JP2008241409A - Apparatus and method for analyzing biopolymer, gene expression analysis method, and antigen detection method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biopolymer detection apparatus, having satisfactory sensitivity, a biopolymer analysis method, a gene expression analysis method, and an antigen detection method. <P>SOLUTION: The biopolymer detection apparatus 70 is provided with an imaging device 10 having a photoelectric conversion element 20, provided in such a way as to orient its light-receiving plane upward; a partition wall 40 fixed to the side of the light-receiving plane of the imaging device 10 to form a well 42, to which a solution is injected inside; a molecular filter 50 for partitioning the inside of the well 42 into an upper part and a lower part; and a probe 61, fixed to a part upper than the molecular filter 50 inside the well 42, to combine with a specific biopolymer 62 in the solution injected in the well 61. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a biopolymer analyzer, a biopolymer analysis method, a gene expression analysis method, and an antigen detection method.

  In order to analyze the expression of genes of various biological species, biopolymer analysis chips such as DNA chips and antibody chips and readers thereof have been developed. A biopolymer analysis chip is obtained by aligning and fixing cDNA and antibodies having a known base sequence serving as a probe on a solid support such as a slide glass in a matrix (for example, see Patent Document 1). For example, gene expression analysis using a DNA chip and its reader is performed as follows.

First, a DNA chip is prepared in which a plurality of types of cDNAs having known base sequences (hereinafter referred to as probe DNA) are aligned and fixed on a solid support such as a slide glass. Next, mRNA is extracted from the specimen, cDNA is synthesized using reverse transcriptase, and prepared by labeling with a labeling substance (hereinafter referred to as labeled DNA). Here, as the labeling substance, a fluorescent substance, a chemiluminescent substrate, an enzyme that emits light from the chemiluminescent substrate, or the like can be used.
Next, when the labeled DNA is added onto the DNA chip, the labeled DNA is immobilized on the DNA chip by hybridizing with the complementary probe DNA.

Next, the DNA chip is set in a reader and analyzed by the reader. The reader condenses the light emitted by the labeling substance that scans the DNA chip with a condensing lens and a photomultiplier that moves two-dimensionally with respect to the DNA chip, and condenses the light intensity with the photomultiplier. By measuring the light intensity distribution in the surface of the DNA chip, the light intensity distribution on the DNA chip is output as a two-dimensional image. In the output image, the portion having a high light intensity indicates that a labeled DNA having a base sequence complementary to the base sequence of the probe DNA is included. Therefore, mRNA expressed in the specimen can be identified based on which part of the two-dimensional image has high fluorescence intensity.
JP 2000-1312237 A

  By the way, a biopolymer analysis chip has been developed in which probe molecules such as DNA and antibodies are spotted on a light receiving surface of a solid-state imaging device in which a plurality of photoelectric conversion elements are arranged in a two-dimensional array. In such a biopolymer analysis chip, light generated by a labeling substance that labels a biopolymer such as labeled DNA attached to a spot is measured by each photoelectric conversion element. Spots are scattered on the light receiving surface of the solid-state imaging device, and attenuation of light emitted from the labeling substance can be suppressed because the distance between the biopolymer attached to the light receiving surface and the photoelectric conversion element is short Therefore, there is an advantage that measurement is possible even with a small amount of light.

  In the biopolymer analysis chip as described above, when an enzyme for emitting a chemiluminescent substrate is used as a labeling substance, a solution containing the chemiluminescent substrate is dropped on the spot and generated based on a chemical reaction by the enzyme. The light emitted when the excited phosphor returns to the ground state is measured.

  However, when the chemiluminescent substrate diffuses in the well, the amount of the phosphor generated by the reaction of the chemiluminescent substrate with the enzyme decreases. As a result, there is a problem that the fluorescence emitted from the phosphor is reduced and the S / N ratio is lowered.

  An object of the present invention is to solve the above problems and provide a biopolymer analyzer, a biopolymer analysis method, a gene expression analysis method, and an antigen detection method with better sensitivity.

  In order to solve the above-described problems, the invention according to claim 1 is directed to an imaging device having a photoelectric conversion element provided with a light receiving surface facing upward, and fixed to the light receiving surface side of the imaging device. A well into which a solution is injected, a molecular filter that partitions the well up and down, a specific biopolymer in the solution that is fixed above the molecular filter in the well and is injected into the well, and And a probe that binds to the biopolymer analyzer.

  Invention of Claim 2 is the biopolymer analyzer of Claim 1, Comprising: In order to attract the fluorescent substance produced by the chemical reaction based on an enzyme electrically, on the light-receiving surface side of each said photoelectric conversion element Each of the electrodes is provided.

  The invention described in claim 3 is the biopolymer analyzer according to claim 1 or 2, further comprising a plurality of electromagnets arranged so as to surround the well.

  Invention of Claim 4 is the biopolymer analyzer as described in any one of Claims 1-3, Comprising: The said probe is single stranded DNA which has a known base sequence, It is characterized by the above-mentioned. To do.

  The invention described in claim 5 is the biopolymer analyzer according to any one of claims 1 to 3, wherein the probe is an antibody that binds to a specific antigen.

  The invention according to claim 6 is a method for analyzing a biopolymer using the biopolymer analyzer according to claim 1, wherein an excited fluorescent substance capable of transmitting the chemiluminescent substrate through the molecular filter is provided. A solution containing a biopolymer labeled with an enzyme that functions as a catalyst for the generated chemical reaction is injected into the well, and then a part of the biopolymer in the solution is bound to the probe, and then the A solution containing an immobilizing substance having a chemiluminescent substrate immobilized thereon and impermeable to the molecular filter is injected into the well, and then the well is shaken, and then released from the generated excited fluorescent substance. The light is detected by the photoelectric conversion element.

  The invention according to claim 7 is a method for analyzing a biopolymer using the biopolymer analyzer according to claim 2, wherein an excited fluorescent substance capable of passing through the molecular filter from a chemiluminescent substrate is provided. A solution containing a biopolymer labeled with an enzyme that functions as a catalyst for the generated chemical reaction is injected into the well, and then a part of the biopolymer in the solution is bound to the probe, and then the A process including injecting into the well a solution containing a fixed body on which the chemiluminescent substrate is immobilized and impermeable to the molecular filter, and then shaking the well, and applying a voltage to attract the fluorescent material to the electrode. Through the process of applying, the photoelectric conversion element detects light emitted from the generated excited fluorescent material.

  The invention according to claim 8 is a method for analyzing a biopolymer using the biopolymer analyzer according to claim 3, wherein an excited fluorescent substance capable of passing through the molecular filter from a chemiluminescent substrate is provided. A solution containing a biopolymer labeled with an enzyme that functions as a catalyst for the generated chemical reaction is injected into the well, and then a part of the biopolymer in the solution is bound to the probe, and then the Through a process of injecting a solution containing magnetic particles having a chemiluminescent substrate fixed and impermeable to the molecular filter into the well, and then applying an appropriate voltage to the plurality of electromagnets to alternately generate a magnetic field. The light emitted from the excited fluorescent material thus generated is detected by the photoelectric conversion element.

  The invention according to claim 9 is a gene expression analysis method using the biopolymer analyzer according to claim 1, wherein a single-stranded DNA having a known base sequence is used as the probe and the bottom of the well Next, an RNA extracted from any cell is used as a template, and is labeled with an enzyme that functions as a catalyst for a chemical reaction that generates a fluorescent substance in an excited state that can pass through the molecular filter from a chemiluminescent substrate. A solution containing the enzyme-labeled DNA is injected into the well, and then a part of the enzyme-labeled DNA in the solution is hybridized to the probe, and then the chemiluminescent substrate is fixed, and the molecular filter Injecting a solution containing a fixed body that cannot pass through the well into the well, and then shaking the well, the fluorescence emitted from the generated fluorescent material in the excited state is emitted. And detecting the serial photoelectric conversion element.

  A tenth aspect of the present invention is a gene expression analysis method using the biopolymer analyzer according to the second aspect, wherein a single-stranded DNA having a known base sequence is used as the probe as a bottom of the well. Next, an RNA extracted from any cell is used as a template, and is labeled with an enzyme that functions as a catalyst for a chemical reaction that generates a fluorescent substance in an excited state that can pass through the molecular filter from a chemiluminescent substrate. A solution containing the enzyme-labeled DNA is injected into the well, and then a part of the enzyme-labeled DNA in the solution is hybridized to the probe, and then the chemiluminescent substrate is fixed, and the molecular filter Injecting a solution containing a fixed body that cannot pass through the well into the well and then shaking the well, and applying a voltage to attract the fluorescent material to the electrode. Through the process of the fluorescence emitted from the fluorescent substance of the generated excited state and detects by the photoelectric conversion element.

  The invention according to claim 11 is a gene expression analysis method using the biopolymer analyzer according to claim 3, wherein a single-stranded DNA having a known base sequence is used as the probe as the bottom of the well. Next, an RNA extracted from any cell is used as a template, and is labeled with an enzyme that functions as a catalyst for a chemical reaction that generates a fluorescent substance in an excited state that can pass through the molecular filter from a chemiluminescent substrate. A solution containing the enzyme-labeled DNA is injected into the well, and then a part of the enzyme-labeled DNA in the solution is hybridized to the probe, and then the chemiluminescent substrate is fixed, and the molecular filter A solution containing magnetic particles that cannot pass through is injected into the well, and then a voltage is applied to the plurality of electromagnets to generate a magnetic field alternately. The fluorescence emitted from the fluorescent substance excited state and detects by the photoelectric conversion element.

  The invention according to claim 12 is an antigen detection method using the biopolymer analyzer according to claim 1, wherein an antibody that binds to a specific antigen is provided as the probe at the bottom of the well, and Injecting a solution containing an arbitrary antigen into the well, allowing the probe to bind to a specific antigen in the solution, then removing the antigen that did not bind to the probe, and the same as the probe. A solution comprising a second antibody labeled with an enzyme that binds to different antigenic determinants of the antigen and functions as a catalyst for a chemical reaction that generates a fluorescent substance in an excited state capable of passing through the molecular filter from a chemiluminescent substrate; It is injected into a well, and a second antibody is bound to a specific antigen bound to the probe. Thereafter, the chemiluminescent substrate is immobilized, and a fixed body that cannot pass through the molecular filter is contained. The solution was injected into the well, then, through a process of shaking the wells, the fluorescence emitted from the fluorescent substance of the generated excited state and detects by the photoelectric conversion element.

  The invention according to claim 13 is an antigen detection method using the biopolymer analyzer according to claim 2, wherein an antibody that binds to a specific antigen is provided as the probe at the bottom of the well, and Injecting a solution containing an arbitrary antigen into the well, allowing the probe to bind to a specific antigen in the solution, then removing the antigen that did not bind to the probe, and the same as the probe. A solution comprising a second antibody labeled with an enzyme that binds to different antigenic determinants of the antigen and functions as a catalyst for a chemical reaction that generates a fluorescent substance in an excited state capable of passing through the molecular filter from a chemiluminescent substrate; It is injected into a well, and a second antibody is bound to a specific antigen bound to the probe. Thereafter, the chemiluminescent substrate is immobilized, and a fixed body that cannot pass through the molecular filter is contained. Fluorescence emitted from the excited fluorescent material generated through a process of injecting the solution into the well and then shaking the well and applying a voltage to attract the fluorescent material to the electrode Is detected by the photoelectric conversion element.

  The invention according to claim 14 is an antigen detection method using the biopolymer analyzer according to claim 3, wherein an antibody that binds to a specific antigen is provided as the probe at the bottom of the well, and Injecting a solution containing an arbitrary antigen into the well, allowing the probe to bind to a specific antigen in the solution, then removing the antigen that did not bind to the probe, and the same as the probe. A solution comprising a second antibody labeled with an enzyme that binds to different antigenic determinants of the antigen and functions as a catalyst for a chemical reaction that generates a fluorescent substance in an excited state capable of passing through the molecular filter from a chemiluminescent substrate; A second antibody is bound to a specific antigen bound to the probe, injected into a well, and then the chemiluminescent substrate is immobilized and magnetic particles that cannot pass through the molecular filter The solution is injected into the well, and then the photoelectric conversion element emits the fluorescence emitted from the excited fluorescent material generated through the process of alternately applying a voltage to the plurality of electromagnets to alternately generate a magnetic field. It is detected by.

  According to the present invention, it is possible to provide a biopolymer analyzer with better sensitivity, a biopolymer analysis method, a gene expression analysis method, and an antigen detection method.

  The best mode for carrying out the present invention will be described below with reference to the drawings. However, although various technically preferable limitations for implementing the present invention are given to the embodiments described below, the scope of the invention is not limited to the following embodiments and illustrated examples.

[First Embodiment]
[1] Overall Configuration of Biopolymer Analysis Chip FIG. 1 is a schematic plan view of a biopolymer analysis chip 1 according to the first embodiment of the present invention, and FIG. 2 is a view taken along arrows II-II in FIG. It is sectional drawing. 3 is an enlarged view of a portion III in FIG. 1, and FIG. 4 is a cross-sectional view taken along arrows IV-IV in FIG. This biopolymer analysis chip 1 is a DNA chip for detecting DNA.
As shown in FIGS. 1 and 2, the biopolymer analysis chip 1 includes an imaging apparatus 2 that includes a solid-state imaging device 10, a partition 40, a molecular filter 50, and a spot 60.

[2] Solid-State Imaging Device Here, the solid-state imaging device 10 will be described with reference to FIGS. As shown in FIG. 2, the solid-state imaging device 10 is formed by laminating a transparent substrate 11, a bottom gate insulating film 13, a top gate insulating film 21, a protective insulating film 23, and a protective insulating film 25. Between these layers, a plurality of bottom gate lines 12a, source lines 18a, drain lines 19a, top gate lines 22a, electrode lines 24a, a bottom gate electrode 12 forming a photosensor 20, a semiconductor film 14, a channel protective film 15, Impurity semiconductor films 16 and 17, source electrode 18, drain electrode 19, top gate electrode 22, and electrode 24 are provided.

  The transparent substrate 11 is a glass substrate such as quartz glass or a plastic substrate such as polycarbonate or PMMA, and has a property of transmitting fluorescence (hereinafter referred to as light transmittance) emitted from a phosphor described later. .

In this solid-state imaging device 10, a double gate type magnetic field effect transistor (hereinafter referred to as a photosensor) 20 is used as a photoelectric conversion element, and a plurality of photosensors 20, 20,. The photosensors 20, 20,... Are collectively covered with a protective insulating film 23 such as silicon nitride (SiN).
1 shows a matrix-like two-dimensional array including 64 photosensors 20, 20,..., 8 rows × 8 columns, the number is arbitrary, and there are more rows and columns. May be.

  As shown in FIGS. 3 and 4, each of the photosensors 20, 20,... Includes a semiconductor film 14 that is a light receiving portion, a channel protective film 15 formed on the semiconductor film 14, and a bottom gate insulating film 13. A bottom gate electrode 12 formed under the semiconductor film 14 with a sandwich, a top gate electrode 22 formed on the semiconductor film 14 with a top gate insulating film 21 in between, and a part of the semiconductor film 14 are formed. An impurity semiconductor film 16, an impurity semiconductor film 17 formed so as to overlap another part of the semiconductor film 14, a source electrode 18 overlapped with the impurity semiconductor film 16, and a drain electrode 19 overlapped with the impurity semiconductor film 17. , And outputs an electrical signal at a level according to the amount of light received by the semiconductor film 14.

  The bottom gate electrode 12 is formed on the transparent substrate 11 for each photosensor 20. Further, a plurality of bottom gate lines 12a, 12a extending in the horizontal direction are formed on the transparent substrate 11, and the bottoms of the photosensors 20, 20,... In the same row arranged in the horizontal direction are formed. The gate electrode 12 is formed integrally with a common bottom gate line 12a. The bottom gate electrode 12 and the bottom gate line 12a have conductivity and light shielding properties, and are made of, for example, chromium, a chromium alloy, aluminum, an aluminum alloy, or an alloy thereof.

The bottom gate electrode 12 and the bottom gate lines 12a, 12a,... Of the photosensors 20, 20,. That is, the bottom gate insulating film 13 is a film formed in common to all the photosensors 20, 20,. The bottom gate insulating film 13 has insulating properties and light transmittance, and is made of, for example, silicon nitride (SiN) or silicon oxide (SiO ₂ ).

  A plurality of semiconductor films 14 are formed on the bottom gate insulating film 13 so as to be arranged in a matrix. The semiconductor film 14 is formed independently for each photosensor 20, is disposed to face the bottom gate electrode 12 in each photosensor 20, and sandwiches the bottom gate insulating film 13 between the bottom gate electrode 12. It is out. The semiconductor film 14 has a substantially rectangular shape in plan view, and is a layer formed of amorphous silicon or polysilicon that generates electron-hole pairs in an amount corresponding to the amount of received fluorescence.

  A channel protective film 15 is formed on the semiconductor film 14. The channel protective film 15 is patterned independently for each photosensor 20, and is formed on the central portion of the semiconductor film 14 in each photosensor 20. The channel protective film 15 has insulating properties and light transmittance, and is made of, for example, silicon nitride or silicon oxide. The channel protective film 15 protects the interface of the semiconductor film 14 from an etchant used for patterning. When light enters the semiconductor film 14, an amount of electron-hole pairs according to the amount of incident light is generated around the interface between the channel protective film 15 and the semiconductor film 14. In this case, holes are generated as carriers on the semiconductor film 14 side, and electrons are generated on the channel protective film 15 side.

An impurity semiconductor film 16 is partially formed on one end portion of the semiconductor film 14 so as to overlap the channel protective film 15, and an impurity semiconductor film 17 is partially formed on the other end portion of the semiconductor film 14. The channel protective film 15 is formed so as to overlap. The impurity semiconductor films 16 and 17 are patterned independently for each photosensor 20. The impurity semiconductor films 16 and 17 are made of amorphous silicon (n ⁺ silicon) containing n-type impurity ions.

  A source electrode 18 is formed on the impurity semiconductor film 16, and a drain electrode 19 is formed on the impurity semiconductor film 17. The source electrode 18 and the drain electrode 19 are formed for each photosensor 20. A plurality of source lines 18 a and 18 a and drain lines 19 a and 19 a extending in the vertical direction are formed on the bottom gate insulating film 13. The source electrodes 18 of the photosensors 20, 20,... In the same row arranged in the vertical direction are formed integrally with the common source line 18a, and the photosensors 20, 20 in the same row arranged in the vertical direction. ,... Are formed integrally with a common drain line 19a. The source electrode 18, the drain electrode 19, the source line 18a, and the drain line 19a have conductivity and light shielding properties, and are made of, for example, chromium, a chromium alloy, aluminum, an aluminum alloy, or an alloy thereof.

  The source electrode 18 and the drain electrode 19 of the photosensors 20, 20,... And the source lines 18a, 18a and the drain lines 19a, 19a are collectively covered with a top gate insulating film 21. The top gate insulating film 21 is a film formed in common to all the photosensors 20, 20,. The top gate insulating film 21 has insulating properties and light transmissive properties, and is made of, for example, silicon nitride or silicon oxide.

  A plurality of top gate electrodes 22 are formed for each photosensor 20 on the top gate insulating film 21. The top gate electrode 22 is disposed to face the semiconductor film 14 in each photosensor 20, and the top gate insulating film 21 and the channel protective film 15 are sandwiched between the top gate electrode 22 and the semiconductor film 14. A plurality of top gate lines 22a and 22a extending in the horizontal direction are formed on the top gate insulating film 21, and the top gate electrodes of the photosensors 20 and 20 in the same row arranged in the horizontal direction are formed. 22 is formed integrally with a common top gate line 22a. The top gate electrode 22 and the top gate line 22a are conductive and light transmissive, for example, indium oxide, zinc oxide, tin oxide, or a mixture containing at least one of them (for example, tin-doped indium oxide ( ITO) and zinc-doped indium oxide).

  The top gate electrode 22 and the top gate lines 22a, 22a of the photosensors 20, 20,... Are collectively covered with a protective insulating film 23, and the protective insulating film 23 is formed in common to all the photosensors 20, 20,. Film. The protective insulating film 23 has insulating properties and light transmittance, and is made of silicon nitride or silicon oxide.

  On the upper surface of the protective insulating film 23, an electrode 24 is provided above the semiconductor film 14 of the photosensors 20, 20,. Further, on the upper surface of the protective insulating film 23, a plurality of electrode lines 24a, 24a,... Extending in the vertical direction are formed on the sides of the photosensors 20, 20,. The electrodes 24 and 24 in the same column are formed integrally with a common electrode line 24a. The electrode 24 and the electrode line 24a are conductive, and a transparent electrode exhibiting high transparency with respect to the fluorescence of the phosphor 92 described later is preferable. For example, indium oxide, zinc oxide, tin oxide, or any of these It is formed of a mixture containing at least one (for example, tin-doped indium oxide (ITO), zinc-doped indium oxide).

  The electrode 24 and the electrode line 24 a are collectively covered with a protective insulating film 25. The protective insulating film 25 has insulating properties and light transmittance, and is made of silicon nitride or silicon oxide.

  The solid-state imaging device 10 configured as described above has the surface of the protective insulating film 25 as a light receiving surface, and is provided so as to convert the amount of light received by the semiconductor film 14 of the photosensor 20 into an electrical signal.

[3] Partition Wall The partition wall 40 is in close contact with the protective insulating film 25 and forms a well 42 on the light receiving surface of the solid-state imaging device 10. The partition wall 40 is opaque and prevents light from entering from the well 42 adjacent to the photosensor 20.

  In FIG. 1, 2 rows × 2 columns of wells 42 are formed on the light receiving surface of the solid-state imaging device 10, but the number thereof is arbitrary. In FIG. 1, 4 rows × 4 columns of photosensors 20 are arranged in one well 42, but it is sufficient that at least one photosensor 20 is arranged in one well, and the number thereof is arbitrary. .

[4] Molecular Filter As shown in FIG. 2, the molecular filter 50 is disposed on the solid-state imaging device 10 and is fixed to the partition wall 40 at the outer peripheral portion. The molecular filter 50 can be fixed to the partition wall 40 by, for example, bonding with an adhesive. The space in the well 42 is partitioned vertically by the molecular filter 50.

  The molecular filter 50 transmits a phosphor (molecular weight of about 185), which will be described later, and does not transmit molecules having a molecular weight larger than that. As the molecular filter 50, for example, an ultrafiltration membrane having a fractional molecular weight of 30 kDa can be used. Specifically, for example, Nanosep (manufactured by PALL) or the like can be used.

[5] Spot As shown in FIGS. 1 and 2, a spot 60 is formed on the upper surface of the molecular filter 50. Each spot 60 is formed by dropping a solution of cDNA (probe DNA 61) having a known base sequence serving as a probe or an antibody into the well 42 and drying it. Hereinafter, a case where cDNA having a known base sequence is used as a probe will be described.

  One spot 60 is formed in each well 42. In one spot 60, a crowd of a large number of single-stranded probe DNAs 61 having the same base sequence is immobilized on the upper surface of the molecular filter 50, and the probe DNA 61 has a different base sequence for each spot 60. As the probe DNA 61, a DNA having a nucleotide sequence identical to or complementary to a known mRNA nucleotide sequence or a part thereof is used. Specifically, for example, a cDNA library prepared from the same cell specimen as used for enzyme-labeled DNA described later can be used.

[6] Analyzing apparatus Since the biopolymer analyzing chip 1 is used by setting the biopolymer analyzing chip 1 in the analyzing apparatus 70, the analyzing apparatus 70 will be described with reference to FIG. FIG. 5 is a block diagram showing the configuration of the analyzer 70.

  The analysis apparatus 70 includes a biopolymer analysis chip 1, an analysis table 71 (see FIG. 9), an electrode driver 73 that is connected to the biopolymer analysis chip 1 and drives the solid-state imaging device 10, a top gate driver 74, a bottom A gate driver 75, a drain driver 76, a control device 80 for controlling the entire analysis device 70, a storage device 82, an output device 77 for outputting (displaying or printing) according to a signal output from the control device 80, and a shaker 78 and an injection device 79.

The biopolymer analysis chip 1 is set on the analysis table 71. When the biopolymer analysis chip 1 is set on the analysis table 71, the electrode line 24 a of the solid-state imaging device 10 is connected to the terminal of the electrode driver 73. Similarly, the top gate lines 22a, 22a,... Are terminals of the top gate driver 74, the bottom gate lines 12a, 12a,... Are terminals of the bottom gate driver 75, and the drain lines 19a, 19a,. Are connected to each other. When the biopolymer analysis chip 1 is set on the analysis table 71, the source lines 18a, 18a,... Of the solid-state imaging device 10 are connected to a constant voltage source, and in this example, the source lines 18a, 18a,. It has come to be.
In FIG. 5, only four photosensors 20, 20,..., 2 rows × 2 columns are illustrated, but the number thereof is arbitrary, and more rows and columns may be provided.

  The electrode driver 73, the top gate driver 74, the bottom gate driver 75, and the drain driver 76 cooperate to drive the solid-state imaging device 10.

  The control device 80 outputs control signals to the electrode driver 73, the top gate driver 74, the bottom gate driver 75, and the drain driver 76, thereby solidifying the electrode driver 73, the top gate driver 74, the bottom gate driver 75, and the drain driver 76. It has a function to drive the imaging device 10. The control device 80 has a function of causing the output device 77 to output an image according to the input two-dimensional image data. The output device 77 is, for example, a plotter, a printer, or a display.

Further, the control device 80 controls the shaker 78 to stir the solution in the well 42 by shaking the analysis table 71.
In addition, the control device 80 drives the injection device 79 and drops a solution containing a fixed body 90 on which a chemiluminescent substrate 91 described later is fixed to each well 42 of the biopolymer analysis chip 1 set in the analysis device 70. .

  In addition, the control device 80 performs A / D conversion on the electrical signal input from the drain driver 76, thereby acquiring the light intensity distribution along the light receiving surface of the solid-state imaging device 10 in the storage device 82 as two-dimensional image data. Have

  In the storage device 82, the light intensity distribution along the light receiving surface of the solid-state imaging device 10 input from the drain driver 76 to the control device 80 and subjected to A / D conversion is stored as two-dimensional image data.

[7] Enzyme labeled DNA
As a sample to be analyzed by the biopolymer analysis chip 1, DNA can be used. As the sample DNA, cDNA obtained by extracting mRNA expressed in an arbitrary cell specimen and using reverse transcriptase can be used. The cDNA is labeled with an enzyme that functions as a catalyst for the reaction of a chemiluminescent substrate described later, such as alkaline phosphatase and peroxidase.

  In order to label the cDNA with an enzyme, for example, an RT-PCR reaction may be carried out using an oligo dT primer labeled with the enzyme or a labeled dNTP mix. Hereinafter, this labeled cDNA is referred to as enzyme-labeled DNA.

[8] Chemiluminescent substrate The chemiluminescent substrate used for detecting the enzyme-labeled DNA will be described. As the chemiluminescent substrate, one that generates a fluorescent substance in an excited state by a chemical reaction using an enzyme used for labeling enzyme-labeled DNA as a catalyst can be used.
Specifically, for example, a dioxetane derivative serving as a substrate for alkaline phosphatase or a luminol compound serving as a substrate for peroxidase can be used.

As an example of the dioxetane derivative, an adamantyl dioxetane chlorinated derivative (C ₁₈ H ₁₉ Cl ₂ O ₇ PNa ₂ ) represented by Chemical Formula 1 will be described as an example. The adamantyl dioxetane chlorinated derivative has a phosphate group and is a substrate for alkaline phosphatase.

Alkaline phosphatase hydrolyzes the phosphate group of an adamantyl dioxetane chlorinated derivative to form an unstable intermediate shown in Formula 2.

The intermediate is spontaneously cleaved and decomposed into adamantanone and phosphor shown in Chemical Formula 3. This phosphor is in an excited state, and energy when the phosphor transitions to the ground state is emitted as light.

  In addition, the chemiluminescent substrate used as the substrate of alkaline phosphatase has a phosphate group and is negatively charged in an aqueous solution. In addition, the phosphor produced by hydrolysis of the chemiluminescent substrate is also negatively charged in the aqueous solution. For this reason, the chemiluminescent substrate and the phosphor move to the positive charge side in the aqueous solution.

  In the present embodiment, as shown in FIG. 6, a substrate in which a chemiluminescent substrate 91 is fixed on the surface of a fixed body 90 is used. The chemiluminescent substrate 91 is fixed to the surface of the fixed body 90 by the adsorption force of the surface of the fixed body 90.

  As the fixed body 90, it is preferable not to inhibit the enzyme reaction, and it is preferable to use a protein having a molecular weight that does not pass through the molecular filter 50, for example, a protein of about 60 kDa. Examples of such proteins include bovine serum albumin (about 66 kDa), streptavidin (about 60 kDa), neutravidin (about 60 kDa), avidin (about 67 kDa), and the like.

[9] Hybridization A method for hybridizing the enzyme-labeled DNA 62 with the probe DNA 61 will be described below with reference to FIGS.
First, an operator injects a solution containing the enzyme-labeled DNA 62 (hereinafter referred to as an enzyme-labeled DNA solution) into each well 42. Before injecting the enzyme-labeled DNA solution, a buffer solution for migrating the enzyme-labeled DNA 62 may be placed in each well 42, or the enzyme-labeled DNA solution itself may also serve as a buffer solution for electrophoresis. Note that the enzyme-labeled DNA solution may be dropped sequentially or simultaneously on the spots 60, 60,. At this time, the enzyme-labeled DNA solution is heated so that the enzyme-labeled DNA 62 becomes a single strand.

Next, each well 42 of the biopolymer analysis chip 1 is cooled to a predetermined temperature so that the probe DNA 61 and the enzyme-labeled DNA 62 cause hybridization. Then, as shown in FIG. 8, among the enzyme-labeled DNA 62 in the enzyme-labeled DNA solution injected into each well 42, those complementary to the probe DNA 61 of the spot 60 in the well hybridize with the probe DNA 61. To do. On the other hand, those that are not complementary to the probe DNA 61 do not bind to the spot 60.
Thereafter, the enzyme-labeled DNA solution in the well 42 is washed away with a washing buffer solution, and the enzyme-labeled DNA that has not hybridized with the probe DNA 61 is removed from the well 42.

  The biopolymer analysis chip 1 subjected to the above processing is set in the analysis device 70, the top gate driver 74, the bottom gate driver 75, and the drain driver 76 are connected to the control device 80, and the control device 80 is activated.

[10] Detection of Sample A method for detecting the enzyme-labeled DNA 62 will be described with reference to FIG.
When a solution containing a fixed body 90 in which the chemiluminescent substrate 91 is immobilized is injected into the well 42 in which the enzyme labeled DNA 62 is hybridized to the probe DNA 61 of the spot 60, the chemiluminescent substrate 91 is hydrolyzed by the enzyme 63 that labels the enzyme labeled DNA 62. Then, an excited phosphor 92 is generated through an unstable intermediate (FIG. 9).

  In the present embodiment, as will be described below, the stirring operation in the well 42 is performed using a shaker 78 to which the chemiluminescent substrate 91 is fixed. Hereinafter, the stirring operation in the well 42 by the control device 80 will be described.

  First, the control device 80 drives the injection device 79 to inject a solution containing the fixed body 90 on which the chemiluminescent substrate 91 is fixed into each well 42 of the biopolymer analysis chip 1 set in the analysis device 70.

When the solution containing the fixed body 90 on which the chemiluminescent substrate 91 is fixed is injected into all the wells 42, the control device 80 drives the electrode driver 73 to apply a positive voltage to the electrode line 24 a and charges the electrode 24 positively. Let
Next, the control device 80 controls the shaker 78 to shake the analysis table 71.

  By shaking the analysis table 71, the fixed body 90 on which the chemiluminescent substrate 91 is fixed moves in the well 42, and the chance that the chemiluminescent substrate 91 is hydrolyzed by the enzyme 63 is increased, so that more phosphors 92 are present. Generated.

  Since the produced phosphor 92 is negatively charged in the aqueous solution, the phosphor 92 passes through the molecular filter 50 and moves toward the positively charged electrode 24.

  The phosphor that has passed through the molecular filter 50 is attracted to the positively charged electrode 24 and concentrated on the upper part of the photosensor 20. Thereafter, fluorescence (mainly in the visible light wavelength region) is emitted when the excited phosphor 92 transitions to the ground state, and fluorescence enters the photosensor 20 to generate electron-hole pairs. Here, since the phosphor 92 is concentrated on the upper part of the photosensor 20, more fluorescence can be incident on the corresponding photosensor 20 to generate electron-hole pairs.

  Even when the chemiluminescent substrate 91 is negatively charged, the chemiluminescent substrate 91 is fixed on the surface of the fixed body 90, and the molecular weight of the fixed body 90 is larger than the fractional molecular weight of the molecular filter 50. It does not pass through the molecular filter 50. Therefore, the chemiluminescent substrate 91 is not attracted to the vicinity of the electrode 24, and the hydrolysis of the chemiluminescent substrate 91 by the enzyme 63 is not hindered.

  After the stirring operation is completed, the control device 80 performs A / D conversion on the output of each photosensor 20, 20,..., So that the light intensity distribution along the light receiving surface of the solid-state imaging device 10 is converted into two-dimensional image data. Store in the storage device 82.

  The worker uses the light intensity data of each photosensor 20, 20,... Stored in the storage device 82 by the output device 77 to output the hybridization at each spot 60, 60,. Can be confirmed. If hybridization has occurred, it can be seen that mRNA having a base sequence complementary to the probe DNA 61 in the spot 60 is expressed in the cell sample.

<Modification 1>
As shown in FIG. 10, the probe DNA 61 may be fixed to the side surface of the partition wall 40. By fixing the probe DNA 61 to the partition wall 40, the effective area of the molecular filter 50 through which the phosphor 92 is transmitted can be increased.

<Modification 2>
In the above embodiment, DNA synthesized by reverse transcriptase from mRNA expressed in a sample is used as a sample to be analyzed by the biopolymer analysis chip 1, but a specific protein expressed in the sample is used. Alternatively, an antibody that binds a sugar chain or the like to an antigen (hereinafter referred to as a probe antibody) may be used as a probe.

  Specifically, as shown in FIG. 11, a solution containing the probe antibody 64 is dropped into each well 42 of the biopolymer analysis chip 1 and dried to form a spot 60. The probe antibody 64 dropped into each well 42 recognizes different antigenic determinants, and the probe antibody 64 forming the same spot 60 recognizes the same antigenic determinant. As such a probe antibody 64, a monoclonal antibody can be used.

Next, a solution containing the antigen 65 serving as a sample (hereinafter referred to as a sample solution) is injected into each well 42.
After a sufficient time has passed for the antigen 65 in the sample solution to bind to the probe antibody 64, the sample solution in the well 42 is washed away with the buffer solution, and the probe antibody 64 out of the antigen 65 in the sample solution does not bind. Are removed from the well 42.

  Next, in each well 42, a solution (hereinafter referred to as enzyme-labeled antibody 66) of a solution in which an antibody that recognizes a different antigenic determinant of the same antigen 65 as that recognized by the probe antibody 64 is labeled with an enzyme 67 (hereinafter referred to as enzyme-labeled antibody 66) A labeled antibody solution).

  After a sufficient time has passed for the antigen 65 bound to the probe antibody 64 and the enzyme-labeled antibody 66 to bind, the enzyme-labeled antibody solution in the well 42 is washed away with a buffer solution, and the antigen 65 in the enzyme-labeled antibody solution is removed. Of these, those not bound to the probe antibody 64 are removed from the well 42.

Alternatively, the antigen 65 previously bound with the enzyme-labeled antibody 66 may be injected into the well 42, and the antigen 65 bound with the enzyme-labeled antibody 66 may be bound to the probe antibody 64.
Thereafter, in the same manner as in [10] sample detection, a solution containing a chemiluminescent substrate is injected into each well 42, and light quantity data is measured by the analyzer 70.

  In the well 42 in which the antigen 65 is bound to the probe antibody 64 and the enzyme-labeled antibody 66 is bound to the antigen 65, the chemiluminescent substrate 91 is hydrolyzed by the enzyme 67, and an excited phosphor 92 is generated through the intermediate. . The fluorescence emitted from the phosphor 92 is detected by the photosensor 20.

The operator uses the antigen 65 at each spot 60, 60,... From the image data obtained by outputting the light quantity data of each photosensor 20, 20,. Can be confirmed. Therefore, it is possible to directly confirm what kind of antigen is expressed in the specimen according to the type of antibody in the well 42.
<Modification 3>
As shown in FIG. 12, the probe antibody 64 may be fixed to the side surface of the partition wall 40. By fixing the probe antibody 64 to the partition wall 40, the effective area of the molecular filter 50 through which the phosphor 92 is transmitted can be increased.

[Second Embodiment]
Next, a second embodiment of the present invention will be described. Note that [2] solid-state imaging device, [3] partition, [4] molecular filter, [5] spot, [7] enzyme-labeled DNA, and [9] hybridization are the same as in the first embodiment. Therefore, the same reference numerals are given and the explanation is omitted.

[6-2] Analyzing Device FIG. 13 is a block diagram showing the configuration of the analyzing device 170 according to the second embodiment of the present invention. In addition, about the structure similar to the analyzer 70 in 1st Embodiment, the same sign is attached | subjected to the last 2 digits, and description is omitted.
The analyzer 170 according to the present embodiment further includes electromagnets 178R and 178L. The electromagnets 178R and 178L are controlled by the control device 180 and change the magnetic field in the well 142 as will be described later.

  The control device 180 has the same function as that of the control device 80, and includes the number of stirrings Mc, the number of stirring times M, the energization time Te per cycle, and the energization time count number T stored in the storage device 182. Data is read, and a voltage for driving the electromagnets 178R and 178L is output as will be described later. In addition, the control device 180 has a subtraction timer function that decreases the count number T by 1 at regular time intervals.

  The storage device 182 stores two-dimensional image data in the same manner as the storage device 82, and also stores the number of stirrings Mc, the number of stirring times M, the energization time Te, and the number of energization times stored in the storage device 182. Data such as T is stored.

[8-2] Chemiluminescent substrate Also in this embodiment, the same chemiluminescent substrate as in the first embodiment can be used. However, in this embodiment, the magnetic particles 190 are used instead of the fixed body 90. A surface in which a chemiluminescent substrate is immobilized is used. The chemiluminescent substrate 91 is fixed to the surface of the magnetic particle 190 by the adsorption force on the surface of the magnetic particle 190. The magnetic particles 190 are approximately the same size as or larger than the fixed body 90.

  Examples of the material of the magnetic particles 190 include nickel particles, iron particles, Fe3O4, γ-Fe2O3, Co-γ-Fe2O3, (NiCuZn) O. (CuZn) O.Fe2O3, (MnZn) O.Fe2O3, and (NiZn) O. Various magnetic materials such as Fe2O3, SrO.6Fe2O3, BaO.6Fe2O3 can be used, and these may be combined with a polymer material (for example, nylon, polyacrylamide, polystyrene, etc.) to form particles.

The method of fixing the chemiluminescent substrate 91 to the magnetic particles 190 is arbitrary. For example, by coating the surface of the magnetic particles 190 with SiO ₂ , the chemiluminescent substrate 91 is fixed to the surfaces of the magnetic particles 190 by the adsorption force of SiO _2. can do.

[10-2] Detection of Sample Next, a method for detecting enzyme-labeled DNA using the analyzer 170 according to the present embodiment will be described with reference to FIGS. FIG. 14 is an explanatory diagram showing a method for detecting enzyme-labeled DNA using the analyzer 170 according to the present embodiment, FIG. 15 is a flowchart showing the stirring operation in the well 42 by the controller 180, and FIG. 6 is a timing chart showing voltages applied to an electrode line 24a and electromagnets 178R and 178L by a control device 180.

  First, the control device 180 drives the injection device 179 to inject a solution containing the magnetic particles 190 on which the chemiluminescent substrate 91 is fixed into each well 42 of the biopolymer analysis chip 1 set in the analysis device 170.

  When the solution containing the magnetic particles 190 on which the chemiluminescent substrate 91 is fixed is injected into all the wells 42 (step S1 → Yes), the controller 180 drives the electrode driver 173 to apply a positive voltage to the electrode line 24a, The electrode 24 is positively charged (step S2).

  Next, the control device 180 sets the count number M of the number of stirrings stored in the storage device 182 to a preset number of stirrings Mc (step S3).

Next, the control device 180 sets the energization time count T stored in the storage device 182 to a preset energization time Te per cycle (step S4).
Next, the control device 180 starts energizing the right electromagnet 178R (step S5). After that, the control device 180 rewrites the count number T stored in the storage device 182 to a value obtained by subtracting 1 for every predetermined time (step S6). This is repeated until T = 0 (step S7 → No).
When T = 0 (step S7 → Yes), the controller 180 stops energization of the right electromagnet 178R (step S8).

Next, the control device 180 sets the energization time count T stored in the storage device 182 to Te again (step S9).
Next, the control device 180 starts energizing the left electromagnet 178L (step S10). After that, the control device 180 rewrites the count number T stored in the storage device 182 to a value obtained by subtracting 1 every fixed time (step S11). This is repeated until T = 0 (step S12 → No).
When T = 0 (step S12 → Yes), the controller 180 stops energization of the left electromagnet 178L (step S13).

When energization of both the left and right electromagnets 178R, 178L is completed, the count number M is decremented by 1 (step S14), and then the operations of steps S4 to S14 are repeated until M = 0 (step S15 → No).
When M = 0 (step S15 → Yes), the control device 180 drives the electrode driver 173 to stop applying a positive voltage to the electrode line 24a (step S16), and ends the stirring operation.

  Since only the right electromagnet 178R is energized during steps S5 to S8, the magnetic particles 190 to which the chemiluminescent substrate 91 is fixed move to the right by the magnetic force of the electromagnet 178R. On the other hand, since only the left electromagnet 178L is energized during steps S10 to S13, the magnetic particles 190 to which the chemiluminescent substrate 91 is fixed move to the left by the magnetic force of the electromagnet 178L. For this reason, the magnetic particles 190 having the chemiluminescent substrate 91 fixed are repeatedly moved left and right within the well 42 by repeating steps S4 to S15 and applying a suitable voltage to the electromagnets 178R and 178L to alternately generate a magnetic field. The chance that the chemiluminescent substrate 91 is hydrolyzed by the enzyme 63 increases, and more phosphors 92 are generated.

  Since the produced phosphor 92 is negatively charged in the aqueous solution, the phosphor 92 passes through the molecular filter 50 and moves toward the positively charged electrode 24.

  The phosphor that has passed through the molecular filter 50 is attracted to the positively charged electrode 24 and concentrated on the upper part of the photosensor 20. Thereafter, fluorescence (mainly in the visible light wavelength region) is emitted when the excited phosphor 92 transitions to the ground state, and fluorescence enters the photosensor 20 to generate electron-hole pairs. Here, since the phosphor 92 is concentrated on the upper part of the photosensor 20, more fluorescence can be incident on the corresponding photosensor 20 to generate electron-hole pairs.

  Even when the chemiluminescent substrate 91 is negatively charged, the chemiluminescent substrate 91 is fixed on the surface of the magnetic particle 190, and the molecular weight of the magnetic particle 190 is larger than the fractional molecular weight of the molecular filter 50. It does not pass through the molecular filter 50. Therefore, the chemiluminescent substrate 91 is not attracted to the vicinity of the electrode 24, and the hydrolysis of the chemiluminescent substrate 91 by the enzyme 63 is not hindered.

  After the stirring operation is completed, the control device 180 performs A / D conversion on the output of each photosensor 20, 20,..., So that the light intensity distribution along the light receiving surface of the solid-state imaging device 10 is converted into two-dimensional image data. Store in the storage device 182.

  The operator uses the light intensity data of each of the photosensors 20, 20,... Stored in the storage device 182 by the output device 177 to obtain the hybridization at each spot 60, 60,. Can be confirmed. If hybridization has occurred, it can be seen that mRNA having a base sequence complementary to the probe DNA 61 in the spot 60 is expressed in the cell sample.

<Modification 4>
As in the first modification, the probe DNA 61 may be fixed to the side surface of the partition wall 40 as shown in FIG. By fixing the probe DNA 61 to the partition wall 40, the effective area of the molecular filter 50 through which the phosphor 92 is transmitted can be increased.

<Modification 5>
Further, as in Modification 2, as shown in FIG. 18, the antigen 65 may be detected using the biopolymer analysis chip 1 in which the spots 60 are formed using the probe antibodies 64.

<Modification 6>
Similarly to the third modification, the probe antibody 64 may be fixed to the side surface of the partition wall 40 as shown in FIG. By fixing the probe antibody 64 to the partition wall 40, the effective area of the molecular filter 50 through which the phosphor 92 is transmitted can be increased.

[Third Embodiment]
FIG. 20 is a block diagram illustrating a configuration of an analyzer 270 according to a modification of the present embodiment. In addition, about the structure similar to the analyzer 170 in 2nd Embodiment, the same sign is attached | subjected to the last 2 digits, and description is omitted.
In this modification, electromagnets 278R and 278L are provided on the left and right of the solid-state imaging device 210, an electromagnet 278F is provided on the front side, and an electromagnet 278B is provided on the rear side.

In the second embodiment, the stationary body 90 is moved left and right by alternately energizing the electromagnets 178R and 178L. However, in this modification, a voltage is applied to each of the electromagnets 278R, 278L, 278F, and 278B. By doing so, the magnetic particle 190 can be moved back and forth and right and left.
In addition, a voltage may be applied to the electromagnets 278R, 278L, 278F, and 278B one by one in order, or two voltages may be alternately applied.

The present invention is not limited to the above embodiment, and various improvements and design changes may be made without departing from the spirit of the present invention.
For example, in the above embodiment, a single-stranded DNA or antibody having a known base sequence is used as a probe, but other known biopolymers or low molecules may be used. For example, a peptide or protein serving as an antigen, a sugar chain, a low molecular ligand, a known cell, or the like may be used.

1 is a schematic plan view of a biopolymer analysis chip 1 according to an embodiment of the present invention. It is II-II arrow sectional drawing of FIG. FIG. 3 is an enlarged view of part III in FIG. 1. FIG. 4 is a cross-sectional view taken along the line IV-IV in FIG. 3. 3 is a block diagram showing a configuration of an analysis device 70. FIG. FIG. 4 is a schematic diagram showing a structure in which a chemiluminescent substrate 91 is fixed on the surface of a fixed body 90. It is explanatory drawing of the method of hybridizing the enzyme label | marker DNA62 with the probe DNA61. It is explanatory drawing of the method of hybridizing the enzyme label | marker DNA62 with the probe DNA61. It is explanatory drawing which shows the detection method of enzyme labeled DNA62. It is explanatory drawing which shows the detection method of enzyme labeled DNA62. It is explanatory drawing which shows the detection method of the antigen 65. FIG. It is explanatory drawing which shows the detection method of the antigen 65. FIG. It is a block diagram which shows the structure of the analyzer 170 which concerns on the 2nd Embodiment of this invention. It is explanatory drawing which shows the detection method of enzyme labeled DNA using the analyzer 170 which concerns on this Embodiment. 5 is a flowchart showing an agitation operation in the well 42 by the control device 180. 6 is a timing chart showing voltages applied to an electrode line 24a and electromagnets 178R and 178L by a control device 180. It is explanatory drawing which shows the detection method of enzyme labeled DNA62. It is explanatory drawing which shows the detection method of the antigen 65. FIG. It is explanatory drawing which shows the detection method of the antigen 65. FIG. 3 is a block diagram showing a configuration of an analyzer 270. FIG.

Explanation of symbols

10 Solid-state imaging device (imaging device)
20 Photosensor (photoelectric conversion element)
40 partition wall 42 well 50 molecular filter 60 spot 61 probe DNA (probe)
62 Enzyme labeled DNA
63,67 Enzyme 64 Probe antibody (probe)
65 antigen 66 enzyme-labeled antibody 70, 170, 270 analyzer (biopolymer analyzer)
178R, 178L, 278R, 278L, 278F, 278B Electromagnet 90 Fixed body 91 Chemiluminescent substrate 92 Phosphor 190 Magnetic particle

Claims (14)

An imaging device having a photoelectric conversion element provided with a light receiving surface facing upward;
A well that is fixed to the light receiving surface side of the imaging device and into which a solution is injected;
A molecular filter that divides the inside of the well vertically,
And a probe fixed above the molecular filter in the well.   The biopolymer analyzer according to claim 1, wherein an electrode is provided on each light receiving surface side of each photoelectric conversion element to electrically attract a fluorescent substance generated by a chemical reaction based on an enzyme.   The biopolymer analyzer according to claim 1, further comprising a plurality of electromagnets arranged so as to surround the well.   The biopolymer analyzer according to any one of claims 1 to 3, wherein the probe is a single-stranded DNA having a known base sequence.   The biopolymer analyzer according to any one of claims 1 to 3, wherein the probe is an antibody that binds to a specific antigen. A biopolymer analysis method using the biopolymer analyzer according to claim 1,
Injecting into the well a solution containing a biopolymer labeled with an enzyme that functions as a catalyst for a chemical reaction that generates an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate,
Thereafter, a solution containing a fixed body on which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
A biopolymer analysis method, wherein the presence or absence of light emitted from a generated fluorescent substance in an excited state is detected by the photoelectric conversion element. A biopolymer analysis method using the biopolymer analyzer according to claim 2,
Injecting into the well a solution containing a biopolymer labeled with an enzyme that functions as a catalyst for a chemical reaction that generates an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate,
Thereafter, a solution containing a fixed body on which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Through a process of applying a voltage to attract the fluorescent material to the electrode,
A biopolymer analysis method, wherein the presence or absence of light emitted from a generated fluorescent substance in an excited state is detected by the photoelectric conversion element. A biopolymer analysis method using the biopolymer analyzer according to claim 3,
Injecting into the well a solution containing a biopolymer labeled with an enzyme that functions as a catalyst for a chemical reaction that generates an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate,
Then, a solution containing magnetic particles to which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Thereafter, through a process of generating a magnetic field alternately by appropriately applying a voltage to the plurality of electromagnets,
A biopolymer analysis method, wherein the presence or absence of light emitted from a generated fluorescent substance in an excited state is detected by the photoelectric conversion element. A gene expression analysis method using the biopolymer analyzer according to claim 1,
A single-stranded DNA having a known base sequence is provided at the bottom of the well as the probe,
Next, an enzyme labeled with an enzyme that is prepared using RNA extracted from any cell as a template and functions as a catalyst for a chemical reaction that generates an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate. Injecting a solution containing labeled DNA into the well,
Next, a part of the enzyme-labeled DNA in the solution is hybridized to the probe,
Thereafter, a solution containing a fixed body on which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Then, through the process of shaking the well,
A gene expression analysis method, characterized in that fluorescence emitted from the generated excited fluorescent substance is detected by the photoelectric conversion element. A gene expression analysis method using the biopolymer analyzer according to claim 2,
A single-stranded DNA having a known base sequence is provided at the bottom of the well as the probe,
Next, an enzyme labeled with an enzyme that is prepared using RNA extracted from any cell as a template and functions as a catalyst for a chemical reaction that generates an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate. Injecting a solution containing labeled DNA into the well,
Next, a part of the enzyme-labeled DNA in the solution is hybridized to the probe,
Thereafter, a solution containing a fixed body on which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Thereafter, a process of shaking the well and a process of applying a voltage to attract the fluorescent material to the electrode,
A gene expression analysis method, characterized in that fluorescence emitted from the generated excited fluorescent substance is detected by the photoelectric conversion element. A gene expression analysis method using the biopolymer analyzer according to claim 3,
A single-stranded DNA having a known base sequence is provided at the bottom of the well as the probe,
Next, an enzyme labeled with an enzyme that is prepared using RNA extracted from any cell as a template and functions as a catalyst for a chemical reaction that generates an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate. Injecting a solution containing labeled DNA into the well,
Next, a part of the enzyme-labeled DNA in the solution is hybridized to the probe,
Then, a solution containing magnetic particles to which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Thereafter, through a process of generating a magnetic field alternately by appropriately applying a voltage to the plurality of electromagnets,
A gene expression analysis method, characterized in that fluorescence emitted from the generated excited fluorescent substance is detected by the photoelectric conversion element. An antigen detection method using the biopolymer analyzer according to claim 1,
An antibody that binds to a specific antigen is provided at the bottom of the well as the probe,
Next, a solution containing an arbitrary antigen is injected into the well, and the probe is allowed to bind to a specific antigen in the solution.
Next, the chemical that removes the antigen that did not bind to the probe and binds to a different antigenic determinant of the same antigen as the probe to generate an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate. A solution containing a second antibody labeled with an enzyme that functions as a catalyst for the reaction is injected into the well, and the second antibody is bound to a specific antigen bound to the probe,
Thereafter, a solution containing a fixed body on which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Then, through the process of shaking the well,
A method for detecting an antigen, comprising detecting fluorescence emitted from a generated fluorescent substance in an excited state by the photoelectric conversion element. An antigen detection method using the biopolymer analyzer according to claim 2,
An antibody that binds to a specific antigen is provided at the bottom of the well as the probe,
Next, a solution containing an arbitrary antigen is injected into the well, and the probe is allowed to bind to a specific antigen in the solution.
Next, the chemical that removes the antigen that did not bind to the probe and binds to a different antigenic determinant of the same antigen as the probe to generate an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate. A solution containing a second antibody labeled with an enzyme that functions as a catalyst for the reaction is injected into the well, and the second antibody is bound to a specific antigen bound to the probe,
Thereafter, a solution containing a fixed body on which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Thereafter, a process of shaking the well and a process of applying a voltage to attract the fluorescent material to the electrode,
A method for detecting an antigen, comprising detecting fluorescence emitted from a generated fluorescent substance in an excited state by the photoelectric conversion element. An antigen detection method using the biopolymer analyzer according to claim 3,
An antibody that binds to a specific antigen is provided at the bottom of the well as the probe,
Next, a solution containing an arbitrary antigen is injected into the well, and the probe is allowed to bind to a specific antigen in the solution.
Next, the chemical that removes the antigen that did not bind to the probe and binds to a different antigenic determinant of the same antigen as the probe to generate an excited fluorescent substance that can pass through the molecular filter from a chemiluminescent substrate. A solution containing a second antibody labeled with an enzyme that functions as a catalyst for the reaction is injected into the well, and the second antibody is bound to a specific antigen bound to the probe,
Then, a solution containing magnetic particles to which the chemiluminescent substrate is fixed and impermeable to the molecular filter is injected into the well,
Thereafter, through a process of generating a magnetic field alternately by appropriately applying a voltage to the plurality of electromagnets,
A method for detecting an antigen, comprising detecting fluorescence emitted from a generated fluorescent substance in an excited state by the photoelectric conversion element.

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