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WO2022071716A1 - Chambre pour réaction d'acide nucléique, procédé de réaction d'acide nucléique l'utilisant, et cartouche pour le traitement d'échantillon comprenant celle-ci - Google Patents

Chambre pour réaction d'acide nucléique, procédé de réaction d'acide nucléique l'utilisant, et cartouche pour le traitement d'échantillon comprenant celle-ci Download PDF

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Publication number
WO2022071716A1
WO2022071716A1 PCT/KR2021/013209 KR2021013209W WO2022071716A1 WO 2022071716 A1 WO2022071716 A1 WO 2022071716A1 KR 2021013209 W KR2021013209 W KR 2021013209W WO 2022071716 A1 WO2022071716 A1 WO 2022071716A1
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WIPO (PCT)
Prior art keywords
flow path
nucleic acid
sample region
acid reaction
chamber
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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
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PCT/KR2021/013209
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English (en)
Inventor
Jae Young Kim
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Seegene Inc
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Seegene Inc
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Priority to KR1020237011819A priority Critical patent/KR20230058722A/ko
Publication of WO2022071716A1 publication Critical patent/WO2022071716A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • 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
    • 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
    • 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
    • B01L2200/04—Exchange or ejection of cartridges, containers or reservoirs
    • 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
    • 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
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/142—Preventing evaporation
    • 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
    • B01L2200/16—Reagents, handling or storing thereof
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • 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
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0883—Serpentine channels
    • 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
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0457—Moving fluids with specific forces or mechanical means specific forces passive flow or gravitation
    • 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
    • C12Q1/686—Polymerase chain reaction [PCR]

Definitions

  • the disclosure relates to a chamber for nucleic acid reaction, a method for the nucleic acid reaction using the same, and a cartridge for sample processing comprising the same.
  • nucleic acid-based in vitro molecular diagnosis such as accurate analysis of pathogens and gene analysis of patients becomes more significant and its demand is on the rise.
  • Nucleic acid-based molecular diagnosis is performed by extracting nucleic acids from a sample and then checking the presence or absence of a target nucleic acid among the extracted nucleic acids.
  • the sample processing process of extracting nucleic acid from a sample includes sequentially mixing the sample and various reagents and removing residues other than the nucleic acid. Such a sample processing process requires an elaborate processing of a small amount of solution and, thus, is mostly performed manually by an experimenter or using a piece of liquid handling equipment that may be precisely controlled. Conventional liquid handling equipment is costly and needs professional manpower.
  • the POC system for nucleic acid detection processes extraction and nucleic acid detection from a sample in one-step in one cartridge.
  • the POC system is designed to proceed with the sample processing process immediately after sample collection, so it has strengths in the local medical field.
  • the POC-based extraction process and the POC-based nucleic acid detection process are performed by sequentially moving the sample to a plurality of sample processing chambers and a plurality of a nucleic acid reaction chamber.
  • the movement of the sample or its processed material between the chambers includes a method of forming an inter-chamber flow path and controlling it with a valve, and a method of moving a solution between the chambers by a liquid transport means.
  • a cartridge used in the POC system for detecting nucleic acid includes an extraction chamber for performing a sample processing process for extracting nucleic acid, as well as a nucleic acid reaction chamber in which amplification of the extracted nucleic acid and optical measurement for detecting a target nucleic acid are performed.
  • Nucleic acid amplification reaction well known as polymerase chain reaction (PCR) includes repeated cycles of doube-stranded DNA denaturation, annealing of the oligonucleotide primers to DNA templates, and extension/elongation of the primers with the DNA polymerase (Mullis et al., U.S. Patent Nos. 4,683,195, 4,683,202, and 4,800,159; Saiki et al., (1985) Science 230, 1350-1354).
  • PCR polymerase chain reaction
  • a sample solution containing the extracted nucleic acid is mixed with a reaction mixture containing dNTPs and the like to perform an amplification reaction, and the temperature of the mixed solution is changed according to a predetermined sequence and an amplification reaction is performed.
  • the DNA denaturation is performed at about 95°C
  • the annealing and primer extension are performed at a temperature lower than 95°C, i.e. a temperature ranging from 55°C to 75°C.
  • the temperature and reaction time for each step of denaturation, annealing, and extension should be set differently depending on each sample, the nucleic acid to be analyzed, and the sequences of oligonucleotides such as primers and probes used for analysis.
  • the sample solution and the reaction mixture used for this reaction are highly viscous, since they include various substances such as dNTPs, enzymes, and buffers. Furthermore, it is difficult to uniformly mix the sample solution and the reaction mixture due to the nature of the POC system that performs the amplification reaction with a small amount of solution. If the sample solution and the reaction mixture are not uniformly mixed, there is a problem in that it is difficult to detect the target nucleic acid by the amplification reaction. In addition, in the POC system, since the amplification reaction is performed with a small amount of solution, there is a problem of causing a fatal error in the detection result if even the slightest evaporation of the mixed solution occurs.
  • the inventors have made intensive researches to develop a nucleic acid reaction chamber and a nucleic acid reaction method capable of uniformly mixing a sample solution containing the extracted nucleic acid and a reaction mixture for performing a nucleic acid amplification reaction. Also efforts have been made to develop a nucleic acid reaction chamber and a nucleic acid reaction method capable of preventing evaporation of the mixed solution during the nucleic acid amplification reaction.
  • a nucleic acid reaction chamber including a body portion comprising a flow path and a sample region, wherein the flow path includes a first flow path and a second flow path, wherein the sample region is individually connected to lower portions of the first flow path and the second flow path, wherein the first flow path and the second flow path communicate with the outside, respectively, a cartridge for sample analysis including the same, and a nucleic acid reaction method using the same.
  • the disclosure aims to provide the nucleic acid reaction chamber including a body portion comprising a flow path and a sample region, wherein the flow path includes a first flow path and a second flow path, whererin individually connected to lower portions of the first flow path and the second flow path, wherein the first flow path and the second flow path communicate with the outside, respectively.
  • the disclosure also aims to provide the cartridge for the sample analysis including the nucleic acid reaction chamber.
  • the disclosure also aims to provide the nucleic acid reaction method using the nucleic acid reaction chamber.
  • a nucleic acid reaction chamber including a body portion comprising a flow path and a sample region, wherein the flow path includes a first flow path and a second flow path, wherein the sample region is individually connected to lower portions of the first flow path and the second flow path, wherein the first flow path and the second flow path communicate with the outside, respectively.
  • a cartridge for the sample analysis including the nucleic acid reaction chamber.
  • nucleic acid reaction method using the chamber for nucleic acid reaction comprising: an injection step of injecting a sample solution through the flow path, a mixing step of mixing the reaction mixture in the nucleic acid reaction chamber and the sample solution to form a mixed solution, a covering step of forming a liquid layer of a water-immiscible material on the top side of the mixed solution and a nucleic acid reaction step of performing a nucleic acid reaction by controlling the temperature of the sample region.
  • the mixing of the sample solution and the reaction mixture may be uniformly performed, and the reliability of the detection result may be improved.
  • the mixed solution may be easily heated or cooled during the nucleic acid amplification reaction, and target nucleic acid detection using the fluorescence of the optical module may be easily performed.
  • FIG. 1 is a perspective view of a nucleic acid reaction chamber according to an embodiment of the disclosure.
  • FIG. 2 is a front view of a nucleic acid reaction chamber according to an embodiment of the disclosure.
  • FIG. 3 is a perspective view of a nucleic acid reaction chamber according to an embodiment of the disclosure.
  • FIG. 4 is a front view of a nucleic acid reaction chamber according to a nucleic acid reaction step according to an embodiment of the disclosure.
  • FIG. 5 illustrates a part of a nucleic acid reaction chamber according to an embodiment of the disclosure.
  • FIG. 6 is a side view of a cartridge for sample analysis according to an embodiment of the disclosure.
  • FIG. 7 is a flowchart of a nucleic acid reaction method according to an embodiment of the disclosure.
  • Such denotations as “first,” “second,” “A,” “B,” “(a),” and “(b),” may be used in describing the components of the present disclosure. These denotations are provided merely to distinguish a component from another, and the essence of the components is not limited by the denotations in light of order or sequence.
  • a component is described as “connected,” “coupled,” or “linked” to another component, the component may be directly connected or linked to the other component, but it should also be appreciated that other components may be “connected,” “coupled,” or “linked” between the components.
  • a nucleic acid reaction chamber including a body portion comprising a flow path and a sample region, wherein the flow path includes a first flow path and a second flow path, wherein the sample region is individually connected to lower portions of the first flow path and the second flow path, wherein the first flow path and the second flow path communicate with the outside, respectively.
  • FIG. 1 is a perspective view of a nucleic acid reaction chamber according to an embodiment of the disclosure.
  • sample may encompass biological samples (e.g., cells, tissues, or fluids from biological sources) and non-biological samples (e.g., foods, water, and soil).
  • the biological samples include virus, germs, tissues, cells, blood (e.g., whole blood, plasma, and serum), lymph, bone marrow fluid, saliva, sputum, swab, aspiration, milk, urine, stool, ocular humor, semen, brain extracts, spinal fluid, joint fluid, thymus fluid, bronchoalveolar lavage fluid, ascites, and amniotic fluid.
  • the sample may also include a natural nucleic acid molecule isolated from biological sources and a synthetic nucleic acid molecule.
  • the sample may include additional substances such as water, deionized saline, pH buffer, acidic solution, and basic solution.
  • Sample processing refers to a series of processes to primarily separate an analyte from the sample to thereby obtain a material in the state capable of detection reaction.
  • the sample processing' may further include the process of detecting a target analyte from the substance in the detection reaction-capable state.
  • the analyte may be, for example, a nucleic acid.
  • the sample processing may include the process of extracting a nucleic acid.
  • a nucleic acid reaction refers to a series of physical and chemical reactions that generate a signal depending on the presence or amount of a nucleic acid of a specific sequence in a sample.
  • the nucleic acid reaction may be a reaction including binding of a nucleic acid of a specific sequence in the sample to another nucleic acid or substance, and replication, cleavage or degradation of the nucleic acid of the specific sequence in the sample.
  • the nucleic acid reaction may be a reaction involving a nucleic acid amplification reaction.
  • the nucleic acid amplification reaction may include amplification of a target nucleic acid.
  • the nucleic acid amplification reaction may be a reaction for specifically amplifying the target nucleic acid.
  • the nucleic acid reaction may be a signal-generating reaction, which is a reaction capable of generating a signal depending on the presence/absence or amount of the target nucleic acid in the sample.
  • This signal-generating reaction may be a genetic analysis process such as PCR, real-time PCR, microarray.
  • Various methods are known for generating an optical signal indicative of the presence of the target nucleic acid using the nucleic acid reaction.
  • Representative examples include: TaqManTM probe method (US Pat. No. 5,210,015), molecular beacon method (Tyagi et al., Nature Biotechnology v.14 MARCH 1996), Scorpion method (Whitcombe et al., Nature Biotechnology 17:804- 807 (1999)), Sunrise or Amplifluor method (Nazarenko et al., 2516-2521 Nucleic Acids Research, 25(12):2516-2521 (1997), and U.S. Patent No. 6,117,635), Lux method (U.S. Patent No. 7,537,886), CPT (Duck P, et al.
  • hybridization probe Bosset PS, et al., Clin Chem 2000, 46, 147-148
  • PTOCE PTO cleavage and extension
  • PCE-SH PTO Cleavage and Extension-Dependent Signaling Oligonucleotide Hybridization
  • PCE-NH PTO Cleavage and Extension-Dependent Non-Hybridization
  • PCT/KR2013/012312 PCT/KR2013/012312
  • CER method WO 2011/ 037306
  • a target nucleic acid may be amplified in a variety of ways.
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • SDA strand displacement amplification
  • the nucleic acid amplification reaction may be performed while accompanying a change in temperature
  • the nucleic acid amplification device may include a denaturing step, an annealing step, an extension (or amplification) step (extension step) in order to amplify DNA (deoxyribonucleic acid) having a specific nucleotide sequence.
  • the nucleic acid reaction chamber 100 includes a body portion 110.
  • the body portion 110 includes a flow path and a sample region 130.
  • the flow path includes a first flow path 130 and a second flow path 140.
  • the body portion 110 includes a first flow path 130, a second flow path 140, and a sample region 150.
  • a nucleic acid reaction of the sample solution is performed in the sample region 150.
  • the nucleic acid reaction chamber 100 may configure a part of the cartridge 600 for analyzing a sample.
  • the port 120 of the nucleic acid reaction chamber 100 may be coupled to the cartridge 600 for sample analysis.
  • the cartridge 600 for the sample analysis may include a plurality of chambers, and some of the plurality of chambers may be the nucleic acid reaction chamber 100.
  • the plurality of chambers may be disposed in one direction such as the longitudinal direction of the cartridge 600.
  • the plurality of chambers are spaces for storing materials necessary for a process of extracting a substance to be detected from a sample and performing physical and chemical processes for extraction.
  • the detection target substance may be, for example, a nucleic acid.
  • the plurality of chambers may include a sample chamber, a holding chamber, and the like.
  • the sample chamber is a chamber in which the collected sample is accommodated
  • the holding chamber is a chamber for holding materials necessary for the sample processing reaction, such as magnetic particles, crushing solution, washing solution, and elution solution, respectively.
  • the number of chambers included in the cartridge 600 of the present disclosure may be configured differently depending on the sample processing method.
  • the number of chambers is not particularly limited, but may be, for example, 5, 6, 7, or 8 or more, and may be 20, 15, 14, 13, or 12 or less.
  • the number of nucleic acid reaction chambers 100 included in the cartridge 600 of the present disclosure is not particularly limited, but may be, for example, 1 or 2 or more, and may be 5, 10, or 20 or less.
  • the cartridge 600 of the present disclosure is operated by a sample processing device (not shown) to perform a desired reaction.
  • the cartridge 600 is accommodated in the sample processing device and may interact with various parts, such as a moving module or a heat transfer module included in the sample processing device.
  • the solution between each chamber may be transferred by a pipette module and the moving module of the sample processing device.
  • the pipette module may move between the plurality of chambers by the moving module to transfer the solution.
  • the sample solution containing the extracted nucleic acid is injected into the nucleic acid reaction chamber 100 by the pipette module. That is, the sample solution may be injected into the nucleic acid reaction chamber 100 through a first opening 121 of the first flow path 130 and/or a second opening 122 of the second flow path 140.
  • nucleic acid reaction chamber 100 of the present disclosure will be described with reference to FIGS. 1 to 4 and the nucleic acid reaction method 700 of the present disclosure with reference to FIG. 7 will be described.
  • the nucleic acid reaction method 700 of the present disclosure is a nucleic acid reaction method using the nucleic acid reaction chamber 100, and includes an injection step S710, a mixing step S720, a covering step S730, and a nucleic acid reaction step S740.
  • the injection step S710 is a step of injecting the sample solution through the first flow path 130 and/or the second flow path 140 (refer to (A) and (B) of FIG. 4), and the injected sample solution is located in the sample region 150.
  • the mixing step S720 is a step of mixing the reaction mixture (R) and the sample solution for the nucleic acid reaction to form a mixed solution (refer to (B) to (E) of FIG. 4), and the reaction mixture may be present in the nucleic acid reaction chamber 100.
  • the covering (masking, coating, anti-vaporizing) step is a step of forming a liquid layer of a water-immiscible (hydrophobia, anti-vaporizing) material on the top side of the mixed solution (refer to (E) and (F) of FIG. 4).
  • the nucleic acid reaction step S740 is a step to prevent evaporation of the mixed solution.
  • the nucleic acid reaction step S740 is a step of performing a nucleic acid reaction by controlling the temperature of the sample region 150. For example, a thermal module of the sample processing device heats or cools the nucleic acid reaction chamber 100.
  • the body portion 110 further includes an accommodating portion 160, a partition portion 112 and the like as well as the first flow path 130, the second flow path 140, and the sample region 150.
  • the body portion 110 is configured in a thin plate shape, and the first flow path 130, the second flow path 140, and the sample region 150 are configured to be engraved on one surface.
  • the first flow path 130, the second flow path 140, the sample region 150 and the like may be covered by a barrier layer 310 attached to the one surface (refer to FIG. 3).
  • the first flow path 130 and the second flow path 140 may be paths which connect the first opening 121 and the first sample region 151 and connect the second opening 122 and the second sample region 152, respectively.
  • At least one accommodating portion 160 configured to communicate with the flow path is provided in the body portion 110. That is, the body portion 110 is provided with at least one accommodating portion 160 configured to communicate with the at least one of the first flow path 130 and the second flow path 140. According to an embodiment of the present disclosure, the body portion 110 is provided with at least one accommodating portion 160 communicating with the first flow path 130 and the second flow path 140 and the first accommodating portion 161 communicates with the first flow path 130 and the second accommodating portion 162 communicates with the second flow path 140.
  • the first flow path 130 includes a first auxiliary sample region 131
  • the second flow path 140 includes a second auxiliary sample region 141
  • the first auxiliary sample region 131 is located on the first sample region 151
  • the second auxiliary sample region 141 is located on the second sample region 152.
  • the sample region 150 is individually connected to the lower portions of the first flow path 130 and the second flow path 140. That is, the lower portion of the first flow path 130 and the lower portion of the second flow path 140 are respectively connected to the sample region 150, and the lower portion of the first flow path 130 is connected to the first sample region 151 and the lower portion of the second flow path 140 is connected to the second sample region 152, respectively.
  • the body portion 110 may include a partition wall 111 provided between the first flow path 130 and the second flow path 140, and the first flow path 130 and the second flow path 140 may be partitioned by the partition wall 111.
  • first flow path 130 and the second flow path 140 communicate with the outside, respectively so that the sample solution may be injected, and the sample solution is injected into the first flow path 130 and/or the second flow path 140 in the injection step S710.
  • the sample solution is located in the sample region 150.
  • the first flow path 130 and the second flow path 140 may be configured to be inclined upwardly or vertically from one end toward the other end.
  • the nucleic acid reaction chamber 100 may further include a port portion 120 provided on the top side of the body portion 110, and the first opening 121 through which the first flow path 130 communicates and the second opening 122through which the second flow path 140 communicates is provided on the top surface of the port portion 120.
  • the body portion 110 and the port portion 120 may be integrally configured.
  • the first flow path 130 and the second flow path 140 may communicate with the outside through the first opening 121 and the second opening 122 provided on the top surface of the port portion 120, respectively.
  • Injection of the sample solution may be performed by the pipette module of the sample processing device, and the pipette tip of the pipette module accommodating the sample solution is inserted into the first opening 121 and/or the second opening 122, and the sample solution may be injected.
  • air is injected or sucked through the first opening 121 or the second opening 122, and the sample solution may be mixed with the reaction mixture (R), and a nozzle for injecting or sucking the air may be inserted into the first opening 121 or the second opening 122.
  • first passage 171 connecting the top portion of the first flow path 130 to the first opening 121 and the second passage 172 connecting the top portion of the second flow path 140 to the second opening 122 may be configured in the inside of the body portion 110.
  • the first flow path 130, the second flow path 140, and the sample region 150 may be engraved on one surface of the body portion 110 as described above, and the first passage 171 and the second passage 172 may connect the passage on one surface of the body portion 110 and the opening on the top surface of the port portion 120 in the inside of the body portion 110 and the port portion 120, respectively.
  • the port portion 120 may include at least one recess 123 formed along the periphery of the first opening and/or second opening.
  • the recess 123 may be configured on the top surface of the port portion 120 around the both of the periphery of the first opening 121 and the periphery of the second opening 122, respectively, or one of the periphery of the first opening 121 and the periphery of the second opening 122.
  • the nucleic acid reaction chamber 100 may be configured of a material having a predetermined elasticity (e.g., polycarbonate (PC) or polypropylene (PP)).
  • PC polycarbonate
  • PP polypropylene
  • the sample solution located in the sample region 150 is mixed with the reaction mixture (R) through the mixing step S720.
  • the reaction mixture (R) refers to a mixture of substances required for the nucleic acid reaction.
  • the reaction mixture (R) may include at least one or more substances from the group consisting of dNTPs, primers, probes, buffers, salts and DNA polymerases.
  • the mixed solution in which the sample solution and the reaction mixture (R) are mixed is heated or cooled in the nucleic acid reaction step S740, and the nucleic acid amplification reaction is performed.
  • the reaction mixture (R) may be provided in the sample region 150.
  • the reaction mixture (R) may be provided in a solid state in the sample region 150, and is injected in the injection step S710 and mixed with the sample solution located in the sample region 150.
  • the solid reaction mixture may be freeze-dried or lyophilization to form pellets or cakes.
  • the lyophilization of the reagent may be performed by a method known in the art, and includes dehydration by sublimation in a vacuum environment.
  • the solid reaction mixture may contain a lyoprotectant such as sugar or polyalcohol for the lyophilization.
  • the reaction mixture (R) may be injected through the opening of the first flow path 130 and/or the opening of the second flow path 140, but it is more convenient and quick to prepare the nucleic acid in advance in the body portion 110.
  • the reaction may be performed, and the amount of the reaction mixture mixed with the sample solution may be more precisely controlled.
  • the first flow path 130, the second flow path 140, and the sample region 150 are configured by being engraved on one surface of the body portion 110 and covered by the barrier layer 310 attached to the engraved surface.
  • the reaction mixture (R) may be prepared in advance inside the body portion 110.
  • the reaction mixture (R) may be provided in the first sample region 151.
  • the mixing of the sample solution and the reaction mixture (R) may be performed by injecting the air or sucking the air through the first flow path 130 or the second flow path 140. That is, according to one embodiment of the present disclosure, the mixing step S720 includes an injection step of injecting the air and a suction step of sucking the air through the first flow path 130 or the second flow path 140. In the mixing step S720, the injection step and the suction step may be alternately performed at least two times or more, respectively. The injection step and the suction step are performed, and the sample solution located in the sample region 150 moves from the first flow path 130 toward the second flow path 140 or from the second flow path 140 toward the first flow path 130 and accordingly, the sample solution and the reaction mixture (R) are mixed.
  • the body portion 110 of the nucleic acid reaction chamber 100 further includes a partition portion 112 partitioning the sample region 150 into the first sample region 151 and the second sample region 152 in in the longitudinal direction so that the sample solution and the reaction mixture (R) may be uniformly mixed, wherein the lower end of the partition portion 112 and the lower surface of the sample region 150 are spaced apart from each other and the first sample region 151 and the second sample region 152 are connected to each other.
  • the body portion 110 includes the partition portion 112, even when the sample solution is small, the sample solution and the reaction mixture (R) may be uniformly mixed. Despite the viscosity of the reaction mixture (R) the sample solution and the reaction mixture (R) may be uniformly mix.
  • the nucleic acid amplification reaction is normally performed only in the region where the content of some reaction mixture (R) is relatively high, and no amplification reaction is performed or only a very small number of amplification reactions are performed in the region where the content of the remaining reaction mixture (R) is relatively low, and even if the amplification reaction is performed, there may be cases in which the target nucleic acid is not amplified, which may reduce the reliability of the detection result.
  • the partition portion 112 is provided to prevent non-uniform mixing of the sample solution and the reaction mixture (R).
  • the partition portion 112 partitioning the sample region 150 in the longitudinal direction means that the sample region 150 is partitioned in the longitudinal direction of the first flow path 130 and the second flow path 140. That is, the sample region 150 is divided into the first sample region 151 connected to the first flow path 130 and the second sample region 152 connected to the second flow path 140 by the partition portion 112.
  • the first sample region 151 and the second sample region 152 are provided to be connected to each other, and the sample solution moves from the first flow path 130 toward the second flow path 140 or from the second flow path 140 toward the first flow path 130, and is mixed with the reaction mixture (R) as it reciprocates between the first sample region 151 and the second sample region 152.
  • the partition portion 112 may be configured in a vertical direction, and may be configured from the lower end of the partition wall 111 downward. That is, the partition wall 111 divides the first flow path 130 and the second flow path 140, and the partition portion 112 divides the first sample region 151 and the second sample region 152.
  • the top end of the partition portion 112 is connected to the partition wall 111 and the lower end thereof is provided to be spaced apart from the lower surface of the sample region 150, and the first sample region 151 and the second sample region 152 are connected to each other.
  • the partition portion 112 may be configured such that the first sample region 151 is larger than the second sample region 152.
  • the first sample region 151 is partitioned larger than the second sample region 152 means that the sample region 150 is not exactly divided in half by the partition portion 112, but that one is larger than the other.
  • the first sample region 151 is larger than the second sample region 152 means that the volume of the first sample region 151 is larger than that of the second sample region 152.
  • the first sample region 151 has an average cross-sectional region larger than that of the second sample region 152.
  • the volume ratio of the first sample region 151 and the second sample region 152 may be greater than a length ratio between a path between a portion connected to the first flow path 130 of the first sample region 151 and a portion connected to the second sample region 152, and the path between the portion connected to the second flow path 140 of the second sample region 152 and the portion connected to the first sample region 151.
  • the first sample region 151 is partitioned larger than the second sample region 152, when the sample solution reciprocates between the first sample region 151 and the second sample region 152, a flow rate in the second sample region 152 is configured faster than that in the first sample region 151, and the sample solution and the reaction mixture (R) are quickly and uniformly mixed by the difference in their flow rates.
  • the partition portion 112 may be located offset from the center of the sample region 150. As the partition portion 112 is located offset from the center of the sample region 150, one of the first sample region 151 and the second sample region 152 may be partition larger than the other.
  • the partition portion 112 is positioned away from the center of the sample region 150 means that it is positioned to be biased toward the flow path 130 or the second flow path 140 based on the center of the portion connected to the first flow path 130 and the portion connected the second flow path 140 of the sample region 150.
  • the partition portion 112 is positioned adjacent to the inner surface of the sample region 150 and the second sample region 152 may be configured with a narrow passage. Accordingly, the first sample region 151 is may be configured with a passage wider than the second sample region 152 as the remaining region.
  • the sample processing device may include an optical module including a light source and a photodetector to detect the target nucleic acid, emit excitation light to the solution that has been subjected to the nucleic acid reaction step S740, and detect the fluorescence emitted from the nucleic acid.
  • the partition portion 112 is located away from the center of the sample region 150.
  • the first flow path 130 includes a first auxiliary sample region 131 provided on the first sample region 151
  • the second flow path 140 includes a second auxiliary sample region 141 provided on the second sample region 152.
  • the first auxiliary sample region 131 and the second auxiliary sample region 141 may prevent the sample solution moving between the first sample region 151 and the second sample region 152 from leaking into the opening of the first flow path 130 or the second flow path 140.
  • the sample solution moves between the first sample region 151 and the second sample region 152.
  • the amount of the sample solution in the first sample region 151 increases, so that a portion of the sample solution may be introduced into the first flow path 130.
  • the sample solution in the first sample region 151 moves to the second sample region 152
  • the amount of the sample solution in the second sample region 152 increases, so that a portion of the sample solution may be introduced into the second flow path 140.
  • the nozzle for injecting the air is contaminated or the sample solution is lost, which may cause an error in the detection result.
  • the prepared solution is accommodated in the first auxiliary sample region 131 (refer to (C) of FIG. 4), and the solution introduced into the second flow path 140 from the second sample region 152 is accommodated in the second auxiliary sample region 141(refer to Fig. 4 (D)) and prevents the nozzle from contaminating or the sample solution from being lost.
  • the first auxiliary sample region 131 and the second auxiliary sample region 141 is provided between the portion connected to the first sample region 151 of the first flow path 130 and the first opening 121, and between a portion connected to the second sample region 152 of the second flow path 140 and the second opening 122, respectively.
  • the first auxiliary sample region 131 may be located adjacent to the first sample region 151
  • the second auxiliary sample region 141 may be located adjacent to the second sample region 152.
  • the first auxiliary sample region 131 and the second auxiliary sample region 141 are parts of the first flow path 130 and the second flow path 140, respectively, and are configured to have a larger cross-sectional region than the remaining of the first flow path 130 and the second flow path 140 and may accommodate the sample solution.
  • the first auxiliary sample region 131 and the second auxiliary sample region 141 may be configured by recessing the partition wall 111.
  • the second auxiliary sample region 141 may have a larger volume than the second sample region 152. That is, since the first sample region 151 is partitioned larger than the second sample region 152, the volume of the solution moved from the first sample region 151 to the second sample region 152 in the mixing step S720 may be larger than that of the second sample region 152. Accordingly, the volume of the solution introducing into the second flow path 140 from the second sample region 152 may be larger than that of the second sample region 152. In order to prevent the solution from leaking int the opening of the second flow path 140, the volume of the second auxiliary sample region 141 is preferably larger than that of the second sample region 152.
  • the second auxiliary sample region 141 may be equal to or larger than the first auxiliary sample region 131.
  • the first auxiliary sample region 131 may be equal or smaller than the second auxiliary sample region 141. Since the first sample region 151 is partitioned larger than the second sample region 152, the amount of the sample solution contained in the first sample region 151 is greater than the amount of the sample solution contained in the second sample region 152.
  • the volume of the solution flowing from the second sample region 152 into the second flow path 140 is larger than the volume of the solution introducing from the sample region 151 into the first flow path 130, so the volume of the second auxiliary sample region 141 is preferably equal to or larger than the volume of the first auxiliary sample region 131.
  • a liquid layer of the water-immiscible material (C) is formed on the top side of the mixed solution through the covering step S730 (refer to (F) of FIG. 4).
  • the nucleic acid reaction step S740 which is the next step of the covering step S730, the nucleic acid reaction is performed by controlling the temperature of the sample region. During the denaturation step of the nucleic acid reaction, the mixed solution is heated to a temperature higher than about 95°C. Evaporation of the mixed solution due to the high temperature as described above may cause fatal errors in the detection result.
  • the evaporation of the mixed solution may be prevented.
  • This water-immiscible material (C) should not substantially evaporate even at 110°C, should have a lower specific gravity than the mixed solution, and should not affect the nucleic acid reaction.
  • the water-immiscible material (C) may be, for example, paraffin, wax or oil, but it is not limited thereto.
  • the water immiscible material (C) is injected into the body portion 110 through the openings of the first flow path 130 and the second flow path 140 after forming the mixed solution of the sample solution and the reaction mixture (R).
  • the reaction mixture (R) it is more convenient and quicker to perform the nucleic acid reaction by preparing the water-immiscible material (C) in advance in the inside of the body portion 110.
  • the body portion 110 is provided with at least one accommodating portion 160 configured to communicate with the flow path.
  • the accommodating portion 160 may be provided with the water-immiscible material (C) in a solid state as will be described later in detail.
  • the accommodating portion 160 is configured to communicate with the first flow path 130 and the second flow path 140.
  • At least one accommodating portion 160 is provided, and when one accommodating portion 160 is provided, the single accommodating portion 160 communicates with both the first flow path 130 and the second flow path 140.
  • at least one accommodating portion communicating with the first flow path 130 and one or more accommodating portions communicating with the second flow path 140 are respectively provided.
  • the accommodating portion 160 is configured to be recessed inside the body portion 110.
  • the accommodating portion 160 is provided in the partition wall 111 and communicates with the flow path by the opening facing the flow path as shown in the drawing.
  • the water-immiscible material (C) is provided in the accommodating portion 160 in the solid state, and the solid water-immiscible material (C) is liquefied and moved to the sample region 150.
  • the portion communicating with the flow path of the accommodating portion 160 may be inclined in the direction toward the flow path so that the miscible material (C) may be completely moved from the accommodating portion 160 to the sample region 150 in the accommodating portion 160.
  • the portion where the accommodating portion 160 communicates with the first flow path 130 and the second flow path 140 may be configured to be inclined downward without a portion protruding upward. Referring to FIG.
  • the opening communicating with the flow path of the accommodating portion 160 is configured between the top and lower surfaces facing in the vertical direction, and the lower surface be configured to be at least flat in the horizontal direction (refer to reference numeral 512) or configured to be inclined downward (refer to reference numeral 514).
  • the accommodating portion 160 may include a first accommodating portion 161 communicating with the first flow path 130 and the second accommodating portion 162 communicating with the second flow path 140.
  • the first accommodating portion 161 and the second accommodating portion 162 may communicate with the first flow path 130 and the second flow path 140 at an upstream position of the sample region 150, respectively.
  • the term "upstream" refers to the direction from the first flow path 130 and the second flow path 140 toward the sample region 150. That is, as shown in the drawing, when the first flow path 130 and the second flow path 140 is configured in the vertical direction, the first accommodating portion 161 and the second accommodating portion 162 communicate the first flow path 130 and the second flow path 140 at the top side of the sample region 150, respectively.
  • the accommodating portion 160 is provided with the water-immiscible material (C). That is, the accommodating portion 160 is configured by being engraved on one surface of the body portion 110 like the first flow path 130, and a water-immiscible material (C) is provided in the accommodating portion 160 through the engraved surface. By attaching the barrier layer 310, the water-immiscible material (C) may be pre-positioned in the accommodating portion 160.
  • the water-immiscible material (C) provided in the accommodating portion 160 may be provided in an amount sufficient to cover both the top sides of the mixed solution in the first sample region 151 and the second sample region 152.
  • the water-immiscible material (C) is preferably provided in the accommodating portion 160 in the solid state. That is, the water-immiscible material (C) in the liquid state may leak from the accommodating portion 160 due to shaking of the nucleic acid reaction chamber 100, etc. In such a case, since it flows out through the opening of the flow path and does not cover all of the top side of the mixed solution, so evaporation occurs or it flows into the sample area 150 and may interfere with the mixing of the sample solution and the reaction mixture (R) in the mixing step S720, it is preferable to provide the water-immiscible material (C) in the solid state in the accommodating portion (160).
  • the shape of the solid water-immiscible material (C) is not particularly limited, and may be, for example, a circle, an oval, a triangle, a square, a polygon, or an irregular shape.
  • the water-immiscible material (C) provided in the solid state in the accommodating portion 160 is heated in the covering step S730 and phase-changed to the liquid state.
  • a thermal module for heating or cooling the mixed solution may heat and liquefy the water-immiscible material (C) in the solid state.
  • the liquefied water-immiscible material (C) is separated from the accommodating portion 160 and moves to the sample region 150, and forms the liquid layer on the top side of the mixed solution.
  • the water-immiscible material (C) accommodated in the first accommodating portion 161 forms the liquid layer on the top side of the mixed solution located in the first sample region 151
  • the water-immiscible material (C) accommodated in the second accommodating portion 162 forms the liquid layer on the top side of the mixed solution located in the second sample region 152.
  • the water-immiscible material (C) is required to have a low specific gravity so that the liquid layer may be located on the top side of the mixed solution (e.g., the specific gravity of paraffin is 0.9 g/cm ⁇ 3).
  • the liquefied water-immiscible material (C) naturally moves to the sample region 150 without going through a separate device or step and forms the liquid layer.
  • the heating of the water-immiscible material (C) may be performed separately from the heating of the mixed solution, or may be automatically performed in the process of heating the sample region 150 to perform the denaturation step. That is, the denaturation step is performed at about 95°C.
  • the solid water-immiscible material (C) is heated and liquefied together in the process of thermal module to heat the body portion 110, and the liquefied water-immiscible material (C) is moved to the sample region 150 and the liquid layer may be configured on the top side of the mixed solution before the mixed solution reaches 95°C and the evaporation may be prevented.
  • a water-immiscible material (C) with a melting point lower than 95°C for example, the melting point of paraffin is 47 ⁇ 64°C
  • the solid water-immiscible material (C) is heated and liquefied together in the process of thermal module to heat the body portion 110, and the liquefied water-immiscible material (C) is moved to the sample region 150 and the liquid layer may be configured on the top side of the mixed solution before the mixed solution reaches 95°C and the evaporation may be prevented.
  • a structure that restricts the movement of the material located at the accommodating portion 160 may be configured in the body portion 110 so that the water-immiscible material (C) provided in the accommodating portion 160 in the solid state is not separated from the first flow path 130 or the second flow path 140. That is, as described above, the portion where the accommodating portion 160 and the flow path communicates with the accommodating portion 160 is inclined downward so that all of the liquefied water-immiscible material (C) moves from the accommodating portion 160 to the sample region 150 without remaining.
  • the opening communicating with the flow path of the accommodating portion 160 is configured between the top and lower surfaces facing each other in the vertical direction.
  • the top surface protrudes in the direction toward the lower surface and a locking protrusion is formed, thereby forming the movement limiting structure in the body portion 110 (refer to reference numeral 511).
  • the locking protrusion may extend in a direction toward the lower surface to form a narrow opening (refer to reference numeral 513).
  • a blocking portion may be provided between the top and lower surfaces to form the movement limiting structure (refer to reference numeral 515).
  • the nucleic acid reaction step S740 of controlling the temperature of the sample region 150 to perform the nucleic acid reaction is performed, for example, by the thermal module of the sample processing device.
  • the thermal module may heat the sample region 150 using a thermal conductive film, a peltier device, or the like, or cool the sample region 150 using a heat dissipation fan, or a heat sink.
  • the flow path and the sample region 150 are configured by being engraved on one surface of the body portion 110, the barrier layer 310 covering the flow path and the sample region 150 may be attached to the engraved surface of the body portion 110, and the temperature control of the sample region 150 may be performed by heat exchange through the barrier layer 310.
  • the barrier layer 310 is configured of a thermally conductive material, and for example, the thermal module is in contact with the barrier layer 310 to heat or cool the sample region 150.
  • the barrier layer 310 may be, for example, an aluminum thin film.
  • the barrier layer 310 may be attached only to the engraved surface of the body portion 110 as shown in (A) of FIG. 3 or the engraved surface and both side surfaces of the body portion 110 as shown in (B) of FIG.3.
  • both side surfaces of the body portion 110 may be surfaces facing 100 faces each other in the nucleic acid reaction chamber as shown in FIG. 6.
  • the heat exchange is performed not only on the engraved side surface of the body portion 110 but also on both side surfaces when the thermal module adjusts the temperature of the sample region 150 in the nucleic acid reaction step S740, so that the heat exchange may be made more quickly and heat loss in the heating process may be prevented.
  • the body portion 110 may be configured of a transparent or translucent material, which is to facilitate the detection of the target nucleic acid after amplifying the nucleic acid through the nucleic acid reaction step S740. That is, as described above, the detection of the target nucleic acid may be performed, for example, by the optical module of the sample processing device.
  • the body portion 110 may be configured of the transparent or translucent material, for example, PC (Polycarbonate) or PP (Polyproplene).
  • the optical module may detect the emitted excitation light or the emitted light through the opposite side surface of the engraved surface of the body portion 110. Therefore, it is preferable that the barrier layer is not attached to the opposite side surface thereof.

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Abstract

L'invention concerne une chambre de réaction d'acide nucléique. L'invention concerne une chambre de réaction d'acide nucléique comprenant une partie corps comprenant un chemin d'écoulement et une région d'échantillon, le chemin d'écoulement comprenant un premier chemin d'écoulement et un second chemin d'écoulement, la région d'échantillon étant individuellement reliée à des parties inférieures du premier chemin d'écoulement et du second chemin d'écoulement, le premier chemin d'écoulement et le second chemin d'écoulement communiquant avec l'extérieur, respectivement. Selon l'invention, en dépit du petit volume de la solution d'échantillon et de la viscosité du mélange réactionnel, le mélange de la solution d'échantillon et du mélange réactionnel peut être effectué de manière uniforme, et la fiabilité du résultat de détection peut être améliorée.
PCT/KR2021/013209 2020-09-29 2021-09-28 Chambre pour réaction d'acide nucléique, procédé de réaction d'acide nucléique l'utilisant, et cartouche pour le traitement d'échantillon comprenant celle-ci Ceased WO2022071716A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
US20150369813A1 (en) * 2014-06-24 2015-12-24 Lifescan Scotland Limited Analytical test strip with tiered capillary chamber
US20160202281A1 (en) * 2012-12-31 2016-07-14 Zhejiang University An application method for automatic micro droplet array screening system with picoliter scale precision
US20170218431A1 (en) * 2007-06-21 2017-08-03 Gen-Probe Incorporated System and method of using multi-chambered receptacles
US20190211396A1 (en) * 2012-09-26 2019-07-11 Cepheid Honeycomb tube
US20200240879A1 (en) * 2011-03-09 2020-07-30 Pixcell Medical Technologies, Ltd. Disposable cartridge for preparing a sample fluid containing cells for analysis

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170218431A1 (en) * 2007-06-21 2017-08-03 Gen-Probe Incorporated System and method of using multi-chambered receptacles
US20200240879A1 (en) * 2011-03-09 2020-07-30 Pixcell Medical Technologies, Ltd. Disposable cartridge for preparing a sample fluid containing cells for analysis
US20190211396A1 (en) * 2012-09-26 2019-07-11 Cepheid Honeycomb tube
US20160202281A1 (en) * 2012-12-31 2016-07-14 Zhejiang University An application method for automatic micro droplet array screening system with picoliter scale precision
US20150369813A1 (en) * 2014-06-24 2015-12-24 Lifescan Scotland Limited Analytical test strip with tiered capillary chamber

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