JP2014226055A - Detection method, detection device, screening method, screening device, and biochip - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a detection method capable of correctly recognizing an inspection position and obtaining a satisfactory inspection result, a detection device, a screening method, a screening device, and a biochip.SOLUTION: A detection method using a biochip comprises: a first detection step of optically detecting a first gap between a plurality of biomolecule support regions arranged on a first surface of a biochip and a second gap different from the first gap; an alignment step of performing positioning to the plurality of biomolecule support regions based on at least a detection result of the second gap; and a second detection step of detecting affinity between the biomolecule formed in the biomolecule support region and a target included in a specimen.

Description

  The present invention relates to a detection method, a detection device, a screening method, a screening device, and a biochip.

  For example, as a technique for measuring biomolecules, a technique is known in which biomolecules arranged in a plurality of regions on a substrate are each reacted with a specimen and the biomolecules after the reaction are inspected (for example, the following patent document) 1).

  For example, in the above examination, the fluorescence intensity is calculated by measuring fluorescence generated in each of a plurality of regions with a microscope device (measuring device). In general, the range (viewing area) in which a substrate can be photographed at once by a microscope apparatus is smaller than the area of the substrate. For this reason, the microscope apparatus captures a part of the substrate and then sequentially captures images at each position while changing the measurement position depending on the stage on which the substrate is arranged. The microscope apparatus confirms the relative position of the substrate on the stage by using, for example, an interferometer or an encoder.

JP 2005-513457 A

  However, in the above prior art, for example, when an encoder or an interferometer breaks down, or when a substrate is photographed in a state where the measurement position is misaligned for some reason, the measurement position on the substrate can be correctly recognized. Therefore, there was a problem that good test results could not be obtained.

  The present invention has been made in view of the above circumstances, and is capable of correctly recognizing an inspection position and obtaining a good inspection result, a detection apparatus, a screening method, a screening apparatus, and a biotechnology. The purpose is to provide chips.

  According to the first aspect of the present invention, there is provided a detection method using a biochip, which is different from the first gap of the plurality of biomolecule support regions arranged on the first surface of the biochip and the first gap. A first detection step for optically detecting the second gap; an alignment step for aligning the plurality of biomolecule support regions based on at least a detection result of the second gap; and formation in the biomolecule support region There is provided a detection method comprising: a second detection step of detecting the affinity between the biomolecule thus made and the target contained in the specimen.

  According to the second aspect of the present invention, there is provided a detection device using a biochip, the stage on which the biochip is arranged, and a plurality of biomolecule support regions arranged on the first surface of the biochip. A sensor that receives the first light through the first gap and the second gap different from the first gap, and the third light obtained by irradiating the biomolecule supporting region with the second light; An alignment unit that aligns the plurality of biomolecule support regions based on the light reception result of the first light, and a living body formed in the biomolecule support region based on the light reception result of the third light A detection device is provided that includes a detection unit that detects the affinity between a molecule and a target contained in a specimen.

  According to the third aspect of the present invention, an optical detection process using the detection method according to the first aspect, a dispensing process for dispensing the specimen onto the biochip, and a drying process for drying the biochip. And a biochip screening method comprising the steps of:

  According to a fourth aspect of the present invention, there is provided a screening apparatus comprising: the detection apparatus according to the second aspect; and a dispensing apparatus that dispenses the specimen onto the biochip.

  According to the fifth aspect of the present invention, there is provided a first surface having a plurality of biomolecules that can specifically react with a target contained in a specimen, and a plurality of biomolecule support regions on which the plurality of biomolecules are formed. There is provided a biochip comprising a substrate body provided with a first gap and a second gap that define the plurality of biomolecule support regions, wherein the width of the first gap and the width of the second gap are different from each other. .

  According to the present invention, it is possible to provide a detection method, a detection device, a screening method, a screening device, and a biochip capable of correctly recognizing the measurement position of the substrate and obtaining a good test result.

It is a figure which shows embodiment of this invention, Comprising: The figure which shows schematic structure of a screening apparatus. The figure which shows the structure of the biochip which concerns on 1st Embodiment. The figure which shows the structure which concerns on an example of the measurement part which concerns on 1st Embodiment. The enlarged plan view which shows the principal part of the biochip which concerns on 1st Embodiment. FIG. 5 is an enlarged plan view showing a main part of a conventional biochip as a comparison with FIG. 4. The flowchart which shows the screening method of the biochip which concerns on 1st Embodiment. Explanatory drawing of the dispensing process with respect to the biochip which concerns on 1st Embodiment. Explanatory drawing of the cleaning method of the biochip which concerns on 1st Embodiment. Explanatory drawing of the drying process of the biochip which concerns on 1st Embodiment. The flowchart which shows the measurement process of the biochip which concerns on 1st Embodiment. The figure which shows the structure of the gap part which concerns on 2nd Embodiment. The figure which is a gap part which concerns on 3rd Embodiment, and shows a + -shaped structure. The figure which is a gap part which concerns on 3rd Embodiment, and shows the structure of a T-shaped gap part. The figure which shows the structure of the gap part which concerns on the modification of 3rd Embodiment. The figure which shows the structure of the gap part which concerns on 4th Embodiment. The figure which shows the structure of the gap part which concerns on the modification of 4th Embodiment. The figure which shows the structure of the gap part which concerns on 5th Embodiment. The figure which shows the structure of the gap part which concerns on 6th Embodiment.

  Hereinafter, an embodiment of the present invention will be described with reference to the drawings. In the following description, an XYZ orthogonal coordinate system is set, and the positional relationship of each member will be described with reference to this XYZ orthogonal coordinate system. The predetermined direction in the horizontal plane is the X-axis direction, the direction orthogonal to the X-axis direction in the horizontal plane is the Y-axis direction, and the direction orthogonal to each of the X-axis direction and the Y-axis direction (that is, the vertical direction) is the Z-axis direction. To do. Further, the rotation (inclination) directions around the X axis, Y axis, and Z axis are the θX, θY, and θZ directions, respectively.

(First embodiment)
FIG. 1 is a diagram showing a schematic configuration of a biomolecule screening apparatus using a biochip. As shown in FIG. 1, the screening device SC includes an assay unit (dispensing device) AS, a measurement unit (detection device) MS, a delivery unit TR, and a control device CONT.
In the present embodiment, the screening device SC can automatically process the biochip in a series by the assay unit AS and the measurement unit MS described above by controlling the drive of each device by the control device CONT. ing.

  Here, the configuration of the biochip (biomolecule array) 1 to be measured will be described. FIG. 2A is a diagram showing the shape of the biochip 1, and FIG. 2B is an enlarged cross-sectional view showing the main part of the biochip 1.

    As shown in FIG. 2A, the biochip (irradiated body) 1 is a plate-like member called a so-called microarray chip, and is formed in a rectangular shape, for example. For example, the biochip 1 is mainly composed of a substrate body 10 formed to be long in one direction. A plurality of biomolecule support regions (spots) S are formed on the surface (first surface) 10 a of the substrate body 10.

  The plurality of biomolecule support regions S are arranged in a matrix along the shape of the biochip 1. In this way, a row of biomolecule support regions is formed on the biochip 1 by the plurality of biomolecule support regions S arranged in a matrix. The biomolecule support region S is formed in a state of being partitioned on the surface 10 a of the substrate body 10 by the gap portion 11. The details of the gap portion 11 will be described later.

  As shown in FIGS. 2A and 2B, each biomolecule support region S is formed, for example, in a rectangular shape in plan view. In each biomolecule support region S, various biomolecules B that can specifically react with a labeled target contained in a specimen (eg, serum) are arranged. For example, when a target labeled with a fluorescent dye is used, predetermined fluorescence is generated by irradiating the biomolecule supporting region S with excitation light after the bioassay.

  The biochip 1 is formed, for example, by forming biomolecules (probes) in a biomolecule support region on a silicon wafer and then dicing the silicon wafer into individual pieces. The probe repeats, for example, a step of arranging a predetermined biomolecule forming material on a silicon wafer and an exposure step of selectively irradiating the biomolecule forming material with light of a predetermined wavelength through a mask. Thus, it is formed by stacking a plurality of biomolecules. For example, the biomolecule formed in this way can react specifically with a fluorescently labeled target contained in the analyte to be measured. Then, predetermined fluorescence is generated by illuminating the biomolecule with predetermined light (excitation light).

  Returning to FIG. 1, the assay unit AS includes a reading unit 4, a dispensing unit 5, a reaction unit 6, a washing unit 7, a drying unit 8, and a delivery unit 9. The reading unit 4 is a device that images and reads the identification information of the biochip 1 formed on, for example, a side surface portion of the biochip 1, and includes an imaging device 4a including, for example, a CCD camera. The reading unit 4 captures the identification information for identifying the biochip 1 to generate an identification information signal, and the identification information signal is output to the control device CONT.

  For example, the dispensing unit 5 can specifically react with the biomolecule 1 (see FIG. 2) formed in each biomolecule support region S of the biochip 1 with respect to the biochip 1 disposed in the reaction unit 6. A dispensing process for injecting (dispensing) a sample containing a target. Further, as shown in FIG. 7, the dispensing unit 5 includes a nozzle 5 a for injecting a specimen B <b> 1 containing a labeled target into each biomolecule support region S.

The reaction unit 6 performs a reaction process in which the biomolecule B formed on the biochip 1 and the target contained in the specimen are reacted under a predetermined temperature condition.
The cleaning unit 7 performs a cleaning process for cleaning the biochip 1 and includes a cleaning container 7A in which a cleaning liquid 7b is stored, as shown in FIG.

  The drying unit 8 includes a drying fan 8a that performs a drying process on the washed biochip 1 and ejects a drying gas, for example, as shown in FIG.

  The delivery unit 9 performs delivery processing of the biochip 1 between the reading unit 4 and the reaction unit 6 and includes a manipulator (for example, a robot arm that can be automatically driven by computer control).

  Next, the configuration of the measurement unit MS will be described with reference to FIG. FIG. 3 is a diagram illustrating a configuration according to an example of the measurement unit MS. As shown in FIG. 3, the measurement unit MS includes a measurement device main body 21 that observes the biochip 1 as an illuminated body, a measurement unit control unit 22 that controls the operation of the measurement device main body 21, and a measurement unit control. And a display device 23 connected to the unit 22. The measurement unit controller 22 includes a computer system. The display device 23 includes a flat panel display such as a liquid crystal display.

  The measuring device main body 21 can receive light via the light source unit 31, the optical system 25 including the objective lens 32, the stage 26 movable while supporting the biochip 1, the eyepiece unit 27, and the object. And an observation camera 29 including a simple sensor (eg, image sensor) 28. For example, the sensor 28 includes a photodetector such as a PMT (photomultiplier tube) and an image sensor. In the present embodiment, the sensor 28 uses an image sensor as an example. The sensor 28 can acquire image information of an object, and includes, for example, a CCD (charge coupled device). The measurement apparatus main body 21 includes a body 24, and each of the light source unit 31, the optical system 25, the stage 26, the eyepiece unit 27, and the observation camera 29 is supported by the body 24.

  The light source unit 31 includes illumination light (first light) in a predetermined wavelength band for observing the biochip 1 and a predetermined wavelength for generating fluorescence from the biochip 1 (each biomolecule support region S formed on the substrate body 10). Band excitation light (second light) can be emitted.

  The optical system 25 includes an illumination optical system 36 that illuminates the biochip 1 using light emitted from the light source unit 31, an image of the biochip 1 illuminated by the illumination optical system 36, a sensor 28, and an eyepiece unit. And an imaging optical system 33 formed in the vicinity of 27. The sensor 28 and the eyepiece 27 are disposed on the image plane side of the imaging optical system 33. Based on such a configuration, the optical system 25 can favorably guide illumination light and excitation light to each biomolecule support region S of the biochip 1.

  The stage 26 supports the biochip 1 on the object plane side of the imaging optical system 33. In the present embodiment, the stage 26 includes a stage surface plate 50 that supports the biochip 1 and a driving device 52 that moves the stage surface plate 50 on the base member 51. The biochip 1 is held on the stage surface plate 50 so that the longitudinal direction is parallel to the X direction.

  The stage surface plate 50 is movable on the base member 51 in the XY plane and in the Z direction. The stage 26 (drive device 52) and the measurement unit control unit 22 are connected by a cable 49. The measurement unit control unit 22 uses the drive device 52 to attach a stage surface plate 50 that supports the biochip 1. It can move in the XY plane. As a result, the biochip 1 is supported by the stage 26 so as to be movable in the XY plane with the upper surface facing the objective lens 32.

  The objective lens 32 is an infinite objective lens and can face the biochip 1 supported by the stage 26. In the present embodiment, the objective lens 32 is disposed on the + Z side (upward) of the biochip 1.

  The illumination optical system 36 uses the light emitted from the light source unit 31 to illuminate the biochip 1 with excitation light or illumination light. The illumination optical system 36 includes an objective lens 32 and an optical unit 37 that can separate excitation light, illumination light, and fluorescence. The objective lens 32 emits excitation light and illumination light for illuminating the biochip 1. The illumination optical system 36 illuminates the biochip 1 supported by the stage 26 with excitation light and illumination light from a predetermined upper side (Z direction). The illumination optical system 36 transmits the fluorescence (third light) generated in the biochip 1 (biomolecule support region S) and guides it to the imaging optical system 33.

  The imaging optical system 33 includes an optical element 47 that separates light from the objective lens 32 and a reflection mirror 45, and forms an image of the biochip 1 in the vicinity of the sensor 28 and the eyepiece 27. The optical element 47 includes a half mirror, transmits a part of incident light, and reflects a part thereof. The optical element 47 may be a dichroic mirror. The optical element 47 may be a total reflection mirror (for example, a quick return mirror) having a function of switching the optical path.

  Part of the light incident on the optical element 47 through the objective lens 32 from the biochip 1 (each biomolecule support region S formed on the substrate body 10) passes through the optical element 47 and is guided to the eyepiece 43. And emitted from the eyepiece 27. An image of the biochip 1 (biomolecule support region S) is formed in the vicinity of the eyepiece 27 by the imaging optical system 33. Thereby, the operator can also confirm the image of the biomolecule support region S through the eyepiece 27.

  Further, part of the light incident on the optical element 47 through the objective lens 32 and the objective lens 32 from the biochip 1 (each biomolecule support region S formed on the substrate body 10) is the optical element 47 and the reflection mirror 45. Are sequentially reflected and enter the sensor 28 of the observation camera 29. An image of the biochip 1 (biomolecule support region S) is formed on the sensor 28 by the imaging optical system 33. Thereby, the sensor 28 of the observation camera 29 can acquire the image information of the biochip 1 (biomolecule support region S). In the present embodiment, the observation camera 29 (sensor 28) is configured to reflect the reflected light (first light) of illumination light by the gap portion 11 that partitions the biomolecule support region S formed on the biochip 1 as will be described later. An image and a fluorescence (third light) image obtained from the biomolecule support region S when irradiated with excitation light (second light) after a dispensing and drying process described later are acquired (received). .

  The sensor 28 of the observation camera 29 and the measurement unit controller 22 are connected via a cable 48, and image information (image signal) of the biochip 1 (biomolecule support region S) acquired by the sensor 28 is as follows. The data is output to the measurement unit controller 22 via the cable 48. The measurement unit controller 22 can also display the image information from the sensor 28 using the display device 23. The display device 23 can enlarge and display the image information of the biochip 1 (biomolecule support region S) acquired by the sensor 28.

  Incidentally, in the measurement unit MS, the size of the observation visual field (detection region) in the measurement unit MS is larger than the size of the arrangement region of the plurality of biomolecule support regions S (the surface 10a of the substrate body 10 constituting the biochip 1). In this case, all the biomolecule support regions S can be imaged collectively. However, when the size of the observation field of view is smaller than the arrangement area of the plurality of biomolecule support areas S, the measurement unit MS needs to divide the arrangement area into a plurality of imaging areas and perform imaging. Then, for example, the measurement unit MS performs the measurement process of the arrangement area by synthesizing (stitching) a plurality of measurement results in the obtained plurality of imaging areas. Therefore, in such a case, the measurement unit MS needs to perform alignment (alignment) of the plurality of biomolecule support regions S measured in the observation visual field. Note that the detection area in the present embodiment includes a detection target area such as a light receiving area and an imaging area in the sensor 28 described above.

  On the other hand, in this embodiment, the measurement unit controller 22 is based on the image of reflected light (or transmitted light) in the gap portion 11 of the biochip 1 as described later, and includes a plurality of biomolecule support regions S. (Alignment) is performed. In addition, the measurement unit control unit 22 uses the fluorescence image (light reception result) obtained from the biomolecule support region S, and the affinity between the biomolecule B formed in each biomolecule support region S and the above target. (For example, reactivity or binding based on the presence or absence of fluorescence generation or the intensity of fluorescence) is calculated.

  FIG. 4 is an enlarged plan view showing a main part of the biochip 1. FIG. 5 is an enlarged plan view showing a main part of a conventional biochip as a comparison with FIG. In FIGS. 4 and 5, the planar shape of the biochip is a substantially square shape for easy viewing.

  In the present embodiment, in the biochip 1, a plurality of biomolecule support regions S formed on the substrate body 10 are partitioned by gap portions 11. The gap portion 11 defines a first gap 12 that partitions adjacent biomolecule support regions S on the substrate body 10 by a predetermined width, and a partition that adjoins biomolecule support regions S by a width different from the first gap 12. Second gap 13 to be included.

  Here, first, as a comparison, a case where a conventional biochip 1A (substrate body 10A) that does not have the gap portion 11 of the present embodiment is observed by the measurement unit MS will be described. In this case, as the observation visual field 100A by the measurement unit MS, as shown in FIG. 5, the observation visual field 101A is in a state that does not include two outline lines of the substrate body 10A (including the case where none is included). An observation visual field 102A including two outline lines of the substrate body 10A is conceivable.

  Here, the observation visual field 102A including the two outline lines of the substrate body 10A includes two outline lines constituting the corners at the four corners of the rectangular substrate body 10A in FIG. On the other hand, the observation visual field 101A that does not include two outline lines of the substrate body 10A is configured to include one outline line that has end sides excluding the corners of the rectangular substrate body 10A in FIG.

  The observation visual field 102A has four patterns when the substrate body 10A is rectangular, for example. The observation visual field 102A includes an observation visual field 102Aa including the upper left corner of the substrate main body 10A in FIG. 5, an observation visual field 102Ab including the upper right corner of the substrate main body 10A in FIG. 5, and a substrate main body 10A in FIG. The observation visual field 102Ac including the lower left corner of FIG. 5 and the observation visual field 102Ad including the lower right corner of the substrate body 10A in FIG.

  Since the observation visual fields 102Aa, 102Ab, 102Ac, and 102Ad have different corner positions, it is possible to determine which position on the biochip 1A (substrate body 10A) is being observed on the measurement unit MS side. .

  On the other hand, the observation visual field 101A has two patterns when the substrate body 10A is rectangular. The observation visual field 101A includes an observation visual field 101Aa that includes only one edge of the substrate body 10A in FIG. 5 and an observation visual field 101Ab that does not include any edge of the substrate body 10A in FIG.

  Unlike the case of the observation visual field 102A, the observation visual field 101A has the same gap 11A that defines the biomolecule support region S included in the visual field, and therefore on the biochip 1A (substrate body 10A) on the measurement unit MS side. It is difficult to determine which of the positions is being observed. Therefore, the positional relationship between each observation visual field 100A and the biochip 1A cannot be specified, and it becomes difficult to specify the position of each observation visual field 100A on the substrate body 10A. Therefore, it becomes difficult for the measurement unit MS to perform alignment (alignment) with respect to the plurality of biomolecule support regions S in the observation visual field (detection region).

  On the other hand, the biochip 1 according to the present embodiment includes a first gap 12 and a second gap 13 that define a plurality of biomolecule support regions S on the substrate body 10 as shown in FIG. 11 is provided. In the present embodiment, the second gap 13 has a width or shape different from that of the first gap 12, and a portion where the biomolecule support region S is not formed on the surface 10a of the substrate body 10 (hereinafter, biomolecule support region). It may be referred to as a non-formed part). The second gap 13 is configured to have a size different from that of the first gap 12.

  Here, in the arrangement of the plurality of biomolecule support regions S, the X direction shown in FIG. 4 is referred to as the row direction of the biomolecule support regions S, and the Y direction shown in FIG. The second gap 13 (the biomolecule support region non-forming part) is a row 11a and a column 11b in which the biomolecule support region S is not formed in the array of biomolecule support regions S formed on the surface 10a of the substrate body 10. Are formed one by one. In FIG. 4, the width of the second gap 13 is indicated by a broken line so as not to overlap the outer shape of the biomolecule support region S in order to make the drawing easier to see.

  As described above, the second gap 13 changes the interval in the X direction or the Y direction between the adjacent biomolecule support regions S with respect to the first gap 12 formed by arranging the biomolecule support regions S at equal intervals. The biomolecule support region S is arranged. For example, in the second gap 13, the distance between adjacent biomolecule support regions S is larger than the width of the first gap 12 by the size of one biomolecule support region S. Note that the width direction of the first gap 12 and the second gap 13 is not limited to the X and Y directions, but may be defined by a direction intersecting the X and Y directions.

  The observation visual field 100 by the measurement unit MS in the present embodiment, as shown in FIG. 4, is an observation visual field (first target region) in a state that does not include two outline lines of the substrate main body 10 (including a case where none is included). ) 101 and an observation visual field 102 including two outline lines of the substrate body 10.

  In the present embodiment, the second gap 13 is provided corresponding to the observation visual field 101 that does not include at least two outline lines of the substrate body 10 (including the case where none is included).

  In the present embodiment, there are four patterns in the observation visual field 102. The observation visual field 102 includes an observation visual field 102a including the upper left corner of the substrate body 10 in FIG. 4, an observation visual field 102b including the upper right corner of the substrate main body 10 in FIG. 4, and the substrate main body 10 in FIG. The observation visual field 102c including the lower left corner of FIG. 4 and the observation visual field 102d including the lower right corner of the substrate body 10 in FIG.

  As in the case described above, the observation visual fields 102a, 102b, 102c, and 102d are different in the positions of the corners in the biochip 1, so on the measurement unit MS side, any position on the biochip 1 (substrate body 10) is set. It is possible to easily determine whether or not the user is observing. Therefore, in the observation visual fields 102a, 102b, 102c, and 102d, it is possible to acquire position information of each biomolecule support region S on the biochip 1 (substrate body 10A). Therefore, the measurement unit MS can easily perform alignment (alignment) with respect to each biomolecule support region S in the observation visual field (detection region) in the observation visual fields 102a, 102b, 102c, and 102d.

  For example, the alignment as described above is performed by moving the stage 26 relative to the objective lens 32 or the like to a predetermined position under the control of the measurement unit controller 22. When the objective lens 32 is configured to be movable with respect to the stage 26, the measurement unit MS may move the objective lens 32 or the like with respect to the stage 26 that supports the biochip 1, or the stage 26 and the objective. The lens 32 or the like may be moved.

  The alignment is the alignment of measurement of the biochip 1 in the measurement unit MS. For example, the observation field of view 100 by the observation camera 29 (sensor 28) or the eyepiece unit 27 is set at a predetermined position (eg, a specific position). The reference of the stitching position when stitching each captured image (each measurement result) corresponding to the plurality of observation visual fields 102 acquired by the observation camera 29 (sensor 28) is matched with the biomolecule support region S). Including prescribing.

  On the other hand, as shown in FIG. 4, two patterns exist in the observation visual field 101. The observation visual field 101 includes an observation visual field 101a that includes only one edge of the substrate body 10 in FIG. 4 and an observation visual field 101b that does not include even one edge of the substrate body 10A in FIG.

  Unlike the case of the observation visual field 102, the biochip 1 of the present embodiment has the second gap 13 in the observation visual field 101 of the measurement unit MS. Since the second gap 13 is different from the first gap 12 that constitutes the majority of the gap portions 11, the second gap 13 functions as a unique region within the gap portion 11. For example, the second gap 13 is for optically specifying the position of the biomolecule support region S on the biochip 1 (substrate body 10A) where the biomolecule support region S and the gap portion 11 are formed over the entire surface. Functions as a reference (position recognition reference).

  Here, for example, conditions such as the size, shape, arrangement position, and the like of the biomolecule support region non-forming portion that constitutes the second gap 13 are the imaging processing of the biomolecule support region S by the measurement unit MS shown in FIG. It is appropriately set corresponding to the size of the observation visual field (target region) 100 defined by the magnification at the time of (predetermined processing).

  In the present embodiment, when the entire surface of the biochip 1 is observed by the measurement unit MS, the measurement unit MS acquires a plurality of observation visual fields 101 including the second gap 13. The sensor 28 of the measurement unit MS receives light through the biomolecule support region S and the gap portion 11 of the biochip 1 corresponding to the observation visual field 101. The sensor 28 acquires an image corresponding to the observation visual field 101 based on the received light, and then outputs the image to the measurement unit controller 22 via the cable 48.

  The measurement unit controller 22 identifies information on the second gap 13 from the information on the gap 11 in the observation visual field 101 output from the sensor 28 (relative position information on the first gap 12 and the second gap 13). Get selectively. The measurement unit controller 22 of the measurement unit MS stores in advance the relative position information of the second gap 13 on the biochip 1 (substrate body 10A). The measurement unit controller 22 acquires position information on the biochip 1 (substrate body 10A) in each observation field 101 based on the relative position information of the second gap 13 stored in advance. This position information may relate to a relative position defined with a predetermined position on the biochip 1 as a reference, or based on an absolute coordinate system serving as a reference of the stage 26 that supports the biochip 1 so as to be movable. It may be related to the absolute position specified by Further, the measurement unit MS can acquire position information (relative position or absolute position) of each biomolecule support region S in each observation visual field 101 based on the information of the gap part 11.

Thus, the second gap 13 can be used as an index when specifying the positional relationship between each observation visual field 101 and the biochip 1. For example, in the present embodiment, the second gap 13 can be suitably used as an alignment mark that serves as an index in an alignment process in which the measurement unit MS aligns a plurality of biomolecule support regions S in each observation field. Therefore, the measurement unit MS in the present embodiment uses a unique gap even when a variation (eg, misalignment) occurs in the positional relationship between each observation visual field 101 and the biochip 1 in the alignment as described above. Therefore, it is not necessary to use an alignment mark formed on the biochip 1.
Therefore, the measurement unit MS (measurement unit control unit 22) performs high-precision alignment (alignment) with respect to the biomolecule support region S in the observation field based on the detection result of the gap unit 11 including the second gap 13. It is possible.

Next, a method for screening the biochip 1 including the biomolecule array processing method using the screening apparatus SC will be described with reference to the flowchart of FIG.
In the present embodiment, as related processes related to the measurement of the biochip 1 having the biomolecule B, for example, a reading process, a dispensing process, a reaction process, a cleaning process, a drying process, a measurement process (detection process), and these processes A transfer process for transferring the biochip 1 is performed appropriately. Hereinafter, these processes will be sequentially described.

  First, the biochip 1 is carried into the reading unit 4 of the assay unit AS by a transport unit (not shown) (for example, a manipulator). The reading unit 4 performs identification information reading processing in the biochip 1 (step SS1). As an example, the imaging device 4 a of the reading unit 4 captures and reads the identification information formed on the biochip 1. Based on the identification information signal generated by the imaging device 4a, the control device CONT determines whether or not the target biochip 1 is used for processing in the assay unit AS. The control device CONT shifts to the next process when the biochip 1 is appropriate, and executes a process of outputting an error to the outside when the biochip 1 is not appropriate.

When the biochip 1 is appropriate, the biochip 1 is transferred to the reaction unit 6 by the delivery unit 9. The reaction unit 6 performs a dispensing process (Step SS2) on the biochip 1.
As an example, as shown in FIG. 7, the dispensing unit 5 of the reaction unit 6 can specifically react with the biomolecule B with respect to the biochip 1 disposed in the reaction unit 6 (for example, a fluorescent dye). A sample B1 containing a target labeled with a liquid is injected (dispensed) by a predetermined amount using the nozzle 5a. The reaction unit 6 may be configured to react the target contained in the sample B1 with the biomolecule B by immersing the biochip 1 in the sample storage tank that stores the sample B1.
After the specimen B1 is injected into each biomolecule support region S, a reaction process for a predetermined time is performed in the reaction unit 6 (step SS3).

  The dispensing process is preferably performed in parallel with the reading process of the identification information of the other biochip 1 or the cleaning process of the other biochip 1 from the viewpoint of improving the inspection efficiency.

  As shown in FIG. 8, after the reaction process is completed, the biochip 1 is moved from the reaction unit 6 to the cleaning unit 7 by a manipulator (not shown). As shown in FIG. 8, the cleaning unit 7 performs cleaning by immersing the biochip 1 in the cleaning liquid 7b stored in the cleaning container 7A. Thereby, the specimen adhering to the biochip 1 can be washed away. The cleaning method of the biochip 1 is not limited to the above-described method (immersion method), and for example, a spraying method in which a cleaning liquid is sprayed on the biochip 1 may be used.

  Then, as shown in FIG. 9, the biochip 1 after the reaction is transferred to a position facing the drying fan 8a of the drying unit 8, and a drying process is performed (step SS5). Note that the above-described cleaning process and drying process (steps SS4 and SS5) of the biochip 1 may be repeated a plurality of times.

  The biochip 1 that has been dried is transferred to the measurement unit MS by the delivery unit TR (see FIG. 1). The biochip 1 is placed on the stage 26 of the measurement unit MS. Thereafter, measurement processing of the biochip 1 is performed (step SS6).

Next, an example of the measurement process (detection process) of the biochip 1 including the detection method using the biochip 1 by the measurement unit MS will be described with reference to the flowchart of FIG.
The measurement method of the biochip 1 is a first detection step (step SS10) for optically detecting the gap portion 11 (first gap 12 and second gap 13) disposed on the surface 10a of the biochip 1 (substrate body 10A). ) And the alignment step (step SS11) for aligning the biomolecule support region S based on the detection result of the gap portion 11, the biomolecule B formed in the biomolecule support region S, and the target included in the specimen And a second detection step (step SS12) for detecting the affinity (for example, reactivity or binding based on the presence / absence of fluorescence or the intensity of fluorescence).

First, step SS10 which is a 1st detection process is demonstrated with reference to FIG.3 and FIG.10.
In step SS10 of FIG. 10, the measurement unit MS adjusts the focus of the objective lens 32 with respect to the biochip 1 and then sets a predetermined (predetermined number) of biomolecule support regions S on the biochip 1 to an imaging region where measurement is possible. The biochip 1 is moved in the XY plane by the stage 26. Then, as shown in FIG. 3, the measurement unit MS selectively emits illumination light (first light) in a predetermined wavelength band (first wavelength band) for observing the biochip 1 from the light source unit 31, The surface 10a on which the gap portion 11 is formed is irradiated. The illumination light emitted from the light source unit 31 is separated into reflected light and transmitted light by the optical unit 37, partially reflected and partially transmitted, and the partially reflected illumination light passes through the objective lens 32, and then the substrate body 10. Illuminate the surface 10a of the (biochip 1). The illumination light reflected by the surface 10 a of the substrate body 10 passes through the objective lens 32 and the optical unit 37 and enters the optical element 47.

  A part of the illumination light incident on the optical element 47 is sequentially reflected by the optical element 47 and the reflection mirror 45 and enters the sensor 28 of the observation camera 29.

  Here, the measurement unit MS receives images of a plurality of biomolecule support regions S in the observation field 100 (the observation field 101 or the observation field 102) having a size corresponding to the imaging characteristics of the sensor 28 and a predetermined magnification. It is formed. The sensor 28 acquires an image of the biomolecule support region S, that is, an image of the gap portion 11 that partitions the biomolecule support region S.

  Based on the image of the observation field 101 including the second gap 13 received in Step SS10, the measurement unit MS performs an alignment process for performing alignment (alignment) with the biomolecule support region S in the observation field 101 (Step SS11). ).

  The image acquired by the measurement unit MS in the observation visual field 101 includes the first gap 12 and the second gap 13. Since the second gap 13 has a wider gap width than the first gap 12 (see FIG. 4), the second gap 13 functions as a singular region in the gap portion 11.

  Therefore, the measurement unit controller 22 of the measurement unit MS easily identifies and acquires information on the second gap 13 from the information on the gap portion 11 of the observation visual field 101 output from the sensor 28. The measurement-unit control unit 22 can acquire the position of the observation visual field 101 on the biochip 1 based on the acquired information and the relative position information of the second gap 13 with respect to the biochip 1 stored in advance. it can. Thus, according to the present embodiment, the measurement unit MS can use the second gap 13 as an index of the alignment mark when specifying the positional relationship of the observation visual field 100 on the biochip 1.

  Further, the measurement unit MS acquires position information (relative position or absolute position) of each biomolecule support region S in the observation visual field 101 based on the information of the gap part 11. Thereby, the measurement unit MS can perform alignment (alignment) with the measurement system including the imaging optical system 33, the objective lens 32, and the like and the biochip 1 (each biomolecule support region S). The alignment is performed, for example, by controlling the measurement unit control unit 22 to move the stage 26 relative to the objective lens 32.

  Thus, the alignment process (step SS11) in FIG. 10 is completed. After the alignment step (step SS11), the measurement unit MS can accurately measure the desired biomolecule support region S on the biochip 1.

  After the alignment process (step SS11), the measurement unit MS performs step SS12 as a second detection process. In step SS12, the measurement unit MS switches the light emitted from the light source unit 31 to excitation light having a wavelength band (second wavelength band) different from the illumination light in order to perform fluorescence measurement. The excitation light emitted from the light source unit 31 is reflected (totally reflected) by the optical unit 37, passes through the objective lens 32, and then illuminates the surface (biomolecule support region S) of the biochip 1 (substrate body 10). .

  Of the biomolecule support region S illuminated with the excitation light, fluorescence is emitted from the biomolecule support region having the biomolecule B specifically reacted with the target contained in the specimen. The generated fluorescence passes through the objective lens 32 and the optical unit 37 and enters the optical element 47.

  An image of the biomolecule support region S that has generated fluorescence is formed in the vicinity of the eyepiece 27 and also in the field of view of the sensor 28. The sensor 28 acquires an image of the biomolecule support region S that has generated fluorescence. The sensor 28 outputs a fluorescence image including the received fluorescence to the measurement unit controller 22. Based on the measurement result of the fluorescence image of each biomolecule support region S, the measurement unit control unit 22 uses the affinity between the biomolecule B and the target (for example, the reactivity based on the presence / absence of fluorescence generation or the intensity of fluorescence). And binding).

The measurement unit MS repeats the second detection step (step SS12) on the entire surface of the biochip 1 by sequentially moving the observation visual field 100 by moving the stage 26. The control unit for measurement unit 22 detects the affinity between the biomolecule B and the above target based on the fluorescence image received in each observation field 100. Thereafter, the measurement unit MS stitches the result of the affinity acquired over the entire surface of the biochip 1 in the plurality of observation fields 100 at the end of step SS12. Here, the stitching includes synthesizing the measurement results of the fluorescent images in each observation visual field 100 on the screen.
According to the present embodiment, the measurement unit MS performs the stitching with high accuracy because the alignment in the biochip 1 is appropriately performed based on the light reception result of the gap unit 11 including the second gap 13. Things will be possible. Therefore, the measurement unit MS can perform measurement with high reliability.

  As described above, according to the present embodiment, the measurement unit MS causes the second gap 13 to function as an alignment mark even when the biochip 1 having no alignment mark is used as an index during alignment. Can do. Therefore, since the measurement part MS can perform the alignment with respect to the biochip 1 appropriately, a favorable measurement result can be obtained about the affinity of each biomolecule support region S.

  In addition, since the second gap 13 is configured by the biomolecule support region non-forming portion, the manufacturing process of the biochip 1 can be relatively simplified. Further, since a printing device or the like for printing the alignment mark on the substrate body 10 is not necessary, the manufacturing cost of the biochip 1 itself can be suppressed.

  As described above, the preferred embodiments according to the present invention have been described with reference to the accompanying drawings, but the present invention is not limited to the examples. Various shapes, combinations, and the like of the constituent members shown in the above-described examples are examples, and various modifications can be made based on design requirements and the like without departing from the gist of the present invention.

For example, in the above embodiment, the gap 11 is arranged only in the observation visual field 101 that does not include two outline lines of the substrate body 10 in the observation visual field 100. You may employ | adopt the structure by which a part of part 11 is arrange | positioned.
Moreover, in the said embodiment, the case where row 11a and column 11b were each comprised by the width | variety for two biomolecule support area | region S as 2nd gap 13 (biomolecule support area | region non-formation part) was mentioned as an example. However, the present invention is not limited to this, and the second gap 13 may be configured by only the row 11a or only the column 11b.

  In the above embodiment, the biochip 1 has the biomolecule support region S directly formed on the surface 10 a of the substrate body 10. In other words, the configuration in which the surface 10a of the substrate body 10 directly supports the biomolecule support region S is adopted, but is not limited thereto. For example, a configuration may be adopted in which the substrate body 10 indirectly supports the biomolecule support region by providing a plurality of biochips on which the biomolecule support region is formed on the substrate body 10. In this case, each biochip is formed by forming a biomolecule support region on a silicon wafer and then dicing the silicon wafer into individual pieces.

(Second Embodiment)
Next, a second embodiment of the biochip 1 will be described. In the second gap 13 in the present embodiment, the widths of the rows 11 a and the columns 11 b are partially different on the surface 10 a of the substrate body 10.

  FIG. 11 is an enlarged plan view showing a main part of the biochip 1B according to the present embodiment. In addition, about the structure and member same as the said embodiment, the same code | symbol is attached | subjected and the detailed description is abbreviate | omitted or simplified.

  In the present embodiment, as shown in FIG. 11, the row 11 a and the column 11 b of the second gap 13 have a width corresponding to six biomolecule support regions S at the center of the surface 10 a of the substrate body 10, It has a width corresponding to two biomolecule support regions S as it moves away from the part to the end part. In FIG. 11, the row 11a and the column 11b have different widths, but only one of the widths may be different.

  Also in the present embodiment, since the second gap 13 functions as the above-described alignment mark, the various related processes described above can be performed, and the affinity between the biomolecule and the target in each biomolecule support region S can be increased. It can measure with high accuracy.

(Third embodiment)
Next, a third embodiment of the biochip 1 will be described. In the present embodiment, a plurality of second gaps 13 are formed on the biochip 1C. In addition, about the structure and member same as the said embodiment, the same code | symbol is attached | subjected and the detailed description is abbreviate | omitted or simplified.

12 and 13 are enlarged plan views showing main parts of the biochip 1C according to the present embodiment. As shown in FIG. 12, unlike the first gap 112, each of the plurality of second gaps 113 has a predetermined planar shape, for example, a + (plus) shape. Unlike the width of the first gap 112, the second gap 113 in FIG. 12 has a width larger than the width of the first gap 112. Also in the present embodiment, since the second gap 113 functions as the alignment mark described above, the various related processes described above can be performed, and the affinity between the biomolecule and the target in each biomolecule support region S can be increased. It can measure with high accuracy.
The plurality of second gaps 113 may have a T-shaped rotationally asymmetric shape as shown in FIG. As shown in FIG. 13, by using the rotationally asymmetric second gap 113, the measurement unit MS is based on the detection result of the second gap 113, and the position information of the biochip 1 on the stage surface plate 50 (eg, in the θZ direction). Rotation angle) can be easily obtained. Therefore, the measurement unit MS can align the biochip 1 supported by the stage 26 in a state rotated in the θZ direction by a predetermined angle, and perform fluorescence observation in this state.

(Modification of the third embodiment)
Next, a modification of the third embodiment of the biochip 1C will be described. Although the case where all the plurality of second gaps 113 in the third embodiment have the same shape has been described as an example, the second gap 213 in the present embodiment is configured such that the shape of each gap portion is different.

  FIG. 14 is a schematic diagram illustrating an example in which the shapes of the plurality of second gaps 213 are different from each other. As shown in FIG. 14, for example, the second gap 213 according to the present modification includes a predetermined living body among a plurality of biomolecule support regions S formed by arranging 3 rows and 3 columns (9 in total) as one arrangement pattern. It is provided in the molecular support region S. Accordingly, the predetermined biomolecule support region S among the plurality of biomolecule support regions S formed as the arrangement pattern of the above 3 rows and 3 columns (9 in total) functions as an alignment mark. It is a non-formation part in which is not formed. As shown in FIG. 14, for example, the non-formed part is provided in a staggered manner. Further, as shown in FIG. 14, the second gaps 211a and 211b are different from each other in the position of the non-forming part of the biomolecule support region S.

  According to this configuration, in addition to the second gaps 211a and 211b, six patterns, that is, a total of eight types of second gaps 213 can be formed. Thus, according to this embodiment, a configuration in which a plurality of types of second gaps 213 are provided on the surface 10a of the substrate body 10 is possible. When many kinds of second gaps 213 are required, for example, a plurality of biomolecule support regions of 5 rows and 5 columns (total 25) or 9 rows and 9 columns (total 81) are arranged in one arrangement pattern. 32 types and 512 types of second gaps 213 can be formed respectively.

  Further, when a plurality of second gaps are formed on the surface 10a of the substrate body 10 and the shapes of the plurality of second gaps are made different from each other, for example, a part of the second gap can be used as a reference for a relative position on the surface 10a. You may make it function as a position reference mark to show. Here, examples of the position reference mark include those indicating the reference position such as the center on the surface 10a of the substrate body 10 or the top, bottom, left, right, and the like. Further, a part of the second gap may function as a substrate information mark indicating information related to the substrate body 10. Here, the board | substrate information mark can illustrate what shows the identification mark which can identify the predetermined information regarding the biochip 1, for example. The predetermined information includes the manufacturing number, the manufacturing date and time, the expiration date, etc. of the biochip 1.

(Fourth embodiment)
Next, a fourth embodiment of the biochip 1 will be described. In the present embodiment, the size or shape of the biomolecule support region S is formed so as to be partially different within the surface 10a of the substrate body 10, and the interval between the biomolecule support regions S is partially made different. A second gap is formed on the surface 10a.

  FIG. 15 is an enlarged plan view showing a main part of the biochip 1D according to the present embodiment. As an example, FIG. 15 is a diagram showing a second gap formed by partially varying the size of a plurality of biomolecule support regions S having the same shape within the surface 10a. In addition, about the structure and member same as the said embodiment, the same code | symbol is attached | subjected and the detailed description is abbreviate | omitted or simplified.

In the present embodiment, as shown in FIG. 15, the second gap 313 is formed so that the size of the plurality of biomolecule support regions S having the same shape as compared with other biomolecule support regions S is partially within the surface 10 a. By forming the first gap 312 differently, the first gap 312 is formed with a different width.
In the present embodiment, the biomolecule support region S has a square shape with a square shape of the first quadrangular biomolecule support region S1 and a planar shape with a square shape different from the first quadrangular biomolecule support region S1. And a second quadrangular biomolecule support region S2 having a large dimension (for example, a large dimension or a small dimension). The first quadrangular biomolecule support region S1 and the second quadrangular biomolecule support region S2 are arranged in a matrix at the same pitch in the surface 10a. In this case, the second gap 313 is constituted by a portion that divides the four second quadrangular biomolecule support regions S2. On the other hand, the 1st gap 312 is comprised by the part except the said 2nd gap 313 among the gap parts 311 formed in the surface 10a, ie, the part which divides 1st square biomolecule support area | region S1.

  That is, in the surface 10a of the substrate body 10, the space S2d between the adjacent biomolecule support regions in the region where the second square biomolecule support region S2 is formed forms the first square biomolecule support region S1. This is narrower than the interval S1d between adjacent biomolecule support regions in the region. Therefore, when the sensor 28 acquires an image of the gap 211 in the first detection step (step SS10), the measurement unit MS can easily determine the second gap 313 as a unique region in the gap 311. It becomes.

  Therefore, since the second gap 313 configured by partially varying the size of the biomolecule support region S within the surface 10a functions as an alignment mark as in the above embodiment, the measurement unit MS can measure each biomolecule support region. The affinity between the biomolecule and the target in S can be measured with high accuracy.

(Modification of the fourth embodiment)
Next, a modification of the fourth embodiment of the biochip 1D will be described. The second gap is configured by making the shapes of the plurality of biomolecule support regions S partially different in the surface 10a.

FIG. 16 is a diagram illustrating a configuration of the second gap according to the present modification.
In the present modification, as shown in FIG. 16, the second gap 413 is formed so that the shape of the specific biomolecule support region S is partially different in the surface 10a as compared with the other biomolecule support regions S. It is composed of gaps generated by
In this modification, the plurality of biomolecule support regions S formed on the biochip 1D include a square biomolecule support region S3 having a square planar shape and a biomolecule support region S4 having a circular planar shape. The diameter of the circular biomolecule support region S4 is set to a size (for example, a large size) different from one side of the square biomolecule support region S3. Note that the rectangular biomolecule support region S3 and the circular biomolecule support region S4 are arranged in a matrix at the same pitch in the surface 10a. In this case, the second gap 313 is constituted by a gap generated by four circular biomolecule support regions S4. For example, the 2nd gap 313 is comprised by the part which divides circular biomolecule support area | region S4. On the other hand, the 1st gap 412 is comprised by the part except the said 2nd gap 413 among the gap parts 411 formed in the surface 10a, ie, the part which divides square biomolecule support area | region S3.

  That is, in the surface 10a of the substrate body 10, the distance S4d between adjacent biomolecule support regions in the region where the circular biomolecule support region S4 is formed is adjacent to the region where the square biomolecule support region S3 is formed. It is narrower than the interval S3d between the biomolecule support regions. According to this, when the sensor 28 acquires the image of the gap part 411 in the first detection step (step SS10), the measurement unit MS easily discriminates the second gap 413 as a unique region in the gap part 411. It becomes possible.

  Therefore, since the second gap 413 configured by partially varying the size of the biomolecule support region S within the surface 10a functions as an alignment mark as in the above embodiment, the measurement unit MS can measure each biomolecule support region. The affinity between the biomolecule and the target in S can be measured with high accuracy.

(Fifth embodiment)
Next, a fifth embodiment of the biochip 1 will be described. In the present embodiment, the second gap is configured by a plurality of rows 11a or a plurality of columns 11b in which the biomolecule support region S is not formed.

  FIG. 17 is an enlarged plan view showing a main part of the biochip 1E according to the present embodiment. In addition, about the structure and member same as the said embodiment, the same code | symbol is attached | subjected and the detailed description is abbreviate | omitted or simplified.

  In the present embodiment, as shown in FIG. 17, the second gap 513 is configured by selecting two rows 511a and three columns 511b. In the present embodiment, the row 511a includes the first row 511a1 and the second row 511a2, and the column 511b includes the first column 511b1, the second column 511b2, and the third column 511b3. Including. In this embodiment, the 1st gap 512 is comprised by the part except the said 2nd gap 513 among the gap parts 511 formed in the surface 10a.

  The first row 511a1 includes a biomolecule support region non-forming portion (non-forming portion) that does not form the biomolecule support region S for two rows, and the second row 511a2 includes the biomolecule support region S for one row. It is composed of a biomolecule support region non-forming part that is not formed. The first row 511b1 is configured by a biomolecule support region non-forming portion that does not form the biomolecule support region S for three rows, and the second row 511b2 is a living body that does not form the biomolecule support region S for two rows. The third column 511b3 includes a biomolecule support region non-forming portion that does not form one row of biomolecule support regions S. As described above, in the present embodiment, the second gap 513 is integrated as a whole, but a plurality of second gaps 513 are provided across the rows and columns, and the gap widths are different in the row direction and the column direction. .

  In the present embodiment, the second gap 513 is provided so as to correspond to the observation visual field 101 that does not include at least two outline lines of the substrate body 10 (including the case where none is included). The second gap 513 is formed such that at least the first row 511a1 and the second row 511a2 of the second gap 513 exist in the observation visual fields 101a and 101b arranged at different positions in the row direction.

  The second gap 513 is at least the first row 511b1, the second row 511b2, and the third row 511b3 of the second gap 513 in the observation visual fields 101c, 101d, and 101e arranged at different positions in the row direction. Are formed to exist respectively.

  According to this embodiment, since the first row 511a1 and the second row 511a2 have different gap widths as described above, the measurement unit MS includes the first row 511a1 in the acquired observation visual field 101. The case and the case where the second row 511a2 is included can be specified. Further, as described above, since the first column 511b1, the second column 511b2, and the third column 511b3 have different gap widths, the measurement unit MS has the first column 511b1 in the acquired observation visual field 101. If included, the case where the second column 511b2 is included and the case where the third column 511b3 is included can be specified.

  Therefore, the measurement unit MS is based on the information on the gap portion 511 in the observation visual field 101 output from the sensor 28 (relative position information on the first gap 512 and the second gap 513), and the biochip 1 in each observation visual field 101. The above position information can be acquired. Therefore, since the second gap 513 configured by the biomolecule support region non-formation part extending over a plurality of rows and columns functions as an alignment mark as in the above embodiment, the measurement unit MS is provided in each biomolecule support region S. The affinity between the biomolecule and the target can be accurately measured.

(Sixth embodiment)
Next, a sixth embodiment of the biochip 1 will be described. This embodiment is different from the above embodiment in that a barcode indicating position information on the biochip 1 is formed in the second gap.

  FIG. 18 is an enlarged plan view showing a main part of the biochip 1 according to the present embodiment. In addition, about the structure and member same as the said embodiment, the same code | symbol is attached | subjected and the detailed description is abbreviate | omitted or simplified.

  As shown in FIG. 18, in the biochip 1F according to the present embodiment, the plurality of second gaps 613 whose planar shape is a cross shape each have a predetermined planar shape (for example, a cross shape). In this embodiment, the 1st gap 612 is comprised by the part except the said 2nd gap 613 among the gap parts 611 formed in the surface 10a.

  In the present embodiment, the second gap 613 is formed in the biochip 1 so as to be disposed in all the observation fields 100 (including the observation fields 101 and 102). The second gap 613 is configured by combining three non-formed portions of the biomolecule support region S in a cross shape in the row and column directions. In the second gap 613, a barcode BC is formed in the biomolecule support region non-forming portion in the row direction. The barcode BC has at least position information on the biochip 1. The barcode BC may include predetermined information in addition to the position information. The predetermined information includes, for example, the type and arrangement position of the biomolecule B formed on the biochip 1 and the type of specimen used, as well as the manufacturing company, serial number, date and time of expiration, and the expiration date. May be. Further, the barcode BC may be either a one-dimensional or a two-dimensional barcode. The barcode BC is configured by being directly printed on the surface 10a of the substrate body 10, for example. The bar code BC may be formed by sticking a sticker on which the bar code is printed on the surface 10a.

According to this embodiment, in the first detection step (step SS10), the measurement unit MS can acquire position information on the biochip 1 in each observation visual field 101 based on the detection result of the barcode BC. . In the present embodiment, since the barcode BC is formed in the second gap 613, the alignment of the biomolecule support region S in the biochip 1F can be performed only by the detection result of the second gap 613. That is, alignment can be performed without using the detection result of the first gap 612.
In addition, the 2nd gap in each embodiment mentioned above is comprised so that it may have a width | variety large or small compared with a 1st gap.

DESCRIPTION OF SYMBOLS 1, 1A, 1B, 1C, 1D, 1E, 1F ... Biochip, S ... Spot (biomolecule support area) 10, 10A ... Substrate body, 10a ... Surface (first surface), 12, 112, 212, 312 , 512, 512 ... 1st gap, 13, 113, 211a, 211b, 213, 313, 413, 513 ... 2nd gap, 11a, 511a ... row, 11b, 511b ... column, 20 ... measuring device, 22 ... measuring unit Control unit, 26 ... stage, 28 ... sensor, 31 ... light source unit, S1 ... first square biomolecule support region, S1d ... interval, S2 ... second square biomolecule support region, S2d ... interval, S3 ... rectangle S4d ... interval, S4 ... circular biomolecule support region, S4d ... interval, 100, 102, 102a, 102b, 102c, 102d ... observation field (target region) , 101 or 101a, 101b ... observation field (first object region), SC ... screening device, AS ... assay unit (dispenser), MS ... measuring unit (detector), BC ... Barcode

Claims (23)

A detection method using a biochip,
A first detection step for optically detecting a first gap of a plurality of biomolecule support regions disposed on the first surface of the biochip and a second gap different from the first gap;
An alignment step of aligning the plurality of biomolecule support regions based on at least the detection result of the second gap;
A second detection step of detecting the affinity between the biomolecule formed in the biomolecule support region and the target contained in the specimen;
A detection method comprising: The detection method according to claim 1, wherein the first detection step includes detecting a width of the first gap and a width of the second gap different from the width of the first gap. The first detection step includes receiving light obtained by irradiating the first gap and the second gap with light of a first wavelength band,
The detection method according to claim 1, wherein the second detection step includes detecting the affinity using light of a second wavelength band different from the first wavelength band. The second detection step divides the plurality of biomolecule support regions into a plurality of imaging regions, and detects the affinity for the plurality of imaging regions based on the detection result of the second gap, respectively. Including
The detection method according to any one of claims 1 to 3, further comprising a step of stitching a plurality of obtained affinity detection results. The detection method according to any one of claims 1 to 4, wherein the first detection step includes detecting a position of the biomolecule support region in the biochip based on a detection result of the second gap. . The detection method according to any one of claims 1 to 5, wherein the first detection step includes detecting a barcode formed in the second gap and having position information on the biochip. A detection device using a biochip,
A stage on which the biochip is disposed;
A first gap of a plurality of biomolecule support regions disposed on the first surface of the biochip and a second light different from the first gap, and a second light on the biomolecule support region. A sensor for receiving a third light obtained by irradiating the light;
An alignment unit for aligning the plurality of biomolecule support regions based on the light reception result of the first light;
Based on the light reception result of the third light, a detection unit that detects the affinity between the biomolecule formed in the biomolecule support region and the target contained in the specimen;
A detection device comprising: The detection apparatus according to claim 7, further comprising a light source unit that emits the first light and the second light. The detection apparatus according to claim 7, further comprising an optical system that guides the first light and the second light to the plurality of biomolecule support regions. An optical detection step using the detection method according to any one of claims 1 to 6;
A dispensing step of dispensing the sample onto the biochip;
A drying step of drying the biochip;
A biochip screening method comprising: The detection device according to any one of claims 7 to 9,
A dispensing device for dispensing the sample onto the biochip;
A screening apparatus comprising: A plurality of biomolecules that can specifically react with the target contained in the specimen,
A substrate body comprising a first surface having a plurality of biomolecule support regions formed with the plurality of biomolecules;
A first gap and a second gap that partition the plurality of biomolecule support regions,
The width of the first gap and the width of the second gap are different from each other. The second gap is provided corresponding to a first target region that does not include at least two outline lines of the substrate body among a plurality of target regions to be subjected to predetermined processing on the first surface, The biochip according to claim 12, wherein an interval between the adjacent biomolecule support regions is partially different with respect to the first gap. The biochip according to claim 13, wherein the predetermined process is at least one of an imaging process of the target area and a synthesis process of an image of the captured target area. A plurality of second gaps corresponding to each of the plurality of first target regions are provided;
The biochip according to claim 13 or 14, wherein the plurality of second gaps have different widths or shapes. The biochip according to any one of claims 12 to 15, wherein the second gap is configured by a non-formation portion of the biomolecule support region on the first surface. The biochip according to claim 16, wherein the non-forming part is set for at least one of a predetermined number of rows or columns in an array of the biomolecule support regions arranged in a matrix on the first surface. The biochip according to any one of claims 12 to 17, wherein the second gap is configured by partially varying the size of a part of the plurality of biomolecule support regions within the first surface. . The biochip according to any one of claims 12 to 18, wherein the second gap is configured by partially changing the shape of a part of the plurality of biomolecule support regions within the first surface. The biochip according to any one of claims 12 to 19, wherein the second gap forms a position reference mark indicating a reference of a relative position on the first surface. The biochip according to any one of claims 12 to 20, wherein the second gap forms a substrate information mark indicating information related to the substrate body. The biochip according to any one of claims 12 to 21, wherein the second gap has a predetermined planar shape. The biochip according to claim 22, wherein the predetermined planar shape is a rotationally asymmetric shape.

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