WO2020103126A1 - 基因测序反应平台、测序芯片及相关方法、系统 - Google Patents

基因测序反应平台、测序芯片及相关方法、系统

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Publication number
WO2020103126A1
WO2020103126A1 PCT/CN2018/117172 CN2018117172W WO2020103126A1 WO 2020103126 A1 WO2020103126 A1 WO 2020103126A1 CN 2018117172 W CN2018117172 W CN 2018117172W WO 2020103126 A1 WO2020103126 A1 WO 2020103126A1
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WO
WIPO (PCT)
Prior art keywords
sequencing
reaction
immersion
chip
control
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/117172
Other languages
English (en)
French (fr)
Inventor
唐琳
倪鸣
魏栋
陈�峰
伍家波
何志标
王文飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MGI Tech Co Ltd
Original Assignee
MGI Tech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MGI Tech Co Ltd filed Critical MGI Tech Co Ltd
Priority to CN201880099660.6A priority Critical patent/CN113242904B/zh
Priority to PCT/CN2018/117172 priority patent/WO2020103126A1/zh
Publication of WO2020103126A1 publication Critical patent/WO2020103126A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters

Definitions

  • the invention relates to the field of gene sequencing, in particular to a gene sequencing reaction platform, a sequencing chip and related methods and systems, including a reaction method, a control method, a reaction system, a control system and the like.
  • the second-generation gene sequencing technology is developed based on the first-generation Sanger sequencing technology, and has the characteristics of low cost, high throughput, and automation, which has greatly promoted the development of the gene sequencing industry.
  • the second-generation gene sequencing technology has been widely used in whole genome sequencing, transcriptome sequencing, metagenomic sequencing, etc. It is a powerful tool for analyzing biochemical evolution and classification, studying genes related to diseases such as cancer and autism, and performing in vitro diagnosis. Tools have promoted people's further understanding of life sciences and also promoted the development of the health industry.
  • the second-generation gene sequencing technology After years of development, the second-generation gene sequencing technology has been relatively mature, and new sequencing platforms and products have also been changed from generation to generation, and the rapid development of low-cost and high-throughput trends.
  • the most commonly used gene sequencing method of sequencing by synthesis determines the sequence of DNA by capturing the newly synthesized terminal markers, which mainly includes: 1) preparation of sequencing libraries, randomly breaking the DNA into small fragments; 2 ) PCR amplification, generating thousands of repeating fragments; 3) adding different fluorescent labels to different bases and performing fluorescent imaging sequencing.
  • An existing sequencing technology mainly includes the following processes:
  • Genomic DNA is first fragmented, coupled with a linker sequence, and circularized to form a single-stranded circular DNA, and then the rolling-circle amplification technology (Rolling Circle Amplification, RCA) can be used to amplify the single-stranded circular DNA 2- In 3 orders of magnitude, the resulting amplification product is called DNA nanoball (DNB).
  • the DNA nanosphere is tiled on a silicon wafer modified with amino surface, and only one nanosphere is fixed at each amino modification point. A regular array of DNA nanospheres is formed on the surface of the silicon wafer, and then encapsulated to form a sequencing chip.
  • the fluid system controls DNA synthesis. Sequencing primers and fluorescent labeled probes with different luminescence wavelengths enter the sequencing chip through the liquid path system. The primers and probes complete the DNA synthesis under the action of DNA ligase, and complete the corresponding elution and excision regeneration process.
  • Imaging detection A laser is used to excite a fluorescent probe to emit light, and different emission wavelengths represent different bases.
  • the emitted fluorescence is recorded by CCD / CMOS through the micro imaging system.
  • the system control software automates the sequencing process.
  • the entire sequencing process includes liquid infusion, optical focusing and photographing, image acquisition and storage, platform movement and scanning, etc., which are automatically controlled by the software.
  • the above test technology has the following disadvantages: a. Precise temperature control and fluid control are required, the cost is high, and the reaction is prone to unevenness; b. The chemical reagents used in the gene sequencing reaction are all disposable, and the utilization rate is low, further Increased the cost of sequencing; c. Gene sequencing systems of the prior art also generally have low throughput.
  • a gene sequencing reaction platform including: an immersion reaction device, the immersion reaction device includes at least one immersion reaction area, an immersion reaction tank is provided in the immersion reaction area, and each of the immersion reaction tanks is used for A chemical reagent for gene sequencing reaction is filled and used to soak a sequencing chip having a DNA sample loading structure on the surface and loaded with a DNA sample in the chemical reagent to perform a gene sequencing reaction.
  • a gene sequencing system which includes the above-described gene sequencing reaction platform, imaging detection device, transfer device, and control platform.
  • the gene sequencing reaction platform, imaging detection device, and transfer device are all controlled by the control platform ,
  • the gene sequencing reaction platform completes the gene sequencing reaction process of at least one sequencing chip under the control of the control platform, and the transfer device transfers the sequencing chip to the imaging detection device under the control of the control platform ,
  • the imaging detection device completes the imaging detection analysis of the sequencing chip under the control of the control platform.
  • a sequencing chip used in conjunction with the above-described gene sequencing reaction platform or the above-described gene sequencing system is provided.
  • the sequencing chip is in an unpackaged form.
  • the sequencing chip includes a silicon chip. At least one side of the silicon chip is used for A DNA sample is loaded, and a handle is provided at one end of the silicon wafer, and the handle is used for clamping to realize the picking and placing of the sequencing chip during the sequencing process.
  • a gene sequencing reaction method which includes: adding a chemical reagent for gene sequencing reaction to a soaking reaction tank and placing the soaking reaction tank in a soaking reaction area; controlling the soaking reaction area The temperature is used to control the temperature of the chemical reagent in the immersion reaction tank to a desired temperature; the sequencing chip with the DNA loading structure on the surface and loaded with the DNA sample is immersed in the chemical reagent one by one in turn for a predetermined time and then taken out.
  • a gene sequencing control system including: a control platform; a plurality of sensing units, each of which is used to sense whether a sequencing chip is placed in a corresponding immersion reaction tank, and sense The signal is sent to the control platform; wherein, the control platform controls at least one transfer device to place the sequencing chip in and out of the immersion reaction tank in order according to the sensing signal sent by each sensing unit and the preset program running .
  • a method for controlling gene sequencing includes: receiving a sensing unit to sense whether a sequencing chip is placed in a corresponding immersion reaction tank; according to the received sensing signal and a preset program to run, control the mobile The loading device places the sequencing chips in and out of the immersion reaction tank in sequence; and controls the time that each sequencing chip stays in the corresponding immersion reaction tank.
  • the above-mentioned gene sequencing reaction platform, sequencing chip, and related methods and systems provided by the embodiments of the present invention solve the problem of one-time use and utilization of reagents in the prior art by placing different sequencing chips in turn in a immersion reaction tank for reaction Low problems reduce the cost of sequencing.
  • the sequencing chip can be taken out and placed in another immersion reaction tank for reaction after the reaction of the previous immersion reaction tank is completed, which increases the sequencing reaction efficiency and greatly improves the sequencing throughput.
  • each immersion reaction zone can be placed with multiple immersion reaction tanks, so it can be flexibly selected and set the type of reagent used.
  • FIG. 1 is a perspective schematic view of a gene sequencing system in an embodiment of the present invention.
  • FIG. 2 is a perspective schematic view of a sequencing chip used with the gene sequencing system shown in FIG. 1 in an embodiment of the present invention.
  • FIG. 3 is an exploded schematic diagram of the sequencing chip shown in FIG. 2.
  • FIG. 4 is a perspective schematic diagram of a gene sequencing reaction platform of the gene sequencing system shown in FIG. 1.
  • FIG. 5 is a perspective schematic view of the feeding device of the gene sequencing reaction platform shown in FIG. 4.
  • Fig. 6 is an exploded schematic view of the feeding device shown in Fig. 5.
  • FIG. 7 is a schematic perspective view of the soaking buffer tank of the feeding device shown in FIG. 5.
  • FIG. 8 is an exploded schematic view of the soaking buffer tank shown in FIG. 7.
  • FIG. 9 is a perspective schematic view of the immersion reaction device of the gene sequencing reaction platform shown in FIG. 4.
  • FIG. 10 is a schematic perspective view of one of the immersion reaction zones shown in FIG. 9.
  • FIG. 11 is a partially exploded schematic view of the soaking reaction zone shown in FIG. 10.
  • FIG. 12 is a schematic perspective view of another immersion reaction zone of the immersion reaction device shown in FIG. 9.
  • FIG. 13 is a schematic perspective view of a part of the immersion reaction tank assembly shown in FIG. 12 in the immersion reaction area.
  • FIG. 14 is a perspective schematic view of another part of the immersion reaction tank assembly shown in FIG. 12.
  • FIG. 15 is a schematic perspective view of the elevating device of the soaking reaction device shown in FIG. 9.
  • FIG. 16 is an exploded schematic view of the lifting device shown in FIG. 15.
  • FIG. 17 is a perspective schematic view of the immersion and transfer device of the gene sequencing reaction platform shown in FIG. 4.
  • FIG. 18 is a schematic perspective view of the immersion transfer device shown in FIG. 17.
  • FIG. 19 is a schematic perspective view of the clamping assembly of the immersion transfer device shown in FIG. 18.
  • FIG. 20 is a schematic perspective view of the discharging device of the gene sequencing reaction platform shown in FIG. 4.
  • Fig. 21 is an exploded schematic view of the discharge device shown in Fig. 20.
  • FIG. 22 is a perspective schematic view of the transfer device of the gene sequencing system shown in FIG.
  • FIG. 23 is a schematic perspective view of the double clamping assembly of the transfer device shown in FIG. 22.
  • FIG. 24 is a schematic perspective view of the identification device on the gene sequencing reaction platform shown in FIG. 4.
  • FIG. 25 is a perspective schematic view of the clean device on the gene sequencing reaction platform shown in FIG. 4.
  • FIG. 26 is a perspective schematic view of the recovery device on the gene sequencing reaction platform shown in FIG. 4.
  • FIG. 27 is a hardware architecture diagram of a gene sequencing control system according to an embodiment of the present invention.
  • An embodiment of the present invention provides a gene sequencing reaction platform.
  • the gene sequencing reaction platform includes an immersion reaction device.
  • the immersion reaction device includes at least one immersion reaction area.
  • a detachable immersion reaction tank is provided in the immersion reaction area.
  • the soaking reaction tank is used for containing chemical reagents for gene sequencing reaction and for immersing a sequencing chip having a DNA sample loading structure on the surface and loaded with DNA samples in the chemical reagent to perform gene sequencing reaction.
  • Embodiments of the present invention also provide a gene sequencing system including the above-mentioned gene sequencing reaction platform, imaging detection device, transfer device and control platform, wherein the gene sequencing reaction platform, imaging detection device and transfer device are all controlled Under the control of the platform, the gene sequencing reaction platform completes the gene sequencing reaction process of at least one sequencing chip under the control of the control platform, and the transfer device transfers the sequencing chip that has completed the gene sequencing reaction process to the imaging detection device under the control of the control platform, imaging The detection device completes the imaging detection analysis of the sequencing chip under the control of the control platform.
  • the present invention also provides a sequencing chip used in conjunction with the above-mentioned gene sequencing reaction platform or gene sequencing system.
  • the sequencing chip adopts an unpackaged form.
  • the sequencing chip includes a silicon chip, and at least one side of the silicon chip is used to load DNA samples.
  • a handle is provided at one end of the silicon wafer, and the handle is used for clamping to realize the pick-and-place of the sequencing chip in the sequencing process.
  • An embodiment of the present invention also provides a gene sequencing reaction method, comprising: adding a chemical reagent for gene sequencing reaction to a soaking reaction tank and placing the soaking reaction tank in a soaking reaction area; controlling the soaking reaction area To control the temperature of the chemical reagent in the immersion reaction tank to the desired temperature; the sequencing chip with the DNA loading structure on the surface and loaded with the DNA sample is immersed in the chemical reagent one by one in turn for a predetermined time and then taken out.
  • the gene sequencing reaction method further includes: adding different chemical reagents for gene sequencing reaction to different immersion reaction tanks, and placing the different immersion reaction tanks in the same or different immersion reactions according to the temperature required for the reaction Area; and soak at least one of the sequencing chips in two or more of the soaking reaction tanks for a predetermined period of time.
  • An embodiment of the present invention also provides a gene sequencing control system, which includes a control platform and a plurality of sensing units, each sensing unit is used to sense whether a sequencing chip is placed in a corresponding immersion reaction tank, and send the sensing signal To the control platform, the control platform controls a transfer device to place the sequencing chip in and out of the immersion reaction tank in sequence according to the sensing signal sent by each sensing unit and the preset program.
  • Embodiments of the present invention also provide a gene sequencing control method, which includes: receiving a sensing unit to sense whether a sequencing chip is placed in a corresponding immersion reaction tank; according to the received sensing signal and a preset program, controlling the shift The loading device places the sequencing chips in and out of the immersion reaction tank in sequence; and controls the time that each sequencing chip stays in the corresponding immersion reaction tank.
  • a component when referred to as “fixed” or “installed” on another component, it can be directly on another component or there can also be a centered component. When a component is considered to be “set on” another component, it may be set directly on another component or there may be a centered component at the same time.
  • the term "and / or” as used herein includes all and any combinations of one or more related listed items.
  • the gene sequencing system 1000 includes a gene sequencing reaction platform 100, an imaging detection device 200, a transfer device 300, and a control platform 400.
  • the gene sequencing reaction platform 100 is used for the chemical reaction before the gene sequencing of the DNA sample on the sequencing chip (in this embodiment, DNA nanosphere, abbreviated as "DNB"); the imaging detection device 200 is used to sequence the completed gene
  • the sequencing chip of the reaction process is used for imaging detection and image analysis.
  • the transfer device 300 is used to transfer the sequencing chip between the gene sequencing reaction platform 100 and the imaging detection device 200, so that the sequencing chip can successfully complete the entire process of gene sequencing.
  • the control platform 400 is used to control the operation process of the sequencing chip on the gene sequencing reaction platform 100 and the imaging detection device 200 and the transfer of the sequencing chip between the above devices.
  • the gene sequencing system 1000 further includes an identification device 500, a cleaning device 600 and a recycling device 700, wherein the identification device 500 is used to identify the ID of each sequencing chip; the cleaning device 600 is used to clean the liquid carried by the sequencing chip after the sequencing chip completes the gene sequencing reaction process and before entering the imaging detection device; the recovery device 700 is used to recover the sequencing chip that has completed all sequencing processes and the sequencing chip that has abnormality in the sequencing process .
  • the identification device 500, the cleaning device 600, and the recovery device 700 are all integrated on the gene sequencing reaction platform 100.
  • the identification device 500 and the cleaning device 600 are both provided on the discharge end of the gene sequencing reaction platform 100, and the sequencing chip is on the gene sequencing reaction platform After 100 completes the sequencing reaction, the identification device 500 recognizes the ID of the sequencing chip, and then is transferred by the transfer device 300 to the cleaning device 600 to clean the carry liquid.
  • the identification device 500, the cleaning device 600, and the recovery device 700 may also be provided separately from the gene sequencing reaction platform 100.
  • the sequencing chip 900 is an unpackaged chip, and includes a main body 910 and a handle 920 disposed on the main body 910 as a portion where the sequencing chip 900 is clamped.
  • the main body 910 is a silicon wafer 911, and the silicon wafer 911 includes a front surface 912 and a back surface 913 opposite to the front surface 912.
  • the front surface 912 is used for loading DNA samples
  • the handle 920 is protrudingly disposed on the front surface 912.
  • the handle 920 is provided at one end of the front surface 912.
  • the back surface 913 is covered with a hydrophobic material 930.
  • the hydrophobic material 930 may be a hydrophobic film.
  • the handle 920 is used for clamping to realize the pick-and-place and transfer of the sequencing chip 900 during the sequencing process.
  • the handle 920 can be used for clamping the transfer device 300 and the gene sequencing immersion transfer device 150 to hold the sequencing chip 900 in Pick and place and transfer between different devices.
  • the handle 920 includes a connecting portion 921 and a clamping portion 922, wherein the connecting portion 921 is used to connect with the main body 910.
  • the connecting portion 921 is pasted to the main body 910 via the glue 940.
  • the clamping portion 922 is fixed to a side of the connecting portion 921 facing away from the main body 910, wherein the clamping portion 922 can be fixed to the connecting portion 921 by integral molding or by using a connecting member such as glue or screws.
  • the side of the clamping part 922 facing away from the connecting part 921 is pasted with the ID information piece 923 of the sequencing chip 900.
  • the ID information piece 923 presents the ID of the sequencing chip 900 in a bar code, a two-dimensional code or other suitable representations.
  • the ID is a unique code of the sequencing chip 900, which is used for chip attribute determination in the sequencing process.
  • a sink 924 is provided on the side of the clamping portion 922 facing away from the connecting portion 921, and the ID information piece 923 of the sequencing chip 900 is pasted on the sink 924.
  • Two recesses 925 are symmetrically provided on the opposite ends of the ID information piece 923 of the holding portion 922, and each recess 925 is recessed from the end where it is located toward the end where the other recess 925 is located, so as to facilitate other devices such as the transfer device 300 or a manual grip Hold the sequencing chip 900 for pick and place and transfer.
  • the recess 925 has a dovetail groove shape.
  • both the front surface 912 and the back surface 913 of the silicon wafer 911 can be used to load DNA samples, and the handle 920 is protrudingly disposed on the front surface 912 or the back surface 913.
  • the gene sequencing reaction platform 100 includes a main architecture platform 110, a feeding device 120, a soaking reaction device 130, a discharging device 140 and a soaking transfer device 150.
  • the main architecture platform 110 is used for arranging the feeding device 120, the immersion reaction device 130, the discharge device 140, the immersion transfer device 150, the identification device 500, the cleaning device 600 and the recovery device 700.
  • the main architecture platform 110 includes a lower frame 111 1.
  • a main platform 112 provided above the lower frame 111, an upper frame 113 provided on the main platform 112, and a top platform 114 provided on the upper frame 113.
  • the feeding device 120 and the discharging device 140 are arranged substantially in parallel at the front end of the main platform 112, the soaking reaction device 130 is disposed at the rear end of the main platform 112, and the feeding device 120, the discharging device 140 and the soaking reaction
  • the three devices 130 are arranged roughly in the form of "product”.
  • the identification device 500 and the cleaning device 600 are disposed on the side of the main platform 112 where the discharging device 140 is located, and the recovery device 700 is disposed on the side of the main platform 112 where the feeding device 120 is located.
  • the immersion transfer device 150 is suspended on the top platform 114 and is disposed toward the immersion reaction device 130.
  • the sequencing chip enters the gene sequencing reaction platform 100 through the feeding device 120, and then transfers to the immersion reaction device 130 through the immersion transfer device 150 to perform the sequencing reaction, and then transfers to the discharge device 140 through the immersion transfer device 150 after the completion of the sequencing reaction.
  • the sequencing chip recognizes the ID at the same time by the identification device 500, then is transferred by the transfer device 300 to the cleaning device 600 to clean the liquid carried, and finally transferred to the imaging detection device 200 via the transfer device 300 for imaging detection, Complete the entire gene sequencing process.
  • the feeding device 120 includes a power source 121, a feed transmission mechanism 122 driven by the power source 121, and a feed module 123 driven by the feed transmission mechanism 122.
  • the feeding module 123 is provided with a plurality of soaking buffer tanks 1231, and each soaking buffer tank 1231 contains a chemical buffer solution that maintains the activity of the DNA sample on the sequencing chip before the gene sequencing reaction is performed.
  • the power source 121 drives the feed transmission mechanism 122 to cause the feed transmission mechanism 122 to move the feed module 123, so that the feed module 123 reciprocates at a loading position and a transfer position.
  • the loading position one or more sequencing chips are correspondingly loaded into one or more immersion buffer tanks 1231, and each immersion buffer tank 1231 is loaded with a sequencing chip; at the transfer position, one or more The sequencing chip is transferred into the immersion reaction device 130.
  • the feed module 123 further includes a mounting base 1232, a shield 1233, and a plurality of detection switches 1234.
  • the mounting base 1232 is fixed on the feed conveying mechanism 122, and is moved between the loading position and the transfer position by the feed conveying mechanism 122.
  • the shield 1233 is installed on the mounting base 1232, and an installation space 1235 for installing a plurality of immersion buffer tanks 1231 is formed between the mounting base 1232, and a plurality of openings 1236 are opened above the shield 1233, and each opening 1236 is connected to the installation space 1235 is in communication and is arranged opposite to the opening 1237 of one of the immersion buffer tanks 1231, so that the sequencing chip can be inserted into the corresponding immersion buffer tank 1231 from the opening 1236.
  • Each detection switch 1234 is corresponding to an immersion buffer tank 1231, and is used to detect whether a sequencing chip is inserted into the immersion buffer tank 1231. Further, in this embodiment, the immersion buffer tank 1231 is mounted on the mounting base 1232 in an array, and the detection switch 1234 is mounted on the shield 1233 corresponding to the array. In other embodiments, the immersion buffer tank 1231 can also be installed on the shield 1233.
  • each immersion buffer tank 1231 includes a main tank body 1231 a, a cover plate 1231 b, a sealing strip 1231 c, and a pipe joint 1231 d.
  • the material of the main tank 1231a and the cover plate 1231b is polyetheretherketone.
  • the cover plate 1231b is locked to the main groove body 1231a by screws or other connecting members to form a groove with one end open, and the sealing strip 1231c is provided at a portion where the main groove body 1231a is connected to the cover plate 1231b.
  • Each soaking buffer tank 1231 is provided with two through holes 1231e near the bottom, and each through hole 1231e is connected with a pipe joint 1231d for injection and pumping.
  • each immersion buffer tank 1231 has replaceability and sealing performance, and the liquid discharge form at the bottom can make the internal liquid easily drained.
  • the immersion buffer tanks 1231 contain chemical buffers that maintain the activity of the DNA samples on the sequencing chips, which not only facilitates the maintenance of DNA sample activities, but also facilitates multiple sequencing chips Queuing and buffering before entering the sequencing reaction process.
  • the immersion reaction device 130 includes at least one immersion reaction area, and a detachable immersion reaction tank is provided in the immersion reaction area, and each immersion reaction tank is used to contain a chemical reagent for gene sequencing reaction, so that The sequencing chip loaded with the DNA sample on the surface can be immersed in the chemical reagent to perform the gene sequencing reaction.
  • the number of the immersion reaction zone is five, including three small immersion reaction zones 131 and two large immersion reaction zones 132.
  • the large and small immersion reaction zones 131 and 132 are arranged around a lifting device 133.
  • Each immersion reaction zone is used to accommodate one or more detachable immersion reaction tanks 134, wherein the difference between the large immersion reaction zone 132 and the small immersion reaction zone 131 is mainly the number of immersion reaction tanks 134 that can be accommodated.
  • the small immersion reaction zone 131 can accommodate three immersion reaction tanks 134
  • the large immersion reaction zone 132 can accommodate more than three immersion reaction tanks 134.
  • each small immersion reaction zone 131 includes an immersion reaction tank 134, a connecting member 1312, a detection bracket 1313, a sensor 1314 and a heating and thermal insulation device 1315.
  • the three immersion reaction tanks 134 are connected upwardly, side by side, and detachably connected to the connecting member 1312.
  • the detection bracket 1313 is disposed above the immersion reaction tank 134.
  • Three sensors 1314 are fixed on the detection bracket 1313. Each sensor 1314 is directly opposite A immersion reaction tank 134 is above the opening to detect whether a sequencing chip is inserted in the immersion reaction tank 134.
  • One end of the detection bracket 1313 is fixed to the connecting piece 1312, and the connecting piece 1312 is fixed to the lifting device 133 again.
  • the senor 1314 is a U-shaped sensor, and the U-shaped sensor is disposed around the notch of the immersion reaction tank 134.
  • One leg of the U-shaped sensor sends a sensing signal, and the other opposite leg receives the sensing signal.
  • the sequencing chip blocks the sensing signal, so that the other leg cannot receive the sensing signal Therefore, the sensor 1314 can sense whether the sequencing chip is inserted into the immersion reaction tank 134.
  • the heating and holding device 1315 includes a water bath 1316 and a temperature control unit (not shown).
  • the water bath is used to contain heat transferable liquid.
  • the immersion reaction tank 134 is suspended in the water bath 1316.
  • the temperature control unit is controlling The temperature of the liquid in the water bath can be controlled under the control of the platform 400 or other control components to control the temperature of the chemical reagent in the soaking reaction tank.
  • the heating and holding device 1315 further includes a high level detector (not shown) and a low level detector (not shown) for detecting the level of the liquid in the water bath 1316.
  • the high level detector is used for automatic liquid injection when the height reaches the high level detector Stop filling and automatically refill when the liquid level is lower than the high level detector.
  • the low level detector is used to stop heating when the liquid level is too low during heating.
  • each large immersion reaction zone 132 includes an immersion reaction tank 134 (three are shown in the figure), connectors 1322 and 1323, detection brackets 1324 and 1325, sensors 1326 and 1327, and heating and insulation devices 1328.
  • Two of the immersion reaction tanks 134 are connected upwardly, side by side, and detachably connected to the connecting member 1322.
  • the detection bracket 1324 is disposed above the immersion reaction tank 134.
  • the two sensors 1326 are fixed to the detection bracket 1324, and the detection bracket 1324 is connected
  • the connecting member 1322 is connected to the lifting device 133 by the connecting member 1322.
  • the other immersion reaction tank 134 has a notch upwardly and detachably connected to the connecting member 1323, and the connecting member 1323 is then connected to the lifting device 133.
  • the detection bracket 1325 is fixed on the immersion reaction tank 134. It should be noted that no matter whether it is the small immersion reaction zone 131 or the large immersion reaction zone 132, the settings of the connectors, detection brackets, and sensors can be changed according to actual needs, for example, one connector can also be fixed more than three In the immersion reaction tank, one detection bracket can fix more than three sensors as needed, and the detection bracket can be connected to the connecting piece or fixed to the immersion reaction tank. In addition, the size of each immersion reaction zone and the number of immersion reaction tanks in the immersion reaction zone can also be set according to actual needs.
  • the required temperature can be the same
  • the soaking reaction tank is placed in the same soaking reaction area.
  • the immersion reaction tanks in the same immersion reaction area can contain the same chemical reagents or different chemical reagents, as long as the immersion reaction area can provide the temperature required for the chemical reagents in the immersion reaction tank.
  • the immersion reaction tanks in different immersion reaction areas can contain the same chemical reagents or different chemical reagents. In short, only the immersion reaction area can provide the chemistry in all the immersion reaction tanks located in the immersion reaction area The temperature required for the reagent is sufficient.
  • the setting of the heating and holding device 1328 in the large immersion reaction zone 132 is the same as or similar to that of the heating and holding device 1315 in the small immersion reaction zone 131, or other conventional means are used, which will not be described here.
  • the structure of the immersion reaction tank 134 is substantially the same as or similar to the structure of the immersion buffer tank 1231, and will not be described here.
  • the lifting device 133 is a lifting platform, including a lifting base 1331, a slider base 1332 fixed on the lifting base 1331, and a lifting slide plate 1333 that cooperates with the slider base 1332, And a top plate 1334 provided on the upper end of the lift rail plate 1333.
  • Two sliders 1332a are fixed on the slider base 1332, and a lifting slide plate 1333 is fixed on the two sliders 1332a, thereby forming a structure in which the top plate 1334 can slide freely relative to the lifting base 1331.
  • Four leveling screws 1335 are fixed on the top plate 1334 for adjusting the top plate 1334 and the lifting base 1331 to be parallel to each other.
  • a power source 1336 (such as a cylinder) is fixed on the lifting base 1331.
  • the end of the power source 1336 is connected to the floating joint 1337.
  • the floating joint 1337 is fixed to a connecting plate 1338, and the connecting plate 1338 is connected to the top plate 1334.
  • the power source 1336 pushes or pulls the top plate 1334 to move up and down through the floating joint 1337, thereby realizing the lifting of the lifting device 133.
  • the immersion reaction tank 134 is connected to the lifting device 133 through a corresponding connection member.
  • the ascent of the lifting device 133 drives the immersion reaction tank 134 to rise, so that the immersion reaction tank 134 leaves the corresponding water bath pot, thereby facilitating the user to remove the immersion reaction tank 134 or Connect a new immersion reaction tank 134 to the connecting piece.
  • the immersion reaction tank 134 connected to the connecting member can be placed in the corresponding water bath.
  • the lifting device 133 can be lifted in many ways or deformations, for example, by driving the slide rail relative movement to raise and lower the lifting device 133,
  • the number of slide rail sliders can be one or three, and these methods are not listed here one by one.
  • the top plate 1334 of the lifting device 133 is not limited to a square structure, it can be U-shaped, bow-shaped, I-shaped structure, etc., regardless of the shape of the top plate 1334, only the edge portion of the lifting device 133 (specifically the side of the top plate 1334 ) Close to or placed above the immersion reaction zone so that one end of the immersion reaction tank can be detachably fixed to the lifting device 133.
  • the top plate 1334 may also have an opening, and part or all of the soaking reaction zone may also be provided corresponding to the opening edge of the top plate 1334.
  • the immersion transfer device 150 is installed on the top platform 114 of the main frame platform 110, and includes a four-axis robot 151 and a clamping assembly 152 placed on the movement terminal of the four-axis robot 151.
  • the four-axis robot 151 provides vertical and horizontal movements for the sequencing chip.
  • the clamping assembly 152 includes a clamp base 1521 fixed to the movement terminal of the four-axis robot 151, the clamp base 1521 is connected to an air claw mounting plate 1522, and a parallel opening and closing cylinder 1523 is mounted on the air claw mounting plate 1522.
  • a left grip 1524 and a right grip 1525 are attached to the opening and closing cylinder 1523.
  • the parallel opening and closing cylinder 1523 is closed, the left clamping hand 1524 and the right clamping hand 1525 are driven to move in parallel to hold the sequencing chip.
  • a limit stop 1526 is also fixed on the parallel opening and closing cylinder 1523, and a limit stop 1527 is fixed on the limit stop 1526, which is used to limit the width of the left clamp 1524 and the right clamp 1515 when the parallel opening and closing cylinder 1523 is opened.
  • the number of the four-axis robot 151, the freedom of motion of the robot used, the running area and trajectory of each robot, and the structure of the clamping assembly 152 can also have various deformations, which will not be repeated here. Enumerate.
  • the discharge device 140 is used to store the sequencing chip through the immersion reaction, and the transfer device 300 is transferred to other devices, such as the cleaning device 600.
  • the discharge device 140 includes a power source 141, a discharge transmission mechanism 142 driven by the power source 141, and a discharge module 143 driven by the discharge transmission mechanism 142.
  • a plurality of immersion buffer tanks 1431 are provided on the discharge module 143, and each immersion buffer tank 1431 contains a chemical buffer solution that maintains the activity of the DNA sample on the sequencing chip after the gene sequencing reaction is performed.
  • the power source 141 drives the discharge transmission mechanism 142, so that the discharge transmission mechanism 142 drives the discharge module 143 to move, so that the discharge module 143 reciprocates at the discharge position and a transfer position.
  • the loading position one or more sequencing chips are removed from the immersion reaction tank 134 and correspondingly loaded into one or more immersion buffer tanks 1431, one sequencing chip is loaded in each immersion buffer tank 1431; at the transfer position, One or more sequencing chips are sequentially transferred by the transfer device 300 to other devices, for example, one by one to the cleaning device 600 to clean the liquid carried by the sequencing chips.
  • the discharge module 143 further includes an installation base 1432, a shield 1433, a plurality of detection switches 1434, and a switch bracket 1435.
  • the mounting base 1432 is fixed on the discharge conveying mechanism 142, and is driven to move between the discharging position and the transfer position by the discharge conveying mechanism 142.
  • the shield 1433 is installed on the mounting base 1432, and an installation space 1436 for installing a plurality of immersion buffer tanks 1431 is formed between the mounting base 1432, and a plurality of openings 1437 are opened above the shield 1433, and each opening 1437 is connected to the installation space 1436 is in communication and is arranged opposite to the opening 1438 of one of the immersion buffer tanks 1431, so that the sequencing chip can be inserted into the corresponding immersion buffer tank 1431 from the opening 1437.
  • the detection switch 1434 is mounted on the switch bracket 1435, and then mounted on the mounting base 1432 by the switch bracket 1435. Each detection switch 1434 is corresponding to an immersion buffer tank 1431, and is used to detect whether a sequencing chip is inserted into the immersion buffer tank 1431.
  • the immersion buffer tank 1431 is mounted on the mounting base 1432 in an array, and the detection switch 1434 is mounted on the mounting base 1432 via the switch bracket 1435 corresponding to the array.
  • the immersion buffer tank 1431 and the switch bracket 1435 can also be installed on the shield 1433.
  • the structure of the immersion buffer tank 1431 is substantially the same as or similar to the structure of the immersion buffer tank 1231, and will not be described here.
  • the transfer device 300 is used to obtain, carry and release the sequencing chip.
  • the transfer device 300 includes a six-axis robot 310, a robot mount 320, and a double clamping assembly 330.
  • the robot mounting base 320 is fixed on a mounting surface such as the ground
  • the six-axis robot 310 is mounted on the robot mounting base 320
  • the double clamping assembly 330 is fixed to the movement terminal of the six-axis robot 310.
  • the double clamping assembly 330 includes a mounting plate 331 fixed to the movement terminal of the six-axis robot 310.
  • a parallel opening and closing cylinder 332 is fixed at each end of the mounting plate 331, and a left clamping hand 333 and a right clamping hand are mounted on the parallel opening and closing cylinder 332 334.
  • the parallel opening and closing cylinder 332 is also fixed with a limit stop 335, and the limit stop 335 is fixed with a limit block 336, which is used to limit the width of the left clamping hand 333 and the right clamping hand 334 when the parallel opening and closing cylinder 332 is opened.
  • the left clamping hand 333 and the corresponding parallel opening and closing cylinder 332, the limit frame 335, and the limit block 336 form a clamping assembly
  • the right clamping hand 334 and the corresponding parallel opening and closing cylinder 332, the limit frame 335, the limit block 336 Constitute another clamping assembly.
  • a dual clamping assembly 330 is provided, and each clamping assembly of the dual clamping assembly 330 is used to clamp a sequencing chip. Under the control of the control platform 400, one of the clamping assemblies is removed from the imaging detection device and the imaging detection sequence has been completed.
  • the chip and another clamping assembly immediately move the sequencing chip to be imaged and tested into the imaging and detection device, thereby saving the operation flow and operation time of the transfer device 300 and improving the operation efficiency.
  • the number of the six-axis robot 310, the freedom of movement of the robot and the structure of the double clamping assembly 330 can also have various modifications, which will not be listed here one by one.
  • the identification device 500 scans the ID information sheet on the front of the sequencing chip by a scanner to identify the ID of the sequencing chip.
  • the identification device 500 is fixed near the discharge device 140.
  • the identification device 500 includes a base 510, a multi-directional adjustment link 520, a scanner 530, and a scanner mounting base 540.
  • the scanner and the scanner mounting base 540 are fixed and connected to the end of the multi-directional adjustment link 520, and the multi-directional adjustment link 520 is fixed to the base 510 to form the identification device 500.
  • the cleaning device 600 includes a cleaning bottom plate 610, a water tank 620, a water-absorbing sponge 630, a sponge pressing plate 640, an air knife 650, and an air knife mounting frame 660.
  • the water tank 620 is installed on the clean bottom plate 610, and the water absorption sponge 630 covers the upper and rear sides of the water tank 620 through the sponge pressure plate 640, the air knife 650 is installed on the air knife mounting frame 660, and the air knife mounting frame 660 is installed on the water tank 620.
  • the air knife 650 can blow out a thin air curtain by passing compressed air, and can clean the liquid on the back of the sequencing chip.
  • the water-absorbing sponge 630 can dissolve the air flow during blowing, and sticky and splashing tiny droplets.
  • the recovery device 700 is used to recover the sequencing chips that have completed all sequencing processes and the sequencing chips that have abnormalities in the sequencing process.
  • the recycling device 700 includes a recycling tank mounting frame 710, a plurality of immersion buffer tanks 720 mounted on the recycling tank mounting frame 710, and a corresponding number of detection switches 730 and switch brackets 740.
  • the detection switch 730 is mounted on the switch bracket 740, and the switch bracket 740 is fixed on the recovery tank mounting frame 710 for detecting the sequencing chip in the immersion buffer tank 720.
  • each soaking buffer tank 1231 is used to soak a sequencing chip, so one or more sequencing chips can be loaded into the feeding device at a time. ⁇ ⁇ 120 ⁇ Material device 120.
  • Each immersion buffer tank 1231 is correspondingly provided with a detection switch 1234, and each detection switch 1234 is connected to the control platform 400, so that the control platform 400 is informed of the loading status of the sequencing chip in each immersion buffer tank 1231 in the feeding device 120.
  • the control platform 400 may include a main control computer, a display, a keyboard, a mouse, a touch screen, a LAN switch, etc.
  • the control platform 400 is used for the control and operation of the entire process of gene sequencing. As shown in FIG. 27, the control platform 400 and multiple sensing units A form a gene sequencing control system 2000 or a part of the gene sequencing control system 2000.
  • the sensing unit A includes detection switches 1234, 1434, 730 and sensors 1314. 1326, 1327, etc.
  • the detection switches 1234, 1434, 730 and the sensors 1314, 1326, and 1327 respectively sense whether the corresponding immersion buffer tanks 1231, 1431 and the immersion reaction tank 134 are loaded with sequencing chips.
  • the control platform 400 according to the detection switches 1234, 1434, 730 and Sensing signals and preset programs sent by sensors 1314, 1326, 1327, control the insertion and removal of sequencing chips into and out of immersion buffer tanks 1231 and 1431, and into and out of immersion reaction tank 134, control of immersion reaction time, and control of different immersion reactions The order of the reaction of the tank 134 and so on.
  • the control platform 400 starts a self-running mode to complete at least one round of sequencing of the sequencing chip.
  • the feeding device 120 completes the loading of the sequencing chip.
  • “Completed” means that all the immersion buffer tanks 1231 are loaded with sequencing chips, or part of the immersion buffer tanks 1231 are loaded with sequencing chips, and the control platform 400 controls the platform 400 according to predetermined rules or signals. It is learned that the loading of the sequencing chip in the feeding device 120 is completed.
  • the control platform 400 controls the feeding device 120 to move one of the soaking buffer tanks 1231 loaded with sequencing chips from the loading position to the moving position according to the sensing signal sent by the detection switch 1234 Loading position (step one), then, under the control of the control platform 400, the four-axis robot 151a carries the clamping assembly 152 to move above the immersion buffer tank 1231, the clamping assembly 152 descends and clamps the immersion buffer tank 1231 Sequencing chips, and then raising the sequencing chips to a certain height (step two).
  • the control platform 400 controls the four-axis robot 151a to move horizontally to one of the immersion reaction tanks 134 in which the sequencing chip is not loaded in the immersion reaction device 130 according to the sensing signals sent by the sensors 1314, 1326, 1327 and the preset program, and then controls the clamp
  • the holding assembly 152 is lowered to insert the sequencing chip into the immersion reaction tank 134 (step three), thereby completing the feeding of the sequencing chip once.
  • the control platform 400 controls the sequencing chip to be immersed in the immersion reaction tank 134 according to a preset procedure to set a reaction time (step 4), and then the control platform 400 controls the four-axis robot 151b to move above the immersion reaction tank 134 to obtain the sequencing chip and carry it down A soaked reaction tank 134 without a sequencing chip loaded and then released (step 5).
  • the control platform 400 controls the sequencing chip to be immersed in the immersion reaction tank 134 for a set reaction time according to a preset program (step 6), and then sequentially controls the sequencing chip to be transferred to the set and the next immersion reaction tank 134 (step 7) .
  • the sequence of the reaction of a sequencing chip in different immersion reaction tanks 134 is independent of the location of the immersion reaction tank 134, and is only related to the sequence of chemical reactions that need to occur on the DNA samples on the sequencing chip.
  • the control platform 400 After the required immersion reaction process is completed, the control platform 400 finally controls the four-axis robot 151c to transfer the sequencing chip to one of the immersion buffer tanks 1431 of the unloading sequencing chip of the discharging device 140 according to the sensing signal of the detection switch 1434 (Step 8).
  • the control platform 400 knows the completion of loading the sequencing chip in the discharging device 140 according to a predetermined rule or signal.
  • the control platform 400 controls the discharging device 140 to run one of the soaking buffer tanks 1431 loaded with sequencing chips to the transfer position (step 9).
  • the transfer position is opposite to the identification device 500.
  • the control platform 400 controls the scanner 530 of the identification device 500 to scan the ID information piece 923 at the center of the front of the sequencing chip and feed back the ID of the sequencing chip to the control platform 400, so that the control platform 400 subsequently associates the ID with the imaging detection result (Step 10).
  • the control platform 400 identifies the optical platform in the imaging detection device corresponding to the sequencing chip, and when it is idle and ready, controls the six-axis robot 310 to carry the dual clamping assembly 330 to move above the immersion buffer tank 1431 and obtain the sequencing chip (Step eleven).
  • the control platform 400 continues to control the movement of the six-axis robot 310 carrying the sequencing chip to the inside of the cleaning device 600 (step twelve).
  • the control platform 400 controls the air knife 650 to blow air to clean the liquid carried by the sequencing chip (step thirteen).
  • the control platform 400 controls the six-axis robot 310 to carry the sequencing chip to the corresponding optical platform in the imaging detection device 200 to complete the imaging detection (step 14).
  • the control platform 400 controls the transfer device 300 to remove the sequencing chip from the optical platform and place it in the immersion buffer tank 1231 of the feeding device 120 where the sequencing chip is not loaded, and perform the next round of sequencing reaction (step 15) ).
  • the control platform 400 controls the six-axis robot 310 to place the sequencing chip into the immersion buffer tank of the recovery device 700 In 720 (step sixteen), complete all sequencing processes of the sequencing chip.
  • control platform 400 also controls the temperature of the chemical reagent in the corresponding immersion reaction tank 134 according to the type of chemical reaction of each sequencing chip in the corresponding immersion reaction tank 134.
  • the identification device 500 is also included in the gene sequencing control system 2000.
  • the identification device 500 identifies the ID of each sequencing chip, and the control platform 400 associates the imaging detection analysis result of a sequencing chip with the ID of the sequencing chip.
  • the embodiments of the present invention provide a gene sequencing reaction platform, sequencing chip, and related methods and systems.
  • the one-time reagent in the prior art is solved The problem of low usage and utilization reduces the cost of sequencing.
  • the sequencing chip can be taken out and placed in another immersion reaction tank for reaction after the reaction of the previous immersion reaction tank is completed, which increases the sequencing reaction efficiency and greatly improves the sequencing throughput.
  • each immersion reaction zone can be placed with multiple immersion reaction tanks, so it can be flexibly selected and set the type of reagent used.

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Abstract

一种基因测序反应平台、测序芯片及相关方法、系统，所述基因测序反应平台(100)包括：浸泡反应装置(130)，所述浸泡反应装置包括至少一个浸泡反应区(131,132)，所述浸泡反应区内设置浸泡反应槽(134)，每一所述浸泡反应槽(134)用于盛放基因测序反应的化学试剂并用于将表面具有DNA样品加载结构且已加载有DNA样品的测序芯片(900)浸泡于所述化学试剂中进行基因测序反应。

Description

基因测序反应平台、测序芯片及相关方法、系统 技术领域
本发明涉及基因测序领域，尤其涉及基因测序反应平台、测序芯片及相关方法及系统，包括反应方法、控制方法、反应系统、控制系统等。
背景技术
第二代基因测序技术基于第一代桑格(Sanger)测序技术发展而来，具有低成本、高通量、自动化等特征，极大地推进了基因测序产业的发展。第二代基因测序技术目前已经广泛应用于全基因组测序、转录组测序、宏基因组测序等，是分析生化的进化与分类，研究癌症、自闭症等疾病相关基因，以及进行体外诊断等的有力工具，促进了人们对于生命科学的进一步了解，也推动了健康产业的发展。
经过多年发展，第二代基因测序技术已相对较为成熟，新的测序平台和产品也代次更迭，朝着低成本和高通量的趋势迅猛发展。以目前最常用的边合成边测序的基因测序方法为例，其通过捕捉新合成的末端的标记来确定DNA的序列，主要包括：1)测序文库制备，将DNA随机打断成小片段；2)PCR扩增，产生成千上万重复片段；3)不同碱基添加不同的荧光标记，进行荧光成像测序。
现有一种测序技术，主要包括以下过程：
测序芯片制备。基因组DNA首先经过片段化处理，再加上接头序列，并环化形成单链环状DNA，随后使用的滚环扩增技术(Rolling circle amplification，RCA)可将单链环状DNA扩增2-3个数量级，所产生的扩增产物称为DNA纳米球(DNA nanoball，DNB)，把DNA纳米球平铺到经过氨基表面修饰的硅片上，每个氨基修饰点位仅固定一个纳米球，在硅片表面形成DNA纳米球规则阵列，再加以封装，形成测序芯片。
液路系统控制DNA合成。测序引物和不同发光波长的荧光标记探针通过液路系统进入测序芯片，引物和探针在DNA连接酶的作用下完成DNA的合成，并且完成相应的洗脱和切除再生过程。
成像检测。使用激光激发荧光探针发光，不同发光波长代表不同的碱基。发出的荧光经显微成像系统被CCD/CMOS记录。
系统控制软件实现测序过程的自动化。整个测序过程包括进液、光学聚焦和拍照，图像采集和存储、平台移动和扫描等都由软件自动控制完成。
图像处理和分析。由CCD/CMOS记录的荧光信号经过计算机进行图像处理和分析，实现碱基识别。
上述测试技术具有如下缺点：a.需要精确的温度控制和流体控制，成本较高，容易出现反应不均匀现象；b.基因测序反应所用的化学试剂都是一次性使用，利用率较低，进一步提高了测序成本；c.现有技术的基因测序系统，还普遍存在通量较低的情况。
发明内容
为了解决现有技术的上述以及其他潜在问题，有必要提出一种一种基因测序反应平台、测序芯片及各种方法、系统。
第一方面，提供一种基因测序反应平台，包括：浸泡反应装置，所述浸泡反应装置包括至少一个浸泡反应区，所述浸泡反应区内设置浸泡反应槽，每一所述浸泡反应槽用于盛放基因测序反应的化学试剂并用于将表面具有DNA样品加载结构且已加载有DNA样品的测序芯片浸泡于所述化学试剂中进行基因测序反应。
第二方面，提供一种基因测序系统，包括上述的基因测序反应平台及成像检测装置、转移装置、控制平台，所述基因测序反应平台、成像检测装置及转移装置均受所述控制平台的控制，所述基因测序反应平台在所述控制平台的控制下完成至少一测序芯片的基因测序反应流程，所述转移装置在所述控制平台的控制下将所述测序芯片转移至所述成像检测装置，所述成像检测装置在所述控制平台的控制下完成对所述测序芯片的成像检测分析。
第三方面，提供一种配合上述的基因测序反应平台或者上述的基因测序系统使用的测序芯片，所述测序芯片采用无封装形式，所述测序芯片包 括硅片，所述硅片至少一面用于装载DNA样品，所述硅片一端设置手柄，所述手柄供夹持以实现测序过程中所述测序芯片的取放。
第四方面，提供一种基因测序反应方法，包括：在一浸泡反应槽内加入基因测序反应用的化学试剂并将所述浸泡反应槽置于一浸泡反应区内；控制所述浸泡反应区的温度以将所述浸泡反应槽内化学试剂的温度控制在所需的温度；将表面具有DNA加载结构并加载有DNA样品的测序芯片一次一个轮流浸泡于所述化学试剂预定时候后取出。
第五方面，提供一种基因测序控制系统，包括：控制平台；多个感测单元，每一所述感测单元用于感测一对应浸泡反应槽内是否放置有测序芯片，并将感测信号发送给所述控制平台；其中，所述控制平台根据每一感测单元发送的感测信号以及运行的预设程序，控制至少一移载装置将测序芯片按顺序置入与移出浸泡反应槽。
第六方面，提供一种基因测序控制方法，包括：接收感测单元感测对应浸泡反应槽内是否放置有测序芯片的感测信号；根据接收的感测信号及运行的预设程序，控制移载装置将测序芯片按顺序置入与移出浸泡反应槽；及控制每一测序芯片在对应浸泡反应槽内停留的时间。
本发明的实施例提供的上述基因测序反应平台、测序芯片及相关方法、系统，通过将不同测序芯片轮流置入一浸泡反应槽中进行反应，解决了现有技术中试剂一次性使用、利用率低的问题，降低了测序成本。同时通过设置不同的浸泡反应槽，测序芯片在前一浸泡反应槽反应完成后，即可取出置入另一浸泡反应槽中进行反应，增加了测序反应效率，极大提高了测序通量。此外，还通过设定不同的浸泡反应区，每一浸泡反应区可放置多个浸泡反应槽，因此可供灵活选择、设定使用的试剂种类。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对本发明实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本 发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1是本发明一实施方式中的基因测序系统的立体示意图。
图2是本发明一实施方式中配合图1所示基因测序系统使用的测序芯片的立体示意图。
图3是图2所示测序芯片的分解示意图。
图4是图1所示基因测序系统的基因测序反应平台的立体示意图。
图5是图4所示基因测序反应平台的进料装置的立体示意图。
图6是图5所示进料装置的分解示意图。
图7是图5所示进料装置的浸泡缓冲槽的立体示意图。
图8是图7所示浸泡缓冲槽的分解示意图。
图9是图4所示基因测序反应平台的浸泡反应装置的立体示意图。
图10是图9所示浸泡反应装置的其中一浸泡反应区的立体示意图。
图11是图10所示浸泡反应区的部分分解示意图。
图12是图9所示浸泡反应装置的另一浸泡反应区的立体示意图。
图13是图12所示浸泡反应区内部分浸泡反应槽组件的立体示意图。
图14是图12所示浸泡反应区内另一部分浸泡反应槽组件的立体示意图。
图15是图9所示浸泡反应装置的升降装置的立体示意图。
图16是图15所示升降装置的分解示意图。
图17是图4所示基因测序反应平台的浸泡移载装置的立体示意图。
图18是图17所示浸泡移载装置的立体示意图。
图19是图18所示浸泡移载装置的夹持组件的立体示意图。
图20是图4所示基因测序反应平台的出料装置的立体示意图。
图21是图20所示出料装置的分解示意图。
图22是图1所示基因测序系统的转移装置的立体示意图。
图23是图22所示转移装置的双夹持组件的立体示意图。
图24是图4所示基因测序反应平台上的识别装置的立体示意图。
图25是图4所示基因测序反应平台上的洁净装置的立体示意图。
图26是图4所示基因测序反应平台上的回收装置的立体示意图。
图27是本发明一实施方式的基因测序控制系统的硬体架构图。
如下具体实施方式将结合上述附图进一步说明本发明。
主要元件符号说明
Figure PCTCN2018117172-appb-000001
Figure PCTCN2018117172-appb-000002
Figure PCTCN2018117172-appb-000003
具体实施方式
本发明实施方式提供一种基因测序反应平台，所述基因测序反应平台包括浸泡反应装置，所述浸泡反应装置包括至少一个浸泡反应区，所述浸泡反应区内设置可卸式浸泡反应槽，每一所述浸泡反应槽用于盛放基因测序反应的化学试剂并用于将表面具有DNA样品加载结构且已加载有DNA样品的测序芯片浸泡于所述化学试剂中进行基因测序反应。
本发明实施方式还提供一种基因测序系统，所述基因测序系统包括上述的基因测序反应平台、成像检测装置、转移装置及控制平台，其中基因测序反应平台、成像检测装置及转移装置均受控制平台的控制，基因测序反应平台在控制平台的控制下完成至少一测序芯片的基因测序反应流程，转移装置在控制平台的控制下将已完成基因测序反应流程的测序芯片转移至成像检测装置，成像检测装置在控制平台的控制下完成对测序芯片的成像检测分析。
本发明还提供一种配合上述基因测序反应平台或者基因测序系统使用的测序芯片，所述测序芯片采用无封装形式，所述测序芯片包括硅片，所述硅片至少一面用于装载DNA样品，所述硅片一端设置手柄，所述手柄供夹持以实现测序过程中所述测序芯片的取放。
本发明实施方式还提供一种基因测序反应方法，包括：在一浸泡反应槽内加入基因测序反应用的化学试剂并将所述浸泡反应槽置于一浸泡反应区内；控制所述浸泡反应区的温度以将所述浸泡反应槽内化学试剂的温度控制在所需的温度；将表面具有DNA加载结构并加载有DNA样品的测序 芯片一次一个轮流浸泡于所述化学试剂预定时候后取出。
进一步地，所述基因测序反应方法还包括：在不同浸泡反应槽内加入不同的基因测序反应用的化学试剂，并将所述不同浸泡反应槽根据反应所需温度置于相同或不同的浸泡反应区；及将其中至少一测序芯片依次在两或多个所述浸泡反应槽内分别浸泡预定时间。
本发明实施方式还提供一种基因测序控制系统，包括控制平台与多个感测单元，每一感测单元用于感测一对应浸泡反应槽内是否放置有测序芯片，并将感测信号发送给所述控制平台，控制平台根据每一感测单元发送的感测信号以及预设程序，控制一移载装置将测序芯片按顺序置入与移出浸泡反应槽。
本发明实施方式还提供一种基因测序控制方法，包括：接收感测单元感测对应浸泡反应槽内是否放置有测序芯片的感测信号；根据接收的感测信号及一预设程序，控制移载装置将测序芯片按顺序置入与移出浸泡反应槽；及控制每一测序芯片在对应浸泡反应槽内停留的时间。
以上是本发明基因测序反应平台、方法及系统的核心思想。以下将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
需要说明的是，当组件被称为“固定于”、“安装于”另一个组件，它可以直接在另一个组件上或者也可以存在居中的组件。当一个组件被认为是“设置于”另一个组件，它可以是直接设置在另一个组件上或者可能同时存在居中组件。本文所使用的术语“及/或”包括一个或多个相关的所列项目的所有的和任意的组合。
请参阅图1所示，为本发明一实施方式中的基因测序系统的立体示意图。所述基因测序系统1000包括基因测序反应平台100、成像检测装置200、转移装置300、及控制平台400。其中基因测序反应平台100用于供测序芯 片上的DNA样品(在本实施方式中为DNA纳米球，简称“DNB”)进行基因测序前的化学反应；成像检测装置200用于对已完成基因测序反应流程的测序芯片进行成像检测及图像分析，转移装置300用于将测序芯片在基因测序反应平台100与成像检测装置200之间进行转移，以使测序芯片顺利完成基因测序的整个过程，控制平台400用于控制测序芯片在基因测序反应平台100及成像检测装置200上的作业过程及测序芯片在上述装置之间的转移。
请同时参阅图4所示，在本实施方式中，所述基因测序系统1000还包括识别装置500、洁净装置600与回收装置700，其中识别装置500用于识别每一测序芯片的ID；洁净装置600用于在测序芯片完成基因测序反应流程后、进入成像检测装置前，清理测序芯片携带的液体；回收装置700用于回收完成所有测序流程的测序芯片，以及在测序流程中出现异常的测序芯片。识别装置500、洁净装置600和回收装置700均整合于基因测序反应平台100上，进一步地，识别装置500与洁净装置600均设置于基因测序反应平台100出料一端，测序芯片在基因测序反应平台100完成测序反应后，由识别装置500识别测序芯片的ID，之后被转移装置300转移至洁净装置600清理携带液体。其他实施方式中，识别装置500、洁净装置600与回收装置700亦可与基因测序反应平台100分开设置。
请参阅图2与图3所示，为一配合基因测序系统1000使用的测序芯片。在本实施方式中，测序芯片900为一无封装芯片，包括主体910及设置于主体910上、作为测序芯片900被夹持部位的手柄920。所述主体910为硅片911，所述硅片911包括正面912及与正面912相背的背面913。其中，正面912用于装载DNA样品，所述手柄920凸出设置于正面912上。具体地，所述手柄920设置于正面912的一端。所述背面913覆盖疏水材质930，具体地，所述疏水材质930可以是疏水膜。
所述手柄920用于供夹持以实现测序过程中测序芯片900的取放与转移，例如，所述手柄920可供转移装置300及基因测序浸泡移载装置150 夹持以将测序芯片900在不同装置之间进行取放与转移。所述手柄920包括连接部921与夹持部922，其中，连接部921用于与主体910进行连接，在本实施方式中，连接部921通过胶体940粘贴至主体910。夹持部922固定于连接部921背向于主体910的一侧，其中夹持部922可以通过一体成型或者借助连接件如胶体或螺钉之类固定于连接部921上。夹持部922背向连接部921的一侧粘贴了测序芯片900的ID信息片923，所述ID信息片923上以条码、二维码或其他合适的表现方式呈现测序芯片900的ID，所述ID为测序芯片900的独有编码，用于在测序过程中的芯片属性判定。进一步地，在本实施方式中，夹持部922背向连接部921的一侧设置了一沉台924，测序芯片900的ID信息片923粘贴于所述沉台924上。在夹持部922位于ID信息片923的相对两端对称设置了两凹部925，每一凹部925从所在的一端朝向另一凹部925所在的一端凹陷，从而方便其他装置如转移装置300或人手夹持测序芯片900进行取放与转移。在本实施方式中，所述凹部925呈燕尾槽状。
可以理解，在其他实施方式中，所述硅片911的正面912与背面913均可用于装载DNA样品，所述手柄920凸出设置于正面912或背面913上。
请参阅图4所示，所述基因测序反应平台100包括主架构平台110、进料装置120、浸泡反应装置130、出料装置140及浸泡移载装置150。其中主架构平台110用于布置进料装置120、浸泡反应装置130、出料装置140、浸泡移载装置150、识别装置500、洁净装置600及回收装置700，主架构平台110包括下机架111、设置于下机架111上方的主平台112、设置于主平台112上的上机架113、及设置于上机架113上的顶平台114。在本实施方式中，进料装置120与出料装置140大致并列设置于主平台112的前端，浸泡反应装置130设置于主平台112的后端，进料装置120、出料装置140与浸泡反应装置130三者大致呈“品”字排布。识别装置500与洁净装置600设置于主平台112上出料装置140所在一侧，回收装置700 设置于主平台112上进料装置120所在一侧。浸泡移载装置150悬吊于顶平台114上、朝向浸泡反应装置130设置。测序芯片经进料装置120进入基因测序反应平台100，再经由浸泡移载装置150移载至浸泡反应装置130进行测序反应，完成测序反应后再经由浸泡移载装置150移载至出料装置140，在出料装置140所在位置，测序芯片同时由识别装置500识别ID，之后被转移装置300转移至洁净装置600清理携带的液体，最后经由转移装置300转移至成像检测装置200进行成像检测，以完成整个基因测序过程。
请参阅图5与图6所示，进料装置120包括动力源121、由动力源121驱动的进料传输机构122、由进料传输机构122带动的进料模块123。所述进料模块123上设置多个浸泡缓冲槽1231，每一浸泡缓冲槽1231内盛放基因测序反应进行前保持测序芯片上DNA样品活性的化学缓冲液。在控制平台400的控制下，动力源121驱动进料传输机构122，使进料传输机构122带动进料模块123移动，从而使进料模块123在一上料位置与一移载位置往复移动，在所述上料位置，一或多个测序芯片被对应加载至一或多个浸泡缓冲槽1231内，每一浸泡缓冲槽1231内加载一个测序芯片；在所述移载位置，一或多个测序芯片被移载至浸泡反应装置130内。
具体地，在本实施方式中，进料模块123还包括安装座1232、护罩1233及多个检测开关1234。安装座1232固定于进料传输机构122上，由进料传输机构122带动在上料位置与移载位置之间移动。护罩1233安装于安装座1232上，与安装座1232之间形成一用于安装多个浸泡缓冲槽1231的安装空间1235，护罩1233上方开设多个开口1236，每一开口1236均与安装空间1235连通且与其中的一浸泡缓冲槽1231的开口1237相对设置，以使测序芯片可从该开口1236插入对应的浸泡缓冲槽1231。每一检测开关1234对应一浸泡缓冲槽1231设置，用于检测该浸泡缓冲槽1231内是否插入了测序芯片。进一步地，在本实施方式中，浸泡缓冲槽1231以阵列的方式安装于安装座1232上，检测开关1234对应阵列安装在护罩1233上。在其他 实施方式中，浸泡缓冲槽1231也可安装在护罩1233上。
请参阅图7与图8所示，在本实施方式中，每一浸泡缓冲槽1231包括主槽体1231a、盖板1231b、密封条1231c及管接头1231d。主槽体1231a与盖板1231b的材质为聚醚醚酮。盖板1231b通过螺钉或其他连接件锁紧至主槽体1231a上，形成一端开口的槽，密封条1231c设置于主槽体1231a与盖板1231b连接的部位。每一浸泡缓冲槽1231靠近底部位置设置两个通孔1231e，每一通孔1231e连接一管接头1231d，用于注液与抽液。采用上述结构，每一浸泡缓冲槽1231具有可替换性、密封性，且其底部出液形式可使其内部液体容易抽干。此外，通过在进料装置120上设置多个浸泡缓冲槽1231，浸泡缓冲槽1231内盛放保持测序芯片上DNA样品活性的化学缓冲液，不仅易于保持DNA样品活性，且同时便于多个测序芯片进入测序反应流程前进行排队缓冲。
请参阅图9所示，浸泡反应装置130包括至少一浸泡反应区，所述浸泡反应区内设置可卸式浸泡反应槽，每一浸泡反应槽用于盛放基因测序反应的化学试剂，以使表面加载有DNA样品的测序芯片可浸泡于所述化学试剂中进行基因测序反应。在本实施方式，所述浸泡反应区的数量为五个，包括三个小浸泡反应区131与两个大浸泡反应区132。大小浸泡反应区131、132环绕一升降装置133设置。
每一浸泡反应区用于容置一或多个可卸式浸泡反应槽134，其中大浸泡反应区132与小浸泡反应区131的不同主要在于可容置的浸泡反应槽134的数量不同。在本实施方式中，小浸泡反应区131可容置三个浸泡反应槽134，而大浸泡反应区132可容置多于三个的浸泡反应槽134。
请参阅图10与图11，每一小浸泡反应区131包括浸泡反应槽134、连接件1312、检测支架1313、传感器1314及加热保温装置1315。三个浸泡反应槽134槽口向上、并列且可卸地连接至连接件1312上，检测支架1313设置于浸泡反应槽134上方，三个传感器1314固定于检测支架1313上，每一传感器1314正对一浸泡反应槽134槽口上方，以检测该浸泡反应槽 134中是否插入测序芯片。检测支架1313一端固定至连接件1312上，连接件1312再固定至升降装置133上。在本实施方式中，传感器1314为U型传感器，所述U型传感器大致环绕浸泡反应槽134槽口上方设置。U型传感器的一个支脚发出感测信号，另一相对的支脚接收感测信号，当浸泡反应槽134中插入了测序芯片时，测序芯片阻挡感测信号，使另一支脚无法接收到感测信号，因此传感器1314能感测浸泡反应槽134内是否插入测序芯片。
加热保温装置1315包括水浴锅1316与温度控制部(图未示)，水浴锅用于盛放能够传热的液体，所述浸泡反应槽134悬于水浴锅1316中，所述温度控制部在控制平台400或其他控制部件的控制下控制水浴锅内的液体温度，以控制浸泡反应槽内化学试剂的温度。进一步地，加热保温装置1315还包括检测水浴锅1316内液位高低的高位检测器(图未示)与低位检测器(图未示)，高位检测器用于自动注液时高度达到高位检测器时停止注液和液位低于高位检测器时自动补液，低位检测器用于加热时液位过低时停止加热。
请参阅图12-14，每一大浸泡反应区132包括浸泡反应槽134(图中示出了三个)、连接件1322与1323、检测支架1324与1325、传感器1326与1327、及加热保温装置1328。其中两个浸泡反应槽134槽口向上、并列且可卸地连接至连接件1322上，检测支架1324设置于浸泡反应槽134上方，两个传感器1326固定于检测支架1324上，检测支架1324再连接至连接件1322上、由连接件1322连接至升降装置133。另一浸泡反应槽134槽口向上、可卸式连接至连接件1323上，连接件1323再连接至升降装置133。检测支架1325固定于浸泡反应槽134上。需说明的是，无论是小浸泡反应区131还是大浸泡反应区132内连接件、检测支架、传感器的设置均可依实际需要作出不同变化，例如，一个连接件也可固定多于三个的浸泡反应槽，一个检测支架可以根据需要固定多于三个的传感器，检测支架可以连接至连接件上，也可以固定至浸泡反应槽上。另外，每一浸泡反应 区的大小以及浸泡反应区内的浸泡反应槽的数量也可根据实际需要设置，例如，当不同浸泡反应槽内化学试剂需要的温度相同时，可将所需温度相同的浸泡反应槽放置于同一浸泡反应区内。同一浸泡反应区内的浸泡反应槽可以盛放相同的化学试剂、也可盛放不同的化学试剂，只要该浸泡反应区可提供浸泡反应槽内化学试剂所需的温度即可。不同浸泡反应区的浸泡反应槽可以盛放相同的化学试剂、也可盛放不同的化学试剂，总之一句话，只需浸泡反应区能提供位于该浸泡反应区内的所有浸泡反应槽内的化学试剂所需的温度即可。
大浸泡反应区132内加热保温装置1328的设置与小浸泡反应区131内加热保温装置1315相同或类似，或者采用其他习知的手段，在此不作介绍。
浸泡反应槽134的结构与浸泡缓冲槽1231的结构大体相同或类似，在此不作介绍。
请参阅图15与图16所示，升降装置133为一升降平台，包括升降底座1331、固定于升降底座1331上的滑块基座1332、与滑块基座1332配合的升降滑轨板1333、及设于升降滑轨板1333上端的顶板1334。滑块基座1332上固定两个滑块1332a，两个滑块1332a上固定一块升降滑轨板1333，从而形成一个顶板1334可相对升降底座1331自由滑动的结构。顶板1334上固定四个调平螺杆1335，用于调节顶板1334与升降底座1331相互平行。升降底座1331上固定一动力源1336(如气缸)，动力源1336端部连接浮动接头1337，浮动接头1337与一连接板1338固定，连接板1338与顶板1334连接。动力源1336通过浮动接头1337推动或拉动顶板1334上下移动，从而实现升降装置133的升降。浸泡反应槽134通过对应的连接件连接至升降装置133上，升降装置133的上升带动浸泡反应槽134的上升、使浸泡反应槽134离开对应的水浴锅，从而便于用户卸下浸泡反应槽134或者连接新的浸泡反应槽134至连接件。而在升降装置133下降时，连接于连接件的浸泡反应槽134又可置入对应的水浴锅内。需说明的是，以上仅例举了升降装置133的一种具体结构，然升降装置133实现升降可以有 很多种方式或变形，例如，通过驱动滑轨滑块相对移动使升降装置133上升下降，滑轨滑块的数量可以是一或者三之类，这些方式在此并不一一例举。另外，升降装置133的顶板1334也并不限于方形结构，其可以是U形、弓形、工字形结构等等，无论顶板1334为何种形状，仅需升降装置133边沿部位(具体为顶板1334侧边)靠近或置于浸泡反应区上方，使浸泡反应槽一端能可卸式固定至升降装置133即可。此外，顶板1334上也可以开口，部分或全部浸泡反应区也可对应顶板1334开口边缘设置。
请参阅图17-19所示，浸泡移载装置150安装于主架构平台110的顶平台114上、包括四轴机器人151以及置于四轴机器人151运动终端的夹持组件152。四轴机器人151为测序芯片提供垂直及水平方向的运动。
在本实施方式中，四轴机器人151为三台，分别为四轴机器人151a、151b、151c，其中四轴机器人151a将测序芯片从进料装置120移转至浸泡反应槽134，四轴机器人151a、151b、151c可将测序芯片在各浸泡反应槽134中移转，四轴机器人151c将测序芯片从浸泡反应槽134中移转至出料装置140。夹持组件152包括固定于四轴机器人151运动终端的夹具座1521，所述夹具座1521与一气爪安装板1522相连，所述气爪安装板1522上安装有平行开闭气缸1523，所述平行开闭气缸1523上安装有左夹手1524和右夹手1525。在平行开闭气缸1523闭合时，带动左夹手1524和右夹手1525平行相向运动以夹持测序芯片。平行开闭气缸1523上还固定有限位架1526，限位架1526上固定有限位块1527，用于限制平行开闭气缸1523打开时，左夹手1524和右夹手1525张开的宽度。当然，需说明的是，所述四轴机器人151的数量、采用机器人的运动自由度、每一机器人的运行区域与轨迹以及夹持组件152的结构还可有各种变形，在此不再一一列举。
请参阅图20与图21所示，出料装置140用于存储通过浸泡反应的测序芯片，供转移装置300转移至其他装置，例如洁净装置600。出料装置140包括动力源141、由动力源141驱动的出料传输机构142、由出料传输机构142带动的出料模块143。所述出料模块143上设置多个浸泡缓冲槽1431，每一浸泡缓冲槽1431内盛放基因测序反应进行后保持测序芯片上DNA样品活性的化学缓冲液。在控制平台400的控制下，动力源141驱动 出料传输机构142，使出料传输机构142带动出料模块143移动，从而使出料模块143在一下料位置与一转移位置往复移动，在所述下料位置，一或多个测序芯片被从浸泡反应槽134移出并对应加载至一或多个浸泡缓冲槽1431内，每一浸泡缓冲槽1431内加载一个测序芯片；在所述转移位置，一或多个测序芯片被转移装置300依次转移至其他装置，例如，被逐一转移至洁净装置600清理测序芯片携带的液体。
具体地，在本实施方式中，出料模块143还包括安装座1432、护罩1433、多个检测开关1434及开关支架1435。安装座1432固定于出料传输机构142上，由出料传输机构142带动在下料位置与转移位置之间移动。护罩1433安装于安装座1432上，与安装座1432之间形成一用于安装多个浸泡缓冲槽1431的安装空间1436，护罩1433上方开设多个开口1437，每一开口1437均与安装空间1436连通且与其中的一浸泡缓冲槽1431的开口1438相对设置，以使测序芯片可从该开口1437插入对应的浸泡缓冲槽1431。检测开关1434安装于开关支架1435上，再由开关支架1435安装至安装座1432上。每一检测开关1434对应一浸泡缓冲槽1431设置，用于检测该浸泡缓冲槽1431内是否插入了测序芯片。进一步地，在本实施方式中，浸泡缓冲槽1431以阵列的方式安装于安装座1432上，检测开关1434经由开关支架1435对应阵列安装在安装座1432上。在其他实施方式中，浸泡缓冲槽1431与开关支架1435也可安装在护罩1433上。
浸泡缓冲槽1431的结构与浸泡缓冲槽1231的结构大体相同或类似，在此不作介绍。
请参阅图22与图23所示，转移装置300用于取得、携带以及释放测序芯片。在本实施方式中，转移装置300包括六轴机器人310、机器人安装座320及双夹持组件330。机器人安装座320固定于一安装面如地面上，六轴机器人310安装于机器人安装座320上，双夹持组件330固定于六轴机器人310的运动终端。双夹持组件330包括固定于六轴机器人310运动终端的安装板331，安装板331的两端各固定一个平行开闭气缸332，平行开闭气缸332上安装有左夹手333和右夹手334。在平行开闭气缸332闭合时，带动左夹手333和右夹手 334平行相向运动以夹持测序芯片。平行开闭气缸332上还固定有限位架335，限位架335上固定有限位块336，用于限制平行开闭气缸332打开时，左夹手333和右夹手334张开的宽度。左夹手333及对应的平行开闭气缸332、限位架335、限位块336构成一夹持组件，右夹手334及对应的平行开闭气缸332、限位架335、限位块336构成另一夹持组件。设置双夹持组件330，双夹持组件330的每一夹持组件用于夹持一测序芯片，在控制平台400的控制下，其中一夹持组件从成像检测装置移出已完成成像检测的测序芯片，另一夹持组件随即将待进行成像检测的测序芯片移入所述成像检测装置中，从而节约了转移装置300的作业流程与作业时间，提高了作业效率。当然，还需说明，所述六轴机器人310的数量、采用机器人的运动自由度以及双夹持组件330的结构还可有各种变形，在此不再一一列举。
请参阅图24所示，识别装置500通过扫码器扫描测序芯片正面的ID信息片，识别测序芯片的ID。在本实施方式中，识别装置500固定于出料装置140附近。识别装置500包括底座510、多向调节连杆520、扫码器530及扫码器安装座540。扫码器与扫码器安装座540固定后与多向调节连杆520尾端相连，多向调节连杆520与底座510固定，组成识别装置500。
请参阅图25所示，洁净装置600包括洁净底板610、水槽620、吸水海绵630、海绵压板640、气刀650及气刀安装架660。水槽620安装于洁净底板610上，吸水海绵630通过海绵压板640将水槽620的上方与后方覆盖，气刀650安装于气刀安装架660上，气刀安装架660安装于水槽620上。气刀650通过通入压缩空气可吹出一道薄气帘，可将测序芯片背面的液体清理干净。所述吸水海绵630可在吹气时疏解气流，粘粘飞溅的微小液滴。
请参阅图26所示，回收装置700用于回收完成所有测序流程的测序芯片，以及在测序流程中出现异常的测序芯片。回收装置700包括回收槽安装架710，以及安装于回收槽安装架710上的多个浸泡缓冲槽720，和对应数量的检测开关730和开关支架740。检测开关730安装于开关支架740上，开关支架740固定于回收槽安装架710上，用于对浸泡缓冲槽720内的测序芯片进行检测。
以下集中对上述各个装置的功能及其执行的方法进行说明。
首先将测序芯片加载至进料装置120，由于进料装置120具有多个浸泡缓 冲槽1231，每一浸泡缓冲槽1231用于浸泡一个测序芯片，因此每次可以加载一或多个测序芯片至进料装置120。每一浸泡缓冲槽1231对应设置了检测开关1234，每一检测开关1234均与控制平台400相连，以使控制平台400获知进料装置120内每一浸泡缓冲槽1231内测序芯片的加载情况。在本实施方式中，控制平台400可包括主控电脑、显示器、键盘、鼠标、触摸屏及局域网交换机等，控制平台400用于基因测序整个流程的控制及操作。请参阅图27所示，控制平台400与多个感测单元A构成基因测序控制系统2000或基因测序控制系统2000的一部分，所述感测单元A包括检测开关1234、1434、730与传感器1314、1326、1327等。检测开关1234、1434、730与传感器1314、1326、1327分别感测各自对应的浸泡缓冲槽1231、1431及浸泡反应槽134中是否加载了测序芯片，控制平台400根据检测开关1234、1434、730与传感器1314、1326、1327发送的感测信号以及预设程序，控制测序芯片置入与移出浸泡缓冲槽1231与1431、置入与移出浸泡反应槽134、控制浸泡反应的时间、控制在不同浸泡反应槽134反应的顺序等等。
具体地，在进料装置120完成测序芯片的加载后，控制平台400启动自运行模式完成测序芯片的至少一轮测序。其中，进料装置120完成测序芯片的加载，“完成”的意思可以是所有浸泡缓冲槽1231均加载测序芯片，也可以是部分浸泡缓冲槽1231加载测序芯片，控制平台400根据预定的规则或信号获知进料装置120内的测序芯片加载完成情况。在进料装置120完成测序芯片的加载后，首先，控制平台400根据检测开关1234发送的感测信号控制进料装置120将其中一装载有测序芯片的浸泡缓冲槽1231从上料位置移动至移载位置(步骤一)，之后，在控制平台400的控制下，四轴机器人151a携带夹持组件152运动至该浸泡缓冲槽1231上方，夹持组件152下降并夹紧该浸泡缓冲槽1231内的测序芯片，之后将测序芯片提升至一定高度(步骤二)。控制平台400根据传感器1314、1326、1327发送的感测信号以及预设程序，控制四轴机器人151a水平运动至浸泡反应装置130中的其中一未加载测序芯片的浸泡反应槽134上方，之后控制夹持组件152下降将测序芯片插入该浸泡反应槽134(步骤三)，从而完成一次测序芯片进料。控制平台400根据预设程序控制测序芯片在浸泡反应槽134中浸泡设定反应时间(步骤四)，之后控制平台400控制四轴机器人151b运动至该浸泡反应槽134上方取得测序芯片，携带 至下一未加载测序芯片的浸泡反应槽134中后释放(步骤五)。控制平台400根据预设程序控制测序芯片在该浸泡反应槽134中浸泡设定反应时间(步骤六)，之后再依次控制测序芯片移载至设定的再下一个浸泡反应槽134(步骤七)。其中，一测序芯片在不同浸泡反应槽134中反应的顺序跟浸泡反应槽134所在位置无关，只跟测序芯片上DNA样品所需发生的化学反应的顺序相关。在所需浸泡反应流程均完成后，控制平台400最后根据检测开关1434的感测信号控制四轴机器人151c将测序芯片移载至出料装置140的其中一未加载测序芯片的浸泡缓冲槽1431中(步骤八)。控制平台400根据预定的规则或信号获知出料装置140内的测序芯片加载完成情况。在进料装置120完成测序芯片的加载后，控制平台400控制出料装置140将其中一装载有测序芯片的浸泡缓冲槽1431运行至转移位置(步骤九)。在本实施方式中，所述转移位置与所述识别装置500相对，在装载有测序芯片的浸泡缓冲槽1431运行至转移位置时，测序芯片的ID信息片923处于识别装置500的扫码器530的扫码范围内。因此，控制平台400控制识别装置500的扫码器530扫描测序芯片正面中央的ID信息片923并将测序芯片的ID反馈至控制平台400，以便控制平台400后续将该ID与成像检测结果进行关联(步骤十)。控制平台400识别测序芯片对应的成像检测装置中的光学平台，并在其空闲并准备好的情况下，控制六轴机器人310携带双夹持组件330运动至该浸泡缓冲槽1431上方并取得测序芯片(步骤十一)。控制平台400继续控制六轴机器人310携带测序芯片运动至洁净装置600内部(步骤十二)。控制平台400控制气刀650吹气以清理测序芯片携带的液体(步骤十三)。随后控制平台400控制六轴机器人310携带测序芯片放置至成像检测装置200中对应的光学平台上以完成成像检测(步骤十四)。在完成成像检测后，控制平台400控制转移装置300将测序芯片从光学平台取下并放置至进料装置120中未加载测序芯片的浸泡缓冲槽1231里，进行下一轮测序反应(步骤十五)。重复上述移载、识别、洁净、转移的过程，直至该测序芯片完成所有设定的测序反应次数和成像检测后，控制平台400控制六轴机器人310将测序芯片放置至回收装置700的浸泡缓冲槽720里(步骤十六)，完成该测序芯片的所有测序流程。
其中，在上述测序流程中，控制平台400还根据每一测序芯片在对应浸泡反应槽134内化学反应的类型控制对应浸泡反应槽134内化学试剂的 温度。
其中，识别装置500亦包含于基因测序控制系统2000中，识别装置500识别每一测序芯片的ID,控制平台400将一测序芯片的成像检测分析结果与该测序芯片的ID进行关联。
综上所述，本发明实施方式提供一种基因测序反应平台、测序芯片及相关方法、系统，通过将不同测序芯片轮流置入一浸泡反应槽中进行反应，解决了现有技术中试剂一次性使用、利用率低的问题，降低了测序成本。同时通过设置不同的浸泡反应槽，测序芯片在前一浸泡反应槽反应完成后，即可取出置入另一浸泡反应槽中进行反应，增加了测序反应效率，极大提高了测序通量。此外，还通过设定不同的浸泡反应区，每一浸泡反应区可放置多个浸泡反应槽，因此可供灵活选择、设定使用的试剂种类。
最后应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或等同替换，而不脱离本发明技术方案的精神和范围。

Claims (37)

  1. 一种基因测序反应平台，其特征在于，包括：浸泡反应装置，所述浸泡反应装置包括至少一个浸泡反应区，所述浸泡反应区内设置浸泡反应槽，每一所述浸泡反应槽用于盛放基因测序反应的化学试剂并用于将表面具有DNA样品加载结构且已加载有DNA样品的测序芯片浸泡于所述化学试剂中进行基因测序反应。
  2. 如权利要求1所述的基因测序反应平台，其特征在于，还包括加热保温装置，用于控制每一所述浸泡反应区内的温度。
  3. 如权利要求2所述的基因测序反应平台，其特征在于，所述加热保温装置包括温度控制部和至少一水浴锅，每一所述水浴锅对应设置于其中一所述浸泡反应区，每一所述水浴锅用于盛放能够传递热量的液体，所述一或多个浸泡反应槽放置于所述水浴锅中，所述温度控制部用于控制所述水浴锅内液体的温度，以此控制所述浸泡反应槽内化学试剂的温度。
  4. 如权利要求1所述的基因测序反应平台，其特征在于，还包括移载装置，用于将所述测序芯片移入或移出所述浸泡反应槽。
  5. 如权利要求4所述的基因测序反应平台，其特征在于，还包括进料装置，所述进料装置包括一或多个浸泡缓冲槽，每一所述浸泡缓冲槽用于盛放基因测序反应进行前保持所述测序芯片上DNA样品活性的化学缓冲液，所述移载装置还用于将所述测序芯片从其中一个所述浸泡缓冲槽移入其中一个所述浸泡反应槽。
  6. 如权利要求5所述的基因测序反应平台，其特征在于，所述进料装置还包括进料传输机构，所述进料传输机构用于在一上料位置与一移载位置之间移动，在所述上料位置，一或多 个所述测序芯片被对应加载至一或多个所述浸泡缓冲槽内；在所述移载位置，一或多个所述测序芯片被所述移载装置从所述浸泡缓冲槽对应移载至一或多个浸泡反应槽内。
  7. 如权利要求4所述的基因测序反应平台，其特征在于，还包括出料装置，所述出料装置包括一或多个浸泡缓冲槽，每一所述浸泡缓冲槽用于盛放基因测序反应进行后保持所述测序芯片上DNA样品活性的化学缓冲液，所述移载装置还用于将所述测序芯片从其中一个所述浸泡反应槽移入所述出料装置的其中一个所述浸泡缓冲槽内。
  8. 如权利要求7所述的基因测序反应平台，其特征在于，所述出料装置还包括出料传输机构，所述出料传输机构用于在一下料位置与一转移位置往复移动，在所述下料位置，一或多个所述测序芯片被所述移载装置从所述浸泡反应槽对应移载至一或多个浸泡缓冲槽内；在所述转移位置，一或多个所述测序芯片被逐一转移至其他装置。
  9. 如权利要求4所述的基因测序反应平台，其特征在于，同一浸泡反应区的至少两个浸泡反应槽盛放不同化学试剂，所述移载装置还用于将所述测序芯片在同一浸泡反应区的盛放不同化学试剂的浸泡反应槽之间移转，及/或，所述浸泡反应区的数量为至少两个，所述浸泡反应区彼此隔离、且每一浸泡反应区的温度可独立控制，所述移载装置还用于将所述测序芯片在不同浸泡反应区的浸泡反应槽之间移转。
  10. 如权利要求1所述的基因测序反应平台，其特征在于，还包括升降装置，所述升降装置相邻所述浸泡反应区设置，所述浸泡反应槽可卸式连接至所述升降装置，所述升降装置用于升降所述浸泡反应槽，以便将所述浸泡反应槽置入所述浸泡反应区或从所述浸泡反应区移出。
  11. 如权利要求10所述的基因测序反应平台，其特征在于，所述升降装置为升降平台，所述升降平台边沿部位靠近或置于所述浸泡反应区的上方，所述浸泡反应槽一端可卸式固定至所述升降平台。
  12. 如权利要求11所述的基因测序反应平台，其特征在于，所述浸泡反应区的数量为两或多个，所述两或多个浸泡反应区环绕所述升降平台设置。
  13. 一种基因测序系统，其特征在于，包括如权利要求1-12任一项所述的基因测序反应平台、成像检测装置、转移装置及控制平台，所述基因测序反应平台、成像检测装置及转移装置均受所述控制平台的控制，所述基因测序反应平台在所述控制平台的控制下完成至少一测序芯片的基因测序反应流程，所述转移装置在所述控制平台的控制下将所述测序芯片转移至所述成像检测装置，所述成像检测装置在所述控制平台的控制下完成对所述测序芯片的成像检测分析。
  14. 如权利要求13所述的基因测序系统，其特征在于，还包括识别装置用于识别所述测序芯片的ID，并将识别到的ID提供给所述控制平台。
  15. 如权利要求13所述的基因测序系统，其特征在于，还包括洁净装置用于在测序芯片转移至所述成像检测装置进行成像检测前，清理所述测序芯片携带的液体，所述转移装置还用于在所述控制平台的控制下，将所述测序芯片转移至所述洁净装置，并在完成清理后将所述测序芯片转移至所述成像检测装置。
  16. 如权利要求13所述的基因测序系统，其特征在于，所述转移装置运动终端设置双夹持组件，每一夹持组件用于夹持一测序芯片，在所述控制平台的控制下，其中一所述夹持组件 从所述成像检测装置移出已完成成像检测的测序芯片，另一所述夹持组件将待进行成像检测的测序芯片移入所述成像检测装置。
  17. 如权利要求13所述的基因测序系统，其特征在于，还包括回收装置，用于回收完成所有测序流程的测序芯片及/或异常的测序芯片，所述回收装置包括多个浸泡缓冲槽，每一所述浸泡缓冲槽用于盛放保持所述测序芯片上DNA样品活性的化学缓冲液，所述转移装置还用于在所述控制平台的控制下，将完成所有测序流程的测序芯片及/或异常的测序芯片转移至所述回收装置的浸泡缓冲槽内。
  18. 一种配合如权利要求1-12任一项所述的基因测序反应平台或者如权利要求14-17任一项所述的基因测序系统使用的测序芯片，其特征在于，所述测序芯片采用无封装形式，所述测序芯片包括硅片，所述硅片至少一面用于装载DNA样品，所述硅片一端设置手柄，所述手柄供夹持以实现测序过程中所述测序芯片的取放。
  19. 如权利要求18所述的测序芯片，其特征在于，所述手柄粘贴于所述硅片上用于装载DNA样品的一面。
  20. 如权利要求18所述的测序芯片，其特征在于，所述手柄相对的两端对称设置两凹部，每一凹部从所在的一端朝向另一凹部所在的一端凹陷。
  21. 如权利要求20所述的测序芯片，其特征在于，所述手柄上粘贴了所述测序芯片的ID信息片；及/或，所述手柄远离所述硅片的一面上粘贴了所述测序芯片的ID信息片；及/或，所述手柄远离所述硅片的一面上设有沉台，所述测序芯片的ID信息片粘贴于所述沉台上。
  22. 如权利要求18所述的测序芯片，其特征在于，所述硅片未 用于装载DNA样品的一面覆盖疏水材质，及/或所述硅片未用于装载DNA样品的一面覆盖疏水膜。
  23. 一种基因测序反应方法，其特征在于，包括：
    在一浸泡反应槽内加入基因测序反应用的化学试剂并将所述浸泡反应槽置于一浸泡反应区内；
    控制所述浸泡反应区的温度以将所述浸泡反应槽内化学试剂的温度控制在所需的温度；
    将表面具有DNA加载结构并加载有DNA样品的测序芯片一次一个轮流浸泡于所述化学试剂预定时候后取出。
  24. 如权利要求23所述的基因测序反应方法，其特征在于，还包括：
    在不同浸泡反应槽内加入不同的基因测序反应用的化学试剂，并将所述不同浸泡反应槽根据反应所需温度置于相同或不同的浸泡反应区；及
    将其中至少一测序芯片依次在两或多个所述浸泡反应槽内分别浸泡预定时间。
  25. 如权利要求23所述的基因测序反应方法，其特征在于，还包括：
    在一或多个浸泡缓冲槽内加入化学缓冲液，所述化学缓冲液用于在基因测序反应进行前保持所述测序芯片上DNA样品活性；
    将待进行测序反应的测序芯片对应置于所述浸泡缓冲槽内。
  26. 如权利要求25所述的基因测序反应方法，其特征在于，还包括：
    将浸泡缓冲槽传送至一移载位置，以便一移载装置依次将所述测序芯片移载至所述浸泡反应槽内。
  27. 如权利要求23所述的基因测序反应方法，其特征在于，还包括：
    在一或多个浸泡缓冲槽内加入化学缓冲液，所述化学缓冲液用于在基因测序反应进行前/后保持所述测序芯片上DNA样品活性；
    将已进行了测序反应的测序芯片取出后对应移载至所述浸泡缓冲槽内。
  28. 一种基因测序控制系统，其特征在于，包括：
    控制平台；
    多个感测单元，每一所述感测单元用于感测一对应浸泡反应槽内是否放置有测序芯片，并将感测信号发送给所述控制平台；
    其中，所述控制平台根据每一感测单元发送的感测信号以及运行的预设程序，控制至少一移载装置将测序芯片按顺序置入与移出浸泡反应槽。
  29. 如权利要求28所述的基因测序控制系统，其特征在于，所述控制平台还用于根据测序芯片在所述浸泡反应槽内化学反应的类型控制所述浸泡反应槽内化学试剂的温度。
  30. 如权利要求29所述的基因测序控制系统，其特征在于，所述控制平台还用于根据每一感测单元发送的感测信号以及预设程序，控制至少一测序芯片按顺序在不同浸泡反应槽内进行化学反应。
  31. 如权利要求28所述的基因测序控制系统，其特征在于，还包括识别装置，用于识别每一测序芯片的ID并将识别到的ID提供给所述控制平台；及所述控制平台还用于控制转移装置将已完成基因测序反应流程的测序芯片转移至成像检测装置进行成像检测分析，并将分析结果与对应ID进行关联。
  32. 如权利要求31所述的基因测序控制系统，其特征在于，所述控制平台还用于控制转移装置将已完成基因测序反应流程的测序芯片转移至洁净装置处清理所述测序芯片携带的液体，并在清理完成后将所述测序芯片移转至成像检测装置。
  33. 一种基因测序控制方法，其特征在于，包括：
    接收感测单元感测对应浸泡反应槽内是否放置有测序芯片的感测信号；
    根据接收的感测信号及运行的预设程序，控制移载装置将测序芯片按顺序置入与移出浸泡反应槽；及
    控制每一测序芯片在对应浸泡反应槽内停留的时间。
  34. 如权利要求33所述的基因测序控制方法，其特征在于，还包括：根据每一测序芯片在对应浸泡反应槽内化学反应的类型控制对应浸泡反应槽内化学试剂的温度。
  35. 如权利要求34所述的基因测序控制方法，其特征在于，还包括：控制至少一测序芯片按顺序在不同浸泡反应槽内进行化学反应。
  36. 如权利要求33所述的基因测序控制方法，其特征在于，还包括：
    接收识别装置识别的测序芯片的ID；
    控制转移装置将已完成一基因测序反应流程的测序芯片转移至成像检测装置进行成像检测分析，并将分析结果与对应ID进行关联。
  37. 如权利要求36所述的基因测序控制方法，其特征在于，还包括：控制转移装置将已完成基因测序反应流程的测序芯片转移至洁净装置处清理所述测序芯片携带的液体，并在清理完成后将所述测序芯片移转至成像检测装置。
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CN117660172A (zh) * 2023-12-01 2024-03-08 苏州拉索生物芯片科技有限公司 一种磁力搅拌式基因芯片杂交装置及其杂交方法
WO2025199703A1 (zh) * 2024-03-25 2025-10-02 深圳华大智造科技股份有限公司 基因测序系统、方法、设备及非易失性存储介质
CN118410823A (zh) * 2024-04-25 2024-07-30 温州豪格防伪科技有限公司 一种防伪二维码的生产工艺

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