WO2024048835A1 - Cartouche pour un diagnostic moléculaire - Google Patents

Cartouche pour un diagnostic moléculaire Download PDF

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Publication number
WO2024048835A1
WO2024048835A1 PCT/KR2022/014190 KR2022014190W WO2024048835A1 WO 2024048835 A1 WO2024048835 A1 WO 2024048835A1 KR 2022014190 W KR2022014190 W KR 2022014190W WO 2024048835 A1 WO2024048835 A1 WO 2024048835A1
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WO
WIPO (PCT)
Prior art keywords
chamber
cartridge
amplification
nucleic acid
amplification chamber
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PCT/KR2022/014190
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English (en)
Korean (ko)
Inventor
박혜린
김지효
봉이선
김영훈
Original Assignee
옴니시스템 주식회사
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Publication of WO2024048835A1 publication Critical patent/WO2024048835A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • 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
    • 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
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • 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]
    • 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
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • 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
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0689—Sealing
    • 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
    • B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
    • 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
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B01L2300/0645—Electrodes

Definitions

  • the present invention relates to a cartridge for molecular diagnostics, comprising a nucleic acid extraction module having an extraction chamber and a first flow path, an amplification chamber, a first warming part, a second warming part, a nucleic acid amplification module having a second flow path, and a plate part. It relates to a cartridge for molecular diagnosis including an analysis module, a nucleic acid extraction module, a nucleic acid amplification module, and a housing with an analysis module built in and a sealing portion at the top.
  • Molecular diagnostics is a field that detects or analyzes biological markers such as DNA, RNA, and proteins using molecular biology techniques. The presence or absence of a target substance is detected by amplifying a small amount of nucleic acid using polymerase chain reaction (PCR).
  • PCR polymerase chain reaction
  • Molecular diagnostic technology is widely used to diagnose various viral diseases, including the recently emerged coronavirus, and rapid diagnosis of the disease through this can lead to optimal treatment.
  • the purpose of the present invention is to provide a molecular diagnostic cartridge that can perform molecular diagnosis simultaneously with sample collection in the field.
  • the purpose of the present invention is to provide a molecular diagnostic cartridge in which the entire process from nucleic acid extraction to analysis is performed automatically.
  • a cartridge for molecular diagnosis includes a nucleic acid extraction module, a nucleic acid amplification module, an analysis module, and a housing.
  • the nucleic acid extraction module may include an extraction chamber with an open top and a first flow path connected to the extraction chamber.
  • the nucleic acid amplification module may include an amplification chamber connected to a first flow path, a first warming part disposed on one side of the amplification chamber, a second warming part disposed on the other side of the amplification chamber, and a second flow path connected to the amplification chamber.
  • the analysis module may include a plate portion connected to the second flow path.
  • the housing may contain a nucleic acid extraction module, a nucleic acid amplification module, and an analysis module, and may be provided with a first sealing portion at the top.
  • a thread is formed on the inside of the top of the extraction chamber, and the extraction chamber can be threadedly coupled to the first seal.
  • the nucleic acid amplification module further includes a second sealing portion connected to one end of the amplification chamber, and a thread is formed on the inside of one end of the amplification chamber, so that the amplification chamber has a second sealing portion. It can be combined with parts and threads.
  • a cartridge for molecular diagnosis according to an embodiment of the present invention may be provided with a sealing ring at the bottom of the first sealing part.
  • a reagent for nucleic acid extraction may be accommodated in the extraction chamber.
  • the amplification chamber may contain a composition for PCR reaction.
  • the first flow path may be provided with a membrane having a ruptured portion.
  • the second heating unit may be capable of moving up and down.
  • the nucleic acid extraction module may further include a third warming unit.
  • the plate portion may include a first plate, a second plate, and a side wall.
  • the first plate may be spaced apart from the second plate by a predetermined distance.
  • the analysis module may further include an optical unit.
  • the housing may further include a driving unit that rotates the first sealing unit.
  • the plate portion may include a first plate, a second plate, a side wall, a microchannel, and a plurality of electrodes.
  • the first plate may be spaced apart from the second plate by a predetermined distance, a micro-channel may be disposed in the space between the first plate and the second plate, and electrodes may be disposed at both ends of the micro-channel.
  • the analysis module may further include an output pulse analysis unit.
  • the molecular diagnostic cartridge according to an embodiment of the present invention can perform molecular diagnosis at the same time as collecting a sample in the field and quickly confirm the test result.
  • the molecular diagnostic cartridge according to an embodiment of the present invention automatically performs the entire process from nucleic acid extraction to analysis, reducing the possibility of contamination and enabling convenient molecular diagnosis.
  • Figure 1 is a block diagram schematically showing a cartridge for molecular diagnosis according to an embodiment of the present invention.
  • Figure 2 is a diagram showing the overall shape of a cartridge for molecular diagnosis according to an embodiment of the present invention.
  • Figure 3 is a diagram showing an extraction chamber of a cartridge for molecular diagnosis according to an embodiment of the present invention.
  • Figure 4 is a diagram showing a first sealing portion of a cartridge for molecular diagnosis according to an embodiment of the present invention.
  • Figure 5 is a diagram showing a first flow path of a cartridge for molecular diagnosis according to an embodiment of the present invention.
  • Figure 6 is a view from above of the nucleic acid amplification module of the molecular diagnostic cartridge according to an embodiment of the present invention.
  • Figure 7 is a diagram showing an amplification chamber of a cartridge for molecular diagnosis according to an embodiment of the present invention.
  • Figure 8 is a diagram showing an analysis module of a molecular diagnostic cartridge according to an embodiment of the present invention.
  • Figure 9 is a diagram showing an analysis module of a molecular diagnostic cartridge according to another embodiment of the present invention.
  • the molecular diagnostic cartridge 1000 includes a housing 1100, a nucleic acid extraction module 1200, a nucleic acid amplification module 1300, and an analysis module 1400.
  • the housing 1100 contains a nucleic acid extraction module 1200, a nucleic acid amplification module 1300, and an analysis module 1400.
  • An opening 1110 is formed at the top of the housing 1100. A sample may be inserted through the opening 1110. The diameter of opening 1110 may be the same as the diameter of extraction chamber 1210. The opening 1110 may be closed by the first seal 1120.
  • a screw thread 1121 may be formed on the outside of the first sealing part 1120.
  • the nucleic acid extraction module 1200 includes an extraction chamber 1210 and a first flow path 1230. In the nucleic acid extraction module 1200, a step of extracting nucleic acids from the collected specimen is performed. The nucleic acid extracted in the extraction chamber 1210 moves to the nucleic acid amplification module 1300 through the first flow path 1230. Nucleic acid can move toward the first flow path 1230 by air pressure.
  • the top of the extraction chamber 1210 is sealed by the first seal 1120.
  • a sample may be introduced into the open extraction chamber 1210, and the extraction chamber 1210 may be closed with the first seal 1120.
  • a membrane 1231 is provided inside the first flow path 1230 connected to the extraction chamber 1210.
  • the extraction chamber 1210 is kept airtight during the nucleic acid extraction process. Nucleic acid contained in the extraction chamber 1210 moves to the amplification chamber 1310 through the first flow path 1230. The movement of nucleic acids is carried out by pneumatic pressure.
  • a screw thread 1211 is formed on the upper inner surface of the extraction chamber 1210.
  • a screw thread 1221 is formed on the outer surface of the first sealing part 1120.
  • the inner thread 1211 of the extraction chamber 1210 engages the thread 1121 of the first seal 1120.
  • a sealing ring 1222 may be formed at the bottom of the first sealing portion 1220. The sealing ring 1222 brings the first seal 1220 and the inside of the extraction chamber 1210 into closer contact, thereby improving airtightness.
  • the first sealing unit 1120 rotates by receiving rotational force from the driving unit.
  • the first seal 1120 moves straight inside the extraction chamber 1210 by rotation.
  • the first sealing unit 1120 may be connected in series to a motor to receive rotational force, or may receive rotational force using a worm gear and a worm wheel.
  • motor placement is free and the device can be miniaturized.
  • the distance that the first seal 1120 moves in a straight line inside the extraction chamber 1210 can be adjusted. As the first seal 1120 moves linearly, the volume within the extraction chamber 1210 decreases and the air pressure increases.
  • a membrane 1231 is provided inside the first flow path 1230 connected to the extraction chamber 1210.
  • the membrane 1231 is arranged to cover the cross section of the first flow path 1230 to prevent the solution contained in the extraction chamber 1210 from moving into the amplification chamber 1310 during the extraction process.
  • a rupture portion 1232 is formed at a random point on the upper surface of the membrane 1231.
  • the ruptured portion 1232 is a portion formed with a thickness thinner than that of the membrane 1231, and is a location where the membrane 1231 ruptures due to air pressure.
  • the volume within the extraction chamber 1210 decreases.
  • the air pressure inside the extraction chamber 1210 increases, and the rupture portion 1232 of the first flow path 1230 ruptures. Accordingly, the first flow path 1230 is opened, and the nucleic acid in the extraction chamber 1210 moves to the amplification chamber 1310 through the first flow path 1230.
  • the nucleic acid amplification module 1300 includes an amplification chamber 1310, a second sealing unit 1320, a second flow path 1330, a first warming unit 1340, and a second warming unit 1350. In the nucleic acid amplification module 1300, a step of amplifying the extracted nucleic acid is performed.
  • a first warming unit 1240 is disposed on one side of the amplification chamber 1310, and a second warming unit 1350 is disposed on the other side.
  • the first and second heating units 1340 and 1350 contact the sides of the amplification chamber 1310 and provide heat to the amplification chamber 1310.
  • the first heating unit 1340 maintains the temperature of the amplification chamber 1310 at 92 to 95°C.
  • the first heating unit 1340 may be a thermoelectric element. When a thermoelectric element is used as the first heating unit 1340, temperature control is easy, and temperature control is possible quickly and precisely up to a specific temperature.
  • the first heating unit 1340 contacts the side wall of the amplification chamber 1310 and transfers heat into the amplification chamber 1310. DNA is denatured by the first warming unit 1340.
  • the second warming unit 1350 is disposed on the other side of the amplification chamber 1310.
  • the second heating unit 1350 maintains the temperature of the amplification chamber 1310 at 58 to 61°C.
  • the second heating unit 1350 may be a thermoelectric element.
  • the second heating unit 1350 contacts the side wall of the amplification chamber 1310 and transfers heat into the amplification chamber 1310 to maintain the inside of the amplification chamber 1310 at a set temperature.
  • the primer and the denatured DNA fragment are combined by the second warming unit 1350.
  • the second heating unit 1350 maintains the temperature of the amplification chamber 1310 at 70 to 73°C after the coupling process.
  • the second heating unit 1350 heats the amplification chamber 1310 for a predetermined period of time so that the temperature within the amplification chamber 1310 is 70 to 73°C, and then turns off when the elongation step is completed.
  • 70-73°C is the temperature at which elongation of bound DNA occurs, and the nucleic acid introduced into the amplification chamber undergoes denaturation, binding, and elongation steps to amplify the DNA.
  • the amplification chamber 1310 may be formed in a cylindrical shape.
  • the amplification chamber 1310 is arranged in the longitudinal direction so that the circular end is located on the side.
  • One end of the amplification chamber 1310 is sealed by the second sealing part 1320.
  • a membrane is provided inside the second flow path 1330 connected to the amplification chamber 1310.
  • the amplification chamber 1310 is kept airtight during the PCR process by the membrane.
  • the PCR result contained in the amplification chamber 1310 moves to the analysis module 1400 through the second flow path 1330. Movement of PCR products is carried out by pneumatic pressure.
  • a screw thread 1311 is formed on the inside of one end of the amplification chamber 1310.
  • a screw thread 1321 is formed on the outer surface of the second sealing part 1320.
  • the inner thread 1311 of the amplification chamber 1310 is coupled to the thread 1321 of the second sealing portion 1320.
  • a sealing ring may be formed at the bottom of the second sealing portion 1320. The sealing ring brings the second seal 1320 into closer contact with the inside of the amplification chamber, thereby improving airtightness.
  • connection point A with the first flow path 1230 is located at one end of the amplification chamber 1310.
  • the second seal 1320 moves straight inside the amplification chamber 1310 and closes the connection point A with the first passage 1230. Accordingly, the inside of the amplification chamber 1310 can be sealed by the second sealing part 1320.
  • the second sealing unit 1320 rotates by receiving rotational force from the motor.
  • the second seal 1320 moves straight inside the amplification chamber 1310 by rotation.
  • the second seal 1320 may be connected in series to a motor to receive rotational force, or may receive rotational force using a worm gear and a worm wheel.
  • motor placement is free and the device can be miniaturized.
  • the volume within the amplification chamber 1310 decreases. As the volume within the amplification chamber 1310 decreases, the air pressure within the amplification chamber 1310 increases.
  • a membrane may be provided inside the second flow path 1330 connected to the amplification chamber 1310, and the membrane prevents the solution contained in the amplification chamber 1310 from moving to the analysis module 1400 during the amplification process.
  • a rupture is formed at a random point on the upper surface of the membrane, and the rupture is ruptured by air pressure.
  • the second seal 1320 passes the connection point A with the first flow path 1230 and continues to move straight inside the amplification chamber 1310, the volume within the amplification chamber 1310 decreases. As the volume within the amplification chamber 1310 decreases, the air pressure inside the amplification chamber 1310 increases, and the ruptured portion of the second flow path 1330 ruptures. Accordingly, the second flow path 1330 is opened, and the PCR results in the amplification chamber 1310 move to the analysis module 1400 through the second flow path 1330.
  • the analysis module 1400 scans the PCR result and determines the presence or absence of the virus.
  • the analysis module 1400 may include a plate unit 1410 and an optical unit 1420.
  • the plate unit 1410 receives PCR results from the amplification chamber 1310.
  • the plate portion 1410 includes a first plate 1411, a second plate 1412, and a side wall 1413.
  • the first plate 1411 is spaced apart from the second plate 1412 by a predetermined distance. PCR results are accommodated in the space between the first plate 1411 and the second plate 1412.
  • the optical unit 1420 may include a plurality of light sources 1421, 1422, 1423, and 1424. Each of the light sources 1421, 1422, 1423, and 1424 can identify different target substances. For example, the optical unit 1420 may include four light sources. Each of the light sources 1421, 1422, 1423, and 1424 may be aligned in a row or a predetermined pattern to irradiate light toward the plate portion 1410. Each light source can detect fluorescent dyes such as FAM, HEX, ROX, and Cy5.
  • Figure 1 is a block diagram schematically showing a cartridge for molecular diagnosis according to an embodiment of the present invention
  • Figure 2 is a diagram showing the overall shape of the cartridge for molecular diagnosis according to an embodiment of the present invention.
  • the molecular diagnostic cartridge 1000 includes a housing 1100, a nucleic acid extraction module 1200, a nucleic acid amplification module 1300, and an analysis module 1400.
  • the housing 1100 contains a nucleic acid extraction module 1200, a nucleic acid amplification module 1300, and an analysis module 1400.
  • An opening 1110 is formed at the top of the housing 1100. A sample may be inserted through the opening 1110. The diameter of opening 1110 may be the same as the diameter of extraction chamber 1210. The opening 1110 may be closed by the first seal 1120.
  • a screw thread 1121 may be formed on the outside of the first sealing part 1120.
  • the nucleic acid extraction module 1200 includes an extraction chamber 1210 and a first flow path 1230. In the nucleic acid extraction module 1200, a step of extracting nucleic acids from the collected specimen is performed. The nucleic acid extracted in the extraction chamber 1210 moves to the nucleic acid amplification module 1300 through the first flow path 1230. Nucleic acid can move toward the first flow path 1230 by air pressure.
  • the top of extraction chamber 1210 is open.
  • the internal space of the extraction chamber 1210 accommodates a sample and a reagent for nucleic acid extraction.
  • the extraction chamber 1210 may be formed in a cylindrical shape, or the inner shape of the extraction chamber 1210 may be cylindrical, and the diameter may be formed to be the same as the diameter of the opening 1110 of the housing 1100.
  • a screw thread 1211 may be formed on the inner upper part of the extraction chamber 1210.
  • the inner thread 1211 of the extraction chamber 1210 engages the thread 1121 of the first seal 1120.
  • the first seal 1120 moves inside the extraction chamber 1210 by rotation. As the first seal 1120 moves, the volume within the extraction chamber 1210 decreases and the air pressure increases.
  • the first flow path 1230 is connected to the bottom of the extraction chamber 1210. By the air pressure within the extraction chamber 1210, the liquid at the bottom of the extraction chamber 1210 moves through the first flow path 1230.
  • the nucleic acid extraction module 1200 may further include a warming means.
  • the heating means may heat the extraction chamber 1210 and maintain the temperature within the extraction chamber 1210 at 50 to 95°C.
  • the nucleic acid amplification module 1300 includes an amplification chamber 1310, a second sealing unit 1320, a second flow path 1330, a first warming unit 1340, and a second warming unit 1350. In the nucleic acid amplification module 1300, a step of amplifying the extracted nucleic acid is performed.
  • the amplification chamber 1310 is connected to the first flow path 1230 and receives the extracted nucleic acid through the first flow path 1230.
  • the nucleic acid introduced from the extraction chamber 1210 is mixed with the composition for PCR reaction in the amplification chamber 1310, causing a polymerase chain reaction.
  • the composition for PCR reaction may be a lyophilized solid or a composition for real-time PCR reaction.
  • the composition for PCR reaction may be Taq polymerase, nucleotides, primers, etc.
  • the composition for PCR reaction that is, Taq polymerase, nucleotides, primers, etc., may be previously accommodated in the amplification chamber 1310.
  • PCR Polymerase chain reaction
  • the polymerase chain reaction consists of the processes of denaturation, annealing, and elongation. DNA is denatured at high temperatures, and by heating to about 92 ⁇ 95°C, the double helix of DNA is unraveled. Afterwards, when the temperature is lowered to 58-61°C, the primer and each denatured DNA fragment are combined. In the elongation process, DNA synthesis occurs at 70-73°C, which is the temperature at which polymerase can operate. By repeating cooling and heating several times, DNA is amplified. Here, accurate temperature control and control of holding time for each temperature are important. To control the temperature within the amplification chamber 1310, first and second heating units 1340 and 1350 are provided.
  • the first and second heating units 1340 and 1350 provide heat to the amplification chamber 1310.
  • the first warming unit 1340 is disposed on one side of the amplification chamber 1310.
  • the first heating unit 1340 maintains the temperature of the amplification chamber 1310 at 92 to 95°C.
  • the first heating unit 1340 may be a thermoelectric element. When a thermoelectric element is used as the first heating unit 1340, temperature control is easy, and temperature control is possible quickly and precisely up to a specific temperature.
  • the first heating unit 1340 contacts the side wall of the amplification chamber 1310 and transfers heat into the amplification chamber 1310. DNA is denatured by the first warming unit 1340.
  • the second warming unit 1350 is disposed on the other side of the amplification chamber 1310.
  • the second heating unit 1350 maintains the temperature of the amplification chamber 1310 at 58 to 61°C.
  • the second heating unit 1350 may be a thermoelectric element.
  • the second heating unit 1350 contacts the side wall of the amplification chamber 1310 and transfers heat into the amplification chamber 1310 to maintain the inside of the amplification chamber 1310 at a set temperature.
  • the primer and the denatured DNA fragment are combined by the second warming unit 1350.
  • the second heating unit 1350 maintains the temperature of the amplification chamber 1310 at 70 to 73°C after the coupling process.
  • the second heating unit 1350 heats the amplification chamber 1310 for a predetermined period of time so that the temperature within the amplification chamber 1310 is 70 to 73°C, and then turns off when the elongation step is completed.
  • 70 ⁇ 73°C is the temperature at which elongation occurs, and DNA is amplified through denaturation, binding, and elongation steps.
  • the denaturation, binding, and elongation steps may be repeated several to dozens of times.
  • the control unit efficiently amplifies DNA by adjusting the temperature and heating time of the first and second heating units 1340 and 1350.
  • the control unit can schedule the temperature and warming time by deriving the optimal time to amplify the DNA to the desired amount.
  • the first and second heating units 1340 and 1350 may efficiently transfer heat by contacting the amplification chamber 1310 in the longitudinal direction.
  • the temperature holding time may vary.
  • the control unit can adjust the temperature maintenance time according to the purpose of molecular diagnosis.
  • PCR results move from the amplification chamber 1310 to the analysis module 1400 through the second flow path 1330.
  • the amplification chamber 1310 may be formed in a cylindrical shape, or the inner shape of the amplification chamber 1310 may be cylindrical.
  • a second seal 1320 is connected to one end of the amplification chamber 1310. The amplification chamber 1310 is sealed by the second sealing part 1320.
  • a screw thread 1311 may be formed inside one end of the amplification chamber 1310.
  • the inner thread 1311 of the amplification chamber 1310 is coupled to the thread 1321 of the second sealing portion 1320.
  • the second seal 1320 moves inside the amplification chamber 1310 by rotation. As the second seal 1320 moves, the volume within the amplification chamber 1310 decreases and the air pressure increases.
  • the second flow path 1330 is connected to the lower end of the other side of the amplification chamber 1310.
  • the liquid contained in the amplification chamber 1310 moves through the second flow path 1330 by the air pressure within the amplification chamber 1310.
  • the analysis module 1400 scans the PCR results introduced from the amplification chamber 1310 and determines the presence or absence of the virus.
  • the analysis module 1400 may include a plate unit 1410 and an optical unit 1420.
  • the plate unit 1410 receives PCR results from the amplification chamber 1310.
  • the plate portion 1410 includes a first plate 1411, a second plate 1412, and a side wall 1413.
  • the first plate 1411 is spaced apart from the second plate 1412 by a predetermined distance. PCR results are accommodated in the space between the first plate 1411 and the second plate 1412.
  • the optical unit 1420 detects the presence or absence of a target fluorescence signal by irradiating a laser. There may be multiple targets to be detected.
  • the optical unit 1420 may include four light sources. Each light source identifies a different target material. Each light source can detect fluorescent dyes such as FAM, HEX, ROX, and Cy5. The wavelength range of fluorescence that can be used may be 450nm-730nm.
  • the sample accommodated in the plate unit 1410 can be excited to obtain a fluorescence signal by four light-emitting diodes. Each light source detects a fluorescence signal to determine whether there is a virus infection.
  • Figure 3 is a view showing the extraction chamber of the cartridge for molecular diagnosis according to an embodiment of the present invention
  • Figure 4 is a view showing the first sealing portion of the cartridge for molecular diagnosis according to an embodiment of the present invention
  • Figure 5 is a view showing the extraction chamber of the cartridge for molecular diagnosis according to an embodiment of the present invention.
  • This is a diagram showing the first flow path of a molecular diagnostic cartridge according to an embodiment of the present invention.
  • the top of the extraction chamber 1210 is sealed by the first seal 1120.
  • a sample may be introduced into the open extraction chamber 1210, and the extraction chamber 1210 may be closed with the first seal 1120.
  • a membrane 1231 is provided inside the first flow path 1230 connected to the extraction chamber 1210.
  • the extraction chamber 1210 is kept airtight during the nucleic acid extraction process. Nucleic acid contained in the extraction chamber 1210 moves to the amplification chamber 1310 through the first flow path 1230. The movement of nucleic acids is carried out by pneumatic pressure.
  • a screw thread 1211 is formed on the upper inner surface of the extraction chamber 1210.
  • a screw thread 1221 is formed on the outer surface of the first sealing part 1120 (FIG. 4).
  • the inner thread 1211 of the extraction chamber 1210 engages the thread 1121 of the first seal 1120.
  • a sealing ring 1222 may be formed at the bottom of the first sealing portion 1220. The sealing ring 1222 brings the first seal 1220 and the inside of the extraction chamber 1210 into closer contact, thereby improving airtightness.
  • the first sealing unit 1120 rotates by receiving rotational force from the driving unit.
  • the first seal 1120 moves straight inside the extraction chamber 1210 by rotation.
  • the first sealing unit 1120 may be connected in series to a motor to receive rotational force, or may receive rotational force using a worm gear and a worm wheel.
  • motor placement is free and the device can be miniaturized.
  • the distance that the first seal 1120 moves in a straight line inside the extraction chamber 1210 can be adjusted. As the first seal 1120 moves linearly, the volume within the extraction chamber 1210 decreases and the air pressure increases.
  • a membrane 1231 is provided inside the first flow path 1230 connected to the extraction chamber 1210.
  • the membrane 1231 is arranged to cover the cross section of the first flow path 1230 to prevent the solution contained in the extraction chamber 1210 from moving into the amplification chamber 1310 during the extraction process.
  • a rupture portion 1232 is formed at a random point on the upper surface of the membrane 1231.
  • the ruptured portion 1232 is a portion formed with a thickness thinner than that of the membrane 1231, and is a location where the membrane 1231 ruptures due to air pressure.
  • the volume within the extraction chamber 1210 decreases.
  • the air pressure inside the extraction chamber 1210 increases, and the rupture portion 1232 of the first flow path 1230 ruptures. Accordingly, the first flow path 1230 is opened, and the nucleic acid in the extraction chamber 1210 moves to the amplification chamber 1310 through the first flow path 1230.
  • Figure 6 is a view from above of the nucleic acid amplification module of the cartridge for molecular diagnosis according to an embodiment of the present invention
  • Figure 7 is a view showing the amplification chamber of the cartridge for molecular diagnosis according to an embodiment of the present invention.
  • the amplification chamber 1310 is controlled to a predetermined temperature.
  • the polymerase chain reaction consists of the processes of denaturation, binding, and elongation, and the temperature in each step is controlled at 92 ⁇ 95°C, 58 ⁇ 61°C, and 70 ⁇ 73°C. This cooling and heating are repeated several times to amplify the target DNA.
  • the first and second heating units 1340 and 1350 maintain the temperature within the amplification chamber 1310 at a predetermined temperature.
  • a first warming unit 1240 is disposed on one side of the amplification chamber 1310, and a second warming unit 1350 is disposed on the other side.
  • the first and second heating units 1340 and 1350 contact the sides of the amplification chamber 1310 and provide heat to the amplification chamber 1310.
  • the first heating unit 1340 maintains the temperature of the amplification chamber 1310 at 92 to 95°C.
  • the first heating unit 1340 may be a thermoelectric element. When a thermoelectric element is used as the first heating unit 1340, temperature control is easy, and temperature control is possible quickly and precisely up to a specific temperature.
  • the first heating unit 1340 contacts the side wall of the amplification chamber 1310 and transfers heat into the amplification chamber 1310. DNA is denatured by the first warming unit 1340.
  • the second warming unit 1350 is disposed on the other side of the amplification chamber 1310.
  • the second heating unit 1350 maintains the temperature of the amplification chamber 1310 at 58 to 61°C.
  • the second heating unit 1350 may be a thermoelectric element.
  • the second heating unit 1350 contacts the side wall of the amplification chamber 1310 and transfers heat into the amplification chamber 1310 to maintain the inside of the amplification chamber 1310 at a set temperature.
  • the primer and the denatured DNA fragment are combined by the second warming unit 1350.
  • the second heating unit 1350 maintains the temperature of the amplification chamber 1310 at 70 to 73°C after the coupling process.
  • the second heating unit 1350 heats the amplification chamber 1310 for a predetermined period of time so that the temperature within the amplification chamber 1310 is 70 to 73°C, and then turns off when the elongation step is completed.
  • 70-73°C is the temperature at which elongation of bound DNA occurs, and the nucleic acid introduced into the amplification chamber undergoes denaturation, binding, and elongation steps to amplify the DNA.
  • the denaturation, binding, and elongation steps may be repeated several to dozens of times.
  • the control unit efficiently amplifies DNA by adjusting the temperature and heating time of the first and second heating units 1340 and 1350.
  • the control unit can schedule the temperature and warming time by deriving the optimal time to amplify the DNA to the desired amount.
  • the first and second heating units 1340 and 1350 may efficiently transfer heat by contacting the amplification chamber 1310 in the longitudinal direction.
  • the side surfaces of the first and second heating units 1340 and 1350 are formed to have the same curvature as the amplification chamber 1310, thereby increasing heat transfer efficiency.
  • the second warming unit 1350 may move up and down to heat the extraction chamber 1210. By heating both the extraction chamber 1210 and the amplification chamber 1310 by the second heating unit 1350, the cartridge can be miniaturized.
  • the amplification chamber 1310 may be formed in a cylindrical shape.
  • the amplification chamber 1310 is arranged in the longitudinal direction so that the circular end is located on the side.
  • One end of the amplification chamber 1310 is sealed by the second sealing part 1320.
  • a membrane is provided inside the second flow path 1330 connected to the amplification chamber 1310.
  • the amplification chamber 1310 is kept airtight during the PCR process by the membrane.
  • the PCR result contained in the amplification chamber 1310 moves to the analysis module 1400 through the second flow path 1330. Movement of PCR products is carried out by pneumatic pressure.
  • a screw thread 1311 is formed on the inside of one end of the amplification chamber 1310.
  • a screw thread 1321 is formed on the outer surface of the second sealing part 1320.
  • the inner thread 1311 of the amplification chamber 1310 is coupled to the thread 1321 of the second sealing portion 1320.
  • a sealing ring may be formed at the bottom of the second sealing portion 1320. The sealing ring brings the second seal 1320 into closer contact with the inside of the amplification chamber, thereby improving airtightness.
  • connection point A with the first flow path 1230 is located at one end of the amplification chamber 1310.
  • the second seal 1320 moves straight inside the amplification chamber 1310 and closes the connection point A with the first passage 1230. Accordingly, the inside of the amplification chamber 1310 can be sealed by the second sealing part 1320.
  • the second sealing unit 1320 rotates by receiving rotational force from the motor.
  • the second seal 1320 moves straight inside the amplification chamber 1310 by rotation.
  • the second seal 1320 may be connected in series to a motor to receive rotational force, or may receive rotational force using a worm gear and a worm wheel.
  • motor placement is free and the device can be miniaturized.
  • the volume within the amplification chamber 1310 decreases. As the volume within the amplification chamber 1310 decreases, the air pressure within the amplification chamber 1310 increases.
  • a membrane may be provided inside the second flow path 1330 connected to the amplification chamber 1310, and the membrane prevents the solution contained in the amplification chamber 1310 from moving to the analysis module 1400 during the amplification process.
  • a rupture is formed at a random point on the upper surface of the membrane, and the rupture is ruptured by air pressure.
  • the second seal 1320 passes the connection point A with the first flow path 1230 and continues to move straight inside the amplification chamber 1310, the volume within the amplification chamber 1310 decreases. As the volume within the amplification chamber 1310 decreases, the air pressure inside the amplification chamber 1310 increases, and the ruptured portion of the second flow path 1330 ruptures. Accordingly, the second flow path 1330 is opened, and the PCR results in the amplification chamber 1310 move to the analysis module 1400 through the second flow path 1330.
  • FIG. 8 is a diagram showing an analysis module of a molecular diagnostic cartridge according to an embodiment of the present invention
  • FIG. 9 is a diagram showing an analysis module of a molecular diagnostic cartridge according to another embodiment of the present invention.
  • the analysis module 1400 scans the PCR result and determines the presence or absence of the virus.
  • the analysis module 1400 may include a plate unit 1410 and an optical unit 1420.
  • the plate unit 1410 receives PCR results from the amplification chamber 1310.
  • the plate portion 1410 includes a first plate 1411, a second plate 1412, and a side wall 1413.
  • the first plate 1411 is spaced apart from the second plate 1412 by a predetermined distance. PCR results are accommodated in the space between the first plate 1411 and the second plate 1412.
  • the optical unit 1420 may include a plurality of light sources 1421, 1422, 1423, and 1424. Each of the light sources 1421, 1422, 1423, and 1424 can identify different target substances.
  • the optical unit 1420 may include four light sources. Each of the light sources 1421, 1422, 1423, and 1424 may be aligned in a row or a predetermined pattern to irradiate light toward the plate portion 1410. Each light source can detect fluorescent dyes such as FAM, HEX, ROX, and Cy5. The wavelength range of fluorescence that can be used may be 450nm-730nm.
  • the light source may be arranged circumferentially and aligned with the target by rotation.
  • the irradiation angle of the light source is the same, there is an advantage that the configuration of the optical unit 1420 can be simpler.
  • the optical unit 1420 detects the presence or absence of a target fluorescence signal by irradiating light. Using multiple light sources, multiple target DNA can be quickly detected.
  • the analysis module 1400 may include a plate unit 1430 and an output pulse analysis unit 1440.
  • the plate portion 1430 includes a first plate 1431, a second plate 1432, a side wall 1433, an opening 1434, a micro channel 1435, and a plurality of electrodes 1436.
  • the first plate 1431 is spaced apart by a predetermined distance from the second plate 1432 and the side wall 1433, and a space is formed therein.
  • a micro channel is formed in the internal space formed by the first plate 1431 and the second plate 1432.
  • the micro flow path 1435 is formed in a ⁇ shape within the plate portion 1430, and a PCR result receiving portion 1435a is provided at each end of the ⁇ shape. Electrodes 1436 are disposed at both ends of the PCR result receiving portion 1435a.
  • the PCR result receiving portion 1435a and the electrode 1436 are electrically connected.
  • PCR results flowing in from the opening 1434 of the plate unit 1430 pass through the micro-channel 1435 and are received in four PCR result receiving parts 1435a.
  • the output pulse analysis unit 1440 analyzes target DNA from the PCR product received in the PCR product receiving unit 1435a.
  • the output pulse analysis unit 1440 includes a substrate 1441, an electrode contact part 1442, and an analysis unit (not shown).
  • the substrate 1440 forms conductive wires by plating a metal material with excellent electrical conductivity, such as copper or gold, on the surface. Electricity is transmitted through conductors, and the number or arrangement of conductors may vary depending on need. In this embodiment, eight conductors are arranged to apply electricity to the eight electrodes 1435 of the plate portion 1430. One end of the plurality of conductors extends to the end of the substrate.
  • the board 1440 may also be compatible with an SD card slot.
  • the electrode contact portion 1442 is disposed on the substrate 1440 at a position corresponding to the electrode 1436 of the plate portion 1430.
  • the electrode contact portion 1442 is formed of metal in the form of a protrusion.
  • the electrode contact portion 1442 is in contact with the electrode 1436 to apply electricity to the electrode 1436.
  • the concentration of DNA is closely correlated with the impedance generated by applying an electric pulse signal with a constant frequency value.
  • an electric pulse signal with a specific frequency is applied to the amplified PCR product, a pulse signal different from the input pulse is generated due to resistance as it passes through the PCR product.
  • Target DNA is detected by analyzing the generated output pulse.
  • the PCR product flowing in from the amplification chamber 1310 passes through the micro-channel 1435 and is received in four PCR product receiving portions 1435a.
  • Electrodes 1436 electrically connected to the PCR product receiving portion 1435a are disposed on both sides of the PCR product receiving portion 1435a.
  • the electrode 1436 is in contact with the electrode contact part 1442 and receives a voltage signal of a specific frequency from the electrical signal processing device through the electrode contact part 1442.
  • the electrical signal processing device may be NI-DAQ and AD9837, a digital signal synthesis device.
  • an electric pulse signal of a specific frequency is applied to the PCR product contained in the PCR product receiving part 1435a.
  • An electric pulse signal of a specific frequency passes through the PCR result and generates a pulse signal that is different from the input pulse due to resistance.
  • the generated output pulse is fed back through a conductor.
  • the fed-back electric pulse signal passes through a transimpedance amplifier provided in the analysis unit, and the current pulse signal is converted into a voltage pulse signal.
  • the voltage pulse signal output from the transimpedance amplifier is input as an analog signal to NI-DAQ, a signal processing device, and then processed into numerical or image data using a mathematical calculation program such as MATLAB. Determine whether target DNA is detected from the processed results.
  • the present invention can provide a molecular diagnostic cartridge that can perform molecular diagnosis simultaneously with sample collection in the field.

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Abstract

La présente invention se rapporte à une cartouche pour un diagnostic moléculaire. La présente invention comprend un module d'extraction d'acide nucléique, un module d'amplification d'acide nucléique, un module d'analyse et un boîtier. Le module d'extraction d'acide nucléique comprend une chambre d'extraction et un premier trajet d'écoulement et le module d'amplification d'acide nucléique comprend une chambre d'amplification et un second trajet d'écoulement. Une première partie d'étanchéité est reliée à l'extrémité supérieure de la chambre d'extraction de telle sorte que le volume de la chambre d'extraction soit réduit par rotation de la première partie d'étanchéité, et un acide nucléique extrait est amené à s'écouler dans la chambre d'amplification à travers le premier trajet d'écoulement par pression d'air. Une seconde partie d'étanchéité est disposée au niveau d'une extrémité de la chambre d'amplification de telle sorte que le volume de la chambre d'amplification soit réduit par la rotation de la seconde partie d'étanchéité, et le produit résultant de PCR est amené à s'écouler dans le module d'analyse à travers le second trajet d'écoulement par pression d'air. Selon la présente invention, la cartouche pour un diagnostic moléculaire permet de vérifier rapidement des résultats de test par collecte d'échantillon et diagnostic moléculaire en même temps sur site, et peut réduire la possibilité de contamination d'échantillons et permet un diagnostic moléculaire simple.
PCT/KR2022/014190 2022-08-29 2022-09-22 Cartouche pour un diagnostic moléculaire WO2024048835A1 (fr)

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KR20050106408A (ko) * 2003-01-31 2005-11-09 휴렛-팩커드 디벨롭먼트 컴퍼니, 엘 피 시료 분석용 미세 유체 장치 및 그 제조 방법
US20060246490A1 (en) * 1995-06-29 2006-11-02 Affymetrix, Inc. Miniaturized genetic analysis systems and methods
KR20160090284A (ko) * 2013-09-18 2016-07-29 캘리포니아 인스티튜트 오브 테크놀로지 이동 및 타이밍 제어를 위한 시스템 및 방법
US20190346422A1 (en) * 2015-03-23 2019-11-14 The University Of North Carolina At Chapel Hill Universal molecular processor for precision medicine
KR20220023948A (ko) * 2020-08-21 2022-03-03 주식회사 토탈바이오센스 시료 분석용 칩의 분석 장치, 그리고 분석 장치를 이용한 시료 분석 방법

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Publication number Priority date Publication date Assignee Title
KR102050161B1 (ko) 2018-05-31 2019-11-28 목포대학교산학협력단 유전체 분자 진단용 휴대용 램프 ｐｃｒ 장치 및 그 장치를 이용한 유전체 분자 진단 방법

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060246490A1 (en) * 1995-06-29 2006-11-02 Affymetrix, Inc. Miniaturized genetic analysis systems and methods
KR20050106408A (ko) * 2003-01-31 2005-11-09 휴렛-팩커드 디벨롭먼트 컴퍼니, 엘 피 시료 분석용 미세 유체 장치 및 그 제조 방법
KR20160090284A (ko) * 2013-09-18 2016-07-29 캘리포니아 인스티튜트 오브 테크놀로지 이동 및 타이밍 제어를 위한 시스템 및 방법
US20190346422A1 (en) * 2015-03-23 2019-11-14 The University Of North Carolina At Chapel Hill Universal molecular processor for precision medicine
KR20220023948A (ko) * 2020-08-21 2022-03-03 주식회사 토탈바이오센스 시료 분석용 칩의 분석 장치, 그리고 분석 장치를 이용한 시료 분석 방법

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