WO2019189753A1 - 全自動遺伝子検査装置 - Google Patents
全自動遺伝子検査装置 Download PDFInfo
- Publication number
- WO2019189753A1 WO2019189753A1 PCT/JP2019/013985 JP2019013985W WO2019189753A1 WO 2019189753 A1 WO2019189753 A1 WO 2019189753A1 JP 2019013985 W JP2019013985 W JP 2019013985W WO 2019189753 A1 WO2019189753 A1 WO 2019189753A1
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- WIPO (PCT)
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- nucleic acid
- unit
- cell
- injection
- fully automatic
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1002—Reagent dispensers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/02—Burettes; Pipettes
- B01L3/021—Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00584—Control arrangements for automatic analysers
- G01N35/00722—Communications; Identification
- G01N35/00732—Identification of carriers, materials or components in automatic analysers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1079—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices with means for piercing stoppers or septums
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0631—Purification arrangements, e.g. solid phase extraction [SPE]
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/06—Fluid handling related problems
- B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
- B01L2200/0663—Stretching or orienting elongated molecules or particles
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/04—Closures and closing means
- B01L2300/041—Connecting closures to device or container
- B01L2300/044—Connecting closures to device or container pierceable, e.g. films, membranes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0672—Integrated piercing tool
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L7/00—Heating or cooling apparatus; Heat insulating devices
- B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6844—Nucleic acid amplification reactions
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
- G01N2035/00099—Characterised by type of test elements
- G01N2035/00158—Elements containing microarrays, i.e. "biochip"
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
Definitions
- the present invention relates to a fully automatic genetic test apparatus. More specifically, a process of extracting and purifying nucleic acid contained in a specimen, a process of injecting a solution containing nucleic acid into a test chip, and a process of amplifying and detecting nucleic acid can be performed fully automatically.
- the present invention relates to a miniaturized fully automatic genetic testing apparatus that can be used nearby.
- genetic testing is mainly used for diagnosis of infectious diseases.
- the doctor conducts the genetic test, identifies the infectious disease in consideration of the result of the genetic test that has been found, and performs appropriate treatment.
- genetic testing is expected to be applied to cancer diagnosis and companion diagnosis.
- next-generation sequencers are being developed, and the speed of genome analysis is increasing. For this reason, genetic testing has become a promising testing tool for cancer diagnosis and companion diagnosis.
- genetic testing still requires a lot of time and a lot of cost to obtain results.
- Examples of genetic testing methods employed for genetic testing include real-time PCR methods that measure nucleic acid amplification processes in real time and real-time LAMP (Loop-Mediated Isothermal Amplification) methods.
- the real-time LAMP method has an advantage in that the gene amplification efficiency is extremely high.
- genetic testing apparatuses to which genetic testing methods such as real-time PCR and real-time LAMP are applied have been commercialized. In general, such a genetic test apparatus performs a pretreatment process for extracting and purifying nucleic acid from a specimen by an extraction and purification apparatus provided separately from the test apparatus, or a skilled operator performs the test. It is carried out by operating the device manually.
- Patent Document 1 An integrated apparatus for performing nucleic acid extraction and diagnostic tests on a large number of biological samples has been proposed (for example, Patent Document 1).
- This integrated device is a system for amplifying and detecting nucleic acids contained in an extracted sample, and for a large number of samples of nucleotides of interest in a microfluidic channel (microchannel), PCR (polymerase chain) Reaction) to detect nucleotides.
- the integrated apparatus for performing nucleic acid extraction and diagnostic test described in Patent Document 1 and the like is configured to operate in association with a complementary rack, and the complementary rack is suitable for detailed inspection and diagnostic analysis. It is configured to accept multiple biological samples in form and multiple holders with various reagents, pipette tips, containers.
- the integrated apparatus is a genetic test apparatus adopting a self-contained type in which a liquid dispenser for achieving extraction from a nucleic acid and a detection unit are integrated. That is, since the liquid dispenser provided in the integrated device does not have a robust structure, the nucleic acid contained in the sample is affected by disturbance in an environment where genetic testing is performed.
- the conventional genetic testing apparatus is a high-throughput screening type large-sized genetic testing apparatus, and has specifications suitable only for genetic testing departments, genetic testing companies, etc. of large hospitals. For this reason, the genetic testing device cannot be installed in a doctor's examination room, and is not a genetic testing device capable of performing genetic testing at a position close to the patient.
- the object of the present invention is to fully automatically execute a step of extracting and purifying nucleic acid from a specimen, a step of injecting a solution containing nucleic acid into a test chip, and a step of amplifying and detecting nucleic acid, and It is an object of the present invention to provide a miniaturized fully automatic genetic testing apparatus capable of performing genetic testing at a position close to a patient while a doctor examines the patient. Another object of the present invention is to provide a fully automatic genetic test apparatus capable of handling various specimens.
- the present inventors have injected a solution containing the nucleic acid into a test unit having a first unit for extracting and purifying nucleic acid from a specimen and a plurality of reaction fields for amplifying the nucleic acid. 2 units and a third unit for optically detecting the nucleic acid amplified in the reaction field, the genetic test can be performed fully automatically, and the doctor examines the patient,
- the present inventors have found that a miniaturized fully automatic genetic test apparatus capable of performing a genetic test at a position close to a patient can be provided, thereby completing the present invention.
- the present invention includes the following technical matters.
- the first unit includes a pipetting mechanism for moving the reagent between a reaction cell and a cartridge including a plurality of reagents used for extraction and purification of the nucleic acid, and a process for pretreating the reaction cell.
- the processing mechanism includes at least one processing unit selected from a heating / cooling processing unit, a stirring processing unit, and a magnetic field application processing unit .
- the cartridge includes a cell with a seal for individually storing the plurality of reagents, a first cell for storing a piercing tip for opening a hole in the seal, and a pipette tip for moving the reagent. And a third cell for storing an injection chip for injecting a solution containing the nucleic acid into the reaction field. .
- the pipetting mechanism includes a first mechanism that opens a hole in the seal by bringing the piercing tip into contact with the seal; A second mechanism for removing the piercing tip from the pipetting mechanism, attaching the pipette tip to the pipetting mechanism, and moving the reagent to the reaction cell (3) Fully automatic genetic testing device described in 1.
- the pipetting mechanism includes the third mechanism with the piercing tip attached thereto, and the injection tip for injecting the solution containing the nucleic acid from the injection hole of the test tip into the reaction field through the injection needle.
- a control mechanism for detecting position information of the tip of the injection needle from at least two directions and correcting the position of the tip of the injection needle at the position of the injection hole based on the position information is provided.
- the inspection chip includes a plurality of flow paths that connect the injection hole and the reaction field, and performs an amplification reaction of the nucleic acid in the reaction field. Fully automatic genetic testing device.
- the cartridge includes a cartridge base having a substantially circular plate shape, Drive with which the sealed cell, the first cell, the second cell, and the third cell are arranged on a circumference that is an outer edge portion of the cartridge base body, and the pipetting mechanism can be moved in the ⁇ direction.
- the fully automatic genetic testing device according to (3) further comprising: a mechanism; and a rotation mechanism capable of rotating the cartridge on a trajectory along which the pipetting mechanism moves.
- a step of extracting and purifying nucleic acid from a specimen, a step of injecting a solution containing nucleic acid into a test chip, and a step of amplifying and detecting nucleic acid can be performed fully automatically, and a doctor can Provided is a fully automatic genetic testing apparatus capable of performing genetic testing at a position close to a patient while examining the patient.
- the pre-processing unit having a robust structure without integrating the pre-processing unit and the optical testing unit included in the genetic testing device, various samples can be used.
- a fully automatic genetic testing device capable of handling is provided.
- FIG. 1 is a model diagram showing a configuration of a fully automatic genetic test apparatus 1.
- FIG. (A) It is the perspective view which showed the structure of the cartridge.
- FIG. 4B is a top view of the cartridge.
- C) It is sectional drawing of a cartridge.
- D) It is the perspective view which showed the structure of the reaction cell.
- A) It is the model which showed the structure of the 1st unit.
- B) It is an enlarged view of each process part of a pre-processing mechanism.
- FIG. 4 is a model diagram showing a relationship between a cartridge and a piercing chip. It is the model figure which showed the relationship between a cartridge and the pipette tip which moves a reagent. It is the model figure which showed operation
- FIG. 1 is a perspective view showing an outline of the genetic test system D.
- the genetic test system D includes a master unit 2 and a test unit 1.
- the master unit 2 and the test unit 1 are electrically connected, and the master unit 2 and the test unit 1 exchange input data and inspection results between each other.
- 1 is a type in which the master unit 2 and the test unit 1 are separated, but the present invention is not limited to this.
- the master unit 2 having a control unit may be incorporated into the test unit 1 to form an integrated genetic test system D.
- Master unit 2 controls genetic test system D.
- the master unit 2 inputs power on / off of the genetic test system D, login and logout, sample data, test items for genetic testing, and displays measured test results and the like on the screen.
- the user of the genetic test system D touches the screen of the master unit 2 to start genetic testing, for example.
- a genetic test is executed inside the test unit 1.
- FIG. 2 is a perspective view showing the internal structure of the drawer portion of the test unit 1 provided in the genetic test system D.
- FIG. A lever is attached to the front surface of the test unit 1.
- the drawer provided at the lower portion of the test unit 1 is locked at the position where the lever is in the horizontal direction (in a collapsed state).
- the drawer provided at the lower part of the test unit 1 is unlocked at the position where the lever is vertically oriented.
- the user of the genetic test system D can pull out the inside of the test unit 1 by releasing the lock of the drawer.
- the user of the genetic test system D pulls up the lever of the test unit 1 from the horizontal position to the vertical position.
- the drawer portion of the test unit 1 can be taken out, a sample can be set, and the genetic test can be executed.
- the technical feature of the genetic test system D resides in the fully automatic genetic test apparatus 1 as a test unit.
- the fully automatic genetic test apparatus 1 of the present invention will be described.
- FIG. 3 is a model diagram showing the configuration of the fully automatic genetic test apparatus 1.
- the fully automatic genetic test apparatus 1 injects a solution containing the nucleic acid into a test unit having a first unit for extracting and purifying nucleic acid from a specimen and a plurality of reaction fields for amplifying the nucleic acid. A second unit; and a third unit for optically detecting the nucleic acid amplified in the reaction field.
- the first unit corresponds to the pretreatment unit 10 for extracting and purifying nucleic acid contained in the specimen.
- the second unit corresponds to the injection unit 20 for injecting the solution containing the nucleic acid extracted and purified by the first unit into the test chip.
- the third unit corresponds to the amplification detection unit 30 that optically detects nucleic acid amplified by the second unit.
- the first unit, the second unit, and the third unit interact with each other to execute a fully automatic genetic test.
- the first unit is a unit for extracting and purifying nucleic acid from a specimen.
- the cartridge 110 includes a plurality of reagents used for extracting and purifying nucleic acid, a reaction cell 120, a pipetting mechanism 130 for moving the reagent, and a reaction cell 120.
- a pre-processing mechanism 140 for pre-processing is provided.
- FIG. 4A is a perspective view showing the configuration of the cartridge 110 provided in the first unit.
- FIG. 4B is a top view of the cartridge 110.
- FIG. 4C is a cross-sectional view of the cartridge 110.
- FIG. 4D is a perspective view showing the configuration of the reaction cell 120 provided in the first unit.
- the cartridge 110 has a basic structure of a cartridge base 111 having a plate-like rectangular shape.
- a reagent cell 113 a with a seal is fitted into a plurality of cartridge base holes 112 provided in the cartridge base 111.
- the sealed reagent cell 113a is a cell for individually storing reagents necessary for extracting and purifying nucleic acids.
- the reagent cell 113a with a seal has a cylindrical shape.
- the reagent cell 113a with a seal has an annular flange 114a provided at the upper edge of the cell.
- the outer diameter of the flange 114 a is larger than the outer diameter of the plurality of cartridge base holes 112 provided in the cartridge base 111. Therefore, the sealed reagent cell 113a is fixed to the cartridge base 111 by the flange 114a.
- the portion of the reagent cell 113a with the seal that holds the reagent is located on the back surface of the cartridge base 111.
- the cartridge 110 shown in FIG. 4 (A) includes ten reagent cells with seals 113 to 113i with seals.
- the number of the reagent cells 113 with seals can be appropriately set according to the shape and size of the cartridge base 111.
- the number of reagent cells 113 with seal is not particularly limited.
- the arrangement of the reagent cell 113 with the seal is not particularly limited, and can be set as appropriate according to the type of reagent, the concentration of the reagent, and the like. It is preferable that the arrangement of the reagent cell 113 with the seal is provided with regularity from the viewpoint of operability for performing the genetic test.
- the cartridge 110 shown in FIG. 4A has flanges 114b to 114i corresponding to the reagent cells 113b to 113i with seals, respectively.
- a seal 115 for storing the reagent is attached to the opening of the reagent cell 113 with a seal. Since the opening of the reagent cell 113 with seal is closed by the seal 115, the inside of the reagent cell 113 with seal is sealed. That is, the seal 115 functions as a lid of the reagent cell 113 with a seal. The reagent held in the sealed reagent cell 113 by the seal 115 does not come into contact with the outside air. For this reason, in each step in which the reagent held in the reagent cell 113 with the seal performs a genetic test, it can be avoided that impurities are mixed into the reagent, and the reagent is oxygen, water, carbon dioxide, etc. Can be avoided by reacting with.
- the seal 115 shown in FIG. 4A covers the surface of the cartridge base 111 in which the two reagent cells 113 with seal, the piercing tip 117, the injection tip 118, and the pipette tip 119 are housed. . Further, the seal 115 shown in FIG. 4A covers a two-dimensional barcode used for identifying the cartridge base 111. That is, the seal 115 has a role of hiding the two-dimensional barcode.
- the seal 115 is in close contact with the surface of the cartridge base 111 and the flange 114.
- the material that can be adopted as the seal 115 needs to be able to be in close contact with the material constituting the cartridge base 111 and the flange 114.
- the material that can be used as the seal 115 needs to be suitable for the temperature, pressure, and humidity when the genetic test is performed, and to have an appropriate mechanical strength.
- the seal 115 requires sufficient adhesion with the cartridge base 111. The reason is that if the adhesive force between the seal 115 and the cartridge base 111 is not sufficient, the entire seal 115 is drawn into the inside of the reagent cell 113 with a seal when the tip of a piercing chip 117 described later contacts the seal 115. Because it will be.
- the seal 115 includes a synthetic rubber such as silicone rubber, nitrile rubber, acrylic rubber, and ethylene propylene rubber, a thin film made of plastic such as polypropylene, polyethylene, polyethylene terephthalate (PET), polystyrene, and tetrafluoroethylene resin, aluminum.
- a metal thin film such as a thin film can be exemplified.
- the seal 115 may be composed of a single layer thin film, or may be a multilayer thin film composed of a plurality of single layers made of the same or different materials. For example, a multilayer thin film composed of an aluminum layer and a polyethylene terephthalate (PET) layer may be used.
- the seal 115 has a thickness capable of forming a hole when the tip of the piercing tip 117 penetrates.
- the thickness of the seal 115 is not particularly limited as long as the sealing property of the reagent cell 113 with the seal can be maintained and a hole can be opened by the tip of the piercing tip 117.
- the seal 115 may be transparent, translucent, or opaque.
- the opening of the sealed reagent cell 113 can be recognized from the outside even after the seal 115 is attached to the opening of the sealed reagent cell 113. it can.
- the seal 115 attached to the opening of the reagent cell 113 with a seal may be marked with a symbol, number, color, or the like.
- a two-dimensional barcode 35 for identifying the cartridge base 111 may be added to the cartridge 110. In this case, the seal 115 may be opaque.
- the first cell 1161 is fitted into one chip hole 116 provided in the cartridge base 111.
- the first cell 1161 houses a piercing chip 117 for making a hole in the seal 115 of the reagent cell 113 with a seal.
- the tip of the piercing tip 117 has a conical shape and a sharp shape. For this reason, a hole through which the pipette tip 119 can be inserted is formed in the seal 115 by bringing the tip of the piercing tip 117 into contact with the surface of the seal 115 and applying pressure.
- a case 1191 for housing the piercing chip 117 is shown. That is, the first cell 1161 may have a case 1191 for storing the piercing chip 117 installed on the cartridge base 111.
- the second cell 1162 is fitted into the other one chip hole 116 provided in the cartridge base 111.
- the second cell 1162 stores an injection chip 118 for holding a solution containing a nucleic acid and injecting the solution containing the nucleic acid into a test chip 220 described later.
- a case 1191 for housing the injection chip 118 is shown. That is, the second cell 1162 may have a case 1191 for housing the injection chip 118 installed on the cartridge base 111.
- a third cell 1163 is fitted in another chip hole 116 provided in the cartridge base 111.
- the third cell 1163 accommodates a pipette tip 119 for aspirating the reagent held in the sealed reagent cell 113 and moving the reagent to the reaction cell 120.
- a case 1191 for storing the pipette tip 119 is shown. That is, the third cell 1163 may have a case 1191 for storing the pipette tip 119.
- the number of the chip holes 116 provided in the cartridge base 111 is not particularly limited, and can be appropriately set as necessary.
- FIG. 4B is a top view of the cartridge 110.
- the seal 115 covers the surface of the cartridge base 111 in which the two reagent cells 113 with a seal, the piercing tip 117, the injection tip 118, and the pipette tip 119 are housed. .
- the seal 115 covers a two-dimensional bar code for identifying the cartridge base 111.
- the seal 115 shown in FIG. 4B covers a part of the cartridge base 111, but is not limited to this.
- the seal 115 may cover the entire surface of the cartridge base 111.
- two or more kinds of sheets may be adopted as the seal 115. Two or more types of sheets may be attached to the respective surfaces of the cartridge base 111 in which the reagent cell 113 with a seal, the piercing tip 117, the injection tip 118, and the pipette tip 119 are stored.
- FIG. 4C is a cross-sectional view of the cartridge 110.
- the cartridge 110 includes a piercing tip 117, an injection tip 118, and a pipette tip 119 in order from the left side.
- the arrangement of the piercing tip 117, the injection tip 118, and the pipette tip 119 is not particularly limited as long as there is no inconvenience in operation.
- the cartridge 110 shown in FIG. 4C includes a case 1191 for storing the piercing tip 117, a case 1191 for storing the injection tip 118, and a case 1191 for storing the pipette tip 119. As shown in FIG.
- the sheet 115 is provided to prevent the piercing tip 117, the injection tip 118, and the pipette tip 119 from falling off the cartridge base 111.
- An injection needle 1181 for injecting a reagent is provided at the tip of the injection chip 118.
- the injection needle 1181 is housed inside the case 1191. For this reason, the injection needle 1181 does not come into contact with the outside air.
- the reaction cell 120 shown in FIG. 4D is a cell into which a sample to be subjected to genetic testing is introduced.
- the reagent held in the sealed reagent cell 113 provided in the cartridge 110 is introduced into the reaction cell 120.
- the specimen reacts with the reagent.
- the nucleic acid contained in the sample is extracted and purified.
- the first unit includes a pipetting mechanism 130 for moving the reagent held in the sealed reagent cell 113 between the cartridge 110 and the reaction cell 120, and a pretreatment mechanism 140 for pretreating the reaction cell 120. I have.
- FIG. 5 is a model diagram showing the configuration of the first unit including the pipetting mechanism 130, the reaction cell 120, and the pretreatment mechanism 140.
- the reagent held in the sealed reagent cell 113 provided in the cartridge 110 is sucked by the pipetting mechanism 130 (pipette tip 119), introduced into the reaction cell 120, and then introduced into the pretreatment mechanism 140. The outline until setting is shown.
- the pipetting mechanism 130 includes a pipette tip 119, a pipette head 131, and a drive unit 132.
- a pipette tip 119 is connected to the lower end portion of the pipette head 131.
- the pipette head 131 has a convex portion at the lower tip.
- Various tips such as a pipette tip 119 can be connected to the convex portion.
- the pipette head 131 is connected to the drive unit 132.
- the drive unit 132 can freely move in the XY plane including the plane of the cartridge 110. Further, the drive unit 132 can freely move in the Z-axis direction including the vertical direction of the cartridge 110. Further, the driving unit 132 can move on the XY plane including the opening of the reaction cell 120. The drive unit 132 can move in the Z-axis direction including the vertical direction of the opening of the reaction cell 120. That is, the driving unit 132 can perform three-dimensional driving on the XYZ axes.
- the driving unit 132 is controlled by the control unit 133.
- the control unit 133 is not particularly limited as long as it is a member that can move the drive unit 132 to a position where an operation necessary for genetic testing can be performed. Examples of the control unit 133 include an XYZ robot and a three-dimensional robot.
- the first unit includes a pretreatment mechanism 140 for pretreating nucleic acid contained in the sample introduced into the reaction cell 120.
- the pretreatment mechanism 140 has processing units for performing operations necessary for extracting and purifying the nucleic acid introduced into the reaction cell 120.
- the pretreatment mechanism 140 includes a heating / cooling processing unit 141, a stirring processing unit 142, and a magnetic field application processing unit 143.
- the pre-processing mechanism 140 includes at least one processing unit selected from the heating / cooling processing unit 141, the stirring processing unit 142, and the magnetic field application processing unit 143.
- the processing unit included in the preprocessing mechanism 140 can be appropriately set according to the processing necessary for the genetic test.
- the heating / cooling processing unit 141 includes a heater 1411 necessary for heating or cooling the reaction cell 120 therein.
- the stirring processing unit 142 is supported by the support member 142.
- the magnetic field application processing unit 143 includes therein a magnet 1431 and the like necessary for applying a magnetic field to the reaction cell 120.
- FIG. 5B is an enlarged view of each processing unit.
- the reaction cell 120 holding the nucleic acid and the reagent is inserted into the stirring processing unit 142.
- the agitation processing unit 142 is connected to the support member 144.
- the connecting portion 1441 of the support member 144 rotates, the stirring processing portion 142 rotates and the reaction cell 120 also rotates.
- the connecting portion 1441 employs a drive motor or the like for generating torque necessary for rotation.
- the stirring processing unit 142 can appropriately set the rotation direction, the rotation speed, the rotation form, and the like as necessary.
- the rotation performed by the stirring processing unit 142 can be set to eccentric rotation.
- the stirring processing unit 142 rotates eccentrically, the stirring effect can be obtained in about one-tenth of the time compared to pipetting stirring that has been conventionally performed.
- the stirring processing unit 142 rotates eccentrically, it can contribute to shortening the total process required for the genetic test.
- FIG. 6 is a model diagram showing the relationship between the cartridge 110 having a plurality of reagents and the piercing chip 117.
- the pipette head 131 stops at a predetermined position in the cartridge 110 when the driving unit 132 moves.
- the pipette head 131 performs positioning above the tip hole 116 in which the piercing tip 117 provided in the cartridge 110 is accommodated.
- the pipette head 131 determines the position of the XY plane corresponding to the upper part of the tip hole 116 in which the piercing tip 117 is accommodated, and stops.
- the pipette head 131 descends downward in the Z-axis direction.
- the tip of the pipette head 131 is fitted with the piercing tip 117.
- the tip of the pipette head 131 is connected to the piercing tip 117.
- the pipette head 131 can pick up the piercing tip 117.
- the pipette head 131 to which the piercing tip 117 is connected is defined as the first mechanism 134.
- the first mechanism 134 moves upward in the Z-axis direction. Subsequently, the first mechanism 134 performs positioning above the sealed reagent cell 113 in which the reagent provided in the cartridge 110 is held. The first mechanism 134 determines the position of the XY plane corresponding to the upper side of the reagent cell 113 with a seal and stops.
- the first mechanism 134 descends downward in the Z-axis direction. As the first mechanism 134 descends downward in the Z-axis direction, the tip of the piercing tip 117 of the first mechanism 134 contacts the seal 115 of the reagent cell 113 with seal. The first mechanism 134 further descends in the Z-axis direction downward. As a result, a predetermined pressure is applied to the seal 115, and the first mechanism 134 opens a hole having a predetermined hole diameter in the seal 115. The hole opened in the seal 115 by the first mechanism 134 is large enough to allow the pipette tip 119 to be inserted therethrough. As will be described later, the reagent is aspirated by the pipette tip 119 using the hole formed in the seal 115.
- the first mechanism 134 after making a hole in the seal 115, returns the piercing tip 117 attached to the pipette head 131 to the tip hole 116 in which the piercing tip 117 was accommodated. When it is necessary to open a plurality of holes in the seal 115, the operation of moving the first mechanism 134 is repeated. Next, the tip of the pipette head 131 prepares to attach the pipette tip 119.
- FIG. 7 is a model diagram showing the relationship between the cartridge 110 having a plurality of reagents and the pipette tip 119 that moves the reagents.
- the pipette head 131 determines the position of the XY plane corresponding to the upper side of the tip hole 116 in which the pipette tip 119 is accommodated, and stops. As the pipette head 131 descends downward in the Z-axis direction, the tip of the pipette head 131 is connected to the pipette tip 119. The pipette head 131 can pick up the pipette tip 119.
- the pipette head 131 to which the pipette tip 119 is connected is defined as the second mechanism 135.
- the second mechanism 135 rises upward in the Z-axis direction.
- the second mechanism 135 determines the position of the XY plane corresponding to the upper side of the hole provided in the seal 115 of the reagent cell with seal 113 and stops.
- the second mechanism 135 descends downward in the Z-axis direction.
- the second mechanism 135 descends downward in the Z-axis direction, passes through the hole, and the tip of the pipette tip 119 comes into contact with the reagent held in the sealed reagent cell 113.
- the pipette tip 119 of the second mechanism 135 aspirates the reagent held in the reagent cell 113 with a seal.
- the pipette tip 119 that has sucked the reagent moves to the reaction cell 120 and discharges the sucked reagent to the reaction cell 120.
- the specimen containing the nucleic acid and the reagent react.
- the pipette tip 119 of the second mechanism 135 can suck the solution containing the nucleic acid and the reagent and discharge them to another sealed reagent cell 113.
- the pipette tip 119 of the second mechanism 135 can repeat the process of sucking the reagent held in the sealed reagent cell 113 and the process of discharging the reagent to the reaction cell 120. Further, the pipette tip 119 of the second mechanism 135 repeats the process of aspirating the solution containing the nucleic acid held in the reaction cell 120 and the reagent and the process of discharging the solution to another sealed reagent cell 113. be able to.
- the control unit 133 controls the movement of the second mechanism 135.
- FIG. 8 is a model diagram showing the operation of the second mechanism 135 until the solution containing the nucleic acid obtained by pretreatment using the first unit is injected into the injection chip 118.
- the second mechanism 135 moves between the reaction cell 120 and the reagent cell 113 with a seal, and aspirates or discharges the reagent held in the reagent cell 113 with a seal, Necessary operations for extracting and purifying nucleic acid from are performed.
- the reaction cell 120 holds a solution containing the nucleic acid in the cell after the extraction and purification process is completed.
- the solution containing the nucleic acid held in the reaction cell 120 is sucked by the second mechanism 135 and then discharged to the injection chip 118 provided in the cartridge 110.
- the first unit can extract and purify nucleic acid from the specimen, and each operation necessary for extracting and purifying the nucleic acid is automatically performed.
- FIG. 9 is a flowchart (protocol) showing each step of extracting and purifying nucleic acid using the first unit.
- a cell lysis buffer such as Lysis Buffer aspirated using a pipette tip 119 is added to a sample containing nucleic acid and dissolved.
- the reaction cell 120 is inserted into the heating / cooling processing unit 141 of the pretreatment mechanism 140 and heated.
- the heated reaction cell 120 is inserted into the agitation processing unit 142 of the pretreatment mechanism 140 and subjected to eccentric agitation to extract nucleic acid contained in the specimen (step 1).
- a buffer such as a magnetic bead solution or a binding buffer held in the reagent cell 113 with a seal is dropped into the reaction cell 120 via step 1.
- the reaction cell 120 is inserted into the heating / cooling processing unit 141 of the pretreatment mechanism 140 and heated.
- the heated reaction cell 120 is inserted into the agitation processing unit 142 of the pretreatment mechanism 140 and agitated eccentrically, and the extracted nucleic acid is adsorbed to the magnetic beads (step 2).
- the 1st unit can also perform operation performed in each process of step 1 and step 2 by one process, without making said step 1 and step 2 into a separate process. That is, the structure of the first unit may be a structure that can complete Step 1 and Step 2 in one step.
- the reaction cell 120 that has passed through step 2 is inserted into the magnetic application processing unit 143 of the pre-processing mechanism, and magnetism is applied to separate the magnetic beads present in the reaction cell 120.
- a cell lysis buffer such as Lysis Buffer existing in the reaction cell 120 is removed by the pipette tip 119 (step 3).
- the cleaning liquid held in the reagent cell 113 with a seal is dropped into the reaction cell 120 that has passed through step 3.
- the reaction cell 120 containing the cleaning liquid is inserted into the heating / cooling processing unit 141 of the pretreatment mechanism and heated.
- the heated reaction cell 120 is inserted into the agitation processing unit 142 of the pretreatment mechanism 140 and eccentrically stirred to wash the magnetic beads (step 4).
- the reaction cell 120 via step 4 is inserted into the magnetic application processing unit 143 of the pre-processing mechanism 140 and magnetism is applied to separate the magnetic beads present in the reaction cell 120.
- the cleaning liquid present inside the reaction cell 120 is removed using the pipette tip 119.
- a buffer such as Elution Buffer is dropped into the reaction cell 120 from which the washing solution has been removed.
- the reaction cell 120 containing the buffer is inserted into the heating / cooling processing unit 141 of the pretreatment mechanism 140 and heated.
- the heated reaction cell 120 is inserted into the agitation processing unit 142 of the pretreatment mechanism 140 and eccentrically stirred to elute the nucleic acid (step 5).
- the reaction cell 120 that has passed through step 5 is inserted into the magnetic application processing unit 143 of the pre-processing mechanism 140 and magnetism is applied to separate the magnetic beads existing in the reaction cell 120. By separating the magnetic beads, the eluted solution is used as an extraction and purification solution (step 6).
- the first unit provided in the fully automatic genetic test apparatus 1 can extract and purify nucleic acid from the specimen by the protocol shown in FIG.
- a solution containing nucleic acid extracted and purified from a sample containing nucleic acid is aspirated by a pipette tip 119. Then, the solution containing the nucleic acid is discharged to the injection chip 118 housed in the cartridge 110. After that, the pipette tip 119 is inserted into the tip hole 116 provided in the cartridge 110 and stored in the pipette tip case 1191.
- the second unit is a unit for injecting a solution containing a nucleic acid into a test chip having a reaction field for amplifying the nucleic acid obtained using the first unit.
- the second unit includes an injection mechanism 210 and a test chip 220 having a reaction field for amplifying nucleic acid.
- FIG. 10 is a schematic diagram showing the configuration of the second unit.
- the injection mechanism 210 provided in the second unit is composed of three members: a pipette head 131, a piercing tip 117, and an injection tip 118.
- the tip of the pipette head 131 has a convex part and is connected to the concave part of the piercing tip 117.
- the lower end portion of the piercing tip 117 has a conical shape and can be fitted with the opening of the injection tip 118.
- An injection needle 1181 is connected to the lower tip of the injection tip 118.
- the injection chip 118 has a syringe 1182 which is a part for holding a solution containing nucleic acid extracted and purified by the first unit, and an injection needle 1181 connected to the syringe 1182.
- the second unit includes a test chip 220 having a plurality of reaction fields for amplifying nucleic acids extracted and purified by using the first unit.
- the inspection chip 220 has a plurality of reaction fields 222 in the interior 221 thereof.
- the inspection chip 220 has a microchannel 223 having a role of connecting one reaction field 222 and another reaction field 222 in the inside 221 thereof.
- the micro flow path 223 is composed of a plurality of flow paths to connect the plurality of reaction fields 222.
- the inspection chip 220 has an injection hole 224.
- the injection hole 224 functions as a valve for inserting the injection needle 1181. Through the injection needle 1181, the solution containing the nucleic acid held on the injection chip 118 is injected into the entire inspection chip 220 through the injection hole 224.
- the member constituting the injection hole 224 is not particularly limited as long as it is a member having a self-sealing property capable of holding the inside 221 of the test chip 220 in a reduced pressure state.
- Specific examples of the material that can be employed as the injection hole 224 include silicon resin, acrylic silicon resin, polyvinyl chloride resin, and styrene / butadiene copolymer resin.
- the inspection chip 220 is a closed system, and the pressure in the interior 221 is a reduced pressure set lower than the atmospheric pressure.
- the inside 221 of the test chip 220 can maintain a sealed system by the injection hole 224 formed of a member having a self-sealing property.
- the reaction field 222 and the microchannel 223 constituting the inspection chip 220 are kept in a decompressed state.
- reagents necessary for nucleic acid amplification and nucleic acid detection are dried and immobilized in advance.
- reagents necessary for amplifying nucleic acids and reagents necessary for detecting nucleic acids include, but are not limited to, reagents such as primers, probes, substrates, and enzymes. Necessary reagents are appropriately selected by a nucleic acid amplification reaction and a nucleic acid detection reaction performed in the reaction field 222.
- the nucleic acid amplification reaction applied in the reaction field 222 of the test chip 220 is not particularly limited.
- the nucleic acid amplification reaction may utilize the following reaction. Specifically, as a nucleic acid amplification reaction, a PCR (Polymerase Chain Reaction) method in which two types of primers are set in the target region and the target gene is amplified 1 million to 10 million times while changing the temperature. It can be illustrated. Furthermore, the LAMP (Loop-mediated ⁇ isothermal Amplification) method and the SDA (Strand Displacement Amplification) method, which are isothermal amplification methods utilizing the strand displacement activity of DNA polymerase, can be exemplified.
- TMA Transcription ⁇ ⁇ ⁇ Mediated ⁇ Amplification
- NASBA Nucleic Acid Sequence Based Amplification
- TRC Transcription-Reverse transcription Concerted
- injection of a solution containing a nucleic acid using the second unit into the test chip 220 will be described.
- the injection of the solution containing the nucleic acid into the test chip 220 means that the solution containing the nucleic acid held inside the injection chip 118 is injected into the injection hole 224.
- the pipette head 131 picks up the piercing chip 117 stored in the cartridge 110 again.
- the pipette head 131 to which the piercing tip 117 is connected is defined as the third mechanism 211.
- the tip of the piercing tip 117 that is the lower tip of the third mechanism 211 is connected to the injection tip 118.
- An injection mechanism 210 is formed from three members, ie, a pipette head 131, a piercing tip 117, and an injection tip 118.
- a solution containing the nucleic acid obtained in the final stage of the pretreatment using the first unit is held in the syringe 1182 of the injection chip 118.
- the injection mechanism 210 holding the solution containing the nucleic acid determines the position of the corresponding XY plane above the injection hole 224 of the test chip 220 and stops.
- the injection needle 1181 provided at the distal end portion of the injection tip 118 pierces the injection hole 224.
- the reaction field 222 and the microchannel 223 existing in the syringe 1182 of the injection chip 118 and the interior 221 of the test chip 220 are connected via the injection needle 1181.
- FIG. 11 is a model diagram showing a state where the injection chip 118 and the piercing chip 117 are connected.
- FIG. 11A is a top view showing a state where the injection tip 118 and the piercing tip 117 are connected.
- FIG. 11B is a cross-sectional view of a state where the injection tip 118 and the piercing tip 117 are connected.
- FIG. 11 shows two forms in which the positions of the air paths 1171 and 1172 penetrating the piercing chip 117 and the injection chip 118 are different.
- the injection chip 118 is an open system through air paths 1171 and 1172 that are air passages connected to the atmosphere, and the solution containing the nucleic acid held in the syringe 1182 of the injection chip 118 , Atmospheric pressure is applied.
- the pressure inside the inspection chip 220 is reduced with respect to the atmospheric pressure. For this reason, when the inside of the syringe 1182 of the injection chip 118 and the inside 221 of the test chip 220 are connected via the injection needle 1181, the solution containing the nucleic acid held in the syringe 1182 of the injection chip 118 is caused by atmospheric pressure. Extruded.
- the injection mechanism 210 constituting the second unit provided in the fully automatic genetic test apparatus 1 of the present invention employs a simple structure provided with air paths 1171 and 1172, so that the atmospheric pressure and the inside 221 of the test chip 220 can be reduced. Using a pressure difference from the pressure, a solution containing a nucleic acid can be injected into the inside 221 of the test chip 220 very easily and safely.
- the form which can apply a pressure to the solution containing a nucleic acid is limited to this Not.
- pressure may be applied to the solution containing the nucleic acid by the pipette head 131 constituting the third mechanism 211.
- the injection mechanism 210 provided in the second unit includes an injection tip 118 at the tip of a third mechanism 211 that is a pipette head 131 to which a piercing tip 117 is connected.
- the existence of the piercing tip 117 intervening between the pipette head 131 and the injection tip 118 means that the pipette head 131 is made of a solution containing nucleic acid extracted and purified obtained by the first unit. Effective in preventing pollution.
- the injection mechanism 210 injects the solution containing the nucleic acid into the test chip 220, and then returns the injection chip 118 and the piercing chip 117 to the respective chip holes 116 provided in the cartridge 110.
- the test chip 220 may include a fourth mechanism that vibrates the test chip 220 after the injection mechanism 210 injects a solution containing a nucleic acid into the test chip 220.
- the vibration by the fourth mechanism may be rotation, stop, or lateral swing.
- the inspection chip 220 vibrates. Due to the vibration of the test chip 220, the solution containing the injected nucleic acid and the reagent such as primer, probe, substrate, enzyme, etc., immobilized on the reaction field 222 is sufficiently mixed to improve the reactivity of the nucleic acid amplification reaction. be able to.
- the vibration by the fourth mechanism is not particularly limited as long as the inspection chip 220 can be vibrated, and can be performed by employing a motor or the like.
- the fourth mechanism is attached to the periphery of the inspection chip 220 that is a position where the inspection chip 220 can be vibrated.
- the fully automatic genetic testing device 1 of the present invention detects position information of the tip of the injection needle 1181 from at least two directions, and based on the position information, the position of the injection needle 1181 at the position of the injection hole 224.
- a control mechanism 225 for correcting the tip end position may be provided.
- FIG. 12 is a model diagram showing the relationship between the injection needle 1181 and the inspection chip 220.
- a camera 2251 and a camera 2252 are installed on the X-axis and the Y-axis of the inspection chip 220, respectively.
- the control mechanism 225 includes a camera 2251 and a camera 2252. Position information 1 on the XY plane of the injection needle 1181 can be acquired by the camera 2251 and the camera 2252. In addition, the control mechanism 225 holds in advance position information 2 on the XY plane that the injection hole 224 provided in the inspection chip 220 has.
- the control mechanism 225 compares the acquired position information 1 and the held position information 2 with each other so that the control mechanism 225 holds the coordinates on the XY plane where the injection needle 1181 is actually located and the control mechanism 225 in advance. The deviation from the coordinates on the XY plane can be recognized.
- the control mechanism 225 recognizes the deviation between the coordinates on the XY plane, and the coordinates on the XY plane where the injection needle 1181 is actually located and the coordinates on the XY plane that the control mechanism has in advance are accurate. To control the position of the injection needle 1181.
- the position of the injection needle 1181 is photographed using a camera from two directions.
- the needle tip position of the injection needle 1181 can be controlled with an accuracy of ⁇ 0.1 mm or less.
- the injection needle 1181 having an outer diameter of about 0.5 mm, a slight bend or an attachment error of the injection tip to the container portion of the injection tip (for example, an injection molded product of polypropylene resin) occurs.
- the position varies about ⁇ 0.3mm.
- the needle tip of the injection needle 1181 may not be inserted into the injection hole 224 due to the positioning error of the inspection chip such as the inspection chip 220 and the variation in the position of the injection needle 1181.
- the needle tip position of the injection needle 1181 can be controlled with an accuracy of ⁇ 0.1 mm or less if the positioning accuracy of the inspection tip such as the inspection tip 220 is about ⁇ 0.2 mm.
- the injection needle 1181 can be inserted into the injection hole 224.
- the position detection of the injection needle 1181 is not limited to image processing by a camera, and may be detection of optical position information using infrared rays or the like.
- the third unit is a unit for optically detecting nucleic acids amplified in the plurality of reaction fields 222 included in the test chip 220 included in the second unit.
- FIG. 13A is a front view showing the configuration of the third unit.
- FIG. 13B is a left side view showing the configuration of the third unit.
- the third unit includes an excitation optical unit 310 disposed at the upper part, a central part 320 including the inspection chip 220, and a detection optical part 330 disposed at the lower part.
- the excitation optical unit 310 includes an excitation light source, a condensing lens 312 and a collimating lens 313 arranged in a straight line from the outside with the base body 311 as an outer frame.
- the excitation light source, the condensing lens 312 and the collimating lens 313 arranged in a straight line form one excitation optical system.
- the third unit shown in FIG. 13A has three optical systems each composed of condensing lenses 312a, 312b, and 312c and collimating lenses 313a, 313b, and 313c in a line shape. Further, an optical filter 314 is attached below the collimating lenses 313a, 313b, and 313c.
- the third unit has a central part 320 for fixing the inspection chip 220.
- the center part 320 is composed of an inspection chip 220 and two heaters 321 for sandwiching the plate-shaped inspection chip 220 from both sides.
- the heater 321 may have an aperture for securing an optical path, or a transparent heater in which a metal oxide thin film such as indium tin oxide (ITO) is formed on a glass substrate.
- ITO indium tin oxide
- the inspection chip 220 has a total of nine reaction fields 222 arranged in a 3 ⁇ 3 matrix. Each reaction field is arranged in a straight line corresponding to one optical system formed in the excitation optical unit 310.
- the detection optical unit 330 includes a condensing lens 332, an optical filter 333, and a detector 334 arranged in a straight line in order from the inspection chip 220 side with the base 331 as an outer frame.
- the condensing lens 332, the optical filter 333, and the detector 334 arranged in a straight line form one detection optical system.
- the third unit shown in FIG. 13A has three detection optical systems formed in a line from the condenser lenses 332a, 332b, 332c and the detectors 334a, 334b, 334c, respectively.
- the optical detection of nucleic acid by the third unit will be described.
- the light generated from the excitation light source in the excitation optical unit 310 passes through the condenser lens 312 and then passes through the collimator lens 313.
- the light that has passed through the collimating lens 313 is filtered by the optical filter 314.
- the filtered excitation light passes through the hole provided in the upper heater 321 and passes through the reaction field 222 of the inspection chip 220.
- the excitation light that has passed through the reaction field 222 of the inspection chip 220 passes through the condenser lens 332 and is filtered by the optical filter 333.
- the excitation light filtered by the optical filter 333 is detected by the detector 334.
- the optical detection by the third unit a plurality of optical systems are formed in a line shape and a line scan is performed.
- the third unit shown in FIG. 13 is provided with an optical filter corresponding to a fluorescent dye for detecting amplification products in the excitation optical unit 310 and the detection optical unit 330, respectively.
- the optical detection of the 3rd unit was the detection using a fluorescent pigment
- the optical detection of the third unit may detect insoluble by-products by the nucleic acid amplification reaction as turbidity.
- the fully automatic genetic test apparatus 1 of Embodiment 1 injects a solution containing the nucleic acid into a test chip having a first unit for extracting and purifying nucleic acid from a specimen and a plurality of reaction fields for amplifying the nucleic acid. Since the second unit that interacts with the third unit for optically detecting the nucleic acid amplified in the reaction field and adopts a robust structure, the genetic test can be executed fully automatically. it can.
- the first unit, the second unit, and the third unit provided in the fully automatic genetic testing apparatus 1 have a compact structure, respectively, and the entire genetic testing apparatus can be downsized. For this reason, the fully automatic genetic test apparatus 1 can perform a genetic test at a position close to the patient.
- FIG. 14 is a model diagram showing an overview of the fully automatic genetic test apparatus 1 of the second embodiment.
- FIG. 14A is a top view showing an outline of the fully automatic genetic test apparatus 1.
- FIG. 14B is a front view showing an outline of the fully automatic genetic test apparatus 1.
- the basic structure of the fully automatic genetic test apparatus 1 of the second embodiment is almost the same as that of the fully automatic genetic test apparatus of the first embodiment.
- the fully automatic genetic test apparatus 1 of Embodiment 2 includes a cartridge base 411 having a substantially circular plate shape.
- Reagent cells with seals 413 are installed along the circumferential edge of the cartridge base 411 so as to draw circles at equal intervals. Further, inside the circle formed by the sealed reagent cell 413, a piercing tip 117, an injection tip 118, a cell for storing the pipette tip 119, and a reaction cell 120 are installed at equal intervals.
- the support member 444 that supports the heating / cooling processing unit 141, the eccentric stirring processing unit 142, and the magnetic field application processing unit 143 constituting the pre-processing mechanism 140 is substantially circular. It has a plate shape. Since the support member 444 can rotate, the position of each processing unit included in the preprocessing mechanism 140 can be changed as necessary.
- the driving unit 432 capable of moving the pipetting mechanism 130 in the ⁇ direction and the cartridge 410 can be rotated on the trajectory along which the pipetting mechanism 130 moves (not shown). And a rotation mechanism. As shown in FIG. 14A, the ⁇ Z driving unit 432 that can move the pipetting mechanism in the ⁇ direction can further drive in the ⁇ direction after positioning the pipetting mechanism in the XYZ space.
- the rotation mechanism can rotate the cartridge 410, the reagent cell 413 in which a plurality of reagents necessary for the pretreatment are held in the reagent cell 413 with a seal is brought close to the pipetting mechanism 130. Can do.
- the ⁇ Z drive unit 432 performs an operation of extracting and purifying nucleic acid from the specimen on the cartridge base 411 and the support member 444 by moving the pipetting mechanism 130 in the ⁇ direction.
- the solution containing the nucleic acid is injected into the injection chip 118.
- the injection chip 118 holding the solution containing the nucleic acid injects the solution containing the nucleic acid into the reaction field 222 by inserting the injection needle 1181 into the injection hole 224 of the test chip 220.
- the nucleic acid amplified in the reaction field 222 is detected by the optical detection unit 330 provided in the third unit.
- the basic structure of the fully automatic genetic test apparatus 1 of Embodiment 3 is almost the same as that of the fully automatic genetic test apparatus 1 of Embodiment 1.
- the fully automatic genetic test apparatus of Embodiment 3 adopts a LAMP (Loop-Mediated Isothermal Amplification) method as a nucleic acid amplification reaction applied in the reaction field 222 of the test chip 220.
- LAMP Loop-Mediated Isothermal Amplification
- the time required for the nucleic acid amplification reaction can be reduced to about 1 hour by adopting the LAMP method in the fully automatic genetic test apparatus 1. Furthermore, the time required for the nucleic acid amplification reaction can be reduced to approximately 15 to 30 minutes by adopting the LAMP method to which the rapid method of adding a loop primer or the like is applied to the fully automatic genetic test apparatus 1.
- the LAMP method is employed in the fully automatic genetic test apparatus 1, a large amount of magnesium pyrophosphate which is a byproduct of the nucleic acid amplification reaction is generated.
- Magnesium pyrophosphate is a white insoluble substance, and the presence or absence of a nucleic acid amplification reaction can be detected only with the naked eye using the white insoluble substance as an index.
- gene detection can be performed by measuring easily using the 3rd unit which can optically detect the degree of turbidity (turbidity) of the solution brought about by the production
- the PCR method is the most widely used nucleic acid amplification reaction at present.
- the reaction temperature must be adjusted stepwise.
- gel electrophoresis must be used to confirm the product generated in the nucleic acid amplification reaction.
- a detection reaction using a probe must be performed separately.
- the fully automatic genetic test apparatus 1 of the third embodiment employs the LAMP method, the temperature adjustment is very easy and the operation becomes very easy.
- the fully automatic genetic test apparatus according to the third embodiment that employs the LAMP method has operability, accuracy, functionality, and rapidity, and has extremely great technical significance.
- the fully automatic genetic test apparatus of the present invention can perform the process from extraction and purification of nucleic acids contained in a sample to the amplification detection process fully automatically and can be used near a patient. It can be expected to be used as a miniaturized fully automatic genetic testing device.
- the fully automatic genetic test apparatus of the present invention can be used particularly in various industries such as the medical equipment industry, the pharmaceutical related industry, and the agricultural related industry.
- D Gene Testing System 1 Fully automatic genetic testing device (test unit) 2 Master unit 10 Pretreatment section (first unit) 20 Injection unit (second unit) 30 Amplification detector (third unit) 35 Two-dimensional barcode 110 Cartridge 111 Cartridge base 112 Cartridge base hole 113 Sealed reagent cell 114 Flange 115 Seal 116 Tip hole 1161 First cell 1162 Second cell 1163 Third cell 117 Piercing tip 1171 Airpass 1172 Airpass 118 Injection tip 1181 Injection Needle 1182 Syringe 119 Pipette tip 1191 Pipette tip case 120 Reaction cell 130 Pipetting mechanism 131 Pipette head 132 Drive unit 133 Control unit 134 First mechanism 135 Second mechanism 140 Pre-processing mechanism 141 Heating / cooling processing unit 1411 Heater 142 Stir processing unit 143 Magnetic field application processing unit 1431 Magnet 144 Support unit 1441 connecting portion 210 injection mechanism 211 third mechanism 220 inspection chip 221 test chip inside 222 reaction field 223 microchannel 224 injection hole 225 control mechanism 2251 camera (X-axis direction) 22
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Abstract
Description
前記核酸を増幅するための複数の反応場を有する検査チップに前記核酸を含む溶液を注入する第2ユニットと、前記反応場において増幅された核酸を光学検出するための第3ユニットと、を備えることを特徴とする全自動遺伝子検査装置。
前記ピアッシングチップを前記ピペッティング機構から取り外した後に、前記ピペットチップを前記ピペッティング機構に取り付け、前記試薬を前記反応セルに移動させる第2機構と、を備えていることを特徴とする(3)に記載の全自動遺伝子検査装置。
前記カートリッジ基体の外縁部である円周上に前記シール付きセルと前記第1セルと前記第2セルと前記第3セルとが配置され、前記ピペッティング機構をθ方向に移動させることができる駆動機構と、前記カートリッジを前記ピペッティング機構が移動する軌道上において回転させることができる回転機構と、を備えることを特徴とする(3)に記載の全自動遺伝子検査装置。
以下、本発明の実施形態について説明する。図1は、遺伝子試験システムDの概要を示した斜視図である。図1に示されるように、遺伝子試験システムDは、マスターユニット2及びテストユニット1を備えている。マスターユニット2とテストユニット1とは、電気的に接続され、マスターユニット2とテストユニット1とは、相互間において入力データ及び検査結果の送受信を行う。なお、図1に示された遺伝子試験システムDは、マスターユニット2とテストユニット1とが分離されたタイプであるが、これに限定されない。例えば、制御部を備えるマスターユニット2をテストユニット1に取り込み一体型の遺伝子試験システムDとしてもよい。
第1ユニットは、検体から核酸を抽出精製するユニットであり、核酸を抽出精製するために用いる複数の試薬を備えたカートリッジ110、反応セル120、試薬を移動させるピペッティング機構130、反応セル120を前処理するための前処理機構140を備えている。図4(A)は、第1ユニットが備えているカートリッジ110の構成を示した斜視図である。図4(B)は、カートリッジ110の上面図である。図4(C)は、カートリッジ110の断面図である。図4(D)は、第1ユニットが備えている反応セル120の構成を示した斜視図である。
なお、図4(A)に示されるとおり、ピアッシングチップ117を収納するためのケース1191が図示されている。すなわち、第1セル1161は、カートリッジ基体111に設置されたピアッシングチップ117を収納するためのケース1191を有していてもよい。
なお、図4(A)に示されるとおり、インジェクションチップ118を収納するためのケース1191が図示されている。すなわち、第2セル1162は、カートリッジ基体111に設置されたインジェクションチップ118を収納するためのケース1191を有していてもよい。
なお、インジェクションチップ118の先端には、試薬を注入するための注射針1181が設けられている。注射針1181は、上記ケース1191の内部に収納されている。このため、注射針1181が外気と接することがない。
次に、第1ユニットを用いた前処理について説明する。第1ユニットを用いた前処理とは、検体から核酸を抽出精製することを意味する。図6は、複数の試薬を備えたカートリッジ110と、ピアッシングチップ117との関係を示したモデル図である。
第2ユニットは、第1ユニットを用いて得られた核酸を増幅するための反応場を有する検査チップに核酸を含む溶液を注入するユニットである。第2ユニットは、インジェクション機構210と、核酸を増幅するための反応場を有する検査チップ220を備えている。図10は、第2ユニットの構成を示した概要図である。図10に示されるように、第2ユニットが備えているインジェクション機構210は、ピペットヘッド131とピアッシングチップ117とインジェクションチップ118の3つの部材から構成されている。
次に、第2ユニットを用いた核酸を含む溶液の検査チップ220への注入について説明する。核酸を含む溶液の検査チップ220への注入とは、インジェクションチップ118の内部に保持されている核酸を含む溶液を注入孔224に注入することを意味する。
第3ユニットは、第2ユニットが備えている検査チップ220が有する複数の反応場222において増幅された核酸を光学検出するためのユニットである。図13(A)は、第3ユニットの構成を示した正面図である。図13(B)は、第3ユニットの構成を示した左側面図である。図13に示されるように、第3ユニットは、上部に配置された励起光学部310と、検査チップ220を備えた中心部320と、下部に配置された検出光学部330から構成されている。
第3ユニットによる核酸の光学検出について、説明する。励起光学部310において励起光源から発生した光は、集光レンズ312を通過した後、さらにコリメートレンズ313を通過する。コリメートレンズ313を通過した光は、光学フィルター314によって、フィルタリングされる。フィルタリングされた励起光は、上側のヒーター321に設けられている孔を通過し、検査チップ220の反応場222を通過する。検査チップ220の反応場222を通過した励起光は、集光レンズ332を通過し、光学フィルター333によってフィルタリングされる。光学フィルター333によってフィルタリングされた励起光は、検出器334によって、検出される。
図14は、実施形態2の全自動遺伝子検査装置1の概要を示したモデル図である。図14(A)は、全自動遺伝子検査装置1の概要を示した上面図である。図14(B)は、全自動遺伝子検査装置1の概要を示した正面図である。実施形態2の全自動遺伝子検査装置1の基本的構造は、実施形態1の全自動遺伝子検査装置とほぼ同一である。
実施形態3の全自動遺伝子検査装置1の基本的構造は、実施形態1の全自動遺伝子検査装置1とほぼ同一である。実施形態3の全自動遺伝子検査装置は1、検査チップ220の反応場222において適用される核酸増幅反応として、LAMP(Loop-Mediated Isothermal Amplification)法を採用している。
1 全自動遺伝子検査装置(テストユニット)
2 マスターユニット
10 前処理部(第1ユニット)
20 注入部(第2ユニット)
30 増幅検出部(第3ユニット)
35 2次元バーコード
110 カートリッジ
111 カートリッジ基体
112 カートリッジ基体孔
113 シール付き試薬セル
114 フランジ
115 シール
116 チップ孔
1161 第1セル
1162 第2セル
1163 第3セル
117 ピアッシングチップ
1171 エアーパス
1172 エアーパス
118 インジェクションチップ
1181 注射針
1182 シリンジ
119 ピペットチップ
1191 ピペットチップケース
120 反応セル
130 ピペッティング機構
131 ピペットヘッド
132 駆動部
133 制御部
134 第1機構
135 第2機構
140 前処理機構
141 加熱冷却処理部
1411 ヒーター
142 撹拌処理部
143 磁界印加処理部
1431 磁石
144 支持部材
1441 連結部
210 インジェクション機構
211 第3機構
220 検査チップ
221 検査チップ内部
222 反応場
223 マイクロ流路
224 注入孔
225 制御機構
2251 カメラ(X軸方向)
2252 カメラ(Y軸方向)
310 励起光学部
311 基体
312 集光レンズ
313 コリメートレンズ
314 光学フィルター
320 中心部
321 ヒーター
330 光学検出部
331 基体
332 集光レンズ
333 光学フィルター
334 検出器
410 カートリッジ
411 カートリッジ基体(円形)
413 シール付き試薬セル(円形)
432 θZ駆動部
444 支持部材(円形)
Claims (12)
- 検体から核酸を抽出精製する第1ユニットと、
前記核酸を増幅するための複数の反応場を有する検査チップに前記核酸を含む溶液を注入する第2ユニットと、
前記反応場において増幅された核酸を光学検出するための第3ユニットと、を備えることを特徴とする全自動遺伝子検査装置。 - 前記第1ユニットは、前記核酸の抽出精製に用いる複数の試薬を備えたカートリッジと反応セルとの間において前記試薬を移動させるピペッティング機構と、
前記反応セルを前処理するための前処理機構と、を備え、
前記前処理機構は、加熱冷却処理部、撹拌処理部、磁界印加処理部から選ばれる少なくとも一つの処理部を有することを特徴とする請求項1に記載の全自動遺伝子検査装置。 - 前記カートリッジは、前記試薬を個別に収納するためのシール付きセルと、
前記シールに孔を開けるためのピアッシングチップを収納する第1セルと、前記試薬を移動させるためのピペットチップを収納する第2セルと、前記核酸を含む溶液を前記反応場に注入するためのインジェクションチップを収納する第3セルと、を有することを特徴とする請求項2に記載の全自動遺伝子検査装置。 - 前記インジェクションチップは、前記核酸を含む溶液を保持するシリンジと注射針から構成され、前記注射針が前記シリンジに接続されていることを特徴とする請求項3に記載の全自動遺伝子検査装置。
- 前記ピペッティング機構は、前記ピアッシングチップを前記シールに接触させることによって前記シールに孔を開ける第1機構と、
前記ピアッシングチップを前記ピペッティング機構から取り外した後に、前記ピペットチップを前記ピペッティング機構に取り付け、前記試薬を前記反応セルに移動させる第2機構と、を備えていることを特徴とする請求項3に記載の全自動遺伝子検査装置。 - 前記ピペッティング機構は、前記ピアッシングチップを取り付けた第3機構と、
前記検査チップが有する注入孔から前記反応場に前記注射針を通じて、前記核酸を含む溶液を注入する前記インジェクションチップを前記第3機構に備えたインジェクション機構と、を備えていることを特徴とする請求項4に記載の全自動遺伝子検査装置。 - 前記検査チップを振動させる第4機構を備えていることを特徴とする請求項6に記載の全自動遺伝子検査装置。
- 前記注射針の先端部が有する位置情報を少なくとも2方向から検出し、前記位置情報に基づいて、前記注入孔の位置に前記注射針の先端部位置を補正するための制御機構を備えることを特徴とする請求項6に記載の全自動遺伝子検査装置。
- 前記検査チップは、前記注入孔と前記反応場とを繋ぐ複数の流路を有しており、前記反応場において前記核酸の増幅反応を行うことを特徴とする請求項6に記載の全自動遺伝子検査装置。
- 前記第3ユニットは、前記反応場で増幅された核酸を濁度及び/又は蛍光によって検出することを特徴とする請求項1に記載の全自動遺伝子検査装置。
- 前記カートリッジは、略円形の板形状を有するカートリッジ基体を備え、
前記カートリッジ基体の外縁部である円周上に前記シール付きセルと前記第1セルと前記第2セルと前記第3セルとが配置され、
前記ピペッティング機構をθ方向に移動させることができる駆動機構と、
前記カートリッジを前記ピペッティング機構が移動する軌道上において回転させることができる回転機構と、を備えることを特徴とする請求項3に記載の全自動遺伝子検査装置。 - 前記検査チップが有する注入孔の位置は、前記ピペッティングが移動する軌道上において配置されていることを特徴とする請求項11に記載の全自動遺伝子検査装置。
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JP2021122197A (ja) * | 2020-02-03 | 2021-08-30 | キヤノンメディカルシステムズ株式会社 | 検体検査装置及び検体検査方法 |
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CN113522385B (zh) * | 2021-07-14 | 2022-07-22 | 中新国际联合研究院 | 一种磁性数字微流体的移动结构及其自动化设备 |
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WO2024044928A1 (zh) * | 2022-08-30 | 2024-03-07 | 深圳华大智造科技股份有限公司 | 试剂存储装置和试剂操作*** |
CN115181661B (zh) * | 2022-09-14 | 2023-01-06 | 深圳市安保医疗感控科技股份有限公司 | 微生物检测方法、装置、***与计算机可读存储介质 |
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