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WO2006048926A1 - Dispositif de scellement hermétique de micro matrice - Google Patents

Dispositif de scellement hermétique de micro matrice Download PDF

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Publication number
WO2006048926A1
WO2006048926A1 PCT/JP2004/016274 JP2004016274W WO2006048926A1 WO 2006048926 A1 WO2006048926 A1 WO 2006048926A1 JP 2004016274 W JP2004016274 W JP 2004016274W WO 2006048926 A1 WO2006048926 A1 WO 2006048926A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
substrate
sealing device
roller
concave structure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2004/016274
Other languages
English (en)
Japanese (ja)
Inventor
Sachio Nomura
Masatoshi Kondo
Toru Egashira
Yoko Kimura
Nobuko Ito
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BML Inc
Original Assignee
BML Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BML Inc filed Critical BML Inc
Priority to PCT/JP2004/016274 priority Critical patent/WO2006048926A1/fr
Priority to JP2006542196A priority patent/JPWO2006048926A1/ja
Publication of WO2006048926A1 publication Critical patent/WO2006048926A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50853—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates with covers or lids
    • 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
    • B01L2200/0642—Filling fluids into wells by specific techniques
    • 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
    • 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
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0819—Microarrays; Biochips
    • 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
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • 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"

Definitions

  • the present invention relates to a microarray, and more particularly to a sealing device for a substrate capable of intensively performing a liquid phase reaction.
  • detection substrate capable of intensively performing a liquid phase reaction, particularly a biochemical liquid phase reaction, and has filed a patent application for this ("detection substrate”: WO 03/0 31972).
  • the detection substrate is a "detection substrate having a large number of wells on the surface of the substrate", and the biochemical liquid phase reaction is intensively performed in each of the many wells provided. It can be carried out.
  • the target is prepared by charging the detection target and the substrate for the liquid phase reaction into each well, and then dispensing the reaction solution for the reaction to the substrate of the liquid phase reaction. Preparation of liquid phase reaction can be mentioned.
  • the substrate is incubated to advance the liquid phase reactions in the individual wells. By detecting these reactions, the necessary biochemical information can also be detected.
  • the present invention should be solved by sealing the reaction side surface with a thin film such as a film as part of preparation for a detection substrate capable of performing biochemical liquid phase reactions intensively. It is to provide an automated means in case.
  • the present inventor has the following (1) and (3), and a sealing device for a substrate capable of collectively performing a liquid phase reaction (1)
  • the present invention has been completed by finding that the above-mentioned problems can be solved by providing this sealing device).
  • a recess capable of mounting a substrate capable of performing a liquid phase reaction in a state where the reaction side surface is substantially exposed.
  • Substrate storage part with structure hereinafter also referred to as “storage part”: equivalent to “lower cassette” described later
  • sliding roller A roller slidable along the reaction side surface of the substrate placed in the storage section (hereinafter also referred to as “sliding roller”)
  • a thin film (hereinafter also referred to as “sealing thin film”) disposed between the roller and the reaction side surface by sliding the roller along the reaction side surface of the substrate.
  • a delivery mechanism (hereinafter also referred to as “delivery mechanism”, which can be sent out while keeping the state in close contact with the reaction side surface, and seals the thin film on the reaction side surface; And a mechanism for operating the ⁇ sliding roller '' according to the method of use described later)
  • This sealing device is basically a state in which the "reaction substrate” prepared for the final liquid phase reaction is substantially exposed in the concave structure of the "housing part” on the reaction side surface. And slide the ⁇ sliding roller '' along the reaction side surface of the ⁇ reaction substrate '' to bring the final reaction liquid near the moving direction side of the ⁇ sliding roller ''. While dripping, the “sealing thin film” disposed between the “sliding roller” and the reaction side surface is sent out while keeping in close contact with the reaction side surface (by the above delivery mechanism), ⁇ Seal film '' on the reaction side It can be used by sealing on the surface (hereinafter, this usage method is referred to as “this usage method.
  • the "housing part” force is detachable from the main body of the sealing device, and the "housing part”
  • the concave structure is sealed in a state where the “reaction substrate” is stored in the concave structure. It is preferable to provide a mechanism capable of
  • the “reception substrate” “housing part” is separated from the sealing device body, and the “housing part”
  • the “reaction substrate” is sealed in a state of being accommodated in the concave structure by attaching a pair of lid members, and the sealed “reservoir” is subjected to a reaction treatment (incubation).
  • a liquid phase reaction on the “reaction substrate” can be performed (hereinafter, this method of use is also referred to as “method of use 2”).
  • the “housing portion” of the present sealing device has the following characteristics (a) to (c) when the device body force is also removable. It can also be grasped as a “reaction substrate” storage tool (hereinafter also referred to as “the present storage device”).
  • the reaction substrate in which the sealing thin film is sealed to the reaction side surface with the sealing device is separated from the device without removing the sealing device force. Install the lid member and apply it to the incubator etc.
  • the phase reaction can proceed. This is not only advantageous in terms of work efficiency, but also prevents the “reaction thin film” from being peeled off when the reaction substrate before the liquid phase reaction is removed from the “housing”, and is also suitable. The yield at which liquid phase reaction conditions are provided can be improved.
  • reaction substrate means a “detection substrate having a number of wells on the surface of the substrate” and means a detection instrument having a surface capable of performing a liquid phase reaction. is there.
  • This detection instrument mainly means a microarray-like substrate, and the shape is mainly a substrate-like force. The shape is not necessarily limited to this shape.
  • FIG. 1 is a drawing showing an embodiment of a "reaction substrate".
  • the reaction substrate 10 can be manufactured by providing a large number (at least two or more) of wells 12 on the surface (only one side) 110 of the original substrate 11.
  • the volume of the wel 12 should be freely selected according to the volume of the liquid phase necessary for the detection of the liquid phase reaction performed in these wels, and is not particularly limited. That is, the well 12 needs to have a volume that is appropriately larger than the volume of the liquid phase necessary for detecting the liquid phase reaction. Specifically, the volume is preferably about 100-6800% with respect to the required volume of the liquid phase.
  • the reaction substrate 10 is preferably a substrate for performing the detection of the liquid phase reaction in each of the wells 12 and is preferably smaller than the necessary volume force ⁇ 1 unit of the liquid phase.
  • the volume of each of the wels 12 is preferably 1 ⁇ 1 or less, and more preferably about 0.01 1 or less.
  • the preferred minimum volume of the well 12 should be specified according to the measurement sensitivity of the liquid phase reaction and the technique of installing the well 12.
  • the existence density of the wells 12 per unit area of the reaction substrate 10 in the reaction substrate 10 should be defined according to the size of each well 12, the technology for providing the well 12, and the detection technique for the liquid phase reaction. Although not particularly limited, in general, it is preferably about 1400,000 pieces Zcm 2 . When the reaction performed on the detection substrate is an invader 1 'assembly method described later, it is particularly preferably about 1 10000 Zcm 2 .
  • the amount of DNA to be detected is small or the number of single nucleotide polymorphisms (SNPs) to be detected is small, for example, the number of individuals to be detected in hundreds, SNP to be detected object is, when performing in a manner that is classified as being a case like] a few mm, very preferably less than 1 one 400 ZCM 2, "high throughput for" [ When carried out in such a manner that the number of single nucleotide polymorphisms (SNPs) to be detected is large (for example, tens of thousands or more), it is extremely preferably about 400-10000 Zcm 2 .
  • the reaction force performed on the detection substrate is a low-density microarray method (for example, about several hundred genes whose expression level is to be examined), or a liquid-phase reaction other than the low-density Invader 'Atsui method (immune reaction, radio I Takeno assay I method, the homogeneous mediation Si method) (liquid phase reaction of each, when the type of the detection target is a few cases, etc.), particularly preferred, 1 one 400 Zcm less than 2 It is.
  • the reaction performed on the detection substrate is performed using a high-density microarray method (for example, about several thousand to several tens of thousands of genes whose expression level is examined), or a liquid other than the above-described high-density Invader Atsey method.
  • a high-density microarray method for example, about several thousand to several tens of thousands of genes whose expression level is examined
  • a liquid other than the above-described high-density Invader Atsey method In the case of phase reaction (in the case of each liquid phase reaction, etc.), particularly preferably 400 to 40,000 Zcm 2 , very preferably 400 to 10,000 Zcm 2 .
  • the shape of the well 12 is not particularly limited, and examples thereof include a hemispherical shape, a cylindrical shape having a hemispherical bottom, a cylindrical shape, a mortar shape, a conical shape, a pyramid shape, and a prism shape. Further, it is preferable that the size of the opening of the well 12 is maintained so that the liquid phase can be easily injected. Specifically, about 0.01 to 0.5 mm (diameter) is preferable.
  • the material of the reaction substrate 10 is not particularly limited as long as it has rigidity enough to withstand practical use.
  • the liquid phase reaction detection means is a detection means using fluorescence.
  • the substrate itself does not have autofluorescence! /
  • a material is suitable for preventing the generation of background during measurement. Therefore, the material of the reaction substrate 10 in such a case includes glass, ceramics, metal, plastic, and the like.
  • thermoplastic resin as a plastic, first, as a polymer whose main chain is almost composed of carbon, an olefin polymer such as a propylene polymer (polypropylene, etc.), 4-methylpentene 1 polymer, etc .; Cycloolefin-based polymers of norbornene-based polymers (ethylene norbornene copolymer, etc.); methyl metatalylate-based polymers, isobornyl Acrylic polymers such as copolymers of metatalylate, dicyclopentamethacrylic copolymers; amorphous styrenic polymers, syndiotactic styrenic polymers, para-tert-butylene styrenic polymers, alphamethylstyrene-methyl methacrylate copolymers
  • Styrene polymers such as ABS resin; cyclohexyl malate polymer, dimethyl itaconate polymer, hardened salt vinyl resin, fluorine polymer (vinylidene fluoride polymer, tetrafluoroethylene polymer, etc.)
  • Other vinyl polymers can be mentioned.
  • thermoplastic resins polyacetal resins, polycarbonates, polyester resins, aromatic polyesters, polyamides, polyurethanes, polyurethane-polyethers, polyolefins are used as polymers containing heteroatoms in the main chain skeleton.
  • thermosetting resins include unsaturated polyesters, epoxy resins (especially alicyclic epoxy resins), three-dimensional curable polyurethanes, unsaturated acrylic resins (epoxy acrylate resins). ), Melamine resin, three-dimensional styrene resin, three-dimensional silicone resin, aryl resin (diaryl phthalate resin, diethylene glycol diallyl carbonate resin, etc.), and the like.
  • silicone treatment is often suitable for preventing adsorption of materials, reagents, and the like used for detection on the reaction substrate 10 on the substrate surface.
  • the silicone treatment can be performed according to a conventional method. For example, by applying a sol-gel method, etc., colloidal silica and other silicone raw materials are hydrolyzed, and a curing catalyst, a solvent, a leveling agent, and an ultraviolet absorber as necessary are added.
  • the silicone coating material to be formed can be performed by a conventional method, for example, preferably by a dip method or a vapor deposition method, or by a spray method, a roll coating method, a flow coating method, a spin coating method or the like.
  • the reaction substrate 10 is colored to prevent self-fluorescence when, for example, fluorescence is used for detection, and Sarako protects against adverse effects of fluorescence emission between adjacent wells. It is possible. For such coloring, saturation, hue, brightness, etc. can be selected as required. However, in this case, it is generally preferable that the color is black. In this case, the substrate material can be colored by mixing a black pigment such as carbon.
  • the specific size and shape of the reaction substrate 10 can be freely specified, and are not particularly limited. However, the actual usage is that the reaction substrate 10 is designed based on a standard widely used as a microarray. Is preferred. In other words, various microarray analyzers, analysis software, and related dispensers are designed to meet the standards, and the reaction substrate 10 is also designed to have a size and shape that match these standards. Is preferred. Specifically, a plate-like shape in the vicinity of “length 26 mm ⁇ width 76 mm ⁇ thickness lmm”, which is the size of a slide glass usually used in Japan, is suitable.
  • the reaction substrate 10 is used in accordance with the microarray shape and size standards in the V, region (for example, the United States (1 inch x 3 inches wide), Europe, etc.). It is preferable to design 10 shapes and sizes. Alternatively, it is desirable that the size is suitable for dispensing and detection equipment. Microarray scanners that can analyze even with a microtiter plate size have been sold, and that size is acceptable.
  • the method for producing the reaction substrate 10 is not particularly limited, but it is usually produced by a method of providing a well directly on a single substrate.
  • a large number of wells 12 were formed on the surface by a micro-wel formation method, such as an embossing method using a die with fine irregularities, a die-cutting method, or a processing with a fine drill.
  • the substrate 10 can be manufactured.
  • the embossing method and the die-cutting method are suitable when the material of the reaction substrate 10 is plastic.
  • reaction substrate 10 can be manufactured.
  • the detection target that can be detected by performing a liquid phase reaction (mainly a biochemical liquid phase reaction) performed on the “reaction substrate” is not particularly limited.
  • Nucleic acids to be analyzed (DNA and Z or RNA, which may be double-stranded or single-stranded, and may have a specific three-dimensional structure such as a hairpin structure)
  • Peptides, antibodies, bacteria, viruses, various clinical samples blood samples, urine samples, lymph fluid samples, synovial fluid samples, saliva samples, etc.
  • various clinical samples blood samples, urine samples, lymph fluid samples, synovial fluid samples, saliva samples, etc.
  • the detection target is preferably contained in a dispensing solution (hereinafter also referred to as a first dispensing solution) in which the first dispensing is usually performed.
  • a dispensing solution hereinafter also referred to as a first dispensing solution
  • the first dispensing solution includes a stabilizer and a treating agent according to the type of detection target.
  • the immobilizing agent and the like can be contained in the solution as necessary.
  • the content of the detection target in the first dispensing solution should be selected according to the type, purpose, etc. of the detection target, and is not limited at all. At least it is necessary that the amount of signal that can be detected by contact with the reactant is more than that which can be detected and less than the amount that noise is observed.
  • the final reaction liquid dropped in the vicinity of the moving direction side of the “sliding roller” can be appropriately selected according to the type of detection target to be used and the liquid phase reaction to be selected.
  • the liquid phase reaction performed in the present invention is not particularly limited.
  • a catalytic reaction of a protein such as an enzyme reaction, an antigen-antibody reaction, an interaction between proteins, and a specific affinity between substances.
  • -Tee including hybridization between nucleotide chains
  • the liquid phase reaction can be detected by utilizing means currently used in the microarray technology. Specifically, for example, fluorescence at each well can be detected by using a highly sensitive fluorescence scanner on the substrate after the liquid phase reaction obtained by the selected detection method. In addition, detection by radioisotope, detection by EIA method, homogenous detection such as AlphaScreen TM [manufactured by PerkinElmer (USA)] can be performed.
  • one of the most preferred embodiments of the liquid phase reaction to be carried out is the so-called Invader _ Atssey method [Third Wave Technologies (USA)].
  • FIG. 2 is a schematic diagram showing an overview of this invader.
  • the first nucleotide chain 22 is first hybridized to the cage nucleotide chain (wild type gene) 21.
  • the first nucleotide chain 22 is a base complementary to the mutation detection base [in this figure, the wild type is T (thymine)] in the cage nucleotide chain 21 [in this figure, A (adenine)].
  • T thymine
  • A adenine
  • the second nucleotide chain 23 is further hybridized with respect to the partial double strand of the cage nucleotide chain 21 and the first nucleotide chain 22.
  • the second nucleotide chain 23 has a “complementary portion” 231 complementary to the saddle-shaped nucleotide chain 21 on the 3 ′ side, and a detection element is provided continuously therewith.
  • the “detection part” 232 that is non-complementary to the type nucleotide chain is a complex nucleotide chain on the 5 ′ side, and the 5 ′ base of the “complementary part” 231 is the base to be detected for mutation.
  • the base (A) is complementary to (T).
  • the mutation detection target base portion (T) of the cage nucleotide chain 21 is replaced with the “complement of the third terminal base of the first nucleotide chain 22 and the second nucleotide chain”.
  • a partial three-base overlap structure with the 5′-most base (A) of the “partial” 231 will be formed.
  • nuclease 24 having an activity of specifically cleaving this partial three-base overlap structure on its 3 'side is allowed to act, so that the second nucleotide strand 23 cleaved by this nuclease
  • the detection portion 232 ′ the 3 ′ end is a complementary base (A) to the base (T) to be detected for mutation
  • the nucleotide sequence 21 is a wild type. Can be detected.
  • the fluorescent dye 251 is near the 5 'end and the fluorescence quencher is near the 3' side.
  • the wild type can be detected by allowing a hairpin type probe (nucleotide chain) 25 labeled with 252 to coexist with the hybrid system.
  • the single-stranded part on the 3 side of the hairpin probe 25 is used for detection of the second nucleotide chain 23. It is designed to be complementary to part 232, and the 5'-side base adjacent to the 5'-most base of this single-stranded part is the mutation detection target base (T). .
  • T mutation detection target base
  • nuclease 24 acts again to cleave between fluorescent dye 251 and fluorescent quenching substance 252 in hairpin probe 25 to release fluorescent dye 251 and to quench fluorescence by fluorescent quenching substance 252. And the original fluorescence can be detected. By detecting this fluorescence, it is possible to detect that the cocoon-type nucleotide chain 21 is a wild-type gene in which no mutation is observed in the mutation detection target base.
  • the target nucleotide for mutation detection of the cocoon-type nucleotide chain 21 is an SNP base that is, for example, G (guanine) rather than a wild-type base (T), and this is detected positively.
  • the complementary bases in the first nucleotide chain 22 and the second nucleotide chain 23 are C (cytosine) complementary to G from the above A, and the sequence of the detection portion 232 and the 25 sequences corresponding thereto.
  • the fluorescent dye 251 and the fluorescence quenching substance 252 in the hairpin type probe 25 are used as a fluorescent dye that emits fluorescence different from the above system and a fluorescence quenching substance corresponding thereto.
  • SNPs in the nucleotide chain 21 can be detected by fluorescence of different fluorescent dyes.
  • nucleotide 21 having a wild type base and a mutant base when mixed (hetero type), it may be detected positively as a mixed fluorescence of the above two types of fluorescence. Is possible.
  • the force exemplified for the detection system using the hairpin type probe in addition to this, for example, the detection portion 232 is directly subjected to fluorescent labeling or isotope labeling for direct detection. It is also possible to detect SNPs etc. by detecting the part. Furthermore, here, an example is shown in which positive detection is performed whether or not SNPs are present, but in either case, it is possible to perform negative detection in which no label such as fluorescence is detected. It is.
  • the Invader Atsey method described above is partially applied as the reaction proceeds.
  • a nuclease that specifically cleaves the base overlap structure cuts out the ⁇ detection moiety '' of the second nucleotide chain (when using a hairpin probe, the labeled fluorescent substance is combined with a fluorescence quencher.
  • This is a very sensitive liquid phase reaction in which the labels used in the Invader's Atsy method are sensitized because it works continuously (even at the separation stage), and in the case of performing a micro liquid phase reaction as in the present invention. Is a very suitable liquid phase reaction.
  • this method is very useful as a method that can efficiently detect SNPs that are the key to customized medicine. By applying the present invention to this method, it is simple and efficient. In particular, it is possible to detect SNPs, which is very significant for industry.
  • the above-described chain-type nucleotide chain 21 is a detection target to be contained in the first dispensing solution, and other invader methods described above are used.
  • the first dispensing solution is dispensed into the microwells of the detection instrument and then dried to detect the detection target on the inner wall of the detection instrument having a plurality of wells.
  • An object is attached, and the final reaction solution containing a reaction material for the detection object is brought into contact with the inner wall of the detection tool to which the detection object is attached, and a signal generated by this contact is detected.
  • the detection object can be evaluated.
  • the second dispensing force seal the detection operation is rushed, and if the force is not performed correctly, the contents will leak from the respective wells onto the surface of the detection instrument, Mixing them may adversely affect the evaluation of the detection object.
  • This working process is made more efficient by the present method of use 1 and 2 using the hermetically sealed device, and the yield of reaction under favorable conditions is improved.
  • the temperature-responsive substance is not particularly limited, but without additives such as salts, it is about 10-90 ° C, preferably about 40-70 ° C.
  • a substance that causes a phase change is preferable. Specifically, gelatin, agar, DPPC (DPPC) (
  • Dipalmitoyl phosphatidylcholine), poly (N-isopropylacrylamide), poly ( ⁇ -capula rataton) and the like can be mentioned, and gelatin is particularly preferable.
  • polyhydric alcohols in general, for example, polysaccharides such as dextran, starch syrup components such as maltose and trehalose, and further powers such as polyethylene glycol, xylitol, etc. Is preferred.
  • the temperature-responsive substance and the slowly-dissolving substance both of them, the holding substance!
  • Either one or both of them are selected, and usually the first It can be used by being contained in a dispensing solution.
  • the content of the retention substance in the first dispensing solution needs to be at least an amount that can sufficiently retain the detection target in a dry state, a moisturized state, or a swollen state.
  • the retained substance hydrates or swells, but if the amount of retained substance is not sufficient at that time, the detection target is completely retained in the retained substance. It will be a little free.
  • the liberated detection object is not preferable because it can be immediately mixed into adjacent wells when the wells communicate with each other via the reaction solution.
  • the temperature-responsive substance is gelatin, it is preferably contained in the range of 0.05-2 mass% with respect to the first dispensing solution. If it is less than 0.05% with respect to the solution, the detection target is not completely retained in the gelatin as the temperature responsive substance as described above, but is eluted in the reaction solution, and other substances are passed through the reaction solution. Detection objects in the well may come into contact with each other and the detection sensitivity may decrease. If the amount exceeds 2% by mass, the first dispensing solution itself will become excessively viscous, which may hinder dispensing. There is a tendency to occur.
  • the first dispensing solution is preferably prepared by adding and dissolving the detection target substance in an aqueous solution of the retentate in a liquefied (solated) state.
  • Other preparation methods are not limited to the method.
  • the first dispensing solution can be prepared immediately before dispensing the detection substrate to the well, and can be prepared in advance several days and several hours before dispensing.
  • the storage period as the first dispensing solution is preferably selected according to the stability of the detection target. Also, at least during dispensing, the first dispensing solution needs to be liquid. Furthermore, after adding the detection object, it is not preferable to set the temperature at which the detection object is decomposed or altered.
  • the detection method is such that the liquid first dispensing solution can be used for each well of the detection instrument described above.
  • a microdispensing machine such as an ink jet type microdispensing machine
  • the first dispensing solution in the well is dried (preferably when the retention substance is a slowly dissolving substance or when the retention substance is not used) or is cooled (at room temperature).
  • Reaction which contains a reactive substance for the detection target in the first dispensing solution after adhering to the well of the detection instrument (e.g., when the holding substance is a temperature-responsive substance).
  • the solution is brought into contact with the inner wall of the well where the first dispensing solution has been attached, and the temperature rises or falls.
  • the poly (N-isopropylacrylamide) described above solidifies as the temperature rises, It has a liquid nature. Therefore, when this is used as a temperature response substance, the temperature of the dispensing solution is lowered to the liquid temperature during the first dispensing, and the reaction temperature is increased to the solidification temperature after the dispensing. It is preferable to lower the temperature of the well to the liquid temperature at the time of detection by bringing the solution into contact with the solution.] By detecting the signal generated by releasing the detection target by dissolving it by leaving it, etc. An object can be evaluated.
  • FIG. 1 is a drawing showing an embodiment of a reaction substrate which is an object of the present sealing device.
  • FIG. 2 This is a schematic diagram of the overview of the Invaders Atssey method.
  • FIG. 3 is an overall perspective view of an embodiment of the sealing device.
  • FIG. 4 is a perspective view of a roller support of the sealing device.
  • FIG. 5 is a longitudinal sectional view of a roller support of the sealing device.
  • FIG. 6 is an explanatory view of a longitudinal section schematically illustrating a sealing process of a sealing film to a reaction substrate using the sealing device.
  • FIG. 7 is an overall perspective view schematically showing a sealing process of a sealing film to a reaction substrate using the sealing device.
  • FIG. 8 is an exploded perspective view of a storage portion of the sealing device.
  • FIG. 9 is a drawing illustrating an aspect of a storage unit capable of changing the horizontal angle.
  • FIG. 10 A drawing showing the manner in which the cassette is tightened with a set screw when the storage unit is also separated from the sealing device force.
  • FIG. 11 is a longitudinal sectional view schematically showing how the sealing device is used.
  • FIG. 3 is an overall perspective view of an embodiment 30 of the sealing device.
  • the sealing device 30 is configured as described below.
  • the pedestal 31 that supports the main body of the sealing device 30 has a pedestal plate 311 and four legs 312A-D (312D not shown) that support the pedestal plate 311 provided at the four corners of the pedestal plate 311! / Each of these four legs 312A-D is provided with a height adjustment mechanism that can adjust the height by, for example, the fitting length by screwing into the base plate 311. Is preferred.
  • a housing 32 and an electric motor 33 are placed on the pedestal plate 311.
  • the housing 32 includes one T-shaped bottom plate 321, two side plates 322A-B (322B not shown) fixed to the bottom plate 321 in a state where both T-shaped arm forces stand up, and the side
  • the top plate 323 is placed and fixed on the upper end of the plates 322A-B, and the plate-like body 324 is placed and fixed on the bottom plate 321.
  • a rail support 331 is placed and fixed on the plate-like body 324, and a rail fitting groove is provided along the length direction of the upper surface of the rail support 331.
  • a long plate-shaped guide rail 332 is fitted and fixed to the upper surface of the rail support 331 by fitting a convex portion 3321 provided in the length direction of the bottom surface of the rail 332 into the rail support 331.
  • a projecting member 333 is provided on one side surface of the rail support 331. This will be described later This is a stopper mechanism that prevents the feeding member 3411 from striking against the protruding member 333 when the slide stage 341 tries to move on the guide rail 332 beyond the limit.
  • a slide stage 341 is guided and supported on the guide rail 332 by a guide rail 332 via a bowl-shaped feeding member 3411 fixed to the bottom thereof.
  • the slide stage 341 can be moved along the rail 332 when the feeding member 3411 slides on the guide rail 332.
  • a recess 3412 into which the lower cassette 351 constituting the cassette 35 can be fitted is provided on the upper surface of the slide stage 341.
  • the lower cassette 351 is provided with a concave structure in which the reaction substrate 36 can be placed with the reaction side surface substantially exposed. Further, it is preferable that the lower cassette 351 is detachable from the recess 3412.
  • the roller support 37 is literally a member for supporting the sliding roller 39 in the sealing device 30.
  • the details of the roller support 37 are described in FIG. 4 (perspective view) and FIG. 5 (FIG. 4: longitudinal section in I).
  • the roller support 37 has a shape composed of a basic portion 371 and two saddle-shaped protrusions (372 mm).
  • the shaft 38 passes through the basic portion 371 in one direction as viewed in the direction of the arrow, and both ends thereof are rotatably supported by the side plates 322 ⁇ .
  • the roller support 37 is rotatable around a shaft rod 38.
  • the roller pressure adjustment dial 373 (which is the axis of the roller support 37) can be adjusted by moving the screw through the top plate 323.
  • the roller pressure adjusting stopper 375 (provided at a position biased in the direction of the arrow 2 in the direction of the arrow from the shaft rod 38 of the roller support 37). Is provided)
  • the roller pressure adjusting dial 373 is a male screw with a head 3731.
  • the elastic body support is provided at the tip thereof.
  • a bracket 3732 can be provided.
  • a washer 3734 is attached to the upper surface opening of the through-hole 3733 provided in the roller support 37 for screwing the roller pressure adjusting dial 373, and the washer 3734 and On the inner surface of the through-hole 3733, a female screw that can be screwed with the male screw of the roller pressure adjusting dial 373 is provided.
  • a cylindrical coil panel 374 suitable as an elastic body is sandwiched between upper surfaces of the elastic body receiving bracket 3732 and the roller support body 37, thereby giving a downward elastic force to the single support body 37. That is, a pressing force generated by screwing the roller pressure adjusting dial 373 through the cylindrical coil panel 374 is applied to the sliding roller 39, and as a result, an elastic and uniform pressure is applied to the reaction substrate 36. be able to.
  • the roller pressure adjusting stopper 375 is a male screw with a head 3751.
  • a washer 3753 is attached to the upper surface of the through hole 3752 provided in the roller support 37 for screwing the roller pressure adjusting stopper 375, and the inner surface of the washer 3753 and the Z or through hole 3752 is attached to the upper surface of the through hole 3752.
  • the roller pressure adjustment stopper 375 is provided with a female screw that can be screwed in with a male screw.
  • a screw contact member 376 is attached to the roller support 37 at a position where it comes into contact when the roller pressure adjusting stopper 375 is screwed.
  • the tip of the screw should be positioned at the desired height of the upper surface force of the roller support 37 at a position of the roller support 37 that is biased to the arrow 2 side of the shaft 38.
  • the two ends of the roller support 37 projecting part (372A.B) are supported by the sliding roller 39 on the side of the arrow 1 side, and round nuts with holes (391 ⁇ ⁇ ⁇ : ⁇ (Not shown) and is attached at the protrusions 372 mm.
  • the roller body 392 of the sliding roller 39 is in contact with the reaction-side surface 361 of the reaction substrate 36 placed in the concave structure of the lower cassette 351, and can slide on the surface 361 by its own rotational movement. It has become.
  • the rotational movement of the sliding roller 39 is supplied from the electric motor 33 connected directly or indirectly to the round nut 391B, and can rotate the sliding roller 39 in the forward direction or the reverse direction.
  • the roller speed of the sliding roller 39 is preferably variable. That is, in order to make it difficult to generate bubbles, it is preferable to slide the sliding roller 39 slowly. However, if it is too slow, the sealing efficiency is deteriorated, and the concave structure is dried in advance. There is a tendency that the substances that have been dissolved dissolve and move to the adjacent recesses and become easily contaminated. Therefore, it is preferable that the motor 33 has a function capable of adjusting the rotation speed, and thereby the sliding speed of the sliding roller 39 can be adjusted.
  • the round nut 391A is provided with a stopper for the rotational motion.
  • a small female screw 394 (FIG. 4) penetrating the round nut 391A is provided, and the corresponding male screw 393 can be used as a stopper for the rotational motion. That is, by screwing the male screw 393, the tip of the male screw 393 applies a frictional force to the protruding portion 372A, and prevents the sliding roller from being inadvertently rotated when the sealing device 30 is stationary. (When the sealing device 30 is activated, the male screw 393 is loosened).
  • the rod-shaped body 377 has an arrow on the slanting upper part and rear side in the vicinity of the sliding roller 39 (based on the two directions of arrows) at the projecting portion (372 ⁇ ⁇ ⁇ ) of the two force points of the single support 37. Visible in one direction.
  • one end of a plate panel 41 which is an elastic body, is fixed to the top plate 323, and a gripping tool 411 is provided at the other end.
  • one end of the wire panel 42 is fixed to the top plate 323, and a gripping tool 421 is provided at the other end.
  • One end of the seal paper 412 (the seal film 4121 and the release paper 4122 are bonded) is clamped and fixed by the gripping tool 411 of the board panel 41, and the seal film 4121 and the release paper 4122
  • the sealing film 4121 is fixed by the pinching force between the sliding roller 39 and the reaction substrate 36, and the release paper 4 122 passes through the lower side of the rod-shaped body 377 and is fixed by the gripping tool 421.
  • the release film 4122 does not sag toward the reaction substrate 36 due to the tension between the one end and the other end, and the sealing film 4121 is in close contact with the reaction substrate 36 with appropriate tension, and the state is maintained. I'm leaning.
  • FIG. 6 ( ⁇ ) — ( ⁇ ) (longitudinal sectional view) and FIG. 7 (overall perspective view) show a seal against the reaction substrate 36 using the sealing device 30.
  • the sliding roller 39 is slid by rotating along the reaction side surface 361 of the reaction substrate 36 by the power of the electric motor 33, so that the unit 39
  • the sealing film 4121 disposed between the reaction side surface 361 and the reaction side surface 361 is sent out while keeping in close contact with the reaction side surface 361, and the sealing film 4121 is sealed to the reaction side surface 361. It is possible to wear.
  • the final reaction liquid 431 is sealed while being dropped near the moving direction side of the sliding roller 39.
  • the dropping of the final reaction solution can be performed manually using a dropper or the like, but it is also preferable to use an automatic dropping mechanism. For example, as shown in FIG.
  • the final reaction liquid 431 is charged into a container 43 equipped with a cylinder / piston mechanism, and the piston 432 portion of the container moves into the cylinder according to the forward movement of the feeding member 3411.
  • the portion 433 to be pushed in the final reaction liquid in the cylinder 433 is synchronized with the forward movement of the feeding member 3411, that is, the sliding of the sliding roller 39 with respect to the reaction substrate 36.
  • 431 can automatically drop the final reaction solution onto a desired position on the reaction substrate 36 via the tube 434.
  • a groove 3513 (FIG. 7) is preferably provided around the reaction substrate 36 placed in a concave structure 3511 (FIG. 8) provided in the lower cassette 351 described later.
  • the incubated reaction substrate 36 ′ can be easily taken out from the lower cassette 351 by hooking the incubated reaction substrate 36 ′ from the groove 3513 with an instrument such as a spatula.
  • a desired sliding motion on the reaction substrate 36 can be performed by the rotation of the roller 39 by transmitting the power of the electric motor 33 to the sliding roller 39. It is not limited to. For example, by transmitting the power of the electric motor 33 to the slide stage 341 and sliding the slide stage on the guide rail 332, the sliding roller 39 slides on the reaction substrate 36 in synchronization with this movement, The same function as the sealing device 30 can be exhibited. Further, the power of the electric motor can be transmitted to both the sliding roller 39 and the slide stage 341, and both can be moved in the same manner as described above, so that the same function as the sealing device 30 can be exhibited.
  • the upper cassette 352 constituting the cassette 35 which is preferably detachable is the lower cassette described above.
  • the cassette 351 When the cassette 351 is separated from the main sealing device 30, it can be attached as a lid member to the lower cassette 351.
  • the upper and lower cassettes are attached by screwing through the assembly holes 3521A-D. It is preferable to fix.
  • a cushioning material such as a urethane pad is interposed between the upper cassette 352 and the lower cassette 351. It is conceivable that the buffer material is bent and the force pressing the reaction substrate 36 is weakened. In order to prevent this, it is preferable that the upper cassette 352 can be always pressed against the lower cassette 351 with a certain force by the coin-like panel.
  • FIG. 8 is an exploded perspective view of the “housing portion” of the main sealing device 30 and the usage mode of the housing portion as the “main housing tool”.
  • the storage portion of the main sealing device 30 is composed of the slide stage 341, and preferably the lower cassette 351, which forms a cassette 35 in a string with the upper cassette 352.
  • the lower cassette 351 can be fitted and placed in a detachable state in a recess 3412 provided on the upper surface of the slide stage 341.
  • the recess 3412 has a cross-sectional shape that allows the lower cassette 351 to be fitted and placed at different plane angles so that the place where the lower cassette 351 is fitted and placed can be changed. Yes.
  • the bottom of the recess 3412 is provided with four force-rotating stage rotation slots 3 413A-D, and each slot has a fixing screw 3414A-D force at its tip that is the feed member.
  • the heads of the fixing screws which are screwed and fixed at 3411 and have a diameter larger than the hole width of the rotation slots 3413A and D, are hooked on the rotation slots. .
  • the fixing screw 341 4A-D slides on the rotating long hole 3413A-D according to the force, and these are moved at the desired position. It is possible to fix the selected horizontal angle of the slide stage 341 on the guide rail 332 by tightening the fixing screws.
  • the lower cassette 351 is provided with a concave structure 3511 having a shape capable of fitting and mounting the reaction substrate 36 in a state where the reaction side surface is substantially exposed.
  • Upper cassette 352 In the upper cassette 352, an assembly screw hole 3512A-D is provided at a position overlapping with the fixing screw hole 3521A-D in the upper cassette 352.
  • FIG. 9 is a drawing showing an example of a stage that can change the horizontal angle.
  • the sealing mode can be varied by controlling the horizontal angle of the reaction substrate 36.
  • the cross-sectional shape of the concave portion 3412 of the slide stage 341 can be fitted and mounted on the lower cassette 351 at different plane angles without using the rotating long holes 3413A and 1D.
  • the lower cassette 351 can be placed at the desired horizontal angle [Fig. 9 (A) (B)].
  • the plane angle of the reaction substrate 36 can be controlled by rotating the slide stage 341 itself to a desired plane angle and fixing it by the function of the stage rotation slot 3413A-D described above. There is [Figure 9 (C)].
  • the horizontal angle of the reaction substrate 36 in the sealing device 30 can be controlled more freely by combining the above-described FIGS. 9 (A)-(C). That is, for example, the means shown in FIGS. 9 (1) and 1 (2) can be used as rough horizontal angle adjusting means, and the means (3) can be used as a horizontal angle fine adjusting means.
  • the above reaction substrate 36 can be obtained by attaching the upper cassette 352 to the lower cassette 351. It is preferable to seal the concave structure 3511 in a state where 'is stored in the concave structure 3511.
  • a cushioning material 354 such as a urethane pad between the reaction substrate 36 ′ and the upper cassette 352 reduces the mounting pressure on the reaction substrate 36 ′ and increases the reliability of storage. It is suitable for planning.
  • the fixing screw hole 3521A-D provided in the upper cassette 352 and the lower force It is preferable to tighten set screw holes 3511A-D with set screws 353A-D. Also in this case, by using the set screw 353A-D as a screw using a panel mechanism, it is possible to prevent the pressure applied to the reaction substrate 36 'from becoming excessively large by tightening the screw.
  • the set screw 353 is capable of tightening the cassette 35 in the manner shown in FIG. 10, for example.
  • the set screw 353 is composed of a head 31 3531 and a shaft ⁇ 3532 force.
  • a screw part 3532A is provided near the tip of the shaft ⁇ 3532 and can be screwed into the female screw provided in the assembly screw hole 3511. It is.
  • the cylindrical portion 3532B has a smaller diameter than the inner diameters of the fixing screw hole 3521 and the assembly screw hole 3511.
  • a panel receiver 3533 is arranged below the head 3531.
  • the lower cassette 351, reaction substrate 36, sealing film 4121, cushioning material 353, and upper cassette 352 are stacked in the same manner as described above, and the coil diameter is set on the shaft 3532 of the set screw 353 than the fixing screw hole.
  • the screw part 3532A is screwed in the screw hole for assembly,
  • the buffering force of the compression coil panel 354 prevents the pressure applied to the reaction substrate 36 ′ from becoming excessively large.
  • FIG. 11 is a longitudinal sectional view schematically showing how the sealing device 30 is used.
  • the reaction substrate 36 is fitted and placed in the concave structure 3511 provided in the lower cassette 351.
  • the depth of the groove structure 3511 is slightly shallower (about 0.1-0. 5 mm) than the thickness of the reaction substrate 36.
  • the reaction-side surface 361 of the reaction substrate 36 is slightly exposed in the lower cassette 351.
  • the lower cassette 351 is provided with the groove 3513, and further, a gradient (35111) from the outside toward the inside is provided in the vicinity of the bottom surface of the side surface of the concave structure 3511.
  • FIG. 11 (B) shows the sealing film 4121 in the same manner as in FIG.
  • the present invention provides an automated means for sealing the reaction side surface with a thin film such as a film as part of preparation for a detection substrate capable of performing biochemical liquid phase reactions intensively. Is done.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

L’invention concerne un moyen automatique de scellement hermétique de la surface latérale de réaction avec un film mince, par exemple un film, comme configuration préliminaire dans un substrat de détection pour réaliser une réaction de phase liquide biochimique de manière collective, comprenant (1) une section contenant le substrat pourvue d’une structure en retrait susceptible d’installer un substrat capable de réaliser une réaction de phase liquide biochimique de manière collective tout en exposant sensiblement la surface latérale de réaction, (2) un galet susceptible de coulisser le long de la surface latérale de réaction du substrat monté sur la section contenant le substrat, et (3) un mécanisme d’évacuation capable de sceller la surface latérale de réaction avec le film mince en faisant coulisser le galet le long de la surface latérale de réaction du substrat en évacuant ainsi le film mince disposé entre le galet et la surface latérale de réaction tout en le maintenant en contact étroit avec la surface latérale de réaction.
PCT/JP2004/016274 2004-11-02 2004-11-02 Dispositif de scellement hermétique de micro matrice Ceased WO2006048926A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP2004/016274 WO2006048926A1 (fr) 2004-11-02 2004-11-02 Dispositif de scellement hermétique de micro matrice
JP2006542196A JPWO2006048926A1 (ja) 2004-11-02 2004-11-02 マイクロアレイの密封装置

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2004/016274 WO2006048926A1 (fr) 2004-11-02 2004-11-02 Dispositif de scellement hermétique de micro matrice

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WO2006048926A1 true WO2006048926A1 (fr) 2006-05-11

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007331817A (ja) * 2006-06-16 2007-12-27 Showa Seiki Kk マイクロプレート用シーラー
JP2009115620A (ja) * 2007-11-06 2009-05-28 Furukawa Co Ltd 分注シール装置およびウェル開口部のシール方法
CN111172008A (zh) * 2018-11-09 2020-05-19 开启基因股份有限公司 自动化核酸萃取的方法及装置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1111405A (ja) * 1997-05-29 1999-01-19 Beckman Coulter Inc 容器を密封する装置及び方法
JP2000335509A (ja) * 1999-05-31 2000-12-05 Micronics Kk マイクロプレートの密封方法およびマイクロプレートの自動密封装置
WO2002025289A1 (fr) * 2000-09-18 2002-03-28 I-Card Corporation Ensemble de micro-coupelles et procede permettant d'enfermer hermetiquement des liquides au moyen de cet ensemble
WO2003031972A1 (fr) * 2001-10-05 2003-04-17 Bml, Inc. Plaque de detection

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1111405A (ja) * 1997-05-29 1999-01-19 Beckman Coulter Inc 容器を密封する装置及び方法
JP2000335509A (ja) * 1999-05-31 2000-12-05 Micronics Kk マイクロプレートの密封方法およびマイクロプレートの自動密封装置
WO2002025289A1 (fr) * 2000-09-18 2002-03-28 I-Card Corporation Ensemble de micro-coupelles et procede permettant d'enfermer hermetiquement des liquides au moyen de cet ensemble
WO2003031972A1 (fr) * 2001-10-05 2003-04-17 Bml, Inc. Plaque de detection

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007331817A (ja) * 2006-06-16 2007-12-27 Showa Seiki Kk マイクロプレート用シーラー
JP2009115620A (ja) * 2007-11-06 2009-05-28 Furukawa Co Ltd 分注シール装置およびウェル開口部のシール方法
CN111172008A (zh) * 2018-11-09 2020-05-19 开启基因股份有限公司 自动化核酸萃取的方法及装置
CN111172008B (zh) * 2018-11-09 2021-09-28 开启基因股份有限公司 自动化核酸萃取的方法及装置

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