Analytical chip manufacturing apparatus, analytical chip manufacturing apparatus operation method, and analytical chip manufacturing method

Abstract

An analysis chip manufacturing apparatus according to the present invention comprises: a rotary table that rotates around a central axis, and upon which substrates, that have not been coated with a selectively bondable material, are placed; a point-application head that comprises a plurality of point-application members that point-apply the selectively bondable material to raised parts, and are capable of moving in a scanning plane; and a control unit that controls, for each substrate, the rotation of the rotary table, the movement of the point-application head in the scanning plane, and the application of the selectively bondable material to the raised parts on the substrate. The control unit rotates the rotary table and / or moves the point-application head to a position such that the point-application members and the raised parts of the substrate corresponding to each of the point-application members overlap when viewed from the direction of the central axis of the rotary table, and causes the selectively bondable material to be applied to the raised parts.

Description

[Technical field]

[0001] The present invention relates to an analytical chip manufacturing apparatus, an operating method of the analytical chip manufacturing apparatus, and a method for manufacturing an analytical chip. [Background technology]

[0002] Research into genetic information analysis of various organisms has begun. Information on numerous genes, including human genes, their base sequences, as well as on proteins encoded by gene sequences and the glycans produced secondarily from these proteins, is being rapidly clarified. The functions of polymers such as genes, proteins, and glycans whose sequences have been clarified can be investigated using a variety of methods. The main methods for investigating nucleic acids are Northern blotting and Southern blotting, which utilize the complementarity between various nucleic acids / nucleic acids to investigate the relationship between various genes and the expression of their biological functions. For proteins, protein functions and expression can be investigated by utilizing protein / protein reactions, as typified by Western blotting.

[0003] The DNA microarray method (analysis chip method) is a method for analyzing the expression of many genes at once. In principle, this method is the same as the conventional method described above in that it is a nucleic acid detection and quantification method based on a nucleic acid / nucleic acid hybridization reaction. This analysis chip method can be applied to the detection and quantification of proteins and sugar chains based on specific reactions between proteins / proteins, sugar chains / sugar chains, or sugar chains / proteins. This technology uses a substrate on which a large number of DNA fragments, proteins, and sugar chains are aligned and immobilized at high density on a flat plate or a substrate with a concave-convex pattern. A typical example of a specific use of the analysis chip method is to hybridize a sample in which the expressed genes of the cells under study are labeled with a fluorescent dye or the like on the convex parts formed on the substrate, to bind complementary nucleic acids (DNA or RNA) to each other, and to read the site at high speed with a high-resolution fluorescence detection device (scanner). There is also a method of detecting responses such as current values ​​based on electrochemical reactions. In this way, the amount of each gene in the sample can be quickly estimated. Moreover, analytical chips are used not only in gene expression analysis for estimating the amount of expressed genes, but also as a means for detecting single nucleotide substitutions (Single Nucleotide Polymorphisms: SNPs) in genes.

[0004] Representative methods for producing analytical chips include a spotting method using a spotting member. Representative methods include a method in which a solution (spot solution) containing pre-synthesized DNA is spotted onto the upper end surface of a convex portion on a substrate using a metal pin such as stainless steel (see, for example, Patent Document 1), and a method in which a spot solution ejected from a nozzle using an inkjet method is spotted onto the upper end surface of a convex portion. Typically, hundreds to tens of thousands of types of DNA are applied to any one of a number of convex portions formed in a matrix array on a substrate. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2006-201035 A Summary of the Invention [Problem to be solved by the invention]

[0006] In Patent Document 1, multiple pins are used as spotting members to simultaneously spot the upper end surfaces of multiple convex portions on a substrate; however, if the arrangement direction of the pins is misaligned with the arrangement direction of the convex portions on the substrate when the pins are arranged on the substrate (convex portions), there is a risk that the spot solution will not be properly spotted on at least some of the convex portions.

[0007] The present invention has been made in consideration of the above-mentioned problems, and aims to provide an analytical chip manufacturing apparatus, an operating method of the analytical chip manufacturing apparatus, and a manufacturing method of an analytical chip, which can reliably apply spotting to each of multiple convex parts when applying spotting to multiple convex parts using multiple spotting members. [Means for solving the problem]

[0008] In order to solve the above problems, the analytical chip manufacturing apparatus of the present invention is an analytical chip manufacturing apparatus having a substrate having a plurality of convex portions to which a plurality of types of selective binding substance are individually applied, the analytical chip manufacturing apparatus comprising: a turntable that rotates around a central axis, on which a substrate not coated with the selective binding substance is placed; a spotting head having a plurality of spotting members for spotting the selective binding substance onto each convex portion on the substrate and capable of moving on a scanning plane positioned parallel to the top of the turntable; and a control unit that controls, for each substrate, the rotation of the turntable and the movement of the spotting head on the scanning plane, and the application of the selective binding substance to the convex portions on the substrate, and the control unit rotates the turntable and / or moves the spotting head to a position where, as viewed from the central axial direction of the turntable, each spotting member of the spotting head overlaps with a convex portion on the substrate corresponding to each spotting member, thereby applying the selective binding substance to each convex portion.

[0009] In addition, the analytical chip manufacturing apparatus of the present invention is characterized in that, in the above invention, at least a portion of the multiple convex portions on the substrate and the multiple spotting members arranged on the spotting head are all arranged in a straight line, the spotting head is movable in two directions that intersect with each other on the scanning plane, the control unit calculates a first angle between a first arrangement direction parallel to a straight line passing through the multiple spotting members arranged on the spotting head and one direction in which the spotting head can move, calculates a second angle between a second arrangement direction that is parallel to a straight line passing through the multiple convex portions arranged on the substrate placed on the rotating table and formed outward from the central axis, and the one direction in which the spotting head can move, and rotates the rotating table so that the difference between the first angle and the second angle is minimized.

[0010] In addition, the analytical chip manufacturing apparatus of the present invention, in the above invention, is characterized in that it comprises a first imaging unit that images the deposition head and a second imaging unit that images the substrate placed on the rotating table, and the control unit detects the first arrangement direction based on a first image captured by the first imaging unit, and detects the second arrangement direction based on a second image captured by the second imaging unit.

[0011] In addition, the analytical chip manufacturing apparatus of the present invention is characterized in that, in the above invention, the control unit detects the first arrangement direction by detecting the positions of the multiple spotting members of the spotting head based on the first image.

[0012] In addition, the analytical chip manufacturing apparatus of the present invention is characterized in that, in the above invention, the control unit detects the second arrangement direction by detecting the positions of multiple convex portions on the substrate based on the second image.

[0013] In addition, the analytical chip manufacturing apparatus of the present invention is characterized in that, in the above invention, the control unit detects the second array direction by detecting a label portion formed on the substrate based on the second image.

[0014] In addition, the analytical chip manufacturing apparatus of the present invention is characterized in that, in the above invention, a plurality of the substrates are placed on the rotating table, and each substrate is placed at a position different from the position through which the central axis of the rotating table passes.

[0015] In addition, the analytical chip manufacturing apparatus according to the present invention is characterized in that, in the above invention, a plurality of the turntables are provided, and one of the substrates is placed on each of the turntables.

[0016] In addition, in the analytical chip manufacturing apparatus according to the present invention, in the above invention, the central axis of the turntable passes through the substrate placed on the turntable.

[0017] In addition, the analytical chip manufacturing apparatus according to the present invention is characterized in that, in the above invention, the central axis of the turntable passes through the center of gravity of the substrate.

[0018] The analytical chip manufacturing apparatus according to the present invention is characterized in that, in the above invention, it further comprises a holding table that holds each of the turntables rotatably about its central axis.

[0019] In addition, a method for operating the analytical chip manufacturing apparatus of the present invention is an analytical chip manufacturing apparatus having a substrate having a plurality of convex portions to which a plurality of types of selective binding substance are individually applied, the method comprising: a turntable that rotates around a central axis, on which a substrate not coated with the selective binding substance is placed; a spotting head having a plurality of spotting members for spotting the selective binding substance onto each convex portion on the substrate and capable of moving on a scanning plane positioned parallel to the top of the turntable; and a control unit that controls the rotation of the turntable and the movement of the spotting head on the scanning plane, as well as the application of the selective binding substance to each convex portion, characterized in that the control unit performs, for each substrate, the rotation of the turntable and / or the movement of the spotting head to a position where, as viewed from the central axial direction of the turntable, each spotting member of the spotting head overlaps with a convex portion on the substrate corresponding to each spotting member, and the process of applying the selective binding substance to each convex portion.

[0020] In addition, the manufacturing method of the analytical chip according to the present invention is characterized in that, when viewed from the direction of the central axis of a turntable on which a substrate not coated with a selective binding substance is placed, the turntable has a plurality of spotting members which individually apply a plurality of types of the selective binding substance to each convex portion on the substrate, and the turntable is rotated and / or the spotting head is moved to a position where each spotting member of a spotting head which is movable on a scanning plane positioned parallel to the top of the turntable overlaps with the convex portion on the substrate corresponding to each spotting member, and a process of applying the selective binding substance to each convex portion is performed for each substrate. Effect of the Invention

[0021] According to the present invention, when a plurality of spotting members are used to spot a spot solution onto a plurality of convex portions, the spot solution can be reliably spotted onto each of the convex portions. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 is a diagram showing a schematic configuration of an analytical chip manufacturing apparatus according to one embodiment of the present invention. [Diagram 2] FIG. 2 is a cross-sectional view of the substrate shown in FIG. 1 taken along line AA. [Diagram 3] FIG. 3 is a perspective view showing a schematic configuration of a spotting head in an analytical chip manufacturing apparatus according to one embodiment of the present invention. [Figure 4] FIG. 4 is a diagram illustrating collection of a spot solution. [Diagram 5] FIG. 5 is a diagram illustrating the application of the spot solution. [Figure 6] FIG. 6 is a diagram for explaining calculation of the angle between the arrangement direction of the pins and the movement direction of the spotting head. [Figure 7] FIG. 7 is a diagram for explaining calculation of the angle between the arrangement direction of the convex portions on the substrate and the movement direction of the spotting head. [Figure 8] FIG. 8 is a flow chart illustrating the spotting process of the spotting solution in the analytical chip manufacturing apparatus according to one embodiment of the present invention. [Figure 9] FIG. 9 is a diagram showing the configuration of an analytical chip manufacturing apparatus according to Modification 1 of the present invention. [Figure 10] FIG. 10 is a diagram showing a schematic configuration of an analytical chip manufacturing apparatus according to Modification 2 of the present invention. [Figure 11] FIG. 11 is a diagram showing a schematic configuration of an analytical chip manufacturing apparatus according to Modification 3 of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Hereinafter, the embodiments of the present invention will be described in detail with reference to the drawings. Note that the present invention is not limited to the following embodiments. Furthermore, each drawing referred to in the following description merely shows the shape, size, and positional relationship in a schematic manner to the extent that the contents of the present invention can be understood. In other words, the present invention is not limited to only the shape, size, and positional relationship exemplified in each drawing. Furthermore, in the description of the drawings, the same parts are given the same reference numerals.

[0024] The analytical chip that is the subject of the present invention is formed by applying and immobilizing a solution containing selective binding substances such as DNA, proteins, and glycans (referred to as a spot solution in the present invention) onto the surface of a carrier, such as a substrate such as a glass substrate or a plastic substrate.

[0025] The analytical chip according to the present invention is used to measure the presence or absence, amount, properties, etc. of a test substance by dropping a sample onto a reaction portion of the analytical chip. Specific examples include biochips that measure the presence or absence, amount, etc. of a test substance by a reaction between a selective binding substance immobilized on a carrier surface and the test substance. More specific examples include DNA chips on which nucleic acids are immobilized on a carrier surface, protein chips on which proteins such as antibodies are immobilized on a carrier surface, sugar chain chips on which sugar chains are immobilized on a carrier surface, and cell chips on which cells are immobilized on a carrier surface.

[0026] (Embodiment) Fig. 1 is a diagram showing a schematic configuration of an analytical chip manufacturing apparatus according to one embodiment of the present invention. The analytical chip manufacturing apparatus 1 shown in Fig. 1 includes a spotting processing device 10 that performs spotting processing, and a control device 20 that controls the driving of the spotting processing device 10.

[0027] The substrate 100 constituting the analytical chip includes a base portion 101 and a plurality of convex portions 102 formed within the base portion 101. The base portion 101 has a rectangular outer edge and is tray-shaped with the outer edge rising up. The inner bottom surface of the base portion 101 extends in a flat plate shape, and convex portions 102 are partially formed thereon. The material of the base portion 101 is preferably a general slide glass or a plastic of a similar size. In addition, the surface of the substrate 100 is preferably a color or material that absorbs light, such as black, in order to suppress light (e.g., autofluorescence) emitted by the substrate 100 itself when detecting the signal intensity.

[0028] Fig. 2 is a cross-sectional view of the substrate shown in Fig. 1 taken along line AA. A plurality of (eight in this embodiment) convex portions 102 are formed inside base portion 101. Convex portions 102 protrude in a convex shape from the inner bottom surface of base portion 101. The upper end surface of convex portion 102 is flat, and a spotting solution containing a selective binding substance is spotted on the upper end surface, immobilizing the selective binding substance. The upper end surface of convex portion 102 corresponds to an immobilization region of the selective binding substance in the spotting solution, and is the region to which the spotting solution is applied.

[0029] The number of protrusions 102 can be set to any number, for example, two, four, eight, .... Moreover, the protrusions 102 are arranged in a matrix. In this embodiment, eight protrusions 102 are arranged in four rows and two columns (4 x 2).

[0030] In the present invention, the selective binding substance refers to various substances that can selectively bind to a test substance directly or indirectly. Representative examples of selective binding substances that can bind to a test substance include nucleic acids, proteins, peptides, sugars, and lipids.

[0031] Among the selective binding substances, examples of the nucleic acid include DNA and RNA, and may be PNA or LNA. Examples of DNA include, but are not limited to, chromosomal DNA, viral DNA, bacterial DNA, fungal DNA, cDNA obtained by reverse transcription of RNA, and fragments thereof. Examples of RNA include, but are not limited to, messenger RNA, ribosomal RNA, small RNA, microRNA, and fragments thereof. Examples of nucleic acids include chemically synthesized DNA or RNA. A single-stranded nucleic acid having a specific base sequence selectively hybridizes and binds to a single-stranded nucleic acid having a base sequence complementary to the base sequence or a portion thereof, and therefore corresponds to the selective binding substance referred to in the present invention. The nucleic acid may be derived from a natural product such as a living cell, or may be synthesized by a nucleic acid synthesizer. Preparation of DNA or RNA from living cells can be carried out by known methods, for example, DNA can be extracted by the method of Blin et al. (Blin et al., Nucleic Acids Res. 3:2303 (1976)) and RNA can be extracted by the method of Favaloro et al. (Favaloro et al., Methods Enzymol. 65:718 (1980)). Examples of nucleic acids to be immobilized include linear or circular plasmid DNA or chromosomal DNA, DNA fragments obtained by cleaving these with restriction enzymes or chemically, DNA synthesized in a test tube with an enzyme or the like, or chemically synthesized oligonucleotides.

[0032] Examples of proteins include antibodies and antigen-binding fragments of antibodies, such as Fab fragments and F(ab')2 fragments, as well as various antigens. Antibodies and antigen-binding fragments thereof selectively bind to their corresponding antigens, and antigens selectively bind to their corresponding antibodies, and thus are considered "selective binding substances."

[0033] Examples of the sugars include various sugar chains such as monosaccharides, oligosaccharides, and polysaccharides.

[0034] The lipid may be a complex lipid as well as a simple lipid.

[0035] Furthermore, antigenic substances other than the above-mentioned nucleic acids, proteins, sugars and lipids can also be immobilized. Furthermore, cells may be immobilized on the surface of the carrier as the selective binding substance.

[0036] Among these selective binding substances, particularly preferred ones include DNA, RNA, proteins, peptides, sugars, sugar chains, and lipids.

[0037] These selective binding substances are applied as a spotting solution to the surface of the carrier and immobilized. The spotting solution may also contain other salts for adjusting the buffer. Examples of such salts include phosphate buffer, citrate buffer, citrate phosphate buffer, borate buffer, and tartrate buffer.

[0038] When the selective binding substance is immobilized on the carrier surface by covalent bonding, the spotting solution may contain a condensing agent. As the condensing agent, a carbodiimide for forming an amide bond, particularly a water-soluble carbodiimide such as 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (EDC) or its hydrochloride, may be preferably used. When EDC is used as the condensing agent, a solution in which EDC and sodium chloride are mixed may be used in the spotting solution.

[0039] The analytical chip is preferably structured such that at least the space in the base portion 101 in which the convex portion 102 is formed is sealed by a cover or the like (not shown) when reacting with the test substance. For example, the inner surface of the cover can be formed in a concave shape so that the upper end surface of the convex portion 102 does not directly contact the cover. In addition, when a flat cover is used, a structure can be adopted in which the convex portion 102 is provided in a concave portion formed in the base portion 101, and the depth of the concave portion is such that the upper end surface of the convex portion 102 does not contact the inner surface of the cover when the cover is placed on the substrate. The cover used in this case may be made of any material, such as glass, various polymers (e.g., polystyrene, polymethyl methacrylate, polycarbonate, polyolefin), silicone, etc.

[0040] The spotting treatment device 10 includes a turntable 11, a spotting head 12, a moving mechanism 13, a first imaging unit 14, a second imaging unit 15, a spot solution holding unit 16, a cleaning unit 17, and a drying unit 18. In the spotting treatment device 10 shown in Fig. 1, the left-right direction is the X direction (the right direction is the positive direction), the up-down direction is the Y direction (the up direction is the positive direction), and the direction perpendicular to the paper surface is the Z direction (the direction toward the viewer is the positive direction).

[0041] The turntable 11 is disk-shaped and places thereon the substrate 100 to be subjected to the spot deposition process. The turntable 11 is rotatable around a central axis N. In FIG. 1, the central axis N extends in a direction perpendicular to the paper surface (Z direction). The surface of the turntable 11 on which the substrate 100 is placed is parallel to the XY plane. The substrates 100 are arranged in a circumferential direction of a circle centered on the central axis N, at positions that are not passed by the central axis N of the turntable 11. Therefore, the substrates 100 revolve around the central axis N as the turntable 11 rotates.

[0042] The spotting head 12 has a holder 121 that holds a number of pins 122 that spot the spot solution on the substrate 100. FIG. 3 is a perspective view that shows a schematic configuration of the spotting head in an analytical chip manufacturing apparatus according to one embodiment of the present invention. The pins 122 extend in a rod shape from the holder 121. The spotting head 12 shown in FIG. 1 is provided with eight pins 122 in accordance with the number of protrusions 102 of the substrate 100. The multiple pins 122 are arranged in two orthogonal directions (in a matrix). In the substrate 100 shown in FIG. 1, the multiple pins 122 are arranged in a 4×2 (number) arrangement that corresponds to the arrangement of the protrusions 102. The pins 122 correspond to the spotting members.

[0043] The movement mechanism 13 holds the holder 121 of the spotting head 12, and moves the spotting head 12 under the control of the control device 20. The movement mechanism 13 drives the spotting head 12 to move in the X, Y, and Z directions. Specifically, the movement mechanism 13 moves the spotting head 12 on the XY plane, which is the scanning plane. Furthermore, this scanning plane can be shifted in the Z direction.

[0044] The moving mechanism 13 has a first shaft 131 extending in the X direction, a first moving part 132 that moves in the X direction along the first shaft 131, a second moving part 133 held by the first moving part 132 and movable in the Z direction, and a second shaft 134 that extends in the Y direction from the second moving part 133 and holds the spotting head 12 movable in the Y direction.

[0045] The first imaging unit 14 captures an image of the side of the spotting head 12 on which the pins 122 are disposed. The second imaging section 15 captures an image of the surface of the substrate 100 on which the convex portions 102 are formed.

[0046] The first imaging unit 14 and the second imaging unit 15 are configured using, for example, a CCD (Charge Coupled Device) image sensor or a CMOS (Complementary Metal Oxide Semiconductor) image sensor. In order to change the imaging field of view of the first imaging unit 14 and the second imaging unit 15, the first imaging unit 14 and the second imaging unit 15 may be configured to be movable. In that case, it is possible to move the first imaging unit 14 and the second imaging unit 15 in order to capture an image for detecting the arrangement direction of the pins 122 or the arrangement direction of the protrusions 102.

[0047] The spot solution holding unit 16 is provided with a replaceable plate 161. The plate 161 is formed with a plurality of holes 162 (eight in this embodiment). The holes 162 contain a spot solution. The holes 162 are arranged corresponding to the arrangement of the pins 122, and the pins 122 are inserted into each hole 162 by the movement of the movement mechanism 13. The plate 161 may be replaced manually by a user or mechanically. In the case of mechanical replacement, for example, a refrigerator chamber for storing a plurality of plates 161 containing a spot solution is provided below the spot solution holding unit 16, and the plate 161 to be replaced is taken out from the refrigerator chamber and placed in the spot solution holding unit 16.

[0048] The cleaning unit 17 is supplied with a cleaning liquid such as water (pure water), physiological saline, or an aqueous solution containing a surfactant, and cleans the pins 122 arranged in the cleaning unit 17 by immersion, stirring, or the like. The drying section 18 is for removing the cleaning liquid adhering to the pins after cleaning. For example, the pins after cleaning are inserted into the drying section 18, and the cleaning liquid adhering to the pins is removed by wind pressure.

[0049] The control device 20 includes a drive unit 21, a calculation unit 22, a storage unit 23, and a control unit 24. The control device 20 is configured using one or more processors, such as a CPU (Central Processing Unit), an FPGA (Field Programmable Gate Array), an ASIC (Application Specific Integrated Circuit), and a memory.

[0050] The driving unit 21 drives and controls each part of the spotting processing device 10 based on a control signal from the control unit 24. For example, the driving unit 21 transmits a pulse signal to each part to move the turntable 11 and the moving mechanism 13 in a set direction and distance, and causes the first imaging unit 14 and the second imaging unit 15 to perform imaging processing.

[0051] The calculation unit 22 executes calculation processing to determine the amount of rotation of the turntable and the position of the spotting head 12 by the movement mechanism 13. The calculation unit 22 has an angle calculation unit 221 and a position determination unit 222.

[0052] The angle calculation unit 221 calculates the angle between the arrangement direction of the pins 122 arranged on the spotting head 12 and the movement direction of the spotting head 12, and the angle between the arrangement direction of the convex portions 102 of the substrate 100 and the movement direction of the spotting head 12.

[0053] Based on the angle calculated by the angle calculation unit 221 , the position determination unit 222 determines the rotation position of the turntable 11 and the movement position of the spotting head 12 by the movement mechanism 13 .

[0054] The storage unit 23 stores various programs for operating the manufacturing apparatus 1, and information including various parameters necessary for the operation of the manufacturing apparatus 1, etc.

[0055] The control unit 24 comprehensively controls each part of the manufacturing apparatus 1.

[0056] Next, an example of a method of using the analytical chip will be described. First, a test substance such as a nucleic acid is extracted from a specimen. Then, a label, for example, a fluorescent label, is bound to the extracted test substance. The labeled test substance is reacted with a selective binding substance on the DNA chip. In the reaction process, the test substance is reacted with the selective binding substance immobilized on the upper end surface of the convex portion 102 by stirring for example at 32°C for several hours. In the stirring process, the solution containing the test substance is stirred by moving the analytical chip by, for example, rotation, vibration, or a combination of these, or by moving stirring beads enclosed in a cover covering the analytical chip.

[0057] The specimens used in the present invention include, but are not limited to, body fluids such as blood, serum, plasma, urine, feces, cerebrospinal fluid, saliva, and various tissue fluids, as well as various foods and beverages and dilutions thereof.

[0058] The test substance used in the present invention may include, but is not limited to, nucleic acids to be measured, such as genes of pathogens, viruses, etc., genes causing genetic diseases, etc. and parts thereof, various biological components having antigenicity, antibodies against pathogens, viruses, etc. The test substance can be reacted with a selective binding substance, for example, by a hybridization reaction in the case of nucleic acids, or by an antigen-antibody reaction in the case of proteins.

[0059] The nucleic acid to be tested may be a nucleic acid extracted from blood or cells and labeled with a fluorescent substance or the like, or may be amplified by a nucleic acid amplification method such as PCR using the nucleic acid as a template. When a nucleic acid amplification product is used as the test substance, it is possible to label the amplified nucleic acid by performing amplification in the presence of a nucleoside triphosphate labeled with a fluorescent substance or the like. In addition, when the test substance is an antigen or an antibody, the test substance, the antigen or antibody, may be directly labeled by a conventional method, or the test substance, the antigen or antibody, may be bound to a selective binding substance, and then the carrier may be washed, and the labeled antibody or antigen that undergoes an antigen-antibody reaction with the antigen or antibody may be reacted to measure the label bound to the carrier. Furthermore, when the test substance is an unamplified nucleic acid, a method in which, for example, the phosphate group at the 5' end of the nucleic acid is removed with alkaline phosphatase, the test substance is labeled with a fluorescent substance, and then reacted with a selective binding substance and the bound label is measured; or a method in which the test substance is captured by a selective binding substance (capture probe), a detection probe labeled with a fluorescent substance or the like is bound to the test substance, and the label of the detection probe is measured (sandwich hybridization method) is suitably used.

[0060] After the reaction, the analytical chip is washed to remove any substances that have not reacted with the selective binding substance from the analytical chip. After the washing, the analytical chip is centrifuged and dried using a general centrifuge dedicated to chips and slide glasses.

[0061] In the case where the test substance is fluorescently labeled, the analytical chip after the washing and drying processes is used for processing to read the image using a high-resolution fluorescence detection device, etc., and to digitize the signal intensity (fluorescence intensity). Suitable high-resolution fluorescence detection devices include, but are not limited to, 3D-Gene (registered trademark) Scanner (manufactured by Toray Industries, Inc.), SureScan microarray scanner (manufactured by Agilent Technologies, Inc.), GenePix (manufactured by Molecular Devices, Inc.), etc.

[0062] Next, a method of spotting a spot solution during the manufacture of an analytical chip will be described with reference to Figs. 3 to 8. Fig. 4 is a diagram for explaining collection of a spot solution. Fig. 5 is a diagram for explaining spotting of a spot solution. A pin 122 (spotting head 12) is moved by driving a moving mechanism 13 under the control of a control unit 24.

[0063] In the spotting process, first, spot solution Q 1 ~Q 4 The pins 122 are inserted into the holes 162 in which the spot solution Q is accommodated (see FIG. 4(a)). 1 ~Q 4 (See FIG. 4(b)).

[0064] Thereafter, the pin 122 having the spot solution attached to its tip is placed on top of the substrate 100 to be spotted (see FIG. 5(a)), and the spot solution is brought into contact with the convex portion 102, thereby transferring the spot solution from the pin 122 to the convex portion 102 (see FIG. 5(b)).

[0065] At this time, if the positions of the pins 122 and the convex portions 102 are misaligned, the spot solution may not be properly applied to the convex portions 102. In this embodiment, the spotting head 12 and the substrate 100 are arranged at positions where the arrangement direction of the pins 122 and the arrangement direction of the convex portions 102 are aligned.

[0066] At this time, the angle calculation unit 221 first calculates the angle between the arrangement direction of the pins 122 arranged on the spotting head 12 and the movement direction of the spotting head 12. Fig. 6 is a diagram for explaining the calculation of the angle between the arrangement direction of the pins and the movement direction of the spotting head. Note that the first imaging unit 14 and the second imaging unit 15 will be described as images captured by an optical system with an optical axis parallel to the Z direction.

[0067] The angle calculation unit 221 acquires an image of the spotting head 12 captured by the first imaging unit 14. Based on the captured image, the angle calculation unit 221 calculates a straight line L passing through all the pins 122 aligned in a predetermined direction from the arrangement of the pins 122. P In this embodiment, a straight line passing through all the pins 122 arranged approximately parallel to the X direction is generated. The angle calculation unit 221 extracts the contour of the outer periphery of each pin 122 by, for example, contour extraction, and obtains the center of the contour. The angle calculation unit 221 obtains an approximation straight line for the position of each obtained center, and calls this a straight line L. P The angle calculation unit 221 calculates the line L P and a straight line L parallel to the moving direction of the spotting head 12 (here, the longitudinal axis direction (X direction) of the first shaft 131). N Angle θ P Calculate.

[0068] Furthermore, the angle calculation unit 221 calculates the angle between the arrangement direction of the protrusions 102 on the substrate 100 and the movement direction of the spotting head 12. FIG. 7 is a diagram for explaining the calculation of the angle between the arrangement direction of the protrusions on the substrate and the movement direction of the spotting head. The angle calculation unit 221 acquires an image of the substrate 100 captured by the second imaging unit 15. Based on the captured image, the angle calculation unit 221 calculates a straight line L that passes through all of the protrusions 102 that are lined up in a predetermined direction from the arrangement of the protrusions 102. CIn this embodiment, a straight line is generated that passes through all the convex portions 102 that are arranged substantially parallel to the arrangement direction of the spotting head 12 (here, the arrangement direction of the convex portions 102 that are arranged in the X direction when the spotting head 12 is placed at the spotting position). The arrangement direction of the convex portions 102 through which this straight line passes is a direction from the center (central axis N) of the turntable 11 toward the outside. The angle calculation unit 221 extracts the outline of the outer periphery of each convex portion 102 by, for example, contour extraction, and determines the center of the outline. The angle calculation unit 221 determines an approximation straight line for each of the determined center positions, and refers to this as the straight line L. C The angle calculation unit 221 calculates the line L C and a straight line L parallel to the moving direction of the spotting head 12 (here, the longitudinal axis direction (X direction) of the first shaft 131). N Angle θ C Calculate.

[0069] The position determination unit 222 determines the angle θ P , θ C Based on this, the rotational position of the turntable 11 (the arrangement of the substrate 100 to be spotted) and the movement position of the spotting head 12 by the movement mechanism 13 are determined. P and angle θ C Difference θ D Calculate the difference θ D corresponds to the deviation in the X direction between the arrangement direction of the pins 122 and the arrangement direction of the protrusions 102.

[0070] The position determination unit 222 determines a reference application position (for example, the reference position P B ) to θ B The position where the turntable 11 is rotated by the angle θ is determined as the position of the substrate 100 to be spot-attached. P and angle θ C Difference between (θ D The rotation angle (θ B) is determined according to the characteristics related to the rotation of the turntable 11, the characteristics related to the drive of the moving mechanism 13, the arrangement area of ​​the convex portions, and the area of ​​the upper ends of the convex portions. B ) for example, θ D It is also possible to set the angle θ within the range of ±0.1°. D It may be set within the range of ±0.06°.

[0071] Furthermore, the position determination unit 222 determines a position above the substrate 100 after the rotation of the turntable 11 as a position for placing the spotting head 12. A virtual coordinate space is set in the spotting processing device 10, and the position determination unit 222 determines coordinates located a predetermined distance above in the Z direction in the XY coordinates of the substrate 100 placed at the spotting position as the position of the spotting head 12. Here, the coordinates of the substrate and the spotting head 12 refer to the coordinates where the representative points of each member are located. The position determination unit 222 may correct the position (coordinates) of the spotting head 12 according to the position and orientation of the substrate 100 in the captured image.

[0072] Next, a flow of a spotting process of the spotting solution in the manufacturing apparatus 1 will be described with reference to Fig. 8. Fig. 8 is a flowchart illustrating a spotting process of the spotting solution in the manufacturing apparatus for an analytical chip according to one embodiment of the present invention.

[0073] First, the substrate 100 is subjected to a surface treatment, and then placed on the rotating table 11. In the surface treatment, a treatment such as introduction of a functional group required for immobilizing a selective binding substance on the substrate surface is carried out. For example, in the case of a substrate made of polymethyl methacrylate (PMMA), hydrolysis of the side chain of PMMA is carried out using an alkaline aqueous solution.

[0074] In the manufacturing apparatus 1, the first imaging unit 14 captures an image of the spotting head 12 in order to detect the arrangement direction of the pins 122 (step S101).

[0075] Thereafter, the angle calculation unit 221 detects the arrangement direction of the pins 122 based on the captured image of the spotting head 12 (step S102). As described above, the angle calculation unit 221 calculates a straight line L that passes through all the pins 122 arranged in a predetermined direction from the arrangement of the pins 122. P (See Figure 6.)

[0076] The angle calculation unit 221 calculates the angle of the generated straight line L P and a straight line L parallel to the moving direction of the spotting head 12. N Angle θ P (arrangement angle) is calculated (step S103). The arrangement angle calculated in step S103 is stored in storage unit 23, and this arrangement angle can be used until spotting head 12 is replaced.

[0077] Here, the control unit 24 assigns a spot deposition process number n to each of the substrates 100 placed on the turntable 11. The number n corresponds to the number of substrates 100 placed on the turntable 11. The maximum value of the number n is n MAX In this embodiment, n MAX = 8 (see FIG. 1). The control unit 24 sets the number n of the spotting process target to n = 1 (step S104). Under the control of the control unit 24, the drive unit 21 rotates the turntable 11 to move the substrate 100 of n = 1 to the reference position (reference position P B At this time, the substrate 100 placed on the turntable 11 is a substrate on which no spotting solution has been applied.

[0078] In step S105, the angle calculation unit 221 detects the arrangement direction of the convex portion 102 of the n-th substrate 100. At this time, the second imaging unit 15 captures an image of the substrate 100. Based on the captured image, the angle calculation unit 221 calculates a straight line L that passes through all the convex portions 102 arranged in a predetermined direction from the arrangement of the convex portions 102. C (See Figure 7.)

[0079] The angle calculation unit 221 calculates the angle of the generated straight line L C and a straight line L parallel to the moving direction of the spotting head 12. N Angle θC is calculated (step S106).

[0080] Thereafter, the position determination unit 222 determines the angle θ P , θ C Based on this, the position of the n-th substrate 100 (the rotation angle of the turntable 11) and the position of the spotting head 12 (the movement position) by the movement mechanism 13 are determined (step S107). B from angle θ P and angle θ C Difference θ D The position where the turntable 11 is rotated by the rotation angle at which the difference θ is smallest is determined as the position of the substrate 100 to be dropped. D The position above the substrate 100 after rotation at the rotation angle at which the difference is smallest is determined as the position at which the spotting head 12 is to be disposed, and is recorded in the memory unit 23.

[0081] Next, the control unit 24 increments the value of the number n of the substrate 100 by 1 (step S108).

[0082] Thereafter, the control unit 24 determines whether the reset number n is equal to or smaller than the maximum value n MAX (here, n=8) (step S109). MAX If it is determined that the number is equal to or less than the number n (step S109: No), the process returns to step S105 and the process is executed on the substrate 100 corresponding to the reset number n. MAXIf it is determined that the n-th substrate 100 is larger than the n-th substrate 100 (step S109: Yes), the control unit 24 performs the spotting process on all substrates 100 placed on the turntable 11 (step S110). The driving unit 21 moves the spotting head 12 to the spot solution holder 16 to apply the spot solution to the pins 122 (see FIG. 4). After the spot solution is applied to the pins 122, the control unit 24 rotates the turntable 11 according to the substrate 100 to be spotted under the control of the control unit 24, and moves the spotting head 12 by the moving mechanism 13, thereby placing the n-th substrate 100 and the spotting head 12 at the position determined in step S107 (the position recorded in the memory unit 23). After placing the substrate 100 and the spotting head 12, the control unit 24 lowers the spotting head 12 in the Z direction to bring the spot solution into contact with the protrusions 102 and spot the solution (see FIG. 5). The control unit 24 performs the above-mentioned process for each substrate 100 in a preset order (for example, n=1, 2, 3, . . . , n). Also, in step S109, n is MAX If it is determined that the value is larger (step S109: Yes), before proceeding to step S110, a position confirmation step can be added in which the second imaging unit 15 detects the arrangement direction of the convex portions again at the position recorded in the memory unit 23 to confirm whether the position recorded in the memory unit 23 is appropriate.

[0083] In the above-described embodiment, the arrangement direction of the pins 122 arranged on the spotting head 12 and the arrangement direction of the convex portions 102 of the substrate 100 are detected, and the rotating table 11 and the spotting head 12 are moved to a position where the arrangement directions are aligned, thereby performing the spotting process. According to this embodiment, the spotting process is performed in which the occurrence of misalignment between the positions of the pins 122 and the positions of the convex portions 102 is suppressed, so that when spotting solution onto multiple convex portions using multiple pins, the spot solution can be reliably spotted onto each convex portion.

[0084] In the above-described embodiment, instead of using a pin that applies the spot solution to the upper end surface of the convex portion by contact with the spot solution, a nozzle that ejects the spot solution from the inside by an inkjet method may be used to apply the spot solution to the convex portion 102.

[0085] In the above-mentioned embodiment, an example was described in which the arrangement directions of the pins 122 and the convex portions 102 were detected from their images, but it would also be possible to provide indicators indicating the arrangement directions of the pins 122 and the convex portions 102 on the holding portion 121 or the base portion 101, and detect the indicators to detect each arrangement direction. The indicators may be characters, or may be figures such as a square (□), a circle (◯), or a straight line (-), or a combination of these, as long as it is possible to detect the arrangement direction.

[0086] In addition, in the above-mentioned embodiment, an example was described in which the number of pins 122 and the number of convex portions 102 of substrate 100 are the same, and spotting on one substrate 100 is completed in one spotting process. However, if the number of pins 122 is fewer than the number of convex portions 102, it is sufficient to move the spotting head 12 back and forth relative to the substrate 100, and if the number of pins 122 is greater than the number of convex portions 102, it is sufficient to control the pins 122 that apply the spot solution by, for example, aligning the arrangement of the spot solution contained in plate 161 of the spot solution holding unit with the convex portions.

[0087] (Variation 1) Next, modified example 1 will be described with reference to Fig. 9. Fig. 9 is a diagram showing the configuration of an analytical chip manufacturing apparatus according to modified example 1 of the present invention. The analytical chip manufacturing apparatus 1A according to modified example 1 includes a spotting processing apparatus 10A instead of the spotting processing apparatus 10 of the analytical chip manufacturing apparatus 1 described above. In the analytical chip manufacturing apparatus 1A, the configuration other than the spotting processing apparatus 10A is the same as the configuration described in the embodiment.

[0088] The spotting treatment device 10A includes a plurality of turntables 11A, a spotting head 12, a moving mechanism 13, a first imaging section 14, a second imaging section 15, a spot solution holding section 16, a cleaning section 17, and a drying section 18. The first imaging section 14, the spot solution holding section 16, the cleaning section 17, and the drying section 18 are the same as those in the above-mentioned embodiment. The moving mechanism 13 is the same as those in the above-mentioned embodiment, except that the lengths of the first shaft 131 and the second shaft 134 differ depending on the arrangement of the turntable 11A.

[0089] The rotating table 11A is disk-shaped and supports one substrate 100. The rotating table 11A is rotated around a central axis N 1 In FIG. 9, the central axis N 1 extends in a direction perpendicular to the paper surface (Z direction). The surface of the turntable 11A on which the substrate 100 is placed is parallel to the XY plane. In addition, when the substrate 100 is placed on the turntable 11A, the central axis N 1 passes through the substrate 100. In this modification 1, the central axis N 1 However, the present invention is not limited to this example, and the light source 10 may pass through a position shifted from the center of gravity.

[0090] In this first modification, the second imaging unit 15 is provided so as to be movable relative to each of the rotary tables 11A. The second imaging unit 15 is moved by a moving mechanism (not shown). The second imaging unit 15 may be attached to the spotting head 12 and move together with the spotting head 12, or may move along the moving mechanism 13 separately from the spotting head 12, or a known moving mechanism other than the moving mechanism 13 may be used.

[0091] The calculation unit 22 executes a calculation process to determine the amount of rotation of the turntable 11A based on the image of the substrate 100. Specifically, the angle calculation unit 221 calculates the angle of the arrangement direction of the pins 122 arranged on the spotting head 12 (the above-mentioned straight line L P ) and the direction of movement of the spotting head 12 (corresponding to the above-mentioned straight line L N The angle θ P1 (The above-mentioned angle θP ) and the arrangement direction of the convex portions 102 of the substrate 100 (for example, the above-mentioned straight line L C The angle θ between the moving direction of the spotting head 12 and the C1 (The above-mentioned angle θ C Here, the angle calculation unit 221 calculates the angle θ between the arrangement direction of the convex portions 102 of the substrate 100 and the movement direction of the spotting head 12. C1 is calculated for each rotary table 11A.

[0092] Thereafter, the position determination unit 222 determines the central axis N of the turntable 11A based on the angle calculated by the angle calculation unit 221. 1 Specifically, the position determination unit 222 determines the rotation angle around the P1 and angle θ C1 Difference between (θ D1 ) and calculate the difference θ D1 The rotation angle (θ B1 In this first modified example, the position to which the spotting head 12 is moved by the moving mechanism 13 is determined based on the image of the substrate 100 captured by the second imaging unit 15. This position is determined, for example, by extracting the outline of the substrate 100 and aligning the outline with the spotting head 12. Also, this position is determined based on the central axis N of each rotary table 11A. 1 is determined for each rotary table 11A based on the position of

[0093] The turntable 11A on which the substrate 100 to be spot-attached is placed is rotated by a rotation angle determined by the position determination unit 222 under the control of the control device 20.

[0094] The movement mechanism 13 moves the spotting head 12 to the movement position described above under the control of the control device 20. The movement mechanism 13 drives the spotting head 12 to move in the X direction, Y direction, and Z direction. The spotting head 12 moves up and down in the Z direction at the movement position, thereby spotting the spot solution onto the convex portion 102 of the substrate 100.

[0095] In the above-mentioned first modification, the arrangement direction of the pins 122 arranged on the spotting head 12 and the arrangement direction of the convex portions 102 of the substrate 100 placed on the turntable 11A are detected, and the turntable 11A is rotated to a position where the arrangement directions are aligned to perform the spotting process. According to the first modification, the spotting process is performed in which the occurrence of misalignment between the positions of the pins 122 and the positions of the convex portions 102 is suppressed, so that when spotting the spot solution on multiple convex portions using multiple pins, the spot solution can be reliably spotted on each convex portion.

[0096] In the above-mentioned variant example 1, a configuration in which one second imaging unit 15 is movably provided with respect to each turntable 11A has been described as an example, but multiple units may be provided, or the second imaging unit 15 may be provided individually with respect to each turntable 11A.

[0097] (Variation 2) Next, modified example 2 will be described with reference to Fig. 10. Fig. 10 is a diagram showing a schematic configuration of an analytical chip manufacturing apparatus according to modified example 2 of the present invention. Analytical chip manufacturing apparatus 1B according to modified example 2 includes a spotting processing apparatus 10B instead of the spotting processing apparatus 10 of the analytical chip manufacturing apparatus 1 described above. In analytical chip manufacturing apparatus 1B, the configuration other than the spotting processing apparatus 10B is the same as the configuration described in the embodiment.

[0098] The spotting treatment device 10B includes a plurality of turntables 11B, a holding table 11C that holds the turntables 11B, a spotting head 12, a moving mechanism 13, a first imaging section 14, a second imaging section 15, a spot solution holding section 16, a cleaning section 17, and a drying section 18. The first imaging section 14, the second imaging section 15, the spot solution holding section 16, the cleaning section 17, and the drying section 18 are the same as those in the above-described embodiment.

[0099] The rotating table 11B is disk-shaped and supports one substrate 100. The rotating table 11B is rotated around a central axis N 2 In FIG. 10, the central axis N 2extends in a direction perpendicular to the paper surface (Z direction). The surface of the turntable 11B on which the substrate 100 is placed is parallel to the XY plane. In addition, when the substrate 100 is placed on the turntable 11B, the central axis N 2 passes through the substrate 100. In the present modified example 2, the central axis N 2 However, the present invention is not limited to this example, and the light source 10 may pass through a position shifted from the center of gravity.

[0100] The holding table 11C is disk-shaped and has a central axis N 2 The holding table 11C is held so as to be rotatable about a central axis N under the control of the control device 20. 3 In FIG. 10, the central axis N 3 extends in a direction perpendicular to the paper surface (Z direction). In the holding table 11C, the rotating table 11B has a central axis N 3 In this case, the central axis N 3 does not pass through the rotary table 11B. The holding table 11C has a central axis N 3 1, the turntable 11B on which the substrate 100 to be spot-attached is placed is placed at an image-taking position for the second image-taking section 15. The image-taking position is, for example, a position around the central axis N of the turntable 11B. 2 is the reference position P B In the present modified example 2, the second imaging unit 15 captures an image of the substrate 100 placed at the position where the spotting head 12 performs spotting.

[0101] In the second modification, the calculation unit 22 executes a calculation process to determine the amount of rotation of the turntable 11B and the position of the spotting head 12 by the moving mechanism 13, based on the image of the substrate 100. Specifically, similarly to the first modification, the position determination unit 222 determines the angle θ P1 and angle θ C1 Difference between (θ D1 ) and calculate the difference θ D1 The rotation angle (θ B1) to determine

[0102] The turntable 11B on which the substrate 100 to be spot-applied is placed is rotated by a rotation angle determined by the position determination unit 222 under the control of the control device 20.

[0103] The moving mechanism 13 moves the spotting head 12 under the control of the control device 20. The moving mechanism 13 drives the spotting head 12 to move in the X direction, the Y direction, and the Z direction. The spotting head 12 moves from a reference position P B The spot solution is applied to the convex portions 102 of the substrate 100 by moving the rotary table 11B upward and downward in the Z direction relative to the rotary table 11B positioned above.

[0104] In the above-mentioned modified example 2, the arrangement direction of the pins 122 arranged on the spotting head 12 and the arrangement direction of the convex portions 102 of the substrate 100 placed on the turntable 11B are detected, and the turntable 11B is rotated to a position where the arrangement directions are aligned to perform the spotting process. According to the modified example 2, the spotting process is performed in which the occurrence of misalignment between the positions of the pins 122 and the positions of the convex portions 102 is suppressed, so that when spotting the spot solution on multiple convex portions using multiple pins, the spot solution can be reliably spotted on each convex portion.

[0105] (Variation 3) Next, modified example 3 will be described with reference to Fig. 11. Fig. 11 is a diagram showing a schematic configuration of an analytical chip manufacturing apparatus according to modified example 3 of the present invention. The analytical chip manufacturing apparatus 1C according to modified example 3 includes a spotting processing apparatus 10C instead of the spotting processing apparatus 10 of the analytical chip manufacturing apparatus 1 described above. In the analytical chip manufacturing apparatus 1C, the configuration other than the spotting processing apparatus 10C is the same as the configuration described in the embodiment.

[0106] The spotting processing device 10C includes a plurality of turntables 11B, a holding table 11D that holds the turntables 11B, a spotting head 12, a moving mechanism 13, a first imaging section 14, a second imaging section 15, a spot solution holding section 16, a cleaning section 17, and a drying section 18. The turntable 11B, the first imaging section 14, the second imaging section 15, the spot solution holding section 16, the cleaning section 17, and the drying section 18 are the same as those in the above-described embodiment.

[0107] The holding table 11D extends in the Y direction and has a central axis N 2 The holding table 11D moves the turntable 11B in the Y direction under the control of the control device 20. The holding table 11D moves the turntable 11B in one direction (downward in FIG. 11) to sequentially place the multiple substrates 100 at the spotting positions by the spotting head 12.

[0108] In the third modification, the calculation unit 22 executes a calculation process to determine the amount of rotation of the turntable 11B and the position of the spotting head 12 by the moving mechanism 13, based on the image of the substrate 100. Specifically, similar to the first modification, the position determination unit 222 determines the angle θ P1 and angle θ C1 Difference between (θ D1 ) and calculate the difference θ D1 The rotation angle (θ B1 ) to determine

[0109] The turntable 11B on which the substrate 100 to be spot-attached is placed is rotated at a rotation angle determined by the position determination unit 222 under the control of the control device 20.

[0110] The moving mechanism 13 moves the spotting head 12 under the control of the control device 20. The moving mechanism 13 drives the spotting head 12 to move in the X direction, the Y direction, and the Z direction. The spotting head 12 moves from a reference position P BThe spot solution is applied to the convex portions 102 of the substrate 100 by moving the rotary table 11B upward and downward in the Z direction relative to the rotary table 11B positioned above.

[0111] In the above-mentioned modified example 3, the arrangement direction of the pins 122 arranged on the spotting head 12 and the arrangement direction of the convex portions 102 of the substrate 100 placed on the turntable 11B are detected, and the turntable 11B is rotated to a position where the arrangement directions are aligned to perform the spotting process. According to the modified example 3, the spotting process is performed in which the occurrence of misalignment between the positions of the pins 122 and the positions of the convex portions 102 is suppressed, so that when spotting the spot solution on multiple convex portions using multiple pins, the spot solution can be reliably spotted on each convex portion.

[0112] The holding table 11D that moves the rotating table 11B is not limited to the configurations of variants 2 and 3, and may be configured to move the rotating table 11B in the X direction or to move the rotating table 11B along a partially curved path. [Industrial Applicability]

[0113] The analytical chip manufacturing apparatus, the operating method of the analytical chip manufacturing apparatus, and the analytical chip manufacturing method of the present invention are useful for reliably spotting a spot solution on each convex portion when using multiple pins to spot the spot solution on multiple convex portions. [Explanation of symbols]

[0114] 1, 1A, 1B, 1C Analytical chip manufacturing equipment 10, 10A, 10B, 10C Spotting processing device 11, 11A, 11B Rotating table 11C, 11D Holding table 12 point head 13 Moving mechanism 14 First imaging unit 15 Second imaging unit 16 Spot solution holder 17 Cleaning section 18 Drying section 20 Control device 21 Drive unit 22 Arithmetic section 23 Memory section 24 Control Unit 100 Substrates 101 Base 102 Convex 121 Holding part 122 pin 131 First Shaft 132 First Mobile Section 133 Second Mobile Section 134 Second Shaft 161 Plate 162 Hole 221 Angle Calculation Unit 222 Positioning section

Claims

1. An analytical chip manufacturing apparatus comprising a substrate having a plurality of convex portions on which a plurality of types of selective binding substances are individually applied, the apparatus comprising: a rotating table that rotates about a central axis, on which a substrate not coated with the selective binding substance is placed; a spotting head having a plurality of spotting members for spotting the selective binding substance on each of the convex portions on the substrate, the spotting head being movable on a scanning plane positioned parallel to an upper portion of the rotary table; a control unit that controls, for each of the substrates, the rotation of the rotary table, the movement of the deposition head in the scanning plane, and the application of the selective binding substance to the convex portions on the substrate; Equipped with At least a portion of the plurality of convex portions on the substrate and the plurality of spotting members disposed on the spotting head are both arranged on a straight line, The spotting head is movable in two directions intersecting each other on the scanning plane; The control unit is Calculating a first angle between a first arrangement direction parallel to a straight line passing through the plurality of spotting members arranged on the spotting head and one direction in which the spotting head can move; calculating a second angle between a second arrangement direction that is parallel to a straight line passing through a plurality of convex portions arranged on the substrate placed on the rotary table and that is formed from the central axis toward an outside and the one direction in which the deposition head is movable; rotating the rotary table so that a difference between the first angle and the second angle is minimized; By doing so, the rotary table is rotated to a position where each spotting member of the spotting head overlaps with a convex portion on the substrate corresponding to each spotting member when viewed from the central axis direction of the rotary table, and the selective binding substance is applied to each convex portion; An analytical chip manufacturing apparatus comprising:

2. A first imaging unit that images the spotting head; A second imaging unit that captures an image of the substrate placed on the turntable; Equipped with The control unit is Detecting the first arrangement direction based on a first image captured by the first imaging unit; detecting the second array direction based on a second image captured by the second imaging unit; 2. The analytical chip manufacturing apparatus according to claim 1 .

3. The control unit is detecting positions of the plurality of spotting members of the spotting head based on the first image, thereby detecting the first arrangement direction; 3. The analytical chip manufacturing apparatus according to claim 2 .

4. The control unit is detecting the second arrangement direction by detecting positions of a plurality of convex portions on the substrate based on the second image; 3. The analytical chip manufacturing apparatus according to claim 2 .

5. The control unit is detecting the second arrangement direction by detecting a mark portion formed on the substrate based on the second image; 3. The analytical chip manufacturing apparatus according to claim 2 .

6. A plurality of the substrates are placed on the rotating table, Each substrate is placed at a position different from a position through which the central axis of the rotary table passes.

2. The analytical chip manufacturing apparatus according to claim 1 .

7. A plurality of the rotary tables are provided, One of the substrates is placed on each of the rotary tables.

2. The analytical chip manufacturing apparatus according to claim 1 .

8. The central axis of the rotary table passes through the substrate placed on the rotary table. The analytical chip manufacturing apparatus according to claim 7 .

9. The central axis of the rotary table passes through the center of gravity of the substrate. The analytical chip manufacturing apparatus according to claim 8 .

10. a holding table for holding each of the rotary tables so as to be rotatable about its respective central axis; The analytical chip manufacturing apparatus according to claim 7, further comprising:

11. An apparatus for manufacturing an analytical chip, comprising a substrate having a plurality of convex portions on which a plurality of types of selective binding substances are individually applied, the apparatus comprising: a turntable which rotates about a central axis, the turntable on which a substrate not coated with the selective binding substance is placed; a spotting head having a plurality of spotting members which spot the selective binding substance onto each of the convex portions on the substrate and which is movable on a scanning plane which is positioned parallel to an upper portion of the turntable; and a control unit which controls the rotation of the turntable, the movement of the spotting head on the scanning plane, and the application of the selective binding substance onto each of the convex portions, the method comprising the steps of: At least a portion of the plurality of convex portions on the substrate and the plurality of spotting members disposed on the spotting head are both arranged on a straight line, The spotting head is movable in two directions intersecting each other on the scanning plane; The control unit: Calculating a first angle between a first arrangement direction parallel to a straight line passing through the plurality of spotting members arranged on the spotting head and one direction in which the spotting head can move; calculating a second angle between a second arrangement direction that is parallel to a straight line passing through a plurality of convex portions arranged on the substrate placed on the rotary table and that is formed from the central axis toward an outside and the one direction in which the deposition head is movable; rotating the rotary table so that a difference between the first angle and the second angle is minimized; By doing so, rotating the rotary table to a position where each spotting member of the spotting head overlaps with a convex portion on the substrate corresponding to each spotting member when viewed from the central axis direction of the rotary table, and applying the selective binding substance to each convex portion for each substrate; A method for operating an analytical chip manufacturing apparatus comprising the steps of:

12. A method for manufacturing an analytical chip, comprising the steps of: applying a plurality of spotting members to respective convex portions of a substrate on which the selective binding substances have not been applied, the method comprising the steps of: manufacturing an analytical chip using a spotting head movable in two intersecting directions on a scanning plane parallel to an upper portion of a rotating table on which the substrate is placed, the method comprising the steps of: At least a portion of the plurality of convex portions on the substrate and the plurality of spotting members disposed on the spotting head are both arranged on a straight line, a first arrangement direction parallel to a line passing through the plurality of spotting members arranged on the spotting head and a first angle formed by a direction in which the spotting head can move, a second arrangement direction parallel to a line passing through the plurality of convex portions arranged on the substrate placed on the turntable and formed from the central axis toward the outside, and a second angle formed by the direction in which the spotting head can move, the second arrangement direction being parallel to a line passing through the plurality of convex portions arranged on the substrate placed on the turntable and formed from the central axis toward the outside, the second arrangement direction being parallel to a line passing through the plurality of convex portions arranged on the substrate placed on the turntable, and the first angle formed by the direction in which the spotting head can move, the second arrangement direction being parallel to a line passing through the plurality of convex portions arranged on the substrate placed on the turntable and formed from the central axis toward the outside, the second arrangement direction being parallel to a line passing through the plurality of convex portions arranged on the substrate placed on the turntable, the second arrangement direction being ... A method for producing an analytical chip comprising the steps of:

Images