WO2019144717A1 - 承载模块、核酸加载装置及用途 - Google Patents

承载模块、核酸加载装置及用途 Download PDF

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Publication number
WO2019144717A1
WO2019144717A1 PCT/CN2018/120525 CN2018120525W WO2019144717A1 WO 2019144717 A1 WO2019144717 A1 WO 2019144717A1 CN 2018120525 W CN2018120525 W CN 2018120525W WO 2019144717 A1 WO2019144717 A1 WO 2019144717A1
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WIPO (PCT)
Prior art keywords
nucleic acid
module
loading device
reactor
acid loading
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PCT/CN2018/120525
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English (en)
French (fr)
Inventor
张松振
姜泽飞
王光明
吴平
周志良
颜钦
Original Assignee
深圳市瀚海基因生物科技有限公司
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Application filed by 深圳市瀚海基因生物科技有限公司 filed Critical 深圳市瀚海基因生物科技有限公司
Priority to EP18901946.6A priority Critical patent/EP3744823A4/en
Priority to US16/960,748 priority patent/US11931742B2/en
Publication of WO2019144717A1 publication Critical patent/WO2019144717A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L7/00—Heating or cooling apparatus; Heat insulating devices
    • B01L7/52—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples
    • B01L7/525—Heating or cooling apparatus; Heat insulating devices with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples with physical movement of samples between temperature zones
    • 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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/50273—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means or forces applied to move the fluids
    • 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
    • C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/143—Quality control, feedback systems
    • B01L2200/147—Employing temperature sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/14—Process control and prevention of errors
    • B01L2200/148—Specific details about calibrations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/16—Reagents, handling or storing thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/04—Closures and closing means
    • B01L2300/041—Connecting closures to device or container
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1805—Conductive heating, heat from thermostatted solids is conducted to receptacles, e.g. heating plates, blocks
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1838—Means for temperature control using fluid heat transfer medium
    • B01L2300/185—Means for temperature control using fluid heat transfer medium using a liquid as fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/18—Means for temperature control
    • B01L2300/1894—Cooling means; Cryo cooling
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B01L2400/049—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics vacuum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00—Supporting devices; Holding devices
    • B01L9/52—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • B01L9/523—Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips for multisample carriers, e.g. used for microtitration plates

Definitions

  • the present invention relates to the field of biological sample processing equipment, and in particular to a carrying module and a nucleic acid loading device and use thereof.
  • a probe oligonucleotide
  • the nucleic acid to be tested is attached to the probe by hybridization so that the nucleic acid to be detected is attached to the chip.
  • nucleic acid sequence determination using chip detection before the measurement of the nucleic acid to be tested, it is generally necessary to first load the nucleic acid molecule to be tested onto the reactor, such as by hybridization on a chip having a probe immobilized on the surface. The reactor containing the sample to be tested is then placed on a sequencing platform for sequencing.
  • the invention provides a carrying module and a nucleic acid loading device and uses.
  • the nucleic acid loading device of the embodiment of the invention comprises a carrying module, a motion module, a liquid path module and a control module.
  • the carrying module comprises a receiving seat and a temperature control unit, wherein the nucleic acid is loaded in the reactor, and the receiving seat is used for accommodating the so-called
  • the temperature control unit comprises a semiconductor refrigerating sheet, a heat conductor and a temperature sensor, the semiconductor refrigerating sheet comprises a first surface and a second opposite surface, and the heat conductor is connected to the first surface and the receiving seat, and the temperature is called
  • the sensor is disposed in the heat conductor for detecting the temperature of the heat conductor;
  • the motion module includes a partition plate, a support platform, a first driving mechanism, a carrier member and a second driving mechanism.
  • the support platform is detachably and movably disposed on the partition plate, and the first driving mechanism is fixed on the so-called partition plate and For driving the movement of the support platform relative to the partition plate in the first direction, the second drive mechanism is fixed on the support platform and is used for driving the movement of the carrier relative to the support platform in the second direction, the so-called second direction and Said that the first direction is vertical;
  • the liquid path module is used for controlling the flow of the reagent into the reactor and the flow out of the reactor.
  • the liquid path module includes a syringe pump, and the so-called syringe pump is used to provide a negative pressure;
  • the control module is connected to the so-called carrying module, the motion module and the liquid path module, and the control module is configured to control and control the operation of the first driving mechanism, the second driving mechanism, the liquid path module and the temperature control unit.
  • the carrying module provided by the embodiment of the present invention includes: a receiving seat, the receiving seat is provided with a receiving groove, the receiving groove is for receiving the reactor, and the receiving seat is provided with a through hole communicating with the receiving groove a semiconductor refrigerating sheet comprising opposite first and second faces; and a heat conductor connected to the first surface and the receiving seat.
  • An embodiment of the present invention also provides a nucleic acid loading device comprising the carrier module of any of the above embodiments.
  • the first surface of the semiconductor refrigerating sheet is heated or cooled during operation, so that heat is supplied to the housing through the heat conductor so that the reactor can be at different ambient temperatures.
  • the design of the structural connection of the carrying module, the motion module, and the liquid path module and the cooperation with the control module can realize the automation and industrialization of the process of loading the sample to be tested into the reactor, the operation is simple, and the running result is consistent and controllable.
  • the invention also provides the use of the above nucleic acid loading device for nucleic acid immobilization and/or hybridization.
  • FIG. 1 is a schematic perspective view of a sample processing device according to an embodiment of the present invention.
  • FIG. 2 is a schematic diagram showing the internal structure of a sample processing apparatus according to an embodiment of the present invention.
  • FIG. 3 is a schematic diagram showing another internal structure of a sample processing apparatus according to an embodiment of the present invention.
  • FIG. 4 is a perspective view of a carrier module according to an embodiment of the present invention.
  • FIG. 5 is a schematic cross-sectional view of a carrier module according to an embodiment of the present invention.
  • FIG. 6 is a perspective view of a heat sink according to an embodiment of the present invention.
  • Figure 7 is a plan view showing a part of the structure of a sample processing apparatus according to an embodiment of the present invention.
  • Figure 8 is a perspective view showing a partial configuration of a sample processing device according to an embodiment of the present invention.
  • FIG. 9 is an exploded perspective view showing a partial configuration of a sample processing device according to an embodiment of the present invention.
  • Figure 10 is a perspective view of a kit according to an embodiment of the present invention.
  • Figure 11 is a block diagram showing a sample processing apparatus according to an embodiment of the present invention.
  • Nucleic acid loading device 1000 housing 100, frame 110, panel 120, first window 121, second window 122, partition 130;
  • the carrying module 200, the reactor 202, the accommodating base 210, the accommodating groove 211, the semiconductor refrigerating sheet 220, the first surface 221, the second surface 222, the heat conductor 230, the heat sink 240, the fins 241, the heat dissipation channel 242, and the cover The plate 243, the insulator 250, the temperature sensor 260, the fixing base 270, the pressing member 280, the engaging structure 281, the protrusion 282, the hole 283, the stopper 290;
  • a second driving mechanism 600 a second motor 610, a second transmission shaft 620, a guide rod 630;
  • the liquid path module 702 the syringe pump 700, and the control module 800.
  • the first feature "on” or “under” the second feature may include direct contact of the first and second features, and may also include first and second features, unless otherwise specifically defined and defined. Not direct contact.
  • the first feature “above”, “above” and “above” the second feature includes the first feature directly above and above the second feature, or merely indicating that the first feature level is higher than the second feature.
  • the first feature “below”, “below” and “below” the second feature includes the first feature directly below and below the second feature, or merely the first feature level being less than the second feature.
  • connection In the description of the present invention, it should be noted that the terms “installation”, “connected”, and “connected” are to be understood broadly, and may be fixed or detachable, for example, unless otherwise explicitly defined and defined. Connected, or integrally connected; may be mechanically connected, may be electrically connected or may communicate with each other; may be directly connected, or may be indirectly connected through an intermediate medium, may be internal communication of two elements or interaction of two elements relationship.
  • Connected, or integrally connected may be mechanically connected, may be electrically connected or may communicate with each other; may be directly connected, or may be indirectly connected through an intermediate medium, may be internal communication of two elements or interaction of two elements relationship.
  • the specific meanings of the above terms in the present invention can be understood on a case-by-case basis.
  • a nucleic acid loading device 1000 includes a housing 100, a carrier module 200, a motion module 302, a fluid path module 702, and a control module 800, in accordance with an embodiment of the present invention.
  • the motion module 302 includes a support platform 300, a first drive mechanism 400, a carrier 500, and a second drive mechanism 600.
  • the fluid circuit module 702 includes a syringe pump 700 and a catheter coupled to the syringe pump 700.
  • the carrier module 200, the support platform 300, the first drive mechanism 400, the carrier 500, the second drive mechanism 600, the syringe pump 700, and the control module 800 are all located within the housing 100.
  • the housing 100 includes a frame 110, a panel 120, and a partition 130.
  • the panel 120 is disposed on the frame 110, for example, the panel 120 is fixed to the panel 120 by fasteners such as screws.
  • the partition 130 partition frame 110 forms a space.
  • the frame 110 is formed using angle steel welding.
  • the syringe pump 700 and the control module 800 are all located on the same side of the partition plate 130, and the carrying module 200, the supporting platform 300, the first driving mechanism 400, the carrier 500 and the second driving mechanism 600 are all located in the partition 130. The other side.
  • the syringe pump 700 is disposed adjacent to the panel 120, and the control module 800 is fixed to the partition 130.
  • the panel 120 adjacent to the syringe pump 700 can be a transparent panel to allow the user to view the syringe pump 700 through the panel 120. For example, the user can observe through the panel 120 whether there is air bubbles in the syringe pump 700.
  • the support platform 300, the first driving mechanism 400, the carrier 500 and the second driving mechanism 600 are disposed close to each other, and the carrying module 200 is located above the supporting platform 300.
  • the positions of the carrier module 200, the support platform 300, the first drive mechanism 400, the carrier 500, the second drive mechanism 600, the syringe pump 700, and the control module 800 can be otherwise disposed.
  • the control module 800 and the syringe pump 700 are respectively located on opposite sides of the partition 130.
  • control module 800 includes a memory and a processor for holding the input data including program instructions, and the processor can execute the program instructions to control the operation of the nucleic acid loading device 1000, for example, to implement a nucleic acid loading test.
  • the so-called nucleic acid loading includes the process of attaching a nucleic acid sequence to a solid phase substrate.
  • the so-called nucleic acid sequence may be DNA and/or RNA, and may be single-stranded and/or double-stranded and/or complexes comprising single-stranded or double-stranded nucleic acid sequences.
  • the so-called solid phase substrate can be any solid support that can be used to immobilize nucleic acid sequences, such as nylon membranes, glass sheets, plastics, silicon wafers, magnetic beads, etc., and the glass can be ordinary glass, quartz glass, ordinary glass containing metal plating. Or quartz glass containing a metal coating.
  • the carrying module 200 includes a receiving base 210 , a temperature control unit 203 , an insulator 250 , a temperature sensor 260 , a fixing base 270 , a pressing member 280 , and a stopping member 290 .
  • the temperature control unit 203 includes The semiconductor refrigerating sheet 220, the heat conductor 230, and the heat sink 240.
  • the receptacle 210 is used to place the reactor 202.
  • the panel 120 is provided with a first window 121 (see FIG. 1 ) corresponding to the carrying module 200 , and the first window 121 is used to implement the placement of the reactor 202 on the receiving seat 210 .
  • the accommodating seat 210 has a substantially rectangular parallelepiped shape, and the accommodating base 210 defines a receiving groove 211 for accommodating the reactor 202.
  • the reactor 202 can accommodate the reaction in the tank 211 with the reagent.
  • the reactor 202 performs a reaction such as hybridization or fixation in the accommodating tank 211.
  • the receiving seat 210 is provided with a through hole communicating with the receiving groove 211, and the reagent can enter the receiving groove 211 from the through hole.
  • the reactor 202 may refer to a chip (no-load chip) to which a probe is not fixed, a chip to which a probe is fixed, or a reaction sheet to which a sample of a nucleic acid molecule has been loaded.
  • the so-called reactor 202 comprises the solid phase substrate.
  • the reactor 202 is a chip which is a glass piece having a chemical group on its surface, and the probe/primer (oligonucleotide) is immobilized on the surface of the chip by the above nucleic acid loading device 1000 to realize Said the nucleic acid loading.
  • This nucleic acid loading belongs to the fixed reaction generally referred to in the field of biochemistry.
  • reactor 202 is a chip that is a glass sheet having a first nucleic acid sequence attached thereto, using the nucleic acid loading device 1000 described above to add a second nucleic acid sequence to the surface of the chip and to effect at least a portion of the second nucleic acid sequence.
  • a linkage to a first nucleic acid sequence is referred to as a probe, and the second nucleic acid sequence is referred to as a nucleic acid sequence to be detected, and the nucleic acid loading process is a hybridization reaction generally referred to in the field of biochemistry.
  • the so-called immobilization and/or hybridization reaction generally comprises a plurality of steps, including, for example, preheating the reactor 202 and/or the first reagent, causing the first reagent to enter the reactor 202 for the ligation reaction, and the second reagent after the ligation reaction is completed.
  • the reactor 202 is introduced at a flow rate for cleaning, etc., and the first reagent is referred to as one or more reagents comprising a reaction substrate.
  • the apparatus can be used to automate all of the steps of a biochemical reaction and can also be used to automate some of the steps of a biochemical reaction.
  • the sample processing device 1000 of the embodiment of the present invention can realize the function of fixing the probe to the chip, and can also combine the sample by hybridization on the chip on which the probe is fixed on the surface, and can also sequence the sample to be tested.
  • the semiconductor refrigerating sheet 220 includes a first surface 221 and a second surface 222 opposite to each other.
  • the semiconductor refrigerating sheet 220 starts to work after being energized. At this time, one of the first surface 221 and the second surface 222 starts to be cooled, and the other one.
  • the surface begins to heat up. For example, after the semiconductor refrigerating sheet 220 is operated, the first surface 221 begins to cool, and the second surface 222 begins to heat. It can be understood that the cooling type of the first surface 221 is different when the operating currents of the semiconductor refrigerating sheets 220 are different.
  • the semiconductor refrigerating sheet 220 has an advantage of being more environmentally friendly and generating no noise with respect to other refrigerating elements.
  • the heat conductor 230 connects the first surface 221 and the receiving seat 210.
  • the thermal conductor 230 can transfer heat from the semiconductor refrigerating sheet 220 to the receptacle 210 such that the reactor 202 can be at different ambient temperatures.
  • a paste with good thermal conductivity such as silicone grease is applied.
  • the material of the heat conductor 230 is a metal material.
  • the heat conductor 230 has a substantially rectangular parallelepiped shape, and the cross-sectional dimension of the heat conductor 230 is substantially the same as the cross-sectional dimension of the semiconductor refrigerating sheet 220, so that the structure between the heat conductor 230 and the semiconductor refrigerating sheet 220 is more compact.
  • the heat sink 240 is connected to the second surface 222.
  • the heat sink 240 is connected to the second surface 222 by a paste-like substance having good heat conductivity such as silicone grease.
  • the heat sink 240 can quickly dissipate the heat of the second surface 222 to the outside of the semiconductor refrigerating sheet 220 to improve the working efficiency of the semiconductor refrigerating sheet 220.
  • the material of the heat sink 240 is a metal material.
  • the material of the heat sink 240 is a material such as copper or aluminum.
  • the heat sink 240 is formed with a plurality of heat dissipating fins 241 disposed at intervals. The plurality of heat dissipating fins 241 can increase the surface area of the heat sink 240, thereby improving the heat dissipation performance of the heat sink 240.
  • the plurality of heat dissipating fins 241 define a heat dissipating channel 242, the heat dissipating channel 242 is used for the coolant to flow through,
  • the carrying module 200 includes a cover plate 243, the cover plate 243 blocks the heat dissipating channel 242, the cover plate 243 and the heat sink 240 sealed connection.
  • the coolant can transfer the heat of the heat sink 240 to the outside of the heat sink 240 to reduce the temperature of the heat sink 240.
  • a seal ring may be disposed between the cover plate 243 and the heat sink 240, and the seal ring may seal the gap between the cover plate 243 and the heat sink 240.
  • the heat dissipation channel 242 has a meandering shape, so that the total length of the heat dissipation channel 242 can be increased, so that the heat dissipation effect of the heat sink 240 is better.
  • the insulator 250 is fixedly connected to the cover plate 243 and the heat conductor 230, so that the short circuit of the cover plate 243 and the heat conductor 230 can be avoided.
  • the material of the insulator 250 is, for example, an insulating material such as rubber.
  • the temperature sensor 260 is disposed within the heat conductor 230, and the temperature sensor 260 is used to detect the temperature of the heat conductor 230.
  • the temperature sensor 260 is inserted into the heat conductor 230 from one side of the heat conductor 230.
  • the control module 800 can detect the operation of the temperature control semiconductor refrigerating sheet 220 according to the temperature sensor 260. In one example, when the temperature sensor 260 detects that the temperature of the thermal conductor 230 is lower than the target temperature, the control module 800 can control the operating current of the semiconductor refrigerating sheet 220 to increase the power of the semiconductor refrigerating sheet 220, thereby making the semiconductor refrigerating sheet 220 can increase the temperature of the heat conductor 230.
  • the temperature sensor 260 is a contact type temperature sensor, that is, the temperature sensor 260 is in contact with the heat conductor 230.
  • the temperature sensor 260 can be a non-contact temperature sensor, for example, the temperature sensor 260 is an infrared temperature sensor.
  • the fixing base 270 is fixed to the partition 130.
  • the fixing base 270 is fixed to the partition 130 by a fastener such as a screw or a bolt.
  • the pressing member 280 is rotatably disposed on the fixing base 270, and the receiving seat 210 is fixed on the fixing base 270.
  • the pressing member 280 is connected to the fixing base 270 through the engaging structure 281 to press the reactor 202 against the receiving seat 210. .
  • the reactor 202 can be stationary relative to the position of the mount 270 to increase the stability of the reactor 202.
  • the receiving seat 210 is partially located in the fixing base 270 , and the heat sink 240 is located below the fixing base 270 .
  • the pressing member 280 has a frame shape, and the rotating shaft position of the pressing member 280 and the engaging structure 281 are respectively located at opposite ends of the pressing member 280, so that the engaging structure 281 can provide a more stable pressing of the pressing member 280.
  • the force of reactor 202 is not limited to be limited to be used to provide a more stable pressing of the pressing member 280.
  • the engaging structure 281 includes a protrusion 282 disposed on the fixing base 270 and a hole 283 formed on the pressing member 280.
  • the protrusion 282 is engaged in the hole 283. It will be appreciated that after the compression member 280 is pressed against the reactor 202, the projection 282 snaps into the aperture 283, thereby securing the position of the compression member 280 to continuously compress the reactor 202.
  • the protrusion 282 is separated from the card hole 283, and then the pressing member 280 is rotated, so that the reactor 202 can be removed, and the loading and unloading process of the reactor 202 is simple and convenient to operate.
  • the engaging structure includes a protrusion disposed on the pressing member and a card hole formed on the fixing seat, and the protrusion is engaged in the hole.
  • the stopper 290 is connected to the fixing seat 270 and the pressing member 280 for limiting the rotation angle of the pressing member 280 with respect to the fixing seat 270.
  • the stopper 290 is, for example, a columnar member such as a screw, and the stopper 290 passes through the pressing member 280 and projects into the holder 270.
  • the stopper 290 can make the frictional force of the surface of the fixing seat 270 in contact with the pressing member 280 large, so that the pressing member 280 is kept in a stationary state after being rotated by an arbitrary angle with respect to the fixing seat 270.
  • the support platform 300 is movably disposed on the partition 130.
  • the support platform 300 is disposed on the partition 130 through the guide rail 302.
  • the support platform 300 is used to connect the reagent cartridge 310, and the reagent cartridge 310 is used.
  • the reactor 202 is connected.
  • kit 310 can be coupled to reactor 202 via a conduit such that reagents can be provided to reactor 202.
  • the so-called kit 310 is a container carrying a reagent, and the so-called reagent may be a liquid reagent, a solid reagent, and/or a gaseous reagent.
  • the kit 310 can be one or more, and one kit 310 can accommodate one or more reagent bottles.
  • the kit 310 is provided with a plurality of positions for accommodating the reagent bottles, and can accommodate a plurality of reagent bottles, and different reagent bottles can be used for storing different reagents.
  • the first drive mechanism 400 is fixed to the partition 130, and the first drive mechanism 400 is configured to drive the support platform 300 to move relative to the partition 130 in the first direction. As shown in the orientation of Figure 7, the first direction is the up and down direction. In this embodiment, the first driving mechanism 400 is located below the supporting platform 300, and the first driving mechanism 400 pushes the supporting platform 300 to move upward or pull the supporting platform 300 to move downward. It will be appreciated that the kit 310 can be moved as the support platform 300 moves, facilitating the switching of different reagents such that one or more reagents enter the fluid path module 702 sequentially and/or together.
  • the first driving mechanism 400 includes a first driving shaft 420 that is coupled to the first motor 410 and is fixed to the first motor 410.
  • the first driving shaft 420 is connected to the supporting platform 300, and the first motor 410 is used for driving.
  • the first drive shaft 420 moves to drive the support platform 300 to move relative to the diaphragm 130.
  • the first motor 410 is, for example, a stepper motor or a servo motor, such that the control module 800 can accurately control the operation of the first motor 410.
  • the first motor 410 is a through-shaft motor, that is, the first transmission shaft 420 penetrates the first motor 410, which makes the structure of the nucleic acid loading device 1000 in the up and down direction more compact.
  • the first transmission shaft 420 is, for example, a lead screw. It can be understood that when the first motor 410 drives the screw to rotate, the screw can move up or down while rotating, thereby driving the support platform 300 to move relative to the partition 130.
  • the carrier 500 is used to carry the reagent cartridge 310
  • the second driving mechanism 600 is fixed on the support platform 300
  • the second driving mechanism 600 is used to drive the carrier 500 to move in the second direction relative to the support platform 300, the second direction and the first
  • the direction is vertical.
  • the second direction is, for example, the front-rear direction shown in FIG.
  • the kit 310 can move in the second direction with the carrier 500.
  • the reagent cartridge 310 can be moved in the first direction and the second direction, that is, the reagent cartridge 310 can be moved in the up and down direction and the front and rear direction.
  • the second drive mechanism 600 includes a second motor 610 and a second drive shaft 620 that is fixed to the support platform 300.
  • the second drive shaft 620 is coupled to the second motor 610.
  • the carrier 500 is sleeved on the second transmission shaft 620, and the second motor 610 is used to drive the second transmission shaft 620 to rotate to drive the carrier 500 to move in the second direction.
  • the second drive shaft 620 is a lead screw
  • the carrier 500 is provided with a screw hole that cooperates with the screw rod, and the screw rod rotation can push the carrier 500 to move by a threaded fit.
  • the carrier 500 includes a slider 510 and a bracket 520.
  • the slider 510 is sleeved on the second transmission shaft 620.
  • the bracket 520 is fixedly coupled to the slider 510 for carrying the reagent cartridge 310.
  • the second motor 610 is coupled to a guide rod 630 that is parallel to the second drive shaft 620, and the guide rod 630 passes through the slider 510.
  • the guide rod 630 can guide the movement of the carrier 500 to ensure a more stable movement of the carrier 500.
  • Syringe pump 700 is used to provide a negative pressure to reactor 202 to allow reagents within reagent cartridge 310 to flow to reactor 202.
  • the advantage of using negative pressure into the liquid phase for positive pressure injection is very obvious, and there is no need to worry about explosions such as squibs caused by blockage of the fluid line.
  • the reactor 202 is made of a fragile material such as glass or silicon wafer, the use of positive pressure liquid may cause the glass or the silicon wafer to burst.
  • the number of syringe pumps 700 can be multiple, and different syringe pumps 700 can control the flow of different reagents into the reactor 202.
  • the reagent cartridge 310 includes a liquid storage portion 311 and a handle portion 312 that connects the liquid storage portion 311 .
  • the liquid storage portion 311 is formed with a plurality of liquid storage tanks 313 , and the reagents can be stored in the liquid storage tank 313 .
  • the handle portion 312 facilitates the user to take the reagent cartridge 310.
  • the panel 120 is provided with a second window 122 through which the reagent cartridge 310 passes, and the user can place the reagent cartridge 310 on the carrier 500 by holding the handle portion 312 through the second window 122.
  • the reagent cartridge 310 is provided with a diaphragm 314 covering a plurality of liquid storage tanks 313 for sealing the liquid storage tank 313.
  • the diaphragm 314 protrudes toward the handle portion 312 to form a flange 315.
  • the flange 315 facilitates the user to tear off the diaphragm 314 and the reagent cartridge 310 after the reagent cartridge 310 is placed on the carrier 500.
  • the nucleic acid loading device 1000 operates as follows: the reactor 202 and the reagent cartridge 310 containing the first reagent are first mounted on the housing 210 and the carrier 500, respectively, and then the control module 800 controls the syringe pump 700.
  • the reactor 202 is supplied with a negative pressure to cause the reagents in the reagent cartridge 310 to flow to the reactor 202.
  • the control module 800 controls the power of the semiconductor refrigeration fins 220 to bring the reactor 202 to a predetermined temperature for biochemical reaction until the preset reaction is reached.
  • control module 800 controls the motion module 203 to switch reagents and control the syringe pump 700 to cause the second reagent in the reagent cartridge 310 to flow to the reactor 202 to cause the first reagent in the reactor 202 to flow out of the reactor 202 at a specific rate, to be reached.
  • the reactor 202 can be removed from the receptacle 210 for a predetermined period of time.
  • the nucleic acid loading device 1000 includes a carrier module 200, a motion module 302, a fluid path module 702, and a control module 800.
  • the carrying module 200 includes a receiving seat 210 and a temperature control unit 203, a receiving seat 210 for placing the reactor 202, and a nucleic acid loaded in the reactor 202.
  • the temperature control unit 203 includes a semiconductor cooling sheet 220, a heat conductor 230, and Temperature sensor 260.
  • the semiconductor refrigerating sheet 220 includes a first surface 221 and a second surface 222 opposite to each other; the heat conductor 230 connects the first surface 221 and the receiving portion 210.
  • the temperature sensor 260 is disposed within the heat conductor 230, and the temperature sensor 260 is used to detect the temperature of the heat conductor 230.
  • the motion module 302 includes a partition 130, a support platform 300, a first drive mechanism 400, a carrier 500, and a second drive mechanism 600.
  • the support platform 300 is detachably and movably disposed on the partition 130.
  • the first drive mechanism 400 is fixed on the partition 130, and the first drive mechanism 400 is configured to drive the support platform 300 to move in the first direction relative to the partition 130.
  • the second driving mechanism 600 is fixed on the supporting platform 300, and the second driving mechanism 600 is used to drive the bearing member 500 to move in the second direction with respect to the supporting platform 300, and the second direction is perpendicular to the first direction.
  • the liquid path module 702 is used to control the flow of reagents into and out of the reactor 202.
  • the liquid circuit module 702 includes a syringe pump 700 for providing a negative pressure to the reactor 202 to allow reagents to flow to the reactor 202.
  • the control module 800 is connected to the load module 200, the motion module 302 and the liquid circuit module 702.
  • the control module 800 is used to control the operation of the first drive mechanism 400 and the second drive mechanism 600 and to control the operation of the liquid path module 70 and the temperature control unit 203. .
  • the first surface 221 of the semiconductor refrigerating sheet 220 is heated or cooled during operation, so that heat is supplied to the housing 210 through the heat conductor 230 so that the reactor 202 can be different. Ambient temperature.
  • the interaction of the motion module 302 and the fluid path module 702 can automate and industrialize the process of loading the sample to be tested into the reactor 202.
  • the nucleic acid loading device 1000 is modular in design and easier to form.
  • control module 800 can control the first driving mechanism 400 to drive the supporting platform 300 to move relative to the partition 130 in the first direction, and the control module 800 can control the driving carrier 500 to move in the second direction relative to the supporting platform 300, the control module The 800 can also control the syringe pump 700 to provide a negative pressure to the reactor 202.
  • the accuracy of the temperature sensor 260 is measured by the ambient temperature, the magnitude of the load such as the receptacle 210, the reactor 202, and the temperature coefficient of the material, the mounting position of the temperature sensor 202, the material and size of the semiconductor refrigerating sheet 220, and the temperature unit.
  • the influence of aging or the like of 203, and temperature sensor 202 have problems of zero drift (zero drift) and temperature drift (warm drift).
  • the temperature sensor 260 acts as a temperature acquisition device, and it is desirable that its acquisition reflects the temperature of the reactor 202/load.
  • temperature sensor 260 is a calibrated temperature sensor, and temperature y detected by temperature sensor 260 satisfies a polynomial equation
  • n is a natural number
  • x is the temperature detected by the temperature sensor 260 before calibration
  • a i is a polynomial coefficient
  • control module 800 includes a machine executable program that executes calibration of temperature sensor 260 using a polynomial equation that calibrates temperature y detected by temperature sensor 260
  • n is a natural number
  • x is the temperature detected by the temperature sensor before calibration
  • a i is a polynomial coefficient
  • temperature sensor 260 is a digital output type sensor that utilizes a software program to eliminate the above offset, for example, where the desired reaction temperature is in the range of 10-70 degrees Celsius, the following polynomial can be used to calibrate the output of temperature sensor 260 temperature:
  • the equations shown can be established based on a series of temperature values measured by the temperature sensor to be calibrated and the calibrated temperature sensor, for example, placing the reactor 202 on the receptacle 210 and placing a calibrated temperature sensor in the reactor 202, Set the temperature sensor to be calibrated in the device to measure temperatures of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70 degrees Celsius, respectively, corresponding to the calibrated temperature sensor measurement
  • the temperature values are 16.10, 20.90, 25.80, 31.21, 35.02, 39.55, 44.05, 48.21, 51.50, 55.03, 58, 60.07 and 62.33 degrees Celsius. Based on the two sets of temperature values, the relationship can be fitted to obtain the polynomial equation. .
  • the nucleic acid loading device 1000 further includes a display screen 900 for controlling the display screen 900 to display the current temperature of the housing 210 .

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Abstract

本发明公开了一种核酸加载装置，其包括壳体、承载模块、运动模块、液路模块和控制模块，运动模块包括支撑平台、第一驱动机构、承载件和第二驱动机构，液路模块用于控制试剂流入反应器和流出反应器，控制模块与运动模块及液路模块连接，控制模块用于控制第一驱动机构和第二驱动机构工作及用于控制第一驱动机构、第二驱动机构、液路模块以及温控单元运行。本发明实施方式的核酸加载装置中，半导体制冷片的第一面在工作时制热或制冷，从而通过导热体为容置座提供热量以使反应器可以处于不同的环境温度。另外，运动模块和液路模块相互配合可以实现将待测样本加载到反应器的过程的自动化及工业化。

Description

承载模块、核酸加载装置及用途 技术领域
本发明涉及生物样本处理设备领域，尤其涉及一种承载模块及核酸加载装置及用途。
背景技术
目前，基于固相芯片检测进行生物大分子检测的试验中，一般需要将待测样本连接到芯片表面上。例如，将探针(寡核苷酸)固定在芯片上，再通过杂交将待测核酸连接到探针上，以使待测核酸连接在芯片上。
例如，在利用芯片检测进行核酸序列测定的平台，在对待测核酸进行上机测定前，一般需先将待测核酸分子加载到反应器上，如通过杂交结合在表面固定有探针的芯片上，进而将包含待测样本的该反应器置于测序平台进行测序。
在相关技术中，将核酸包括探针和待测序列加载到反应器的过程中往往需要不同的反应温度和条件，如何为该过程提供良好的温度环境以及实现该过程的自动化工业化，值得关注。
发明内容
本发明提供一种承载模块及核酸加载装置及用途。
本发明实施方式的核酸加载装置包括承载模块、运动模块、液路模块和控制模块，承载模块包括容置座和温控单元，核酸加载于反应器中进行，容置座用于容置所称的反应器，温控单元包括半导体制冷片、导热体和温度传感器，半导体制冷片包括相背的第一面和第二，导热体连接所称的第一面及容置座，所称的温度传感器设置在导热体内，用于检测导热体的温度；
运动模块包括隔板、支撑平台、第一驱动机构、承载件和第二驱动机构，支撑平台可拆卸地且可移动地设置在隔板上，第一驱动机构固定在所称的隔板上且用于驱动支撑平台相对于隔板沿第一方向的移动，第二驱动机构固定在支撑平台上且用于驱动承载件相对于支撑平台沿第二方向的移动，所称的第二方向与所称的第一方向垂直；
液路模块用于控制试剂流入反应器和流出反应器，该液路模块包括注射泵，所称的注射泵用于提供负压；
控制模块与所称的承载模块、运动模块及液路模块连接，控制模块用于控制控制所述第一驱动机构、所述第二驱动机构、所述液路模块以及所述温控单元运行。
本发明实施方式提供的承载模块包括：容置座，该容置座开设有容置槽，容置槽用于容置反应器，该容置座开设有与所述容置槽连通的通孔；半导体制冷片，该 半导体制冷片包括相背的第一面和第二面；和导热体，该导热体连接所称的第一面及容置座。
本发明实施方式还提供一种包括以上任一实施方式的承载模块的核酸加载装置。
本发明实施方式的承载模块及核酸加载装置中，半导体制冷片的第一面在工作时制热或制冷，从而通过导热体为容置座提供热量以使反应器可以处于不同的环境温度。另外，承载模块、运动模块、液路模块的结构连接的设计以及与控制模块的相互配合，可以实现将待测样本加载到反应器的过程的自动化及工业化，操作简单且运行结果一致可控。
本发明还提供了以上的核酸加载装置在核酸固定和/或杂交中的用途。
本发明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，或通过本发明的实践了解到。
附图说明
本发明的上述和/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：
图1是本发明实施方式的样本处理装置的立体示意图；
图2是本发明实施方式的样本处理装置的内部结构示意图；
图3是本发明实施方式的样本处理装置的另一个内部结构示意图；
图4是本发明实施方式的承载模块的立体示意图；
图5是本发明实施方式的承载模块的剖面示意图；
图6是本发明实施方式的散热体的立体示意图；
图7是本发明实施方式的样本处理装置的部分结构的平面示意图；
图8是本发明实施方式的样本处理装置的部分结构的立体示意图；
图9是本发明实施方式的样本处理装置的部分结构的分解示意图；
图10是本发明实施方式的试剂盒的立体示意图；
图11是本发明实施方式的样本处理装置的模块示意图。
主要元件符号说明：
核酸加载装置1000、壳体100、框架110、面板120、第一窗口121、第二窗口122、隔板130；
承载模块200、反应器202、容置座210、容置槽211、半导体制冷片220、第一面221、第二面222、导热体230、散热体240、翅片241、散热通道242、盖板243、绝缘体250、温度传感器260、固定座270、压紧件280、卡合结构281、凸起 282、卡孔283、止动件290；
运动模块302、支撑平台300、试剂盒310、存液部311、把手部312、存液槽313、膜片314、凸缘315；
第一驱动机构400、第一电机410、第一传动轴420；
承载件500、滑块510、托架520；
第二驱动机构600、第二电机610、第二传动轴620、导杆630；
液路模块702、注射泵700、控制模块800。
具体实施方式
下面详细描述本发明的实施方式，所述实施方式的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施方式是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
在本发明中，除非另有明确的规定和限定，第一特征在第二特征之“上”或之“下”可以包括第一和第二特征直接接触，也可以包括第一和第二特征不是直接接触。而且，第一特征在第二特征“之上”、“上方”和“上面”包括第一特征在第二特征正上方和斜上方，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”包括第一特征在第二特征正下方和斜下方，或仅仅表示第一特征水平高度小于第二特征。
在本发明的描述中，需要说明的是，除非另有明确的规定和限定，术语“安装”、“相连”、“连接”应做广义理解，例如，可以是固定连接，也可以是可拆卸连接，或一体地连接；可以是机械连接，也可以是电连接或可以相互通讯；可以是直接相连，也可以通过中间媒介间接相连，可以是两个元件内部的连通或两个元件的相互作用关系。对于本领域的普通技术人员而言，可以根据具体情况理解上述术语在本发明中的具体含义。
请一并参阅图1-图3及图11，根据本发明的一个实施例，核酸加载装置1000包括壳体100、承载模块200、运动模块302、液路模块702和控制模块800。
运动模块302包括支撑平台300、第一驱动机构400、承载件500和第二驱动机构600。液路模块702包括注射泵700和与注射泵700连接的导管。承载模块200、支撑平台300、第一驱动机构400、承载件500、第二驱动机构600、注射泵700和控制模块800均位于壳体100内。
壳体100包括框架110、面板120和隔板130。面板120设置在框架110上，例如，面板120通过螺钉等紧固件固定在面板120上。隔板130间隔框架110形成 空间。在一个例子中，框架110采用角钢焊接形成。
本实施方式中，注射泵700及控制模块800均位于隔板130的同一侧，承载模块200、支撑平台300、第一驱动机构400、承载件500和第二驱动机构600均位于隔板130的另一侧。
具体地，注射泵700靠近面板120设置，控制模块800固定在隔板130上。靠近注射泵700的面板120可以为透明的板件，以使用户可以通过面板120观察注射泵700的情况。例如，用户可以通过面板120观察到注射泵700内是否有气泡。支撑平台300、第一驱动机构400、承载件500和第二驱动机构600靠近设置，承载模块200位于支撑平台300上方。
可以理解，在其他实施方式中，承载模块200、支撑平台300、第一驱动机构400、承载件500、第二驱动机构600、注射泵700和控制模块800的位置可以为其他方式设置。例如，控制模块800与注射泵700分别位于隔板130相背的两侧。
可以理解，控制模块800包括存储器和处理器，存储器用于保存输入的数据包括程序指令，处理器可以运行程序指令，以实现控制该核酸加载装置1000工作，例如实现核酸加载试验。
所称的核酸加载，包括使核酸序列连接到固相基底的过程。所称的核酸序列可以是DNA和/或RNA，可以是单链和/或双链和/或包含单链或双链核酸序列的复合物。所称的固相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，玻璃可以是普通玻璃、石英玻璃、含有金属镀层的普通玻璃或者含有金属镀层的石英玻璃。
请一并参阅图4-图6，承载模块200包括容置座210、温控单元203、绝缘体250、温度传感器260、固定座270、压紧件280和止动件290，温控单元203包括半导体制冷片220、导热体230和散热体240。
容置座210用于放置反应器202。面板120开设有与承载模块200对应的第一窗口121(见图1)，第一窗口121用于实现放置反应器202于容置座210上。容置座210大致呈长方体形，容置座210开设有容置槽211，容置槽211用于容置反应器202。反应器202可以容置槽211内与试剂发生反应。例如，反应器202在容置槽211内进行杂交或固定等反应。可以理解，容置座210开设有与容置槽211连通的通孔，试剂可以从通孔进入容置槽211内。
需要指出的是，反应器202可以指未固定有探针的芯片(空载芯片)，也可以指固定有探针的芯片，也可以指已经加载有测核酸分子样本的反应片。
所称的反应器202包含所说的固相基底。在一个例子中，反应器202为芯片， 该芯片为表面带有化学基团的玻璃片，利用上述核酸加载装置1000将探针/引物(寡核苷酸)固定在该芯片表面上以实现所说的核酸加载。该核酸加载属于进行生化领域中一般所说的固定反应。
在一个例子中，反应器202为芯片，该芯片为表面连接有第一核酸序列的玻璃片，利用上述核酸加载装置1000加入第二核酸序列至所述芯片表面以及实现至少一部分的第二核酸序列与第一核酸序列的连接。在一个具体例子中，所称的第一核酸序列是探针，所称的第二核酸序列是待检测核酸序列，该核酸加载过程属于进行生化领域中一般所说的杂交反应。
所称的固定和/或杂交反应一般包括多个步骤，例如包括预热反应器202和/或第一试剂，使第一试剂进入反应器202以进行连接反应，连接反应完成后使第二试剂以某个流速进入反应器202以进行清洗等，所称的第一试剂为包含反应底物的一种或多种试剂。可以理解的，该装置能够用于自动化实现某种生化反应的全部步骤，也能够用于自动化实现某种生化反应的部分步骤。
本发明实施方式的样本处理装置1000可以实现将探针固定至芯片的功能，也可以实现将样本通过杂交结合在表面固定有探针的芯片上，还可以对待测样本进行测序。
半导体制冷片220包括相背的第一面221和第二面222，半导体制冷片220在通电后开始工作，此时，第一面221和第二面222中的其中一个面开始制冷，另外一个面开始制热。例如，半导体制冷片220工作后，第一面221开始制冷，而第二面222开始制热。可以理解，当半导体制冷片220的工作电流不同时，第一面221的制冷类型不同。例如，当半导体制冷片220的工作电流为正向时，第一面221制冷；当半导体制冷片220的工作电流为反向时，第一面221制热。半导体制冷片220相对于其他的制冷元件，具有更加环保，且不会产生噪声的优点。
导热体230连接第一面221及容置座210。如此，导热体230可以将半导体制冷片220的热量传至容置座210，以使反应器202可以处于不同的环境温度。为了使导热体230更好地将热量传至容置座210，导热体230与容置座210之间，及/或导热体230与第一面221之间涂抹有硅脂等导热良好的膏状物质。较佳地，导热体230的材料为金属材料。导热体230大致呈长方体形，导热体230的截面尺寸与半导体制冷片220的截面尺寸大致相同，以使导热体230与半导体制冷片220之间的结构配合得更加紧凑。
散热体240连接第二面222，例如，散热体240通过硅脂等导热良好的膏状物质与第二面222连接。这样使得散热体240可以将第二面222的热量快速地散至半 导体制冷片220外，以提高半导体制冷片220的工作效率。散热体240的材料为金属材料，例如，散热体240的材料为铜、铝等材料。较佳地，散热体240形成有间隔设置的多个散热翅片241。多个散热翅片241可以增加散热体240的表面积，从而提高散热体240的散热性能。
本实施方式中，多个散热翅片241限定出散热通道242，散热通道242用于供冷却液流过，承载模块200包括盖板243，盖板243遮蔽散热通道242，盖板243与散热体240密封连接。如此，冷却液可以将散热体240的热量传至散热体240外，以降低散热体240的温度。盖板243与散热体240之间可以设置有密封圈，密封圈从而可以密封盖板243与散热体240之间的间隙。
进一步地，散热通道242呈迂回曲折形，这样可以增加散热通道242的总长度，以使散热体240的散热效果更佳。
绝缘体250固定连接盖板243及导热体230，这样可以避免盖板243与导热体230出现短路等现象。绝缘体250的材料例如为橡胶等绝缘材料。
温度传感器260设置在导热体230内，温度传感器260用于检测导热体230的温度。例如，温度传感器260从导热体230的一侧插入导热体230内。控制模块800可以根据温度传感器260检测到温度控制半导体制冷片220的工作过程。在一个例子中，温度传感器260检测到导热体230的温度低于目标温度时，控制模块800可以控制加大半导体制冷片220的工作电流，以提高半导体制冷片220的功率，从而使得半导体制冷片220可以提高导热体230的温度。本实施方式中，温度传感器260为接触式温度传感器，即，温度传感器260与导热体230接触。当然，温度传感器260可以为非接触式温度传感器，例如，温度传感器260为红外温度传感器。
固定座270固定在隔板130上，例如，固定座270通过螺钉或螺栓等紧固件固定在隔板130上。压紧件280转动设置在固定座270上，容置座210固定在固定座270上，压紧件280与固定座270通过卡合结构281连接以将反应器202压紧在容置座210上。如此，反应器202可以相对于固定座270的位置静止，以提高反应器202的稳定性。
本实施方式中，容置座210部分地位于固定座270中，散热体240位于固定座270的下方。压紧件280呈框型，压紧件280的转轴位置与卡合结构281分别位于压紧件280相背的两端，以使卡合结构281可以为压紧件280提供更加稳定的压紧反应器202的力。
具体地，本实施方式中，卡合结构281包括设置在固定座270上的凸起282和形成在压紧件280上的卡孔283，凸起282卡合在卡孔283内。可以理解，在压紧 件280压紧反应器202后，凸起282卡入卡孔283内，从而使得压紧件280的位置固定以持续压紧反应器202。当需要取下反应器202时，凸起282脱离卡孔283，然后转动压紧件280，这样就可以将反应器202取下，反应器202加载和卸载过程简单，操作方便。
可以理解，在其他的实施方式中，卡合结构包括设置在压紧件上的凸起和形成在固定座上的卡孔，凸起卡合在卡孔内。
止动件290连接固定座270及压紧件280，止动件290用于限制压紧件280相对于固定座270的转动角度。止动件290例如为螺钉等柱状元件，止动件290穿过压紧件280后伸入固定座270内。止动件290可以使得固定座270与压紧件280接触的表面的摩擦力较大，从而使得压紧件280相对于固定座270转动任意角度后保持静止状态。
请一并图7-图9，支撑平台300能够移动地设置在隔板130，例如，支撑平台300通过导轨302设置在隔板130上，支撑平台300用于连接试剂盒310，试剂盒310用于连接反应器202。例如，试剂盒310可以通过导管连接反应器202，从而可以为反应器202提供试剂。
所称的试剂盒310为承载试剂的容器，所称的试剂可以是液态试剂、固态试剂和/或气态试剂。试剂盒310可以为一个或多个，一个试剂盒310可容置一个或多个试剂瓶。在一个示例中，试剂盒310设置有多个容置试剂瓶的位置，可容置多个试剂瓶，不同试剂瓶可用于不同试剂的存放。
第一驱动机构400固定在隔板130上，第一驱动机构400用于驱动支撑平台300相对于隔板130沿第一方向移动。如图7的方位所示，第一方向为上下方向。本实施方式中，第一驱动机构400位于支撑平台300的下方，第一驱动机构400推动支撑平台300向上移动或拉动支撑平台300向下移动。可以理解，试剂盒310可以随着支撑平台300的移动而移动，方便切换不同试剂，以使一种或多种试剂依次和/或一并进入液路模块702。
具体地，第一驱动机构400包括固定在隔板130上的第一电机410与第一电机410连接的第一传动轴420，第一传动轴420连接支撑平台300，第一电机410用于驱动第一传动轴420移动从而驱动支撑平台300相对于隔板130移动。
第一电机410例如为步进电机或伺服电机，从而使得控制模块800可以精确地控制第一电机410的工作过程。较佳地，第一电机410为贯穿轴电机，也就是说，第一传动轴420贯穿第一电机410，这样使得核酸加载装置1000在上下方向的结构更加紧凑。
第一传动轴420例如为丝杆，可以理解，第一电机410驱动丝杆转动时，丝杆在转动的同时可以向上或向下移动，从而驱动支撑平台300相对于隔板130移动。
承载件500用于承载试剂盒310，第二驱动机构600固定在支撑平台300上，第二驱动机构600用于驱动承载件500相对于支撑平台300沿第二方向移动，第二方向与第一方向垂直。本实施方式中，第二方向例如为图7所示的前后方向。可以理解，试剂盒310可以随着承载件500沿第二方向移动。如此，试剂盒310可以沿第一方向及第二方向移动，即试剂盒310可以沿着上下方向及前后方向移动。
具体地，第二驱动机构600包括第二电机610和第二传动轴620，第二电机610固定在支撑平台300。第二传动轴620连接第二电机610。承载件500套设在第二传动轴620上，第二电机610用于驱动第二传动轴620转动以驱动承载件500沿第二方向移动。在一个例子中，第二传动轴620为丝杆，承载件500开设有与丝杆配合的螺孔，丝杆转动可以通过螺纹配合推动承载件500移动。
具体地，承载件500包括滑块510和托架520，滑块510套设在第二传动轴620上，托架520与滑块510固定连接，托架520用于承载试剂盒310。第二电机610连接有与第二传动轴620平行的导杆630，导杆630穿过滑块510。导杆630可以导引承载件500移动，以保证承载件500移动的更加平稳。
注射泵700用于为反应器202提供负压以使试剂盒310内的试剂流至反应器202。采用负压进液相对于正压进液具有的优势非常明显，不用担心由于流体管路堵塞而导致的爆管等故障。在反应器202采用玻璃或硅片等易碎材质制造时，采用正压进液可能会导致玻璃或硅片出现爆裂的现象。
需要指出的是，注射泵700的数量可为多个，不同的注射泵700可以控制不同的试剂流入反应器202。
请参阅图8及图10，试剂盒310包括存液部311和连接存液部311的把手部312，存液部311形成有多个存液槽313，试剂可以存放在存液槽313内。把手部312方便用户拿去试剂盒310。在一个例子中，面板120开设有供试剂盒310通过的第二窗口122，用户可以手持把手部312通过第二窗口122而将试剂盒310放置在承载件500上。试剂盒310上设置有覆盖多个存液槽313的膜片314，膜片314用于密封存液槽313。膜片314向把手部312的方向凸出形成有凸缘315，凸缘315方便用户在试剂盒310放置到承载件500后将膜片314从而试剂盒310上撕开取下。
在一个示例中，核酸加载装置1000操作过程如下：先将反应器202以及装有第一试剂的试剂盒310分别装置在容置座210和机承载件500上，然后控制模块800控制注射泵700为反应器202提供负压以使试剂盒310内的试剂流向反应器202， 控制模块800控制半导体制冷片220的功率以使反应器202达到预定的温度以进行生化反应，待达到预设的反应时间，控制模块800控制运动模块203切换试剂以及控制注射泵700以使试剂盒310内的第二试剂流向反应器202以使反应器202中的第一试剂以特定速度流出反应器202，待达到预设的时间，可将反应器202从容置座210上取下。
综上，该核酸加载装置1000包括承载模块200、运动模块302、液路模块702和控制模块800。
承载模块200包括容置座210和温控单元203、容置座210用于放置反应器202，核酸加载于所述反应器202中进行；温控单元203包括半导体制冷片220、导热体230和温度传感器260。半导体制冷片220包括相背的第一面221和第二面222；导热体230连接第一面221及容置座210。温度传感器260设置在导热体230内，温度传感器260用于检测导热体230的温度。
运动模块302包括隔板130、支撑平台300、第一驱动机构400、承载件500和第二驱动机构600。支撑平台300可拆卸地且可移动地设置在隔板130上，第一驱动机构400固定在隔板130上，第一驱动机构400用于驱动支撑平台300相对于隔板130沿第一方向移动。第二驱动机构600固定在支撑平台300上，第二驱动机构600用于驱动承载件500相对于支撑平台300沿第二方向移动，第二方向与第一方向垂直。
液路模块702用于控制试剂流入反应器202和流出反应器202，液路模块702包括注射泵700，注射泵700用于为反应器202提供负压以使试剂流至反应器202。
控制模块800与承载模块200、运动模块302及液路模块702连接，控制模块800用于控制第一驱动机构400和第二驱动机构600工作及用于控制液路模块70及温控单元203运行。
本发明一实施方式中的核酸加载装置1000中，半导体制冷片220的第一面221在工作时制热或制冷，从而通过导热体230为容置座210提供热量以使反应器202可以处于不同的环境温度。另外，运动模块302和液路模块702相互配合可以实现将待测样本加载到反应器202的过程的自动化及工业化。再有，核酸加载装置1000采用模块化设计，更加容易形成。
可以理解，控制模块800可以控制第一驱动机构400驱动支撑平台300相对于隔板130沿第一方向移动，控制模块800可以控制驱动承载件500相对于支撑平台300沿第二方向移动，控制模块800还可以控制注射泵700为反应器202提供负压。
一般地，温度传感器260测量温度的精度受环境温度、负载如容置座210、反 应器202等的大小和材质温度系数、温度传感器202的安装位置、半导体制冷片220的材质和尺寸、温度单元203的老化等的影响，且温度传感器202都存在零点漂移(零漂)和温度漂移(温漂)问题。可以理解地，在该核酸加载装置1000中，温度传感器260作为温度采集设备，希望其采集反映的是反应器202/负载的温度。
在某些实施方式中，温度传感器260为经过校准的温度传感器，温度传感器260检测的温度y满足多项式方程
Figure PCTCN2018120525-appb-000001
其中，n为自然数，4≤n≤6，x为校准前的温度传感器260检测的温度，a i为多项式系数。
在某些实施方式中，控制模块800包括机器可执行程序，执行所述机器可执行程序包括利用以下多项式方程对温度传感器260进行校准，校准后的温度传感器260检测的温度y满足
Figure PCTCN2018120525-appb-000002
其中，n为自然数，4≤n≤6，x为校准前的温度传感器检测的温度，a i为多项式系数。
在一个示例中，温度传感器260为数字输出类型的传感器，利用软件程序来消除上述偏移，例如，所需反应温度在10-70摄氏度范围内的，可利用以下多项式来校准温度传感器260输出的温度：
y＝-1.7345e -7*x 4-3.1059e -5*x 3+0.0001456*x 2+1.0044*x+6.032，
该核酸加载装置1000中，在10-30摄氏度范围内，基本可利用线性关系y＝1.004x+6.032来消除温度偏移。
所示方程可基于待校准温度传感器和已校准的温度传感器测量的系列温度值来建立，例如，将反应器202置于容置座210上，置一校准过的温度传感器于反应器202内，设定该装置中的待校准的温度传感器测量温度分别为10、15、20、25、30、35、40、45、50、55、60、65和70摄氏度，对应得到已校准的温度传感器测量的温度值分别为16.10、20.90、25.80、31.21、35.02、39.55、44.05、48.21、51.50、55.03、58、60.07和62.33摄氏度，基于这两组温度值，可拟合其关系式，获得该 多项式方程。
请参图1，在某些实施方式中，核酸加载装置1000还包括显示屏900，控制模块800用于控制显示屏900显示当前的容置座210的温度。
在本说明书的描述中，参考术语“一个实施方式”、“某些实施方式”、“示意性实施方式”、“示例”、“具体示例”、或“一些示例”等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发明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。
尽管已经示出和描述了本发明的实施方式，本领域的普通技术人员可以理解：在不脱离本发明的原理和宗旨的情况下可以对这些实施方式进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。
虽然在各种实施例中已经示出了本文的原理，但是许多特别适用于特定环境和操作要求的结构、布置、比例、元件、材料和部件的修改可以在不脱离本披露的原则和范围内使用。以上修改和其他改变或修正将被包含在本文的范围之内。
前述具体说明已参照各种实施例进行了描述。然而，本领域技术人员将认识到，可以在不脱离本披露的范围的情况下进行各种修正和改变。因此，对于本披露的考虑将是说明性的而非限制性的意义上的，并且所有这些修改都将被包含在其范围内。同样，有关于各种实施例的优点、其他优点和问题的解决方案已如上所述。然而，益处、优点、问题的解决方案以及任何能产生这些的要素，或使其变得更明确的解决方案都不应被解释为关键的、必需的或必要的。本文中所用的术语“包括”和其任何其他变体，皆属于非排他性包含，这样包括要素列表的过程、方法、文章或设备不仅包括这些要素，还包括未明确列出的或不属于该过程、方法、系统、文章或设备的其他要素。此外，本文中所使用的术语“耦合”和其任何其他变体都是指物理连接、电连接、磁连接、光连接、通信连接、功能连接和/或任何其他连接。
具有本领域技术的人将认识到，在不脱离本发明的基本原理的情况下，可以对上述实施例的细节进行许多改变。因此，本发明的范围应根据以下权利要求确定。

Claims (23)

  1. 一种核酸加载装置，其特征在于，包括：
    承载模块，包括容置座和温控单元，所述容置座用于容置反应器，所述核酸加载于所述反应器中进行，所述温控单元包括半导体制冷片、导热体和温度传感器，所述半导体制冷片包括相背的第一面和第二面，所述导热体连接所述第一面及所述容置座，所述温度传感器设置在所述导热体内，所述温度传感器用于检测所述导热体的温度；
    运动模块，包括隔板、支撑平台、第一驱动机构、承载件和第二驱动机构，所述支撑平台可拆卸地且可移动地设置在所述隔板上，所述第一驱动机构固定在所述隔板上且用于驱动所述支撑平台相对于所述隔板沿第一方向移动，所述第二驱动机构固定在所述支撑平台上且用于驱动所述承载件相对于所述支撑平台沿第二方向移动，所述第二方向与所述第一方向垂直；
    液路模块，用于控制试剂流入所述反应器和流出所述反应器，所述液路模块包括注射泵，所述注射泵用于提供负压；
    与所述承载模块、所述运动模块及所述液路模块连接的控制模块，用于控制所述第一驱动机构、所述第二驱动机构、所述液路模块以及所述温控单元运行。
  2. 如权利要求1所述的核酸加载装置，其特征在于，所述温度传感器为经过校准的温度传感器，所述温度传感器检测的温度y满足多项式方程
    Figure PCTCN2018120525-appb-100001
    其中，
    n为自然数，4≤n≤6，
    x为校准前的温度传感器检测的温度；
    a i为多项式系数。
  3. 如权利要求1所述的核酸加载装置，其特征在于，所述控制模块包括机器可执行程序，执行所述机器可执行程序包括利用以下多项式方程对所述温度传感器进行校准，校准后的所述温度传感器检测的温度y满足
    Figure PCTCN2018120525-appb-100002
    其中，
    n为自然数，4≤n≤6，
    y为校准前的温度传感器检测的温度；
    a i为多项式系数。
  4. 如权利要求1所述的核酸加载装置，其特征在于，所述第一驱动机构包括固定在所述隔板上的第一电机与所述第一电机连接的第一传动轴，所述第一传动轴连接所述支撑平台，所述第一电机用于驱动所述第一传动轴移动从而驱动所述支撑平台相对于所述隔板移动。
  5. 如权利要求1所述的核酸加载装置，其特征在于，所述第二驱动机构包括固定在所述支撑平台的第二电机和连接所述第二电机的第二传动轴，所述承载件套设在所述第二传动轴上，所述第二电机用于驱动所述第二传动轴转动以驱动所述承载件沿所述第二方向移动。
  6. 如权利要求1所述的核酸加载装置，其特征在于，所述核酸加载装置包括壳体，所述壳体包括面板，所述面板开设有与所述承载模块对应的窗口，所述窗口用于实现放置所述反应器于所述容置座上。
  7. 一种承载模块，其特征在于，包括：
    容置座，所述容置座开设有容置槽，所述容置槽用于容置反应器，所述容置座开设有与所述容置槽连通的通孔；
    半导体制冷片，所述半导体制冷片包括相背的第一面和第二面；和
    导热体，所述导热体连接所述第一面及所述容置座。
  8. 如权利要求7所述的承载模块，其特征在于，所述承载模块包括散热体，所述散热体连接所述第二面。
  9. 如权利要求8所述的承载模块，其特征在于，所述散热体形成有间隔设置的多个散热翅片。
  10. 如权利要求9所述的承载模块，其特征在于，所述多个散热翅片限定出散热通道，所述散热通道用于供冷却液流过，所述承载模块包括盖板，所述盖板遮蔽所述散热通道，所述盖板与所述散热体密封连接。
  11. 如权利要求10所述的承载模块，其特征在于，所述散热通道呈迂回曲折 形。
  12. 如权利要求10-11任意一项所述的承载模块，其特征在于，所述承载模块包括绝缘体，所述绝缘体固定连接所述盖板及所述导热体。
  13. 如权利要求7-12任意一项所述的承载模块，其特征在于，所述承载模块包括固定座和压紧件，所述压紧件转动设置在所述固定座上，所述容置座固定在所述固定座上，所述压紧件与所述固定座通过卡合结构连接。
  14. 如权利要求13所述的承载模块，其特征在于，所述卡合结构包括设置在所述固定座上的凸起和形成在所述压紧件上的卡孔，所述凸起卡合在所述卡孔内；或
    所述卡合结构包括设置在所述压紧件上的凸起和形成在所述固定座上的卡孔，所述凸起卡合在所述卡孔内。
  15. 如权利要求13所述的承载模块，其特征在于，所述承载模块包括止动件，所述止动件连接所述固定座及所述压紧件，所述止动件用于限制所述压紧件相对于所述固定座的转动角度。
  16. 一种核酸加载装置，其特征在于包括权利要求7-15任意一项所述的承载模块。
  17. 如权利要求16所述的核酸加载装置，其特征在于，所述核酸加载装置还包括壳体，所述壳体包括面板，所述面板开设有与所述反应器承载模块对应的窗口，所述窗口用于实现放置所述反应器于所述容置座上。
  18. 如权利要求17所述的核酸加载装置，其特征在于，所述核酸加载装置还包括壳体，所述壳体包括隔板，所述核酸加载装置包括：
    能够移动地设置在所述隔板的支撑平台，所述支撑平台用于连接试剂盒，所述试剂盒与所述反应器连接；
    和，
    固定在所述隔板上的第一驱动机构，所述第一驱动机构用于驱动所述支撑平台相对于所述隔板沿第一方向移动。
  19. 如权利要求18所述的核酸加载装置，其特征在于，所述第一驱动机构包括固定在所述隔板上的第一电机与所述第一电机连接的第一传动轴，所述第一传动轴连接所述支撑平台，所述第一电机用于驱动所述第一传动轴移动从而驱动所述支撑平台相对于所述隔板移动。
  20. 如权利要求18-19任意一项所述的核酸加载装置，其特征在于，所述核酸加载装置包括：
    用于承载所述试剂盒的承载件；
    和，
    固定在所述支撑平台上的第二驱动机构，所述第二驱动机构用于驱动所述承载件相对于所述支撑平台沿第二方向移动，所述第二方向与所述第一方向垂直。
  21. 如权利要求20所述的核酸加载装置，其特征在于，所述第二驱动机构包括固定在所述支撑平台的第二电机和连接所述第二电机的第二传动轴，所述承载件套设在所述第二传动轴上，所述第二电机用于驱动所述第二传动轴转动以驱动所述承载件沿所述第二方向移动。
  22. 如权利要求20所述的核酸加载装置，其特征在于，所述核酸加载装置包括注射泵，所述注射泵用于为所述反应器提供负压以使所述试剂盒内的试剂流至所述反应器。
  23. 权利要求16-22任意一项所述的核酸加载装置在核酸固定和/或杂交中的用途。
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