JP2010071928A - Biological macromolecule analysis support apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To readily specify the sequence of sample DNAs. <P>SOLUTION: A biological macromolecule analysis: support apparatus 70 comprises a solid-state image sensing device 10; a plurality of types of spots 60 made of a known biological macromolecule and dotted on a light-receiving surface of the solid-state imaging device 10; and light sources 81-84 for making a light irradiate toward the solid-state imaging device 10. The peak wavelengths of the light sources 81-84 are different from one another. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a biopolymer analysis support apparatus using a solid-state imaging device.

  In recent years, we have been analyzing gene expression of various species. Gene expression analysis is to identify a gene expressed in a cell, and specifically, to identify mRNA transcribed from DNA encoding the gene.

  A DNA microarray and its reader have been developed for gene expression analysis. A DNA microarray is obtained by aligning and fixing cDNA having a known base sequence serving as a probe in a matrix on a solid support such as a slide glass (see, for example, Patent Document 1). Here, as a cDNA having a known base sequence, a cDNA having the same base sequence as that of a known mRNA in a specimen or a part thereof is used. Gene expression analysis using a DNA microarray and its reader is performed as follows.

  First, a DNA microarray is prepared in which a plurality of types of cDNAs with known 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, and cDNA labeled with a fluorescent substance (hereinafter referred to as sample DNA) is synthesized using reverse transcriptase. Next, when sample DNA labeled with a fluorescent substance is added onto the DNA microarray, the sample DNA is immobilized on the DNA microarray by hybridizing with the probe DNA having a complementary base sequence. When excited, the fluorescent substance that labels the sample DNA emits fluorescence from the position of the probe DNA to which the sample DNA is bound.

Next, the DNA microarray is set in a reader and analyzed by the reader. The reader moves the irradiation point of excitation light two-dimensionally with respect to the DNA microarray, and simultaneously scans the DNA microarray two-dimensionally with a condenser lens and a photomultiplier. The fluorescence emitted from the fluorescent material excited by the excitation light is collected by a condensing lens, and the fluorescence intensity is measured with a photomultiplier to measure the fluorescence intensity distribution in the surface of the DNA microarray. The fluorescence intensity distribution on the microarray is output as a two-dimensional image. In the output image, the portion having high fluorescence intensity indicates that sample DNA having a base sequence complementary to the base sequence of the probe DNA is included. Therefore, it is possible to identify which mRNA of the known sequence is expressed in the specimen depending on which part of the two-dimensional image has high fluorescence intensity.
JP 2000-1312237 A

  Incidentally, the inventors have developed a biopolymer analysis chip in which probe DNA is spotted on the light receiving surface of a solid-state imaging device. In such a biopolymer analysis chip, a bright part of an image acquired by a solid-state imaging device corresponds to a spot to which sample DNA is attached. Therefore, by specifying the bright part, the spot to which the sample DNA is attached can be specified, and the sequence of the sample DNA can be specified. In such a biopolymer analysis chip, since the spots are scattered on the light receiving surface of the solid-state imaging device, there is an advantage that a lens or the like is not required and the apparatus is downsized.

Here, various types of labeled fluorescent substances exist, and the absorption peak wavelength and the fluorescence peak wavelength of the excitation light are different. For this reason, sufficient fluorescence may not be obtained unless the light source emits light corresponding to the absorption peak wavelength of the excitation light of the specific fluorescent substance applied to the hybridization, which is an obstacle to specify the base sequence of the sample DNA. It was.
Therefore, the present invention has been made to solve such problems, and is to make it possible to easily specify the sequence of sample DNA.

In order to solve the above problems, according to the present invention,
A solid-state imaging device;
A plurality of types of spots made of known biopolymers and scattered on the light receiving surface of the solid-state imaging device,
There is provided a biopolymer analysis support apparatus, comprising: a plurality of light sources that irradiate light having different peak wavelength ranges toward the solid-state imaging device.
Preferably, the biopolymer analysis support apparatus sequentially turns on the plurality of light sources, and causes the solid-state imaging device to perform an imaging operation when the light sources are turned on to obtain a control unit. In addition.
Preferably, the control unit performs processing such as addition and subtraction of image data acquired when the light sources are turned on.

  According to the present invention, images from a plurality of light sources are acquired by a solid-state imaging device, and when these images are used, the difference in brightness between a bright portion and a non-light portion of the image can be increased. Therefore, a spot in a bright part can be easily identified, and the sample DNA sequence can be easily identified.

  Hereinafter, preferred embodiments for carrying out the present invention will be described 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.

[1] Overall Configuration of Biopolymer Analysis Chip FIG. 1 is a perspective view showing the biopolymer analysis chip 1 and four light sources 81 to 84. The biopolymer analysis chip 1 includes a solid-state imaging device 10 and a plurality of spots 60 spotted on the light receiving surface of the solid-state imaging device 10.

  The solid-state imaging device 10 is attached under the light sources 81 to 84. In addition, the solid-state imaging device 10 can be removed from a position below the light sources 81 to 84. The light sources 81 to 84 are disposed on the light receiving surface of the solid-state imaging device 10. The light sources 81 to 84 have different peak wavelengths of emitted light. Specifically, the characteristics of the light sources 81 to 84 are shown in FIG. As shown in FIG. 2, the light source 81 emits first excitation light and has a peak at 380 nm. The light source 82 emits second excitation light and has a peak at 390 nm. The light source 83 emits third excitation light and has a peak at 400 nm. The light source 84 emits fourth excitation light and has a peak at 435 nm. These wavelengths are merely examples, and are arbitrary depending on the type of fluorescent label. This is particularly effective under conditions where the optimum excitation wavelength in fluorescent labels cannot be applied. Fluorescence output using these light sources 81 to 84 as excitation light is expressed as a difference in output voltage based on the relationship between the excitation light wavelength of the fluorescent label and the fluorescence output intensity on the light receiving surface of the solid-state imaging device. In the spot portion that does not generate the fluorescence output, the difference in the output voltage is smaller than the change in the fluorescence output portion, and the fluorescent label of the spot 60 can be easily identified.

  FIG. 3 is an enlarged plan view of one spot 60 in FIG. In the solid-state imaging device 10, light receiving elements 20 including a plurality of double gate transistors are arranged vertically and horizontally as photoelectric conversion elements.

[2] Solid-State Imaging Device The solid-state imaging device 10 will be described with reference to FIGS. 4 is a plan view showing one light receiving element 20, and FIG. 5 is a cross-sectional view taken along line VV in FIG.

  As shown in FIG. 5, in the solid-state imaging device 10, a transparent substrate 11, a bottom gate insulating film 13, a top gate insulating film 21, a protective insulating film 23, and a spot fixing layer 24 are stacked. As shown in FIG. 3, the solid-state imaging device 10 is provided with a plurality of bottom gate lines 12a, source lines 18a, drain lines 19a, and top gate lines 22a.

  The transparent substrate 11 has a property of transmitting light (hereinafter referred to as “light transmissive”) and an insulating property, and is a glass substrate (for example, a quartz glass substrate), a plastic substrate (for example, made of polycarbonate or PMMA). Substrate) Other insulating transparent substrate.

  The bottom gate insulating film 13, the top gate insulating film 21, and the protective insulating film 23 have an insulating property and a light transmitting property. The bottom gate insulating film 13, the top gate insulating film 21, and the protective insulating film 23 have insulating properties and optical transparency, and are, for example, a silicon nitride film or a silicon oxide film.

In the solid-state imaging device 10, the light receiving element 20 is used as a photoelectric conversion element. A plurality of light receiving elements 20, 20,... Are arranged on the transparent substrate 11 in a two-dimensional array, particularly in a matrix. These light receiving elements 20, 20,... Are collectively covered with a protective insulating film 23.
3 shows 100 light receiving elements 20, 20,... Of 10 rows × 10 columns, the number of rows and the number of columns can be arbitrarily set.

  4 and 5, the light receiving element 20 includes a bottom gate electrode 12, a bottom gate insulating film 13, a semiconductor film 14, a channel protective film 15, an impurity semiconductor film 16, an impurity semiconductor film 17, a source electrode 18, and a drain. The electrode 19, the top gate insulating film 21, and the top gate electrode 22 are included.

  The bottom gate electrode 12 is formed between the transparent substrate 11 and the bottom gate insulating film 13. The semiconductor film 14, the channel protective film 15, the impurity semiconductor film 16, the impurity semiconductor film 17, the source electrode 18 and the drain electrode 19 are formed between the bottom gate insulating film 13 and the top gate insulating film 21. The top gate electrode 22 is formed between the top gate insulating film 21 and the protective insulating film 23.

  The bottom gate electrode 12 is formed on the transparent substrate 11 for each light receiving element 20. Further, ten bottom gate lines 12a, 12a,... Are formed between the transparent substrate 11 and the bottom gate insulating film 13, and these bottom gate lines 12a, 12a,. It is extended. The bottom gate electrodes 12 of the light receiving elements 20, 20,... In the same row arranged in the horizontal direction are 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 semiconductor film 14 is opposed to the bottom gate electrode 12 with the bottom gate insulating film 13 sandwiched between the semiconductor film 14 and the bottom gate electrode 12. The semiconductor film 14 is formed independently for each light receiving element 20. The semiconductor film 14 is a light receiving portion, and electron-hole pairs in an amount corresponding to the amount of fluorescence incident on the semiconductor film 14 are formed in the semiconductor film 14. The semiconductor film 14 is made of amorphous silicon or the like.

  The channel protective film 15 is formed on the central portion of the semiconductor film 14. The channel protective film 15 is patterned independently for each light receiving element 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 is a transparent insulating film that protects the semiconductor film 14 from an etchant used for patterning. When light is incident on the semiconductor film 14, electron-hole pairs generated in the semiconductor film 14 in an amount according to the amount of incident light accumulate in the vicinity of the interface between the channel protective film 15 and the semiconductor film 14.

The impurity semiconductor film 16 is formed so as to overlap a part of the semiconductor film 14. Part of the impurity semiconductor film 16 overlaps the channel protective film 15. The impurity semiconductor film 17 is formed so as to overlap another part of the semiconductor film 14. Part of the impurity semiconductor film 17 overlaps the channel protective film 15. The impurity semiconductor films 16 and 17 are patterned independently for each light receiving element 20. The impurity semiconductor films 16 and 17 are made of amorphous silicon (n ⁺ silicon) containing n-type impurities (for example, phosphine).

  The source electrode 18 overlaps the impurity semiconductor film 16. The drain electrode 19 overlaps the impurity semiconductor film 17. The source electrode 18 and the drain electrode 19 are formed for each light receiving element 20. Ten source lines 18a, 18a,... And drain lines 19a, 19a,... Are formed between the bottom gate insulating film 13 and the top gate insulating film 21, respectively, and these source lines 18a, 18a,. Lines 19a, 19a,... Extend in the column direction. The source electrodes 18 of the light receiving elements 20, 20,... In the same column arranged in the vertical direction are formed integrally with the common source line 18a, and the light receiving elements 20 in the same column arranged in the vertical direction. , 20,... 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 top gate electrode 22 is opposed to the semiconductor film 14 with the channel protective film 15 and the top gate insulating film 21 sandwiched between the top gate electrode 22 and the semiconductor film 14. The top gate electrode 22 is formed on the top gate insulating film 21 for each light receiving element 20. Further, a plurality of top gate lines 22a, 22a,... Are formed between the top gate insulating film 21 and the protective insulating film 23, and these top gate lines 22a, 22a,. It extends to. The top gate electrodes 22 of the light receiving elements 20, 20,... In the same row arranged in the horizontal direction are 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).
Corrugated rack

  A spot fixing layer 24 is formed on the surface of the protective insulating film 23. The spot fixing layer 24 fixes the spot 60 by being covalently bonded to the later-described probe to be the spot 60 with a silane coupling agent or the like.

  The solid-state imaging device 10 configured as described above uses the surface of the spot fixing layer 24 as a light-receiving surface, and the amount of light received by the semiconductor film 14 of the light-receiving element 20 when the solid-state imaging device 10 is driven is converted into an electrical signal. Is done.

[3] Spots As shown in FIGS. 1 and 3, a plurality of spots 60 are formed on the light receiving surface of the solid-state imaging device 10 (the surface of the spot fixing layer 24). 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 onto the light receiving surface of the solid-state imaging device 10 and drying it. Hereinafter, a case where cDNA having a known base sequence is used as a probe will be described.

In one spot 60, a crowd of many single-stranded probe DNAs having the same base sequence is immobilized, and the base sequences of the probe DNAs are different for each spot 60. As the probe DNA, a known mRNA base sequence is used, or a DNA having the same or complementary base sequence as a part thereof is used. Specifically, for example, a cDNA library prepared from the same cell specimen as that used for fluorescently labeled DNA can be used.
As shown in FIG. 3, one spot 60 is formed so as to overlap a plurality of light receiving elements 20.

[4] Biopolymer Analysis Support Device A biopolymer analysis support device 70 for setting the biopolymer analysis chip 1 will be described with reference to FIG. FIG. 6 is a block diagram showing the configuration of the biopolymer analysis support device 70.

The biopolymer analysis support device 70 includes the biopolymer analysis chip 1, a control unit 71, a storage device 72, drivers 74 to 76, an output device 77, and light sources 81 to 84.
As shown in FIG. 1, when the solid-state imaging device 10 is mounted under the light sources 81 to 84, the top gate lines 22a, 22a,... Of the solid-state imaging device 10 are connected to the terminals of the top gate driver 74, Lines 12a, 12a,... Are connected to the terminals of the bottom gate driver 75, and drain lines 19a, 19a,. Further, 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,. 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 top gate driver 74 sequentially outputs a reset pulse for eliminating carriers such as holes accumulated in the semiconductor film 14 and the like of the light receiving element 20 for each top gate line 22a, 22a,. (See FIG. 7). The level of the reset pulse is, for example, a high level of +5 [V]. On the other hand, when the top gate driver 74 does not output a reset pulse, the top gate driver 74 has a low level of −20 [V] for holding a hole which is one carrier of the electron-hole pairs formed in the semiconductor film 14. Is applied to each top gate line 22a. As the top gate driver 74, a shift register can be used.

  The bottom gate driver 75 sequentially outputs a read pulse for forming a channel in the semiconductor film 14 of the light receiving element 20 to the bottom gate lines 12a, 12a,... Of each row (see FIG. 7). The level of the read pulse is +10 [V] on level (high level), and the level when the read pulse is not output is ± 0 [V] off level (low level). As the bottom gate driver 75, a shift register can be used.

  After the top gate driver 74 outputs a reset pulse to the top gate line 22a of any row, carrier accumulation for accumulating holes that are carriers of one of electron-hole pairs generated according to the incidence of fluorescence. The top gate driver 74 and the bottom gate driver 75 shift the output signal so that the bottom gate driver 75 outputs a read pulse to the bottom gate line 12a of the same row after a period. That is, in each row, the timing at which the read pulse is output is delayed from the timing at which the reset pulse is output. The period from the start of reset pulse input to the top gate line 22a of any row to the end of read pulse input to the bottom gate line 12a of the same row is the selection period of that row. is there. The level of the reset pulse is a high level of +5 [V], and the level when the reset pulse is not output is a low level of −20 [V].

  The drain driver 76 outputs a precharge pulse to all the drain lines 19a, 19a,... Between the reset pulse output and the read pulse output in the selection period of each row. ing. Thereafter, the potential of the drain line 19a due to the precharge pulse is attenuated in accordance with the current flowing through the semiconductor film 14 of the light receiving element 20 in accordance with the amount of incident fluorescent light. The level of the precharge pulse is a high level of +5 [V], and the level when the precharge pulse is not output is a low level of ± 0 [V]. Further, the drain driver 76 amplifies the voltage of the drain lines 19a, 19a,... Displaced by the incidence of fluorescence and outputs the amplified voltage to the A / D converter of the control unit 71.

The control unit 71 has a function of turning on / off the light sources 81 to 84.
The control unit 71 outputs control signals to the top gate driver 74, the bottom gate driver 75, and the drain driver 76, thereby driving the solid-state imaging device 10 to the top gate driver 74, the bottom gate driver 75, and the drain driver 76. It has a function to perform. The controller 71 inputs an electrical signal from the drain driver 76 by driving the solid-state imaging device 10, and A / D-converts the electrical signal to thereby convert the light amount distribution along the light receiving surface of the solid-state imaging device 10 into a two-dimensional image. Get as data.
The control unit 71 has a function of causing the output device 77 to output an image according to the image data. The output device 77 is, for example, a plotter, a printer, or a display.
The control unit 71 has a function of recording image data in the storage device 72.

  The storage device 72 is a hard disk drive or a semiconductor storage device.

[5] Analysis procedure [5-1] Preparation of fluorescently labeled DNA As a sample to be analyzed by the biopolymer analysis chip 1, DNA can be used. As a sample DNA, mRNA obtained by extracting mRNA expressed in an arbitrary cell specimen and performing RT-PCR reaction using reverse transcriptase can be used. The cDNA is labeled with a fluorophore. Examples of the phosphor include Cy2 (absorption peak wavelength 491 nm, fluorescence peak wavelength 509 nm), Cy3 (absorption peak wavelength 553 nm, fluorescence peak wavelength 569 nm), Cy5 (absorption peak wavelength 645 nm, fluorescence peak) manufactured by GE Healthcare Biosciences. For example, a wavelength of 664 nm).

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

[5-2] Hybridization First, as shown in FIG. 7, a solution containing fluorescently labeled DNA (hereinafter, fluorescently labeled DNA) is applied to the light receiving surface of the solid-state imaging device 10. It should be noted that the fluorescently labeled DNA solution may be dropped on each of the spots 60, 60,. At this time, the fluorescently labeled DNA solution is heated so that the DNA becomes a single strand. Further, the light receiving surface of the solid-state imaging device 10 is also heated so that the DNA of the spot 60 becomes a single strand.

  Next, the solid-state imaging device 10 is cooled. Then, of the fluorescently labeled DNA in the fluorescently labeled DNA solution, the fluorescently labeled DNA complementary to the probe DNA of the spot 60 hybridizes with the probe DNA. On the other hand, fluorescently labeled DNA that is not complementary to the probe DNA does not bind to the spot 60.

  Thereafter, the fluorescence-labeled DNA solution is washed away from the light-receiving surface of the solid-state imaging device 10 with a washing buffer solution, and the non-hybridized fluorescent-labeled DNA is removed from the light-receiving surface of the solid-state imaging device 10.

[5-3] Detection of Sample After performing the above processing, the biopolymer analysis chip 1 is set in the biopolymer analysis support device 70. Thereby, the top gate driver 74, the bottom gate driver 75, and the drain driver 76 are connected to the top gate lines 22a, 22a,..., The bottom gate lines 12a, 12a,. Further, the source lines 18a, 18a,... Are connected to a constant voltage source. Thereafter, the control unit 71 is activated.

  When the control unit 71 is activated, the control unit 71 turns on the light source 81. The first excitation light is irradiated to the spots 60, 60,. Then, fluorescence is emitted from the spot 60 where the fluorescently labeled DNA is bound to the probe DNA. On the other hand, no fluorescence is emitted from the spot 60 where the fluorescently labeled DNA is bound to the probe DNA.

  Then, the control unit 71 drives the solid-state imaging device 10 by outputting control signals to the top gate driver 74, the bottom gate driver 75, and the drain driver 76 with the light source 81 turned on. Thereby, the control unit 71 acquires image data from the drain driver 76 and records the image data in the storage device 72.

Here, the imaging operation of the solid-state imaging device 10 will be described.
The top gate driver 74 sequentially outputs reset pulses from the top gate line 22a of the first row to the top gate line 22a of the last row, and the bottom gate driver 75 sequentially reads read pulses to the bottom gate lines 12a, 12a, 12a,. Is output. At that time, the drain driver 76 outputs a precharge pulse to all the drain lines 19a, 19a,... Between the reset period in which the reset pulse is output in each row and the period in which the read pulse is output in each row. .

  The operation of each light receiving element 20 in the i-th row will be described in detail. As shown in FIG. 7, when the top gate driver 74 outputs a reset pulse to the i-th top gate line 22a, the i-th top gate line 22a goes to a high level. While the i-th top gate line 22a is at a high level (this period is referred to as a reset period), in each light-receiving element 20 in the i-th row, the semiconductor film 14, the semiconductor film 14, the channel protective film 15, Carriers accumulated in the vicinity of the interface (here, holes) are repelled and discharged by the voltage of the top gate electrode 22.

  Next, the top gate driver 74 finishes outputting the reset pulse to the i-th top gate line 22 a, and the electron-hole generated in the semiconductor film 14 when the fluorescence enters the semiconductor film 14. A negative potential (−20 [V]) is output to the top gate line 22a in order to electrically capture holes in the pair. That is, the reset pulse of the top gate line 22a in the i-th row ends. Until the read pulse is output to the bottom gate line 41 in the i-th row (this period is referred to as a carrier accumulation period), an amount of electron-hole pairs according to the amount of light is generated in the semiconductor film 14. However, the holes are accumulated in the semiconductor film 14 or in the vicinity of the interface between the semiconductor film 14 and the channel protective film 15 by the electric field of the top gate electrode 22.

  Next, during the carrier accumulation period, the drain driver 76 outputs a precharge pulse to all the drain lines 19a, 19a,. While the precharge pulse is output (referred to as a precharge period), in each light receiving element 20 in the i-th row, the potential applied to the top gate electrode 22 is −20 [V]. Then, the electric field due to the holes accumulated in the semiconductor film 14 or in the vicinity of the interface between the semiconductor film 14 and the channel protective film 15 due to the negative electric field inevitably cancels the negative electric field completely, so that the channel region of the semiconductor film 14 Therefore, it cannot be a positive electric field that can form an n-channel. Then, since the potential applied to the bottom gate electrode 12 is ± 0 [V], a channel is formed in the semiconductor film 14 even if a potential difference of the precharge pulse occurs between the drain electrode 19 and the source electrode 18. In other words, no current flows between the drain electrode 19 and the source electrode 18. Since no current flows between the drain electrode 19 and the source electrode 18 in the precharge period, the precharge pulse output to the drain lines 19a, 19a,. Charge is charged.

  Next, the drain driver 76 finishes outputting the precharge pulse, and the bottom gate driver 75 outputs a read pulse to the i-th bottom gate line 12a. While the bottom gate driver 75 outputs a read pulse to the i-th bottom gate line 12a (this period is referred to as a read period), the bottom gate electrode 12 of each light-receiving element 20 in the i-th row is +10 [ Since the potential V] is applied, each light receiving element 20 in the i-th row is turned on.

  In the read period, the carriers accumulated in the carrier accumulation period work so as to alleviate the negative electric field of the top gate electrode 22, so that the amount of incident light is sufficient and the amount of carriers is sufficient, the bottom gate electrode 12 An n channel is formed in the semiconductor film 14 together with the positive electric field, and a current flows from the drain electrode 19 to the source electrode 18. Therefore, in the read period, the voltages of the drain lines 19a, 19a,... Tend to gradually decrease with time due to the drain-source current.

  As the amount of light incident on the semiconductor film 14 in the carrier accumulation period increases, the number of accumulated carriers also increases. As the number of accumulated carriers increases, the level of the current flowing from the drain electrode 19 to the source electrode 18 in the lead period also increases. Become. Therefore, the decreasing tendency of the voltage of the drain lines 19a, 19a,... During the read period is deeply related to the amount of light incident on the semiconductor film 14 during the carrier accumulation period.

  .. Between the i-th read period and the next (i + 1) -th precharge period, the voltages on the drain lines 19a, 19a,. 76. The voltage indicates the amount of light, and the voltage is input to the control unit 71 and A / D converted.

  The above-described series of image reading operations is set as one cycle, and the light quantity distribution on the light receiving surface of the solid-state imaging device 10 is acquired as image data by the control unit 71 by repeating the same processing procedure for each light receiving element 20 in all rows. Is done.

  After the imaging by the solid-state imaging device 10 as described above, the control unit 71 turns off the light source 81 and continues to turn on the light source 82. Then, the control unit 71 drives the solid-state imaging device 10 by the top gate driver 74, the bottom gate driver 75, and the drain driver 76 with the light source 82 turned on. Thereby, the control unit 71 acquires image data from the drain driver 76 and records the image data in the storage device 72.

  Next, the control unit 71 turns off the light source 82 and continues to turn on the light source 83. Then, the control unit 71 drives the solid-state imaging device 10 with the top gate driver 74, the bottom gate driver 75, and the drain driver 76 with the light source 83 turned on. Thereby, the control unit 71 acquires image data from the drain driver 76 and records the image data in the storage device 72.

  Next, the control unit 71 turns off the light source 83 and continues to turn on the light source 84. Then, the control unit 71 drives the solid-state imaging device 10 with the top gate driver 74, the bottom gate driver 75, and the drain driver 76 with the light source 84 turned on. Thereby, the control unit 71 acquires image data from the drain driver 76 and records the image data in the storage device 72. Thereafter, the control unit 71 turns off the light source 84. The image data includes the position of each light receiving element 20 in the solid-state imaging device 10 and the output of each light receiving element 20, and the control unit 71 performs hybridization because no probe DNA is provided. The sum or average value of the outputs of the light receiving elements 20 corresponding to the spots 60 that did not exist is used as the background output, and the output of the region having the highest sum or average of the outputs of the light receiving elements 20 corresponding to the spots 60 provided with the probe DNA is used. Set the value as the signal output by hybridization. Here, the background output and signal output acquired by the light source 81 are 100 and 110, respectively, the background output and signal output acquired by the light source 82 are 100 and 108, and the background output and signal acquired by the light source 83 are respectively. The outputs were 100 and 115, respectively, and the background output and signal output acquired by the light source 84 were 100 and 100, respectively.

  As described above, each image data from the light sources 81 to 84 is recorded in the storage device 72. The control unit 71 selects the image data having the largest ratio of the signal output to the background output from these image data, and causes the output device 77 to output an image according to the image data, thereby easily performing the hybridization. Judgment can be made. Alternatively, even if the background output is subtracted from the added value of the signal output obtained by adding the outputs of the light receiving elements 20 at the same positions of the respective image data by the light sources 81 to 84, the difference is larger than the difference in the case of a single light source. Large, hybridization can be easily determined.

As described above, according to the present embodiment, after processing the image data from the light sources 81 to 84, an image according to the processed image data is output to the output device 77, so fluorescence was emitted from the image. The difference (contrast) between the darkness and the darkness between the portion and the portion other than the portion becomes large. For this reason, it is easy to specify a portion emitting fluorescence from the output image. That is, it is easy to specify the probe DNA spot 60 complementary to the fluorescently labeled DNA. If a light source that emits light in a wavelength region that is not excited, such as the light source 84, is used, the background output and the signal output are almost the same value, and the background output can be grasped more.
In the above embodiment, the double gate transistor is a light receiving element, but the present invention is not limited to this as long as the element can receive fluorescence.

It is the perspective view which showed the principal part of the biopolymer analysis assistance apparatus. It is the graph which showed the characteristic of the light source. It is the top view which showed a part of biopolymer analysis chip. It is the top view which showed the pixel of the solid-state imaging device. It is VV arrow sectional drawing. It is the block diagram which showed roughly the structure of the biophotopolymer analysis assistance apparatus. It is the chart which showed transition of the signal of a solid imaging device.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Solid-state imaging device 60 Spot 70 Biopolymer analysis assistance apparatus 71 Control part 81-84 Light source

Claims (3)

A solid-state imaging device;
A plurality of types of spots made of known biopolymers and scattered on the light receiving surface of the solid-state imaging device,
A biopolymer analysis support apparatus comprising: a plurality of light sources that irradiate light having different peak wavelength ranges toward the solid-state imaging device.   2. The apparatus according to claim 1, further comprising a control unit that sequentially turns on the plurality of light sources, and causes the solid-state imaging device to perform an imaging operation when the light sources are turned on to acquire image data. Biopolymer analysis support device.   The biopolymer analysis support apparatus according to claim 2, wherein the control unit performs processing such as addition and subtraction of image data acquired when the light sources are turned on.

Images