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WO2023157711A1 - Puce d'inspection, dispositif de détection de réaction et procédé de détection de réaction - Google Patents

Puce d'inspection, dispositif de détection de réaction et procédé de détection de réaction Download PDF

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Publication number
WO2023157711A1
WO2023157711A1 PCT/JP2023/003927 JP2023003927W WO2023157711A1 WO 2023157711 A1 WO2023157711 A1 WO 2023157711A1 JP 2023003927 W JP2023003927 W JP 2023003927W WO 2023157711 A1 WO2023157711 A1 WO 2023157711A1
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Prior art keywords
chamber
group
chambers
reaction
reaction detection
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Ceased
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English (en)
Japanese (ja)
Inventor
清一郎 東
宏明 花房
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Hiroshima University NUC
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Hiroshima University NUC
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Priority to JP2024501307A priority Critical patent/JPWO2023157711A1/ja
Publication of WO2023157711A1 publication Critical patent/WO2023157711A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems

Definitions

  • the present invention relates to a test chip, a reaction detection device, and a reaction detection method, and more particularly to a test chip, a reaction detection device, and a reaction detection method for detecting reactions related to nucleic acid amplification.
  • PCR polymerase chain reaction
  • RCA rolling circle amplification
  • a detection method using a fluorescent substance is used to detect nucleic acid amplification products.
  • detection methods using fluorescent substances have problems such as the need to hybridize a fluorescent probe and the detection process is complicated, and the fluorescence detector is expensive.
  • Other detection methods have been developed (eg, US Pat.
  • Patent Document 1 proton release is detected by an ion selective field effect transistor (ISFET) during the primer elongation step of nucleic acid amplification such as the PCR method.
  • ISFET ion selective field effect transistor
  • in order to detect changes in the pH value due to released protons it is necessary to inject a solution containing a nucleic acid as a specimen into a microvolume chamber and measure the pH value for each chamber. .
  • the present invention has been made in view of the circumstances described above, and aims to provide a test chip, a reaction detection device, and a reaction detection method that can easily and quickly detect a nucleic acid amplification reaction.
  • the test chip includes: a plurality of chambers having ion-sensitive field effect transistors and reference electrodes for detecting the pH value of the analyte;
  • the chamber is The sources and drains of the ion-sensitive field effect transistors are grouped by a first group consisting of a plurality of first groups connected to each other, and the reference electrodes are grouped by a first group consisting of a plurality of second groups connected to each other. grouped by groups, The chambers of each of the first groups included in each of the second groups are wired so that there is no more than one.
  • the reference electrode is arranged on a lid covering the opening of the chamber, You can do it.
  • the inspection chip comprising a channel that communicates the adjacent chambers with each other; You can do it.
  • the volume of the chamber is 10 pL or less, You can do it.
  • the reaction detection device includes: A test chip according to the first aspect; a control unit that is connected to the test chip and detects a reaction of the specimen in the chamber; The control unit selecting one said chamber by selecting one said first group from said first group and selecting one said second group from said second group; By measuring the pH value with the ion sensitive field effect transistor, the reaction of the analyte in the selected chamber is detected.
  • reaction detection method Injecting a specimen into the chamber of the test chip according to the first aspect, selecting one said chamber by selecting one said first group from said first group and selecting one said second group from said second group; By measuring the pH value with the ion sensitive field effect transistor, the reaction of the analyte in the selected chamber is detected.
  • the selection of chambers and the presence or absence of reactions accompanied by changes in pH value occurring in each chamber can be electrically performed using ion-sensitive field effect transistors. Therefore, it is possible to detect the nucleic acid amplification reaction easily and quickly.
  • FIG. 1 is a perspective view showing the configuration of a reaction detection device according to an embodiment of the present invention
  • FIG. It is a side view of a test chip concerning an embodiment. It is a figure which shows the structure of the chamber which concerns on embodiment, (A) is a top view, (B) is side sectional drawing. (A) shows an array of chambers in a chamber layer, and (B) is an enlarged view of (A) showing one chamber.
  • FIG. 10 is a side cross-sectional view of a chamber with a lid having a reference electrode; It is a conceptual diagram which shows the wiring example of ISFET which concerns on embodiment, and a reference electrode. It is a functional block diagram showing the configuration of a control unit according to the embodiment.
  • FIG. 6 is a flowchart showing the flow of reaction detection processing according to the embodiment; 4 is a graph showing an example of the relationship between the amount of specimen and the pH value; It is a conceptual diagram which shows the relationship between selection of a chamber and the output of ISFET.
  • FIG. 10 is a diagram showing an example of annularly arranged chambers;
  • FIG. 4 is a schematic diagram showing chamber layers in a flow-down configuration;
  • FIG. 4 is a schematic diagram showing the chamber layers of a multi-layer flow-down structure;
  • test chip the reaction detection device, and the reaction detection method according to the embodiments of the present invention will be described as a reaction detection device that detects an amplification product contained in a sample by detecting a proton release reaction in nucleic acid amplification by the RCA method.
  • a reaction detection device that detects an amplification product contained in a sample by detecting a proton release reaction in nucleic acid amplification by the RCA method.
  • the reaction detection apparatus 1 includes a test chip 10 having a plurality of chambers 12 into which specimens are injected, and a detection unit 50 connected to the test chip 10 to detect a target substance. Prepare.
  • the inspection chip 10 includes a substrate 15 having a sensor and a chamber layer 11 in which a microcapacity chamber 12 is formed.
  • ISFETs 16 which are a plurality of ion-sensitive field effect transistors (Ion Selective Field Effect Transistors) as sensors.
  • a wiring 17 for operating the ISFET 16 is formed.
  • the substrate 15 includes connection terminals 15a for connecting the wiring 17 and the circuits in the detection unit 50.
  • the material of the substrate 15 is not particularly limited, and a semiconductor such as silicon, a glass substrate, a plastic substrate, or the like can be used.
  • the substrate 15 according to this embodiment is a plastic substrate.
  • the ISFET 16 is formed by a known method.
  • An insulating layer 18 is formed on the ISFET 16 .
  • a slit 18a is formed in the insulating layer 18, and the gate portion of the ISFET 16 is opened.
  • the size of the slit 18 a is not particularly limited, and may be set to a size corresponding to the size of the gate portion of the ISFET 16 .
  • the slit 18a has a rectangular shape with a side of 0.5 ⁇ m to 1000 ⁇ m (micrometers).
  • the chambers 12 are containers into which specimens are injected, and are formed on the substrate 15 so as to contain one ISFET 16 each.
  • a reference electrode 19 is formed on the substrate 15 , and the reference electrode 19 is opened inside each chamber 12 so that a voltage can be applied.
  • the chamber layer 11 including the chamber 12 is made of epoxy resin on the substrate 15 using photolithography.
  • the method of making the chamber layer 11 is not limited to photolithography.
  • chamber layer 11 may be molded onto substrate 15 .
  • the chamber layer 11 may be created by a three-dimensional printer such as stereolithography using an ultraviolet curable resin.
  • the chamber layer 11 including the chamber 12 is formed on the substrate 15, the present invention is not limited to this. It is also possible to
  • the chamber 12 is formed as a microcapacity container in order to detect a minute amount of protons released during nucleic acid amplification by the RCA method as a change in pH value.
  • the volume of chamber 12 is preferably 10 pL or less, more preferably 1 pL or less.
  • the shape of the chamber 12 is not particularly limited. Chamber 12 according to the present embodiment is formed in a cylindrical shape.
  • the inner diameter of chamber 12 is preferably between 1 ⁇ m and 1000 ⁇ m in diameter.
  • the height of the chamber 12 is preferably 1 ⁇ m to 1000 ⁇ m.
  • the chamber 12 according to this embodiment has a diameter of 20 ⁇ m, a height of 16 ⁇ m, and a capacity of about 5 pL (picoliters).
  • FIG. 4(A) is an enlarged view of the surface of the inspection chip 10
  • FIG. 4(B) is an enlarged view of one chamber 12 in FIG. 4(A).
  • the chambers 12 are arranged in a matrix, more specifically, in an alternating matrix.
  • the sample is distributed in a fixed amount to each chamber 12 .
  • the chamber layer 11 according to the present embodiment has a channel 13 , and the adjacent chambers 12 communicate with each other through the channel 13 . Thereby, the specimen introduced into the chamber 12 is diffused to other chambers 12 through the channel 13 .
  • a coating agent may be applied to the inner walls of the chamber 12 and the channel 13 to improve the fluidity of the specimen.
  • the coating agent is not particularly limited, and for example, a vitreous coating agent such as polysilazane, a hydrophobic coating agent, a water-repellent coating agent, and the like can be used.
  • the distance between the adjacent chambers 12 is not particularly limited, it is preferable that the channels 13 are arranged so that the length of the channels 13 is 1000 ⁇ m or less from the viewpoint of the fluidity of the sample and the rapidity of the detection process. In the present embodiment, since the chambers 12 are arranged in an alternate matrix, the distance between the chambers 12 can be shortened and the fluidity of the sample can be improved.
  • the reference electrode 19 is formed on the substrate 15 in the present embodiment, it is not limited to this, and may be formed so that a voltage can be applied to each chamber 12 .
  • a reference electrode 19 arranged on a lid 20 that covers the openings of the chambers 12 may be configured to be inserted into each chamber 12 .
  • the wiring of the reference electrode 19 and the wiring of the ISFET 16 can be divided between the lid portion 20 and the substrate 15, so that the wiring of the substrate 15 is facilitated and the structure can be simplified.
  • Each chamber is grouped into a first group group A and a second group group B, as shown in the conceptual diagram of FIG. Specifically, the sources and drains of the ISFETs 16 in each chamber 12 are connected for each first group Ai (i is a natural number from 1 to n) to form a first group A.
  • the sources and drains of the ISFETs 16 of the first group Ai are connected to the power supply in the detection unit 50, and voltages can be selectively applied to the ISFETs 16 of the first group Ai by the controller 51, which will be described later.
  • the chambers 12 arranged in a matrix form a first group Ai for each column in one of the directions (horizontal direction in FIG. 6) in which the chambers 12 are arranged in series. Thereby, a voltage can be simultaneously applied to the ISFETs 16 in the same first group Ai.
  • each chamber 12 is connected to each second group Bj (j is a natural number from 1 to m) to form a second group B.
  • the reference electrodes 19 of the second group Bj are connected to the power supply in the detection unit 50, and a voltage can be selectively applied to the reference electrodes 19 of the second group Bj by the control section 51, which will be described later.
  • the chambers 12 arranged in a matrix form a second group Bj for each row in a direction orthogonal to the first group Ai (vertical direction in FIG. 6). Thereby, the voltage can be applied simultaneously to the reference electrodes 19 in the same second group Bj.
  • each second group Bj is wired so as to include one or less chambers 12 of each first group Ai.
  • each first group Ai is wired so as to include one or less chambers 12 of each second group Bj. Accordingly, by selecting either one of the first group Ai and one of the second group Bj, it is possible to select one or less chambers 12 and measure the pH value without selecting a plurality of chambers 12 at the same time. can be done. That is, in the present embodiment, the ISFET 16 is wired in an active matrix system, the chambers 12 are sequentially selected, and the pH value is measured to determine whether or not the amplified product of the nucleic acid to be detected is present in the chambers 12. can judge.
  • the detection unit 50 is connected to the test chip 10 and detects the nucleic acid amplification reaction by measuring the pH value inside each chamber 12 .
  • the detection unit 50 includes a control section 51, a storage section 52, a display section 53, an input section 54, and a reader 55, as shown in the functional block diagram of FIG.
  • the control unit 51 is composed of a CPU (Central Processing Unit), a ROM (Read Only Memory), a RAM (Random Access Memory), etc., and controls the operation of the reaction detection device 1 as a whole. In addition, the control unit 51 sequentially selects the first group Ai and the second group Bj for the chambers 12 formed in the test chip 10, thereby measuring the pH value of the sample in each chamber 12 and amplifying the nucleic acid. Detects the presence or absence of reaction.
  • a CPU Central Processing Unit
  • ROM Read Only Memory
  • RAM Random Access Memory
  • the control unit 51 reads various operation programs and data stored in the ROM of the control unit 51, the storage unit 52, etc. into the RAM and operates the CPU, thereby realizing each function of the control unit 51 shown in FIG. Let Thereby, the control unit 51 operates as a selection unit 511 that selects the chamber 12 to be measured and a measurement unit 512 that measures the pH value of the selected chamber 12 .
  • the selection unit 511 sequentially selects the first group Ai and the second group Bj according to a predetermined order. Accordingly, the chamber 12 to be measured is selected from among the chambers 12 formed in the chamber layer 11 .
  • the measurement unit 512 applies voltage to the ISFET 16 and the reference electrode 19 of the chamber 12 selected by the selection unit 511 to measure the pH value of the sample in the chamber 12 .
  • the storage unit 52 is a non-volatile memory such as a hard disk or flash memory, and stores programs for selecting the chambers 12, pH values measured for each chamber 12, and the like.
  • the display unit 53 is a display device provided in the detection unit 50, such as a liquid crystal monitor.
  • the display unit 53 displays information such as the measured pH value and the number of chambers 12 in which the amplified product of the nucleic acid to be detected has been confirmed.
  • the input unit 54 is an input device for inputting the start and end of reaction detection processing, various set values of the reaction detection device 1, and the like.
  • the input unit 54 is a keyboard, touch panel, mouse, etc. provided in the detection unit 50 .
  • the reader 55 connects the connection terminal 15a provided on the inspection chip 10 to the power supply circuit, switch circuit, etc. in the detection unit 50 via contacts. Thereby, the controller 51 applies a voltage to the ISFET 16 and the reference electrode 19 associated with the selected chamber 12 and measures the pH value of the sample in the chamber 12 .
  • a specimen to be detected by the reaction detection device 1 is prepared. Specifically, a nucleic acid amplification process such as the RCA method or the PCR method is performed to generate a sample that causes a primer extension reaction. In the present embodiment, a solution containing an amplification product obtained by amplifying DNA of a given virus by the RCA method is used as a specimen. Then, the sample is injected into the chamber 12 of the inspection chip 10 to prepare for inspection (step S11). At this time, the specimen solution injected into some of the chambers 12 of the chamber layer 11 is diffused to all the chambers 12 of the chamber layer 11 via the channel 13 .
  • a nucleic acid amplification process such as the RCA method or the PCR method is performed to generate a sample that causes a primer extension reaction.
  • a solution containing an amplification product obtained by amplifying DNA of a given virus by the RCA method is used as a specimen.
  • the sample is injected into the chamber 12 of the inspection chip 10 to prepare for inspection (step
  • the test chip 10 into which the sample is injected is connected to the detection unit 50 via the reader 55, and reaction detection is started.
  • reaction detection is started, the selector 511 of the controller 51 scans the chamber 12 to detect the nucleic acid amplification reaction. Specifically, the selector 511 selects one second group Bj from the second group B, and applies voltage to the reference electrodes 19 of the chambers 12 belonging to the second group Bj (step S12).
  • the selection unit 511 selects one first group Ai from the first group group A (step S13).
  • the measurement unit 512 measures the drain current of the first group Ai. Thereby, the measuring unit 512 measures the pH value of one chamber 12 belonging to the first group Ai and the second group Bj (step S14).
  • the release amount and release rate of protons that change the pH value differ depending on the method used for nucleic acid amplification. For example, when viruses are detected using the Rha-RCA (RNase H-assisted RCA) method, about 1 ⁇ 10 4 protons are generated in 5 minutes by performing nucleic acid amplification for one virus.
  • the volume of the chamber 12 is preferably 10 pL or less. , is more preferably 1 pL or less. As described above, the volume of chamber 12 according to this embodiment is approximately 5 pL.
  • the selection unit 511 sequentially switches the first group Ai until all the first groups Ai from the first group A have been selected (NO in step S15), and the measurement unit 512 detects the drain current from the first group Ai. Measure the pH value. Thereby, the measuring unit 512 can sequentially measure the pH values of the chambers 12 belonging to the selected second group Bj.
  • the selection unit 511 selects another second group Bj from the second group B, and selects the newly selected second group Bj. A voltage is applied to the reference electrodes 19 of the chambers 12 belonging to group Bj.
  • the selection unit 511 and the measurement unit 512 select all the second groups Bj of the second group B, and repeat the selection and measurement of the second groups Bj until the measurement is completed (NO in step S16).
  • FIG. 10 is a conceptual diagram showing the flow of nucleic acid amplification reaction detection within the chamber 12.
  • the voltage is applied to the reference electrodes 19 of the second group B2 selected by the selector 511.
  • drain current values measured by the measuring unit 512 when the first group Ai of the first group group A is sequentially selected.
  • the chambers 12 belonging to the first group A3 and the second group B2 contain amplification products of nucleic acids to be detected.
  • the pH value in the chamber 12 changes due to protons released during the primer elongation step in the RCA method. Therefore, as shown in FIG.
  • FIG. 10 indicates that the chamber 12 contains the amplification product of the nucleic acid to be detected. In this way, by sequentially scanning a plurality of chambers 12 arranged in an active matrix system, the nucleic acid amplification reaction can be rapidly detected.
  • the first group A consisting of a plurality of first groups Ai that share the wiring of the source and drain of the ISFET 16, and the reference
  • the first group Ai and the second group Bj are sequentially selected for the small-capacity chambers 12 specified by the second group B consisting of a plurality of second groups Bj sharing the wiring of the electrodes 19, and the selection is performed.
  • the pH value of the chamber 12 is measured.
  • the selection of the chamber 12 can be electrically performed by the switch circuit, so that the reaction can be detected at high speed.
  • the detection since the presence or absence of reaction can be electrically detected by measuring the pH value using the ISFET 16, the detection can be performed inexpensively and easily compared to the detection of amplification products using a fluorescence detector.
  • each chamber since the volume of each chamber is as small as 10 pL or less, it is possible to accurately change the pH value based on proton release by the primer extension reaction.
  • the chambers 12 according to the present embodiment are communicated with each other by the flow paths 13, it is possible to rapidly diffuse the specimen to each chamber 12, thereby improving the detection efficiency.
  • the chambers 12 are arranged in a matrix, and the ISFETs 16 and the reference electrodes 19 are wired in an active matrix system, but this is not the only option.
  • the chambers 12 may be arranged in an annular shape consisting of a plurality of concentric circles.
  • a group of chambers 12 arranged on circles of the same diameter is defined as a first group Ai, and the sources and drains are connected to form a first group A.
  • a second group B may be formed by connecting the reference electrodes 19 to the group of the chambers 12 arranged in the radial direction of the annular arrangement as the second group Bj.
  • the sample injected into the chamber 12 is homogenized through the channel 13 in the present embodiment, it is not limited to this.
  • the sample solution may be flowed down and injected into each chamber 12 .
  • a sloped portion 12a that slopes downward from the upper edge of the chamber 12 may be formed.
  • the chamber layer 11 is one layer in the present embodiment, the present invention is not limited to this, and a plurality of chamber layers 11 may be laminated.
  • the chambers 12 of each layer are provided with the above-described inclined portions 12a so that the specimen overflowing from the chambers 12 of the upper chamber layer 11 sequentially flows into the chambers 12 of the lower chamber layer 11. can be configured to This makes it possible to easily equalize the amount of specimen injected into the chamber 12 of each layer.
  • the detection unit 50 including the reader 55 is connected to the inspection chip 10, but this is not the only option.
  • a program for operating as a control unit 51, a storage unit 52, a display unit 53, and an input unit 54 is installed in a mobile communication terminal such as a smartphone, and the detection unit 50 is detected by connecting the mobile communication terminal and the reader 55. It may be operated as As a result, reaction detection can be easily performed using a general smartphone or the like.
  • detection data can be transmitted to the server via a network, so that a large amount of detection data can be quickly collected and analyzed. Become.
  • the present invention is suitable for reaction detection that detects reactions related to nucleic acid amplification.
  • it is suitable for reaction detection when rapid and inexpensive detection of amplification products is required, such as detection of viruses associated with infectious diseases.
  • reaction detection device 10 inspection chip, 11 chamber layer, 12 chamber, 12a inclined portion, 13 flow path, 15 substrate, 15a connection terminal, 16 ISFET, 17 wiring, 18 insulating layer, 18a slit, 19 reference electrode, 20 lid section, 50 detection unit, 51 control section, 511 selection section, 512 measurement section, 52 storage section, 53 display section, 54 input section, 55 reader

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Abstract

L'invention concerne une puce d'inspection (10) qui comprend plusieurs chambres (12) chacune dotées d'une électrode de référence (19) et d'un transistor à effet de champ sensible aux ions (ISFET) (16) pour détecter la valeur du pH d'un échantillon, les chambres (12) étant regroupées en une première collection de groupes A comprenant plusieurs premiers groupes Ai dans lesquels la source et le drain de l'ISFET (16) sont connectés l'un à l'autre, et une seconde collection de groupes B comprenant plusieurs seconds groupes Bj dans lesquels les électrodes de référence (19) sont connectées les unes aux autres. La puce d'inspection est également câblée de manière à ce qu'il n'y ait pas plus d'une chambre (12) dans chaque premier groupe Ai incluse dans chaque second groupe Bj. Grâce à cette configuration, la sélection d'une chambre (12) et la présence ou l'absence d'une réaction accompagnant un changement de la valeur du pH dans chaque chambre (12) peuvent être facilement et rapidement détectées à l'aide de l'ISFET (16).
PCT/JP2023/003927 2022-02-15 2023-02-07 Puce d'inspection, dispositif de détection de réaction et procédé de détection de réaction Ceased WO2023157711A1 (fr)

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