. 2A illustrates a schematic upper surface view, and FIG. 2B illustrates a schematic sectional view corresponding to a cross-section cut along line P-P of FIG. 2A . In addition, FIG. 3 is a diagram for schematically describing a configuration of an orifice 21 of the microchip 2 , and FIG. 3A illustrates an upper surface view, FIG. 3B illustrates a sectional view, and FIG. 3C illustrates a front view. FIG. 3B corresponds to the cross-section cut along line P-P of FIG. 2A .
(1) Irradiation Detection Unit
The flow cytometer 1 is provided with an irradiation detection unit which includes a light source 61 for irradiating the microchip 2 with laser L 1 , and a detector 62 for detecting light to be detected which is generated by irradiation of the laser L 1 . An irradiation direction of the laser L 1 with respect to the microchip 2 (an optical axis of the laser L 1 ) is illustrated as a Z-axis forward direction of FIG. 1 . The light source 61 may be an LD, an LED, or the like.
The laser L 1 is applied into a cell which flows through a sample flow passage 22 of the microchip 2 . The detector 62 detects scattering light of the laser L 1 caused by the cell, and fluorescence generated by exciting the cell or fluorescent pigment marked on the cell with the laser L 1 . In FIG. 1 , the fluorescence generated from the cell which flows through the sample flow passage 22 is indicated by a reference mark F 1 .
The irradiation detection unit includes an irradiation system provided with a condensing lens for condensing light by guiding the laser L 1 emitted from the light source 61 to the cell, a dichroic mirror, a band pass filter, or the like. In addition, the irradiation detection unit is configured by a detection system for guiding the light to be detected which is generated from the cell by the irradiation of the laser L 1 to the detector 62 by condensing the light. The detection system is configured by, for example, a photo multiplier tube (PMT), an area imaging element such as a CCD or a CMOS element, or the like.
The light to be detected which is detected by the detection system of the irradiation detection unit is the light which is generated from the cell by the irradiation of the laser L 1 , and may be, for example, forward scattering light or lateral scattering light, scattering light such as Rayleigh scattering or Mie scattering, fluorescence, or the like. The fluorescence may be generated from the cell or the fluorescent pigment marked on the cell. The light to be detected is converted to an electric signal, and is used for optical characteristic determination of the cell and automatic adjustment of an optical position (described later).
(2) Position Adjustment Unit
The flow cytometer 1 includes a position adjustment unit 9 which changes a relative position of the microchip 2 with respect to the irradiation detection unit. The position adjustment unit 9 moves the position of the microchip 2 and/or the position of the irradiation detection unit on a plane (an XY plane) perpendicular to the optical axis of the laser L 1 . Accordingly, the position adjustment unit 9 adjusts the position of the microchip 2 with respect to the optical axis of the laser L 1 , and optimizes the laser L 1 to be applied to a through-flow position of the cell inside the sample flow passage 22 .
The position adjustment unit 9 may move at least one of the position of the microchip 2 and the position of the irradiation detection unit including the light source 61 and the detector 62 to an X-axial direction and a Y-axial direction. The position adjustment unit 9 is configured by, for example, a stepping motor or the like. Furthermore, the position adjustment unit 9 may move the relative position of the microchip 2 with respect to the irradiation detection unit to a Z-axial direction (a focus direction of the laser L 1 ).
(3) Oscillating Element
The flow cytometer 1 includes an oscillating element 3 for discharging laminar flow of sample liquid and sheath liquid including the cell which is ejected from the orifice 21 to be liquid droplets by applying oscillation to the orifice 21 formed in the microchip 2 . The oscillating element 3 may be, for example, a piezo element. The discharged liquid droplets are injected to a Y-axis forward direction indicated by an arrow in the drawings as fluid stream S. Furthermore, in the flow cytometer 1 , the microchip 2 is exchangeably mounted.
In the flow cytometer 1 , the oscillating element 3 may be integrated with the microchip 2 , and may be disposed on the apparatus side to be contactable with the mounted microchip 2 .
(4) Charging Unit
Positive or negative electric charges are applied to the liquid droplets discharged from the orifice 21 by a charging unit 41 . The charging of the liquid droplets is performed by an electrode 42 which is electrically connected to the charging unit 41 and inserted into a sample inlet 23 disposed in the microchip 2 . Furthermore, the electrode 42 may be inserted into any one portion of the microchip 2 to electrically come in contact with the sample liquid or the sheath liquid flowing through the flow passage.
In the flow cytometer 1 , a frequency of a driving voltage of the oscillating element 3 , and switching timing of a voltage (a charge voltage) of the charging unit 41 are synchronized, so that any one of plus and minus electric charges is applied to a part of the liquid droplets discharged from the orifice 21 . The electric charge may not be applied to a part of the liquid droplets, and thus a part of the liquid droplets may be uncharged.
(5) Deflection Plate
Further, the flow cytometer 1 includes a pair of deflection plates
51 and 52 which are disposed to face each other and to interpose the fluid stream S. The deflection plates
51 and 52 change a travelling direction of each of the liquid droplets in the fluid stream S by an electric force which acts with respect to the electric charges applied to the liquid droplets. The deflection plates
51 and 52 may be an ordinary electrode. In FIG. 1 , a facing direction of the polarizing plates
51 and 52 is illustrated by the X-axial direction.
(6) Collection Container
The fluid stream passed between the deflection plates
51 and 52 is received in any one of a collection container 81 , a collection container 82 , or a collection container 83 . For example, when the deflection plate 51 is positively charged and the deflection plate 52 is negatively charged, the liquid droplets which are negatively charged by the charging unit 41 are collected in the collection container 82 , and the positively charged liquid droplets are collected in the collection container 83 , respectively. In addition, the liquid droplets which are not charged by the charging unit 41 directly drop to be collected in the collection container 81 without receiving an electrical acting force from the deflection plates
51 and 52 . In the flow cytometer 1 , the travelling direction of the liquid droplets is controlled according to the characteristic of the cell included in each of the liquid droplets, thereby allowing a target cell having a desired characteristic and a non-target cell other than the target cell to be collected in separate collection containers.
The
collection containers
81 , 82 , and 83 may be a general-purpose plastic tube or a glass tube for laboratory use. It is preferable that the collection containers be exchangeably disposed in the flow cytometer 1 . In addition, the collection container for receiving the non-target cell among the collection containers may be connected to a drainage route of the collected liquid droplets. Furthermore, in the flow cytometer 1 , the number of collection containers to be disposed is not particularly limited. When more than 3 collection containers are disposed, the respective liquid droplets are induced toward any one of the collection containers according to presence or absence of the electrical acting force between the deflection plates
51 and 52 , and the magnitude thereof, and collected in the collection container.
(7) Control Unit or the Like
The flow cytometer 1 includes a data analysis unit for determining the optical characteristic of the cell, a tank unit for accumulating the sample liquid and the sheath liquid, a control unit 10 for controlling each configuration, and the like, which are provided in a usual flow cytometer, in addition to the configuration described above.
The control unit 10 is able to be configured by a general-purpose computer provided with a CPU, a memory, hard disk, and the like, and stores an OS, a program for executing a control step (described later), and the like in the hard disk.
The control unit 10 outputs a movement signal for a position in which a variation becomes small, that is, a position in which an integrated value or an average value of a detected intensity of the light generated from the microchip by the irradiation of the laser L 1 becomes higher (preferably, becomes a maximum value) among regions set in advance to the position adjustment unit 9 .
(8) Microchip
The microchip 2 is configured by bonding substrate layers
2 a and 2 b in which the sample flow passage 22 is formed. The sample flow passage 22 is able to be formed in the substrate layers 2 a and 2 b according to injection molding of a thermoplastic resin with a mold. As the thermoplastic resin, plastics which are known as microchip material in the related art, such as polycarbonate, polymethylmethacrylate (PMMA) resin, cyclic polyolefin, polyethylene, polystyrene, polypropylene, and polydimethylsiloxane (PDMS) are able to be adopted.
The sample liquid is introduced to the sample inlet 23 , merged into the sheath liquid introduced to a sheath inlet 24 , and flows through the sample flow passage 22 . The flow of the sheath liquid introduced from the sheath inlet 24 is divided into two directions, and then is merged into the sample liquid at a merging portion with the sample liquid introduced from the sample inlet 23 , by sandwiching the sample liquid from the two directions. Accordingly, three-dimensional laminar flow in which sample liquid laminar flow is positioned in the center of sheath liquid laminar flow is formed at the merging portion.
A reference numeral â 25 â indicates a suction flow passage for removing clogging or air bubbles by applying a negative pressure to the inside of the sample flow passage 22 and by temporarily regurgitating the flow when the clogging or the air bubbles is generated in the sample flow passage 22 . One end of the suction flow passage 25 is provided with a suction outlet 251 which is connected to a negative pressure source such as a vacuum pump, and the other end is connected to the sample flow passage 22 at a communication port 252 .
A laminar flow width of the three-dimensional laminar flow is narrowed at a throttle portions 261 (refer to FIG. 2 ) and 262 (refer to FIG. 3 ) which are formed such that the area of a cross section vertical to a flow direction gradually or progressively becomes smaller upstream to downstream in the flow direction. Subsequently, the three-dimensional laminar flow is ejected from the orifice 21 disposed on one end of the flow passage.
The characteristic of the cell is detected between the throttle portion 261 and the throttle portion 262 of the sample flow passage 22 . The cell which is arranged in line at the center of the three-dimensional laminar flow and flows through the sample flow passage 22 is irradiated with the laser L 1 by the irradiation detection unit, and thus the fluorescence F 1 and the scattering light which are generated from the cell are detected (refer to FIG. 2 ).
A connection portion with respect to the orifice 21 of the sample flow passage 22 is configured as a straight portion 27 which is linearly formed. The straight portion 27 functions to directly inject the fluid stream S from the orifice 21 to the Y-axis forward direction.
The three-dimensional laminar flow ejected from the orifice 21 becomes the liquid droplets by the oscillation applied to the orifice 21 according to the oscillating element 31 , and is injected as the fluid stream S (refer to FIG. 1 ). The orifice 21 is open to an end surface direction of the substrate layers 2 a and 2 b , and a cutout portion 211 is formed between an opening position of the orifice and the end surfaces of the substrate layers. The cutout portion 211 is formed by cutting out the substrate layers 2 a and 2 b between the opening position of the orifice 21 and the end surfaces of the substrates such that the diameter L of the cutout portion 221 is larger than the opening diameter 1 of the orifice 21 (refer to FIG. 3C ). It is preferable that the diameter L of the cutout portion 211 be equal to or greater than two times larger than the <figure-callout id="1" label="opening diameter" filenames="US
CLAIMS
Claims ( 14 )
The invention claimed is:
1. An optical measuring apparatus, comprising:
an irradiation detector configured to detect light generated by irradiating microparticles with a laser, the microparticles flowing through a channel, wherein the light is detected at a plurality of points, the plurality of points comprising a first plurality of points along a focus direction of the laser and a second plurality of points along a direction perpendicular to the focus direction of the laser; and
at least one motor configured to change a relative position of the channel with respect to the irradiation detector based on a movement signal for a position selected based on an integrated value or an average value of a detected intensity of the light at the first plurality of points along a focus direction of the laser or at the second plurality of points along a direction perpendicular to the focus direction of the laser,
wherein a stochastic method is used to estimate a distribution parameter of a probability distribution for modeling a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light, and the movement signal for a selected position is based on using the stochastic method to estimate the distribution parameter.
2. The optical measuring apparatus of claim 1 , wherein the at least one motor is at least one stepping motor.
3. The optical measuring apparatus of claim 2 , wherein the at least one motor is configured to change a relative position of the channel with respect to the irradiation detector along at least a first axis and a second axis.
4. The optical measuring apparatus of claim 1 , wherein the at least one motor is further configured to change a relative position of the channel with respect to the irradiation detector along a third axis.
5. The optical measuring apparatus of claim 1 , wherein the probability distribution is selected according to an irradiation profile of the laser.
6. The optical measuring apparatus of claim 1 , wherein the movement signal is based on a variation coefficient of the integrated value or the average value of the detected intensity of the light.
7. The optical measuring apparatus of claim 1 , wherein the movement signal for an area is based on an area average of the integrated value of the detected intensity of the light.
8. The optical measuring apparatus of claim 1 , further comprising a processor configured to output the movement signal.
9. An optical measuring method, comprising:
detecting light by an irradiation detector, the light being generated by irradiating microparticles with a laser, the microparticles flowing through a channel, wherein the light is detected at a plurality of points, the plurality of points comprising a first plurality of points along a focus direction of the laser and a second plurality of points along a direction perpendicular to the focus direction of the laser; and
performing a position adjustment using at least one motor, wherein the position adjustment changes a relative position of the channel with respect to the irradiation detector based on a movement signal for a position selected based on an integrated value or an average value of a detected intensity of the light at the first plurality of points along a focus direction of the laser or at the second plurality of points along a direction perpendicular to the focus direction of the laser,
wherein a stochastic method is used to estimate a distribution parameter of a probability distribution for modeling a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light, and the movement signal for a selected position is based on using the stochastic method to estimate the distribution parameter.
10. The optical measuring method of claim 9 , wherein the position adjustment changes a relative position of the channel with respect to the irradiation detector along at least a first axis.
11. The optical measuring method of claim 10 , wherein the position adjustment changes a relative position of the channel with respect to the irradiation detector along a second axis.
12. The optical measuring method of claim 9 , wherein the probability distribution is selected according to an irradiation profile of the laser.
13. The optical measuring method of claim 9 , wherein the movement signal is based on a variation coefficient of the integrated value or the average value of the detected intensity of the light.
14. The optical measuring method of claim 9 , wherein the movement signal for an area is based on an area average of the integrated value of the detected intensity of the light.
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