WO2021120651A1 - Liquid path system, biomolecule analysis system and nucleotide sequencing system - Google Patents

Liquid path system, biomolecule analysis system and nucleotide sequencing system Download PDF

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Publication number
WO2021120651A1
WO2021120651A1 PCT/CN2020/109734 CN2020109734W WO2021120651A1 WO 2021120651 A1 WO2021120651 A1 WO 2021120651A1 CN 2020109734 W CN2020109734 W CN 2020109734W WO 2021120651 A1 WO2021120651 A1 WO 2021120651A1
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Prior art keywords
reaction
way valve
reagent
pump
reaction device
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PCT/CN2020/109734
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French (fr)
Chinese (zh)
Inventor
潘健昌
吴平
姜泽飞
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深圳市真迈生物科技有限公司
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Publication of WO2021120651A1 publication Critical patent/WO2021120651A1/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6869—Methods for sequencing

Definitions

  • This application relates to the technical field of biomolecular analysis, and more specifically, to a fluid path system, a biomolecular analysis system, and a nucleic acid sequence determination system.
  • nucleic acid analysis of nucleic acid samples placed on a solid substrate usually involves the so-called sample processing before the computer and the computer.
  • the sample processing before the computer is to make the sample to be tested meet the computer requirements, such as connecting to the chip, the so-called computer refers to loading the processed sample into the sequencer for sequencing.
  • sequencing platforms often include two or more independent or functionally linked devices.
  • these devices are generally sold or purchased in sets.
  • a sequencing platform that includes two supporting equipment
  • one of the equipment is used to process the nucleic acid sample to be tested, including connecting it to a reaction device such as a chip.
  • This equipment is often referred to as a hybridization instrument or a sample injection instrument.
  • a sample processor another device detects the chip connected to the nucleic acid sample output by the previous device to achieve nucleic acid sequence determination.
  • This device is the most important hardware of the sequencing platform and is often called a sequencer.
  • a commercial sequencing platform contains multiple automated equipment to process and test samples. At least part of the reason is that the processing of samples before the computer and the control of the liquid path involved in the computer sequencing are more complicated. For example, the sample processing before the computer is often It includes multiple steps and multiple reactions, involving multiple reagents and multiple inlet and outlet sequences. Moreover, some reagents or reactions may also have special requirements for pipe material, flow rate, pressure, etc. Furthermore, sequencing itself generally involves multiple Reagents and multiple reactions; part of the reason is that biochemical reactions are susceptible to interference, including easy contamination between reagents.
  • liquid path system for sample processing before the computer and the liquid path system for sequencing are integrated to construct a set that can realize both the processing of the samples before the computer and the sequencing of the processed samples without mutual interference. Or pollution, and it is also suitable for industrialized fluid system, which is very difficult.
  • the embodiments of the present application provide a fluid path system, a biomolecule analysis system, and a nucleic acid sequence determination system.
  • the liquid path system of the embodiment of the present application is used to provide a solution environment for analyzing biomolecules.
  • the analyzing biomolecules includes performing a first reaction and a second reaction on a reaction device.
  • the first reaction includes using a first reagent to make the The biomolecules are connected to the reaction device, the second reaction includes using a second reagent to detect the biomolecules connected to the reaction device,
  • the liquid path system includes a valve body assembly and a drive assembly, the valve
  • the body assembly includes a first multi-way valve and a second multi-way valve.
  • the first multi-way valve can communicate with the second reagent and the reaction device, and the second multi-way valve can communicate with the first reagent and the reaction device.
  • the reaction device; the drive assembly includes a first pump and a second pump, the first pump is connected to the first multi-way valve, the second pump is connected to the second multi-way valve;
  • the first pump is used to drive
  • the first reagent enters the reaction device along a first direction to perform the first reaction;
  • the second multi-way valve communicates the reaction device and the second pump, and the first multi-way valve communicates with the reaction device and the second pump.
  • the second pump is used to drive the second reagent to enter the reaction device in a second direction to perform the second reaction.
  • the so-called biological molecules are biological macromolecules, such as proteins or nucleic acids.
  • the biomolecule referred to is a nucleic acid
  • the first reaction includes a hybridization reaction
  • the second reaction includes a sequencing reaction.
  • the valve body assembly further includes a third multi-way valve, and the third multi-way valve can communicate with the second reagent and the first multi-way valve.
  • the third multi-way valve includes a stator and a rotor that are communicable, the third multi-way valve includes a common port, the stator includes a plurality of ports, the rotor includes a communication slot, the The rotor can rotate so that the common port communicates with at least one of the ports through the communication groove.
  • the first multi-port valve includes a plurality of ports, and the plurality of ports are connected to at least the second reagent, the reaction device, and the first pump, respectively, and the first multi-port Any two of the ports on the valve can communicate.
  • the reaction device includes a first unit and a second unit
  • the first multi-way valve is a four-way valve
  • the four ports of the four-way valve are respectively connected to the second reagent and the second unit.
  • the second multi-port valve includes three ports, and the three ports are respectively connected to the first reagent, the reaction device, and the second pump, and the second multi-port valve Any two of the ports can be connected.
  • the second multi-way valve is a three-way valve.
  • the reaction device includes a plurality of channels, and the number of the second multi-way valves and the number of the second pumps are not less than the number of the channels, and one second multi-way valve One said channel and one said second pump can be connected.
  • the fluid path system further includes a current collecting component, the current collecting component is in communication with the first pump, and the current collecting component is used to collect the first reaction after the first reaction.
  • Reagent; and/or the current collecting component is in communication with the second pump, and the current collecting component is used to collect the second reagent after the second reaction.
  • the current collecting assembly is also used to collect the second pump driven by the first pump. Reagents.
  • the current collecting assembly includes a liquid collecting member and a waste liquid bottle
  • the liquid collecting member includes a first port and a plurality of second ports, the first port and the plurality of second ports In communication, the first pump is in communication with the second port, the second pump is in communication with the second port, and the waste liquid bottle is in communication with the first port.
  • the first multi-way valve can communicate with the first pump and the second reagent, and/or the The second pump and the first reagent, the first pump and/or the second pump are used to drive the second reagent to fill the flow path of the first multi-way valve.
  • the first direction is opposite to the second direction.
  • the biomolecule analysis system of the embodiment of the present application includes the fluid path system described in any of the embodiments of the present application.
  • the biomolecule analysis system further includes a reaction device connected to the first multi-way valve and the second multi-way valve.
  • the biomolecule is a nucleic acid
  • the reaction device includes a first unit and a second unit
  • the biomolecule analysis system includes a signal acquisition device, and the signal acquisition device is used for signal acquisition
  • the second reaction is a nucleic acid sequence determination reaction, the nucleic acid sequence determination reaction includes a plurality of repeated reactions, and one of the repeated reactions includes a base extension reaction, reaction signal collection, and group excision; the first unit and the second unit While one of the units performs the base extension reaction or the group excision, the signal acquisition device is used to collect the reaction signal on the other of the first unit and the second unit, so The signal acquisition device performs signal acquisition on the first unit or the second unit that performs the reaction signal acquisition.
  • the nucleic acid sequence determination system of the embodiment of the present application includes the fluid path system described in any of the embodiments of the present application.
  • the nucleic acid sequence determination system further includes a reaction device, and the reaction device is detachably connected to the first multi-way valve and the second multi-way valve.
  • the reaction device and the first pump are connected by switching the first multi-way valve
  • the reaction device and the first pump are connected by switching the second multi-way valve.
  • Reagents the first reaction can be carried out in the reaction device, by switching the second multi-way valve to connect the reaction device and the second pump, and switching the first multi-way valve to connect the reaction device and the second reagent
  • the second reaction can be carried out in the reaction device
  • the first reaction and the second reaction can be carried out on the reaction device through a liquid circuit system.
  • the structure of the liquid circuit system for realizing the first reaction and the second reaction is relatively simple, and the integrated liquid circuit system is constructed. The cost is much lower than the sum of the cost of building a liquid circuit system that realizes the first reaction alone and a liquid circuit system that realizes the second reaction alone.
  • FIG. 1 is a schematic diagram of a module of a biomolecule analysis system according to an embodiment of the present application in a state;
  • FIG. 2 is a schematic diagram of modules of the biomolecule analysis system of the embodiment of the present application in another state
  • FIG. 3 is a schematic diagram of the structure of a third multi-way valve and a first multi-way valve according to an embodiment of the present application;
  • FIG. 4 is a schematic diagram of modules of the biomolecule analysis system of the embodiment of the present application in another state.
  • Biomolecular analysis system 1000 fluid path system 100, valve body assembly 10, first multi-port valve 11, ports 111, 112, 113, 114, second multi-port valve 12, ports 121, 122, 123, third multi-port
  • the valve 13 the stator 131, the rotor 132, the common port 133, the port 134, the communication groove 135, the drive assembly 20, the first pump 21, the second pump 22, the collecting assembly 30, the liquid collecting part 31, the second port 311, the first A port 312, a waste liquid bottle 32, a reaction device 200, a first unit 201, a second unit 202, a channel 203, a second reagent 300, and a first reagent 400.
  • the first feature “on” or “under” the second feature may be in direct contact with the first and second features, or the first and second features may be indirectly through an intermediary. contact.
  • the "above”, “above” and “above” of the first feature on the second feature may mean that the first feature is directly above or diagonally above the second feature, or it simply means that the level of the first feature is higher than that of the second feature.
  • the “below”, “below” and “below” of the second feature of the first feature may mean that the first feature is directly below or obliquely below the second feature, or it simply means that the level of the first feature is smaller than the second feature.
  • the biomolecule analysis system 1000 includes a liquid path system 100 and a detachable reaction device 200 connected to the liquid path system 100.
  • the biomolecule analysis system 1000 may specifically be a nucleic acid sequence determination system.
  • the liquid path system 100 is used to provide a solution environment for analyzing biomolecules.
  • the biomolecule analysis includes performing a first reaction and a second reaction in the reaction device 200. Wherein, the first reaction includes using the first reagent 400 to connect the biomolecules to the reaction device 200, and the second reaction includes using the second reagent 300 to detect the biomolecules connected to the reaction device 200.
  • the fluid path system 100 includes a valve body assembly 10 and a driving assembly 20.
  • the valve body assembly 10 includes a first multi-way valve 11 and a second multi-way valve 12.
  • the first multi-way valve 11 can connect the second reagent 300 and the reaction device 200
  • the second multi-way valve 12 can connect the first reagent 400 and the reaction device 200.
  • the driving assembly 20 includes a first pump 21 and a second pump 22.
  • the first pump 21 is connected to the first multi-way valve 11, and the second pump 22 is connected to the second multi-way valve 12.
  • the reaction device 200 is connected between the first multi-way valve 11 and the second multi-way valve 12.
  • the first pump 21 is used to drive the first reagent 400 along Enter the reaction device 200 in the first direction to perform the first reaction.
  • the second pump 22 is used to drive the second reagent 300 along The second direction enters the reaction device 200 to perform the second reaction.
  • the reaction device 200 by switching the first multi-port valve 11 to communicate the reaction device 200 and the first pump 21, and switching the second multi-port valve 12 to communicate the reaction device 200 and the first reagent 400, The first reaction is performed in the reaction device 200.
  • the reaction device 200 By switching the second multi-way valve 12 to connect the reaction device 200 and the second pump 22, and the first multi-way valve 11 to connect the reaction device 200 and the second reagent 300, the reaction device 200 can be connected to the reaction device 200 and the second reagent 300.
  • the first reaction and the second reaction can be carried out in the reaction device 200 through one liquid path system 100.
  • the structure of the liquid path system 100 for realizing the first reaction and the second reaction is relatively simple and does not need to be separated.
  • the cost of building the integrated liquid circuit system 100 is much lower than that of building a liquid circuit system that realizes the first reaction alone and the second reaction alone. The sum of the cost of the hydraulic system.
  • FIG. 1 is a schematic diagram of a module when the first reaction is performed on the reaction device 200
  • FIG. 2 is a schematic diagram of a module when the second reaction is performed on the reaction device 200.
  • the first reaction in the embodiment of the present application includes a reaction in which biomolecules are connected to the reaction device 200, or is referred to as a hybridization reaction.
  • the so-called biomolecules include DNA and/or RNA, etc.
  • biomolecules include ribonucleotides, deoxyribonucleotides and their analogs, including A, T, C, G, and U and their analogs.
  • reaction device 200 may be a reaction site including a substrate.
  • the reaction device 200 may specifically be in the form of a chip, and the reaction device 200 may be detachably connected to the liquid path system 100.
  • the substrate can be any solid support that can be used to immobilize nucleic acid sequences, such as nylon membranes, glass sheets, plastics, silicon chips, magnetic beads, and the like. Probes can be randomly distributed on the surface of the substrate.
  • the probes can be a segment of DNA and/or RNA sequences.
  • the probes can also be called primers, capture strands or fixed strands.
  • the biomolecule can be fixedly connected to the probe, for example, based on the principle of base complementarity, so that the biomolecule can be connected to the reaction device 200.
  • the first reagent 400 may include a hybridization solution for performing the first reaction, and the hybridization solution includes the above-mentioned biomolecules.
  • the second reaction includes a reaction for detecting biomolecules connected to the reaction device 200.
  • the second reaction may be a sequence determination reaction, which is generally called sequencing, including a measurement of DNA or RNA.
  • the hierarchical structure or sequence includes determining the sequence of nucleotides/bases of a given nucleic acid fragment.
  • the second reaction may include one or more sub-reactions.
  • the DNA is sequenced.
  • the second reaction is sequencing based on sequencing while synthesizing or sequencing while ligating.
  • the sequencing includes multiple sub-reactions, and the multiple sub-reactions include Base extension reaction, reaction signal collection, and group excision; performing the multiple sub-reactions once can be called performing a repeated reaction or a round of reaction. Sequencing includes multiple repeated reactions or multiple rounds of reactions to detect nucleic acid molecules ( The nucleotide/base sequence of at least one sequence of the template).
  • the base extension reaction includes the nucleic acid molecule immobilized reaction device 200, for sequencing-by-synthesis (SBS) or sequencing-by-ligation (SBL), under the action of polymerase or ligase, based on the principle of base complementation
  • the nucleic acid glycoside (including the modified nucleotide) is bound to the nucleic acid molecule, and the corresponding reaction signal is collected.
  • modified nucleotides may refer to nucleotides with a certain label that allows the modified nucleotides to be detected under certain circumstances, such as nucleotides labeled with fluorescent molecules.
  • modified nucleotides Under the excitation of a laser of a specific wavelength, it will emit fluorescence; in general, for SBS, modified nucleotides usually also have the function of inhibiting the binding of other nucleotides to the next position of the same nucleic acid molecule, such as with a blocking group.
  • the blocking group can prevent other nucleotides from binding to the next position of the template.
  • the blocking group is, for example, an azide group (-N 3 ) attached to the 3'position of the sugar group of the nucleotide.
  • the second reagent 300 includes polymerase and modified nucleotides. In one example, the second reagent 300 is loaded in five independent containers, and the five independent containers are loaded with polymerase and four modified nucleosides. Acid, the polymerase and one or more nucleotides are mixed in the reaction device 200, and a controllable polymerase chain reaction is performed under suitable conditions, that is, the base extension reaction is realized.
  • Collecting reaction signals includes collecting signals from modified nucleotides bound to nucleic acid molecules, for example, irradiating a specific area in the reaction device 200 after the base extension reaction with a laser, and the nuclear labeled with a fluorescent molecule in the specific area is irradiated with a laser.
  • the glycidyl acid emits fluorescence.
  • the second reagent 300 further includes an information collection reagent such as an imaging reagent.
  • the imaging reagent is, for example, an antioxidant to help collect fluorescent signals.
  • the information collection reagent can be independently carried in a container.
  • a second reagent 300 (hereinafter also referred to as information collection reagent) is added to the reaction device 200 so that the information of the modified nucleotide can be collected easily, for example, the light emitted by the modified nucleotide or the fluorescent molecule on it can be The image is captured by the imaging device.
  • Group excision includes removing the detectable label and/or blocking group on the modified nucleotide of the nucleic acid molecule after the base extension reaction, so that other nucleotides (including modified nucleotides) can bind To the next position of the nucleic acid molecule, proceed to the next repeated reaction or the next round of reaction.
  • the second reagent 300 further includes an excision reagent, which is independently carried in a container. When the sub-reaction of the group excision is performed, the excision reagent is passed in to simultaneously remove the modified nucleotides. The detectable label and blocking group.
  • the second reagent 300 introduced into the reaction device 200 may be different.
  • the second reagent 300 including modified nucleotides may be introduced, and when the reaction signal is collected
  • the second reagent 300 that is, a kind of information collection reagent
  • the second reagent 300 can be introduced to remove the detectable label and blocking group on the modified nucleotide when performing group excision. (Hereinafter referred to as excision reagent).
  • cleaning reagents can also be introduced to remove unreacted substances remaining in the reaction device 200 or in the liquid path system 100, substances that interfere with the reaction or signal collection.
  • the cleaning reagent can also be used as a kind of the second reagent 300, and the cleaning reagent can be a buffer solution.
  • the second reaction described below is sequencing, including any one or more sub-reactions in the second reaction described above, and a cleaning process between the two sub-reactions.
  • the reaction device 200 can provide a reaction place for the first reaction and the second reaction.
  • the reaction device 200 may include one or more channels 203.
  • the first reagent 400 may flow through the channel 203 in a first direction (the first direction X as shown in FIG. 1).
  • the second reagent 300 may flow through the channel 203 in a second direction (the second direction Y as shown in FIG. 1, the second direction Y may be opposite to the first direction X).
  • the reaction device 200 includes a first unit 201 and a second unit 202.
  • the first unit 201 includes one or more channels 203
  • the second unit 202 includes one or more channels 203.
  • the same reaction can be performed on the first unit 201 and the second unit 202 respectively, or different reactions can be performed separately.
  • the first reaction or the second reaction can be carried out in the second unit 202, or no reaction can be carried out in the second unit 202; the second reaction is carried out in the first unit 201
  • the first reaction or the second reaction can be carried out in the second unit 202, or no reaction can be carried out in the second unit 202;
  • a sub-reaction of the second reaction such as base extension
  • additional sub-reactions of the second reaction for example, reaction signal collection
  • the first unit 201 includes a plurality of channels 203.
  • One end of the plurality of channels 203 of the first unit 201 close to the first multi-way valve 11 may be connected to one port 112 of the first multi-way valve 11 in common.
  • One end of each channel 203 of the first unit 201 close to the second multi-way valve 12 can be connected to a port 121 of the second multi-way valve 12, so that during the first reaction, different channels 203 can be introduced into different first ports.
  • different biomolecules can be connected in different channels 203, and different first reagents 400 will not cross-contamination before the first reaction.
  • the arrangement of the channel 203 in the second unit 202 can be the same as the arrangement of the channel 203 in the first unit 201, and will not be repeated here.
  • the first multi-way valve 11 can connect the first pump 21 and the reaction device 200, the first multi-way valve 11 can also connect the second reagent 300 and the reaction device 200, the first multi-way valve 11
  • the second reagent 300 and the first pump 21 can also be connected.
  • the first multi-way valve 11 includes a plurality of ports 111, 112, 113, and 114.
  • the plurality of ports 111, 112, 113, and 114 are connected to at least the second reagent 300, the reaction device 200 and the first pump 21, respectively.
  • the multi-way valve 11 can communicate with any two of the plurality of ports 111, 112, 113, and 114.
  • the first multi-way valve 11 may be a four-way valve, a five-way valve, a six-way valve, etc., which is not limited here.
  • the first multi-way valve 11 may also be a three-way valve.
  • the port 111 is connected to the second reagent 300
  • the port 112 is connected to the first unit 201
  • the port 113 is connected to the second unit 202
  • the port 114 is connected to the first pump 21.
  • the first multi-way valve 11 can communicate with any two of the multiple ports 111, 112, 113, and 114 to communicate the flow passages connected by any two ports 111, 112, 113, and 114.
  • the port 112 can be connected to the port 114 to communicate the first pump 21 and the first unit 201;
  • the port 113 can be connected to the port 114 to communicate the first pump 21 and the first unit 201.
  • the second unit 202; the port 111 can be connected to the port 112 to connect the second reagent 300 and the first unit 201; the port 111 can be connected to the port 113 to connect the second reagent 300 and the second unit 202; the port can be connected 111 communicates with the port 114 to communicate the second reagent 300 with the first pump 21.
  • the second multi-way valve 12 can connect the first reagent 400 and the reaction device 200, the second multi-way valve 12 can connect the second pump 22 and the reaction device 200, the second multi-way valve 12 also The first reagent 400 and the second pump 22 can be connected.
  • the second multi-way valve 12 includes three ports 121, 122, and 123.
  • the three ports 121, 122, and 123 are respectively connected to the reaction device 200, the first reagent 400 and the second pump 22.
  • the second multi-way valve 12 can Connect any two of the three ports 121, 122, 123.
  • the second multi-way valve 12 may be a three-way valve, a four-way valve, a five-way valve, etc., which is not limited here.
  • the second multi-way valve 12 can communicate with any two of the three ports 121, 122, and 123 to communicate the flow passages connected by any two ports 121, 122, and 123.
  • the port 121 can be connected to the port 122 to connect the first reagent 400 and the reaction device 200; the port 121 can be connected to the port 123 to connect the second pump 22 and the reaction device. 200 (the first unit 201 or the second unit 202); by switching the state of the second multi-way valve 12, the port 122 and the port 123 can be connected to communicate the first reagent 400 and the second pump 22.
  • the number of second multi-way valves 12 can also be multiple, the number of second multi-way valves 12 is not less than the number of channels 203, one second multi-way valve 12 and one channel 203 Connected. At this time, the communication states of the plurality of second multi-way valves 12 may not affect each other. For example, some of the second multi-way valves 12 communicate with the first reagent 400 and the reaction device 200, and another part of the second multi-way valves 12 communicate with the second The pump 22 and the reaction device 200 enable different channels 203 of the reaction device 200 to perform different reactions.
  • the first pump 21 is connected to the first multi-way valve 11.
  • the first pump 21 can be used to drive the second reagent 300 into the first pump 21; when the first multi-way valve 11 communicates with the first pump 21 and When the reaction device 200 is used, the first pump 21 can be used to drive the reagent in the reaction device 200 to enter the first pump 21.
  • the second pump 22 is connected to the second multi-way valve 12.
  • the second pump 22 can be used to drive the first reagent 400 into the second pump 22; when the second multi-way valve 12 connects the reaction device 200 with the second pump 22 When the second pump 22 is used, the second pump 22 can be used to drive the reagent in the reaction device 200 into the second pump 22.
  • the number of second pumps 22 may be multiple, and the number of second pumps 22 may be the same as the number of second multi-way valves 12, and each second pump 22 is connected to one second multi-way valve 12.
  • the first multi-port valve 11 may be directly connected to the second reagent 300.
  • the first multi-port valve 11 may be indirectly connected to the second reagent 300.
  • the first multi-port valve 11 and the second reagent 300 may be connected indirectly.
  • a valve body may be provided between the reagents 300.
  • the valve body assembly 10 further includes a third multi-way valve 13.
  • the third multi-way valve 13 can connect the second reagent 300 and the first multi-way valve 11.
  • the third multi-way valve 13 may specifically be a rotary valve.
  • the third multi-way valve 13 includes a stator 131 and a rotor 132 that are communicable, the third multi-way valve 13 includes a common port 133, and the stator 131 includes a plurality of ports 134.
  • the rotor 132 includes a communication groove 135, and the rotor 132 can rotate so that the common port 133 and at least one port 134 communicate through the communication groove 135.
  • the common port 133 can be connected to the first multi-way valve 11, and specifically can be connected to the port 111 of the first multi-way valve 11.
  • the second reagent 300 of different composition is connected, for example, one port 134 is connected to the reagent I, the other port 134 is connected to the reagent II, and the other port 134 is connected to the reagent III.
  • the second reagent 300 can be installed in a reagent tube, and the second reagent 300 of different components can be installed in different reagent tubes respectively.
  • the number of ports 134 can be the same as the number of reagent tubes, and one port 134 is connected to one through a pipeline.
  • the second reagent 300 in the reagent tube By rotating the rotor 132, the common port 133 can be communicated with different ports 134 through the communication groove 135, so that the first multi-way valve 11 can communicate with the second reagent 300 of different composition, so as to meet the requirements of different types in the current second reaction.
  • the demand for the second reagent 300 is the same as the number of reagent tubes, and one port 134 is connected to one through a pipeline.
  • the second reagent 300 in the reagent tube By rotating the rotor 132, the common port 133 can be communicated with different ports 134 through the communication groove 135, so that the first multi-way valve 11 can communicate with the second reagent 300 of different composition, so as to meet the requirements of different types in the current second reaction.
  • the demand for the second reagent 300 The demand for the second reagent 300.
  • the liquid path system 100 further includes a collecting assembly 30, the collecting assembly 30 is in communication with the first pump 21, and the collecting assembly 30 is used to collect the first reaction after the first reaction.
  • One reagent 400 When the first pump 21 and the second reagent 300 are in communication through the first multi-way valve 11, the collecting assembly 30 can also be used to collect the second reagent 300 driven by the first pump 21. At this time, the second reagent 300 may not pass the reaction.
  • the second reagent 300 enters the collecting assembly 30 after passing through the first pump 21.
  • the current collecting assembly 30 may also be in communication with the second pump 22, and the current collecting assembly 30 is used to collect the second reagent 300 after the second reaction.
  • the current collecting assembly 30 can be used to collect the waste liquid after the first reaction and the second reaction, so as to facilitate the centralized treatment of the waste liquid.
  • the current collecting assembly 30 includes a liquid collecting member 31 and a waste liquid bottle 32.
  • the liquid collecting member 31 includes a first port 312 and a plurality of second ports 311, and the first port 312 is in communication with the plurality of second ports 311.
  • the first pump 21 is in communication with the second port 311, the second pump 22 is in communication with the second port 311, and the waste liquid bottle 32 is in communication with the first port 312.
  • the first reagent 400 after the first reaction or the second reagent 300 after the second reaction can enter the liquid collecting part 31 through the second port 311, and the reagent entering the liquid collecting part 31 flows out of the first port 312 to the waste liquid bottle. 32 in.
  • biomolecule analysis system 1000 in the examples shown in FIG. 1, FIG. 2 and FIG. 4 as an example to illustrate the process of performing the first reaction and the second reaction:
  • the port 121 of the second multi-way valve 12 communicates with the port 122, so that the second multi-way valve 12 communicates the reaction device 200 and the first reagent 400, and the first multi-way valve 12 communicates with the first reagent 400.
  • the port 112 or 113 of the valve 11 communicates with the port 114 so that the first multi-way valve 11 communicates with the reaction device 200 and the first pump 21.
  • the first pump 21 is turned on, so that the first pump 21 drives the first reagent 400 into the reaction device 200 along the first direction X to perform the first reaction.
  • the first reagent 400 can also enter the first pump 21 and further enter the liquid collecting member 31 and the waste liquid bottle 32.
  • the multiple channels 203 of the reaction device 200 are connected to the multiple second multi-way valves 12 in one-to-one correspondence, and the multiple second multi-way valves 12 are connected to the multiple first reagents 400 in a one-to-one correspondence, therefore, different channels 203 are Different first reagents 400 can be flowed into, different channels 203 can be connected with different biomolecules, and different channels 203 will not produce cross-contamination during the first reaction.
  • the first reagent 400 enters the reaction device 200 along the first direction X. Before the first reagent 400 enters the reaction device 200 for the first reaction, it does not need to pass through the first multi-way valve 11 and the third multi-way valve 13 and other pipelines. , The wall hanging of the first reagent 400 on the pipeline is reduced, the first reagent 400 can be passed through in a small amount, the loss of the first reagent 400 is reduced, and the cost is saved.
  • the cleaning reagent in the second reagent 300 can be used to clean the liquid path system 100.
  • the port 134 in the third multi-way valve 13 communicating with the cleaning reagent is connected to the common port 133; the port 111 of the first multi-way valve 11 and the port 112 or 113 are switched.
  • the first multi-way valve 11 communicate with the reaction device 200 and the second reagent 300; switch the port 121 of the second multi-way valve 12 to communicate with the port 123, so that the second multi-way valve 12 connects the reaction device 200 with the second reagent.
  • Pump 22 is the port 121 of the second multi-way valve 12 to communicate with the port 123.
  • the second pump 22 is turned on, so that the second pump 22 drives the cleaning reagent into the reaction device 200 along the second direction Y, and the cleaning reagent cleans the first reagent 400 remaining in the reaction device 200.
  • the cleaning reagent can also enter the second pump 22, and further enter the liquid collecting member 31 and the waste liquid bottle 32.
  • the first pump 21 drives the second reagent 300 to quickly fill the flow path from the second reagent 300 to the first multi-way valve 11 to increase the flow rate of the second reagent 300, specifically, the reagent I In the pipeline filled with the second reagent 300 and the port 134, in the pipeline inside the third multi-way valve 13, in the pipeline between the common port 133 and the first multi-way valve 11, and inside the first multi-way valve 11 In the pipeline, so that when the second reaction is subsequently performed, there is no need to fill the flow path from the second reagent 300 to the first multi-way valve 11 with the reagent I again, and the reagent I can quickly enter the reaction device 200 for the second reaction.
  • the reagent I can also fill the pipeline between the first multi-way valve 11 and the first pump 21, the pipeline inside the first pump 21, and the first pump 21 and the liquid collection. In the pipeline between the components.
  • the port 111 of the first multi-way valve 11 can be switched to communicate with the port 112 or 113, and the port 121 of the second multi-way valve 12 can be switched to communicate with the port 123 to
  • the first multi-way valve 11 and the second multi-way valve 12 are connected to the common port 133 (in this case, the common port 133 is connected to the reagent 1) and the second pump 22.
  • the second pump 22 is turned on, so that the second pump 22 drives the second reagent 300 to quickly fill the second reagent 300 into the flow path of the first multi-way valve 11.
  • the port 111 of the first multi-way valve 11 can be in communication with the port 114, while the port 111 of the first multi-way valve 11 is in communication with the port 112 or 113, and the port 121 of the second multi-way valve 12 is in communication with the port 123 to Make the first multi-way valve 11 communicate with the common port 133 (at this time the common port 133 communicates with the reagent I) and the first pump 21, while the first multi-way valve 11 and the second multi-way valve 12 communicate with the common port 133 and the second pump 22 ,
  • the first pump 21 and the second pump 22 are turned on at the same time, so that the first pump 21 and the second pump 22 simultaneously drive the second reagent 300 to quickly fill the second reagent 300 into the flow path of the first multi-way valve 11. Second, the flow rate of the reagent 300.
  • the port 111 of the first multi-way valve 11 communicates with the port 112 or 113, so that the first multi-way valve 11 communicates with the reaction device 200 and the second reagent 300, and the second multi-way valve 11 communicates with the reaction device 200 and the second reagent 300.
  • the port 121 of the through valve 12 communicates with the port 123 so that the second multi-way valve 12 communicates with the reaction device 200 and the second pump 22.
  • the second pump 22 is turned on, so that the second pump 22 drives the second reagent 300 into the reaction device 200 along the second direction Y to perform the second reaction.
  • the second reaction includes multiple sub-reactions.
  • the process of carrying out the second reaction in the reaction device 200 may be successively performing sub-reactions such as base extension reaction, reaction signal collection, and group excision in the reaction device 200. Between sub-reactions, a cleaning process can be carried out.
  • the first multi-way valve 11 communicates with the common port 133 and the reaction device 200
  • the second multi-way valve 12 communicates with the reaction device 200 and the second pump 22. The state remains unchanged.
  • the base extension reaction is performed, the third multi-way valve is rotated.
  • the rotor 132 of the valve 13 connects the port 134 that communicates the modified nucleotide in the third multi-way valve 13 with the common port 133; when the reaction signal is collected, the rotor 132 of the third multi-way valve 13 is rotated to make the third multi-way valve 13 communicate with the common port 133.
  • the port 134 that communicates the information collection reagent in the through valve 13 communicates with the common port 133; when performing group removal, the rotor 132 of the third multi-way valve 13 is rotated so that the port 134 of the third multi-way valve 13 that communicates the removal reagent is connected to the common port 133.
  • the port 133 is connected; during the cleaning process, the rotor 132 of the third multi-way valve 13 is rotated, so that the port 134 in the third multi-way valve 13 communicating with the cleaning reagent is connected to the common port 133.
  • the reaction device 200 when the reaction device 200 includes only one reaction unit, the sub-reactions in the second reaction and the cleaning process between the two sub-reactions can be performed on the reaction unit successively.
  • the reaction device 200 when the reaction device 200 includes a plurality of reaction units, different sub-reactions in the second reaction may be performed on different reaction units.
  • the reaction device 200 includes a first unit 201 and a second unit 202.
  • the first unit 201 and the second unit 202 are respectively connected to the port 112 and the port 113 of the first multi-way valve 11, so that the first The unit 201 and the second unit 202 can introduce different second reagents 300 respectively, and the first unit 201 and the second unit 202 can respectively perform different sub-reactions, thereby improving the overall efficiency of the second reaction.
  • the second reaction includes a nucleic acid sequence determination reaction, which includes a plurality of repeated reactions, and one repeated reaction includes a base extension reaction, reaction signal collection, and group excision. While one of the first unit 201 and the second unit 202 is performing base extension reaction or group excision, the other of the first unit 201 and the second unit 202 is performing reaction signal collection. In one example, the sum of the reaction time required for the group excision and the reaction time required for the base extension reaction is approximately the same as the time required to collect the reaction signal.
  • the biomolecule analysis system 1000 may also include a signal acquisition device, which may be used for signal acquisition.
  • the signal acquisition device may be an imaging device, and the signal acquisition device may respond to the first unit 201 or the second unit that is performing response signal acquisition. 202 performs signal acquisition. Since at the same time, only one of the first unit 201 and the second unit 202 can collect response signals, therefore, the number of signal collection devices can be set to one set, and this set of signal collection devices collects the response signals in progress.
  • the first unit 201 or the second unit 202 performs signal collection without setting two sets of signal collection devices, which saves costs.
  • first and second are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Therefore, the features defined with “first” and “second” may explicitly or implicitly include at least one of the features. In the description of the present application, "a plurality of” means at least two, for example two, three, unless otherwise specifically defined.

Abstract

Disclosed are a liquid path system and a biomolecule analysis system. The liquid path system is used for providing a solution environment for analyzing biomolecules. A first reaction comprises using a first reagent to connect the biomolecules to a reaction device, and a second reaction comprises using a second reagent to test the biomolecules that are connected to the reaction device. The liquid path system comprises a valve body assembly and a driving assembly, wherein the valve body assembly comprises a first multi-way valve and a second multi-way valve; and the driving assembly comprises a first pump and a second pump. When the first multi-way valve is in communication with the reaction device and the first pump and the second multi-way valve is in communication with the reaction device and the first reagent, the first pump is used for driving the first reagent to enter the reaction device in a first direction so as to carry out the first reaction; and when the second multi-way valve is in communication with the reaction device and the second pump and the first multi-way valve is in communication with the reaction device and the second reagent, the second pump is used for driving the second reagent to enter the reaction device in a second direction so as to carry out the second reaction.

Description

液路***、生物分子分析***及核酸序列测定***Liquid path system, biomolecular analysis system and nucleic acid sequence determination system
优先权信息Priority information
本申请请求2019年12月18日向中国国家知识产权局提交的专利申请号为CN 201911309913.0的优先权和权益，并且通过参照将其全文并入此处。This application requests the priority and rights of the patent application number CN 201911309913.0 filed with the State Intellectual Property Office of China on December 18, 2019, and the full text is incorporated herein by reference.
技术领域Technical field
本申请涉及生物分子分析技术领域，更具体而言，涉及一种液路***、生物分子分析***和核酸序列测定***。This application relates to the technical field of biomolecular analysis, and more specifically, to a fluid path system, a biomolecular analysis system, and a nucleic acid sequence determination system.
背景技术Background technique
相关技术中，对置于固相基质上的核酸样本进行核酸分析例如基于芯片检测实现核酸序列测定(测序)的装置中，通常涉及一般所称的上机前的样本处理和上机，所称的上机前的样本处理为使待测样本满足上机要求例如连接至芯片上，所称的上机指将处理后的样本载入测序仪中进行测序。In related technologies, nucleic acid analysis of nucleic acid samples placed on a solid substrate, such as a device for nucleic acid sequence determination (sequencing) based on chip detection, usually involves the so-called sample processing before the computer and the computer. The sample processing before the computer is to make the sample to be tested meet the computer requirements, such as connecting to the chip, the so-called computer refers to loading the processed sample into the sequencer for sequencing.
伴随着自动化相关技术的发展，相关的市售测序平台经常包括两个或多个独立的或者功能衔接的设备，出售或者购买某个测序平台时，这些设备一般成套出售或购买。With the development of automation-related technologies, relevant commercially available sequencing platforms often include two or more independent or functionally linked devices. When a certain sequencing platform is sold or purchased, these devices are generally sold or purchased in sets.
对于包括两个配套的设备的测序平台，通常地，其中的一个设备用于对待检核酸样本进行处理，包括将其连接到反应装置例如芯片上，该设备常被称为杂交仪、进样仪或者样本处理仪；另一个设备对上一个设备输出的连接有核酸样本的芯片进行检测，从而实现核酸序列测定，该设备是测序平台最主要的硬件，常被称为测序仪。For a sequencing platform that includes two supporting equipment, usually one of the equipment is used to process the nucleic acid sample to be tested, including connecting it to a reaction device such as a chip. This equipment is often referred to as a hybridization instrument or a sample injection instrument. Or a sample processor; another device detects the chip connected to the nucleic acid sample output by the previous device to achieve nucleic acid sequence determination. This device is the most important hardware of the sequencing platform and is often called a sequencer.
一个商业化的测序平台，包含多个自动化设备来处理和检测样本，至少一部分原因是实现上机前样本的处理和上机测序涉及的液路控制较复杂，例如，上机前的样本处理经常包括多个步骤和多种反应，涉及多种试剂和多种进出液顺序，而且，有些试剂或反应可能还对管道材质、流速、压力等有特殊要求，进一步地，测序本身一般也涉及多种试剂和多个反应；还有一部分原因是生化反应易受干扰，包括试剂之间易互相污染。A commercial sequencing platform contains multiple automated equipment to process and test samples. At least part of the reason is that the processing of samples before the computer and the control of the liquid path involved in the computer sequencing are more complicated. For example, the sample processing before the computer is often It includes multiple steps and multiple reactions, involving multiple reagents and multiple inlet and outlet sequences. Moreover, some reagents or reactions may also have special requirements for pipe material, flow rate, pressure, etc. Furthermore, sequencing itself generally involves multiple Reagents and multiple reactions; part of the reason is that biochemical reactions are susceptible to interference, including easy contamination between reagents.
因此，将上机前的样本处理的液路***和测序的液路***进行集成，构建一套既能实现上机前样本的处理又能实现对处理后的样本的测序，而且不 会互相干扰或污染，并且还适合于工业化的液路***，十分困难。Therefore, the liquid path system for sample processing before the computer and the liquid path system for sequencing are integrated to construct a set that can realize both the processing of the samples before the computer and the sequencing of the processed samples without mutual interference. Or pollution, and it is also suitable for industrialized fluid system, which is very difficult.
发明内容Summary of the invention
本申请实施方式提供一种液路***、生物分子分析***及核酸序列测定***。The embodiments of the present application provide a fluid path system, a biomolecule analysis system, and a nucleic acid sequence determination system.
本申请实施方式的液路***用于为分析生物分子提供溶液环境，所述分析生物分子包括在反应装置上进行第一反应和第二反应，所述第一反应包括利用第一试剂使所述生物分子连接至所述反应装置中，所述第二反应包括利用第二试剂对连接至所述反应装置中的生物分子进行检测，所述液路***包括阀体组件及驱动组件，所述阀体组件包括第一多通阀及第二多通阀，所述第一多通阀可连通所述第二试剂和所述反应装置，所述第二多通阀可连通所述第一试剂和所述反应装置；所述驱动组件包括第一泵及第二泵，所述第一泵与所述第一多通阀连接，所述第二泵与所述第二多通阀连接；在所述第一多通阀连通所述反应装置和所述第一泵，且所述第二多通阀连通所述反应装置和所述第一试剂的状况下，所述第一泵用于驱动使所述第一试剂沿第一方向进入所述反应装置，以进行所述第一反应；在所述第二多通阀连通所述反应装置和所述第二泵，且所述第一多通阀连通所述反应装置和所述第二试剂的状况下，所述第二泵用于驱动使所述第二试剂沿第二方向进入所述反应装置，以进行所述第二反应。The liquid path system of the embodiment of the present application is used to provide a solution environment for analyzing biomolecules. The analyzing biomolecules includes performing a first reaction and a second reaction on a reaction device. The first reaction includes using a first reagent to make the The biomolecules are connected to the reaction device, the second reaction includes using a second reagent to detect the biomolecules connected to the reaction device, the liquid path system includes a valve body assembly and a drive assembly, the valve The body assembly includes a first multi-way valve and a second multi-way valve. The first multi-way valve can communicate with the second reagent and the reaction device, and the second multi-way valve can communicate with the first reagent and the reaction device. The reaction device; the drive assembly includes a first pump and a second pump, the first pump is connected to the first multi-way valve, the second pump is connected to the second multi-way valve; When the first multi-way valve communicates the reaction device and the first pump, and the second multi-way valve communicates the reaction device and the first reagent, the first pump is used to drive The first reagent enters the reaction device along a first direction to perform the first reaction; the second multi-way valve communicates the reaction device and the second pump, and the first multi-way valve communicates with the reaction device and the second pump. When the valve is connected to the reaction device and the second reagent, the second pump is used to drive the second reagent to enter the reaction device in a second direction to perform the second reaction.
所称的生物分子为生物大分子，例如蛋白质或核酸等。在某些实施方式中，所称的生物分子为核酸，所述第一反应包括杂交反应，及/或所述第二反应包括序列测定反应。The so-called biological molecules are biological macromolecules, such as proteins or nucleic acids. In some embodiments, the biomolecule referred to is a nucleic acid, the first reaction includes a hybridization reaction, and/or the second reaction includes a sequencing reaction.
在某些实施方式中，所述阀体组件还包括第三多通阀，所述第三多通阀可连通所述第二试剂和所述第一多通阀。In some embodiments, the valve body assembly further includes a third multi-way valve, and the third multi-way valve can communicate with the second reagent and the first multi-way valve.
在某些实施方式中，所述第三多通阀包括可连通的定子和转子，所述第三多通阀包括公共口，所述定子包括多个端口，所述转子包括连通槽，所述转子能够转动以使所述公共口与至少一个所述端口通过所述连通槽连通。In some embodiments, the third multi-way valve includes a stator and a rotor that are communicable, the third multi-way valve includes a common port, the stator includes a plurality of ports, the rotor includes a communication slot, the The rotor can rotate so that the common port communicates with at least one of the ports through the communication groove.
在某些实施方式中，所述第一多通阀包括多个端口，多个所述端口至少分别连接所述第二试剂、所述反应装置及所述第一泵，所述第一多通阀上的任意两个所述端口可连通。In some embodiments, the first multi-port valve includes a plurality of ports, and the plurality of ports are connected to at least the second reagent, the reaction device, and the first pump, respectively, and the first multi-port Any two of the ports on the valve can communicate.
在某些实施方式中，所述反应装置包括第一单元和第二单元，所述第一 多通阀为四通阀，所述四通阀的四个端口分别连接所述第二试剂、所述第一单元、所述第二单元和所述第一泵。In some embodiments, the reaction device includes a first unit and a second unit, the first multi-way valve is a four-way valve, and the four ports of the four-way valve are respectively connected to the second reagent and the second unit. The first unit, the second unit and the first pump.
在某些实施方式中，所述第二多通阀包括三个端口，三个所述端口分别连接所述第一试剂、所述反应装置及所述第二泵，所述第二多通阀的任意两个所述端口可连通。In some embodiments, the second multi-port valve includes three ports, and the three ports are respectively connected to the first reagent, the reaction device, and the second pump, and the second multi-port valve Any two of the ports can be connected.
在某些实施方式中，所述第二多通阀为三通阀。In some embodiments, the second multi-way valve is a three-way valve.
在某些实施方式中，所述反应装置包括多个通道，所述第二多通阀的数量和所述第二泵的数量均不小于所述通道的数目，一个所述第二多通阀可连通一个所述通道及一个所述第二泵。In some embodiments, the reaction device includes a plurality of channels, and the number of the second multi-way valves and the number of the second pumps are not less than the number of the channels, and one second multi-way valve One said channel and one said second pump can be connected.
在某些实施方式中，所述液路***还包括集流组件，所述集流组件与所述第一泵连通，所述集流组件用于收集所述第一反应后的所述第一试剂；及/或所述集流组件与所述第二泵连通，所述集流组件用于收集所述第二反应后的所述第二试剂。In some embodiments, the fluid path system further includes a current collecting component, the current collecting component is in communication with the first pump, and the current collecting component is used to collect the first reaction after the first reaction. Reagent; and/or the current collecting component is in communication with the second pump, and the current collecting component is used to collect the second reagent after the second reaction.
在某些实施方式中，所述第一泵及所述第二试剂通过所述第一多通阀连通时，所述集流组件还用于收集由所述第一泵驱动的所述第二试剂。In some embodiments, when the first pump and the second reagent are connected through the first multi-way valve, the current collecting assembly is also used to collect the second pump driven by the first pump. Reagents.
在某些实施方式中，所述集流组件包括集液件及废液瓶，所述集液件包括第一端口及多个第二端口，所述第一端口与多个所述第二端口连通，所述第一泵与所述第二端口连通，所述第二泵与所述第二端口连通，所述废液瓶与所述第一端口连通。In some embodiments, the current collecting assembly includes a liquid collecting member and a waste liquid bottle, the liquid collecting member includes a first port and a plurality of second ports, the first port and the plurality of second ports In communication, the first pump is in communication with the second port, the second pump is in communication with the second port, and the waste liquid bottle is in communication with the first port.
在某些实施方式中，在进行所述第一反应之后或者开始所述第二反应前，所述第一多通阀能够连通所述第一泵及所述第二试剂、和/或所述第二泵和所述第一试剂，所述第一泵和/或所述第二泵用于驱动所述第二试剂充满至所述第一多通阀的流路中。In some embodiments, after performing the first reaction or before starting the second reaction, the first multi-way valve can communicate with the first pump and the second reagent, and/or the The second pump and the first reagent, the first pump and/or the second pump are used to drive the second reagent to fill the flow path of the first multi-way valve.
在某些实施方式中，所述第一方向与所述第二方向相反。In some embodiments, the first direction is opposite to the second direction.
本申请实施方式的生物分子分析***包括本申请任一实施方式所述的液路***。The biomolecule analysis system of the embodiment of the present application includes the fluid path system described in any of the embodiments of the present application.
在某些实施方式中，所述生物分子分析***还包括反应装置，所述反应装置连接所述第一多通阀与所述第二多通阀。In some embodiments, the biomolecule analysis system further includes a reaction device connected to the first multi-way valve and the second multi-way valve.
在某些实施方式中，所述生物分子为核酸，所述反应装置包括第一单元及第二单元，所述生物分子分析***包括信号采集装置，所述信号采集装置用于信号采集；所述第二反应为核酸序列测定反应，所述核酸序列测定反应 包括多个重复反应，一个所述重复反应包括碱基延伸反应、反应信号采集和基团切除；所述第一单元及所述第二单元中的一个进行所述碱基延伸反应或所述基团切除的同时，利用所述信号采集装置对所述第一单元及所述第二单元中的另一个进行所述反应信号采集，所述信号采集装置对进行所述反应信号采集的所述第一单元或所述第二单元进行信号采集。In some embodiments, the biomolecule is a nucleic acid, the reaction device includes a first unit and a second unit, the biomolecule analysis system includes a signal acquisition device, and the signal acquisition device is used for signal acquisition; The second reaction is a nucleic acid sequence determination reaction, the nucleic acid sequence determination reaction includes a plurality of repeated reactions, and one of the repeated reactions includes a base extension reaction, reaction signal collection, and group excision; the first unit and the second unit While one of the units performs the base extension reaction or the group excision, the signal acquisition device is used to collect the reaction signal on the other of the first unit and the second unit, so The signal acquisition device performs signal acquisition on the first unit or the second unit that performs the reaction signal acquisition.
本申请实施方式的核酸序列测定***包括本申请任一实施方式所述的液路***。The nucleic acid sequence determination system of the embodiment of the present application includes the fluid path system described in any of the embodiments of the present application.
在某些实施方式中，所述核酸序列测定***还包括反应装置，所述反应装置可拆装地连接所述第一多通阀与所述第二多通阀。In some embodiments, the nucleic acid sequence determination system further includes a reaction device, and the reaction device is detachably connected to the first multi-way valve and the second multi-way valve.
本申请任一实施方式的液路***、生物分子分析***及核酸序列测定***中，通过切换第一多通阀连通反应装置和第一泵，且切换第二多通阀连通反应装置和第一试剂，可以在反应装置中进行第一反应，通过切换第二多通阀连通反应装置和第二泵，且切换第一多通阀连通反应装置和第二试剂，可以在反应装置中进行第二反应，通过一个液路***即可实现在反应装置上进行第一反应及第二反应，实现第一反应及第二反应的液路***的结构较简单，而且，搭建该集成的液路***的成本远低于搭建单独实现第一反应的液路***和单独实现第二反应的液路***的成本之和。In the liquid path system, biomolecule analysis system, and nucleic acid sequence determination system of any embodiment of the present application, the reaction device and the first pump are connected by switching the first multi-way valve, and the reaction device and the first pump are connected by switching the second multi-way valve. Reagents, the first reaction can be carried out in the reaction device, by switching the second multi-way valve to connect the reaction device and the second pump, and switching the first multi-way valve to connect the reaction device and the second reagent, the second reaction can be carried out in the reaction device For the reaction, the first reaction and the second reaction can be carried out on the reaction device through a liquid circuit system. The structure of the liquid circuit system for realizing the first reaction and the second reaction is relatively simple, and the integrated liquid circuit system is constructed. The cost is much lower than the sum of the cost of building a liquid circuit system that realizes the first reaction alone and a liquid circuit system that realizes the second reaction alone.
本申请的实施方式的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本申请的实施方式的实践了解到。The additional aspects and advantages of the embodiments of the present application will be partly given in the following description, and part of them will become obvious from the following description, or be understood through the practice of the embodiments of the present application.
附图说明Description of the drawings
本申请的上述和/或附加的方面和优点从结合下面附图对实施方式的描述中将变得明显和容易理解，其中：The above and/or additional aspects and advantages of the present application will become obvious and easy to understand from the description of the embodiments in conjunction with the following drawings, in which:
图1是本申请实施方式的生物分子分析***在一个状态下的模块示意图；FIG. 1 is a schematic diagram of a module of a biomolecule analysis system according to an embodiment of the present application in a state;
图2是本申请实施方式的生物分子分析***在另一个状态下的模块示意图；2 is a schematic diagram of modules of the biomolecule analysis system of the embodiment of the present application in another state;
图3是本申请实施方式的第三多通阀与第一多通阀的结构示意图；3 is a schematic diagram of the structure of a third multi-way valve and a first multi-way valve according to an embodiment of the present application;
图4是本申请实施方式的生物分子分析***在又一个状态下的模块示意图。FIG. 4 is a schematic diagram of modules of the biomolecule analysis system of the embodiment of the present application in another state.
主要元件符号说明：Symbol description of main components:
生物分子分析***1000、液路***100、阀体组件10、第一多通阀11、 端口111、112、113、114、第二多通阀12、端口121、122、123、第三多通阀13、定子131、转子132、公共口133、端口134、连通槽135、驱动组件20、第一泵21、第二泵22、集流组件30、集液件31、第二端口311、第一端口312、废液瓶32、反应装置200、第一单元201、第二单元202、通道203、第二试剂300、第一试剂400。Biomolecular analysis system 1000, fluid path system 100, valve body assembly 10, first multi-port valve 11, ports 111, 112, 113, 114, second multi-port valve 12, ports 121, 122, 123, third multi-port The valve 13, the stator 131, the rotor 132, the common port 133, the port 134, the communication groove 135, the drive assembly 20, the first pump 21, the second pump 22, the collecting assembly 30, the liquid collecting part 31, the second port 311, the first A port 312, a waste liquid bottle 32, a reaction device 200, a first unit 201, a second unit 202, a channel 203, a second reagent 300, and a first reagent 400.
具体实施方式Detailed ways
以下结合附图对本申请的实施方式作进一步说明。附图中相同或类似的标号自始至终表示相同或类似的元件或具有相同或类似功能的元件。The implementation of the present application will be further described below in conjunction with the accompanying drawings. The same or similar reference numerals in the drawings indicate the same or similar elements or elements with the same or similar functions throughout.
另外，下面结合附图描述的本申请的实施方式是示例性的，仅用于解释本申请的实施方式，而不能理解为对本申请的限制。In addition, the implementation manners of the present application described below in conjunction with the drawings are exemplary, and are only used to explain the implementation manners of the present application, and should not be construed as limiting the application.
在本申请中，除非另有明确的规定和限定，第一特征在第二特征“上”或“下”可以是第一和第二特征直接接触，或第一和第二特征通过中间媒介间接接触。而且，第一特征在第二特征“之上”、“上方”和“上面”可是第一特征在第二特征正上方或斜上方，或仅仅表示第一特征水平高度高于第二特征。第一特征在第二特征“之下”、“下方”和“下面”可以是第一特征在第二特征正下方或斜下方，或仅仅表示第一特征水平高度小于第二特征。In this application, unless expressly stipulated and defined otherwise, the first feature “on” or “under” the second feature may be in direct contact with the first and second features, or the first and second features may be indirectly through an intermediary. contact. Moreover, the "above", "above" and "above" of the first feature on the second feature may mean that the first feature is directly above or diagonally above the second feature, or it simply means that the level of the first feature is higher than that of the second feature. The “below”, “below” and “below” of the second feature of the first feature may mean that the first feature is directly below or obliquely below the second feature, or it simply means that the level of the first feature is smaller than the second feature.
请参阅图1，本申请实施方式提供一种生物分子分析***1000，生物分子分析***1000包括液路***100及与液路***100连接的可装拆的反应装置200。生物分子分析***1000具体可以是核酸序列测定***，液路***100用于为分析生物分子提供溶液环境，分析生物分子包括在反应装置200中进行第一反应和第二反应。其中，第一反应包括利用第一试剂400使生物分子连接至反应装置200中，第二反应包括利用第二试剂300对连接至反应装置200中的生物分子进行检测。Referring to FIG. 1, an embodiment of the present application provides a biomolecular analysis system 1000. The biomolecule analysis system 1000 includes a liquid path system 100 and a detachable reaction device 200 connected to the liquid path system 100. The biomolecule analysis system 1000 may specifically be a nucleic acid sequence determination system. The liquid path system 100 is used to provide a solution environment for analyzing biomolecules. The biomolecule analysis includes performing a first reaction and a second reaction in the reaction device 200. Wherein, the first reaction includes using the first reagent 400 to connect the biomolecules to the reaction device 200, and the second reaction includes using the second reagent 300 to detect the biomolecules connected to the reaction device 200.
液路***100包括阀体组件10及驱动组件20。阀体组件10包括第一多通阀11及第二多通阀12。第一多通阀11可连通第二试剂300和反应装置200，第二多通阀12可连通第一试剂400和反应装置200。驱动组件20包括第一泵21及第二泵22，第一泵21与第一多通阀11连接，第二泵22与第二多通阀12连接。反应装置200连接在第一多通阀11与第二多通阀12之间。The fluid path system 100 includes a valve body assembly 10 and a driving assembly 20. The valve body assembly 10 includes a first multi-way valve 11 and a second multi-way valve 12. The first multi-way valve 11 can connect the second reagent 300 and the reaction device 200, and the second multi-way valve 12 can connect the first reagent 400 and the reaction device 200. The driving assembly 20 includes a first pump 21 and a second pump 22. The first pump 21 is connected to the first multi-way valve 11, and the second pump 22 is connected to the second multi-way valve 12. The reaction device 200 is connected between the first multi-way valve 11 and the second multi-way valve 12.
在第一多通阀11连通反应装置200和第一泵21，且第二多通阀12连通反应装置200和第一试剂400的状况下，第一泵21用于驱动使第一试剂400 沿第一方向进入反应装置200，以进行第一反应。在第二多通阀12连通反应装置200和第二泵22，且第一多通阀11连通反应装置200和第二试剂300的状况下，第二泵22用于驱动使第二试剂300沿第二方向进入反应装置200，以进行第二反应。Under the condition that the first multi-way valve 11 communicates the reaction device 200 and the first pump 21, and the second multi-way valve 12 communicates the reaction device 200 and the first reagent 400, the first pump 21 is used to drive the first reagent 400 along Enter the reaction device 200 in the first direction to perform the first reaction. Under the condition that the second multi-way valve 12 connects the reaction device 200 and the second pump 22, and the first multi-way valve 11 connects the reaction device 200 and the second reagent 300, the second pump 22 is used to drive the second reagent 300 along The second direction enters the reaction device 200 to perform the second reaction.
本申请实施方式的生物分子分析***1000中，通过切换第一多通阀11连通反应装置200和第一泵21，且切换第二多通阀12连通反应装置200和第一试剂400，可以在反应装置200中进行第一反应，通过切换第二多通阀12连通反应装置200和第二泵22，且切换第一多通阀11连通反应装置200和第二试剂300，可以在反应装置200中进行第二反应，通过一个液路***100即可实现在反应装置200中进行第一反应及第二反应，实现第一反应及第二反应的液路***100的结构较简单，不需要分开在不同的***中进行第一反应及第二反应，用户操作更简便，而且，搭建该集成的液路***100的成本远低于搭建单独实现第一反应的液路***和单独实现第二反应的液路***的成本之和。In the biomolecule analysis system 1000 of the embodiment of the present application, by switching the first multi-port valve 11 to communicate the reaction device 200 and the first pump 21, and switching the second multi-port valve 12 to communicate the reaction device 200 and the first reagent 400, The first reaction is performed in the reaction device 200. By switching the second multi-way valve 12 to connect the reaction device 200 and the second pump 22, and the first multi-way valve 11 to connect the reaction device 200 and the second reagent 300, the reaction device 200 can be connected to the reaction device 200 and the second reagent 300. The first reaction and the second reaction can be carried out in the reaction device 200 through one liquid path system 100. The structure of the liquid path system 100 for realizing the first reaction and the second reaction is relatively simple and does not need to be separated. Performing the first reaction and the second reaction in different systems makes it easier for users to operate. Moreover, the cost of building the integrated liquid circuit system 100 is much lower than that of building a liquid circuit system that realizes the first reaction alone and the second reaction alone. The sum of the cost of the hydraulic system.
具体地，请参阅图1及图2，图1为在反应装置200上进行第一反应时的模块示意图，图2为在反应装置200上进行第二反应时的模块示意图。本申请实施方式的第一反应包括使生物分子连接至反应装置200中的反应，或者称为杂交反应。所称的生物分子包括DNA和/或RNA等，生物分子包括核糖核苷酸、脱氧核糖核苷酸及其类似物，包括A、T、C、G和U及其类似物。其中，C表示胞嘧啶或者胞嘧啶类似物，G表示鸟嘌呤或者鸟嘌呤类似物，A表示腺嘌呤或者腺嘌呤类似物，T表示胸腺嘧啶或者胸腺嘧啶类似物，U表示尿嘧啶或者尿嘧啶类似物。所称的反应装置200可以是包括基底的反应场所，反应装置200具体可以是以芯片的形式存在，反应装置200可拆装地连接到液路***100中。基底可以是任何可用于固定核酸序列的固体支持物，例如尼龙膜、玻璃片、塑料、硅片、磁珠等。基底表面上可以随机分布有探针，探针可以是一段DNA和/或RNA序列等，探针也可称为引物、捕获链或固定链。第一反应可将生物分子与探针固定连接，例如基于碱基互补原则，以使生物分子连接至反应装置200中。第一试剂400可以包括用于进行第一反应的杂交液，杂交液中包括上述的生物分子。Specifically, please refer to FIG. 1 and FIG. 2. FIG. 1 is a schematic diagram of a module when the first reaction is performed on the reaction device 200, and FIG. 2 is a schematic diagram of a module when the second reaction is performed on the reaction device 200. The first reaction in the embodiment of the present application includes a reaction in which biomolecules are connected to the reaction device 200, or is referred to as a hybridization reaction. The so-called biomolecules include DNA and/or RNA, etc., and biomolecules include ribonucleotides, deoxyribonucleotides and their analogs, including A, T, C, G, and U and their analogs. Where C represents cytosine or cytosine analogue, G represents guanine or guanine analogue, A represents adenine or adenine analogue, T represents thymine or thymine analogue, U represents uracil or uracil analogue Things. The so-called reaction device 200 may be a reaction site including a substrate. The reaction device 200 may specifically be in the form of a chip, and the reaction device 200 may be detachably connected to the liquid path system 100. The substrate can be any solid support that can be used to immobilize nucleic acid sequences, such as nylon membranes, glass sheets, plastics, silicon chips, magnetic beads, and the like. Probes can be randomly distributed on the surface of the substrate. The probes can be a segment of DNA and/or RNA sequences. The probes can also be called primers, capture strands or fixed strands. In the first reaction, the biomolecule can be fixedly connected to the probe, for example, based on the principle of base complementarity, so that the biomolecule can be connected to the reaction device 200. The first reagent 400 may include a hybridization solution for performing the first reaction, and the hybridization solution includes the above-mentioned biomolecules.
第二反应包括对连接至反应装置200中的生物分子进行检测的反应，例如，生物分子为核酸，第二反应可以为序列测定反应，即一般所称的测序， 包括测定DNA或RNA等的一级结构或序列，包括测定给定的核酸片段的核苷酸/碱基的次序。第二反应可以包括一个或多个子反应，在一个例子中，对DNA进行序列测定，第二反应为测序，基于边合成边测序或者边连接边测序，测序包括多个子反应，该多个子反应包括碱基延伸反应、反应信号采集及基团切除；进行该多个子反应一次，可称为进行一个重复反应或一轮反应，测序包括多个重复反应或多轮反应，以测读得核酸分子(模板)的至少一段序列的核苷酸/碱基次序。The second reaction includes a reaction for detecting biomolecules connected to the reaction device 200. For example, if the biomolecule is a nucleic acid, the second reaction may be a sequence determination reaction, which is generally called sequencing, including a measurement of DNA or RNA. The hierarchical structure or sequence includes determining the sequence of nucleotides/bases of a given nucleic acid fragment. The second reaction may include one or more sub-reactions. In one example, the DNA is sequenced. The second reaction is sequencing based on sequencing while synthesizing or sequencing while ligating. The sequencing includes multiple sub-reactions, and the multiple sub-reactions include Base extension reaction, reaction signal collection, and group excision; performing the multiple sub-reactions once can be called performing a repeated reaction or a round of reaction. Sequencing includes multiple repeated reactions or multiple rounds of reactions to detect nucleic acid molecules ( The nucleotide/base sequence of at least one sequence of the template).
其中，碱基延伸反应包括在固定有核酸分子的反应装置200上，对于边合成边测序(SBS)或者边连接边测序(SBL)，在聚合酶或者连接酶的作用下，基于碱基互补原则使核酸苷(包括改造的核苷酸)结合到核酸分子上，并采集相应的反应信号。例如，改造的核苷酸可以是指带有某种标记的核苷酸，该标记使得改造的核苷酸在某些环境下可被检测到，例如带有荧光分子标记的核苷酸，在特定波长的激光的激发下，会发出荧光；一般地，对于SBS，改造的核苷酸通常也具有抑制另外的核苷酸结合到相同核酸分子的下一个位置的功能，例如带有阻断基团，该阻断基团可以阻止其它核苷酸结合到该模板的下一个位置，阻断基团例如为连接在该核苷酸的糖基的3'位的叠氮基(-N 3)。第二试剂300包括聚合酶和改造的核苷酸，在一个示例中，第二试剂300分别装载在五个独立的容器内，该五个独立的容器分别装载聚合酶和四种改造的核苷酸，在反应装置200中聚合酶和一种或多种核苷酸得以混合，且在合适的条件下进行可控的聚合酶链式反应，即实现该碱基延伸反应。 Among them, the base extension reaction includes the nucleic acid molecule immobilized reaction device 200, for sequencing-by-synthesis (SBS) or sequencing-by-ligation (SBL), under the action of polymerase or ligase, based on the principle of base complementation The nucleic acid glycoside (including the modified nucleotide) is bound to the nucleic acid molecule, and the corresponding reaction signal is collected. For example, modified nucleotides may refer to nucleotides with a certain label that allows the modified nucleotides to be detected under certain circumstances, such as nucleotides labeled with fluorescent molecules. Under the excitation of a laser of a specific wavelength, it will emit fluorescence; in general, for SBS, modified nucleotides usually also have the function of inhibiting the binding of other nucleotides to the next position of the same nucleic acid molecule, such as with a blocking group. The blocking group can prevent other nucleotides from binding to the next position of the template. The blocking group is, for example, an azide group (-N 3 ) attached to the 3'position of the sugar group of the nucleotide. . The second reagent 300 includes polymerase and modified nucleotides. In one example, the second reagent 300 is loaded in five independent containers, and the five independent containers are loaded with polymerase and four modified nucleosides. Acid, the polymerase and one or more nucleotides are mixed in the reaction device 200, and a controllable polymerase chain reaction is performed under suitable conditions, that is, the base extension reaction is realized.
采集反应信号包括采集结合到核酸分子的改造的核苷酸发出的信号，例如对碱基延伸反应后的反应装置200中的特定区域进行激光照射，该特定区域中的带有荧光分子标记的核苷酸发出荧光，可选地，第二试剂300还包括信息采集试剂例如成像试剂，成像试剂例如为抗氧化剂，以有助于采集荧光信号，信息采集试剂可独立承载于一个容器中，将该种第二试剂300(下也称信息采集试剂)加入反应装置200，以使改造的核苷酸的信息便于被采集到，例如便于改造的核苷酸或者其上的荧光分子发出的光能被成像装置获取到影像。Collecting reaction signals includes collecting signals from modified nucleotides bound to nucleic acid molecules, for example, irradiating a specific area in the reaction device 200 after the base extension reaction with a laser, and the nuclear labeled with a fluorescent molecule in the specific area is irradiated with a laser. The glycidyl acid emits fluorescence. Optionally, the second reagent 300 further includes an information collection reagent such as an imaging reagent. The imaging reagent is, for example, an antioxidant to help collect fluorescent signals. The information collection reagent can be independently carried in a container. A second reagent 300 (hereinafter also referred to as information collection reagent) is added to the reaction device 200 so that the information of the modified nucleotide can be collected easily, for example, the light emitted by the modified nucleotide or the fluorescent molecule on it can be The image is captured by the imaging device.
基团切除包括去除碱基延伸反应后，结合到核酸分子的改造的核苷酸上的可检测标记和/或阻断基团，以使得其它核苷酸(包括改造的核苷酸)能够结合到该核酸分子的下一个位置，进行下一个重复反应或下一轮反应。在一 个示例中，第二试剂300还包括切除试剂，该切除试剂独立承载于一个容器中，在进行该基团切除的子反应时，通入该切除试剂，以同时除去改造的核苷酸上的可检测标记和阻断基团。Group excision includes removing the detectable label and/or blocking group on the modified nucleotide of the nucleic acid molecule after the base extension reaction, so that other nucleotides (including modified nucleotides) can bind To the next position of the nucleic acid molecule, proceed to the next repeated reaction or the next round of reaction. In one example, the second reagent 300 further includes an excision reagent, which is independently carried in a container. When the sub-reaction of the group excision is performed, the excision reagent is passed in to simultaneously remove the modified nucleotides. The detectable label and blocking group.
依据正在进行的不同的子反应，导入反应装置200中的第二试剂300可以是不同的，例如进行碱基延伸反应时可以导入包括改造的核苷酸的第二试剂300，进行反应信号采集时可以导入利于进行成像的第二试剂300(即信息采集试剂的一种)，进行基团切除时可以导入用于除去改造的核苷酸上的可检测标记和阻断基团的第二试剂300(下称切除试剂)。另外，在前一个子反应进行完成后且在后一个子反应开始前，还可以导入清洗试剂以除去反应装置200中或液路***100中残留的未反应物质、干扰反应或信号采集的物质，清洗试剂也可作为第二试剂300的一种，清洗试剂可以是缓冲液。According to the different sub-reactions in progress, the second reagent 300 introduced into the reaction device 200 may be different. For example, when performing a base extension reaction, the second reagent 300 including modified nucleotides may be introduced, and when the reaction signal is collected The second reagent 300 (that is, a kind of information collection reagent) that is good for imaging can be introduced, and the second reagent 300 can be introduced to remove the detectable label and blocking group on the modified nucleotide when performing group excision. (Hereinafter referred to as excision reagent). In addition, after the completion of the previous sub-reaction and before the start of the next sub-reaction, cleaning reagents can also be introduced to remove unreacted substances remaining in the reaction device 200 or in the liquid path system 100, substances that interfere with the reaction or signal collection, The cleaning reagent can also be used as a kind of the second reagent 300, and the cleaning reagent can be a buffer solution.
如无特别说明，下述的第二反应为测序，包括上述的第二反应中的任意一个或多个子反应，以及两个子反应之间的清洗流程。Unless otherwise specified, the second reaction described below is sequencing, including any one or more sub-reactions in the second reaction described above, and a cleaning process between the two sub-reactions.
请继续参阅图1及图2，反应装置200可以为第一反应及第二反应提供反应场所。具体地，反应装置200可以包括一个或多个通道203，在进行第一反应时，第一试剂400可以沿第一方向(如图1所示的第一方向X)从通道203中流过，在进行第二反应时，第二试剂300可以沿第二方向(如图1所示的第二方向Y，第二方向Y可以与第一方向X方向相反)从通道203中流过。Please continue to refer to FIG. 1 and FIG. 2, the reaction device 200 can provide a reaction place for the first reaction and the second reaction. Specifically, the reaction device 200 may include one or more channels 203. During the first reaction, the first reagent 400 may flow through the channel 203 in a first direction (the first direction X as shown in FIG. 1). During the second reaction, the second reagent 300 may flow through the channel 203 in a second direction (the second direction Y as shown in FIG. 1, the second direction Y may be opposite to the first direction X).
在本申请实施例中，反应装置200包括第一单元201及第二单元202。第一单元201包括一个或多个通道203，第二单元202包括一个或多个通道203。第一单元201与第二单元202上可以分别进行相同的反应，也可以分别进行不同的反应。例如，第一单元201中进行第一反应时，第二单元202中可以进行第一反应或者第二反应，或者第二单元202中也可以不进行任何反应；第一单元201中进行第二反应时，第二单元202中可以进行第一反应或者第二反应，或者第二单元202中也可以不进行任何反应；第一单元201中进行一个第二反应的子反应(例如碱基延伸)时，第二单元202中可以进行第二反应的另外的子反应(例如反应信号采集)，在此不作限制。In the embodiment of the present application, the reaction device 200 includes a first unit 201 and a second unit 202. The first unit 201 includes one or more channels 203, and the second unit 202 includes one or more channels 203. The same reaction can be performed on the first unit 201 and the second unit 202 respectively, or different reactions can be performed separately. For example, when the first reaction is carried out in the first unit 201, the first reaction or the second reaction can be carried out in the second unit 202, or no reaction can be carried out in the second unit 202; the second reaction is carried out in the first unit 201 When the first reaction or the second reaction can be carried out in the second unit 202, or no reaction can be carried out in the second unit 202; when a sub-reaction of the second reaction (such as base extension) is carried out in the first unit 201 In the second unit 202, additional sub-reactions of the second reaction (for example, reaction signal collection) can be performed, which is not limited herein.
在如图1及图2所示的例子中，第一单元201包括多个通道203。第一单元201的多个通道203靠近第一多通阀11的一端可以共同连接第一多通阀11的一个端口112。第一单元201的每个通道203靠近第二多通阀12的 一端可以连接一个第二多通阀12的一个端口121，以使得在进行第一反应时，不同通道203内可以引入不同的第一试剂400，不同通道203内可以连接不同的生物分子，且不同的第一试剂400在进行第一反应前，不会发生交叉污染。第二单元202内通道203的设置可以与第一单元201内通道203的设置方式相同，在此不再赘述。In the examples shown in FIGS. 1 and 2, the first unit 201 includes a plurality of channels 203. One end of the plurality of channels 203 of the first unit 201 close to the first multi-way valve 11 may be connected to one port 112 of the first multi-way valve 11 in common. One end of each channel 203 of the first unit 201 close to the second multi-way valve 12 can be connected to a port 121 of the second multi-way valve 12, so that during the first reaction, different channels 203 can be introduced into different first ports. For one reagent 400, different biomolecules can be connected in different channels 203, and different first reagents 400 will not cross-contamination before the first reaction. The arrangement of the channel 203 in the second unit 202 can be the same as the arrangement of the channel 203 in the first unit 201, and will not be repeated here.
请继续参阅图1及图2，第一多通阀11可连通第一泵21与反应装置200，第一多通阀11还可连通第二试剂300和反应装置200，第一多通阀11还可连通第二试剂300与第一泵21。具体地，第一多通阀11包括多个端口111、112、113、114，多个端口111、112、113、114至少分别连接第二试剂300、反应装置200及第一泵21，第一多通阀11可连通多个端口111、112、113、114中的任意两个。第一多通阀11可以是四通阀、五通阀、六通阀等，在此不作限制。当反应装置200仅包括第一单元201及第二单元202中的一个时，第一多通阀11还可以是三通阀。在如图1及图2所示的示例中，端口111与第二试剂300连接、端口112与第一单元201连接、端口113与第二单元202连接、端口114与第一泵21连接。Please continue to refer to Figures 1 and 2, the first multi-way valve 11 can connect the first pump 21 and the reaction device 200, the first multi-way valve 11 can also connect the second reagent 300 and the reaction device 200, the first multi-way valve 11 The second reagent 300 and the first pump 21 can also be connected. Specifically, the first multi-way valve 11 includes a plurality of ports 111, 112, 113, and 114. The plurality of ports 111, 112, 113, and 114 are connected to at least the second reagent 300, the reaction device 200 and the first pump 21, respectively. The multi-way valve 11 can communicate with any two of the plurality of ports 111, 112, 113, and 114. The first multi-way valve 11 may be a four-way valve, a five-way valve, a six-way valve, etc., which is not limited here. When the reaction device 200 includes only one of the first unit 201 and the second unit 202, the first multi-way valve 11 may also be a three-way valve. In the example shown in FIGS. 1 and 2, the port 111 is connected to the second reagent 300, the port 112 is connected to the first unit 201, the port 113 is connected to the second unit 202, and the port 114 is connected to the first pump 21.
第一多通阀11可连通多个端口111、112、113、114中的任意两个，以连通任意两个端口111、112、113、114连接的流道。例如通过切换第一多通阀11的状态，可以使得端口112与端口114连通，以连通第一泵21与第一单元201；可以使得端口113与端口114连通，以连通第一泵21与第二单元202；可以使得端口111与端口112连通，以连通第二试剂300与第一单元201；可以使得端口111与端口连113通，以连通第二试剂300与第二单元202；可以使得端口111与端口114连通，以连通第二试剂300与第一泵21。The first multi-way valve 11 can communicate with any two of the multiple ports 111, 112, 113, and 114 to communicate the flow passages connected by any two ports 111, 112, 113, and 114. For example, by switching the state of the first multi-way valve 11, the port 112 can be connected to the port 114 to communicate the first pump 21 and the first unit 201; the port 113 can be connected to the port 114 to communicate the first pump 21 and the first unit 201. The second unit 202; the port 111 can be connected to the port 112 to connect the second reagent 300 and the first unit 201; the port 111 can be connected to the port 113 to connect the second reagent 300 and the second unit 202; the port can be connected 111 communicates with the port 114 to communicate the second reagent 300 with the first pump 21.
请继续参阅图1及图2，第二多通阀12可连通第一试剂400与反应装置200，第二多通阀12可连通第二泵22与反应装置200，第二多通阀12还可连通第一试剂400与第二泵22。具体地，第二多通阀12包括三个端口121、122、123，三个端口121、122、123分别连接反应装置200、第一试剂400及第二泵22，第二多通阀12可连通三个端口121、122、123中的任意两个。第二多通阀12可以是三通阀、四通阀、五通阀等，在此不作限制。Please continue to refer to Figures 1 and 2, the second multi-way valve 12 can connect the first reagent 400 and the reaction device 200, the second multi-way valve 12 can connect the second pump 22 and the reaction device 200, the second multi-way valve 12 also The first reagent 400 and the second pump 22 can be connected. Specifically, the second multi-way valve 12 includes three ports 121, 122, and 123. The three ports 121, 122, and 123 are respectively connected to the reaction device 200, the first reagent 400 and the second pump 22. The second multi-way valve 12 can Connect any two of the three ports 121, 122, 123. The second multi-way valve 12 may be a three-way valve, a four-way valve, a five-way valve, etc., which is not limited here.
第二多通阀12可连通三个端口121、122、123中的任意两个，以连通任意两个端口121、122、123连接的流道。例如通过切换第二多通阀12的 状态，可以使得端口121与端口122连通，以连通第一试剂400与反应装置200；可以使得端口121与端口123连通，以连通第二泵22与反应装置200(第一单元201或和第二单元202)；通过切换第二多通阀12的状态，可以使得端口122与端口123连通，以连通第一试剂400与第二泵22。The second multi-way valve 12 can communicate with any two of the three ports 121, 122, and 123 to communicate the flow passages connected by any two ports 121, 122, and 123. For example, by switching the state of the second multi-way valve 12, the port 121 can be connected to the port 122 to connect the first reagent 400 and the reaction device 200; the port 121 can be connected to the port 123 to connect the second pump 22 and the reaction device. 200 (the first unit 201 or the second unit 202); by switching the state of the second multi-way valve 12, the port 122 and the port 123 can be connected to communicate the first reagent 400 and the second pump 22.
在通道203的数量为多个时，第二多通阀12的数量也可以是多个，第二多通阀12的数量不小于通道203的数量，一个第二多通阀12与一个通道203连通。此时，多个第二多通阀12的连通状态可以是互不影响的，例如部分第二多通阀12连通第一试剂400与反应装置200，另一部分第二多通阀12连通第二泵22与反应装置200，以使反应装置200的不同通道203可以进行不同的反应。When the number of channels 203 is multiple, the number of second multi-way valves 12 can also be multiple, the number of second multi-way valves 12 is not less than the number of channels 203, one second multi-way valve 12 and one channel 203 Connected. At this time, the communication states of the plurality of second multi-way valves 12 may not affect each other. For example, some of the second multi-way valves 12 communicate with the first reagent 400 and the reaction device 200, and another part of the second multi-way valves 12 communicate with the second The pump 22 and the reaction device 200 enable different channels 203 of the reaction device 200 to perform different reactions.
请继续参阅图1及图2，第一泵21与第一多通阀11连接。当第一多通阀11连通第一泵21与第二试剂300时，第一泵21可用于驱动第二试剂300进入第一泵21中；当第一多通阀11连通第一泵21与反应装置200时，第一泵21可用于驱动反应装置200中的试剂进入第一泵21中。第二泵22与第二多通阀12连接。当第二多通阀12连通第一试剂400与第二泵22时，第二泵22可用于驱动第一试剂400进入第二泵22中；当第二多通阀12连通反应装置200与第二泵22时，第二泵22可用于驱动反应装置200中的试剂进入第二泵22中。第二泵22的数量可以是多个，第二泵22的数量可以与第二多通阀12的数量相同，每个第二泵22与一个第二多通阀12连接。Please continue to refer to FIGS. 1 and 2, the first pump 21 is connected to the first multi-way valve 11. When the first multi-way valve 11 communicates with the first pump 21 and the second reagent 300, the first pump 21 can be used to drive the second reagent 300 into the first pump 21; when the first multi-way valve 11 communicates with the first pump 21 and When the reaction device 200 is used, the first pump 21 can be used to drive the reagent in the reaction device 200 to enter the first pump 21. The second pump 22 is connected to the second multi-way valve 12. When the second multi-way valve 12 connects the first reagent 400 with the second pump 22, the second pump 22 can be used to drive the first reagent 400 into the second pump 22; when the second multi-way valve 12 connects the reaction device 200 with the second pump 22 When the second pump 22 is used, the second pump 22 can be used to drive the reagent in the reaction device 200 into the second pump 22. The number of second pumps 22 may be multiple, and the number of second pumps 22 may be the same as the number of second multi-way valves 12, and each second pump 22 is connected to one second multi-way valve 12.
在一个例子中，第一多通阀11可以直接连接第二试剂300，在另一个例子中，第一多通阀11可以间接连接第二试剂300，例如在第一多通阀11与第二试剂300之间可以设置阀体。请结合图3，在本申请实施例中，阀体组件10还包括第三多通阀13。第三多通阀13可连通第二试剂300和第一多通阀11。第三多通阀13具体可以是旋转阀。In one example, the first multi-port valve 11 may be directly connected to the second reagent 300. In another example, the first multi-port valve 11 may be indirectly connected to the second reagent 300. For example, the first multi-port valve 11 and the second reagent 300 may be connected indirectly. A valve body may be provided between the reagents 300. Referring to FIG. 3, in the embodiment of the present application, the valve body assembly 10 further includes a third multi-way valve 13. The third multi-way valve 13 can connect the second reagent 300 and the first multi-way valve 11. The third multi-way valve 13 may specifically be a rotary valve.
具体地，第三多通阀13包括可连通的定子131和转子132，第三多通阀13包括公共口133，定子131包括多个端口134。转子132包括连通槽135，转子132能够转动以使公共口133与至少一个端口134通过连通槽135连通。Specifically, the third multi-way valve 13 includes a stator 131 and a rotor 132 that are communicable, the third multi-way valve 13 includes a common port 133, and the stator 131 includes a plurality of ports 134. The rotor 132 includes a communication groove 135, and the rotor 132 can rotate so that the common port 133 and at least one port 134 communicate through the communication groove 135.
公共口133可以与第一多通阀11连接，具体可以与第一多通阀11的端口111连接。端口134的数量为多个，例如可以是六个、七个、八个、十个、十一个、十二个、十三个、十四个、十六个等，每个端口134可以与不同成分的第二试剂300连通，例如一个端口134与试剂I连通，另一个端口134 与试剂II连通，再一个端口134与试剂III连通等。第二试剂300可以承装于试剂管中，不同成分的第二试剂300可以分别承装于不同的试剂管中，端口134的数量可以与试剂管的数量相同，一个端口134通过管路连接一个试剂管内的第二试剂300。通过转动转子132可以使得公共口133与不同的端口134通过连通槽135连通，以使第一多通阀11与不同成分的第二试剂300连通，以满足当前进行的第二反应中对不同类型的第二试剂300的需求。The common port 133 can be connected to the first multi-way valve 11, and specifically can be connected to the port 111 of the first multi-way valve 11. There are multiple ports 134, such as six, seven, eight, ten, eleven, twelve, thirteen, fourteen, sixteen, etc. Each port 134 can be connected to The second reagent 300 of different composition is connected, for example, one port 134 is connected to the reagent I, the other port 134 is connected to the reagent II, and the other port 134 is connected to the reagent III. The second reagent 300 can be installed in a reagent tube, and the second reagent 300 of different components can be installed in different reagent tubes respectively. The number of ports 134 can be the same as the number of reagent tubes, and one port 134 is connected to one through a pipeline. The second reagent 300 in the reagent tube. By rotating the rotor 132, the common port 133 can be communicated with different ports 134 through the communication groove 135, so that the first multi-way valve 11 can communicate with the second reagent 300 of different composition, so as to meet the requirements of different types in the current second reaction. The demand for the second reagent 300.
请参阅图1及图2，在某些实施方式中，液路***100还包括集流组件30，集流组件30与第一泵21连通，集流组件30用于收集第一反应后的第一试剂400。在第一泵21及第二试剂300通过第一多通阀11连通时，集流组件30还可用于收集由第一泵21驱动的第二试剂300，此时第二试剂300可以未通过反应装置200，第二试剂300经过第一泵21后进入集流组件30。集流组件30还可以与第二泵22连通，集流组件30用于收集第二反应后的第二试剂300。1 and 2, in some embodiments, the liquid path system 100 further includes a collecting assembly 30, the collecting assembly 30 is in communication with the first pump 21, and the collecting assembly 30 is used to collect the first reaction after the first reaction. One reagent 400. When the first pump 21 and the second reagent 300 are in communication through the first multi-way valve 11, the collecting assembly 30 can also be used to collect the second reagent 300 driven by the first pump 21. At this time, the second reagent 300 may not pass the reaction. In the device 200, the second reagent 300 enters the collecting assembly 30 after passing through the first pump 21. The current collecting assembly 30 may also be in communication with the second pump 22, and the current collecting assembly 30 is used to collect the second reagent 300 after the second reaction.
如此，集流组件30可以用于收集第一反应及第二反应后的废液，便于对废液集中处理。具体地，集流组件30包括集液件31及废液瓶32。集液件31包括第一端口312及多个第二端口311，第一端口312与多个第二端口311连通。第一泵21与第二端口311连通，第二泵22与第二端口311连通，废液瓶32与第一端口312连通。第一反应后的第一试剂400，或者第二反应后的第二试剂300均能够通过第二端口311进入集液件31，进入集液件31的试剂从第一端口312流出到废液瓶32中。In this way, the current collecting assembly 30 can be used to collect the waste liquid after the first reaction and the second reaction, so as to facilitate the centralized treatment of the waste liquid. Specifically, the current collecting assembly 30 includes a liquid collecting member 31 and a waste liquid bottle 32. The liquid collecting member 31 includes a first port 312 and a plurality of second ports 311, and the first port 312 is in communication with the plurality of second ports 311. The first pump 21 is in communication with the second port 311, the second pump 22 is in communication with the second port 311, and the waste liquid bottle 32 is in communication with the first port 312. The first reagent 400 after the first reaction or the second reagent 300 after the second reaction can enter the liquid collecting part 31 through the second port 311, and the reagent entering the liquid collecting part 31 flows out of the first port 312 to the waste liquid bottle. 32 in.
下面将以图1、图2及图4所示例子中的生物分子分析***1000为例，对进行第一反应及第二反应的过程进行举例说明：The following will take the biomolecule analysis system 1000 in the examples shown in FIG. 1, FIG. 2 and FIG. 4 as an example to illustrate the process of performing the first reaction and the second reaction:
如图1所示，在需要进行第一反应时，第二多通阀12的端口121与端口122连通，以使第二多通阀12连通反应装置200和第一试剂400，第一多通阀11的端口112或113与端口114连通，以使第一多通阀11连通反应装置200和第一泵21。开启第一泵21，以使第一泵21驱动第一试剂400沿第一方向X进入反应装置200，以进行第一反应。在第一泵21的驱动下，第一试剂400还可以进入第一泵21，并进一步进入集液件31及废液瓶32。由于反应装置200的多个通道203与多个第二多通阀12一一对应连接，多个第二多通阀12与多个第一试剂400一一对应连接，因此，不同的通道203内可以流入不同的第一试剂400，不同的通道203内可以连接不同的生物分 子，不同的通道203在进行第一反应时，不会产生交叉污染。另外，第一试剂400沿第一方向X进入反应装置200，第一试剂400进入反应装置200中进行第一反应前，不需要经过第一多通阀11及第三多通阀13等管路，减少第一试剂400在管路上的挂壁，可实现微量第一试剂400的通液，减少第一试剂400的损失，节约成本。As shown in FIG. 1, when the first reaction is needed, the port 121 of the second multi-way valve 12 communicates with the port 122, so that the second multi-way valve 12 communicates the reaction device 200 and the first reagent 400, and the first multi-way valve 12 communicates with the first reagent 400. The port 112 or 113 of the valve 11 communicates with the port 114 so that the first multi-way valve 11 communicates with the reaction device 200 and the first pump 21. The first pump 21 is turned on, so that the first pump 21 drives the first reagent 400 into the reaction device 200 along the first direction X to perform the first reaction. Driven by the first pump 21, the first reagent 400 can also enter the first pump 21 and further enter the liquid collecting member 31 and the waste liquid bottle 32. Since the multiple channels 203 of the reaction device 200 are connected to the multiple second multi-way valves 12 in one-to-one correspondence, and the multiple second multi-way valves 12 are connected to the multiple first reagents 400 in a one-to-one correspondence, therefore, different channels 203 are Different first reagents 400 can be flowed into, different channels 203 can be connected with different biomolecules, and different channels 203 will not produce cross-contamination during the first reaction. In addition, the first reagent 400 enters the reaction device 200 along the first direction X. Before the first reagent 400 enters the reaction device 200 for the first reaction, it does not need to pass through the first multi-way valve 11 and the third multi-way valve 13 and other pipelines. , The wall hanging of the first reagent 400 on the pipeline is reduced, the first reagent 400 can be passed through in a small amount, the loss of the first reagent 400 is reduced, and the cost is saved.
如图2及图3所示，第一反应完成后，可以使用第二试剂300中的清洗试剂对液路***100进行清洗。具体地，通过转动第三多通阀13的转子132，使得第三多通阀13中连通清洗试剂的端口134与公共口133连通；切换第一多通阀11的端口111与端口112或113连通，以使第一多通阀11连通反应装置200和第二试剂300；切换第二多通阀12的端口121与端口123连通，以使第二多通阀12连通反应装置200和第二泵22。开启第二泵22，以使第二泵22驱动清洗试剂沿第二方向Y进入反应装置200，清洗试剂将反应装置200中残留的第一试剂400清洗干净。在第二泵22的驱动下，清洗试剂还可以进入第二泵22，并进一步进入集液件31及废液瓶32。As shown in FIGS. 2 and 3, after the first reaction is completed, the cleaning reagent in the second reagent 300 can be used to clean the liquid path system 100. Specifically, by rotating the rotor 132 of the third multi-way valve 13, the port 134 in the third multi-way valve 13 communicating with the cleaning reagent is connected to the common port 133; the port 111 of the first multi-way valve 11 and the port 112 or 113 are switched. To make the first multi-way valve 11 communicate with the reaction device 200 and the second reagent 300; switch the port 121 of the second multi-way valve 12 to communicate with the port 123, so that the second multi-way valve 12 connects the reaction device 200 with the second reagent. Pump 22. The second pump 22 is turned on, so that the second pump 22 drives the cleaning reagent into the reaction device 200 along the second direction Y, and the cleaning reagent cleans the first reagent 400 remaining in the reaction device 200. Driven by the second pump 22, the cleaning reagent can also enter the second pump 22, and further enter the liquid collecting member 31 and the waste liquid bottle 32.
如图4所示，在开始第二反应前或者进行第一反应之后。先确定即将需要引入反应装置200以进行第二反应的第二试剂300的类型，例如试剂I，通过转动第三多通阀13的转子132，使得第三多通阀13中连通试剂I的端口134与公共口133连通；切换第一多通阀11的端口111与端口114连通，以使第一多通阀11连通公共口133(此时公共口133连通试剂I)和第一泵21。开启第一泵21，以使第一泵21驱动第二试剂300快速充满第二试剂300至第一多通阀11的流路中，提高第二试剂300的流动速度，具体地，使试剂I充满第二试剂300与端口134的管路中、第三多通阀13内部的管路中、公共口133与第一多通阀11之间的管路中、及第一多通阀11内部的管路中，以使在后续进行第二反应时，不需要再次将试剂I充满第二试剂300至第一多通阀11的流路中，试剂I能够快速进入反应装置200中进行第二反应，同时避免气泡进入反应装置200而中影响第二反应的进行。在第一泵21的驱动下，试剂I还可以充满第一多通阀11至第一泵21之间的管路中、第一泵21内部的管路中、及第一泵21与集液组件之间的管路中。As shown in Figure 4, before starting the second reaction or after performing the first reaction. First determine the type of the second reagent 300 that will be introduced into the reaction device 200 for the second reaction, such as reagent I, by rotating the rotor 132 of the third multi-way valve 13 so that the third multi-way valve 13 communicates with the port of the reagent I 134 communicates with the common port 133; the port 111 of the first multi-way valve 11 is switched to communicate with the port 114, so that the first multi-way valve 11 communicates with the common port 133 (at this time, the common port 133 communicates with the reagent 1) and the first pump 21. Turn on the first pump 21 so that the first pump 21 drives the second reagent 300 to quickly fill the flow path from the second reagent 300 to the first multi-way valve 11 to increase the flow rate of the second reagent 300, specifically, the reagent I In the pipeline filled with the second reagent 300 and the port 134, in the pipeline inside the third multi-way valve 13, in the pipeline between the common port 133 and the first multi-way valve 11, and inside the first multi-way valve 11 In the pipeline, so that when the second reaction is subsequently performed, there is no need to fill the flow path from the second reagent 300 to the first multi-way valve 11 with the reagent I again, and the reagent I can quickly enter the reaction device 200 for the second reaction. The reaction, while preventing bubbles from entering the reaction device 200 and affecting the progress of the second reaction. Driven by the first pump 21, the reagent I can also fill the pipeline between the first multi-way valve 11 and the first pump 21, the pipeline inside the first pump 21, and the first pump 21 and the liquid collection. In the pipeline between the components.
另外，在开始第二反应前或者进行第一反应之后，还可以切换第一多通阀11的端口111与端口112或者113连通，切换第二多通阀12的端口121与端口123连通，以使第一多通阀11及第二多通阀12连通公共口133(此 时公共口133连通试剂I)和第二泵22。开启第二泵22，以使第二泵22驱动第二试剂300快速充满第二试剂300至第一多通阀11的流路中。进一步地，第一多通阀11的端口111可以与端口114连通，同时第一多通阀11的端口111与端口112或113连通，第二多通阀12的端口121与端口123连通，以使第一多通阀11连通公共口133(此时公共口133连通试剂I)和第一泵21，同时第一多通阀11及第二多通阀12连通公共口133和第二泵22，第一泵21及第二泵22同时开启，以使第一泵21及第二泵22同时驱动第二试剂300快速充满第二试剂300至第一多通阀11的流路中，提高第二试剂300的流动速度。In addition, before starting the second reaction or after the first reaction, the port 111 of the first multi-way valve 11 can be switched to communicate with the port 112 or 113, and the port 121 of the second multi-way valve 12 can be switched to communicate with the port 123 to The first multi-way valve 11 and the second multi-way valve 12 are connected to the common port 133 (in this case, the common port 133 is connected to the reagent 1) and the second pump 22. The second pump 22 is turned on, so that the second pump 22 drives the second reagent 300 to quickly fill the second reagent 300 into the flow path of the first multi-way valve 11. Further, the port 111 of the first multi-way valve 11 can be in communication with the port 114, while the port 111 of the first multi-way valve 11 is in communication with the port 112 or 113, and the port 121 of the second multi-way valve 12 is in communication with the port 123 to Make the first multi-way valve 11 communicate with the common port 133 (at this time the common port 133 communicates with the reagent I) and the first pump 21, while the first multi-way valve 11 and the second multi-way valve 12 communicate with the common port 133 and the second pump 22 , The first pump 21 and the second pump 22 are turned on at the same time, so that the first pump 21 and the second pump 22 simultaneously drive the second reagent 300 to quickly fill the second reagent 300 into the flow path of the first multi-way valve 11. Second, the flow rate of the reagent 300.
如图2所示，在进行第二反应时，第一多通阀11的端口111与端口112或113连通，以使第一多通阀11连通反应装置200和第二试剂300，第二多通阀12的端口121与端口123连通，以使第二多通阀12连通反应装置200和第二泵22。开启第二泵22，以使第二泵22驱动第二试剂300沿第二方向Y进入反应装置200，以进行第二反应。As shown in Figure 2, during the second reaction, the port 111 of the first multi-way valve 11 communicates with the port 112 or 113, so that the first multi-way valve 11 communicates with the reaction device 200 and the second reagent 300, and the second multi-way valve 11 communicates with the reaction device 200 and the second reagent 300. The port 121 of the through valve 12 communicates with the port 123 so that the second multi-way valve 12 communicates with the reaction device 200 and the second pump 22. The second pump 22 is turned on, so that the second pump 22 drives the second reagent 300 into the reaction device 200 along the second direction Y to perform the second reaction.
结合上述，第二反应包括多个子反应，在反应装置200中进行第二反应的过程，可以是先后在反应装置200中进行碱基延伸反应、反应信号采集及基团切除等子反应，在两个子反应之间，可以进行清洗流程。具体地，第一多通阀11连通公共口133与反应装置200，第二多通阀12连通反应装置200和第二泵22的状态不变，进行碱基延伸反应时，转动第三多通阀13的转子132，使得第三多通阀13中连通改造的核苷酸的端口134与公共口133连通；进行反应信号采集时，转动第三多通阀13的转子132，使得第三多通阀13中连通信息采集试剂的端口134与公共口133连通；进行基团切除时，转动第三多通阀13的转子132，使得第三多通阀13中连通切除试剂的端口134与公共口133连通；进行清洗流程时，转动第三多通阀13的转子132，使得第三多通阀13中连通清洗试剂的端口134与公共口133连通。In combination with the above, the second reaction includes multiple sub-reactions. The process of carrying out the second reaction in the reaction device 200 may be successively performing sub-reactions such as base extension reaction, reaction signal collection, and group excision in the reaction device 200. Between sub-reactions, a cleaning process can be carried out. Specifically, the first multi-way valve 11 communicates with the common port 133 and the reaction device 200, and the second multi-way valve 12 communicates with the reaction device 200 and the second pump 22. The state remains unchanged. When the base extension reaction is performed, the third multi-way valve is rotated. The rotor 132 of the valve 13 connects the port 134 that communicates the modified nucleotide in the third multi-way valve 13 with the common port 133; when the reaction signal is collected, the rotor 132 of the third multi-way valve 13 is rotated to make the third multi-way valve 13 communicate with the common port 133. The port 134 that communicates the information collection reagent in the through valve 13 communicates with the common port 133; when performing group removal, the rotor 132 of the third multi-way valve 13 is rotated so that the port 134 of the third multi-way valve 13 that communicates the removal reagent is connected to the common port 133. The port 133 is connected; during the cleaning process, the rotor 132 of the third multi-way valve 13 is rotated, so that the port 134 in the third multi-way valve 13 communicating with the cleaning reagent is connected to the common port 133.
在一个例子中，在反应装置200仅包括一个反应单元时，在该反应单元上可以先后进行第二反应中的子反应，及两个子反应之间的清洗流程。In an example, when the reaction device 200 includes only one reaction unit, the sub-reactions in the second reaction and the cleaning process between the two sub-reactions can be performed on the reaction unit successively.
在另一个例子中，在反应装置200包括多个反应单元时，在不同的反应单元上可以分别进行不同的第二反应中的子反应。在本申请实施例中，反应装置200包括第一单元201及第二单元202，第一单元201与第二单元202分别与第一多通阀11的端口112及端口113连通，以使得第一单元201与 第二单元202可以分别引入不同的第二试剂300，第一单元201与第二单元202可以分别进行不同的子反应，提高进行第二反应的总的效率。In another example, when the reaction device 200 includes a plurality of reaction units, different sub-reactions in the second reaction may be performed on different reaction units. In the embodiment of the present application, the reaction device 200 includes a first unit 201 and a second unit 202. The first unit 201 and the second unit 202 are respectively connected to the port 112 and the port 113 of the first multi-way valve 11, so that the first The unit 201 and the second unit 202 can introduce different second reagents 300 respectively, and the first unit 201 and the second unit 202 can respectively perform different sub-reactions, thereby improving the overall efficiency of the second reaction.
例如，第二反应包括核酸序列测定反应，核酸序列测定反应包括多个重复反应，一个重复反应包括碱基延伸反应、反应信号采集和基团切除。在第一单元201及第二单元202中的一个进行碱基延伸反应或基团切除的同时，第一单元201及第二单元202中的另一个进行反应信号采集。在一示例中，基团切除所需的反应时间与碱基延伸反应所需的反应时间之和，与采集反应信号所需的时间大致相等。For example, the second reaction includes a nucleic acid sequence determination reaction, which includes a plurality of repeated reactions, and one repeated reaction includes a base extension reaction, reaction signal collection, and group excision. While one of the first unit 201 and the second unit 202 is performing base extension reaction or group excision, the other of the first unit 201 and the second unit 202 is performing reaction signal collection. In one example, the sum of the reaction time required for the group excision and the reaction time required for the base extension reaction is approximately the same as the time required to collect the reaction signal.
生物分子分析***1000还可包括信号采集装置，信号采集装置可用于信号采集，具体地，信号采集装置可以是成像装置，信号采集装置可以对正在进行反应信号采集的第一单元201或第二单元202进行信号采集。由于在同一个时刻，第一单元201及第二单元202中可以仅有一个进行反应信号采集，因此，信号采集装置的数量可以设置为一套，该一套信号采集装置对正在进行反应信号采集的第一单元201或者第二单元202进行信号采集，而不需要设置两套信号采集装置，节约成本。The biomolecule analysis system 1000 may also include a signal acquisition device, which may be used for signal acquisition. Specifically, the signal acquisition device may be an imaging device, and the signal acquisition device may respond to the first unit 201 or the second unit that is performing response signal acquisition. 202 performs signal acquisition. Since at the same time, only one of the first unit 201 and the second unit 202 can collect response signals, therefore, the number of signal collection devices can be set to one set, and this set of signal collection devices collects the response signals in progress. The first unit 201 or the second unit 202 performs signal collection without setting two sets of signal collection devices, which saves costs.
在本说明书的描述中，参考术语“某些实施方式”、“一个实施方式”、“一些实施方式”、“示意性实施方式”、“示例”、“具体示例”、或“一些示例”的描述意指结合所述实施方式或示例描述的具体特征、结构、材料或者特点包含于本申请的至少一个实施方式或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施方式或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施方式或示例中以合适的方式结合。In the description of this specification, reference is made to the terms “certain embodiments”, “one embodiment”, “some embodiments”, “exemplary embodiments”, “examples”, “specific examples”, or “some examples”. The description means that a specific feature, structure, material, or characteristic described in combination with the embodiment or example is included in at least one embodiment or example of the present application. In this specification, the schematic representation of the above-mentioned terms does not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner.
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个所述特征。在本申请的描述中，“多个”的含义是至少两个，例如两个，三个，除非另有明确具体的限定。In addition, the terms "first" and "second" are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Therefore, the features defined with "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, "a plurality of" means at least two, for example two, three, unless otherwise specifically defined.
尽管上面已经示出和描述了本申请的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本申请的限制，本领域的普通技术人员在本申请的范围内可以对上述实施例进行变化、修改、替换和变型，本申请的范围由权利要求及其等同物限定。Although the embodiments of the present application have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present application. A person of ordinary skill in the art can comment on the foregoing within the scope of the present application. The embodiments are subject to changes, modifications, substitutions and modifications, and the scope of this application is defined by the claims and their equivalents.

Claims (19)

  1. 一种液路***，其特征在于，用于为分析生物分子提供溶液环境，所述分析生物分子包括在反应装置上进行第一反应和第二反应，所述第一反应包括利用第一试剂使所述生物分子连接至所述反应装置中，所述第二反应包括利用第二试剂对连接至所述反应装置中的生物分子进行检测，所述液路***包括：A liquid path system is characterized in that it is used to provide a solution environment for analyzing biomolecules, the analyzing biomolecules includes performing a first reaction and a second reaction on a reaction device, and the first reaction includes using a first reagent to make The biomolecules are connected to the reaction device, the second reaction includes detecting the biomolecules connected to the reaction device using a second reagent, and the liquid path system includes:
    阀体组件，所述阀体组件包括第一多通阀及第二多通阀，所述第一多通阀可连通所述第二试剂和所述反应装置，所述第二多通阀可连通所述第一试剂和所述反应装置；及The valve body assembly includes a first multi-way valve and a second multi-way valve, the first multi-way valve can communicate the second reagent and the reaction device, and the second multi-way valve can Connecting the first reagent and the reaction device; and
    驱动组件，所述驱动组件包括第一泵及第二泵，所述第一泵与所述第一多通阀连接，所述第二泵与所述第二多通阀连接；A drive assembly, the drive assembly includes a first pump and a second pump, the first pump is connected to the first multi-way valve, and the second pump is connected to the second multi-way valve;
    在所述第一多通阀连通所述反应装置和所述第一泵，且所述第二多通阀连通所述反应装置和所述第一试剂的状况下，所述第一泵用于驱动使所述第一试剂沿第一方向进入所述反应装置，以进行所述第一反应；Under the condition that the first multi-way valve communicates the reaction device and the first pump, and the second multi-way valve communicates the reaction device and the first reagent, the first pump is used for Driving the first reagent to enter the reaction device in a first direction to perform the first reaction;
    在所述第二多通阀连通所述反应装置和所述第二泵，且所述第一多通阀连通所述反应装置和所述第二试剂的状况下，所述第二泵用于驱动使所述第二试剂沿第二方向进入所述反应装置，以进行所述第二反应。Under the condition that the second multi-way valve communicates the reaction device and the second pump, and the first multi-way valve communicates the reaction device and the second reagent, the second pump is used for The second reagent is driven to enter the reaction device in a second direction to perform the second reaction.
  2. 根据权利要求1所述的液路***，其特征在于，所述生物分子为核酸，所述第一反应包括杂交反应，及/或所述第二反应包括序列测定反应。The fluid path system according to claim 1, wherein the biomolecule is a nucleic acid, the first reaction includes a hybridization reaction, and/or the second reaction includes a sequencing reaction.
  3. 根据权利要求1所述的液路***，其特征在于，所述阀体组件还包括第三多通阀，所述第三多通阀可连通所述第二试剂和所述第一多通阀。The fluid circuit system according to claim 1, wherein the valve body assembly further comprises a third multi-way valve, and the third multi-way valve can communicate with the second reagent and the first multi-way valve .
  4. 根据权利要求3所述的液路***，其特征在于，所述第三多通阀包括可连通的定子和转子，所述第三多通阀包括公共口，所述定子包括多个端口，所述转子包括连通槽，所述转子能够转动以使所述公共口与至少一个所述端口通过所述连通槽连通。The fluid circuit system according to claim 3, wherein the third multi-port valve includes a stator and a rotor that can be communicated, the third multi-port valve includes a common port, and the stator includes a plurality of ports, so The rotor includes a communicating groove, and the rotor can rotate so that the common port and at least one of the ports communicate through the communicating groove.
  5. 根据权利要求1所述的液路***，其特征在于，所述第一多通阀包括多个端口，多个所述端口至少分别连接所述第二试剂、所述反应装置及所述第一泵，所述第一多通阀上的任意两个所述端口可连通。The fluid path system according to claim 1, wherein the first multi-port valve includes a plurality of ports, and the plurality of ports are connected to at least the second reagent, the reaction device, and the first For the pump, any two of the ports on the first multi-way valve can be communicated.
  6. 根据权利要求5所述的液路***，其特征在于，所述反应装置包括第一单元和第二单元，所述第一多通阀为四通阀，所述四通阀的四个端口分别 连接所述第二试剂、所述第一单元、所述第二单元和所述第一泵。The fluid path system according to claim 5, wherein the reaction device comprises a first unit and a second unit, the first multi-way valve is a four-way valve, and the four ports of the four-way valve are respectively Connect the second reagent, the first unit, the second unit and the first pump.
  7. 根据权利要求1所述的液路***，其特征在于，所述第二多通阀包括三个端口，三个所述端口分别连接所述第一试剂、所述反应装置及所述第二泵，所述第二多通阀的任意两个所述端口可连通。The fluid path system according to claim 1, wherein the second multi-way valve includes three ports, and the three ports are respectively connected to the first reagent, the reaction device, and the second pump , Any two of the ports of the second multi-way valve can be communicated.
  8. 根据权利要求7所述的液路***，其特征在于，所述第二多通阀为三通阀。The fluid circuit system according to claim 7, wherein the second multi-way valve is a three-way valve.
  9. 根据权利要求7或8所述的液路***，其特征在于，所述反应装置包括多个通道，所述第二多通阀的数量和所述第二泵的数量均不小于所述通道的数目，一个所述第二多通阀可连通一个所述通道及一个所述第二泵。The fluid path system according to claim 7 or 8, wherein the reaction device includes a plurality of channels, and the number of the second multi-way valves and the number of the second pumps are not less than the number of the channels. Number, one said second multi-way valve can communicate with one said channel and one said second pump.
  10. 根据权利要求1所述的液路***，其特征在于，所述液路***还包括集流组件，所述集流组件与所述第一泵连通，所述集流组件用于收集第一反应后的所述第一试剂；及/或The fluid path system according to claim 1, wherein the fluid path system further comprises a current collecting component, the current collecting component is in communication with the first pump, and the current collecting component is used to collect the first reaction The first reagent after; and/or
    所述集流组件与所述第二泵连通，所述集流组件用于收集第二反应后的所述第二试剂。The current collecting component is in communication with the second pump, and the current collecting component is used to collect the second reagent after the second reaction.
  11. 根据权利要求10所述的液路***，其特征在于，所述第一泵及所述第二试剂通过所述第一多通阀连通时，所述集流组件还用于收集由所述第一泵驱动的所述第二试剂。The fluid circuit system according to claim 10, wherein when the first pump and the second reagent are connected through the first multi-way valve, the collecting assembly is also used to collect the The second reagent is driven by a pump.
  12. 根据权利要求10或11所述的液路***，其特征在于，所述集流组件包括集液件及废液瓶，所述集液件包括第一端口及多个第二端口，所述第一端口与多个所述第二端口连通，所述第一泵与所述第二端口连通，所述第二泵与所述第二端口连通，所述废液瓶与所述第一端口连通。The liquid circuit system according to claim 10 or 11, wherein the collecting assembly includes a liquid collecting member and a waste liquid bottle, the liquid collecting member includes a first port and a plurality of second ports, the first One port is in communication with a plurality of the second ports, the first pump is in communication with the second port, the second pump is in communication with the second port, and the waste liquid bottle is in communication with the first port .
  13. 根据权利要求1所述的液路***，其特征在于，在进行所述第一反应之后或者开始所述第二反应前，所述第一多通阀能够连通所述第一泵及所述第二试剂、和/或所述第二泵和所述第一试剂，所述第一泵和/或所述第二泵用于驱动所述第二试剂充满至所述第一多通阀的流路中。The fluid path system according to claim 1, wherein after the first reaction is performed or before the second reaction is started, the first multi-way valve can communicate with the first pump and the first pump. Two reagents, and/or the second pump and the first reagent, the first pump and/or the second pump is used to drive the second reagent to fill the flow of the first multi-way valve In the road.
  14. 根据权利要求1所述的液路***，其特征在于，所述第一方向与所述第二方向相反。The fluid path system according to claim 1, wherein the first direction is opposite to the second direction.
  15. 一种生物分子分析***，其特征在于，包括权利要求1至14任意一项所述的液路***。A biomolecule analysis system, characterized by comprising the fluid path system according to any one of claims 1 to 14.
  16. 根据权利要求15所述的生物分子分析***，其特征在于，所述生物分子分析***还包括反应装置，所述反应装置连接所述第一多通阀与所述第 二多通阀。The biomolecule analysis system according to claim 15, wherein the biomolecule analysis system further comprises a reaction device connected to the first multi-way valve and the second multi-way valve.
  17. 根据权利要求16所述的生物分子分析***，其特征在于，所述生物分子为核酸，所述反应装置包括第一单元及第二单元，所述生物分子分析***还包括信号采集装置，所述信号采集装置用于反应信号采集；The biomolecule analysis system according to claim 16, wherein the biomolecule is a nucleic acid, the reaction device includes a first unit and a second unit, and the biomolecule analysis system further includes a signal acquisition device, the The signal acquisition device is used for reaction signal acquisition;
    所述第二反应为核酸序列测定反应，所述核酸序列测定反应包括多个重复反应，一个所述重复反应包括碱基延伸反应、反应信号采集和基团切除；The second reaction is a nucleic acid sequence determination reaction, and the nucleic acid sequence determination reaction includes a plurality of repeated reactions, and one of the repeated reactions includes a base extension reaction, reaction signal collection, and group excision;
    所述第一单元及所述第二单元中的一个进行所述碱基延伸反应和/或所述基团切除的同时，利用所述信号采集装置对所述第一单元及所述第二单元中的另一个进行所述反应信号采集。While one of the first unit and the second unit is performing the base extension reaction and/or the group excision, the signal acquisition device is used for the first unit and the second unit The other one performs the reaction signal collection.
  18. 一种核酸序列测定***，其特征在于，包括权利要求1-14任意一项所述的液路***。A nucleic acid sequence determination system, which is characterized by comprising the fluid path system of any one of claims 1-14.
  19. 根据权利要求18所述的核酸序列测定***，其特征在于，所述核酸序列测定***还包括反应装置，所述反应装置可拆装地连接所述第一多通阀和所述第二多通阀。The nucleic acid sequence determination system according to claim 18, wherein the nucleic acid sequence determination system further comprises a reaction device, and the reaction device is detachably connected to the first multi-way valve and the second multi-way valve. valve.
PCT/CN2020/109734 2019-12-18 2020-08-18 Liquid path system, biomolecule analysis system and nucleotide sequencing system WO2021120651A1 (en)

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