JP2003174543A - Method for correcting jitter in scanner and scanner capable of correcting jitter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for correcting jitter in a scanner structured to convert rotation motion of a motor into linear motion so that a sample stage may perform reciprocating. <P>SOLUTION: In this method for correcting jitter in the scanner, a linear scale is provided whose resolution is lower than that of a rotary encoder, a linear encoder sensor 48 fixed to a substrate detects a black-and-white pattern of the linear scale of a linear encoder 47 fixed to the sample stage to generate analog data. Timing clock of the rotary encoder used to fetch an image supported by a sample is used to threshold process the analog data generated by the linear encoder sensor with the same resolution as that of image data, generating binarized data for correction. Image data generated by an optical detector is corrected on the basis of data about the position of a boundary pixel wherein the threshold processed data for correction changes from 0 to 1 or from 1 to 0. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for correcting jitter in a scanner configured to convert a rotary motion of a motor into a linear motion to reciprocate a sample stage, and a rotary motion of a motor capable of correcting the jitter. To a linear motion to reciprocate the sample stage, and more particularly, to convert the rotary motion of the motor into a linear motion to reciprocate the sample stage. Jitter in a configured scanner can be corrected easily and at low cost. Jitter correction method and jitter can be corrected easily and at low cost. The present invention relates to a high resolution scanner configured to convert motion into reciprocating motion of a sample stage.

[0002]

2. Description of the Related Art When a radiation is irradiated, the energy of the radiation is absorbed, stored and recorded, and then excited by using an electromagnetic wave of a specific wavelength range. A photostimulable phosphor having the property of emitting a stimulating amount of light is used as a radiation detection material, and a substance having a radioactive label is administered to an organism, and then the organism or tissue of the organism is treated. A portion of the sample is used as a sample, and this sample is overlapped with a stimulable phosphor sheet provided with a stimulable phosphor layer for a certain period of time to store and record radiation energy in the stimulable phosphor. , Scanning the stimulable phosphor layer with electromagnetic waves to excite the stimulable phosphor and photoelectrically detecting the stimulable light emitted from the stimulable phosphor to generate a digital image signal. Image processing, CRT On a recording material such as a display unit or on the photographic film, the autoradiographic analyzing system is configured to reproduce an image has been known (for example, Kokoku 1-70884 and JP Kokoku 1-70
882, Japanese Patent Publication No. 4-3962, etc.).

An autoradiography analysis system using a stimulable phosphor sheet as a radiation detecting material not only requires a chemical treatment called a developing treatment, unlike the case where a photographic film is used, but also was obtained. By subjecting the digital data to data processing, there is an advantage that the analysis data can be reproduced or a quantitative analysis by a computer can be performed as desired.

On the other hand, there is known a fluorescence analysis system using a fluorescent substance such as a fluorescent dye as a labeling substance instead of the radioactive labeling substance in the autoradiography analysis system. According to this fluorescence analysis system, by detecting the fluorescence emitted from the fluorescent substance, the gene sequence, the expression level of the gene, the metabolism, absorption, and excretion routes of the administered substance in the experimental mouse, the state, the separation of the protein, Identification or evaluation of molecular weight and characteristics can be performed. For example, a solution containing plural kinds of protein molecules to be electrophoresed is electrophoresed on the gel support, and then the gel support is subjected to fluorescence. An image is generated by staining the electrophoresed protein by immersing it in a solution containing a dye, exciting the fluorescent dye with excitation light, and detecting the resulting fluorescence, and then producing an image on the gel support. The position and quantitative distribution of protein molecules can be detected. Alternatively, by Western blotting,
A probe and a protein molecule prepared by transferring at least a part of the electrophoresed protein molecule onto a transfer support such as nitrocellulose and labeling an antibody that specifically reacts with the target protein with a fluorescent dye are prepared. By selectively associating and selectively labeling a protein molecule that binds only to an antibody that specifically reacts,
By exciting the fluorescent dye with the excitation light and detecting the generated fluorescence, an image can be generated and the position and quantitative distribution of the protein molecule on the transfer support can be detected. In addition, after adding a fluorescent dye to a solution containing a plurality of DNA fragments to be electrophoresed, the plurality of DNA fragments are electrophoresed on a gel support, or on a gel support containing a fluorescent dye. , A plurality of DNA fragments are electrophoresed, or a plurality of DNA fragments are electrophoresed on a gel support, and then the gel support is immersed in a solution containing a fluorescent dye. DNA fragments are labeled, a fluorescent dye is excited by excitation light, and the resulting fluorescence is detected to generate an image, and the distribution of DNA on the gel support is detected, or a plurality of DNAs are detected.
The fragments are electrophoresed on a gel support, followed by DNA
Denaturation, and then by Southern blotting, at least a part of the denatured DNA fragment is transferred onto a transfer support such as nitrocellulose, and DNA or RNA complementary to the target DNA is fluorescent dye. A probe DNA or probe RN prepared by hybridizing a probe prepared by labeling with
Only the DNA fragment complementary to A is selectively labeled, the fluorescent dye is excited by the excitation light, and the resulting fluorescence is detected to generate an image, so that the DNA of interest on the transfer support is detected. The distribution can be detected. further,
DN containing a target gene labeled with a labeling substance
A DNA probe complementary to A is prepared, hybridized with the DNA on the transcription support, and the enzyme is allowed to bind to the complementary DNA labeled with a labeling substance, and then contacted with a fluorescent substrate for fluorescence. An image is generated by changing the substrate to a fluorescent substance that emits fluorescence, exciting the generated fluorescent substance with excitation light, and detecting the generated fluorescence,
It is also possible to detect the distribution of the target DNA on the transcription support. This fluorescence analysis system has an advantage that gene sequences and the like can be easily detected without using radioactive substances.

Furthermore, in recent years, cells at different positions on the surface of a carrier such as a slide glass plate or a membrane filter,
Viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, cDNA
A specific binding substance, such as A, DNA, or RNA, which can be specifically bound to a substance of biological origin and whose base sequence, base length, composition, etc. is known, is dropped using a spotter device. , Forming a large number of independent spots, then cells, viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, c
A substance derived from a living body, such as DNA, DNA, or mRNA, which is collected from the living body by extraction or isolation, or which is further subjected to a chemical treatment, a chemical modification, or the like, such as a fluorescent substance or a dye. A substance labeled with a labeling substance is bound to a specific binding substance by hybridization or the like, to a microarray that is specifically bound,
A microarray analysis system has been developed which irradiates excitation light and photoelectrically detects light such as fluorescence emitted from a labeling substance such as a fluorescent substance or a dye to analyze a substance derived from a living body. According to this microarray analysis system,
A large number of spots of specific binding substances are formed at high density at different positions on the surface of a carrier such as a slide glass plate or a membrane filter, and the substance of biological origin labeled with the labeling substance is hybridized, thus In time, there is an advantage that it is possible to analyze a substance of biological origin.

[0006] In addition, cells, viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, cDNAs, DNAs, RNAs, etc. derived from living organisms are located at different positions on the surface of a carrier such as a membrane filter. The specific binding substance that can specifically bind to the substance of which the base sequence, base length, composition, etc. are known is dropped using a spotter device to form a large number of independent spots. , Then, cells, viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, cDNAs, DNAs, mRNAs, etc., collected from the living body by extraction or isolation, or
Furthermore, a substance derived from a living body, which has been subjected to a chemical treatment, a chemical modification, or the like, and which is labeled with a radioactive labeling substance, is specifically bound to a specific binding substance by hybridization or the like. Macro array,
The stimulable phosphor layer containing the stimulable phosphor is brought into close contact with the stimulable phosphor sheet, and the stimulable phosphor layer is exposed.
After that, the photostimulable phosphor layer is irradiated with excitation light, the photostimulable light emitted from the photostimulable phosphor layer is photoelectrically detected, and biochemical analysis data is generated. A macroarray analysis system using a radiolabeled substance for analyzing is also developed.

In all of these systems, a sample is irradiated with excitation light to excite a labeling substance such as a stimulable phosphor or a fluorescent substance, and the stimulable light emitted from the stimulable phosphor or Photochemical analysis data is generated by photoelectrically detecting fluorescence emitted from a fluorescent substance. The biochemical analysis data generation device used for these systems uses a scanner. , And those using a two-dimensional sensor.

Compared to the case of using a two-dimensional sensor, the use of a scanner has an advantage that data can be generated with high resolution.

[0009]

When generating data for biochemical analysis using a scanner,
Since it is efficient to generate data for biochemical analysis using a bidirectional scanning scanner configured to reciprocate the excitation light in the main scanning direction and scan the sample with the excitation light, It is common to use bi-directional scanning scanners.

In such a bidirectional scanning scanner, the position of the sample stage or the scanning optical system is monitored by an absolute position counter, and based on the position monitored by the absolute position counter, for each scanning line,
Although it is configured to start and stop the reading of data, the position of the sample stage or scanning optical system is monitored by an absolute position counter, depending on the mechanical precision of the scanning mechanism and the load to be moved, etc. Even if the reading is started and ended, the reading start position and the reading end position of the data are different for each scanning line depending on the scanning direction or the device, and so-called generated data is called There was a problem that jitter occurred.

In particular, in the case of a microarray system, fluorescence from a fluorescent substance labeling a substance of biological origin hybridized with a specific binding substance is photoelectrically detected on the surface of a slide glass plate or the like. Therefore, it is desirable to use a confocal optical system in order to improve the S / N ratio when generating data. For that purpose, it is necessary to reciprocate the stage on which the sample is placed in the main scanning direction. As a result, jitter is likely to occur remarkably, which is a serious problem.

Further, in order to reduce the cost, a crank mechanism is used to convert the rotational movement of the output shaft of the motor into a linear reciprocating movement, and a rotary encoder attached to the output shaft of the motor converts the rotational movement of the sample stage. When the sample stage is configured to reciprocate in the main scanning direction using a timing belt while detecting the position, the rotation of the output shaft of the motor detected by the rotary encoder due to the elongation of the timing belt, etc. Since the angle and the positional relationship of the sample stage change, jitter is likely to occur, and it has been desired to develop a method for effectively preventing the occurrence of jitter.

Therefore, according to the present invention, it is possible to easily and inexpensively correct the jitter in the scanner configured to reciprocate the sample stage by converting the rotational motion of the motor into the linear motion. Jitter correction method that can be performed and a high-resolution scanner that can correct jitter easily and at low cost, is configured to reciprocate the sample stage by converting the rotational motion of the motor into linear motion. It is intended to provide.

[0014]

The object of the present invention is to:
The rotary stage attached to the rotary shaft of the motor detects the position of the sample stage on which the sample carrying the image is set by converting the rotary motion of the motor into a linear motion. While reciprocating in the scanning direction, the substrate is moved in the sub-scanning direction orthogonal to the main scanning direction, the excitation light is used to scan the sample set on the sample stage, and the sample is emitted from the sample. A method for correcting jitter in a scanner that is configured to generate image data by photoelectrically detecting light that is generated by a photodetector, and has a linear scale that is coarser than the resolution of the rotary encoder. White of the linear scale of a linear encoder mounted on one of the sample stage and the substrate A pattern is detected by a linear encoder sensor attached to the other of the sample stage and the substrate to generate analog data and using the timing clock of the rotary encoder used to capture the image carried on the sample. , The analog data generated by the linear encoder sensor is binarized with the same resolution as the image data to generate correction binary data, and the correction binary data is 0 to 1 or 1 This is achieved by a method for correcting jitter in a scanner, characterized in that the image data generated by the photodetector is corrected based on the data regarding the position of the boundary pixel which changes to 0.

According to the present invention, the black and white pattern of the linear scale of the linear encoder, which has a coarser linear scale than the resolution of the rotary encoder and is attached to one of the sample stage and the substrate, is attached to the other of the sample stage and the substrate. The analog data generated by the linear encoder sensor, using the timing clock of the rotary encoder used to capture the image carried on the sample by generating the analog data detected by the linear encoder sensor.
Binarization is performed with the same resolution as the image data to generate correction binarization data, and the correction binarization data is based on data regarding the position of a boundary pixel that changes from 0 to 1 or from 1 to 0. Since the correction binarized data is configured to correct the image data generated by the photodetector, the main scanning is performed based on the data regarding the position of the boundary pixel in which 0 to 1 or 1 to 0 changes. For each line,
Image data is divided into blocks to generate a plurality of blocks of image data, the number of pixels n included in the corresponding binarized data for correction is obtained for each block of image data, and a black-and-white pattern of a linear scale of a linear encoder is obtained. Cycle
Compared to the ideal standard number of pixels m divided by the pixel size, due to the mechanical precision of the scanning mechanism, the weight of the sample stage, the expansion and contraction of the timing belt, etc., the rotary attached to the rotation axis of the motor The rotation angle of the output shaft of the motor detected by the encoder and the positional relationship of the sample stage change, the main scanning speed varies, and jitter occurs in the image data, and the pixel number n and the reference pixel number m differ. Also in this case, the number of pixel data equal to the number n of pixels forming the image data in the block is interpolated so as to become the number of pixel data equal to the reference number m of pixels, and the number equal to the number m of reference pixels is obtained. It is possible to easily correct the jitter that occurred in the image data by correcting the pixel data of the above, and the linear resolution that is coarser than the resolution of the rotary encoder. Since may be used an inexpensive linear encoder having a scale, the jitter generated in the image data, at low cost, can be corrected.

In a preferred embodiment of the present invention, the image data is divided into blocks at the position of the boundary pixel for each main scanning line to generate a plurality of blocks of image data, and each block of the image data is generated. , The number of pixels n included in the corresponding binary data for correction is calculated, and the period of the black-and-white pattern of the linear scale of the linear encoder is compared with the reference number of pixels m divided by the pixel size to obtain the number of pixels n. And the reference pixel number m is not equal, the pixel data forming the image data in the block is corrected based on the pixel number n and the reference pixel number m.

According to a preferred embodiment of the present invention, the image data is divided into blocks at the positions of the boundary pixels for each main scanning line to generate a plurality of blocks of the image data,
For each block of image data, the number of pixels n included in the corresponding binary data for correction is obtained, and the period of the black and white pattern of the linear scale of the linear encoder is compared with the reference number of pixels m divided by the pixel size. Pixel number n and reference pixel number m
Is not equal, the pixel data forming the image data in the block is configured to be corrected based on the pixel number n and the reference pixel number m. Due to the weight of the stage and the expansion and contraction of the timing belt, the positional relationship of the sample stage changes with the rotation angle of the motor output shaft detected by the rotary encoder attached to the shaft during motor rotation, and the main scanning When the number of pixels is different from the reference number of pixels m due to the variation in speed and the occurrence of jitter in the image data, the number of pixels n forming the image data in the block
Is generated in the image data simply by interpolating the pixel data of the number equal to 1 to the pixel data of the number equal to the reference number of pixels m and correcting to the number of pixel data equal to the number of the reference pixels m. Since it is possible to correct the generated jitter, and an inexpensive linear encoder having a coarser linear scale than the resolution of the rotary encoder can be used, it is possible to correct the jitter generated in the image data at low cost. Will be possible.

In a further preferred aspect of the present invention, when the pixel number n and the reference pixel number m are not equal to each other, a number of pixel data equal to the pixel number n forming the image data in the block are Interpolation is performed so that the pixel data has the number equal to the reference pixel number m, and the pixel data is corrected to have the number equal to the reference pixel number m.

According to a further preferred embodiment of the present invention, due to the mechanical precision of the scanning mechanism, the weight of the sample stage, the expansion and contraction of the timing belt, etc., the rotary encoder mounted on the rotating shaft of the motor is used. The detected rotation angle of the output shaft of the motor and the positional relationship of the sample stage change, the main scanning speed varies,
When jitter occurs in the image data and the number of pixels n is different from the reference number of pixels m, the number of pixel data equal to the number of pixels n forming the image data in the block is equal to the reference number of pixels m. Interpolate to obtain several pixel data,
Since it is configured to correct the number of pixel data equal to the reference number of pixels m, it is possible to easily correct the jitter generated in the image data, and the linear resolution is coarser than the resolution of the rotary encoder. Since an inexpensive linear encoder having a scale may be used, it is possible to correct the jitter generated in the image data at low cost.

The object of the present invention is also to convert at least one excitation light source that emits excitation light, a sample stage on which an image-bearing sample is set, a motor, and a rotary motion of a rotary shaft of the motor into a linear motion. A main scanning mechanism that reciprocates the sample stage in the main scanning direction on the substrate, a sub-scanning mechanism that moves the substrate in the sub-scanning direction orthogonal to the main scanning direction, and the motor. A rotary encoder attached to the rotating shaft of the sample stage for detecting the position of the sample stage in the main scanning direction,
The sample set on the sample stage,
A scanner comprising a photodetector for detecting light emitted from the sample by scanning with excitation light, further comprising a linear scale coarser than the resolution of the rotary encoder, the sample stage and the substrate. A linear encoder attached to one side, a linear encoder sensor attached to the other side of the sample stage and the substrate, which detects a black-and-white pattern of the linear scale of the linear encoder, and generates analog data; By using the timing clock of the rotary encoder used to capture the carried image, the analog data generated by the linear encoder sensor is binarized with the same resolution as the image data to obtain the binarized data for correction. Binary data generator to generate And the correction binary data generated by the generating means by the binarization is generated by the photodetector based on the data regarding the position of the boundary pixel changing from 0 to 1 or from 1 to 0. This is achieved by a scanner including a data correction unit that corrects image data.

According to the invention, the scanner has a linear scale which is coarser than the resolution of the rotary encoder,
A linear encoder attached to one of the sample stage and substrate, a linear encoder sensor attached to the other of the sample stage and substrate to detect the black and white pattern of the linear scale of the linear encoder, and generate analog data. A binary clock for correction is generated by binarizing the analog data generated by the linear encoder sensor with the same resolution as the image data using the timing clock of the rotary encoder used to capture the captured image. The binarized data for generating generated by the binarized data generating unit and the binarizing unit is generated by the photodetector based on the data regarding the position of the boundary pixel changing from 0 to 1 or from 1 to 0. Is equipped with a data correction means for correcting the captured image data. From the data regarding the position of the boundary pixel at which the binary data for correction generated by the binary data generation means changes from 0 to 1 or from 1 to 0, the data correction means for each main scanning line , The image data is divided into blocks, a plurality of blocks of the image data are generated, the number of pixels n included in the corresponding correction binarized data is calculated for each block of the image data, and the linear scale black-and-white pattern of the linear encoder is obtained. Is compared with the ideal reference number of pixels m divided by the pixel size, and due to the mechanical precision of the scanning mechanism, the weight of the sample stage, the expansion and contraction of the timing belt, etc., The rotation angle of the output shaft of the motor detected by the attached rotary encoder and the positional relationship of the sample stage change, and the main scanning speed Variation,
When jitter occurs in the image data and the number of pixels n is different from the reference number of pixels m, the number of pixel data equal to the number of pixels n forming the image data in the block is equal to the reference number of pixels m. Interpolate to obtain several pixel data,
By correcting the pixel data to the number equal to the reference pixel number m, it is possible to easily correct the jitter generated in the image data, and the cost is low because the linear scale is coarser than the resolution of the rotary encoder. Since it suffices to use a linear encoder, it is possible to correct the jitter generated in the image data at low cost.

In a preferred embodiment of the present invention, the linear encoder is attached to the sample stage, and the linear encoder sensor is attached to the substrate.

In another preferred embodiment of the present invention, the linear encoder is attached to the substrate, and the linear encoder sensor is attached to the sample stage.

In a preferred embodiment of the present invention, the data correction means divides the image data into blocks at the position of the boundary pixel for each main scanning line to generate a plurality of blocks of the image data, For each block of the data, the number of pixels n included in the corresponding binary data for correction is obtained, and the period of the black and white pattern of the linear scale of the linear encoder is compared with the reference number of pixels m divided by the pixel size. Then, when the pixel number n and the reference pixel number m are not equal, the pixel data forming the image data in the block is corrected based on the pixel number n and the reference pixel number m. Has been done.

According to a preferred embodiment of the present invention, the data correction means divides the image data into blocks at the position of the boundary pixel for each main scanning line to generate a plurality of blocks of the image data. For each block, the number of pixels n included in the corresponding binary data for correction is calculated, and the period of the black and white pattern of the linear scale of the linear encoder is compared with the reference number of pixels m divided by the pixel size to determine the number of pixels. When n is not equal to the reference pixel number m, the pixel data forming the image data in the block is configured to be corrected based on the pixel number n and the reference pixel number m. Accuracy, the weight of the sample stage, the expansion and contraction of the timing belt, etc. The rotation angle of the motor output shaft, the positional relationship of the sample stage is changed, variation in the main scanning speed,
When a jitter occurs in the image data and the number of pixels n and the number of reference pixels m are different, the data correction means
The number of pixel data equal to the number of pixels n forming the image data in the block is interpolated so as to be the number of pixel data equal to the number of reference pixels m, and corrected to the number of pixel data equal to the number of reference pixels m. By doing so, it is possible to easily correct the jitter generated in the image data, and since an inexpensive linear encoder having a linear scale coarser than the resolution of the rotary encoder can be used, it is possible to The generated jitter can be corrected at low cost.

In a further preferred aspect of the present invention, the data correction means is equal to the number of pixels n forming the image data in the block when the number of pixels n is not equal to the reference number of pixels m. Number of pixel data,
Interpolation is performed so that the pixel data has the number equal to the reference pixel number m, and the pixel data is corrected to have the number equal to the reference pixel number m.

According to a further preferred embodiment of the present invention, the data correction means, when the number of pixels n and the number of reference pixels m are not equal, sets the number of pixel data equal to the number n of pixels forming the image data in the block. Is interpolated so that the number of pixel data is equal to the reference pixel number m, and the reference pixel number m
Since it is configured to correct the number of pixel data equal to, the mechanical accuracy of the scanning mechanism, the weight of the sample stage, the expansion and contraction of the timing belt, etc. The rotation angle of the output shaft of the motor detected by the rotary encoder and the positional relationship of the sample stage change, the main scanning speed fluctuates, jitter occurs in the image data, and the pixel number n and the reference pixel number m are When different, the data correction means interpolates the pixel data of the number equal to the pixel number n forming the image data in the block to become the pixel data of the number equal to the reference pixel number m, and the reference pixel Since it is configured to correct the number of pixel data equal to a few m,
It becomes possible to correct the jitter generated in the image data, and since an inexpensive linear encoder having a linear scale coarser than the resolution of the rotary encoder can be used, the jitter generated in the image data can be
It becomes possible to correct at a low cost.

[0028]

Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

FIG. 1 is a schematic perspective view of a scanner according to a preferred embodiment of the present invention. The scanner according to the present embodiment excites a labeling substance contained in a sample and emits light emitted from the labeling substance. It is configured to detect and generate biochemical analysis data.

As shown in FIG. 1, the scanner according to this embodiment includes a first laser excitation light source 1 which emits a laser light 4 having a wavelength of 635 nm and a second laser excitation light source 4 which emits a laser light 4 having a wavelength of 532 nm. An excitation light source 2 and a third laser excitation light source 3 which emits a laser beam 4 having a wavelength of 473 nm are provided.

In the present embodiment, the first laser excitation light source is composed of a semiconductor laser light source, and the second laser excitation light source 2 and the third laser excitation light source 3 are second harmonic generation (Second Harmonic Generation). ) It is composed of elements.

The laser light 4 generated by the first laser excitation light source 1 is collimated by the collimator lens 5 and then reflected by the mirror 6. In the optical path of the laser light 4 emitted from the first laser excitation light source 1 and reflected by the mirror 6, the first dichroic mirror 7 and 532 nm that transmit the 635 nm laser light 4 and reflect the 532 nm wavelength light are provided. A second dichroic mirror 8 that transmits light of the above wavelength and reflects light of the wavelength of 473 nm is provided, and the laser light 4 generated by the first laser excitation light source 1 is the first dichroic mirror. The light passes through the second dichroic mirror 7 and the second dichroic mirror 8 and enters the optical head 15.

On the other hand, the laser light 4 generated by the second laser excitation light source 2 is collimated by the collimator lens 9 and then reflected by the first dichroic mirror 7 to change its direction by 90 degrees. Then, the light passes through the second dichroic mirror 8 and enters the optical head 15.

The laser light 4 generated from the third laser excitation light source 3 is collimated by the collimator lens 10 and then reflected by the second dichroic mirror 8 to change its direction by 90 degrees. Then, the light enters the optical head 15.

The optical head 15 is provided with a mirror 16, a perforated mirror 18 having a hole 17 formed in the center thereof, and a lens 19, and the laser light 4 incident on the optical head 15 is reflected by the mirror 16. Reflected by a perforated mirror 1
Sample carrier 2 set on sample stage 20 through hole 17 and lens 19 formed in
Incident on 1. Here, the sample stage 20 is configured to be movable in a main scanning direction indicated by an arrow X and a sub scanning direction indicated by an arrow Y in FIG. 1 by a scanning mechanism (not shown in FIG. 1). There is.

The scanner according to the present embodiment uses a slide glass plate as a carrier, and numerous spot-like regions of a sample selectively labeled with a fluorescent dye are formed on the slide glass plate to record fluorescence data. The microarray is scanned by the laser beam 4 to excite the fluorescent dye, and the fluorescence emitted from the fluorescent dye is photoelectrically detected to generate biochemical analysis data. Using a transfer support containing a selectively labeled sample as a carrier, a fluorescent sample on which fluorescence data is recorded is scanned by a laser beam 4 to excite the fluorescent dye and photoelectrically emit the fluorescence emitted from the fluorescent dye. Is configured to be capable of generating biochemical analysis data, and further includes a substrate having a plurality of holes separated from each other,
A plurality of absorptive regions formed by filling an absorptive material in a plurality of pores include a sample selectively labeled with a fluorescent dye, and a biochemical analysis unit recording fluorescence data, Scanning with the laser light 4 excites the fluorescent dye, photoelectrically detects the fluorescence emitted from the fluorescent dye,
In addition to being configured to generate biochemical analysis data,
The stimulable phosphor layer of the stimulable phosphor sheet on which the radiation data relating to the positional information of the radiolabeled substance is recorded is scanned by the laser beam 4 to excite the stimulable phosphor, and the stimulable phosphor is removed. The emitted photostimulable light is photoelectrically detected to generate biochemical analysis data.

When the laser beam 4 enters the sample carrier 21 from the optical head 15, the sample carrier 21
The sample 22 held inside is irradiated with the laser beam 4, and when the sample 22 is a microarray, a fluorescent sample or a biochemical analysis unit, the laser beam 4 excites the fluorescent substance to emit fluorescence. On the other hand, when the sample 22 is a stimulable phosphor sheet, the stimulable phosphor contained in the stimulable phosphor layer is excited and stimulable light is emitted.

The fluorescence or photostimulated light 25 emitted from the sample 22 is collimated by the lens 19 of the optical head 15 and reflected by the perforated mirror 17,
Any one of the filters 28a, 28b of the filter unit 27 including the four filters 28a, 28b, 28c, 28d,
It is incident on 28b, 28c and 28d.

The filter unit 27 is configured to be movable in the left-right direction in FIG. 1 by a motor (not shown), and predetermined filters 28a, 28b, 28c, 28d are provided depending on the type of laser excitation light source used. , And is located in the optical path of fluorescence or stimulated emission 25.

Here, the filter 28a is a filter used when the fluorescent substance contained in the sample 22 is excited by using the first laser excitation light source 1 and the fluorescence 25 is read, and the wavelength of 635 nm. Cut the light of 63
It has a property of transmitting light having a wavelength longer than 5 nm.

The filter 28b is a filter used when the fluorescent dye contained in the sample 22 is excited by using the second laser excitation light source 2 and the fluorescence 25 is read, and it has a wavelength of 532 nm. Cuts light, 532
It has a property of transmitting light having a wavelength longer than nm.

Further, the filter 28c is a filter used when the fluorescent dye contained in the sample 22 is excited by using the third laser excitation light source 3 and the fluorescence 25 is read, and the wavelength of 473 nm. Cut the light, 47
It has a property of transmitting light having a wavelength longer than 3 nm.

When the sample 22 is a stimulable phosphor sheet, the filter 28d uses the first laser excitation light source 1 to excite the stimulable phosphor contained in the stimulable phosphor sheet. , Photostimulable light emitted from photostimulable phosphor 25
Is a filter used for reading the light, and has a property of transmitting only the light in the wavelength range of the stimulable light 25 emitted from the stimulable phosphor and cutting the light of the wavelength of 635 nm.

Therefore, these filters 28a, 2a and 2b are selected depending on the type of laser excitation light source to be used, that is, the type of sample and the type of fluorescent substance labeling the sample.
By selectively using 8b, 28c, 28d,
It becomes possible to cut light in the wavelength range that becomes noise.

The filter 28a of the filter unit 27,
After the light in the predetermined wavelength range is cut off after passing through 28 b and 28 c, the fluorescence or stimulable light 25 enters the mirror 29, is reflected, and is condensed by the lens 30.

In this embodiment, the lenses 19 and 30 form a confocal optical system. in this way,
The confocal optical system is adopted when the sample 22 is a microarray using a slide glass plate as a carrier,
This is so that the fluorescence emitted from the minute spot-like sample formed on the slide glass plate can be read at a high S / N ratio.

A confocal switching member 31 is provided at the focal position of the lens 30.

FIG. 2 is a schematic front view of the confocal switching member 31.

As shown in FIG. 2, the confocal switching member 31 has a plate shape and has three pinholes 3 having different diameters.
2a, 32b, 32c are formed.

When the sample 22 is a microarray having a slide glass plate as a carrier, the pinhole 32a having the smallest diameter is fluorescence 25 emitted from the microarray.
The pinhole 32c having the largest diameter is disposed in the optical path of the transfer support or the biochemical analysis when the sample 22 is a fluorescent sample or a biochemical analysis unit using the transfer support as a carrier. It is arranged in the optical path of the fluorescent light 25 emitted from the unit.

Also, a pinhole 32b having an intermediate diameter
When the sample 22 is a stimulable phosphor sheet, is arranged in the optical path of the stimulable light 25 emitted from the stimulable phosphor layer.

Thus, at the focal position of the lens 30,
When the confocal switching member 31 is provided and the sample 22 is a microarray using a slide glass plate as a carrier,
The pinhole 32a having the smallest diameter is positioned in the optical path of the fluorescent light 25. When the sample 22 is a microarray using a slide glass plate as a carrier, the fluorescent dye is excited by the laser light 4, and Since 25 is emitted from the surface of the slide glass plate and the light emitting point is almost constant in the depth direction, it is possible to improve the S / N ratio by using a confocal optical system to form an image on the pinhole 32a having a small diameter. This is because it is desirable for the purpose.

On the other hand, in the case where the sample 22 is a fluorescent sample or biochemical analysis unit using the transfer support as a carrier, the pinhole 32c having the largest diameter is located in the optical path of the fluorescent light 25. When the sample 22 is a fluorescent sample or a biochemical analysis unit using a transfer support as a carrier, when the fluorescent dye is excited by the laser beam 4, the fluorescent dye is transferred to the transfer support or the biochemical analysis unit. Are distributed in the depth direction of the absorptive region, and since the light emitting points fluctuate in the depth direction, the fluorescence 25 emitted from the fluorescent dye is changed by the confocal optical system.
An image cannot be formed on a pinhole with a small diameter, and if a pinhole with a small diameter is used, the fluorescence 25 emitted from the fluorescent dye will be cut, and a sufficient signal strength will be obtained when the fluorescence 25 is photoelectrically detected. This is because it is necessary to use the pinhole 32c having a large diameter because

On the other hand, when the sample 22 is a stimulable phosphor sheet, the pinhole 32b having an intermediate diameter is positioned in the optical path of the stimulable light 25 by the laser light 4. When the photostimulable phosphor contained in the body layer is excited, the light emission points of the photostimulable light 25 are distributed in the depth direction of the photostimulable phosphor layer, and the light emission points fluctuate in the depth direction. Therefore, the confocal optical system cannot form an image of the chamber 25 on the pinhole having a small diameter, and when the pinhole having a small diameter is used, the photostimulable light emitted from the stimulable phosphor 2
5 is cut and sufficient signal intensity is not obtained when photoelectrically detecting the stimulated emission 25, but the distribution in the depth direction of the light emitting points and the fluctuation in the depth direction of the light emitting points are not transferred. This is because it is preferable to use the pinhole 32b having an intermediate diameter because it is not as large as a fluorescent sample using a body as a carrier or a biochemical analysis unit.

Fluorescence 2 which has passed through the confocal switching member 31
5 or stimulated emission 25 is photoelectrically detected by the photomultiplier 33, and analog data is generated.

The analog data generated by the photomultiplier 33 is converted into digital data by the A / D converter 34 and sent to the data processor 35.

FIG. 3 is a schematic perspective view showing details of the main scanning mechanism of the scanning mechanism of the sample stage 20.

As shown in FIG. 3, a pair of guide rails 41 are provided on a movable substrate 40 which is movable in the sub-scanning direction indicated by arrow Y in FIG. 3 by a sub-scanning motor (not shown). , 41 are fixed, and the sample stage 20 has three slide members 42, 42 slidably attached to the pair of guide rails 41, 41.
(Only two are shown in FIG. 3).

As shown in FIG. 3, a main scanning motor 43 is fixed on the movable substrate 40, and an output shaft 43a of the main scanning motor 43 has a timing belt wound around a pulley 44. 45 is wound and a rotary encoder 46 is attached.

Therefore, by driving the main scanning motor 43, the sample stage 20 is reciprocally moved along the pair of guide rails 41, 41 in the main scanning direction indicated by the arrow X in FIG. By moving the movable substrate 40 in the sub-scanning direction by a sub-scanning motor (not shown), the sample stage 20 is two-dimensionally moved, and the entire surface of the sample 22 set on the sample stage 20 is laser-scanned. The light 4 makes it possible to scan.

Here, the position of the sample stage 20 is
The rotary encoder 46 is configured so that it can be monitored.

As shown in FIG. 3, a linear encoder 47 is fixed to the sample stage 20, and a linear encoder sensor 48 for detecting the black and white pattern of the linear scale of the linear encoder 47 is fixed on the movable substrate 40. ing.

FIG. 4 is a schematic perspective view of a sample carrier 21 which holds a microarray having a slide glass plate as a carrier and is set on the sample stage 20. The sample carrier 21 is placed on the back surface side, that is, on the sample stage 20. It is the drawing seen from the mounting side.

As shown in FIG. 4, the sample carrier 21 is provided with a frame body 50 made by processing one plate-shaped member, and the sample 22 is set inside the frame body 50. 5 possible openings 5
1, 52, 53, 54, 55 are formed.

Rectangular plate members 60, 61, 62, 63, 64 and 65 are respectively formed on the surfaces of the frame body 50 on both sides of the openings 51, 52, 53, 54 and 55, respectively.
The side regions on the side of the openings 51, 52, 53, 54, 55 are located on the openings 51, 52, 53, 54, 55 along the longitudinal direction of the openings 51, 52, 53, 54, 55. It is attached so as to project.

As shown in FIG. 4, each opening 51, 5
L-shaped leaf springs 5 are provided in 2, 53, 54 and 55.
1a, 52a, 53a, 54a, 55a are attached to the rear surface side of the sample carrier 21 so as to exert a spring force, and the openings 51, 52, 53, 5 are provided.
Each of the openings 51, 52, 5 is provided on one of the inner walls of 4, 55.
Leaf springs 51b, 5 for aligning the sample 22 set in 3, 54, 55 along the other inner wall portion facing each other.
2b, 53b, 54b, 55b are attached.

The sample carrier 21 is a frame body 50.
Both side parts 50a and 50b are mounted on the sample stage 20 and set on the sample stage 20.

When the microarray having the slide glass plate, which is the sample 22, as a carrier is set on the sample carrier 21, the sample 22 is placed in the directions indicated by the arrow A in FIG. 53, 5
It is inserted in 4, 55.

Leaf springs 51b, 52b, 53b, 5 are provided on one inner wall of each opening 51, 52, 53, 54, 55.
4b and 55b are attached, so sample 22
In each opening 51, 52, 53, 54, 55 is aligned along the other opposing inner wall.

At the same time, each opening 51, 52, 53, 5
The bent portions of the L-shaped leaf springs 51a, 52a, 53a, 54a, 55a come into contact with the sample 22 inserted in the blades 4, 55, and the leaf springs 51a, 52a, 53a, 54a.
Due to the spring force of a and 55a, the sample 22 has side regions on the side of the openings 51, 52, 53, 54 and 55 along the longitudinal direction of the openings 51, 52, 53, 54 and 55, respectively. , The plate members 60, 6 mounted so as to project above the openings 51, 52, 53, 54, 55.
It is held by the sample carrier 21 by being biased to the surfaces of 1, 62, 63, 64 and 65.

In the sample carrier 21 shown in FIG. 4, the plate members 60, 61,
62, 63, 64 and 65 have openings 51, 52 and 5 thereof.
The side regions on the side of 3, 54, 55 are openings 51, 52, 5
Along the longitudinal direction of 3, 54, 55, the openings 51, 5
2, the sample 22 is mounted so as to project above 2, 53, 54, 55, and the sample 22 has leaf springs 51a, 52a, 53a,
The plate members 6 are respectively caused by the spring forces of 54a and 55a.
It is configured to be held by the sample carrier 21 by being urged by the surfaces of 0, 61, 62, 63, 64 and 65.

On the other hand, the sample carrier 21 is a frame body 50 made by processing one plate member.
Both side parts 50a and 50b are mounted on the sample stage 20 and set on the sample stage 20.

Therefore, the surface of the plate members 60, 61, 62, 63, 64, 65 on which the sample 22 is supported and the sample carrier 21 are the sample stage 20.
The surface supported by is always in the same plane, and therefore the five samples 22 are always relative to the sample stage 20 without the need for the cumbersome operation of adjusting the position of the sample carrier 21. It is possible to set them with the same positional relationship.

Further, the frame body 50 is simply made by processing one plate-shaped member, and the plate members 60, 61, 62, 63,
By simply mounting 64 and 65 on the surface of the frame body 50, the five samples 22 can be set to the sample stage 20 always in the same positional relationship, so that the cost of the sample carrier 21 is greatly increased. Can be reduced to.

FIG. 5 is a block diagram showing the detection system, drive system, input system and control system of the scanner according to the preferred embodiment of the present invention.

As shown in FIG. 5, the detection system of the scanner comprises a photomultiplier 33 and a sample stage 2
A rotary encoder 46 for detecting the position of 0 in the main scanning direction, a linear encoder sensor 48 for detecting the linear scale of the linear encoder 47, a position sensor 49 for detecting the position of the sample stage 20 in the sub scanning direction,
A carrier sensor 70 that detects the type of carrier that holds the sample 22 set on the sample stage 20 is provided.

As shown in FIG. 5, the drive system of the scanner includes a filter unit motor 71 for moving the filter unit 27, a switching member motor 72 for moving the confocal switching member 31, and a sample stage 20 in the main scanning direction. And a sub-scanning motor 73 for moving the sample stage 20 in the sub-scanning direction.

Further, as shown in FIG. 5, the input system of the scanner is provided with a keyboard 74, and the control system of the scanner is generated by the control unit 75, the data processing device 35 and the photomultiplier 33. A / D converter 34 for digitizing analog data
And a binarizing means 76 for binarizing the analog data generated by the linear encoder sensor 48.

As shown in FIG. 3, the scanner according to this embodiment is configured such that the main scanning motor 43 causes the sample stage 20 to reciprocate in the main scanning direction. In the configured scanner, generally, the position of the sample stage 20 is monitored by the rotary encoder 46 that is an absolute position counter, and the sampling of data is performed when the sample stage 20 reaches a certain position for each scanning line. The sampling stage 20 is configured to end sampling of data when the sample stage 20 reaches a predetermined position. However, since the sample stage 20 is reciprocally moved at high speed in the main scanning direction, scanning is performed. Due to the mechanical accuracy of the mechanism and the weight of the sample stage 20, the absolute position counter The position of the sample stage 20 Lee encoder 46 is monitored, the sample stage 20
Often, the actual position of is different, and therefore, when the sampling of the data is performed according to the detection signal of the rotary encoder 46, the number of pixels sampled differs depending on each sampling period.
As a result, it is recognized that so-called jitter often occurs in the generated image data.

In particular, the scanner according to this embodiment is
Through the timing belt 45, the sample stage 20
However, since the main scanning motor 43 reciprocates at high speed in the main scanning direction, jitter easily occurs due to expansion or contraction of the timing belt.

Such a problem can be solved by detecting the position of the sample stage 20 in the main scanning direction using a linear encoder having a linear scale equivalent to the pixel size. Since a linear encoder having a linear scale as small as μm and having a pixel size equivalent to that of a pixel is extremely expensive, the linear encoder is used to measure the sample stage 20.
It is neither economical nor realistic to solve such a problem by detecting the position in the main scanning direction.

Therefore, in the present embodiment, a linear encoder 47 having a linear scale coarser than the resolution of the rotary encoder 46 is provided, the linear encoder sensor 48 detects the linear scale of the linear encoder 47, and the correction image data is obtained. The image data of each main scanning line is divided into blocks according to the generated correction image data, and each block of the image data includes a predetermined number of pixels based on the number of pixels included in the correction image data. In addition, the image data is corrected to remove the jitter.

That is, in this embodiment, the linear encoder 47 attached to the sampling stage 20 has a coarser T than the resolution of the rotary encoder 46, that is, the sampled pixel size P μm.
It has a linear scale with a period of L μm.

FIG. 6 shows that the resolution of the rotary encoder 46, that is, the sampled pixel size is 5 μm.
Then, the cycle of the linear scale of the linear encoder 47 is 2
In the case of 00 μm, one cycle of the linear scale of the linear encoder sensor 48 and one cycle of the linear scale generated by the linear encoder sensor 48 using the timing clock from the rotary encoder 46 used when capturing the image of the sample 22. FIG. 6A is a conceptual diagram showing a relationship with the correction image data obtained by binarizing the analog data of FIG.
6B shows a case in which the sample stage 20 is moved at a constant speed, and FIG. 6B shows a case in which the moving speed of the sample stage 20 is slower than the constant speed due to the timing belt 45 extending or the like. There is.

Using the timing clock from the rotary encoder 46 used when capturing the image of the sample 22, the analog data of one cycle of the linear scale generated by the linear encoder sensor 48 is binary-coded with the same resolution as the image data. The number of pixels m included in the correction image data obtained by the conversion is m = TL / when the sample stage 20 is ideally moved at a constant speed.
P, the sampled pixel size is 5 μm,
The linear scale of the linear encoder 47 has a cycle of 200
In the case of μm, m = 2 as shown in FIG.
00/5 = 40.

However, the sample stage 20
Since it reciprocates at high speed in the main scanning direction, in reality,
It is generated by the linear encoder sensor 48 using the timing clock from the rotary encoder 46 used when capturing the image of the sample 22 due to the mechanical accuracy of the scanning mechanism, the weight of the sample stage 20, the expansion and contraction of the timing belt, and the like. The number of pixels m included in the correction image data obtained by binarizing one cycle of analog data of the linear scale often does not equal TL / P, and as a result, jitter occurs in the image data. become.

For example, when the moving speed of the sample stage 20 is slower than a certain speed due to the elongation of the timing belt 45, the timing clock from the rotary encoder 46 used when capturing the image of the sample 22 is used. The number n of pixels included in the correction image data obtained by binarizing the analog data of one cycle of the linear scale generated by the linear encoder sensor 48 with the same resolution as the image data is larger than m. , For example, as shown in FIG.
41.

Therefore, the linear encoder sensor 48 takes in the linear scale by using the timing clock from the rotary encoder 46 used when taking the image of the sample 22, and the generated correction image data of one period of the linear scale. Number of pixels included in
Then, based on the ideal number of pixels m, it is possible to correct the image data so that the jitter does not occur.

First, the main scanning motor 43 causes the sampling stage 20 to reciprocate in the main scanning direction, and the laser light 4 scans the sample 22 in the main scanning direction, so that the fluorescence emitted from the sample 22 is emitted. 25 or stimulated emission 25 is photoelectrically detected to generate image data, and a linear encoder sensor 48 attached to the movable substrate 40 detects a linear scale of the linear encoder 47 to generate analog data. It

The linear scale analog data detected and generated by the linear encoder sensor 48 is input to the binarizing means 76, and the linear scale analog data is input to the image data of the sample 22 by the binarizing means 76. Using the timing clock from the rotary encoder 46 that is used when taking in, the image data for correction is binarized with the same resolution as the image data.

The binarized correction image data is input to the data processing device 35, and the data processing device 35 changes the binarized data from 0 to 1 based on the input binarized data. The image data is divided into blocks for each main scanning line, and a plurality of blocks L of the image data are provided for each main scanning line.
(I) is generated.

The data processing device 35 has the number of pixels n included in the block of binarized data corresponding to the block L (i) of the image data thus generated and the ideal number to be included in each cycle of the linear scale. The number of pixels m is compared.

As a result, the block L (i) of the image data
The number of pixels n included in the block of binarized data corresponding to
And the ideal number m of pixels to be included in each cycle of the linear scale are equal, the data processing device 35
The image data of the block L (i) input from the D converter 34 is captured as the image data of the block without correction.

On the other hand, the block L of image data
If the number of pixels n included in the block of binarized data corresponding to (i) is not equal to the ideal number of pixels m that should be included in each cycle of the linear scale, the data processing device 3
5 is based on the number n of pixels included in the block of binarized data corresponding to the block L (i) of image data and the ideal number m of pixels that should be included in each period of the linear scale. According to the pixel data f (0), f (1), ..., F (n
-1) is interpolated and corrected, and corrected pixel data g (0), g (1), which forms the image data of the block L (i),
, G (m-1) is generated.

G (i) = f (i × n / m) = {(m−k) × f (j) + k × f (j + 1)} / m where j is the maximum integer and j = [I × n / m],
k is a remainder when i × n is divided by m.

As described above, the sample stage 20
However, since it is reciprocally moved at high speed in the main scanning direction, the jitter that occurs in the image data due to the mechanical precision of the scanning mechanism, the weight of the sample stage 20, the timing belt extension and contraction, etc. is corrected, Image data without jitter can be generated.

The scanner according to the present embodiment configured as described above uses the slide glass plate as a carrier and slides many spot-like regions of the sample selectively labeled with the fluorescent dye as follows. A microarray formed on a glass plate and having fluorescence data recorded therein is scanned by a laser beam 4 to excite a fluorescent dye,
The fluorescence emitted from the fluorescent dye is photoelectrically detected to generate data for biochemical analysis.

A microarray using a slide glass plate as a carrier is produced, for example, as follows.

First, the surface of the slide glass plate was
Pretreatment with an L-lysine solution or the like, and then, at a predetermined position on the surface of the slide glass plate, a plurality of specific binding substances having different known base sequences
Is dropped using a spotter device.

On the other hand, RNA as a sample was extracted from living cells, and m having poly A at the 3'end was further extracted from RNA.
Extract RNA. When cDNA is synthesized from the thus extracted mRNA having poly A at the end, Cy5 (registered trademark) as a labeling substance is allowed to exist to generate a probe DNA labeled with Cy5.

The thus obtained probe DNA labeled with Cy5 is adjusted to a predetermined solution, gently placed on the surface of a slide glass onto which cDNA as a specific binding substance has been dropped, and hybridized.

FIG. 7 is a schematic perspective view of the microarray 22 thus obtained. In FIG. 7, reference numeral 80 denotes a spot-like region formed by dropping cDNA on the surface of a slide glass plate 81. There is.

First, the five microarrays 22 using the slide glass plate 81 as the sample 22 as a carrier are shown in FIG.
In, the sample carrier 21 is inserted into the openings 51, 52, 53, 54, 55 in the direction indicated by the arrow A.

Each opening 51, 5 of the sample carrier 21
The leaf spring 51 is attached to one of the inner walls of 2, 53, 54 and 55.
Since b, 52b, 53b, 54b, 55b are attached, the microarray 22 is aligned along the other inner wall portion facing each other in each opening 51, 52, 53, 54, 55, respectively.

At the same time, each opening 51, 52, 53, 5
The L-shaped leaf springs 51a, 52a, 53a, 54a, 55 are attached to the microarray 22 inserted into the microarrays 4, 55.
The tops of a contact and the leaf springs 51a, 52a, 53a, 5
Due to the spring force of 4a, 55a, the microarray has side regions on the side of the openings 51, 52, 53, 54, 55 along the longitudinal direction of the openings 51, 52, 53, 54, 55, respectively. Openings 51, 52, 53, 54, 55
A plate member 60 attached so as to project upward,
The sample carriers 21 are held by being biased by the surfaces of 61, 62, 63, 64 and 65.

Here, the plate members 60, 61, 62, 63, 64, 65 are provided on the surface of the frame body 50 in the openings 5 thereof.
The side regions on the side of 1, 52, 53, 54, 55 are the openings 5
Along the longitudinal direction of 1, 52, 53, 54, 55 so as to project above the openings 51, 52, 53, 54, 55,
Attached, the microarray 22 has leaf springs 51a,
The spring force of 52a, 53a, 54a, 55a biases the surfaces of the plate members 60, 61, 62, 63, 64, 65 to be held by the sample carrier 21, respectively, while the sample is In the carrier 21, both side portions 50 a and 50 b of the frame body 50 made by processing one plate-shaped member are
Since it is mounted on the sample stage 20 and set on the sample stage 20, the surface of the plate members 60, 61, 62, 63, 64, 65 on which the microarray 22 is supported and the sample carrier 21 are supported by the sample stage 20. The surface to be supported is always in the same plane, and therefore, after the sample stage 21 is set on the sample stage 20, there is no need for a complicated operation of adjusting the positions of the sample carrier 21 and each microarray 22 in the height direction, 5
It is possible to always set one microarray 22 to the sample stage 20 in the same positional relationship.

Thus, when the sample carrier 21 holding the five microarrays 22 with the slide glass plate 81 as a carrier is set on the sample stage 20,
The carrier sensor 70 detects the type of the sample carrier 21 and outputs a carrier detection signal to the control unit 75.

When the carrier detection signal is received from the carrier sensor 70, the control unit 75 outputs a drive signal to the switching member motor 72 based on the carrier detection signal to cause the confocal switching member 31 to move to the pinhole having the smallest diameter. It is moved so that 32a is located in the optical path.

Next, when the operator inputs a labeling substance specifying signal and a start signal for identifying the type of the fluorescent substance which is the labeling substance to the keyboard 74, the keyboard 74 sends the labeling substance specifying signal and the start signal to the control unit. It is output to 75.

For example, as the type of fluorescent substance, Cy5
(Registered trademark) is input, the control unit 7
5 outputs a drive signal to the filter unit motor 71 in accordance with the input instruction signal, moves the filter unit 27, and cuts light having a wavelength of 635 nm,
The filter 28a having a property of transmitting light having a wavelength longer than 635 nm is positioned in the optical path, and a drive signal is output to the first laser excitation light source 1 to turn it on.

The laser light 4 emitted from the first laser excitation light source 1 is collimated by the collimator lens 5 and then reflected by the mirror 6, and the first dichroic mirror 7 and the second dichroic mirror are reflected. After passing through 8, the light enters the optical head 15.

The laser beam 4 incident on the optical head 15 is
The light is reflected by the mirror 16, passes through the hole 17 formed in the perforated mirror 18, is condensed by the lens 19, and is incident on the microarray 22 held by the sample carrier 21 set on the sample stage 20.

The sample stage 20 is moved at high speed by the main scanning motor 43 in the main scanning direction indicated by arrow X in FIG. 3, and by the sub-scanning motor 73 indicated by arrow Y in FIG. Since the laser beam 4 is moved in the sub-scanning direction, the sample stage 2
The entire surfaces of the five microarrays 22 held by the sample carrier 21 set to 0 are sequentially scanned.

When the laser beam 4 is irradiated, the probe D
A fluorescent dye that labels NA, for example, Cy5 is excited and fluorescence 25 is emitted. In this embodiment,
A slide glass plate is used as a carrier of the microarray, and the fluorescent dye is distributed only on the surface of the slide glass plate 81.
Emitted from surface 1 only.

The fluorescent light 25 emitted from the surface of the slide glass plate 81 is collimated by the lens 19 and reflected by the perforated mirror 18, and the filter unit 2
It is incident on 7.

The filter unit 27 has a filter 28a.
Has been moved so that it is located in the optical path, fluorescence 2
No. 5 is incident on the filter 28a, the light having a wavelength of 635 nm is cut, and only the light having a wavelength longer than 635 nm is transmitted.

The fluorescent light 25 that has passed through the filter 28a is reflected by the mirror 29 and is imaged by the lens 30.

Prior to irradiation with the laser beam 4, the confocal switching member 31 is moved so that the pinhole 32a having the smallest diameter is located in the optical path, so that the fluorescent light 25 forms an image on the pinhole 32a. The photomultiplier 33 photoelectrically detects the analog data.

As described above, fluorescence 25 emitted from the fluorescent dye on the surface of the slide glass plate is used by using the confocal optical system.
Is guided to the photomultiplier 33 and photoelectrically detected, so that noise in the data can be minimized.

The analog data generated by the photomultiplier 33 is converted into digital data by the A / D converter 34 and output to the data processor 35.

On the other hand, as the sample stage 20 is moved in the main scanning direction by the main scanning motor 43, the linear scale of the linear encoder 47 attached to the sample stage 20 is attached to the movable substrate 40. The analog data detected by the linear encoder sensor 48 is output to the binarizing means 76.

The analog data of the linear scale is binarized by the binarizing means 76 with the same resolution as the image data by using the timing clock from the rotary encoder 46 which is used when the image data of the microarray 22 is fetched, Correction image data is generated.

The binarized correction image data is input to the data processing device 35, and the data processing device 35 changes the binarized data from 0 to 1 based on the input binarized data. The image data of the microarray input from the A / D converter 34 is divided into blocks, and a plurality of blocks L (i) of image data are provided for each main scanning line.
To generate.

Next, the data processing device 35 corresponds to the block L (i) of the image data thus generated.
The number of pixels n included in the block of digitized data is compared with the ideal number of pixels m that should be included in each period of the linear scale.

As a result, the block L (i) of the image data
The number of pixels n included in the block of binarized data corresponding to
And the ideal number m of pixels to be included in each cycle of the linear scale are equal, the data processing device 35
The image data of the block L (i) input from the D converter 34 is captured as the image data of the block without correction.

On the other hand, the block L of image data
If the number of pixels n included in the block of binarized data corresponding to (i) is not equal to the ideal number of pixels m that should be included in each cycle of the linear scale, the data processing device 3
5 is based on the number n of pixels included in the block of binarized data corresponding to the block L (i) of image data and the ideal number m of pixels that should be included in each period of the linear scale. According to the pixel data f (0), f (1), ..., F (n
-1) is interpolated and corrected, and corrected pixel data g (0), g (1), which forms the image data of the block L (i),
, G (m-1) is generated.

G (i) = f (i × n / m) = {(m−k) × f (j) + k × f (j + 1)} / m where j is the maximum integer and j = [I × n / m],
k is a remainder when i × n is divided by m.

On the other hand, by using the scanner according to the present embodiment, a fluorescent sample composed of a transfer support containing a sample selectively labeled with a fluorescent dye and recording fluorescent data is scanned by a laser beam 4. Then, when the fluorescent dye is excited and the fluorescence emitted from the fluorescent dye is photoelectrically detected by the photomultiplier 33 to generate data for biochemical analysis, the fluorescent sample is Loaded in the sample carrier.

A fluorescent sample is prepared, for example, by recording an electrophoretic image of denatured DNA labeled with a fluorescent dye on a transfer support as follows.

First, a plurality of DNA fragments including a DNA fragment consisting of a gene of interest are electrophoresed on a gel support medium to be separated and developed, and then denatured (denaturation) by alkali treatment to obtain a single-stranded DNA. Of DNA.

Then, the gel support medium and the transfer support were superposed by a known Southern blotting method, and at least a part of the denatured DNA fragment was transferred onto the transfer support, followed by heating treatment and ultraviolet irradiation. Fixed by

Then, a probe prepared by labeling DNA or RNA complementary to the DNA of the target gene with a fluorescent dye and the denatured DNA fragment on the transcription support 12 are
Double-stranded DN hybridized by heat treatment
The renaturation of A or the formation of a DNA / RNA conjugate is performed. Then, for example, Cy3 (registered trademark) is used to label the DNA or RNA complementary to the DNA of the gene of interest to prepare the probe. At this time, since the denatured DNA fragment on the transcription support is fixed, only the DNA fragment complementary to the probe DNA or the probe RNA hybridizes to capture the fluorescently labeled probe. Thereafter, by washing away the probe that did not form a hybrid with an appropriate solution, only the DNA fragment having the gene of interest forms a hybrid with the fluorescently labeled DNA or RNA on the transcription support, A fluorescent label is attached. Thus, an electrophoretic image of the denatured DNA labeled with Cy3 is recorded on the transfer support.

The fluorescent sample prepared as described above is housed in a sample carrier (not shown) for the fluorescent sample, and the sample carrier 21 for the microarray is used.
The sample carrier for the fluorescent sample is set on the sample stage 20 in exactly the same manner as.

When the sample carrier is set on the sample stage 20 in this way, the carrier sensor 70 detects the type of the sample carrier and outputs a carrier detection signal to the control unit 75.

Upon receiving the carrier detection signal from the carrier sensor 70, the control unit 75 outputs a drive signal to the switching member motor 72 based on the carrier detection signal to cause the confocal switching member 31 to move to the pinhole having the largest diameter. It is moved so that 32c is located in the optical path.

Next, when the operator inputs a labeling substance specifying signal and a start signal for specifying the type of the fluorescent substance as the labeling substance to the keyboard 74, the keyboard 74 sends the labeling substance specifying signal and the start signal. It is output to 75.

For example, when the sample is labeled with Cy3 (registered trademark), Cy3 can be excited most efficiently by a laser having a wavelength of 532 nm, so that the control unit 75 causes the second laser excitation. Select the light source 2 and the filter 28b,
A drive signal is output to the filter unit motor 71 to move the filter unit 27 to cut light having a wavelength of 532 nm and to transmit a light having a wavelength longer than 532 nm. And the drive signal is output to the second laser excitation light source 2 to turn it on.

5 emitted from the second laser excitation light source 2
The laser light 4 having a wavelength of 32 nm is collimated by the collimator lens 9 into parallel light, and then enters the first dichroic mirror 7 and is reflected.

The laser beam 4 reflected by the first dichroic mirror 7 is reflected by the second dichroic mirror 8.
And is incident on the optical head 15.

The laser beam 4 incident on the optical head 15 is
The light is reflected by the mirror 16, passes through the hole 17 formed in the perforated mirror 18, is condensed by the lens 19, and is incident on the fluorescent sample 22 held by the sample carrier set on the sample stage 20.

The sample stage 20 is moved at high speed in the main scanning direction indicated by arrow X in FIG. 3 by the main scanning motor 43, and is indicated by arrow Y in FIG. 3 by the sub scanning motor 73. Since the laser beam 4 is moved in the sub-scanning direction, the sample stage 2
The entire surface of the fluorescent sample held by the sample carrier set to 0 is sequentially scanned.

When irradiated with the laser beam 4, a fluorescent dye for labeling the denatured DNA as a sample, for example, Cy3.
Are excited and fluorescence 25 is emitted. Fluorescent sample 22
When a transfer support is used as the carrier of
Since the fluorescent dye is distributed in the depth direction of the transfer support, the fluorescent dye can be emitted from a predetermined range in the depth direction of the transfer support with fluorescence 25.
Is emitted, and the position of the light emitting point in the depth direction also changes.

Fluorescent sample 22 using transfer support as carrier
The fluorescence 25 emitted from the light is converted into parallel light by the lens 19, is reflected by the perforated mirror 18, and is incident on the filter unit 27.

The filter unit 27 includes a filter 28b.
Has been moved so that it is located in the optical path, fluorescence 2
No. 5 is incident on the filter 28b, light having a wavelength of 532 nm is cut, and only light having a wavelength longer than 532 nm is transmitted.

The fluorescence transmitted through the filter 28b is reflected by the mirror 29 and condensed by the lens 30, but since the fluorescence 25 is emitted from a predetermined range in the depth direction of the transfer support, the fluorescence is not formed. Not a statue.

Prior to the irradiation of the laser beam 4, the confocal switching member 31 is moved so that the pinhole 32c having the largest diameter is located in the optical path, so that the fluorescence 25 has the largest pinhole 32c. And is photoelectrically detected by the photomultiplier 33 to generate analog data.

Therefore, although the confocal optical system is used to detect the fluorescence 25 emitted from the fluorescent dye on the surface of the microarray using the slide glass plate as a carrier at a high S / N ratio. Also, the fluorescence 25 emitted from a predetermined range in the depth direction of the transfer support can be detected with high signal intensity.

The analog data generated by the photomultiplier 33 is converted into digital data by the A / D converter 34 and output to the data processing device 35.

On the other hand, as the sample stage 20 is moved in the main scanning direction by the main scanning motor 43, the linear scale of the linear encoder 47 attached to the sample stage 20 is attached to the movable substrate 40. The analog data detected by the linear encoder sensor 48 is output to the binarizing means 76.

The analog data of the linear scale is binarized by the binarizing means 76 with the same resolution as the image data by using the timing clock from the rotary encoder 46 used when capturing the image data of the microarray 22, Correction image data is generated.

The binarized correction image data is input to the data processing device 35, and based on the binarized correction image data, the data processing device 35 performs the same operation as the image data of the microarray 22. , The image data of the fluorescent sample input from the A / D converter 34 is corrected, and the image data is captured.

On the other hand, by using the scanner according to the present embodiment, a biochemical analysis including a plurality of absorptive regions containing a sample selectively labeled with a fluorescent dye and recording fluorescence data. The unit is scanned by the laser beam 4 to excite the fluorescent dye contained in the plurality of absorptive regions, and the fluorescence emitted from the fluorescent dye is photoelectrically detected by the photomultiplier 33, When generating data for biochemical analysis, the biochemical analysis unit is set in the sample carrier.

FIG. 8 is a schematic perspective view of the biochemical analysis unit.

As shown in FIG. 8, the biochemical analysis unit 91 is made of a material having a property of attenuating light such as aluminum, and a large number of substantially circular through holes 93 are formed at high density. The substrate 92 is provided, and a large number of through holes 93 are filled with an absorptive material such as nylon 6 to form a large number of absorptive regions 94.

Although not shown exactly in FIG.
Approximately 000 through holes 93 having a size of approximately 0.01 mm 2 are formed in the substrate 92 regularly at a density of approximately 5000 holes / cm 2.
The adsorptive region 94 is formed by filling the through holes 93 with an adsorptive material such as nylon 6 so that the surface thereof is located at the same height as the surface of the substrate 92.

Fluorescence data is recorded in a large number of absorptive regions 94 of the biochemical analysis unit 91, for example, as follows.

First, in a large number of absorptive regions 94 formed in the biochemical analysis unit 91, as a specific binding substance, a plurality of cDNAs having different base sequences and different from each other are known.
Are dropped using a spotting device.

Next, the biochemical analysis unit 91 is housed in a hybridization container containing a hybridization solution containing a fluorescent substance, for example, a substance derived from a living body which is a probe labeled with Fluorescein (registered trademark). It

As a result, the specific binding substance adsorbed on the large number of adsorptive regions 94 is selectively hybridized with the substance of biological origin labeled with fluoroscein.

The biochemical analysis unit 91 prepared as described above is housed in a sample carrier (not shown) for the biochemical analysis unit, and in exactly the same manner as the sample carrier 21 for the microarray, The sample carrier for the biochemical analysis unit is the sample stage 2
It is set to 0.

When the sample carrier is set on the sample stage 20 in this way, the carrier sensor 70 detects the type of the sample carrier and outputs a carrier detection signal to the control unit 75.

When the carrier detection signal is received from the carrier sensor 70, the control unit 75 outputs a drive signal to the switching member motor 72 based on the carrier detection signal to cause the confocal switching member 31 to move to the pinhole having the largest diameter. It is moved so that 32c is located in the optical path.

Next, when the operator inputs a labeling substance specifying signal and a start signal for specifying the kind of the fluorescent substance as the labeling substance to the keyboard 74, the keyboard 74 sends the labeling substance specifying signal and the start signal. It is output to 75.

For example, when the sample is labeled with Fluorescein®, the fluorescein can be excited most efficiently by the laser at the wavelength of 473 nm, so the control unit 75
Selects the third laser excitation light source 3 and also selects the filter 28c and outputs a drive signal to the filter unit motor 71 to move the filter unit 27,
A filter 28c having a property of cutting light having a wavelength of 73 nm and transmitting light having a wavelength longer than 473 nm is positioned in the optical path of the fluorescence 25, and outputs a drive signal to the third laser excitation light source 2. , Turn it on.

The laser light 4 generated from the third laser excitation light source 3 is collimated by the collimator lens 10 and then reflected by the second dichroic mirror 8 to change its direction by 90 degrees. After the optical head 1
It is incident on 5.

The laser beam 4 incident on the optical head 15 is
The biochemical analysis unit 91 is reflected by the mirror 16, passes through the hole 17 formed in the perforated mirror 18, is condensed by the lens 19, and is held by the sample carrier set on the sample stage 20. Incident.

The sample stage 20 is moved at high speed in the main scanning direction indicated by arrow X in FIG. 3 by the main scanning motor 43, and by the sub-scanning motor 73 indicated by arrow Y in FIG. Since the laser beam 4 is moved in the sub-scanning direction, the sample stage 2
The entire surface of the biochemical analysis unit 91 held by the sample carrier set to 0 is sequentially scanned.

Upon irradiation with laser light 4, fluorescein labeling the sample cDNA is excited,
Fluorescent light 25 is emitted. When the sample 22 is the biochemical analysis unit 91, the fluorescent dye is used in the adsorptive region 94.
The fluorescent light 25 is emitted from a predetermined range in the depth direction of the absorptive region 94, and the position of the light emitting point in the depth direction also changes.

Adsorbent region 9 of biochemical analysis unit 91
The fluorescent light 25 emitted from the laser light 4 is made into parallel light by the lens 19, is reflected by the perforated mirror 18, and enters the filter unit 27.

The filter unit 27 includes a filter 28c.
Has been moved so that it is located in the optical path, fluorescence 2
No. 5 is incident on the filter 28c, the light having a wavelength of 473 nm is cut, and only the light having a wavelength longer than 473 nm is transmitted.

The fluorescence transmitted through the filter 28c is reflected by the mirror 29 and condensed by the lens 30, but the fluorescence 25 is in a predetermined range in the depth direction of the absorptive region 94 of the biochemical analysis unit 91. Since it is emitted from, no image is formed.

Prior to the irradiation of the laser beam 4, the confocal switching member 31 is moved so that the pinhole 32c having the largest diameter is located in the optical path, so that the fluorescent light 25 has the largest pinhole 32c. And is photoelectrically detected by the photomultiplier 33 to generate analog data.

Therefore, although the confocal optical system is used to detect the fluorescence 25 emitted from the fluorescent dye on the surface of the microarray using the slide glass plate as a carrier at a high S / N ratio. The fluorescence 25 emitted from a predetermined range in the depth direction of the adsorptive region 94 of the biochemical analysis unit 91 can also be detected with high signal intensity.

The analog data generated by the photomultiplier 33 is converted into digital data by the A / D converter 34 and output to the data processor 35.

On the other hand, as the sample stage 20 is moved in the main scanning direction by the main scanning motor 43, the linear scale of the linear encoder 47 attached to the sample stage 20 is attached to the movable substrate 40. The analog data detected by the linear encoder sensor 48 is output to the binarizing means 76.

The analog data of the linear scale is binarized by the binarizing means 76 with the same resolution as the image data by using the timing clock from the rotary encoder 46 which is used when the image data of the microarray 22 is taken in, Correction image data is generated.

The binarized correction image data is input to the data processing device 35, and based on the binarized correction image data, the data processing device 35 performs exactly the same as the image data of the microarray 22. , The image data of the biochemical analysis unit 91 input from the A / D converter 34 is corrected, and the image data is captured.

On the other hand, by using the scanner according to the present embodiment, the stimulable phosphor layer of the stimulable phosphor sheet on which the radiation data relating to the positional information of the radiolabeled substance is recorded is scanned by the laser beam 4, By exciting the stimulable phosphor, photoelectrically detecting the stimulable light emitted from the stimulable phosphor,
When generating data for biochemical analysis, the stimulable phosphor sheet is set in a sample carrier for the stimulable phosphor sheet.

On the stimulable phosphor layer of the stimulable phosphor sheet, the positional information of the radioactive labeling substance is recorded, for example, as follows.

Using a spotter device, a plurality of specific binding substances having different base sequences, which are different from each other, are attached to a large number of absorptive regions 94 of the biochemical analysis unit 1 shown in FIG. , Drop.

On the other hand, RNA as a sample was extracted from living cells, and m having poly A at the 3'end was further extracted from RNA.
Extract RNA. When a cDNA is synthesized from the thus extracted mRNA having poly A at its end, a radioactive labeling substance is allowed to be present to generate a probe DNA labeled with the radioactive labeling substance.

The probe DNA labeled with the radiolabeling substance thus obtained is adjusted to a predetermined solution, and gently placed on the biochemical analysis unit 91 on which the cDNA which is the specific binding substance is dropped, and Analysis unit 91
Of the specific binding substance contained in the large number of absorptive regions 94 of the above.

Next, the biochemical analysis unit 91 and the stimulable phosphor layer formed on the stimulable phosphor sheet are overlapped and held in an adhered state for a predetermined time, whereby the biochemical analysis unit 91 At least a part of the radiation emitted from the radio-labeled substance selectively contained in the large number of absorptive regions 94 of 91 is absorbed by the stimulable phosphor layer formed on the stimulable phosphor sheet, and the radioactive substance is radioactive. Radiation data regarding the positional information of the labeling substance is recorded in the stimulable phosphor layer.

As described above, the stimulable phosphor sheet provided with the stimulable phosphor layer on which the radiation data relating to the positional information of the radiolabeled substance is recorded is the sample carrier (not shown) for the stimulable phosphor sheet. No.), and in exactly the same manner as the sample carrier 21 for the microarray,
A sample carrier for the stimulable phosphor sheet is set on the sample stage 20.

In this way, when the sample carrier is set on the sample stage 20, the carrier sensor 70 detects the type of the sample carrier and outputs a carrier detection signal to the control unit 75.

When the carrier detection signal is received from the carrier sensor 70, the control unit 75 outputs a drive signal to the switching member motor 72 based on the carrier detection signal to cause the confocal switching member 31 to move to a pin having an intermediate diameter. The hole 32b is moved so that it is located in the optical path.

Next, when a start signal is input to the keyboard 74 by the operator, the keyboard 74 is
From, a start signal is output to the control unit 75.

The stimulable phosphor contained in the stimulable phosphor layer of the stimulable phosphor sheet can be excited most efficiently by a laser having a wavelength of 635 nm. The laser excitation light source 1 is selected, the filter 28d is selected, a drive signal is output to the filter unit motor 71, the filter unit 27 is moved, the light of the wavelength of 635 nm is cut, and the wavelength range of the stimulated emission light is selected. 28 having the property of transmitting the light of
d in the optical path of the photostimulable light 25, and
A drive signal is output to the laser excitation light source 1 to turn it on.

The laser beam 4 emitted from the first laser excitation light source 1 is collimated by the collimator lens 5 and then reflected by the mirror 6, and is reflected by the first dichroic mirror 7 and the second dichroic mirror. After passing through 8, the light enters the optical head 15.

The laser beam 4 incident on the optical head 15 is
The stimulable phosphor sheet, which is reflected by the mirror 16, passes through the hole 17 formed in the perforated mirror 18, is condensed by the lens 19, and is held by the sample carrier set on the sample stage 20, is stored. It is incident on the exhaustive phosphor layer.

The sample stage 20 is moved at high speed in the main scanning direction indicated by arrow X in FIG. 3 by the main scanning motor 43, and is indicated by arrow Y in FIG. 3 by the sub scanning motor 73. Since the laser beam 4 is moved in the sub-scanning direction, the sample stage 2
The entire surface of the stimulable phosphor layer of the stimulable phosphor sheet held by the sample carrier set to 0 is sequentially scanned.

When the laser beam 4 is irradiated, the stimulable phosphor contained in the stimulable phosphor layer is excited, and the stimulable light 2 is emitted.
5 is released. In the case of the stimulable phosphor sheet, the stimulable phosphor is contained in the stimulable phosphor layer and is distributed to some extent in the depth direction of the stimulable phosphor layer. The photostimulable phosphor layer emits stimulated light from a predetermined range in the depth direction, and the position of the light emitting point in the depth direction also changes. However, since the stimulable phosphor layer is thin, the light emitting points are not distributed in the depth direction as in the case of the transfer support or the biochemical analysis unit.

The photostimulable light 25 emitted from the photostimulable phosphor layer of the stimulable phosphor sheet is collimated by the lens 19, reflected by the perforated mirror 18, and incident on the filter unit 27. .

The filter unit 27 includes a filter 28d.
Is moved so as to be located in the optical path, the photostimulable light 25 enters the filter 28d, the light having a wavelength of 635 nm is cut, and only the light in the wavelength region of the photostimulable light 25 is transmitted.

The photostimulable light 25 transmitted through the filter 28d is
Although reflected by the mirror 29 and condensed by the lens 30, the photostimulable light is emitted from a predetermined range in the depth direction of the photostimulable phosphor layer formed on the stimulable phosphor sheet. , No image is formed.

Prior to the irradiation of the laser beam 4, the confocal switching member 31 is moved so that the pinhole 32b having the intermediate diameter is located in the optical path, so that the photostimulable light has the intermediate diameter. After passing through the pinhole 32b, it is photoelectrically detected by the photomultiplier 33 and analog data is generated.

Therefore, although the confocal optical system is used to detect the fluorescence 25 emitted from the fluorescent dye on the surface of the microarray 22 having the slide glass plate as a carrier at a high S / N ratio. Instead, it becomes possible to detect the photostimulable light 25 emitted from a predetermined range in the depth direction of the photostimulable phosphor layer formed on the stimulable phosphor sheet with high signal intensity.

The analog data generated by the photomultiplier 33 is converted into digital data by the A / D converter 34 and output to the data processor 35.

On the other hand, as the sample stage 20 is moved in the main scanning direction by the main scanning motor 43, the linear scale of the linear encoder 47 attached to the sample stage 20 is attached to the movable substrate 40. The analog data detected by the linear encoder sensor 48 is output to the binarizing means 76.

The analog data of the linear scale is binarized by the binarizing means 76 with the same resolution as the image data by using the timing clock from the rotary encoder 46 which is used when capturing the image data of the microarray 22, Correction image data is generated.

The binarized correction image data is input to the data processing device 35, and based on the binarized correction image data, the data processing device 35 performs exactly the same as the image data of the microarray 22. , The image data of the stimulable phosphor sheet input from the A / D converter 34 is corrected, and the image data is captured.

In this embodiment, the main scanning motor 4
3, the sample stage 20 moves in the main scanning direction,
Since it is configured to reciprocate at high speed, the position of the sample stage 20 monitored by the rotary encoder 46, which is an absolute position counter, is caused by the mechanical accuracy of the scanning mechanism, the weight of the sample stage 20, and the like. , The actual position of the sample stage 20 is often different and therefore the rotary encoder 46
When data sampling is performed in accordance with the detection signal of, the number of pixels sampled differs depending on each sampling period, and as a result, so-called jitter often occurs in the generated image data, in particular,
The scanner according to the present embodiment is provided with the timing belt 45.
Through the sample stage 20 through the main scanning motor 4
3, the reciprocating motion is performed at a high speed in the main scanning direction, so that the timing belt is likely to be stretched or contracted to cause jitter. Therefore, in this embodiment,
The resolution of the rotary encoder 46, that is, a linear encoder 47 having a linear scale with a cycle of TL μm in which the sampled pixel size is coarser than P μm is attached to the sample stage 20, and the linear scale of the linear encoder 47 is detected to convert analog data. The linear encoder sensor 48 that generates the movable substrate 4
The analog data of one cycle of the linear scale generated by the linear encoder sensor 48 by the binarizing means 76 is converted into an image by using the timing clock from the rotary encoder 46 which is attached to 0 and used when capturing the image of the sample 22. The image data for correction is generated by binarizing with the same resolution as the data, the image data is divided into blocks each time the binary data changes from zero to 1, and the image data is converted for each main scanning line. A plurality of blocks L (i) of the image data, and the number n of pixels included in the block of the binarized data corresponding to the block L (i) of the image data generated in this way, and should be included in each cycle of the linear scale. The ideal number of pixels m is compared, and the number of pixels n included in the block of binarized data corresponding to the block L (i) of image data is compared with When the ideal number of pixels m to be included in each period of the near scale is not equal, the number of pixels n included in the block of the binarized data corresponding to the block L (i) of the image data and the linear scale Pixel data f (0), f (1), ..., F (n that compose the image data of the block L (i) are calculated according to the following equation based on the ideal number of pixels m to be included in each cycle. -1) is interpolated, corrected, and corrected pixel data g (0), g (1), ..., G (m-1) that constitutes the image data of the block L (i)
Is configured to generate.

G (i) = f (i × n / m) = {(m−k) × f (j) + k × f (j + 1)} / m where j is the maximum integer and j = [I × n / m],
k is a remainder when i × n is divided by m.

Therefore, according to this embodiment, even if the main scanning motor 43 moves the sample stage 20 back and forth in the main scanning direction at high speed, the mechanical accuracy of the scanning mechanism and the weight of the sample stage 20 are increased. It is possible to correct the jitter that occurs in the image data due to the expansion and contraction of the timing belt, and therefore it is possible to generate the image data without the jitter.

Further, according to the present embodiment, the resolution of the rotary encoder 46, that is, the linear encoder 47 having a linear scale with a period of TL μm coarser than the sampled pixel size P μm is used to generate image data. Since it is possible to correct the jitter, it is possible to generate image data without jitter without increasing the cost of the scanner.

The present invention is not limited to the above embodiments, and various modifications can be made within the scope of the invention described in the claims, and these are also included in the scope of the present invention. It goes without saying that it is a thing.

For example, in the above embodiment, the linear encoder 47 is attached to the sample stage 20, and the linear encoder sensor 48 is attached to the movable substrate 40.
7 may be attached to the movable substrate 40, and the linear encoder sensor 48 may be attached to the sample stage 20.

In the above embodiment, the period is 2
Linear encoder 4 having a linear scale of 00 μm
7 is used, it is not always necessary to use the linear encoder 47 having a linear scale having a cycle of 200 μm, and the linear encoder having a cycle coarser than the resolution of the rotary encoder 46, that is, the sampled pixel size is used. As the linear encoder 47, the linear encoder 47 having a linear scale with an arbitrary cycle can be used.

Furthermore, in the above-mentioned embodiment, the scanner uses a slide glass plate as a carrier, and a large number of spot-like regions of the sample selectively labeled with a fluorescent dye are
A microarray, which is formed on a slide glass plate and has fluorescence data recorded therein, is scanned with a laser beam 4 to excite the fluorescent dye, and photoelectrically detect the fluorescence emitted from the fluorescent dye, for biochemical analysis. Data is generated, and a transfer support containing a sample selectively labeled with a fluorescent dye is used as a carrier, and a fluorescent sample on which fluorescent data is recorded is scanned by a laser beam 4 to generate fluorescent data. It is configured to excite the dye and photoelectrically detect the fluorescence emitted from the fluorescent dye to generate biochemical analysis data, and further includes a substrate having a plurality of holes separated from each other. A biochemical analysis unit in which a plurality of absorptive regions formed by filling an absorptive material in the pores of the sample contains a sample selectively labeled with a fluorescent dye and fluorescence data is recorded. Scanning with the laser beam 4 excites the fluorescent dye, photoelectrically detects the fluorescence emitted from the fluorescent dye, and is configured to generate biochemical analysis data. The stimulable phosphor layer of the stimulable phosphor sheet on which the radiation data is recorded is scanned by the laser beam 4 to excite the stimulable phosphor and to emit the stimulable light emitted from the stimulable phosphor. Although it is configured to generate data for biochemical analysis by photoelectrically detecting it, the scanner uses at least a slide glass plate as a carrier and has many spot-shaped regions of a sample selectively labeled with a fluorescent dye. , A microarray formed on a slide glass plate and having fluorescence data recorded thereon is scanned by a laser beam 4 to excite a fluorescent dye, and photoelectrically detect fluorescence emitted from the fluorescent dye. Therefore, it is sufficient that the data for biochemical analysis is generated, and the fluorescence data recorded in the fluorescent sample, the fluorescence data recorded in the absorptive region of the biochemical analysis unit, and the fluorescence of the stimulable phosphor sheet are used. It is not always necessary that the radiation data relating to the positional information of the radiolabeled substance recorded in the exhaustive phosphor layer be readable.

In the above embodiment, the scanner has three pinholes 32a, 32 having different diameters.
Although the confocal switching member 31 in which b and 32c are formed is provided, it is not necessary that the confocal switching member 31 has three pin holes 32a, 32b, and 32c having different diameters. When two different pinholes are formed in the confocal switching member 31 and the fluorescence data recorded in the microarray is read, the pinhole with the smallest diameter is used and the stimulable phosphor layer of the stimulable phosphor sheet is used. When reading the radiation data related to the recorded positional information of the radiolabeled substance, use a pinhole with a large diameter, and also record the fluorescence data recorded in the fluorescent sample or the fluorescence recorded in the adsorptive area of the biochemical analysis unit. When reading the data, the confocal switching member 31 can be configured to be retracted from the optical path of the fluorescent light 25. Or, one pinhole is formed in the confocal switching member 31, and the pinhole is positioned in the optical path of the fluorescence 25 only when the fluorescence data recorded in the microarray is read, and the fluorescence data recorded in the fluorescence sample is recorded. , When reading the radiation data recorded in the adsorptive area of the biochemical analysis unit or the radiation data relating to the positional information of the radiolabeled substance recorded in the stimulable phosphor layer of the stimulable phosphor sheet, confocal switching Member 31
May be retracted from the optical path of the fluorescent light 25.

Further, in the above embodiment, the sample carrier 21 has the frame body 50 made by processing one plate-shaped member, but the frame body 51 of the sample carrier 21 has one frame body 50. It is not always necessary to be made by processing a plate-shaped member. Further, in the present invention, the means does not necessarily mean a physical means, but also includes a case where the function of each means is realized by software. Further, the function of one means may be realized by two or more physical means, or the functions of two or more means may be realized by one physical means.

[0212]

According to the present invention, the jitter in a scanner configured to reciprocate a sample stage by converting the rotational motion of a motor into a linear motion can be simply and easily achieved.
Also, it is possible to correct jitter at low cost and to correct jitter easily and at low cost. The rotary motion of the motor is converted into linear motion to reciprocate the sample stage. It is possible to provide a high resolution scanner configured to.

[Brief description of drawings]

FIG. 1 is a schematic perspective view of a scanner according to a preferred embodiment of the present invention.

FIG. 2 is a schematic front view of a confocal switching member.

FIG. 3 is a schematic diagram of a scanning mechanism of a sample stage.
It is a schematic perspective view which shows the detail of a main scanning mechanism.

FIG. 4 is a schematic perspective view of a sample carrier that holds a microarray having a slide glass plate as a carrier and is set on a sample stage.

FIG. 5 is a block diagram showing a detection system, a drive system, an input system and a control system of the scanner according to the preferred embodiment of the present invention.

FIG. 6 shows that the sampled pixel size is 5 μm.
m, the linear scale cycle of the linear encoder is 20
In the case of 0 μm, one cycle of the linear scale of the linear encoder sensor and one cycle of the linear scale of the linear scale generated by the linear encoder sensor are used by using the timing clock from the rotary encoder used when capturing the image of the sample. FIG. 3 is a conceptual diagram showing a relationship with correction image data obtained by binarization with the same resolution as image data.

FIG. 7 is a schematic perspective view of a microarray.

FIG. 8 is a schematic perspective view of a biochemical analysis unit.

[Explanation of symbols]

1 First laser excitation light source 2 Second laser excitation light source 3 Third laser excitation light source 4 laser light 5 Collimator lens 6 mirror 7 First dichroic mirror 8 Second dichroic mirror 9 Collimator lens 10 Collimator lens 15 Optical head 16 mirror 17 holes 18 perforated mirror 19 lenses 20 sample stages 21 sample carrier 22 samples 23 Dropped cDNA 25 Fluorescence or stimulated emission 27 Filter unit 28a, 28b, 28c, 28d filters 29 mirror 30 lenses 31 Confocal switching member 32a, 32b, 32c, 32d, 32e Pinhole 33 Photomultiplier 34 A / D converter 35 Data processing device 40 movable substrate 41, 41 a pair of guide rails 42 Slide member 43 Main scanning motor 43a Output shaft of main scanning motor 44 pulley 45 Timing belt 46 rotary encoder 47 Linear encoder 48 linear encoder sensor 49 Position sensor 50 frame body 51, 52, 53, 54, 55 openings 51a, 52a, 53a, 54a, 55a Leaf spring 51b, 52b, 53b, 54b, 55b Leaf spring 60, 61, 62, 63, 64, 65 Plate member 70 Carrier sensor 71 Filter unit motor 72 Switching member motor 73 Sub-scanning motor 74 keyboard 75 Control unit 76 Binarization means 80 spot-shaped areas 81 Slide glass plate 91 Biochemical analysis unit 92 substrate 93 through hole 94 Adsorbable area

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) H04N 1/40 101Z F term (reference) 2G043 AA01 BA16 DA02 DA06 EA01 EA19 FA01 GA07 GB01 GB19 GB21 HA01 HA02 HA15 JA02 KA02 KA05 KA09 LA02 NA01 NA05 5B047 AA07 AA17 AB04 BA01 BB08 BC05 BC07 BC09 BC16 CA02 CA05 CA06 CB07 DB01 5C072 AA01 BA04 BA17 CA06 CA07 DA02 DA04 DA06 DA21 EA02 HA02 AK01 NA01 MM011817 LL0117L0117A17 LL0117C17 CA17 CA02 CA01 CA02 CA01

Claims (5)

[Claims] 1. A rotary stage attached to a rotary shaft of the motor detects the position of a sample stage on which a sample carrying an image is set by converting the rotary motion of the motor into a linear motion. On the substrate, in the main scanning direction, while reciprocating, the substrate is moved in the sub-scanning direction orthogonal to the main scanning direction, by excitation light, to scan the sample set on the sample stage, A method for correcting jitter in a scanner configured to photoelectrically detect light emitted from the sample by a photodetector to generate image data, the linear correction being coarser than the resolution of the rotary encoder. A linear encoder having a scale and mounted on one of the sample stage and the substrate; A timing clock of the rotary encoder used to detect a black and white pattern of scale by a linear encoder sensor mounted on the other of the sample stage and the substrate to generate analog data and capture the image carried on the sample. Is used to binarize the analog data generated by the linear encoder sensor with the same resolution as the image data to generate binarized data for correction, and the binarized data for correction is from 0 to 1 Alternatively, a method for correcting jitter in a scanner, characterized in that the image data generated by the photodetector is corrected based on data regarding the position of a boundary pixel changing from 1 to 0. 2. A plurality of blocks of image data is generated by dividing the image data into blocks at the position of the boundary pixel for each main scanning line, and a corresponding binary value for correction is provided for each block of the image data. The number of pixels n included in the converted data is calculated, and the period of the black-and-white pattern of the linear scale of the linear encoder is divided by the pixel size to be the reference number of pixels m.
When the number of pixels n and the number of reference pixels m are not equal to each other, the pixel data forming the image data in the block is corrected based on the number of pixels n and the number of reference pixels m. The method for correcting jitter in a scanner according to claim 1, wherein 3. When the number of pixels n is not equal to the number of reference pixels m, a number of pixel data equal to the number of pixels n forming the image data in the block is equal to the number of reference pixels m. 3. The method for correcting jitter in a scanner according to claim 2, wherein the pixel data is interpolated so as to be corrected to a pixel data of a number equal to the reference pixel number m. 4. At least one excitation light source that emits excitation light, a sample stage on which a sample carrying an image is set, a motor, and a rotary motion of a rotation shaft of the motor is converted into a linear motion to obtain the sample. The stage is attached to a main scanning mechanism that reciprocates on the substrate in the main scanning direction, a sub scanning mechanism that moves the substrate in the sub scanning direction orthogonal to the main scanning direction, and a rotation shaft of the motor. A rotary encoder that detects the position of the sample stage in the main scanning direction, and a photodetector that detects the light emitted from the sample when the sample set on the sample stage is scanned by excitation light. A scanner having a linear scale coarser than the resolution of the rotary encoder,
A linear encoder attached to one of the sample stage and the substrate, and a linear encoder attached to the other of the sample stage and the substrate to detect a monochrome pattern of the linear scale of the linear encoder to generate analog data Using the sensor and the timing clock of the rotary encoder used to capture the image carried on the sample,
The analog data generated by the linear encoder sensor is binarized with the same resolution as the image data,
Binarized data generating means for generating the correction binary data, and the correction binary data generated by the generating means by the binarization, for the boundary pixels changing from 0 to 1 or from 1 to 0. A scanner comprising data correction means for correcting image data generated by the photodetector based on position data. 5. The data correction unit divides the image data into blocks at the positions of the boundary pixels for each main scanning line to generate a plurality of blocks of image data, and for each block of the image data, The number of pixels n included in the corresponding binary data for correction is obtained, and the period of the black-and-white pattern of the linear scale of the linear encoder is compared with the reference number of pixels m divided by the pixel size to obtain the number of pixels n. When the reference pixel number m is not equal, the pixel data forming the image data in the block is corrected based on the pixel number n and the reference pixel number m. The scanner according to claim 4.