Reaction apparatus

Abstract

To provide a reaction device capable of maintaining the same dispensing amount accuracy of a chemical liquid between a plurality of array plates.SOLUTION: A reaction device for producing a reaction product of a living body-derived material contained in a spot on an array plate and a target material in a sample liquid includes a container placement section on which a reaction container including the array plate is placed, a chemical solution placement section on which a chemical solution container containing a chemical solution is placed, a pipetter to which a pipette tip is attached and which the chemical solution from the chemical solution container and dispenses the chemical solution into the reaction container, and a control section that changes a dispensing operation of the pipetter according to at least any of a type of the chemical solution, a state of the chemical solution, an operation history of the pipetter, and a state of the pipette tip.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a reactor for producing a reaction product on an array plate, and a method for controlling the reaction process. [Background technology]

[0002] Array plates such as protein arrays, peptide arrays, and DNA arrays are known, in which a large number of biologically derived substances, such as proteins, peptides, and nucleic acids, are immobilized as array spots on a substrate. Using an array plate, it is possible to simultaneously observe the interactions between the large number of substances immobilized on the array plate and substances in a sample. Therefore, by using an array plate, it is possible to comprehensively analyze the interactions between the large number of substances immobilized as array spots and various substances contained in biologically derived sample fluids, such as blood, cell extracts, saliva, and interstitial fluid.

[0003] Patent Document 1 discloses a sample analyzer that uses an array plate having a plurality of spots containing biological substances in an array, performs a reaction process including labeling the biological substances contained in each spot with various substances contained in a sample liquid, and then automatically performs an optical measurement process in which the pattern of labeled spots on the array plate is optically acquired. Furthermore, a method is disclosed in which the reaction state of the spots is protected during optical measurement by filling the upper surface of the array plate with a highly viscous observation liquid. Furthermore, Non-Patent Document 1 discloses that when an electric pipettor is used to repeatedly dispense high-temperature or low-temperature chemical solutions using the same pipette tip, the amount dispensed varies between the first time immediately after attaching the pipette tip and the second time and thereafter. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2023-12426 [Non-patent literature]

[0005] [Non-Patent Document 1] Millet, F., Barthlen, T., Securing accuracy and precision when pipetting hot and cold liquids with Microman(TM). Nat Methods 4, iii-iv (2007) Summary of the Invention [Problem to be solved by the invention]

[0006] The sample analyzer described in Patent Document 1 discloses a technology for automatically optically measuring reaction products generated by repeatedly supplying and draining multiple chemical solutions to an array plate. However, the technology described in Patent Document 1 requires consideration of an appropriate method or means for supplying chemical solutions depending on the type and properties of the chemical solutions, the state of the chemical solutions, and how the pipette tips are used. In particular, when analyzing multiple array plates, careful attention must be paid to minimizing differences in the amount of chemical solutions dispensed between the array plates.

[0007] The present invention has been made in consideration of the above-mentioned problems, and aims to provide a reaction device that can automatically perform the process up to producing a reaction product on an array plate and then provide it for optical measurement, in which the amount of chemical solution dispensed between array plates is kept as uniform as possible by controlling the dispensing operation in accordance with the type of chemical solution, the state of the chemical solution at the time of use, the timing of use of the chemical solution, the usage history of the pipette tip, etc. [Means for solving the problem]

[0008] In order to solve the above problems, the reaction device of the present invention is a reaction device for dispensing a sample liquid into a reaction vessel including an array plate on a substrate on which a plurality of spots containing a biological substance are arranged in an array, and for generating a reaction product between the biological substance and a substance in the sample liquid on the spots by bringing the sample liquid into contact with the plurality of spots, the reaction device comprising: a vessel mounting section for mounting the reaction vessel; a chemical liquid mounting section for mounting a plurality of chemical liquid vessels each containing a sample liquid and a chemical liquid; and a hollow pipette tip attached to the pipette tip. the pipetter unit including a pipetter section that draws in and exhausts gas between the inside of the tip and the pipetter section, and a position change section that changes the position of the pipetter section; a tip placement section on which the pipette tip is placed; and a control section that controls the pipetter section so that a dispensing operation is performed in which at least one of the amount of the chemical liquid aspirated from the chemical liquid container, the amount of the chemical liquid dispensed into the reaction vessel, and the position of the pipetter section is adjusted according to at least one of the type of the chemical liquid, the state of the chemical liquid, the operation history of the pipetter unit, and the state of the pipette tip. [Effects of the Invention]

[0009] According to the reaction apparatus of the present invention, when automatically performing operations up to producing a reaction product on an array plate, the operation of the pipetter can be controlled according to the type of chemical solution, the state of the chemical solution at the time of use, the timing of use of the chemical solution, and the usage history of the pipetter and pipette tip, thereby suppressing variations in the amount of chemical solution dispensed between array plates. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows the procedure of an inspection method in which the reaction apparatus of the present invention is preferably used, where (a) shows the flow, (b) shows process control information, and (c) shows the chemical properties in each process. [Figure 2] FIG. 1 is a schematic diagram illustrating the configuration of a reaction apparatus according to the present invention. [Figure 3] 3 is a schematic diagram illustrating an example of the specific structure of the reaction apparatus in Fig. 2. (a), (b), and (c) show the internal structure of the reaction apparatus as seen from above, the front, and the right, respectively. [Figure 4] FIG. 4 is a schematic diagram illustrating an example of the specific structure of the chemical solution mounting section and the chip mounting section of the reaction apparatus shown in FIG. 2 or 3. [Figure 5] 1 is a flow diagram illustrating the antibody liquid dispensing sequence of Example 1. (a) shows the reaction sequence, (b) shows the reagent replacement sequence, (c) shows the drainage sequence, and (d) shows the dispensing sequence. [Figure 6] 1 is a schematic diagram illustrating the antibody liquid dispensing operation of Example 1, (a) to (g) showing the operation in each step of the dispensing sequence. [Figure 7] FIG. 10 is a flow diagram illustrating a sample liquid dispensing sequence according to the second embodiment. [Figure 8] 10 is a schematic diagram illustrating the sample liquid dispensing operation of Example 2. (a) to (f) show the operation in each step of the dispensing sequence. [Figure 9] FIG. 10 is a flow chart illustrating the observation liquid dispensing sequence of the third embodiment. [Figure 10] FIG. 10 is a flow chart illustrating a stop solution dispensing sequence in the fourth embodiment. [Figure 11] FIG. 10 is a flow chart illustrating a cleaning liquid dispensing sequence according to the fifth embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0011] The reaction apparatus of the present invention is preferably used in a testing method in which a sample liquid, primarily derived from a living organism, is supplied to an array plate on which a variety of biological substances are immobilized as multiple spots in an array, and the presence or absence of a target in the sample liquid is detected by detecting a reaction between the target substance contained in the sample liquid and the biological substances immobilized on the array plate. Figure 1(a) shows the basic steps of this testing method. As shown in Figure 1(a), this testing method generally comprises a reaction initiation step S101, a reaction termination step S102, a labeling step S103, an observation liquid introduction step S104, and an information acquisition step (not shown).

[0012] The reaction initiation step S101 is a step in which a sample liquid is brought into contact with an array plate, and targets contained in the sample liquid are reacted with biological substances fixed as array spots on the surface of the array plate. Here, "reaction" includes bonding between the targets and biological substances, chemical reactions, enzymatic reactions, etc. Reagents may be added to the sample liquid depending on the purpose. The sample liquid is supplied to the array plate so as to cover the spots. The reaction vessel containing the array plate to which the sample liquid has been supplied is maintained at a temperature suitable for the reaction for a predetermined period of time, allowing the reaction between the targets in the sample and the biological substances on the array plate to proceed.

[0013] The reaction stopping step S102 is a step of stopping the reaction between the targets in the sample liquid and the biological substance on the array plate by reducing the sample liquid supplied to the array plate by, for example, aspirating it with a nozzle. At this time, the targets that reacted with the biological substance in the reaction initiation step remain on the spot side, and the targets that did not react are removed together with the sample liquid, reducing the amount of remaining targets.

[0014] The labeling step S103 is a step of labeling the spots that have reacted with the targets with an (optical) labeling substance such as a fluorescent substance. The labeling substance is specifically introduced into the target that has reacted with the spot and bound thereto, or into the biological substance that has been changed by the reaction with the target. This makes the spots that have reacted with the targets detectable by optical observation.

[0015] The observation liquid introduction step S104 is a step of covering the spots in the array with the observation liquid in order to protect them after the labeling step S103. This eliminates the need for a drying step, and allows the optical observation (information acquisition step) to be carried out without interruption.

[0016] The procedure of the testing method in which the reaction device of the present invention is preferably used is as described above, but the array plate, biological material, sample solution, labeling substance, observation solution and reaction process of the present invention will be further explained below.

[0017] <Array plate> An array plate has multiple spots, each containing a different biological substance, fixed in an array (arranged) on the surface of a substrate and is used for comprehensive analysis of samples. Array plates are also called microchips, microarrays, protein chips, DNA chips, etc. The position of each spot on an array plate is called an address within the array plate. Each spot can be assigned a symbol as an address. The address may be determined by a name that represents the physical location of each spot on the array plate. For example, it can be determined by the distance or coordinates from each edge of the array plate.

[0018] In the following description of this specification, an array plate is defined as having at least 16 or more spots containing biological substances, including at least two spots that differ from each other in at least one of the composition, content, and amount of the biological substances. Generally, an array plate (or its substrate) is flat, with multiple spots containing biological substances arranged in an array on one main surface. The main surface on which the spots are formed is sometimes referred to as the first surface. The main surface opposite the first surface is sometimes referred to as the back surface, other surface, or second surface. A typical array plate is a flat plate with dimensions of 10 mm to 128 mm in length and width and a thickness of 0.1 mm to 2.5 mm. The three-dimensional shape of the plate, taking into account its thickness, is a hexahedron (with small dimensions in the thickness and height directions), such as a rectangular parallelepiped or a truncated square pyramid, or a disk shape, such as a cylinder, elliptical cylinder, or truncated cone. The edges defining the periphery of the plate's main surface may be rounded or tapered. A plurality of spots are arranged on one (first surface) of two opposing main surfaces so as to define the thickness of the plate. The diameter of the spots is adjusted depending on the size of the plate, the imaging field of view, and the number of spots, but is typically 0.1 μm to 5000 μm. Each spot is arranged with a distance between adjacent spots. The array pattern may be a square, rectangle, circle, or ellipse. The arrangement period between spots is approximately 1.1 to 10 times the spot diameter. Preferably, each array plate has at least 16 spots, more preferably 64 or more, and even more preferably 1000 or more spots.

[0019] Commercially available array plates can be used. For example, microarray plates are sold by Agilent Technologies Inc., RayBiotech, and others. Alternatively, array plates can be prepared using known methods. Array plates are prepared by immobilizing desired biological substances as an array of spots on one main surface of a suitable flat substrate. Immobilization can also be referred to as adsorption, and includes adsorption immobilization via hydrophobic interactions, electrostatic interactions, van der Waals interactions, hydrogen bonds, and covalent bonds. Considering the case where excitation light is irradiated from the main surface (second surface) opposite the main surface on which the spots are formed, the array plate substrate is preferably translucent at the wavelength of the excitation light. Furthermore, considering the optical arrangement of the detection system, the substrate is preferably translucent at the wavelength of the fluorescence. Note that "translucent" refers to the property of transmitting at least light of the excitation light and fluorescence wavelengths. "Translucent" also includes the case where light of the wavelengths is partially transmitted. Typically, substrates with low scattering at the wavelengths of the excitation light and fluorescence are preferably used. Examples of substrate materials include glass, synthetic quartz, quartz, and borosilicate glass. Other examples include resins such as polystyrene, polypropylene, (meth)acrylic resin, polyamide, polyimide, melamine, ABS, polyphenylene oxide urethane, silicone, epoxy, and polydimethylsiloxane. Alternatively, membranes such as nitrocellulose and polyvinylidene fluoride, and gels such as agarose and acrylamide can also be used. These materials can be fixed or supported on a frame or other substrate, as needed. Immobilization of biological substances can be performed by known methods, such as using an arrayer, a stamp, semiconductor technology, or pipetting. Furthermore, to prevent substances contained in the sample solution from directly binding to the substrate, the array plate is preferably treated with a nonspecific adsorption inhibitor containing a blocking agent.

[0020] <Biologically derived substances> As used herein, a biologically-derived substance (hereinafter sometimes simply referred to as "biological substance") refers to a substance that is immobilized on an array plate and binds to or reacts with a target in a sample solution. The biologically-derived substance can be appropriately determined by the practitioner of the present invention depending on the purpose. Examples of biologically-derived substances include proteins, peptides, nucleic acids, low-molecular-weight compounds, viruses, and cells, all of which may be naturally-occurring, synthetic, or recombinant. More specifically, biologically-derived substances include antibodies, antigens, phosphorylated proteins, dephosphorylated proteins, low-molecular-weight compounds, receptors, enzymes, substrates, kinase substrates, allergens, cytokines, hormones, bacteria, viruses, microorganisms, DNA, RNA, cDNA, cells, cell membrane components, cancer markers, disease markers, other biologically-derived substances, extracts from living organisms, blood, blood-derived substances, foods, food-derived substances, natural products, substances derived from natural products, and culture medium-derived substances.

[0021] <Sample liquid> The reaction device of the present invention is intended to test a sample liquid, i.e., a liquid containing a liquid sample or a test substance. The sample can be appropriately selected by the user of the reaction device of the present invention depending on the purpose. Sample liquids include, for example, biologically derived substances, extracts from living organisms, blood, blood-derived substances, food, food-derived substances, natural products, natural product-derived substances, and culture medium-derived substances. A substance contained in the sample liquid and expected to react with a biological substance contained in a spot on an array plate is called a target (target substance). Targets include antibodies, antigens, phosphorylated proteins, dephosphorylated proteins, nucleic acids, low-molecular-weight compounds, receptors, enzymes, substrates, allergens, cytokines, hormones, bacteria, viruses, microorganisms, DNA, RNA, cDNA, cells, cell membrane components, cancer markers, disease markers, and the like. A testing method using the device of the present invention can obtain information regarding the interaction between a target in the sample liquid and a biological substance, and based on that, information regarding the sample can be obtained. The sample liquid can be appropriately pretreated depending on the purpose and procedure. Treatments such as reduction and heating may be performed. Furthermore, a reagent may be added to the sample liquid beforehand. A labeling substance may be bound to the target in the sample solution in advance. The sample itself may be solid, liquid, or gas, but is used as the sample solution after being diluted, suspended, or extracted in a liquid such as water, physiological saline, or a buffer solution as appropriate. The sample solution may contain surfactants, preservatives, nonspecific adsorption inhibitors, and other additives. Reagents may also be added to the sample solution as needed.

[0022] <Labeling substance> A labeling substance is a substance that is bound to or introduced into a target or a spot that has reacted with the target to visualize the spot that has reacted with the target. Labeling substances are optically detectable. Examples of labeling substances include fluorescent substances, chemiluminescent substances, phosphorescent substances, dyes, gold nanoparticles, fluorescent particles, enzymes for enzymatic chemiluminescence or color reactions, and microparticles that absorb specific wavelengths. Labeling substances may also include antibodies, ligands, or other binding moieties. Labeling can be accomplished by binding the labeling substance via hydrophobic interactions, electrostatic interactions, van der Waals interactions, hydrogen bonds, covalent bonds, or other methods, or by introducing the labeling substance during PCR or synthesis, or by other known methods.

[0023] Typically, the labeling substance is a fluorescent substance. In the labeling step (or the first labeling step) described below, labeling is typically performed using a fluorescent substance. Fluorescent substances are advantageous in that they are suitable for two-dimensional analysis because they provide stable light emission, do not require a substrate, and enable region-specific labeling, and also allow multiple labeling using fluorescent substances with different wavelengths. The type of fluorescent substance is appropriately selected according to the reaction system and optical system. Fluorescent substances include fluorescein, cyanine, rhodamine, Texas Red, coumarin-based dyes, fluorescent proteins, quantum dots, etc. Those skilled in the art can select a fluorescent substance that has appropriate excitation wavelengths and fluorescent wavelengths and is easy to use, depending on the optical system and experimental system.

[0024] Chemiluminescent substances are advantageous in that they emit light upon addition of a substrate, eliminating the need for an excitation light source, and are highly sensitive. When using a chemiluminescent substance, an enzyme that catalyzes chemiluminescence or a substrate is used as the labeling substance. Substrates include enzymes such as alkaline phosphatase and horseradish peroxidase, as well as acridinium-containing substrates. Chemiluminescence can generally be observed using a highly sensitive CCD camera. However, the substrate or catalyst must be supplied for luminescence during detection. These are preferably added to the observation solution.

[0025] Gold nanoparticles have the property of absorbing light in the vicinity of a specific wavelength depending on their particle size. When the labeling substance is gold nanoparticles, the labeled spot can be detected by measuring the amount of light absorbed or reflected at a selective wavelength. Gold has a high affinity for sulfur, nitrogen, and oxygen atoms, and the target to be labeled is bound to the surface of the gold nanoparticles through thiolation (addition of an -SH group) and a sulfur-gold atom bond.

[0026] <Observation solution> The observation liquid is sometimes called a purge liquid, since it replaces, or purges out, optical background noise components. The observation liquid is placed so that it contacts at least the spots on the array plate when acquiring optical information. The observation liquid is placed so that it contacts part or all of the first surface of the array plate (the main surface on which the spots are formed, out of the two main surfaces). The observation liquid preferably has good affinity with the chemical solution used in the immediately preceding process. It is desirable that the observation liquid have a refractive index close to that of the array plate substrate and prevent oxidation of substances on the array plate, especially labeled substances. It is also desirable that the observation liquid does not emit fluorescence when irradiated with excitation light for acquiring optical information. A glycerol solution is preferably used as a liquid that meets these conditions, but it can be selected appropriately based on the properties of the labeled substance, biological substance, and specimen. The observation liquid may also be used as a washing liquid to wash away unfixed labeled substances in the labeling process. Alternatively, the washing liquid present on the array plate, the reagents used in the labeling process, or other liquids used in other processes may be used as the observation liquid as long as their properties allow.

[0027] Since the observation liquid is a liquid, its refractive index is closer to that of the array plate substrate than air. Therefore, using an observation liquid during optical observation reduces the reflection rate of excitation light irradiated from the second surface (the main surface opposite the first surface) at the first surface. The observation liquid preferably has a refractive index of 1.3 or higher. To be closer to the refractive index of the array plate substrate, the refractive index is preferably 1.33 to 1.60, and even more preferably 1.40 to 1.46. Furthermore, the observation liquid preferably has a viscosity of 1.7 cp to 220 cp at 20°C. For example, a liquid containing 40 vol% to 90 vol% of glycerol in water, physiological saline, phosphate buffer, Tris-HCl buffer, or other buffer solution can be used as a buffer solution. A glycerol content of more than 90 vol% is difficult to use, while a glycerol content of less than 40 vol% deviates slightly from the refractive index of the array plate. Typically, the observation liquid is a buffer solution containing 80 vol% glycerol. The observation solution may contain surfactants, preservatives, and nonspecific adsorption inhibitors as appropriate. The observation solution may also contain a commercially available anti-fading agent for preventing fading of dyes. Examples of anti-fading agents include Prolong, manufactured by ThermoFisher Scientific.

[0028] <Reaction process> In the reaction process performed using the reaction apparatus of the present invention, some operations may be performed manually, but preferably all steps are performed automatically in the apparatus. The operations performed in the reaction apparatus of the present invention do not include a drying step. Therefore, there is no need to transport the array plate to a dryer, and all steps can be performed within the apparatus, making it more advantageous for automation. Figure 1 is a schematic diagram of the steps involved in the reaction process of this embodiment, with Figure 1(a) showing the flow, Figure 1(b) showing process control information 111, and Figure 1(c) showing chemical control information 112 used in each step.

[0029] (Reaction initiation step S101) This process brings the sample liquid into contact with the spots, causing some or all of the targets to react with the biological material contained in the spots. Reactions include binding between the targets and the biological material, chemical reactions, and enzymatic reactions. Depending on the purpose, a reagent may be added to the sample liquid. The sample liquid is added in an amount sufficient to cover the spots. The first surface of the array plate may be partially or entirely covered with the sample liquid. The reaction between the substances in the sample liquid and the biological material in the spots is carried out at a temperature suitable for the reaction and for a desired time. As a liquid retention mechanism, the array plate may be provided with a frame (bank) surrounding the area where the spots are arranged in an array, or the entire array plate may be placed in a suitable container. These frames or containers can hold the sample liquid, as well as liquids such as the observation liquid, antibody liquid, and other chemical liquids used in the following processes, on the array plate. In this specification, a device that can be handled by the reaction device of the present invention is referred to as a reaction container.

[0030] (Reaction termination step S102) This step reduces the amount of sample liquid introduced in the reaction initiation step. Through this step, the target bound to the biological material in the reaction initiation step remains on the spot, while the amount of unreacted target or target remaining after a chemical or enzymatic reaction with the biological material is reduced. The sample liquid on the spot is reduced by aspirating it with a nozzle. The nozzle here refers to an aspiration mechanism including a pipette tip, needle, pipette, syringe, pump, etc. The array plate or the container containing the array plate may be tilted relative to the horizontal. Alternatively, the sample liquid may be reduced by simply tilting the array plate and decanting it without using a nozzle. After decanting, the sample liquid may be further reduced by aspirating it with a nozzle. Note that "reducing" refers to reducing the volume of the liquid to less than 10% of the volume before reduction. This applies not only to reducing the sample liquid, but also to reducing other liquids. In this step, a stop solution containing an inhibitor is typically dispensed onto the plate following the reduction of the sample liquid. In this step, the inhibitor binds to the biological material contained in the spot, thereby preventing the reaction between the biological material and the target in the sample solution from proceeding after this step.

[0031] (Labeling process S103) This step is performed after the reaction termination step, and labels the spots that have reacted with the target. That is, a labeling substance is introduced specifically to the target bound to the spot or to the change in the biological material caused by the target. By this step, the spots that have reacted with the target are labeled, and by optically observing them, it can be determined that a reaction has occurred.

[0032] After the reaction initiation step S101 and the reaction termination step S102, the target reacts with the spot, causing a specific change in the biological material at the spot. In this labeling step, a labeling substance is introduced that is specific to the change in the biological material. An example of a change in the biological material is phosphorylation. The labeling substance is introduced via an antibody or ligand that recognizes the change in the biological material and its secondary antibody. Other known methods can also be used in this step. In this labeling step, the labeling substance is not introduced (fixed) to unreacted spots that have not reacted with the target, but if left as is, the labeling substance will remain unfixed on the unreacted spots and on the substrate between the spots, causing background noise in the acquisition step.

[0033] To complete this labeling process with the labeled substance introduced into some of the spots, washing is performed to reduce unimmobilized (unintroduced) labeled substance present on the unreacted spots and on the substrate between the spots from the first surface. Washing reduces the labeled substance-containing reagent from the first surface of the substrate, thereby reducing the unimmobilized labeled substance present on the unreacted spots and on the substrate between the spots. In other words, washing is an operation that selectively leaves only the labeled substance introduced into the spots that reacted with the target by reducing the unimmobilized labeled substance present on the unreacted spots and on the substrate between the spots. The residue of the reagent used in this labeling process on the first surface is replaced with a washing solution used for washing. Therefore, the washing solution can be referred to as a reagent replacement solution. By replacing the washing solution multiple times, the residue of the reagent on the first surface decreases asymptotically to zero. As described below, in an embodiment in which the washing solution is used as the observation solution, the observation solution is essentially a replacement solution that replaces the reagent. The process of reducing the concentration of a specific component to near zero by liquid replacement is called purging or purging, so the observation liquid and cleaning liquid are sometimes referred to as purge liquids.

[0034] (Observation liquid introduction step S104) This step brings the observation liquid into contact with the spots. By performing this step, the drying step is unnecessary, leaving no drying marks, and the process from the reaction initiation step to the acquisition step can be carried out without interruption. The observation liquid is added so that it covers at least the spots. As long as the target spots are in contact with the observation liquid, only a portion of the first surface of the array plate may be covered with the observation liquid. It is preferable that only the first surface side of the array plate comes into contact with the observation liquid, and that the second surface does not come into contact with the observation liquid.

[0035] As mentioned above, if the properties of the solution allow, the wash solution or other reagent solution may be used as the observation solution. In this case, the process of contacting these solutions corresponds to this process. The observation solution introduction process can also serve as part of the reaction termination process. Specifically, by repeatedly reducing a portion of the sample solution on the spot, introducing the observation solution, and then reducing a portion of the mixture, the amount of sample solution can be reduced to less than 10% of the introduced amount, or to a desired level. This method allows all processes to be performed while maintaining some kind of liquid on the spot. In this case, the sample solution that comes into contact with the spot is immediately replaced with the observation solution. In other words, the introduced sample solution is replaced with the observation solution without any prior replacement with any other liquid. This procedure is also possible in exceptional cases where a labeling process is not necessary (for example, when the target itself is a fluorescent substance).

[0036] (Information acquisition process) Although this step may not be considered part of the reaction process, it is described here because it acquires information about the sample by optically observing the spots that have undergone the reaction process. The information acquired by optical observation provides information about the presence or absence of a labeling substance for each spot, making it possible to determine whether the biological substance contained in each spot has reacted with the target.

[0037] Optical information from the multiple spots is obtained when the spots are in contact with the observation liquid. The information is acquired by an optical system, and the optical information includes at least one of light intensity information and spectral information from the spots. The optical system is provided on the second surface side of the array plate. If the labeling substance is a fluorescent substance, the optical system irradiates the spots with excitation light from the second surface side and detects fluorescence emitted from the spots from the second surface side. The light intensity information and spectral information can be acquired in association with the address of each spot in the array plate. Based on the acquired optical information, further information about the sample liquid can be acquired. This can be called the (sample) information acquisition process.

[0038] Because the refractive index of the observation liquid is closer to that of the array plate than that of air, using the observation liquid reduces the reflection of light emitted from the optical system at the interface between the array plate and the observation liquid, resulting in optical information with a higher signal-to-noise ratio. When the labeling substance is a fluorescent substance, the optical system can be configured in any way as long as it can excite the fluorescent substance and detect fluorescence from the spot. When an excitation light source is used to excite the fluorescent substance, examples of the excitation light source include a laser light source, a light-emitting diode (LED), a mercury arc, and a tungsten halogen lamp. Fluorescence detection can be performed using a CCD camera or a photodiode. The optical system can optionally include a filter and be configured to irradiate or detect light of a limited wavelength. It can also include a lens. The optical system can be scanning or non-scanning. A typical optical system is a confocal optical unit. Note that an excitation light source is not required when chemiluminescence, gold colloid, dyes, or other labeling substances are used.

[0039] (Washing operation) As mentioned above, each step in the reaction process performed using the device of the present invention may include a washing operation. A washing operation is performed when sequentially supplying different chemical solutions to a reaction vessel (array plate) to replace the previous reagent to prevent components from contaminating the subsequent chemical solution. A washing solution is supplied onto the spots to replace the previous reagent, and then the amount of washing solution is reduced. Washing operations may be repeated. Water, physiological saline, phosphate buffer, Tris-HCl buffer, or other buffer solutions, with additives such as surfactants, preservatives, nonspecific adsorption inhibitors, and glycerol, are often used as washing solutions. A typical washing solution is TBST, a Tris-buffered solution containing polysorbate. The washing solution may also be used directly as the observation solution. In other words, the washing operation may be included as part of the observation solution introduction step.

[0040] <Control of reaction process> (Process control information) FIG. 1(b) shows an example of process control information 111 that manages the control of each of the steps of the reaction initiation step S101, reaction termination step S102, labeling step S103, and observation liquid introduction step S104, which constitute the reaction process performed using the apparatus of the present invention. According to FIG. 1(b), in the reaction initiation step S101, a reaction initiation liquid is specified as the chemical liquid to be used, 2.5 ml is specified as the amount of chemical liquid to be dispensed (supplied) to the array plate, and 100 minutes is specified as the reaction processing time on the array plate after dispensing. In the subsequent reaction termination step S102, 2.5 ml of reaction termination liquid is specified to be dispensed to the array plate and a 5-minute reaction processing is performed. Then, in the next labeling step 1, 2.5 ml of primary antibody liquid is specified to be dispensed to the array plate and a 60-minute reaction processing is performed. In the subsequent labeling step 2, 2.0 ml of secondary antibody liquid is specified to be dispensed to the array plate and a 60-minute reaction processing is performed. Therefore, the primary antibody solution and secondary antibody solution are used at least 105 minutes and 165 minutes after the start of the reaction initiation step, respectively. Finally, the reaction process is completed by introducing 2.5 ml of observation solution in the observation solution introduction step. In addition to the chemical solution type, chemical solution amount, and processing time shown in Figure 1(b), the process control information 111 can also specify temperature control information and shaking control information for each step. For example, process control information such as temperature control of 37°C / shaking at 60 rpm for the reaction initiation step and temperature control of 30°C / shaking at 60 rpm for the labeling step can be specified for each step.

[0041] (Chemical control information) FIG. 1(c) shows an example of chemical liquid control information 112 for each step of the reaction process, including the storage state of the chemical liquids used in the reaction device of the present invention until they are used and whether or not the pipette tips used for dispensing the chemical liquids can be reused between plates when dispensing the chemical liquids to the array plates. The reaction initiation liquid is kept refrigerated in the refrigerated chemical liquid storage unit of the reaction device. The reaction initiation liquid is mixed with the sample liquid, which is also kept refrigerated, and then dispensed into each array plate. Since the pipette tips used for dispensing come into contact with the sample liquid during this process, new pipette tips are used to dispense the sample liquid into each array plate to prevent contamination with other samples. In other words, pipette tips cannot be reused between plates when dispensing the reaction initiation liquid in the reaction initiation step.

[0042] On the other hand, for the reaction stop solution, primary antibody solution, secondary antibody solution, and observation solution, the pipette tip used for dispensing does not come into contact with the sample liquid when dispensing into the array plate, so the same pipette tip can be used between plates, and the dispensing operation differs from that for dispensing the reaction start solution. Note that for the observation solution, which has a higher viscosity than the other chemical solutions, an additional unique dispensing operation is required. The reaction stop solution and observation solution are kept at room temperature in the room-temperature chemical solution storage section of the reaction device, while the primary antibody solution and secondary antibody solution are kept refrigerated in the refrigerated chemical solution storage section.

[0043] The control unit in the reaction apparatus of the present invention controls the dispensing sequence based on chemical control information 112 in accordance with at least one of the type and properties of the chemical, its holding state, and whether or not the tip can be reused between plates.

[0044] <Examples of information acquired> (Detection of protein-protein interactions) The reaction apparatus of the present invention can be used to observe protein-protein interactions. As an example, a method for detecting antibodies in a sample solution using an array plate on which antigens are immobilized will be described below. When detecting antibodies in a sample solution, antigens are used as the biological material to be immobilized on the array plate. After the above-mentioned reaction initiation step, antibodies contained in the sample solution that exhibit specific interactions with a predetermined antigen contained in a corresponding spot (a spot that specifically interacts with a target antibody in the sample solution) bind to the antigen in that spot and are immobilized to that spot. Subsequently, in the labeling step, which is performed after the reaction termination step (including a washing step, if necessary), a labeling substance is introduced to the target bound to the spot via a specific substance. This is followed by an observation liquid introduction step and an information acquisition step. Washing steps are performed as appropriate between each step. The washing solution used in the washing step may be used as the observation liquid.

[0045] Next, a method for detecting an antigen in a sample solution using an array plate on which an antibody is immobilized will be described below. After the reaction initiation step and the reaction termination step, a labeling substance is introduced in the labeling step. In the reaction initiation step, the antigen in the sample solution binds to the antibody immobilized on the corresponding spot and is immobilized on the corresponding spot (a spot that specifically interacts with the target antigen in the sample solution). In the labeling step, the labeling substance can be introduced using an antibody that recognizes the antigen. This antibody may be the same antibody as the antibody used as the biological substance, or an antibody with a different recognition site from the antibody used as the biological substance may be used. Note that in this specification, the elementary steps of each step may be described focusing on spots that specifically interact with the target in the sample solution, antibodies in the reagent solution, or reaction-promoting components, and the like. Such spots of interest may also be referred to as the "relevant spots." Spots containing biological substances that specifically interact with the target in the sample may also be referred to as the "relevant spots."

[0046] (Detection of kinases) The reaction device of the present invention can also be used for detection using a kinase in a sample solution. A method for detecting a kinase in a sample solution is described below. When a kinase is detected, the biological material immobilized on the array plate is a kinase substrate. A kinase substrate refers to a substrate that is phosphorylated by a kinase and is a subclass of a protein or peptide. In the reaction initiation step, the substrate at the corresponding spot is phosphorylated by a kinase contained in the sample solution. Here, the corresponding spot refers to a spot containing, as a biological material, a kinase substrate that undergoes a specific phosphorylation reaction by a kinase in the sample solution. After the reaction termination step, in the labeling step, a labeling substance is introduced to the corresponding spot via a phosphorylation site recognition substance. A phosphorylation site recognition substance is a substance that specifically recognizes the phosphorylated site in a substrate that has been phosphorylated by a kinase. An example of a phosphorylation site recognition substance is an anti-phosphorylated amino acid antibody. If a labeling substance is not bound to the phosphorylation site recognition substance, the labeling substance is introduced via a secondary antibody or a specific reaction including a biotin-avidin reaction. Thereafter, an observation liquid introduction step and an information acquisition step are performed. During this time, a washing operation is performed as necessary. The washing liquid used in the washing operation may be used as the observation liquid. The reagent solution used in the labeling step contains at least a primary antibody containing a phosphorylation site-recognizing substance that recognizes the phosphorylation site, and optionally a secondary antibody containing a labeling substance.

[0047] <Reaction apparatus> The reactor of the present invention will be described below with reference to the drawings. However, the dimensions, materials, shapes, and relative positions of the components described below should be appropriately changed depending on the configuration of the apparatus to which the invention is applied and various conditions. Therefore, the scope of the present invention is not intended to be limited to the following description. Figure 2 is a schematic diagram illustrating the configuration of the reactor of the present invention, and Figure 3 is a schematic diagram illustrating an example of its specific structure. Note that Figures 3(a), (b), and (c) show the internal structure of the reactor as viewed from above, front, and right, respectively.

[0048] As shown in Figure 2, the reaction apparatus 300 of the present invention comprises a container mounting section 201 on which a reaction container 303 (see Figure 3) consisting of an array plate 301 on which spots containing biological substances are provided and a bank section 302 for holding liquid on the spot surface is mounted, a chemical liquid mounting section 202 on which a chemical liquid container containing a liquid to be brought into contact with the spots (including sample liquid, reagent liquid, cleaning liquid, observation liquid, etc., collectively referred to as "chemical liquid") is mounted, a liquid supply and drainage section 203 for supplying and discharging the chemical liquid to the reaction container 303, a moving section 204 for moving the liquid supply and drainage section 203 relative to the container mounting section 201, an optical system 206 for irradiating light onto multiple spots and detecting light from the spots, and a scanning section 205 for moving the optical system 206 relative to the array plate. This reaction apparatus also includes a control unit 210 that controls the liquid supply / discharge unit 203, the moving unit 204, the optical system 206, and the scanning unit 205 to sequentially execute the above-mentioned reaction initiation step S101, reaction termination step S102, labeling step S103, observation liquid introduction step S104, and information acquisition step of acquiring optical information of the plurality of spots while they are in contact with the observation liquid.

[0049] (Container placement section 201) As shown in Figures 3(a) and 3(c), the vessel mounting unit 201 can position and mount a reaction vessel 303 using pins or the like, and is equipped with a temperature control block that is in thermal contact with the underside of the array plate 301. The vessel mounting unit 201 is further fixed to a shaking mechanism 305 that can reciprocate in the Y-axis direction. Figure 3(a) shows five vessel mounting units 201 and shaking mechanisms 305 arranged on a table 306, with reaction vessels 303 placed on the four vessel mounting units 201 from the left. Each vessel mounting unit 201 can be independently controlled for temperature and shaking. Combining temperature and shaking controls maintains the reaction vessel 303 at a predetermined temperature, promoting reactions between the chemical solution and multiple spots on the array plate 301, and achieving uniformity of reaction across the multiple spots on the array plate 301.

[0050] The vessel mounting unit 201 may be equipped with a mechanism for tilting the reaction vessel 303 relative to the horizontal plane to facilitate drainage of the reaction-treated liquid from the reaction vessel 303. This tilting mechanism is composed of an actuator arranged to lift one end of the vessel mounting unit 201 in the Y-axis direction upward or push the other end downward, and a rotating shaft that enables tilting. By designing the end of the reaction vessel 303 to be lower than other points when the reaction vessel 303 is tilted, the liquid can be collected in one place, facilitating drainage. The shape of the bottom of the reaction vessel 303 can be set to any shape, taking into account the ease of suction of the liquid. It may be not only a typical rectangular shape, but also a triangular, pentagonal, other polygonal, sectoral, circular, elliptical, or other shape.

[0051] (Chemical solution placement section 202) A plurality of chemical liquid containers each containing a sample liquid and a chemical liquid are placed on the chemical liquid placement section 202. The chemical liquid placement section 202 is composed of a refrigerated chemical liquid placement section 312 equipped with a cooling section that cools and maintains the chemical liquid containers in the reaction device 300, and a room-temperature chemical liquid placement section 311 that maintains the chemical liquid at room temperature. In this embodiment, the refrigerated chemical liquid placement section 312 is placed with each chemical liquid container storing a reaction initiation liquid, multiple types of sample liquid, a primary antibody liquid, and a secondary antibody liquid. These chemical liquids are not frozen until they are used in each process, and are maintained at a low temperature that limits the activity of the components in the liquid as much as possible. The room-temperature chemical liquid placement section 311 is placed with each chemical liquid container storing a reaction stop liquid, an observation liquid, and a washing liquid. The primary antibody liquid and the secondary antibody liquid may be described as antibody liquids whose respective fluorescent activity decreases when cooled or cooled.

[0052] Figure 4 is a schematic diagram illustrating the chemical liquid placing section 202 (311, 312) and the tip placing section (here, the dispensing tip placing section 314), where Figure 4(a) shows the room temperature chemical liquid placing section 311, Figure 4(b) shows the refrigerated chemical liquid placing section 312, and Figure 4(c) shows the dispensing tip placing section 314 (similar to the drainage tip placing section 316).

[0053] (Room-temperature chemical solution placement section 311) The room-temperature liquid medicine placing section 311 is composed of a room-temperature liquid medicine container holding section 401 and a positioning section 403 for determining the position of the liquid medicine container 402 in the Z direction.

[0054] (Refrigerated chemical solution placement section 312) Refrigerated liquid medicine placement unit 312 is composed of a Peltier module 413, a heat transfer unit 414 for transferring the cooling heat of Peltier module 413 to liquid medicine container 402, a heat insulation unit 415 for insulating against heat from the external environment, a protective unit 416 for protecting heat insulation unit 415, and a refrigerated liquid medicine container holder 411 for holding liquid medicine container 402. Refrigerated liquid medicine container holder 411 is equipped with a positioning unit 418 having a position reference for determining the position of liquid medicine container 402 in the Z direction on heat transfer unit 414, which transfers the cooling heat from Peltier module 413. Positioning unit 418 holds liquid medicine container 402 at a position lower than the opening of the liquid medicine container, and sets the liquid level of the liquid medicine to be cooled to be below the upper surface of heat transfer unit 414. Heat transfer unit 414 is preferably made of a material with high thermal conductivity, such as aluminum. By adjusting the shape of the refrigerated medicinal liquid container holding portion 411 to the shape of the medicinal liquid container 402, the surface area of ​​the heat transfer surface 417 that is in thermal contact with the outer surface of the medicinal liquid container 402 can be maximized, allowing the cooling heat to be more efficiently transferred to the medicinal liquid in the medicinal liquid container 402.

[0055] (chip placement part) The tip mounting section is composed of a dispensing tip mounting section 314 that holds pipette tips for dispensing (supplying) each liquid drug placed in the refrigerated liquid drug mounting section 312 or the room temperature liquid drug mounting section 311 into the reaction vessel 303, and a discharge tip mounting section 316 that holds pipette tips for aspirating waste liquid including used specimen liquid and treated liquid from the reaction vessel 303. The tip mounting section is composed of a pipette tip holder 421 that has an opening for holding a disposable pipette tip 422, and the pipette tip is held in an ambient temperature environment.

[0056] (liquid supply / drain section 203) The liquid supply / discharge unit 203 has a pipetter unit to which a hollow pipette tip is attached and which draws and discharges gas between the pipette tip and the inside of the pipette tip. In the reaction apparatus of Fig. 3, the pipetter unit is composed of a dispensing pipetter 322 that dispenses a predetermined chemical solution into a reaction vessel 303, and a drainage pipetter 332 that drains the chemical solution held in the reaction vessel 303. By installing independent pipetters for dispensing and draining, the reaction apparatus 300 of the present invention can, for example, perform the suction of treated liquid from the reaction vessel 303 and the mixing operation of the reaction initiation liquid and the sample liquid by pipetting in parallel.

[0057] (Mobile unit 204) The moving unit 204 has a position changing unit that changes the position of the pipettor unit of the liquid supply / discharge unit 203. In the reaction apparatus of Fig. 3, the position changing unit (moving unit 204) is composed of a dispensing moving unit (323, 324, 325) that controls the position of the dispensing pipettor 322, and a drainage moving unit (333, 334, 335) that controls the position of the drainage pipettor 332. The moving unit 204 controls the positions of the dispensing pipettor 322 and the drainage pipettor 332 relative to the tip mounting units (314, 316), the chemical solution mounting units 202 (311, 312), and the container mounting unit 201. That is, the pipette tip for dispensing (hereinafter referred to as "dispensing tip 321") and the pipette tip for discharging (hereinafter referred to as "discharge tip 331") attached to each pipetter are controlled to XY and Z positions suitable for aspirating the chemical liquid from each chemical liquid container and dispensing it into reaction vessel 303, and for aspirating the treated liquid held in reaction vessel 303 and discharging it into waste liquid section 310. The combination of the pipetter section constituting liquid supply / discharge section 203 and the position change section constituting moving section 204 will be referred to as pipetter unit 207.

[0058] The moving section 204 also includes an actuator (table moving section) 341 that can move the table 306 in the X-axis direction, below the table 306, thereby controlling the position of the reaction vessel 303 in the X-axis direction.

[0059] As described above, the drainage and dispensing operations can be performed in parallel within the movement range where the structures of the dispensing and moving units (323, 324, 325) and the drainage and moving units (333, 334, 335) do not interfere with each other. If there are areas or conditions where they interfere, drainage and dispensing will be performed serially in a time-division manner in those areas.

[0060] (scanning unit 205) When the area that can be observed by the optical system 206 is limited, the scanning unit 205 scans the optical system 206 to observe optical information of the entire required area of ​​the array plate. Note that only a part of the optical system 206 may be scanned, or only the excitation light source or the excitation light may be scanned.

[0061] (Optical system 206) The optical system 206 irradiates excitation light onto a plurality of spots on the array plate 301 of the reaction vessel 303 placed on the vessel placement section 201, and detects the resulting fluorescence.

[0062] (control unit 210) The control unit 210 functions as a computer that controls the operation of the reaction device 300 according to its purpose. The control unit 210 may be integrated with a general-purpose computer such as a desktop PC (Personal Computer), laptop PC, tablet PC, or smartphone. The control unit 210 controls the operations of the liquid supply / discharge unit 203, the moving unit 204, the scanning unit 205, and the optical system 206 to sequentially execute the following steps: a reaction initiation step in which a sample liquid is brought into contact with the multiple spots to react with targets contained in the sample liquid at least some of the spots; a reaction termination step in which the amount of sample liquid in contact with the multiple spots is reduced to terminate the reactions of the spots thereafter; a labeling step in which the spots that have reacted with the targets are labeled; an observation liquid introduction step in which a spot surface on which the multiple spots are provided is brought into contact with an observation liquid; and an information acquisition step in which optical information is acquired from the multiple spots while the multiple spots are in contact with the observation liquid. The control unit controls the pipette unit so that a dispensing operation is performed in which at least one of the amount of liquid medicine drawn from the liquid medicine container, the amount of liquid medicine dispensed into the reaction container, and the position of the pipette unit is adjusted, particularly depending on at least one of the type of liquid medicine, the state of the liquid medicine, the operation history of the pipette unit, and the state of the pipette tip.

[0063] (CPU 211, RAM 212, ROM 213) As shown in FIG. 2, the control unit 210 includes a CPU 211, a RAM 212, a ROM 213, and a storage device 214 to function as a computer that performs calculations and storage. CPU stands for Central Processing Unit, RAM stands for Random Access Memory, and ROM stands for Read Only Memory. The control unit 210 also includes a communication I / F (interface) 219, a display device 215, and an input device 216. The CPU 211, RAM 212, ROM 213, storage device 214, communication I / F 219, display device 215, and input device 216 are interconnected via a bus 1012. The display device 215 and input device 216 may be connected to the bus 1012 via a drive device (not shown) for driving these devices. While FIG. 2 illustrates the components constituting the control unit 210 as an integrated device, some of these functions may be configured as external devices. The display device 215 and input device 216 may be external devices separate from the components constituting the computer functions, including the CPU 211.

[0064] The CPU 211 performs predetermined operations in accordance with programs stored in the RAM 212, the storage device 214, etc., and also has the function of controlling each component of the control unit 210. The RAM 212 is a volatile storage medium and provides temporary memory space necessary for the operation of the CPU 211. The ROM 213 is a nonvolatile storage medium and stores information necessary for the programs used in the operation of the control unit 210. The CPU 211 loads information stored in the ROM 213 into the RAM 212 and executes it, thereby realizing functions of the container placement unit 201, the liquid supply / drainage unit 203, the optical system 206, etc. The storage device 214 is a nonvolatile storage medium such as a hard disk drive (HDD), and stores information regarding the number and positions of spots on the array plate 301, light intensity information, or spectral information. The storage device 214 may be configured as a solid state drive (SSD) using semiconductor elements including flash memory instead of an HDD, or cloud storage may be used.

[0065] (Display device 215) The display device 215 is a liquid crystal display, an OLED (Organic Light Emitting Diode) display, or the like, and is used to display moving images, still images, characters, and the like.

[0066] (input device 216) The input device 216 is a button, a touch panel, a keyboard, a pointing device, or the like, and is used by the user to operate the control unit 210. The display device 215 and the input device 216 may be integrally formed as a touch panel.

[0067] (Communication I / F 219) The communication I / F 219 is a module for communicating data with information terminals and devices on the network. The data communication method can be wired LAN, wireless LAN, or a mobile communication interface based on standards such as 5G.

[0068] (program) As described above, the control unit 210 operates by the CPU 211 reading the program stored in the storage device 214 and the information stored in the ROM 213 into the RAM 212 and executing them, but the program may be read from the outside by the CPU 211 into the storage device 214 based on the information in the ROM 213. In this way, it is also possible to make a general-purpose computer function as the control unit 210 in the reaction device 300 of the present invention.

[0069] 2 is merely a schematic representation of the configuration of this embodiment, and in reality, devices other than those shown in FIG. 2 may be added, or some devices may not be provided. Also, some devices may be replaced with other devices having similar functions. Furthermore, some functions may be provided by other devices via a network, and the functions constituting this embodiment may be distributed and realized among multiple devices.

[0070] Furthermore, the control unit 210 can control the operation of the optical system 206 and the operation of the liquid supply / drain unit 203 to be performed in parallel. That is, in parallel with the execution of the information acquisition step for the first array plate, it can execute and control a step for the second array plate, including any one of a reaction initiation step, a reaction termination step, an observation liquid introduction step, and a labeling step. This allows the analysis of multiple array plates to proceed simultaneously, saving analysis time. [Example]

[0071] Example 1 <Antibody solution dispensing sequence> In this example, the antibody liquid dispensing sequence and its operation in the reaction apparatus of the present invention will be described with reference to Figures 5 and 6. The antibody liquid dispensing sequence is executed at the start of the labeling step S103. Figure 5 is a flow diagram of the antibody liquid dispensing sequence, with Figure 5(a) showing the reaction sequence S500, Figure 5(b) showing the reagent replacement sequence S501, Figure 5(c) showing the drainage sequence S510, and Figure 5(d) showing the dispensing sequence S520. Figure 6 is a schematic diagram explaining the antibody liquid dispensing operation, with Figures 6(a) to 6(g) explaining the operation in each step of the dispensing sequence S520.

[0072] (Reaction sequence S500) The reaction sequence S500 shows the basic sequence for executing each of the steps S101 to S104 of the reaction process shown in Fig. 1(a). When a reaction process is carried out for multiple reaction vessels 303, the reaction sequence S500 is started sequentially at predetermined time intervals starting from the first reaction vessel 303, and the flow described below is executed while maintaining a predetermined time interval, thereby progressing the reaction process for each reaction vessel 303.

[0073] In step S501, a reagent replacement sequence S501 for starting each process in FIG. 1(a) is executed. At the start of the reaction process, a buffer solution is held in the reaction vessel 303 so as not to dry the spots on the array plate 301. The reaction sequence S500 starts from draining this buffer solution and dispensing a mixture of the reaction start solution and the test sample solution. As the buffer solution, for example, Tris-buffered saline (TBST) containing a nonionic surfactant, Tris-buffered saline (TBS), or the like is used.

[0074] In step S502, each process S101 to S104 is executed according to the process control information 111 shown in FIG. 1(b). The control unit 210 controls the temperature adjustment and shaking of the container placement unit 201 according to the process control information 111 and the shaking control information specified by the chemical solution control information 112 shown in FIG. 1(c), and stops the temperature adjustment and shaking when the specified processing time elapses.

[0075] In step S503, the control unit 210 determines whether the array plate has completed all processes. If not, it returns to step S501 and executes the reagent replacement sequence S501 for the subsequent process.

[0076] (Reagent replacement sequence S501) As shown in FIG. 5(b), the reagent replacement sequence S501 is composed of a drainage sequence S510 for discharging the processed solution in the reaction vessel 303 and a dispensing sequence S520 for supplying the next chemical solution to the reaction vessel 303. In this embodiment, FIG. 5(b) shows that these operations are performed in parallel. By performing them in parallel, the time from draining the processed solution in the reaction vessel 303 to supplying the next chemical solution can be shortened, thereby preventing the spots on the array plate 301 from drying due to exposure to air. However, when the dispensing sequence takes a long time, or when the chemical solution containers are arranged in an area where the dispensing moving parts 323, 324, 325 and the drainage moving parts 333, 334, 335 interfere with each other, etc., it is executed as a serial operation in which the drainage sequence and the dispensing sequence are sequentially executed.

[0077] (Drainage sequence S510) 5(c) shows the drainage sequence S510. At the start of the labeling step S103, the reaction vessel 303 holds the reaction stop solution that has been treated in the previous reaction stopping step S102, so the reaction stop solution is drained according to this sequence. Note that, if the chemical liquid control information 112 is followed, the drainage tip 331 does not come into contact with the sample liquid during the drainage operation of the reaction stop solution, so the drainage tip 331 can be reused between plates.

[0078] In step S511, the drainage moving units 333, 334, and 335 control the XY position of the drainage pipetter 332 above the drainage tip 331 installed on the drainage tip mounting unit 316, and then press the tip of the drainage pipetter 332 against the tip to attach the drainage tip 331 to the drainage pipetter 332. Prior to the start of the reaction sequence S500, multiple drainage tips 331 are installed on the drainage tip mounting unit 316, and the control unit 210 controls the moving unit 204 (drainage moving units 333, 334, and 335) to sequentially use the installed drainage tips 331. After the drainage tip 331 is attached, the moving unit 204 (drainage moving units 333, 334, and 335) returns the drainage pipetter 332 to a height that allows XY movement.

[0079] In step S512, the table moving unit 341 moves the target reaction vessel 303 to the drainage position, and if a tilting mechanism for the reaction vessel 303 is provided, the tilting mechanism tilts the reaction vessel 303. The drainage moving units 333, 334, and 335 control the XY position of the drainage pipetter 332 above the reaction vessel 303, and then tilt the tip of the drainage tip 331 to a position near the point where the treated liquid in the reaction vessel 303 collects. At this position, the drainage pipetter 332 aspirates the treated liquid. After aspirating, the drainage moving units 333, 334, and 335 return the drainage pipetter 332 to a height that allows XY movement, and the tilting mechanism returns the reaction vessel 303 to a horizontal position.

[0080] In step S513, the waste liquid moving units 333, 334, and 335 control the XY position of the waste liquid pipetter 332 to the waste liquid unit 310, and then control the position of the tip of the waste liquid tip 331 to a height where it can be inserted into the waste liquid container in the waste liquid unit 310, and then discharge all of the treated liquid sucked by the waste liquid pipetter 332 into the waste liquid container. After discharge, the waste liquid moving units (333, 334, and 335) return the waste liquid pipetter 332 to a height where it can be moved in the XY direction.

[0081] In step S514, the control unit 210 determines whether draining of the treated liquid has been completed for all plates. If not, the process waits for the completion of the previous step for the next target plate before proceeding to step S512. Note that this draining completion determination step S514 is executed in conjunction with the dispensing completion determination step S527 described below, i.e., it determines whether reagent replacement for all plates has been completed.

[0082] In step S515, if the drainage of the treated liquid has been completed for all plates, the drainage transfer unit (333, 334, 335) controls the position of the drainage pipetter 332 to above the drainage tip disposal unit 317, and the drainage pipetter 332 removes the drainage tip 331.

[0083] (Dispensing sequence S520) The antibody liquid dispensing sequence S520 in the reaction apparatus of the present invention will be described with reference to Figure 5(d). According to the chemical liquid control information 112, the dispensing tip 321 does not come into contact with the sample liquid during the dispensing operation of the primary antibody liquid and the secondary antibody liquid, so the dispensing tip 321 can be reused between plates. This sequence S520 can be executed as a dispensing operation of both the primary antibody liquid and the secondary antibody liquid, so for the sake of explanation, the term "antibody liquid" will be used here without distinguishing between the two chemical liquids. The antibody liquid dispensing operation in the reaction apparatus of the present invention will also be described with reference to the schematic diagram of Figure 6. Figures 6(a) to (g) explain the operating states at each step of the dispensing sequence S520.

[0084] In step S521, the dispensing movement units 323, 324, and 325 control the XY position of the dispensing pipetter 322 over one dispensing tip 321 installed on the dispensing tip mounting unit 314, and then press the tip of the dispensing pipetter 322 against the dispensing tip 321 to attach the dispensing tip 321 to the dispensing pipetter 322. Prior to the start of the reaction sequence, multiple dispensing tips 321 are installed on the dispensing tip mounting unit 314, and the control unit 210 controls the dispensing movement units to use the installed tips sequentially. After the dispensing tip 321 is attached, the dispensing movement units 323, 322, and 325 return the dispensing pipetter 322 to a height that allows XY movement. In the state shown in FIG. 6(a), the dispensing pipetter 322 aspirates a predetermined amount of air in advance for the operation described below. The dispensing pipetter 322 has a pipetter hollow portion (not shown) that communicates with the tip hollow portion of the connected dispensing tip 321, and is equipped with a piston (not shown) that changes the volume of the pipetter hollow portion to change the amount of air in the communicating tip hollow portion and the pipetter hollow portion. By displacing the piston end, air in the tip hollow portion is sucked in and expelled, and the target chemical solution is sucked in and expelled.

[0085] In step S522, the dispensing movement units 323, 324, and 325 control the XY position of the dispensing pipettor 322 over the antibody liquid container 611 held in the refrigerated reagent placement unit 312, and insert the tip of the dispensing tip 321 a predetermined distance 601 from the opening of the container 611. As shown in FIG. 6(b), the tip of the dispensing tip 321 is brought close to the bottom of the container 611, and the dispensing pipettor 322 mixes the antibody liquid by pipetting, alternately aspirating and dispensing the antibody liquid multiple times within the container. According to the process control information 111, the antibody liquid is dispensed approximately 105 minutes after the start of the reaction sequence, and the secondary antibody liquid is dispensed approximately 165 minutes after the start of the reaction sequence. Therefore, this mixing step S522 has the effect of eliminating imbalances in the components due to precipitation over a long period of time and achieving homogenization. Furthermore, regardless of the volume (level) of the antibody liquid in the container 611, moving the liquid near the bottom can further homogenize the antibody liquid.

[0086] On the other hand, during the stirring process, the air trapped inside the dispensing tip 321 is cooled by the refrigerated primary antibody solution, causing its volume to decrease. If dispensing into the reaction vessel 303 in this reduced volume state, the actual amount dispensed will decrease relative to the piston control amount of the dispensing pipetter 322. Furthermore, because the degree of temperature drop in the air inside the tip differs between a new pipette tip that has just been attached in step S521 and kept at room temperature and a pipette tip that has already been cooled through steps S522 to S526, when reusing the dispensing tip 321 between plates, it becomes impossible to maintain the same amount dispensed between plates. This effect leads to differences in reactivity between plates.

[0087] In step S523, the dispensing movement unit 325 pulls the tip of the dispensing tip 321 out of the liquid surface. At this time, the volume of air in the tip has decreased during the stirring operation, so even though the same amount of dispensing and dispensing has been repeated and the final dispensing has been completed, residual liquid 613 remains in the tip as shown in Figure 6(c). At this point, the dispensing pipetter 322 discharges all of the air sucked in in step S521 and returns the residual liquid 613 to the container 611. This allows the inside of the tip to be returned to the atmosphere.

[0088] In step S524, the dispensing movement unit 325 again inserts the tip of the dispensing tip 321 a predetermined distance 601 from the container opening of the container 611. As shown in FIG. 6( e), the tip of the dispensing tip 321 is brought close to the bottom of the container 611, and the dispensing pipetter 322 aspirates the amount of chemical liquid specified in the process control information 111.

[0089] In step S525, the dispensing movement unit 325 pulls the tip of the dispensing tip 321 out of the liquid surface, and the dispensing pipettor 322 aspirates a predetermined volume of air. As shown in Figure 6(f), the level of the liquid held in the dispensing tip 321 is raised to prevent dripping when the dispensing pipettor 322 is moved. After aspirating the drip prevention air 614, the dispensing movement unit 325 returns the dispensing pipettor 322 to a height that allows XY movement. The drip prevention air 614 corresponds to the predetermined amount of air aspirated by the dispensing pipettor 322.

[0090] In step S526, the table moving unit 341 moves the target reaction vessel 303 to the dispensing position, and the dispensing moving units (323, 324, 325) control the XY position of the dispensing pipettor 322 above the reaction vessel 303 to insert the tip of the dispensing tip 321 a predetermined distance into the reaction vessel 303. As shown in Figure 6(g), the dispensing pipettor dispenses the amount of chemical liquid specified in the process control information 111 into the reaction vessel 303. After dispensing, the dispensing moving unit 325 returns the dispensing pipettor 322 to a height that allows XY movement.

[0091] Up to this point, the drainage sequence S510 and the dispensing sequence S520 have been described as being capable of operating in parallel, but since simultaneously executing the drainage suction step S512 and the chemical liquid discharge step S526 for one reaction vessel 303 requires a complex configuration, it is necessary to complete the drainage suction step S512 before the chemical liquid discharge step S526. The control unit 210 controls the order of the drainage suction step S512 and the chemical liquid discharge step S526. In this way, the control unit 210 performs synchronization control (not shown) of the drainage sequence and the dispensing sequence.

[0092] In step S527, the control unit 210 determines whether dispensing of antibody liquid has been completed for all plates. If not, the process waits for the completion of the previous step for the next target plate before proceeding to step S522. This dispensing completion determination step S527 is executed in conjunction with the aforementioned drainage completion determination step S515, i.e., it determines whether reagent replacement has been completed for all plates.

[0093] In step S528, if dispensing of the primary antibody solution has been completed for all plates, the dispensing transfer unit (323, 324, 325) controls the position of the dispensing pipetter 322 to above the dispensing tip disposal unit 315, and the dispensing pipetter 322 removes the dispensing tip 321.

[0094] (Effects of this embodiment) With the reaction device, control unit, and antibody liquid dispensing sequence configured as described above, the antibody liquid is kept refrigerated for a long period of time from the start of the reaction process through to the labeling step, and the dispensing tip can be reused between plates. By providing a stirring step, it is possible to eliminate component imbalances caused by precipitation, etc., and dispense a homogeneous antibody liquid into the reaction vessel, thereby maintaining the same reactivity between plates.

[0095] Furthermore, the difference in volume reduction between a newly installed tip that has been kept at room temperature and filled with room-temperature air and a reused tip that already has cooled air inside the tip can be eliminated by providing a step of exposing the air inside the tip to the atmosphere. This helps to eliminate the decrease in dispensing accuracy caused by the state of use of the tip, and as a result, it becomes possible to dispense antibody liquid into reaction vessels while maintaining the same dispensing volume between plates.

[0096] Furthermore, by arranging the movement ranges of the dispensing and draining movement sections and the tips and chemical containers so that they can be operated independently, the draining sequence and dispensing sequence can be operated in parallel, and the period from draining to dispensing, during which the spots on the plate can be exposed to air and dry, can be shortened as much as possible.

[0097] Example 2 <Sample liquid dispensing sequence> In this example, the sample liquid dispensing sequence and its operation in the reaction device of the present invention will be described with reference to Figures 7 and 8. The sample liquid dispensing sequence is executed at the start of the reaction initiation step S101. Figure 7 is a flow diagram of the sample liquid dispensing sequence, Figure 8 is a schematic diagram explaining the sample liquid dispensing operation, and Figures 8(a) to (f) explain the operation in each step of the dispensing sequence S720.

[0098] (Dispensing sequence S720) In the sample liquid dispensing sequence S720 according to this embodiment, the dispensing tip 321 comes into contact with the sample liquid, and therefore the dispensing tip 321 cannot be reused between array plates. Therefore, the dispensing operation is performed after replacing the dispensing tip 321 for each array plate. Therefore, unlike the dispensing sequence S520 in the antibody liquid dispensing sequence of Example 1, the dispensing tip attachment step S521 and disposal step S528 are included in the repetition of the dispensing operation. Below, a description of the steps common to the antibody liquid dispensing sequence S520 of Example 1 will be omitted, and only steps unique to the sample liquid dispensing sequence S720 will be described.

[0099] In the reaction start liquid suction step S722, the dispensing pipetter 322 first suctions a predetermined amount of air in preparation for the operation described below, and then the dispensing movement unit (323, 324, 325) controls the XY position of the dispensing pipetter 322 above the reaction start liquid container 811 held in the refrigerated reagent loading unit 312, and as shown in Figure 8(b), inserts the tip of the dispensing tip 321 a predetermined distance 813 from the container opening of the reaction start liquid container 811, and aspirates the reaction start liquid 812 while the tip of the dispensing tip 321 is close to the bottom of the reaction start liquid container 811.

[0100] In the sample mixing step S723, the dispensing and moving unit (323, 324, 325) controls the XY position of the dispensing pipetter 322 above a sample liquid container 821 held in the refrigerated reagent mounting unit 312. As shown in FIG. 8(c), approximately 0.1 ml of sample liquid 822 has been placed in the sample liquid container 821 beforehand. The dispensing and moving unit (323, 324, 325) inserts the tip of the dispensing tip 321 holding the reaction initiation liquid 812 a predetermined distance 823 from the container opening of the container 821, and with the tip of the dispensing tip 321 inserted into the sample liquid 822 as shown in FIG. 8(d), the dispensing pipetter 322 mixes the reaction initiation liquid 812 and the sample liquid 822 by pipetting with multiple suctions and discharges, thereby producing a mixed liquid 831.

[0101] In the mixed liquid aspirating step S724, the dispensing pipetter 322 aspirates the amount of mixed liquid 831 designated by the process control information 111 and holds it in the dispensing tip 321 as shown in FIG. 8(e).

[0102] In mixed liquid dispensing step S726, the dispensing movement unit (323, 324, 325) controls the XY position of the dispensing pipettor 322, which has raised the level of the mixed liquid 831 held in the dispensing tip 321 by suctioning anti-drip air 832 in air suction step S525, above the reaction vessel 303, to insert the tip of the dispensing tip 321 a predetermined distance into the reaction vessel 303, and at the position shown in Figure 8(f), the dispensing pipettor dispenses the amount of mixed liquid 831 specified in the process control information 111 into the reaction vessel 303. After dispensing, the dispensing movement unit (325) returns the dispensing pipettor 322 to a height that allows XY movement.

[0103] During the reaction initiation liquid aspirating step S722, specimen mixing step S723, mixed liquid aspirating step S724, and mixed liquid dispensing step S726, the air inside the dispensing tip 321 is cooled by the reaction initiation liquid 812 and specimen liquid 822 that are kept refrigerated, reducing the volume of the air inside the dispensing tip 321. If dispensing is performed into the reaction vessel 303 while the air volume inside the dispensing tip 321 has been reduced due to a drop in temperature, the actual amount of dispensing relative to the piston control amount of the dispensing pipetter 322 will be reduced.

[0104] The control unit 210 of the reaction apparatus 300 of this embodiment prevents this decrease in the amount of mixed liquid dispensed by increasing the pipetter control amount during dispensing using the pipetter control amount used to aspirate air before the reaction start liquid aspirating step S722. That is, the control unit controls the pipetter unit so that a larger amount of the chemical liquid is aspirated than the amount aspirated at room temperature and dispensed into the reaction vessel placed on the vessel placement unit. This increment can be set as a fixed value based on, for example, prior experimental values ​​under the same process conditions or the same external environment. Alternatively, it can be determined by referring to a conversion table divided into several stages based on the amount of chemical liquid, reagent type, etc. specified in the process control information 111. It can also be calculated using a correction formula.

[0105] (Effects of this embodiment) With the control unit and specimen liquid dispensing sequence configured as described above, the reaction initiation liquid and specimen liquid used immediately after the start of the reaction process are each refrigerated. Even for specimen liquid 822, for which the dispensing tip 321 cannot be reused between array plates, and the mixture of the reaction initiation liquid and the specimen liquid, the dispensing sequence is performed after newly attaching a tip to all array plates, i.e., by performing the dispensing sequence under the same tip usage condition, it is possible to eliminate any decrease in dispensing accuracy due to the tip usage condition and maintain the same specimen liquid dispensing accuracy between plates. Furthermore, by increasing the pipettor control amount to the reaction vessel 303 to compensate for the decrease in the volume of air in the tip due to the mixture kept refrigerated, a decrease in the actual amount of the mixture dispensed can be prevented. That is, the amount of air aspirated and expelled by the pipettor unit (dispensing pipetter 322), whose volume changes depending on the temperature at which the liquid is held in the liquid container in the liquid placement unit 202 (311, 312) where the liquid container containing the liquid to be dispensed is placed, changes. In other words, the control unit 210 controls the displacement amount of the piston so as to compensate for the change in air volume of the pipette unit (dispensing pipette 322), which undergoes volumetric changes due to the temperature of the drug solution placement unit 202 in which the drug solution to be dispensed is held.

[0106] Example 3 <Observation liquid dispensing sequence> In this example, the observation liquid dispensing sequence in the reaction apparatus of the present invention will be described with reference to FIG. 9. The observation liquid dispensing sequence is executed in the observation liquid introduction step S104. In the observation liquid dispensing sequence S920 according to this embodiment, a highly viscous observation liquid is dispensed, which is inactive for a long time against the reaction products on the array plate and is selected based on its optical properties relative to the array plate. Therefore, dispensing takes a longer time than other chemical liquids. Therefore, the control unit 210 controls the execution of each step of the draining sequence S910 in accordance with the dispensing sequence S920, thereby keeping the period during which the spot on the plate is exposed to air and may dry short even in the observation liquid dispensing sequence, just as when other chemical liquids are dispensed.

[0107] (Drainage sequence S910) The drainage sequence S910 of this embodiment is identical to the drainage sequence S510 in the antibody liquid dispensing sequence of Example 1 in the order and content of steps S511 to S512, but the timing of each step is different. Specifically, the drainage suction step S512 is executed after the slow lifting step S923 or the air suction step S525 for preventing dripping in the observation liquid dispensing sequence S920 is completed. This sequence control prevents the spots on the plate from being exposed to air during the long period required for the slow lifting step S923. The reaction vessel 303 holds the treated antibody liquid or buffer solution dispensed in the preceding labeling step S103, and this is drained according to this sequence. Note that the drainage tip 331 does not come into contact with the sample liquid during the drainage operation of these treated liquids, so the drainage tip 331 can be reused between plates.

[0108] (Dispensing sequence S920) In the observation liquid dispensing operation, the dispensing tip 321 does not come into contact with the sample liquid, so the dispensing tip 321 can be reused between plates. Below, explanations of steps common to the antibody liquid dispensing sequence S520 of Example 1 will be omitted, and explanations will be given of steps unique to the observation liquid dispensing sequence S920.

[0109] In the observation liquid aspirating step S922, the dispensing movement unit (323, 324, 325) controls the XY position of the dispensing pipetter 322 above the observation liquid container held in the room-temperature chemical liquid placing unit 311, inserts the tip of the dispensing tip 321 a predetermined distance from the opening of the container, and aspirates the observation liquid at a position close to the bottom of the observation liquid container regardless of the liquid level. At this time, if the dispensing pipetter 322 can control the aspirating operation speed, it is preferable to aspirate at a slower speed than other chemical liquids. Aspirating at a slower speed allows the highly viscous observation liquid to be accurately aspirated in the amount specified in the process control information 111.

[0110] In the slow-speed lifting step S923, the dispensing / moving unit 325 lifts the dispensing tip 321 holding the observation liquid from the liquid in the observation liquid container at a predetermined speed to reduce the adhesion of the observation liquid in the container to the outer wall of the dispensing tip 321. This predetermined lifting speed is set to be equal to or less than the upper limit speed so that the amount of observation liquid remaining in the observation liquid container is relatively increased by suction of the observation liquid contained in the observation liquid container and the observation liquid in contact with the outer wall of the dispensing tip 321, thereby reducing the adhesion of the observation liquid to the outer wall of the dispensing tip 321. The upper limit of the lifting speed depends on the viscosity of the observation liquid, the outer diameter and material of the tip, etc., but is typically 20.0 mm / sec or less, and more preferably 5.0 mm / sec or less. By lifting the dispensing tip 321 within this range of upper limit lifting speed, the dispensing tip 321 can be lifted while the observation liquid that has adhered to the outer wall of the tip falls into the container. If the depth of the observation liquid container is 120 mm and the top of the liquid volume for multiple plates is 90 mm, and the dispensing tip is pulled up from the observation liquid suction depth of 119 mm over a distance of approximately 100 mm at a rate of 5.0 mm / sec or less, this step S923 will require more than 20 seconds, which is more than 20 times longer than other chemical liquids, which can be pulled up in around 1 second.

[0111] In the observation liquid discharge step S926, the dispensing movement unit (323, 324, 325) controls the XY position of the dispensing pipetter 322, which has raised the level of the observation liquid held in the dispensing tip 321 by suctioning air to prevent dripping in the air suction step S525, above the reaction vessel 303, and inserts the tip of the dispensing tip 321 a predetermined distance into the reaction vessel 303. The dispensing pipetter then discharges the amount of mixed liquid 831 specified in the process control information 111 into the reaction vessel 303. After dispensing, the dispensing movement unit (323, 324, 325) returns the dispensing pipetter 322 to a height that allows XY movement.

[0112] (Effects of this embodiment) According to the observation liquid dispensing sequence of Example 3 having the above configuration, the observation liquid is maintained at room temperature until the final observation liquid introduction step of the reaction process, is inactive for a long time against the reaction products on the plate, and is selected for its optical properties with the plate. By providing a step of slowly withdrawing the dispensing tip from the chemical solution container, it is possible to prevent the observation liquid from clinging to the outer wall of the dispensing tip, and to dispense the highly viscous observation liquid into the reaction apparatus without dripping it. This demonstrates that the control unit according to this embodiment can select and control an appropriate dispensing sequence based on the characteristics of the chemical solution, namely, high viscosity.

[0113] Example 4 <Stop solution dispensing sequence> In this example, the stop solution dispensing sequence and its operation in the reaction apparatus of the present invention will be described with reference to Fig. 10. The stop solution dispensing sequence is executed at the start of the reaction stopping step S102.

[0114] (Drainage sequence S1010) The reaction vessel 303 holds sample liquid that has been treated in the previous reaction initiation step S101, and the discharge tip 331 cannot be reused between plates when draining this treated sample liquid. Therefore, the discharge tip 331 is replaced for each plate before the drainage operation is performed. Unlike the antibody liquid dispensing sequence S510 in Example 1, the dispensing tip attachment step S511 and the disposal step S514 are included in the repeated drainage operation.

[0115] (Dispensing sequence S1020) In the dispensing operation of the reaction stop solution, the dispensing tip 321 does not come into contact with the sample liquid, so the dispensing tip 321 can be reused between plates. Below, explanations of steps common to the antibody solution dispensing sequence S520 of Example 1 will be omitted, and only explanations of steps unique to the stop solution dispensing sequence S1020 will be given.

[0116] In stop solution aspirating step S1022, the dispensing movement unit (323, 324, 325) controls the XY position of the dispensing pipetter 322 above the reaction stop solution container held in the room temperature chemical solution placing unit 311, inserts the tip of the dispensing tip 321 a predetermined distance from the opening of the container, and aspirates the reaction stop solution at a position close to the bottom of the observation solution container regardless of the liquid level. After aspirating, the dispensing movement unit (323, 322, 325) returns the dispensing pipetter 322 to a height that allows XY movement.

[0117] In stop solution dispensing step S1024, the dispensing movement unit (323, 324, 325) controls the XY position of the dispensing pipetter 322, which has raised the level of the reaction stop solution 831 held in the dispensing tip 321 by air suction to prevent dripping in step S525, above the reaction vessel 303, and inserts the tip of the dispensing tip 321 a predetermined distance into the reaction vessel 303. The dispensing pipetter then dispenses the amount of reaction stop solution 831 specified in the process control information 111 into the reaction vessel 303. After dispensing, the dispensing movement unit (323, 324, 325) returns the dispensing pipetter 322 to a height that allows XY movement.

[0118] (Effects of this embodiment) According to the stop solution dispensing sequence of this example, in the reagent replacement sequence from the processed mixed solution to the reaction stop solution when transitioning from the reaction initiation step to the reaction termination step, for the processed mixed solution for which the drained tip cannot be reused, replacement with the reaction stop solution can be performed by attaching a new tip to all array plates and then executing the drainage sequence. In other words, this shows that the control unit according to this embodiment can control an appropriate reagent replacement sequence based on the characteristics of the processed liquid to be drained.

[0119] Example 5 <Washing solution dispensing sequence> In this example, the washing solution dispensing sequence and its operation in the reaction apparatus of the present invention will be described with reference to FIG. 11. Because the washing process may be repeatedly performed during the labeling process S103, it is expected that the washing solution container placed in the room-temperature chemical solution placement unit 311 will need to be larger and have a larger capacity than the reaction stop solution container or the observation solution container. In this case, for example, a vial or bottle with a capacity of several hundred ml will be placed instead of a centrifuge tube with a capacity of several tens of ml. In this example, a washing solution dispensing sequence will be described for the case where a large washing solution container is placed in the interference area between the dispensing and transfer units (323, 324, 325) and the waste transfer unit (333, 334, 335). The control unit 210 synchronizes and controls each step of the draining sequence S1110 and the dispensing sequence S1120 in order.

[0120] (Drainage sequence S1110) The reaction vessel 303 holds a reaction stop solution or antibody solution that has been treated in the preceding reaction stop step S102 or labeling step S103, and the discharge tip 331 can be reused between plates when discharging these treated solutions. When replacing the target reaction vessel 303 with new washing solution, the control unit 210 completes the waste solution suction step S512 and the waste solution discharge step S513, thereby completing the discharge of the treated solution.

[0121] (Dispensing sequence S1120) In the washing solution dispensing operation, the dispensing tip 321 does not come into contact with the sample solution, so the dispensing tip 321 can be reused between plates. Below, explanations of steps common to the antibody solution dispensing sequence S520 of Example 1 will be omitted, and only steps unique to the stop solution dispensing sequence S1120 will be explained.

[0122] After completing the waste liquid aspirating step S512 and the waste liquid discharging step S513, the control unit 210 executes the cleaning liquid aspirating step S1122 and the cleaning liquid discharging step S1124. In the cleaning liquid aspirating step S1122, the quenching liquid aspirating step S1022 of the fourth embodiment is executed for the cleaning liquid container and the cleaning liquid held in the room temperature chemical liquid placing unit 311. In the cleaning liquid discharging step S1124, the cleaning liquid held in the dispensing tip 321 is discharged into the target reaction vessel 303, similar to the quenching liquid discharging step S1024 of the fourth embodiment.

[0123] (Effects of this embodiment) With the control unit and cleaning liquid dispensing sequence having the above configuration, a cleaning liquid replacement sequence can be executed by sequentially and synchronously executing the drainage sequence and dispensing sequence for the cleaning liquid placed in the interference area between the dispensing and moving unit and the drainage and moving unit.

[0124] <Program for executing dispensing sequence> In the present invention, a storage medium (or recording medium) storing software program code for realizing the functions of the above-described embodiments is supplied to a system or device, and the computer (or CPU or MPU) of the system or device reads and executes the program code stored in the storage medium. In this case, the program code read from the storage medium itself realizes the functions of the above-described embodiments, and the storage medium storing the program code constitutes the present invention.

[0125] Furthermore, by executing the program code read by the computer, an operating system (OS) running on the computer performs some or all of the actual processing based on the instructions of the program code, which of course also includes cases where the functions of the above-described embodiments are realized by such processing.

[0126] Furthermore, suppose the program code read from the storage medium is written to a memory provided in a function expansion card inserted into a computer or a function expansion unit connected to the computer, and then, based on the instructions of the program code, a CPU or the like provided in the function expansion card or the function expansion unit performs part or all of the actual processing, thereby realizing the functions of the above-mentioned embodiments.

[0127] When the present invention is applied to the storage medium, the storage medium stores program code corresponding to the flowcharts described above.

[0128] The present invention includes a reaction apparatus, a control method, and a program having the following configurations. (Configuration 1) A reaction device for dispensing a sample liquid into a reaction vessel including an array plate having a substrate on which a plurality of spots containing a biological substance are arranged in an array, and for producing a reaction product between the biological substance and a substance in the sample liquid on the spots by bringing the sample liquid into contact with the plurality of spots, a container placement section for placing the reaction container; a liquid medicine placement unit for placing a plurality of liquid medicine containers each containing a sample liquid and a liquid medicine; a pipetter unit including a pipetter section to which a hollow pipet tip is attached and which draws and exhausts gas between the inside of the pipet tip and the pipetter section, and a position change section which changes the position of the pipetter section; a tip placement portion on which the pipette tip is placed; a control unit that controls the pipette unit so that a dispensing operation is performed in which at least one of the amount of chemical liquid aspirated from the chemical liquid container, the amount of chemical liquid dispensed into the reaction container, and the position of the pipette unit is adjusted depending on at least one of the type of chemical liquid, the state of the chemical liquid, the operating history of the pipette unit, and the state of the pipette tip. (Configuration 2) 2. The reaction apparatus of claim 1, wherein the chemical solution placement unit is configured to hold a plurality of chemical solution containers. (Configuration 3) 2. The reaction apparatus of claim 1, wherein the chemical solution placement unit includes a cooling unit for cooling the chemical solution container to a temperature lower than room temperature. (Configuration 4) The reaction apparatus of Configuration 3, wherein the cooling unit has a heat transfer surface that is in thermal contact with the outer surface of the chemical solution container. (Configuration 5) 5. The reaction apparatus of configuration 4, wherein the chemical liquid mounting portion is configured to hold a plurality of chemical liquid containers, and the heat transfer surface is configured to be in thermal contact with outer surfaces of the plurality of chemical liquid containers. (Configuration 6) The reaction device of any one of configurations 3 to 5, wherein the tip mounting portion is configured so that the pipette tip is placed at a temperature higher than that of the drug solution container, and the pipette tip placed on the tip mounting portion is attached to the pipetter portion. (Configuration 7) 7. The reaction apparatus of any one of claims 3 to 6, wherein a first chemical liquid container storing a first chemical liquid and a second chemical liquid container storing a second chemical liquid are placed on the chemical liquid placing section, and a pipette tip is placed on the tip placing section, the control unit controls the pipette unit to attach the pipette tip placed on the tip placing section to the pipette unit, insert the pipette tip that has aspirated a predetermined amount of the first chemical liquid from the first chemical liquid container into the second chemical liquid container, and mix the first chemical liquid and the second chemical liquid by alternately aspirating and dispensing the first chemical liquid and the second chemical liquid in the second chemical liquid container. (Configuration 8) 8. The reaction apparatus of claim 7, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the pipette tip into the second chemical liquid container. (Configuration 9) The reaction apparatus of configuration 8, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the pipette tip into the second chemical liquid container after inserting the pipette tip, which has aspirated a predetermined amount of the first chemical liquid from the first chemical liquid container, into the second chemical liquid container. (Configuration 10) The reaction apparatus of Configuration 8, wherein the control unit controls the pipetter unit so that the amount of the first chemical liquid supplied from the pipette tip to the second chemical liquid container is greater than the amount of the second chemical liquid stored in the second chemical liquid container before the first chemical liquid is supplied. (Configuration 11) The reaction device of any one of configurations 7 to 10, wherein the control unit controls the pipetter unit to perform an operation of aspirating and discharging at least a portion of the first chemical liquid and at least a portion of the second chemical liquid multiple times while the pipette tip is inserted into the second chemical liquid container. (Configuration 12) a first pipette tip and a second pipette tip are placed on the tip placement portion, and the first chemical liquid container, the second chemical liquid container, and a third chemical liquid container storing a third chemical liquid are placed on the chemical liquid placement portion; the first pipette tip placed on the tip placement section is attached to the pipetter unit, the first pipette tip having aspirated a first predetermined amount of the first chemical liquid from the first chemical liquid container is inserted into the second chemical liquid container, and the first pipette tip is used to alternately aspirate and discharge the first chemical liquid in the second chemical liquid container, thereby mixing the first chemical liquid and the second chemical liquid; Remove the first pipette tip from the pipetter unit; The reaction apparatus of configuration 7, wherein the control unit controls the pipetter unit to attach the second pipette tip placed on the tip placement unit to the pipetter unit, insert the second pipette tip that has aspirated a second predetermined amount of the first chemical liquid from the first chemical liquid container into the third chemical liquid container, and mix the first chemical liquid and the third chemical liquid by alternately aspirating and discharging the liquid using the second pipette tip in the third chemical liquid container. (Configuration 13) 13. The reaction apparatus of claim 12, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the first pipette tip into the second chemical liquid container. (Configuration 14) The reaction apparatus of configuration 13, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the first pipette tip into the second chemical liquid container after inserting the first pipette tip, which has aspirated the first predetermined amount of the first chemical liquid from the first chemical liquid container, into the second chemical liquid container. (Configuration 15) 13. The reaction apparatus of claim 12, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the second pipette tip into the third chemical liquid container. (Configuration 16) The reaction apparatus of configuration 15, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the second pipette tip into the third chemical liquid container after inserting the first pipette tip, which has aspirated the second predetermined amount of the first chemical liquid from the first chemical liquid container, into the third chemical liquid container. (Configuration 17) The reaction apparatus of configuration 12, wherein the control unit controls the pipetter unit to aspirate the first chemical liquid from the first chemical liquid container while the tip of the second pipette tip is inserted a predetermined distance from the opening of the first chemical liquid container. (Configuration 18) a first reaction vessel and a second reaction vessel are placed on the vessel placement unit, the first pipette tip is attached to the pipetter unit, and the first pipette tip is inserted into the second chemical liquid vessel, a first mixture obtained by mixing the first chemical liquid and the second chemical liquid is aspirated into the first pipette tip, and the first mixture is dispensed into the first reaction vessel; a first reaction vessel and a second reaction vessel are placed on the vessel placement section, the second pipette tip is attached to the pipetter section, and the second pipette tip is inserted into the third chemical liquid vessel, a second mixture obtained by mixing the first chemical liquid and the third chemical liquid is aspirated into the second pipette tip, and the second mixture is dispensed into the second reaction vessel; 13. The reaction apparatus of claim 12, wherein the control unit controls the pipetter unit. (Configuration 19) 19. The reaction device of any one of Configurations 12 to 18, wherein a reaction initiator liquid is stored in the first chemical liquid container, and different specimen liquids are stored in the second chemical liquid container and the third chemical liquid container. (Configuration 20) The control unit controls the pipetter unit to attach a pipette tip placed on the tip mounting unit, insert the pipette tip into the chemical liquid in a chemical liquid container placed on the chemical liquid mounting unit, and perform an operation of aspirating and discharging the chemical liquid multiple times while the pipette tip is inserted into the chemical liquid, and then pull the pipette tip out of the chemical liquid to aspirate a predetermined volume of gas, and then insert the pipette tip back into the chemical liquid and dispense a predetermined amount of the aspirated chemical liquid into a reaction container placed on the container mounting unit. (Configuration 21) The control unit controls the pipetter unit to perform the operation of aspirating and discharging the chemical liquid multiple times while the first reaction vessel and the second reaction vessel are placed on the vessel placement unit, inserting the pipette tip dispensed into the first reaction vessel into the chemical liquid in the chemical liquid container, and then withdrawing the pipette tip from the chemical liquid to aspirate a predetermined volume of gas, and then inserting the pipette tip back into the chemical liquid to dispense a predetermined amount of the aspirated chemical liquid into the second reaction vessel. (Configuration 22) 22. The reaction device of claim 20 or 21, wherein the chemical solution is at least one of a primary antibody solution and a secondary antibody solution whose fluorescent activity decreases when cooled. (Configuration 23) The pipetter unit has a pipetter hollow portion communicating with a hollow portion of the pipette tip and a piston for changing the volume of the pipetter hollow portion, The reaction apparatus of configuration 3, wherein the control unit controls the displacement amount of the piston of the pipetter unit according to the temperature of the chemical liquid placement unit on which the chemical liquid container in which the chemical liquid to be dispensed is stored is placed, so as to compensate for volume fluctuations of air during the process of aspirating and discharging by the pipetter unit. (Configuration 24) 24. The reaction apparatus according to any one of configurations 1 to 23, wherein the chemical liquid mounting section is configured to mount an observation liquid container that stores an observation liquid having a viscosity of 1.7 cp or more and 220 cp or less at 20°C. (Configuration 25) 25. The reaction device of claim 24, wherein the observation liquid has a refractive index of 1.40 or more and 1.46 or less. (Configuration 26) 26. The reaction apparatus of Configuration 24 or 25, wherein the control unit controls the pipetter unit so as to aspirate the observation liquid from the observation liquid container and then raise the pipette tip from the liquid surface of the observation liquid stored in the observation liquid container at a predetermined ascending speed. (Configuration 27) 27. The reactor of claim 26, wherein the predetermined rising speed is 20.0 mm / sec or less. (Configuration 28) The reaction apparatus of any one of configurations 1 to 27, wherein the pipetter unit includes a first pipetter unit including a first pipetter part that dispenses the chemical solution aspirated from the chemical solution container into the reaction container, and a second pipetter unit including a second pipetter part that aspirates the chemical solution stored in the reaction container and discharges it into a waste liquid part. (Configuration 29) The control unit controls the first pipette unit and the second pipette unit so that the second pipette unit aspirates the liquid stored in the reaction vessel and discharges it into the waste liquid section during a period overlapping with a period during which the first pipette unit is aspirating or mixing the chemical liquid, and moves the pipette tip attached to the first pipette unit that aspirated the chemical liquid to the reaction vessel after the pipette tip attached to the second pipette unit is separated from the reaction vessel. (Configuration 30) The reaction apparatus of configuration 29, wherein the control unit controls the first pipetter unit and the second pipetter unit so as to move the pipette tip attached to the first pipetter unit that has aspirated the chemical solution to the reaction vessel, and then dispense the chemical solution into the reaction vessel. (Configuration 31) The reaction apparatus of any one of configurations 1 to 30, wherein the control unit controls the pipetter unit so that after the chemical solution is aspirated from the chemical solution container into a pipette tip attached to the pipetter unit, the pipetter unit rises until the tip of the pipette tip is withdrawn from the chemical solution, and then aspirates a predetermined volume of gas while the tip of the pipette tip is withdrawn from the chemical solution. (Configuration 32) A reaction apparatus of configuration 3, wherein the control unit controls the pipette unit so that the amount of the chemical liquid dispensed does not change whether the chemical liquid placed on the chemical liquid placement unit is cooled or not. (Configuration 33) 1. A method for controlling a reaction apparatus for dispensing a sample liquid into a reaction vessel including an array plate having a substrate on which a plurality of spots containing a biological substance are arranged in an array, and for contacting the sample liquid with the plurality of spots to generate a reaction product between the biological substance and a substance in the sample liquid on the spots, the method comprising: a container placement section on which the reaction container is placed; a liquid medicine placement section on which a plurality of liquid medicine containers each containing the sample liquid and the liquid medicine are placed; a pipetter unit including a pipetter section to which a hollow pipet tip is attached and which draws and exhausts gas between the inside of the pipet tip and the pipetter section, and a position change section which changes the position of the pipetter section; a tip placement portion on which a pipette tip is placed; a control unit for controlling the dispensing operation of the pipetter unit; and adjusting the dispensing operation of the pipetter unit, and operating the pipetter unit with the adjusted dispensing operation. (Configuration 34) A control method for a reaction apparatus of configuration 33, wherein the step of adjusting the dispensing operation is performed so that the amount of chemical liquid aspirated from the chemical liquid container or the amount dispensed into the reaction container is adjusted depending on at least one of the type of chemical liquid, the state of the chemical liquid, the operating history of the pipette unit, and the state of the pipette tip. (Configuration 35) A program that runs on a computer to execute each step of the reactor control method of configuration 33 or 34. [Explanation of symbols]

[0129] S101: Reaction initiation step S102: Reaction termination step S103: Labeling process S104: Observation liquid introduction process S500: Reaction sequence S501: Reagent replacement S502: Reaction process S503: All processes completed? S510: Drain sequence (non-analyte liquid) S511: Drainage tip attached S512: Drainage suction S513: Discharge of waste fluid S514: Drain all plates? S515: Dispose of drainage tip S520: Dispensing sequence (antibody solution) S521: Dispensing tip attached S522: Chemical Mixing S523: Total discharge S524: Chemical suction S525: Air suction S526: Chemical solution discharge S527: Whole plate dispense? S528: Disposal of dispensing tip S720: Dispensing sequence (sample liquid) S722: Reaction start liquid suction S723: Sample mixing S724: Mixed liquid suction S726: Mixed liquid discharge S910: Drain sequence (non-analyte liquid) S920: Dispensing sequence (sample liquid) S922: Observation fluid suction S923: Slow pulling S926: Observation liquid discharge S1010: Drain sequence (sample fluid) S1020: Dispensing sequence (stop solution) S1022: Stop liquid suction S1024: Stop liquid discharge S1110: Drain sequence (non-analyte liquid) S1120: Dispensing sequence (cleaning solution) S1122: Cleaning fluid suction S1124: Discharge of cleaning solution 111: Process control information 112: Chemical control information 201: Container placement section 202: Chemical solution placement section 203: Liquid supply and drainage section 204: Mobile unit 205: Scanning unit 206:Optical system 207: Pipetter unit 210: Control unit 211:CPU 212:RAM 213:ROM 214: Storage device 215:Display device 216: Input device 219: Communication I / F 300: Reactor 301: Array plate 302: Bank part 303: Reaction vessel 305: Shaking mechanism 306: Table 310: Waste liquid section 311: Room temperature chemical solution holding section 312: Refrigerated reagent storage area 314: Dispensing tip mounting section 315: Dispensing tip disposal unit 316: Drainage tip mounting part 317: Drainage tip disposal part 321: Dispensing tip 322: Dispensing pipetter 323: Dispensing and moving part 324: Dispensing and moving unit 325: Dispensing and moving part 331: Drainage tip 332: Drainage pipetter 333: Drainage transfer section 334: Drainage transfer section 335: Drainage transfer section 341: Actuator (table moving part) 401: Room temperature chemical liquid container holder 402: Chemical container 403: Positioning unit 411: Refrigerated drug solution container holder 413: Peltier module 414: Heat transfer section 415: Insulation section 416:Protection Department 417: Heat transfer surface 418: Positioning unit 421: Pipette tip holder 422: Pipette tip 601:Predetermined distance 611:Antibody solution container 613: Residual liquid 614: Anti-drip air 811: Reaction start liquid container 812: Reaction start solution 813:Predetermined distance 821: Sample liquid container 822: Sample liquid 831: Mixture (reaction stop solution) 832: Anti-drip air 1012: Bus

Claims

1. A reaction device for dispensing a sample liquid into a reaction vessel including an array plate having a substrate on which a plurality of spots containing a biological substance are arranged in an array, and for producing a reaction product between the biological substance and a substance in the sample liquid on the spots by bringing the sample liquid into contact with the plurality of spots, a container placement section for placing the reaction container; a liquid medicine placement unit for placing a plurality of liquid medicine containers each containing a sample liquid and a liquid medicine; a pipetter unit including a pipetter section to which a hollow pipet tip is attached and which draws and exhausts gas between the inside of the pipet tip and the pipetter section, and a position change section which changes the position of the pipetter section; a tip placement portion on which the pipette tip is placed; a control unit that controls the pipette unit so that a dispensing operation is performed in which at least one of the amount of chemical liquid aspirated from the chemical liquid container, the amount of chemical liquid dispensed into the reaction container, and the position of the pipette unit is adjusted depending on at least one of the type of chemical liquid, the state of the chemical liquid, the operating history of the pipette unit, and the state of the pipette tip.

2. The reaction apparatus according to claim 1 , wherein the chemical solution placement unit is configured to hold a plurality of chemical solution containers.

3. The reaction apparatus according to claim 1 , wherein the chemical solution placement unit includes a cooling unit for cooling the chemical solution container to a temperature lower than room temperature.

4. The reaction apparatus according to claim 3 , wherein the cooling unit has a heat transfer surface that is in thermal contact with an outer surface of the chemical solution container.

5. 5. The reaction apparatus according to claim 4, wherein the chemical solution mounting portion is configured to hold a plurality of chemical solution containers, and the heat transfer surface is configured to be in thermal contact with outer surfaces of the plurality of chemical solution containers.

6. 4. The reaction apparatus according to claim 3, wherein the tip mounting portion is configured so that a pipette tip is mounted at a temperature higher than that of the chemical solution container, and the pipette tip mounted on the tip mounting portion is attached to the pipetter portion.

7. 4. The reaction apparatus according to claim 3, wherein the control unit controls the pipetter unit so that, with a first chemical liquid container storing a first chemical liquid and a second chemical liquid container storing a second chemical liquid mounted on the chemical liquid mounting unit and a pipette tip mounted on the tip mounting unit, the control unit attaches the pipette tip mounted on the tip mounting unit to the pipette unit, inserts the pipette tip that has aspirated a predetermined amount of the first chemical liquid from the first chemical liquid container into the second chemical liquid container, and alternately aspirates and discharges the first chemical liquid and the second chemical liquid in the second chemical liquid container.

8. The reaction apparatus according to claim 7 , wherein the control unit controls the pipetter unit to supply the first chemical liquid from the pipette tip into the second chemical liquid container.

9. 9. The reaction apparatus according to claim 8, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the pipette tip into the second chemical liquid container after inserting the pipette tip that has aspirated a predetermined amount of the first chemical liquid from the first chemical liquid container into the second chemical liquid container.

10. 9. The reaction apparatus according to claim 8, wherein the control unit controls the pipette unit so that the amount of the first chemical liquid supplied from the pipette tip to the second chemical liquid container is greater than the amount of the second chemical liquid stored in the second chemical liquid container before the first chemical liquid is supplied.

11. The reaction apparatus of claim 7, wherein the control unit controls the pipette unit to perform multiple operations of aspirating and discharging at least a portion of the first chemical liquid and at least a portion of the second chemical liquid while the pipette tip is inserted into the second chemical liquid container.

12. a first pipette tip and a second pipette tip are placed on the tip placement portion, and the first chemical liquid container, the second chemical liquid container, and a third chemical liquid container storing a third chemical liquid are placed on the chemical liquid placement portion; the first pipette tip placed on the tip placement section is attached to the pipetter unit, the first pipette tip having aspirated a first predetermined amount of the first chemical liquid from the first chemical liquid container is inserted into the second chemical liquid container, and the first pipette tip is used to alternately aspirate and discharge the first chemical liquid in the second chemical liquid container, thereby mixing the first chemical liquid and the second chemical liquid; Remove the first pipette tip from the pipetter unit; 8. The reaction apparatus according to claim 7, wherein the control unit controls the pipetter unit to attach the second pipette tip placed on the tip placement portion to the pipetter unit, insert the second pipette tip that has aspirated a second predetermined amount of the first chemical liquid from the first chemical liquid container into the third chemical liquid container, and mix the first chemical liquid and the third chemical liquid by alternately aspirating and discharging the first chemical liquid and the third chemical liquid in the third chemical liquid container using the second pipette tip.

13. The reaction apparatus according to claim 12 , wherein the control unit controls the pipetter unit to supply the first chemical liquid from the first pipette tip into the second chemical liquid container.

14. The reaction apparatus according to claim 13, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the first pipette tip into the second chemical liquid container after inserting the first pipette tip, which has aspirated the first predetermined amount of the first chemical liquid from the first chemical liquid container, into the second chemical liquid container.

15. The reaction apparatus according to claim 12 , wherein the control unit controls the pipetter unit to supply the first chemical liquid from the second pipette tip into the third chemical liquid container.

16. The reaction apparatus of claim 15, wherein the control unit controls the pipetter unit to supply the first chemical liquid from the second pipette tip into the third chemical liquid container after inserting the first pipette tip, which has aspirated the second predetermined amount of the first chemical liquid from the first chemical liquid container, into the third chemical liquid container.

17. The reaction apparatus of claim 12, wherein the control unit controls the pipetter unit to aspirate the first chemical liquid from the first chemical liquid container while the tip of the second pipette tip is inserted a predetermined distance from the opening of the first chemical liquid container.

18. a first mixed liquid obtained by mixing the first chemical liquid and the second chemical liquid is aspirated into the first pipette tip while a first reaction vessel and a second reaction vessel are placed on the vessel placement section, the first pipette tip is attached to the pipetter section, and the first pipette tip is inserted into the second chemical liquid vessel; and a first reaction vessel and a second reaction vessel are placed on the vessel placement section, the second pipette tip is attached to the pipetter section, and the second pipette tip is inserted into the third chemical liquid vessel, a second mixture obtained by mixing the first chemical liquid and the third chemical liquid is aspirated into the second pipette tip, and the second mixture is dispensed into the second reaction vessel; The reaction device according to claim 12, wherein the control unit controls the pipetter unit.

19. 13. The reaction device according to claim 12, wherein a reaction initiator liquid is stored in the first chemical liquid container, and different specimen liquids are stored in the second and third chemical liquid containers.

20. 7. The reaction apparatus according to claim 6, wherein the control unit controls the pipetter unit to: attach a pipette tip placed on the tip mounting unit; insert the pipette tip into the chemical liquid in a chemical liquid container placed on the chemical liquid mounting unit; perform an operation of aspirating and discharging the chemical liquid multiple times; then withdraw the pipette tip from the chemical liquid to aspirate a predetermined volume of gas; and then insert the pipette tip back into the chemical liquid to dispense a predetermined amount of the aspirated chemical liquid into a reaction container placed on the container mounting unit.

21. 21. The reaction apparatus according to claim 20, wherein the control unit controls the pipetter unit so that, with a first reaction vessel and a second reaction vessel placed on the vessel placement unit, the pipette tip dispensed into the first reaction vessel is inserted into the chemical liquid in the chemical liquid container, and the pipette tip is then inserted into the chemical liquid, and the pipette tip is then withdrawn from the chemical liquid to aspirate a predetermined volume of gas, and the pipette tip is then reinserted into the chemical liquid to dispense a predetermined amount of the aspirated chemical liquid into the second reaction vessel.

22. 21. The reaction device according to claim 20, wherein the chemical solution is at least one of a primary antibody solution and a secondary antibody solution whose fluorescent activity decreases when cooled.

23. The pipetter unit has a pipetter hollow portion communicating with a hollow portion of the pipette tip and a piston for changing the volume of the pipetter hollow portion, The reaction apparatus according to claim 3, wherein the control unit controls the displacement amount of the piston of the pipette unit so as to compensate for changes in air volume during the process of aspirating and discharging the pipette unit, depending on the temperature of the chemical liquid loading unit on which the chemical liquid container in which the chemical liquid to be dispensed is stored is loaded.

24. 2. The reaction apparatus according to claim 1, wherein an observation liquid container for storing an observation liquid having a viscosity of 1.7 cp or more and 220 cp or less at 20° C. is placed on the chemical liquid placement part.

25. 25. The reaction device according to claim 24, wherein the observation liquid has a refractive index of 1.40 or more and 1.46 or less.

26. 25. The reaction apparatus according to claim 24, wherein the control unit controls the pipetter unit so that, after aspirating the observation liquid from the observation liquid container, the pipette tip is raised from the liquid surface of the observation liquid stored in the observation liquid container at a predetermined rising speed.

27. 27. The reactor of claim 26, wherein the predetermined rising speed is 20.0 mm / sec or less.

28. 2. The reaction apparatus according to claim 1, wherein the pipetter unit includes: a first pipetter unit including a first pipetter part that dispenses the chemical solution aspirated from the chemical solution container into the reaction container; and a second pipetter unit including a second pipetter part that aspirates the chemical solution stored in the reaction container and discharges it into a waste liquid section.

29. 29. The reaction apparatus according to claim 28, wherein the control unit controls the first pipette unit and the second pipette unit so that the second pipette unit aspirates the liquid stored in the reaction vessel and discharges it into the waste liquid section during a period overlapping with a period during which the first pipette unit is aspirating or mixing the chemical liquid, and moves the pipette tip attached to the first pipette unit that aspirated the chemical liquid to the reaction vessel after the pipette tip attached to the second pipette unit is separated from the reaction vessel.

30. 30. The reaction apparatus of claim 29, wherein the control unit controls the first pipetter unit and the second pipetter unit so as to move a pipette tip attached to the first pipetter unit that has aspirated the chemical solution to the reaction vessel, and then dispense the chemical solution into the reaction vessel.

31. 2. The reaction apparatus according to claim 1, wherein the control unit controls the pipetter unit so that after the chemical solution is aspirated from the chemical solution container into a pipette tip attached to the pipetter unit, the pipetter unit rises until the tip of the pipette tip is withdrawn from the chemical solution, and then aspirates a predetermined volume of gas while the tip of the pipette tip is withdrawn from the chemical solution.

32. The reaction apparatus according to claim 3, wherein the control unit controls the pipette unit so that the amount of the chemical liquid dispensed does not change whether the chemical liquid placed on the chemical liquid placement unit is cooled or not.

33. 1. A method for controlling a reaction apparatus for dispensing a sample liquid into a reaction vessel including an array plate having a substrate on which a plurality of spots containing a biological substance are arranged in an array, and for contacting the sample liquid with the plurality of spots to generate a reaction product between the biological substance and a substance in the sample liquid on the spots, the method comprising: a container placement section on which the reaction container is placed; a liquid medicine placement section on which a plurality of liquid medicine containers each containing the sample liquid and the liquid medicine are placed; a pipetter unit including a pipetter section to which a hollow pipet tip is attached and which draws and exhausts gas between the inside of the pipet tip and the pipetter section, and a position change section which changes the position of the pipetter section; a tip placement portion on which a pipette tip is placed; a control unit for controlling the dispensing operation of the pipetter unit; and adjusting the dispensing operation of the pipetter unit, and operating the pipetter unit with the adjusted dispensing operation.

34. 34. The method for controlling a reaction apparatus according to claim 33, wherein the step of adjusting the dispensing operation is performed so that the amount of chemical liquid aspirated from the chemical liquid container or the amount dispensed into the reaction container is adjusted depending on at least one of the type of chemical liquid, the state of the chemical liquid, the operating history of the pipette unit, and the state of the pipette tip.

35. A program that runs on a computer to execute each step of the method for controlling a reaction apparatus according to claim 33 or 34.

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