WO2024027119A1 - 核酸测序系统及测序控制方法 - Google Patents

核酸测序系统及测序控制方法 Download PDF

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Publication number
WO2024027119A1
WO2024027119A1 PCT/CN2023/074795 CN2023074795W WO2024027119A1 WO 2024027119 A1 WO2024027119 A1 WO 2024027119A1 CN 2023074795 W CN2023074795 W CN 2023074795W WO 2024027119 A1 WO2024027119 A1 WO 2024027119A1
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WO
WIPO (PCT)
Prior art keywords
reaction
chip
reagent
liquid
nucleic acid
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PCT/CN2023/074795
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English (en)
French (fr)
Inventor
王谷丰
赵陆洋
Original Assignee
深圳赛陆医疗科技有限公司
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Publication of WO2024027119A1 publication Critical patent/WO2024027119A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6869—Methods for sequencing
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids

Definitions

  • the present application relates to the technical field of nucleic acid sequencing, and in particular to a nucleic acid sequencing system and a sequencing control method.
  • the biochemical reaction part is usually implemented using a microfluidic system, which mainly uses the power source, selection valve and pipeline to controllably flow the kit fluid through the fluid channel of the flow cell and combine it with the flow cell.
  • the nucleic acid chain to be sequenced connected to the flow cell substrate comes into contact to achieve a biochemical reaction.
  • This process requires a precise temperature control system and a closed fluid system to ensure the full progress of the entire biochemical reaction. It is costly and prone to uneven reactions. Problems affecting test results and low reagent utilization.
  • this application aims to solve at least one of the technical problems existing in the prior art. To this end, this application proposes a nucleic acid sequencing system that can adopt an open biochemical reaction method to realize the inlet and outlet of reagents and the movement of test chips, thereby facilitating the loading, reaction, detection and unloading of the chip. Helps improve detection efficiency. This application also proposes a sequencing control method.
  • the nucleic acid sequencing system includes a biochemical reaction device, a sample loading device, a detection device and a transfer device.
  • the biochemical reaction device includes a reaction container, a moving mechanism, a liquid inlet mechanism and a liquid discharge mechanism.
  • the reaction vessel is provided with a plurality of reagent tanks with openings, the reagent tanks are used to hold reagents and soak the chips to be tested, and the moving mechanism is used to transfer the chips between the set reagent tanks;
  • the liquid inlet mechanism is connected to the reagent tank and is used to transfer the set reagent to the set reagent.
  • the tank is filled with liquid, and the liquid discharge mechanism is connected to the reagent tank and is used to discharge the reagents in the reagent tank;
  • the sample loading device includes a feeding and discharging mechanism, and the feeding and discharging mechanism includes a number of bearing parts and moving mechanisms.
  • the carrier is used to carry a chip, and the moving mechanism is connected to the carrier and used to drive the carrier close to or away from the reaction vessel to inject or sample the chip;
  • the detection device is used to Receive the chip transferred from the biochemical reaction device and perform imaging detection and analysis on the chip; the transfer device is used to obtain the chip and use the chip to transfer the chip to the loading device, the biochemical reaction device or the detection device. transfer between devices.
  • the reaction container of the embodiment of the first aspect of the present application at least has the following beneficial effects: the biochemical reaction device realizes the open immersion of the chip, realizes the repeated practical use of reagents, and realizes the sample loading and unloading of the test chip into the biochemical reaction device through the loading device; As well as filling and draining the reagent tank, this can facilitate the perfusion of reagents before the reaction, the replenishment of the reagents during the reaction, and the discharge of the reagents after the entire sequencing is completed.
  • the detection device is used to collect chip pictures after the set biochemical reaction and Detection and analysis, in which the chip is transferred between the sample loading device, biochemical reaction device and detection device through a transfer device to ensure the continuity of reaction and testing.
  • the sample loading device, biochemical reaction device and detection device are connected by a transfer device.
  • the number of each device can be reasonably configured according to the specific rhythm.
  • the combination method is relatively flexible, so that the process or each device can be adjusted.
  • the addition, removal, and replacement of devices further develops the sequencing capabilities of the system without the need for overall system upgrades and iterations, thus saving costs.
  • the reaction container includes a supporting member and a plurality of reaction cells.
  • the plurality of reaction cells are arranged in a set manner and connected to the supporting member.
  • Each of the reaction cells The reagent tank is provided inside.
  • the reagent tank penetrates the top surface of the reaction tank to form the opening for the chip to enter and exit.
  • the wall of the reaction tank is provided with an inlet connected to the reagent tank.
  • the liquid inlet mechanism includes a liquid inlet assembly and a liquid inlet pipeline, each of the liquid inlet holes is connected to the liquid inlet pipeline respectively, and the liquid inlet assembly is used to remove the setting reagent, And the liquid is fed into the reagent tank through the set liquid inlet pipeline;
  • the liquid drainage mechanism includes a liquid drainage component and a liquid drainage pipeline, and each of the liquid outlet holes is connected to the liquid drainage pipeline respectively.
  • the drain assembly is used to drain the reagent in the reagent tank through the drain pipe.
  • At least part of the reaction pool is also provided with a first temperature control module for temperature control of the reagents in the corresponding reagent tank, so
  • the first temperature control module includes a temperature protection switch, and the temperature protection switch is used to limit the maximum temperature of the reagent tank.
  • the moving mechanism includes a moving component and a clamping component, the clamping component is suitable for holding the chip, and the moving mechanism is connected to the clamping component for The clamping assembly is driven to move relative to the reaction vessel to transfer the chip between the set reagent tanks.
  • a plurality of the reagent tanks are distributed in a set manner to form a plurality of reaction areas, and each of the reaction areas has a plurality of the reagent tanks, corresponding to
  • the moving mechanism is provided at each reaction zone.
  • Each moving mechanism is used to pick up, place and move the chip in the corresponding reaction zone.
  • the transfer mechanism can pick up and move the chip in each reaction zone. Place and move the chip.
  • the reaction vessel further includes a buffer area, the buffer area has a plurality of the reagent tanks, the buffer area is located between adjacent reaction areas, and adjacent
  • the moving mechanism can pick up, place and move the chip in the buffer area, and the transfer mechanism can pick up, place and move the chip in the buffer area.
  • the sample loading device further includes a storage mechanism, the storage mechanism includes several storage areas, the storage area is used to store reagents required for nucleic acid sequencing, and the liquid inlet mechanism also It includes a pipette, the pipette is connected to the liquid inlet component through the liquid inlet pipeline, and the pipette is used to obtain the reagents stored in the storage area.
  • the storage mechanism includes a first storage area and a second storage area, the first storage area is configured to store reagents at normal temperature, and the second storage area is provided with a second storage area.
  • Temperature control module the second temperature control module is used to maintain the temperature of the second storage area within a set temperature range so as to store reagents within the temperature range, and the temperature range is lower than normal temperature.
  • the detection device includes a picture acquisition platform and an image acquisition device.
  • the image acquisition platform is used to locate the chip removed from the biochemical reaction device.
  • the image acquisition device corresponds to the The image acquisition platform is configured to collect images from a chip placed on the image acquisition platform.
  • the detection device further includes a workstation configured with an image processing module.
  • the workstation is configured to receive images generated by the image collector and obtain nucleic acid sequence information through image processing module processing.
  • the acquisition platform includes an adsorption disc, a vacuum pipeline and a waste pipeline.
  • the vacuum pipeline is used to connect a vacuum air source and is connected to the adsorption disc.
  • the adsorption disc generates negative pressure to adsorb the chip, and the waste discharge pipeline is connected to a set position of the vacuum pipeline for collecting and removing waste liquid entering the vacuum pipeline from the adsorption disc.
  • the transfer device includes a walking mechanism and a robotic arm.
  • the walking mechanism is connected to the robotic arm and is used to carry and drive the robotic arm to move in a set direction.
  • the execution end of the robotic arm is provided with an end gripper for picking and placing chips; the walking mechanism and the robotic arm can drive the end gripper to move between the loading device, the biochemical reaction device and the detection device. Move between devices.
  • the end gripper includes a finger driving component and a finger.
  • the finger driving component is connected to the finger and is used to drive the finger to open or close; on the end gripper There are also grab sensors, release sensors and chip presence/absence sensors.
  • one or more of the detection devices are provided corresponding to one of the biochemical reaction devices.
  • the biochemical reaction device further includes a main control computer and a plurality of sensing units.
  • Each of the reagent tanks is provided with a sensing unit, and the sensing unit is used to sense corresponding Whether there is a chip contained in the reagent tank, and the sensing signal is sent to the main control machine; the main control machine can control the moving mechanism according to the sensing signal to pick up and move at least A chip.
  • the biochemical reaction device further includes a control box, which is communicatively connected to the liquid inlet component and used to control the liquid inlet operation of the liquid inlet component; the control box The box is also communicatively connected to the liquid drainage component and is used to control the liquid drainage operation of the liquid drainage component; the main control machine is also used to instruct the control box to control the liquid inlet component according to the set reagent tank status. Inlet liquid or control the drainage component to drain liquid.
  • the sampling device, the transfer device and the detection device are communicatively connected to the main control computer, and the main control computer is used to control the loading device to the chip.
  • Reaction and detection Detect whether there is a chip in the reagent tank and form a sensing signal. Sense the signal and control the moving mechanism according to the preset sequencing mode to move the chip to the corresponding reagent tank for immersion reaction, and control the transfer device to transfer the chip that has completed the set reaction process to the detection device for imaging detection;
  • Liquid inlet and drain Before reaction and detection, the liquid inlet mechanism is controlled to inject set reagents into multiple reagent tanks according to the preset program; during the reaction and detection process, the liquid inlet mechanism is controlled in response to the set reaction parameter signal. The liquid mechanism replenishes the liquid in the set reagent tank; after the reaction and detection are completed, the liquid discharge mechanism controls the liquid discharge mechanism to drain the reagent tank in response to the signal that the total number of chips has been processed.
  • the nucleic acid sequencing method of the second embodiment of the present application has at least the following beneficial effects: by perfusing reagents into multiple reagent tanks, biochemical reactions can be supported by soaking, and by moving the chip to a reagent tank such as During the immersion reaction, the same reagent tank can soak multiple chips one after another to realize the reuse of reagents. Moreover, by replenishing the corresponding reagent tank during the reaction and detection process, it can ensure the continuous progress of the biochemical reaction, and the chip can be continuously loaded and loaded. Soaking reaction and imaging detection can effectively improve reaction efficiency, thereby increasing sequencing throughput.
  • the sequencing mode includes: PCR process, one-strand sequencing process, BARCODE1 sequencing process, BARCODE2 sequencing process and two-strand sequencing process, where the PCR process precedes the other processes, and the one-strand sequencing process The sequencing process precedes the second-strand sequencing process.
  • the reaction parameter signal includes a quantity signal generated by counting the chip during the reaction and detection process, or a time signal generated by sensing the reaction time, or a time signal generated by sensing the reaction time.
  • the liquid level of the reagent tank is sensed to generate a liquid level signal.
  • the method further includes temperature control: controlling the temperature of the reagent tank containing the set reagent according to a preset program to adjust the reagent temperature required for the set immersion reaction. controlled within the required temperature range.
  • the method further includes chip loading and unloading: controlling the sample inlet and outlet mechanism according to the sensing signal and according to a preset program to drive the carrier close to the reaction vessel, and controlling the transfer device
  • the chip to be tested is transferred to the reaction vessel for loading, or the chip after the reaction and detection is completed is transferred to the carrier for unloading.
  • Figure 1 is a schematic structural diagram of a nucleic acid sequencing system according to an embodiment of the present application.
  • Figure 2 is a top view of the embodiment shown in Figure 1;
  • FIG. 3 is a schematic structural diagram of the biochemical reaction device in the embodiment of the present application.
  • Figure 4 is a schematic structural diagram of the reaction vessel in the embodiment of the present application.
  • Figure 5 is a top view of the reaction vessel according to the embodiment of the present application.
  • Figure 6 is a cross-sectional view of the A-A section in Figure 5;
  • Figure 7 is a cross-sectional view of the B-B section in Figure 5;
  • Figure 8 is an exploded schematic diagram of a reaction vessel in an embodiment of the present application.
  • Figure 9 is a schematic diagram of the connection between the liquid inlet mechanism and the liquid discharge mechanism in the embodiment of the present application.
  • Figure 10 is a partial connection diagram of the liquid inlet mechanism in the embodiment of the present application.
  • Figure 11 is a partial connection schematic diagram of the liquid drainage mechanism in the embodiment of the present application.
  • Figure 12 is a schematic connection diagram of another part of the liquid drainage mechanism in the embodiment of the present application.
  • Figure 13 is a simplified diagram of the reaction vessel in the embodiment of the present application.
  • Figure 14 is a schematic structural diagram of the sample loading device in the embodiment of the present application.
  • Figure 15 is a partial structural schematic diagram of the sample loading device in the embodiment of the present application.
  • Figure 16 is a top view of the sample loading device in the embodiment shown in Figure 14;
  • Figure 17 is a partial structural schematic diagram of the sample loading and unloading mechanism of the sample loading device in the embodiment of the present application.
  • Figure 18 is a schematic diagram of the sample loading device and biochemical reaction device in the embodiment of the present application.
  • Figure 19 is a schematic structural diagram of the detection device in the embodiment of the present application.
  • Figure 20 is a partial control schematic diagram of the image acquisition platform of the detection device
  • Figure 21 is a schematic structural diagram of the end gripper of the transfer device in the embodiment of the present application.
  • Figure 22 is the control principle diagram of the end gripper
  • Figure 23 is a schematic workflow diagram of the nucleic acid sequencing system according to the embodiment of the present application.
  • Figure 24 is a schematic diagram of a distribution scheme of the reagent tanks of the reaction vessel in the embodiment of the present application.
  • Figure 25 is a flow chart of the chip performing biochemical reactions in the reaction vessel
  • Figure 26 is a schematic flow chart of paired-end sequencing using the sequencing control method according to the embodiment of the present application.
  • Reaction vessel 100 Reaction vessel 100, reagent tank 101, liquid inlet hole 102, liquid outlet hole 103, supporting member 104, tray 105, side wall 106, reaction tank 107, installation part 108, liquid collecting tank 109, waste drain hole 110, installation port 111, reaction area 112, buffer area 113;
  • Liquid inlet mechanism 120 liquid inlet assembly 121, liquid inlet pipeline 122, liquid inlet pump 123, first control valve 124, second control valve 125;
  • Drainage mechanism 130 Drain assembly 131, drain pipeline 132, drain pump 133, third control valve 134, waste liquid container 135, waste liquid pump 136, waste liquid pipeline 137;
  • Moving mechanism 150 moving component 151, clamping component 152;
  • Rack 210 platform 211, cabinet 212, position sensor 213;
  • Image collector 310 image acquisition platform 320, adsorption disk 321, vacuum pipeline 322, waste discharge pipeline 323, isolation cavity 324, waste discharge pump 325, vacuum pump 326;
  • an open fluid system is used to realize an open biochemical reaction by repeatedly soaking the chip to be tested in a variety of reagents.
  • reagents are required, and the chip needs to be transferred among a variety of reagents to facilitate the corresponding reaction.
  • the reaction can reuse reagents, reducing sequencing costs, and the open reaction system can meet sequencing requirements and spatiotemporal omics research needs.
  • the current detection equipment adds reagents in a complicated manner, resulting in complicated operations. It is difficult to perfuse and replenish multiple reagents multiple times.
  • the embodiments of the present application provide a nucleic acid sequencing system and a sequencing control method that can adopt an open biochemical reaction method to realize the inlet and outlet of reagents and the transfer of test chips, thereby facilitating chip loading, reaction, and detection. and blanking, which helps to improve detection efficiency.
  • a nucleic acid sequencing system includes a biochemical reaction device 10, a sample loading device 20, a detection device 30 and a transfer device 40, where the biochemical reaction device 10 is used to provide chips with In the place of biochemical reaction, the sampling device 20 is used for chip inlet and outlet and reagent inlet and outlet.
  • the detection device 30 is used for receiving the chip transferred from the biochemical reaction device 10 and performing imaging detection and analysis on the chip.
  • the transfer device 40 is used to transfer the chip between the biochemical reaction device 10, the sample loading device 20 and the detection device 30 to realize the transfer of the chip in the entire sequencing process.
  • the biochemical reaction device 10 includes a reaction container 100, a moving mechanism 150, a liquid inlet mechanism 120 and a liquid discharge mechanism.
  • the reaction vessel 100 is provided with a plurality of reagent tanks 101 with openings, and the reagent tanks 101 are used for Hold the reagent and soak the chip to be tested to achieve open soaking of the chip.
  • the moving mechanism 150 is used to transfer the chip between the set reagent tanks 101.
  • the chip can perform corresponding biochemical reactions.
  • a single reagent tank 101 can soak multiple chips one after another to realize the repeated use of reagents.
  • the liquid feeding mechanism 120 is connected to the reagent tank 101 and is used to remove the set reagent and feed the liquid into the set reagent tank 101 .
  • the liquid discharge mechanism is connected to the reagent tank 101 and is used to discharge the reagents in the reagent tank 101 so that the reagent tank 101 can be filled and drained. This facilitates the perfusion of reagents before the reaction, the replenishment of the reagents during the reaction, and the discharge of the reagents after the entire sequencing is completed.
  • the sample loading device 20 includes a loading and unloading mechanism 220.
  • the loading and unloading mechanism 220 includes a number of carriers and a moving mechanism 150.
  • the carrier is used to carry chips.
  • the moving mechanism 150 is connected to the carrier and is used to drive the carrier. Move closer to or farther away from the reaction vessel 100 to inject or remove samples from the chip.
  • the sample loading device 20 is used to realize the sample loading and unloading of the test chip into the biochemical reaction device 10 to ensure the continuity of reaction and testing.
  • the transfer device 40 includes a walking mechanism 410 and a robotic arm 420.
  • the walking mechanism 410 is connected to the robotic arm 420 and is used to carry and drive the robotic arm 420 to move in a set direction.
  • the robotic arm The execution end of 420 is provided with an end gripper 430 for picking and placing chips; the traveling mechanism 410 and the mechanical arm 420 cooperate to drive the end gripper 430 to move between the sample loading device 20, the biochemical reaction device 10 and the detection device 30, thereby Carry out relevant operations, reactions or detections in each device to ensure the progress of the sequencing process.
  • each biochemical reaction device 10 can be provided with one or more detection devices 30 . What is shown in Figures 1 and 2 is that one biochemical reaction device 10 is provided with two detection devices 30 . plan.
  • the robot arm 420 can use a commonly used six-axis robot arm 420, and the walking mechanism 410 can use a commonly used linear motion mechanism, thereby expanding the movement space of the robot arm 420 and allowing the end gripper 430 to move within a wider range.
  • the walking mechanism 410 can also be omitted.
  • Each of the above devices can be placed in a symmetrical layout, for example, two detection devices 30 are configured.
  • the biochemical reaction device 10 and the sample loading device 20 are respectively disposed on both sides of the transfer device 40, and two detection devices 30 are symmetrically disposed on both sides of the transfer device 40 corresponding to the biochemical reaction device 10 and the sample loading device 20, respectively. Therefore, a movable channel is formed in the middle, and the transfer device 40 can drive the mechanical arm 420 to move in the channel through the walking mechanism 410, so as to reach the corresponding position of each device to facilitate the pick-up, placement and transfer of chips.
  • each reagent tank 101 of the reaction vessel 100 is connected with a liquid inlet 102 and a liquid outlet 103 respectively;
  • the liquid inlet mechanism 120 includes a liquid inlet assembly 121 and a liquid inlet pipeline 122.
  • Each liquid inlet hole 102 is connected to a liquid inlet pipe 122 respectively.
  • the liquid inlet assembly 121 is used to remove the set reagent and inject liquid into the reagent tank 101 through the set liquid inlet pipe 122 .
  • the drain mechanism includes a drain assembly and a drain pipeline. Each outlet hole 103 is connected to the drain pipeline respectively. The drain assembly is used to drain the reagent in the reagent tank 101 through the drain pipeline.
  • the reagent tank 101 can be filled and drained through the liquid inlet hole 102, the liquid outlet hole 103, the liquid inlet mechanism 120 and the liquid discharge mechanism, thereby facilitating the filling, replenishing and updating of reagents, and facilitating the chip to be soaked for multiple times.
  • the continuous operation helps to improve the reaction efficiency, thereby improving the efficiency of nucleic acid sequencing.
  • the sequencing system has a certain degree of flexibility. It can adjust the tempo of chip loading and immersion and unloading after immersion as needed, and configure the working tempo of the front and back processes accordingly. For example, the number of sample loading devices 20 can be adjusted. Injection operations, sample extraction operations, etc., as well as adjusting the number of matching detection devices 30, detection time, etc., form a system that supports a variety of flexible combination solutions, which is convenient for further exploring the sequencing efficiency of the sequencing system, and is easy to adjust without the need for overall upgrades and iterations. This saves upgrade costs.
  • the biochemical reaction device 10 further includes a moving mechanism 150, wherein the moving mechanism 150 includes a moving component 151 and a clamping component 152.
  • the clamping component 152 is suitable for holding the chip, and the moving mechanism 150 is connected to the clamping component 152, and is used to drive the clamping component 152 to move relative to the reaction vessel 100 to be placed in the set reagent tank 101 for soaking.
  • the movement of the chip between different reagent tanks 101 is realized through the moving mechanism 150, so as to facilitate the continuous immersion operation of the chip for multiple times, which helps to improve the reaction efficiency and thereby improve the efficiency of nucleic acid sequencing.
  • the moving component 151 can be implemented by a multi-axis manipulator commonly used in mechanical equipment.
  • the clamping component 152 can be a cylinder-driven gripper, including two fingers and a cylinder.
  • the cylinder drives the fingers to move toward or away from each other to close or open. Capable of capturing and releasing chips.
  • the clamping component 152 can also be provided with multiple Sensors include grab sensors, release sensors and chip presence/absence detection sensors.
  • the grasp sensor is used to sense whether the two fingers are closed correctly. This detection can be achieved by a distance sensor or a photoelectric sensor set in the closed position.
  • the release sensor is used to sense whether two fingers are opened correctly. This detection can be achieved by a distance sensor or a photoelectric sensor set in the open position.
  • the chip presence/absence detection sensor is used to sense whether there is a chip in the corresponding position of the gripper when starting to grasp, and is used to sense whether the chip is held on the gripper during the transfer process, and is used to sense whether the gripper is released. Whether there is a chip on the chip, this ensures that the chip can be grasped smoothly before grabbing, that the chip can be identified when grabbing, and that the chip can be released smoothly after release.
  • Chip detection can be achieved through contact or non-contact sensors. Multiple sensors realize related detection of chip picking and transfer operations, thereby improving the safety of operations, facilitating the identification of abnormal situations, and improving the efficiency of chip grabbing and transfer.
  • the biochemical reaction device 10 may also include a main control computer 50 and a plurality of sensing units.
  • Each reagent tank 101 is provided with a sensing unit, and the sensing unit is used to sense the corresponding reagent tank 101 Whether there is a chip inside, and the sensing signal is sent to the main control computer 50;
  • the main control computer 50 is communicatively connected to the moving mechanism 150, and is used to control the moving operation of the moving component 151 on the clamping component 152 and control the clamping component 152 Pick and place operations on chips.
  • the main control computer 50 can control the moving mechanism 150 to pick up, place and move at least one chip according to the set program according to the sensing signal.
  • the setting program can set the order and soaking time for each chip to soak in different types of reagents, etc., and an identification code can be set on the chip, and the reading module can read the identification code to obtain the sample information of each chip, thereby Chip soaking and transfer are performed through preset programs.
  • the main control computer 50 is a feedback loop component widely used in industrial control applications, such as a programmable memory, which stores instructions for performing logical operations, sequence control, timing, counting and arithmetic operations, etc., through digital or Analog input and output to control various types of mechanical equipment or production processes. It can be seen from this that the embodiment of the present application implements the moving operation of the moving component 151 on the clamping component 152 and controls the picking and placing operations of the clamping component 152 on the chip through setting programs and sensing signals.
  • the controller function can be easily realized, and its principle and control method will not be described in detail here.
  • the reaction vessel 100 can adopt an integrated structure or a split structure formed by multiple structural components.
  • the reagent tank 101, the liquid inlet hole 102 and the liquid outlet hole 103 can be implemented in a variety of ways.
  • the reaction vessel 100 includes a supporting member 104 and a plurality of reaction cells 107.
  • the plurality of reaction cells 107 are arranged in a set manner and connected to
  • the supporting member 104 has a reagent tank 101 inside each reaction tank 107.
  • the reagent tank 101 penetrates the reaction tank 107. An opening is formed on the top surface for the chip to enter and exit.
  • the liquid inlet hole 102 and the liquid outlet hole 103 are provided on the wall of the reaction tank 107 and connected to the reagent tank 101 . Therefore, the supporting member 104 and the plurality of reaction cells 107 can be processed separately, and the reagent tank 101 has a set depth to accommodate the chip, and the size of the reaction tank 107 can be configured according to the required size of the reagent tank 101 to accommodate the chip.
  • the bracket 104 only needs to be able to connect and support the reaction tank 107, thereby reducing the overall weight and material consumption of the reaction vessel 100.
  • some reagents in the biochemical reaction process have certain temperature requirements.
  • some systems that currently use open sequencing methods set up lifting devices and water baths to perform reactions that require temperature control.
  • the lifting device places the container loaded with chips and reagents into the water bath to control the reaction temperature.
  • the temperature control solution is simpler, eliminating the need for a precise temperature control system and saving money. The cost is reduced, but the entire sequencing process requires multiple lifting and moving of the container, which increases the complexity of the mechanism and the difficulty of control.
  • the reaction pool 107 of the reaction vessel 100 can also be provided with a first temperature control module for adjusting the temperature of the reagents in the reagent tank 101 to facilitate reactions with certain temperature requirements. , there is no need to move the reaction vessel 100.
  • the first temperature control module may include a temperature controller, a heater, a temperature sensor and a temperature protection switch.
  • the heater may be connected to the outer wall of the reaction tank 107, and the temperature of the reagents in the reagent tank 101 can be adjusted by heating the reaction tank 107.
  • the heater can be a heating patch in the form of a patch, which can be attached to the outer wall of the reaction tank 107, or can be formed on the wall of the reaction tank 107 in an embedded manner.
  • the temperature protection switch can be used as a safety device to limit the maximum temperature of the reagent tank 101.
  • the temperature sensor and the temperature protection switch are connected to the thermostat through communication.
  • the temperature sensor can sense the temperature of the reaction pool 107 to form a temperature signal.
  • the thermostat receives the temperature signal and instructs the heater to work. When the temperature exceeds the set value, it can also Use the temperature protection switch to switch the heater on and off to stop heating.
  • At least part of the wall of the reaction tank 107 is also provided with several mounting parts 108. Temperature sensors and/or temperature protection switches are connected to the mounting parts 108.
  • This part of the reaction tank 107 can be used to perform equipment with equipment.
  • the installation part 108 can facilitate the installation of a temperature sensor and/or a temperature protection switch.
  • the installation part 108 can be a hole-like or groove-like structure provided on the outer wall of the reaction tank 107.
  • the temperature sensor and/or temperature protection switch can be arranged inside the hole-like or groove-like structure to avoid protruding out of the
  • the outer wall of the reaction tank 107 may reduce the portion protruding from the outer wall of the reaction tank 107 to avoid collision damage.
  • the supporting member 104 includes a tray 105 and a side wall 106.
  • the tray 105 is connected to the top of the side wall 106.
  • the tray 105 is provided with a plurality of through-mounting openings 111.
  • the reaction tank 107 It is disposed in the installation opening 111 and resists the top of the tray 105, thereby supporting the reaction pool 107.
  • the side wall 106 of the supporting member 104 is supported on the bottom of the tray 105, so that the tray 105 can be lifted.
  • the reaction container 100 can be positioned and fixed through the installation of the side wall 106 and the workbench, so that the chip can be processed by a robot. Pick-up and transfer.
  • the top of the tray 105 can also be provided with a liquid collection tank 109 for collecting the dripping liquid during the transfer of the chip.
  • the tray 105 is also provided with a number of waste holes 110.
  • the waste holes 110 are connected to the liquid collection tank 109.
  • the waste hole 110 is also connected to a drain pipe, and the drain assembly is used to drain the liquid in the liquid collecting tank 109 through the drain pipe to prevent the liquid from overflowing and contaminating the countertop or other electrical devices.
  • the reaction vessel 100 can also adopt an integrated structure.
  • the reaction vessel 100 includes a body with reagent tanks 101 provided at multiple positions on the body.
  • the reagent tanks 101 penetrate the top of the body to form a channel for chips to enter and exit. Opening, the bottom of the body closes the reagent tank 101, thereby being able to hold the reagent; the side or bottom of the body is provided with a liquid inlet hole 102 and a liquid outlet hole 103 that communicate with the reagent tank 101 to meet the liquid inlet and drain requirements.
  • the body can be configured as a one-piece structure, which can simplify assembly.
  • the liquid inlet assembly 121 includes a liquid inlet pump 123, a first control valve 124 and a second control valve 125.
  • the first control valve 124 is adapted to pass through the liquid inlet pipeline.
  • 122 introduces the test set reagents
  • the second control valve 125 is connected to the liquid inlet hole 102 of the reagent tank 101 through the liquid inlet pipe 122
  • the liquid feed pump 123 is connected to the first control valve 124 and the second liquid inlet pipe 122 through the liquid inlet pipe 122.
  • the control valves 125 it is used to pass the required reagent into the reagent tank 101 through the liquid inlet pipe 122, the first control valve 124 and the second control valve 125.
  • the first control valve 124 is used to selectively pass in the set reagent.
  • the second control valve 125 is used to select the set reagent tank 101.
  • the liquid inlet pump 123 can be a syringe pump or a plunger pump to realize pumping of reagents
  • the control valve can be a rotary valve or a three-way valve to realize the on-off switching of the corresponding liquid inlet pipeline 122.
  • 7 and 8 illustrate the connection relationship by taking the first control valve 124 and the second control valve 125 using rotary valves as an example. The embodiments of the present application are not limited to the connection methods shown in the figures.
  • the first control valve 124 includes a plurality of first valves, and the first valves are used to connect containers for storing reagents through the liquid inlet pipeline 122, by This can select the required reagent by turning on and off a plurality of first valves among the plurality of first control valves 124 .
  • the second control valve 125 includes a plurality of second valves, and the second valves are used to connect the liquid inlet 102 of the reagent tank 101.
  • the reagent introduced through the first control valve 124 can be injected into the reagent tank 101 set by the on-off selection of a plurality of second valves in the second control valve 125 .
  • the liquid inlet mechanism 120 includes multiple groups of liquid inlet assemblies 121.
  • the sum of the number of second valves of the plurality of second control valves 125 is not less than the number of reagent tanks 101.
  • Each reagent tank 101 passes through the liquid inlet hole 102 and the inlet.
  • the liquid pipeline 122 is connected to each second valve in a one-to-one correspondence, so that each reagent tank 101 can select the type of reagent to be injected through the first control valve 124 and the second control valve 125 .
  • FIG 11 is a partial connection diagram of the drainage mechanism in the embodiment of the present application.
  • the drainage assembly includes a drainage pump and a third control valve.
  • the third control valve passes through the drainage pipe.
  • the drain pump is connected to the liquid outlet hole 103 of the reagent tank 101 through the drain pipe, and is used to discharge the set reagents in the reagent tank 101.
  • the third control valve is used to select and set reagent tank 101.
  • the liquid draining mechanism may also include a waste liquid container 135 for collecting liquid discharged by the liquid draining mechanism.
  • the third control valve can be a rotary valve or a three-way valve.
  • Figures 7 and 9 illustrate the connection relationship by taking a rotary valve as the third control valve as an example. The embodiments of the present application are not limited to the connection methods shown in the figures.
  • the third control valve may include a plurality of third valves.
  • the third valve is used to connect the liquid outlet hole 103 of the reagent tank 101.
  • the liquid inlet mechanism 120 includes multiple sets of liquid drainage components. The sum of the number of the third valves of the valves is not less than the number of the reagent tanks 101, and each reagent tank 101 is connected to each third valve in a one-to-one correspondence through the liquid outlet hole 103 and the drainage pipeline. Therefore, each reagent tank 101 can select the reagent tank 101 required for liquid discharge through the third control valve.
  • Figure 12 is a schematic connection diagram of another part of the liquid drainage mechanism in the embodiment of the present application.
  • the liquid drainage mechanism can also be equipped with a waste liquid pump 136 and a waste liquid pipe.
  • the path 137 is used to connect the drain hole 110 on the tray 105 to drain the liquid in the liquid collecting tank 109 to remove the dripping liquid generated during the chip transfer process.
  • the biochemical reaction device 10 also includes a control box 140.
  • the control box 140 is communicatively connected to the liquid inlet assembly 121 and is used to control the liquid inlet operation of the liquid inlet assembly 121; the control box 140 is also communicatively connected to the liquid inlet assembly 121.
  • the drain component is used to control the drain operation of the drain component, such as controlling each control valve to select on-off of each valve, and controlling the liquid inlet pump 123 and the drain pump. Controlling the pump valve through the control box 140 is a mature technology in this field, and its principles and control methods will not be described in detail here.
  • control box 140 is also communicatively connected to the drainage component and is used to control the drainage operation of the drainage component; the main control computer 50 is also used to instruct the control box 140 to control the process according to the set status of the reagent tank 101.
  • the liquid component 121 supplies liquid or controls the liquid discharge component to discharge liquid.
  • the status of the reagent tank 101 may include the number of soaked chips fed back through a counter, or the duration of the reaction fed back through a timer or setting program, or the liquid level position sensed through a liquid level sensor.
  • multiple reagent tanks 101 of the reaction vessel 100 are distributed in a set manner to form multiple reaction areas 112, and each reaction area 112 has multiple reagent tanks 101 respectively.
  • a moving mechanism 150 is provided corresponding to the position of each reaction area 112, and each moving mechanism 150 is used to pick up, place and move chips in the corresponding reaction area 112.
  • the reaction vessel 100 may also include a buffer area 113 (illustrated by a dotted box in the figure).
  • the buffer area 113 has several reagent tanks 101.
  • the buffer area 113 is located between adjacent reaction areas 112.
  • the adjacent moving mechanisms 150 Chips can be picked up, placed, and moved within the buffer 113.
  • the cooperation of adjacent moving mechanisms 150 can be realized.
  • the chip When the chip is transferred between adjacent reaction areas 112, the chip can first be placed in the reagent tank 101 of the buffer area 113 through the moving mechanism 150 of one reaction area 112, and then The moving mechanism 150 of another reaction area 112 grabs the chips in the buffer area 113 and transfers them to another reaction area 112 for soaking to avoid interference caused by the intersection of time and space.
  • the buffer 113 can also be used to temporarily store chips that have completed reactions and are waiting to be transferred to the optical device for image acquisition.
  • the set position in each reaction zone 112 can also reserve part of the reagent tank 101 as a loading position or a discharging position.
  • a plurality of (three in the figure) reagent tanks 101 are reserved on the side of the left reaction area 112 away from the moving mechanism 150 as loading positions for receiving the reagents from the sample loading device 20
  • the transfer device 40 loads the chip to be tested transferred from the first carrier 221 to the loading position, so that the moving mechanism 150 can obtain the chip and perform a subsequent soaking reaction.
  • a plurality of reagent tanks 101 are reserved on the side of the reaction area 112 away from the moving mechanism 150 as unloading positions for storing chips waiting to be removed from the reaction vessel 100 after the reaction is completed.
  • the moving mechanism 150 will The chip is placed at the lowering position, so that the transfer device 40 obtains the chip at the lowering position and removes it from the reaction vessel 100 .
  • the sample loading device 20 includes a frame 210, a material inlet and outlet mechanism 220 and a storage mechanism 240.
  • the material inlet and outlet mechanism 220 includes a first bearing member 221, a second bearing member 222 and a transfer mechanism.
  • the transfer mechanism is connected
  • the rack 210 is used to drive the first bearing member 221 and the second bearing member 222 to reciprocate in the incoming and outgoing direction.
  • the first bearing member 221 is used to carry the chips to be sequenced, and the second bearing member 222 is used to carry the chips after the sequencing is completed. of chips.
  • the storage mechanism 240 is connected to the rack 210 and includes a first storage area and a second storage area.
  • the first storage area is configured to store reagents at normal temperature and can be used to store reagents without additional temperature requirements. For example, some intermediate buffers and cleaning solutions used in the detection process.
  • the second storage area is provided with a second temperature control module.
  • the second temperature control module is used to maintain the temperature of the second storage area within a set temperature range so as to store reagents in the corresponding temperature range.
  • the temperature range is lower than normal temperature. , so reagents with low temperature requirements can be stored, such as some reagents containing enzymes or samples.
  • the chip to be tested can be carried by the first carrying member 221 of the sample inlet and outlet mechanism, and the sample can be injected through the transfer mechanism, so that the subsequent transfer device 40 can carry out the chip to be tested.
  • the chips are loaded into the reaction vessel 100, and the chips that have been detected in the biochemical reaction device 10 are unloaded through the transfer device 40 and carried on the second carrier 222, and are removed through the transfer mechanism to achieve sample extraction.
  • the storage and supply of reagents with different temperature requirements are achieved through the first storage area and the second storage area of the storage mechanism 240 .
  • the sampling device 20 realizes the inlet and outlet of the chip, and stores and supplies a variety of reagents that meet different temperature requirements, thereby facilitating the external interaction of the chip and reagents in the nucleic acid sequencing system and realizing the orderly management of the chips and reagents. To facilitate the orderly conduct of nucleic acid sequencing.
  • the transfer mechanism includes a first transfer component 223 and a second transfer component 224 .
  • the first transfer component 223 is connected to the first carrier 221 and is used to drive the first carrier 221 to reciprocate along the material discharging and discharging directions to the first position 227 or the second position 228, so that the first carrier carrying the chip to be tested can be moved.
  • the carrier 221 is placed in the first position 227 and moved to the second position 228 by the first transfer component 223 to implement chip injection, which facilitates subsequent chip loading and inspection.
  • the second transfer component 224 is connected to the second bearing member 222 and is used to drive the second bearing member 222 to reciprocate along the material discharging and discharging direction to the third position 229 or the fourth position 230, thereby moving the second bearing member 222 to the third position.
  • the position 229 is used to carry the chip after the inspection is completed, and is moved out to the fourth position 230 through the second transfer component 224 to realize the discharging of the chip.
  • the second position 228 corresponds to the third position 229, which facilitates the feeding and discharging of the same biochemical reaction device 10.
  • the rack 210 is provided with a position sensor 213 corresponding to the second position 228 for sensing the movement of the first carrier 221 to the second position 228 to facilitate chip loading.
  • the rack 210 is also provided with a position sensor 213 corresponding to the third position 229 for sensing the movement of the second carrier 222 to the third position 229 so that the chip can be unloaded onto the second carrier 222 .
  • first transfer component 223 and the second transfer component 224 can be independent of each other, thereby realizing separate operations of sample introduction and sample removal, which helps optimize the cycle time.
  • the first transfer component 223 and the second transfer component 224 can be implemented using stepper motors, servo motors or linear motors.
  • Figure 17 is a partial structural schematic diagram of the sample loading and unloading mechanism of the sample loading device 20 in the embodiment of the present application, which shows the first bearing member 221 and the first transfer component 223.
  • the first carrying member 221 is provided with a plurality of first receiving grooves 225, and the first receiving grooves 225 are suitable for receiving chips to be sequenced.
  • the first receiving grooves 225 can be provided with a narrow slit structure that matches the shape of the chip, and can It contains the chip and can achieve effective positioning of the chip, thereby facilitating mechanized loading operations.
  • the number of the first receiving grooves 225 may be one or more, such as 2, 3, 4, 5, 6 or more, and the plurality of first receiving grooves 225 are spaced apart along the first set direction.
  • the arrangement is arranged to achieve orderly feeding of the chips to be tested.
  • the first set direction can be consistent with the feeding direction of the first carrier 221, or perpendicular to the feeding direction.
  • the specific arrangement direction can be determined according to the subsequent The structure of the process should be properly configured.
  • a first sensor is provided in the first accommodating groove 225 for detecting the presence or absence of chips in the first accommodating groove 225.
  • the first sensor can be a presence detection sensor commonly used in industrial production, such as a limiter. Switches or photoelectric sensors, etc., thereby facilitating the subsequent detection process to accurately obtain the chip on the first carrier 221. For example, when a manipulator is used to grasp the chip, the manipulator is prevented from empty grasping, thereby ensuring the accuracy and safety of the capture.
  • the second carrier 222 is provided with a plurality of second receiving slots 226, and the second receiving slots 226 are suitable for receiving the chips after sequencing.
  • the second receiving slots 226 can be configured to match the shape of the chip.
  • the narrow slit structure can accommodate chips.
  • the number of the second receiving grooves 226 may be one or more, such as 2, 3, 4, 5, 6 or more, and the plurality of second receiving grooves 226 are spaced apart along the second set direction. Arrange settings to achieve orderly recycling and discharging of chips.
  • a second sensor can also be disposed in the second accommodating groove 226 for detecting the presence or absence of the chip in the second accommodating groove 226.
  • the second sensor is a presence detection sensor commonly used in industrial production, such as a limit switch or a photoelectric sensor. etc. This can avoid the risk of collision caused by overlapping chips placed in the same second receiving groove 226 and ensure safety.
  • the structure of the second bearing member 222 and the structure of the first bearing member 221 may be the same or different.
  • the first carrier 221 and the second carrier 222 With the same structure, since the chip needs to maintain a certain positional accuracy when feeding so that it can be accurately obtained by subsequent processes, the first carrier 221 needs to be cleaned and maintained frequently to maintain the first chip.
  • the accuracy of the positioning of the chip by the receiving groove 225 is low, and the positioning requirements for the chip during discharging are low. Therefore, the maintenance requirements of the second carrier 222 are lower than those of the first carrier 221.
  • the second carrier 222 may not be provided with the plurality of second receiving slots 226 mentioned above, but only needs to have a carrier for supporting the chips. Just the loading part is enough, which can avoid the alignment of the chip during recycling, and can effectively simplify the structure and operation control.
  • the second temperature control module can use semiconductor refrigeration or compression refrigeration to cool the reagents in the second storage area.
  • the second temperature control module includes a semiconductor refrigerator or a compression refrigerator.
  • the semiconductor refrigerator or compression refrigerator is used to refrigerate the reagents in the second storage area to maintain it within a required temperature range.
  • the second temperature control module is used to keep the reagents in the second storage area between 4°C and 8°C. This temperature is suitable for storing some reagents containing enzymes or samples.
  • a common thermostat can be used to achieve temperature feedback. And adjust the working status of the semiconductor refrigerator or compression refrigerator to maintain the required temperature range.
  • the compression refrigerator mainly includes a compressor, a condenser, a throttle valve and an evaporator. It uses the suction and compression of the compressor, the exothermic condensation of the condenser, the throttling and pressure reduction of the throttle valve, and the endothermic vaporization of the evaporator.
  • the continuous circulation process achieves the purpose of lowering the temperature of the object to be cooled, and has a high cooling coefficient. Both refrigeration methods can achieve effective cooling in the second storage area, and can be reasonably selected and configured according to actual cooling and installation requirements during specific implementation.
  • the storage mechanism 240 further includes a reagent needle and a third transfer component.
  • the third transfer component is connected to the reagent needle and is used to drive the reagent needle to move relative to the first storage area and the second storage area. Draw the required reagents for priming and rehydration.
  • a pipette is a measuring device usually used in experimental equipment to accurately transfer a certain volume of solution. Therefore, the storage mechanism 240 can also select a pipette of appropriate specifications according to the volume of the reagent and the requirements for perfusion or rehydration to achieve the measurement of each reagent. Quantitative pipetting for perfusion or rehydration.
  • the rack 210 includes a platform 211 and a cabinet 212.
  • the platform 211 is located on the top of the cabinet 212.
  • the inlet and outlet mechanism 220 is disposed on the platform 211, and the storage mechanism 240 is disposed inside the cabinet 212. , thus forming a structure with an upper and lower layout, which is relatively compact overall and can reduce the occupied area.
  • the transfer device 40 can be used to move the transfer chip between the first carrier 221 , the biochemical reaction device 10 and the second carrier 222 .
  • the transfer device 40 can be located on the same side of the first bearing member 221 and the second bearing member 222.
  • the first bearing member 221 and the second bearing member 222 can be close to or away from the transfer mechanism along the sample feeding direction, thereby facilitating the feeding and unloading of chips. material.
  • the transfer device 40 can use a multi-axis mechanical arm 420 to realize the position transfer of the clamping mechanism, and the clamping mechanism can use a mechanical gripper or a suction cup to realize the holding of the chip.
  • the first carrier 221 loaded with the chip to be tested can be placed on the first transfer component 223, and the first carrier 221 can be moved toward the biochemical reaction device 10 through the first transfer component 223 to realize the transfer of the chip.
  • the transfer device 40 moves to the first carrier 221 relative to the sample loading device 20 to obtain the chip to be tested carried on the first carrier 221, and transfers it to the biochemical reaction device 10, thereby loading the chip to be tested to Biochemical reaction device 10.
  • the chips that have been detected by the biochemical reaction device 10 can be obtained from the biochemical reaction device 10 through the transfer device 40, and then moved to the second carrier 222 for placement, and driven by the first transfer component 223.
  • the second carrier 222 moves to send out the collected chips to realize discharging.
  • the loading device 20 provides reagents to the reagent container of the biochemical reaction device 10, provides the chip to be tested to the biochemical reaction device 10, and recovers the chip after testing, thereby realizing external interaction between the chip and the reagent. , and facilitates the perfusion and rehydration of reagents required during the detection process, which helps speed up the processing pace and improve sequencing efficiency.
  • the detection device 30 includes a picture acquisition platform 320 and an image acquisition instrument 310 .
  • the image acquisition platform 320 is used to locate the chip removed from the biochemical reaction device 10 .
  • the image acquisition instrument 310 corresponds to the image acquisition platform 320 Settings are used to collect images against the chip placed on the imaging platform 320 .
  • the chip can be removed from the biochemical reaction device 10 through the transfer device 40 and placed on the image acquisition platform 320 for image acquisition.
  • the detection device 30 can also include a workstation configured with an image processing module, and the workstation is used to receive the image generated by the image acquisition device 310.
  • the image is processed by the image processing module to analyze and obtain nucleic acid sequence information.
  • Image processing modules commonly used in this field can be used to implement the above processing and analysis, and their principles and algorithms will not be described in detail here.
  • the imaging platform 320 includes an adsorption disc 321, a vacuum pipeline 322 and a waste discharge pipeline 323.
  • the vacuum pipeline 322 is used to connect the vacuum air source and communicate with the adsorption disc 321 for use in The adsorption disc 321 forms a negative pressure to adsorb the chip.
  • the waste discharge pipeline 323 is connected to the set position of the vacuum pipeline 322 to collect and remove the waste liquid entering the vacuum pipeline 322 from the adsorption disc 321, and an isolation cavity 324 is provided. It will first enter the isolation cavity 324 and be extracted by the waste discharge pump 325, thereby preventing the waste liquid from entering the vacuum air source, thereby greatly extending the service life of the vacuum pump 326.
  • the vacuum air source can be the vacuum pipeline 322 laid out on the site, and the vacuum pipeline 322 is connected through the pipeline to realize the vacuum adsorption function of the adsorption disc 321, or it can be a self-contained vacuum pump 326, and the vacuum pump 326 is connected through the vacuum pipeline 322 to realize the adsorption disc. 321’s vacuum adsorption function.
  • the image acquisition platform 320 is also configured to break the vacuum. The valve can break the vacuum very well, allowing the chip to be released faster and helping to speed up the processing cycle.
  • the end gripper 430 of the transfer device 40 includes a finger driving assembly 431 and a finger 432.
  • the finger driving assembly 431 is connected to the finger 432 and is used to drive the finger 432 to open or close; the end gripper 430 includes a finger driving assembly 431 and a finger 432.
  • the hand 430 is also provided with a grasping sensor, a release sensor and a chip presence/absence sensor, whose functions are similar to the clamping component 152 of the biochemical reaction device 10 in the previous embodiment, and will not be described again here.
  • the finger drive assembly 431 can be implemented using a bidirectional cylinder. The opening and closing motion control of the finger 432 driven by the cylinder is a common technology in this field.
  • the control principle diagram is shown in Figure 22.
  • the cylinder connection The compressed air source 433 is connected to the finger 432 through a pressure regulating filter 434, a two-position five-way valve 435 and two speed regulators 436. Two mufflers 437 can also be provided at the two-position five-way valve 435 to reduce noise.
  • the pressure regulating filter 434 is used to adjust the air pressure entering the cylinder from the compressed air source 433.
  • the clamping component 152 in the biochemical reaction device 10 can also adopt a similar structure and control method to the end gripper 430 .
  • the biochemical reaction device 10 is equipped with the above-mentioned main control computer 50, and the sample loading device 20, the transfer device 40 and the detection device 30 are communicatively connected to the main control computer 50.
  • the main control computer 50 can be connected via TCP. /IP protocol controls the sample loading device 20, transfer device 40 and detection device 30.
  • the main control computer 50 is used to control the sample loading device 20 to inject and sample out the chip, and the biochemical reaction device 10 to soak the chip.
  • the detection device performs imaging detection and analysis operations on the chip, and controls the transfer device 40 to transfer the chip between the sample loading device 20 , the biochemical reaction device 10 and the detection device 30 .
  • the sequencing control method according to the second embodiment of the present application includes reaction and detection as well as control of liquid inlet and outlet, wherein:
  • Reaction and detection Detect whether there is a chip in the reagent tank 101 and form a sensing signal. According to the sensing signal and according to the preset sequencing mode, the moving mechanism 150 is controlled to move the chip to the corresponding reagent tank 101 for immersion reaction. , and control the transfer device 40 to transfer the chip that has completed the set reaction process to the detection device 30 for imaging detection;
  • Liquid inlet and liquid discharge Before reaction and detection, the liquid inlet mechanism is controlled to inject set reagents into multiple reagent tanks 101 respectively according to the preset program; during the reaction and detection process, the liquid inlet mechanism is controlled in response to the set reaction parameter signal. The liquid inlet mechanism replenishes the liquid in the set reagent tank 101; after the reaction and detection are completed, the liquid discharge mechanism is controlled to discharge the liquid in the reagent tank 101 in response to the signal that the total number of chips has been processed.
  • the above-mentioned reaction parameter signal may include counting the chip during the reaction and detection process to generate A quantitative signal, or a time signal generated by sensing the reaction progress time, or a liquid level signal generated by sensing the liquid level of the reagent tank 101 .
  • a counter can be used to count the reaction chip, and when the count reaches a set number, a quantity signal is generated, and the quantity signal is sensed and used to control the liquid inlet mechanism to replenish the set reagent tank 101; or a timer can be used to time the reaction time.
  • the nucleic acid sequencing system of the embodiment of the present application is based on open biochemical reactions, flexible device combinations and process control, making the synthesis and sequencing of random sequences a possible.
  • the nucleic acid sequencing system and sequencing control method of the embodiments of the present application are also suitable for conducting spatiotemporal omics research.
  • the sequencing control method also includes chip loading and unloading: controlling the sample inlet and outlet mechanism according to the sensing signal and according to a preset program to drive the carrier close to the reaction vessel 100, and controlling the transfer device 40 to transfer the chip to be tested to the reaction vessel 100. Realize loading, or transfer the chip after reaction and detection to the carrier for unloading.
  • chip loading and unloading controlling the sample inlet and outlet mechanism according to the sensing signal and according to a preset program to drive the carrier close to the reaction vessel 100, and controlling the transfer device 40 to transfer the chip to be tested to the reaction vessel 100. Realize loading, or transfer the chip after reaction and detection to the carrier for unloading. Referring to Figure 23, the sequencing process is as follows:
  • Hybridization amplification and the first step of the synthesis reaction are performed sequentially through the above reaction and detection methods. After the reaction is completed, it is transferred to the detection device 30 (opto-mechanical module) for photography, imaging and detection analysis;
  • the sequencing control method also includes temperature control: controlling the temperature of the reagent tank 101 containing the set reagents according to a preset program to control the temperature of the reagents required for the set soaking reaction within a required temperature range.
  • the temperature control of the corresponding reagent tank 101 can be realized through the first temperature control module, and the opening, working time and closing of the first temperature control module can be controlled by setting a program.
  • the reaction vessel 100 is provided with multiple reagent tanks 101 to accommodate a variety of reagents. The arrangement of the reagent tanks 101 can be reasonably configured according to the biochemical reaction process, the heating requirements of the reagent tanks 101, the cycle reaction method, etc.
  • Figure 24 shows a layout of the reagent tanks 101 of the reaction vessel 100, where the reaction vessel 100 includes 39 reagent tanks 101, arranged in three rows of 13 in each row, as For convenience of explanation, the three rows of reagent tanks 101 are marked A, B, and C respectively, and the corresponding 13 columns are marked with numbers from one side to the other.
  • the reagent tanks 101 (or reagents) at the corresponding positions can be expressed by a combination of row numbers and column numbers. ), for example, A1 represents the reagent tank 101 located in the first column of row A.
  • multiple reagents are included: re-amplification reagent, sample reagent, amplification reagent, denaturation reagent, digestion reagent, U reagent, blocking reagent, sequencing primer 1, sequencing primer 2, tag primer 1, tag primer 2.
  • the three reagent tanks 101 A7, B7, and C7 located in the middle are used to hold cleaning reagents and pre-cleaning reagents, and serve as buffer zones.
  • the buffer zone divides the reagent tank 101 into two reaction areas.
  • the reagent tanks 101 are respectively provided with corresponding reagents, and each has a cleaning reagent.
  • Each reaction zone includes a reagent tank 101 with a first temperature control module and a reagent tank 101 at normal temperature.
  • Moving mechanisms 150 are respectively provided corresponding to the positions of the two reaction areas to realize the separate transfer of chips in each reaction area.
  • the chip When the chip needs to span two reaction areas, the chip can be placed in the buffer area first, and then the chip can be moved by another moving mechanism 150 Move to the set reagent tank 101 to avoid interference of time and space. This allows the reaction to be controlled based on the reagent tank 101 and the reagents respectively.
  • the set position in each reaction zone can also reserve part of the reagent tank 101 as a loading position or a discharging position.
  • C1, C2, and C3 are the loading positions
  • C11, C12, and C13 are the discharging positions.
  • the transfer device 40 Load the chip to the loading position so that the moving mechanism 150 can obtain the chip and perform subsequent soaking reaction.
  • the moving mechanism 150 places the reacted chip at the lowering position, so that the transfer device 40 obtains the chip at the lowering position and moves it out of the reaction container 100 .
  • the workflow of the reagent tank 101 in the reaction area is as shown in Figure 25.
  • the control of the reagent tank 101 can be carried out as follows:
  • S6 determine whether all chips have been processed, if so, proceed to S8; if not, proceed to S7;
  • S7 determine whether the set number of chips has been reached. If so, proceed to S2 to S6; if not, proceed to S4 to S6 and replenish fluid;
  • the reagents used include: re-amplification reagent, sample reagent, amplification reagent, denaturation reagent, digestion reagent, U reagent, blocking reagent, sequencing primer 1, sequencing primer 2.
  • Tag primer 1 tag primer 2, G reagent, CLEAVE reagent, synthesis reagent A, synthesis reagent B, cleaning reagent, and pre-cleaning reagent.
  • the selection of reagent types and the reagents in each reagent tank 101 can be reasonably distributed according to the specific reaction requirements and the movement mode of the chip.
  • each reagent tank 101 and its reagents are distributed as follows: A1: Re-amplification reagent (temperature control) A7: Cleaning reagent A13: Cleaning reagent A2: Sample reagent (temperature control) A8: Digestion reagent (temperature control) B1: Cleaning reagent A3: Amplification reagent (temperature control) A9: Amplification reagent (temperature control) B2: U reagent (temperature control) A4: Denaturing reagent A10: Denaturing reagent B3: Blocking reagent (temperature control) A5: Cleaning reagent A11: Cleaning reagent B4: Sequencing primer 1 (temperature control) A6: Cleaning reagent (temperature control) A12: Cleaning reagent (temperature control) B5: Tag primer 1 (temperature control) B6: Cleaning reagent B13: Cleaning reagent C7: Pre-cleaning reagent B7: Cleaning reagent C1: Loading position C8:
  • each reagent tank 101 and its reagents can be adjusted according to actual conditions.
  • reaction and detection control are performed according to the set sequencing mode.
  • Figure 26 which shows the double-end sequencing mode, including: PCR process, one-strand sequencing process, BARCODE1 sequencing process, BARCODE2 sequencing process and two-strand sequencing process. .
  • the PCR process precedes the other processes, and the first-strand sequencing process precedes the second-strand sequencing process.
  • the specific process is as follows:
  • the chip When starting sequencing, the chip is placed on the loading device 20 (for example, placed on the first carrier) and fed through the loading device 20. The chip is transferred to the loading positions C1 to C3 of the reaction vessel 100 through the transfer device 40. Then proceed to PCR process 1 or PCR process 2. Combined with the above example of the distribution of reagent tank 101, the details of PCR process 1 or PCR process 2 are as follows:
  • the FIRST process is performed, and after the FIRST process reaction is completed, the moving mechanism 150 is controlled to transfer the chip to the unloading positions C11 to C13; combined with the above example of the distribution of the reagent tank 101, the FIRST process can be: C5-C6-C7 -C8-C9-C10-C11(C12,C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • the SEQENCE process is performed. After the SEQENCE process reaction is completed, the moving mechanism 150 is controlled to transfer the chip to the unloading positions C11 to C13; combined with the above example of the distribution of the reagent tank 101, the SEQENCE process can be: C1 (C2, C3)- C4-C5-C6-C7-C8-C9-C10-C11(C12,C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • control transfer device 40 transfers the chip back to the reaction container 100 to determine whether the specified number of rounds has been completed. If not, return to the SEQENCE process to continue the reaction; if so, enter the BARCODE1 sequencing process.
  • the control transfer device 40 transfers the chip to the loading positions C1 to C3 to perform the BARCODE1 process;
  • the BARCODE1 process can be: C1 (C2, C3)-A4-A5-A7-C8-C9-C10-C11 (C12, C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • the SEQENCE process is performed. After the SEQENCE process reaction is completed, the moving mechanism 150 is controlled to transfer the chip to the unloading positions C11 to C13; combined with the above example of the distribution of the reagent tank 101, the SEQENCE process can be: C1 (C2, C3)- C4-C5-C6-C7-C8-C9-C10-C11(C12,C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • control transfer device 40 transfers the chip back to the reaction container 100 to determine whether the specified number of rounds has been completed. If not, return to the SEQENCE process to continue the reaction; if so, enter the BARCODE2 sequencing process.
  • the control transfer device 40 transfers the chip to the loading positions C1 to C3 to perform the BARCODE2 process;
  • the BARCODE2 process can be: C1 (C2, C3)-A7-A10-B10-C8-C9-C10-C11 (C12, C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • the SEQENCE process is performed. After the SEQENCE process reaction is completed, the moving mechanism 150 is controlled to transfer the chip to the unloading positions C11 to C13; combined with the above example of the distribution of the reagent tank 101, the SEQENCE process can be: C1 (C2, C3)- C4-C5-C6-C7-C8-C9-C10-C11(C12,C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, selection can be made through sensing to transfer to the free detection device 30;
  • control transfer device 40 transfers the chip back to the reaction container 100 to determine whether the specified number of rounds has been completed. If not, return to the SEQENCE process to continue the reaction; if so, enter the second-strand sequencing process.
  • Subsequent chips are placed into the loading device 20 (for example, placed on the first carrier) and fed through the loading device 20, and the chips are transferred to the loading positions C1 to C3 of the reaction vessel 100 through the transfer device 40;
  • PE process 1 or PE process 2 Perform PE process 1 or PE process 2. Combined with the above example of reagent tank 101 distribution, the details of PE process 1 or PE process 2 are as follows:
  • the FIRST process is performed, and after the FIRST process reaction is completed, the moving mechanism 150 is controlled to transfer the chip to the unloading positions C11 to C13; combined with the above example of the distribution of the reagent tank 101, the FIRST process can be: C5-C6-C7-C8-C9-C10-C11(C12, C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • the SEQENCE process is performed. After the SEQENCE process reaction is completed, the moving mechanism 150 is controlled to transfer the chip to the unloading positions C11 to C13; combined with the above example of the distribution of the reagent tank 101, the SEQENCE process can be: C1 (C2, C3)- C4-C5-C6-C7-C8-C9-C10-C11(C12,C13);
  • the control transfer device 40 transfers the chips at the loading positions C11 to C13 to the detection device 30 for photographing and imaging detection. When there are multiple detection devices 30, the transfer to the free detection device 30 can be selected through sensing;
  • control transfer device 40 transfers the chip back to the reaction container 100 to determine whether the specified number of rounds has been completed. If not, return to the SEQENCE process to continue the reaction; if so, the control transfer device 40 transfers the chips from the lower material positions C11 to C13.
  • the chip is transferred to the sample loading device 20 (for example, the second carrier) for sample extraction, and the sequencing process is completed.
  • the nucleic acid sequencing system and sequencing control method of the embodiment of the present application can be used for nucleic acid detection, and can complete the following functions: hybridization, amplification, single-end or double-end nucleic acid detection, and biotag detection of researcher samples. And can be equipped with a server to output fastQ files.
  • a server to output fastQ files.
  • it due to its open reaction system and fluid design, it can also be used for spatiotemporal omics research. In addition to completing the entire sequencing process, it can also complete all biochemical tasks required for spatiotemporal omics research. process.

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Abstract

一种核酸测序系统及测序控制方法，核酸测序系统包括生化反应装置（10）、上样装置（20）、检测装置（30）和转移装置（40）。通过生化反应装置（10）实现芯片的开放式浸泡及试剂的重复使用，通过上样装置（20）实现芯片向生化反应装置（10）进样、出样以及对试剂槽（101）进液、排液，通过转移装置（40）将芯片在上样装置（20）、生化反应装置（10）和检测装置（30）间转移，保证反应和测试的连续性。各装置的数量可分别进行合理配置，从而可通过调整流程或各装置的增减、替换进一步开发系统的测序能力。

Description

核酸测序系统及测序控制方法
本发明要求于2022年08月03日提交中国专利局、申请号为202210927120.0，申请名称为“核酸测序系统及测序控制方法”的中国专利申请的优先权，其全部内容通过引用结合在本发明中。
技术领域
本申请涉及核酸测序技术领域，尤其是涉及一种核酸测序系统及测序控制方法。
背景技术
目前的二代测序技术中，生化反应部分通常是采用微流控系统实现，主要是通过动力源、选择阀和管路等配合，将试剂盒流体可控地流过流动池的流体通道并和连接于流动池衬底上的待测序的核酸链接触，实现生化反应，该过程需要精准的温控系统和封闭流体系统，确保整个生化反应的充分进行，成本较高且易出现反应不均衡而影响检测结果的问题，并且试剂利用率低。
发明内容
本申请旨在至少解决现有技术中存在的技术问题之一。为此，本申请提出一种核酸测序系统，能够采用开放式的生化反应方式，实现试剂的进液和排液，以及测试芯片的移动，从而便于芯片的上料、反应、检测和下料，有助于提高检测效率。本申请还提出一种测序控制方法。
根据本申请第一方面实施例的核酸测序系统，包括生化反应装置、上样装置、检测装置和转移装置，所述生化反应装置包括反应容器、移动机构、进液机构和排液机构，所述反应容器设置有多个具有开口的试剂槽，所述试剂槽用于盛放试剂并且浸泡待测的芯片，所述移动机构用于将所述芯片在设定的所述试剂槽之间转移；所述进液机构连通于所述试剂槽，用于移取设定试剂并向设定的所述试剂 槽进液，所述排液机构连通于所述试剂槽，用于排出所述试剂槽内的试剂；所述上样装置包括进出料机构，所述进出料机构包括若干承载件和移动机构，所述承载件用于承载芯片，所述移动机构连接于所述承载件，并用于驱使所述承载件靠近或远离所述反应容器，以对芯片进样或出样；所述检测装置用于承接从所述生化反应装置转移出的芯片并对所述芯片进行成像检测分析；所述转移装置用于获取芯片并用于所述芯片在所述上样装置、所述生化反应装置或所述检测装置之间的相互转移。
本申请第一方面实施例的反应容器至少具有如下有益效果：生化反应装置实现芯片的开放式浸泡，实现试剂的重复实用，通过上样装置实现测试芯片向生化反应装置的进样和出样，以及对试剂槽进液和排液，由此可便于反应前试剂的灌注、反应过程中试剂的补液以及整个测序完成后试剂的排出，检测装置用于在设定的生化反应后采集芯片图片并检测分析，其中，通过转移装置将芯片在上样装置、生化反应装置和检测装置间转移，保证反应和测试的连续性。另外，本测序系统中，上样装置、生化反应装置和检测装置之间由转移装置衔接，各装置的数量分别可根据具体的节拍进行合理配置，组合方式较为灵活，从而可通过调整流程或各装置的增减、替换进一步开发系统的测序能力，无需系统整体升级迭代，由此能够节省成本。
根据本申请一些实施例的核酸测序系统，所述反应容器包括承托件和多个反应池，多个所述反应池按设定方式排布，并连接于承托件，各所述反应池内部设有所述试剂槽，所述试剂槽贯通所述反应池的顶部表面形成所述开口，以供所述芯片进出，所述反应池的壁体上设置有连通于所述试剂槽的进液孔和出液孔；所述进液机构包括进液组件和进液管路，各所述进液孔分别连接所述进液管路，所述进液组件用于移取设定试剂，并通过设定的所述进液管路向所述试剂槽进液；所述排液机构包括排液组件和排液管路，各所述出液孔分别连接所述排液管路，所述排液组件用于将所述试剂槽内的试剂通过所述排液管路排出。
根据本申请一些实施例的核酸测序系统，所述生化反应装置中，至少部分所述反应池上还设置有第一温控模块，用于对相应的所述试剂槽内的试剂进行温度控制，所述第一温控模块包括温度保护开关，所述温度保护开关用于限制所述试剂槽的最大温度。
根据本申请一些实施例的核酸测序系统，所述移动机构包括移动组件和夹持组件，所述夹持组件适于持取所述芯片，所述移动机构连接于所述夹持组件，用于驱使所述夹持组件相对所述反应容器移动以将所述芯片在设定的所述试剂槽之间转移。
根据本申请一些实施例的核酸测序系统，所述反应容器中，多个所述试剂槽以设定方式分布形成多个反应区，各所述反应区分别具有多个所述试剂槽，对应于各所述反应区的位置分别设置有所述移动机构，各所述移动机构用于在对应的所述反应区内取放和移动所述芯片，所述转移机构能够在各所述反应区取放和移动所述芯片。
根据本申请一些实施例的核酸测序系统，所述反应容器中，还包括缓冲区，所述缓冲区具有若干所述试剂槽，所述缓冲区位于相邻所述反应区之间，相邻的所述移动机构能够在所述缓冲区内取放和移动所述芯片，所述转移机构能够在所述缓冲区取放和移动所述芯片。
根据本申请一些实施例的核酸测序系统，所述上样装置还包括存储机构，所述存储机构包括若干存储区，所述存储区用于存储核酸测序所需的试剂，所述进液机构还包括移液器，所述移液器通过所述进液管路连接于所述进液组件，所述移液器用于获取存储于所述存储区的试剂。
根据本申请一些实施例的核酸测序系统，所述存储机构包括第一存储区和第二存储区，所述第一存储区配置为在常温下存储试剂，所述第二存储区设置有第二温控模块，所述第二温控模块用于使所述第二存储区的温度维持在设定温度范围内，以便在所述温度范围内存储试剂，所述温度范围低于常温。
根据本申请一些实施例的核酸测序系统，所述检测装置包括采图平台和图像采集仪，所述采图平台用于定位从所述生化反应装置移出的芯片，所述图像采集仪对应于所述采图平台设置，用于对置于所述采图平台上的芯片采集图像。
根据本申请一些实施例的核酸测序系统，所述检测装置还包括配置有图像处理模块的工作站，所述工作站用于接收所述图像采集仪生成的图像并通过图像处理模块处理获取核酸序列信息。
根据本申请一些实施例的核酸测序系统，所述采图平台包括吸附盘、真空管路和排废管路，所述真空管路用于连接真空气源并连通于所述吸附盘，用于在所 述吸附盘形成负压以吸附芯片，所述排废管路连通于所述真空管路的设定位置，用于收集和排除从吸附盘进入所述真空管路的废液。
根据本申请一些实施例的核酸测序系统，所述转移装置包括行走机构和机械臂，所述行走机构连接于所述机械臂，用于承载并驱使所述机械臂沿设定方向移动，所述机械臂的执行端设置有末端抓手，用于取放芯片；所述行走机构和所述机械臂配合能够驱使所述末端抓手在所述上样装置、所述生化反应装置和所述检测装置之间移动。
根据本申请一些实施例的核酸测序系统，所述末端抓手包括手指驱动组件和手指，所述手指驱动组件连接于所述手指并用于驱动所述手指张开或闭合；所述末端抓手上还设置有抓取传感器、释放传感器和芯片有无传感器。
根据本申请一些实施例的核酸测序系统，所述系统中，1台所述生化反应装置对应设置1台或多台所述检测装置。
根据本申请一些实施例的核酸测序系统，所述生化反应装置还包括主控机和多个感测单元，各所述试剂槽分别设置有一感测单元，所述感测单元用于感测对应的所述试剂槽内是否容纳有芯片，并将感测信号发送至所述主控机；所述主控机能够根据所述感测信号控制所述移动机构按设定程序取放和移动至少一个芯片。
根据本申请一些实施例的核酸测序系统，所述生化反应装置还包括控制箱，所述控制箱通讯连接于所述进液组件，用于控制所述进液组件的进液操作；所述控制箱还通讯连接于所述排液组件，用于控制所述排液组件的排液操作；所述主控机还用于根据设定的试剂槽状态指示所述控制箱控制所述进液组件进液或控制所述排液组件排液。
根据本申请一些实施例的核酸测序系统，所述上样装置、所述转移装置和所述检测装置通讯连接于所述主控机，所述主控机用于控制所述上样装置对芯片的进样和出样操作、所述生化反应装置对芯片的浸泡操作、所述检测装置对芯片的成像检测分析操作，以及控制所述转移装置件将芯片在所述上样装置、所述生化反应装置和所述检测装置之间转移。
本申请第二方面实施例的测序控制方法，包括：
反应及检测：对所述试剂槽内是否置有芯片进行感测并形成感测信号，根据 感测信号并按预设的测序模式控制移动机构将芯片移动至相应的试剂槽中进行浸泡反应，以及控制转移装置将已完成设定反应过程的芯片转移至检测装置进行成像检测；
进液和排液：在反应及检测前，控制进液机构按预设程序向多个试剂槽分别灌注设定的试剂；在反应及检测的过程中，响应于设定的反应参数信号控制进液机构对设定的试剂槽补液；在反应及检测结束后，响应于芯片总数处理完成信号控制排液机构对试剂槽排液。
本申请第二方面实施例的核酸测序方法，至少具有如下有益效果：通过对多个试剂槽灌注试剂，从而能够支持通过浸泡的方式进行生化反应，通过将芯片移动至像一个的试剂槽中进行浸泡反应，同一试剂槽能够先后浸泡多个芯片，实现试剂的重复使用，并且，通过在反应及检测的过程中对相应的试剂槽补液，能够保证生化反应的持续进行，芯片可持续上料、浸泡反应和成像检测，能够有效提高反应效率，从而提高测序通量。
根据本申请一些实施例的测序控制方法，所述测序模式包括：PCR过程、一链测序过程、BARCODE1测序过程、BARCODE2测序过程和二链测序过程，其中，PCR过程在其余各过程之前，一链测序过程在二链测序过程之前。
根据本申请一些实施例的测序控制方法，所述反应参数信号包括在反应及检测过程中对芯片进行计数生成的数量信号，或者，对反应进行的时间进行感测生成的时间信号，或者，对试剂槽的液位进行感测生成的液位信号。
根据本申请一些实施例的测序控制方法，所述方法还包括温度控制：根据预设程序控制盛放有设定试剂的所述试剂槽的温度，以将设定的浸泡反应所需的试剂温度控制在所需的温度范围内。
根据本申请一些实施例的测序控制方法，所述方法还包括芯片上下料：根据所述感测信号并按预设程序控制进出样机构驱使承载件靠近所述反应容器，并控制所述转移装置将待测芯片转移至所述反应容器实现上料，或将反应及检测完成后的芯片转移至所述承载件实现下料。
本申请的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本申请的实践了解到。
附图说明
图1为本申请实施例核酸测序系统的结构示意图；
图2为图1所示出实施例的俯视图；
图3为本申请实施例中生化反应装置的结构示意图；
图4为本申请实施例中反应容器的结构示意图；
图5为本申请实施例反应容器的俯视图；
图6为图5中的A-A截面的剖视图；
图7为图5中的B-B截面的剖视图；
图8为本申请一实施例中反应容器的分解示意图；
图9为本申请实施例中进液机构和排液机构的连接示意图；
图10为本申请实施例中进液机构的部分连接示意图；
图11为本申请实施例中排液机构的部分连接示意图；
图12为本申请实施例中排液机构的另一部分连接示意图；
图13为本申请实施例中反应容器的简化图；
图14为本申请实施例中上样装置的结构示意图；
图15为本申请实施例中上样装置的部分结构示意图；
图16为图14示出实施例中上样装置的俯视图；
图17为本申请实施例中上样装置的进出样机构的部分结构示意图；
图18为本申请实施例中上样装置和生化反应装置的示意图；
图19为本申请实施例中检测装置的结构示意图；
图20为检测装置的采图平台的部分控制原理图；
图21为本申请实施例中转移装置的末端抓手的结构示意图；
图22为末端抓手的控制原理图；
图23为本申请实施例的核酸测序系统的工作流程示意图；
图24为本申请实施例中反应容器的试剂槽的一种分布方案示意图；
图25为芯片在反应容器中进行生化反应的一个流程图；
图26为本申请实施例的测序控制方法进行双端测序的流程示意图。
附图标记：
生化反应装置10；
反应容器100，试剂槽101，进液孔102，出液孔103，承托件104，托盘105，侧壁106，反应池107，安装部108，集液槽109，排废孔110，安装口111，反应区112，缓冲区113；
进液机构120，进液组件121，进液管路122，进液泵123，第一控制阀124，第二控制阀125；
排液机构130，排液组件131，排液管路132，排液泵133，第三控制阀134，废液容器135，废液泵136，废液管路137；
控制箱140；
移动机构150，移动组件151，夹持组件152；
上样装置20；
机架210，平台211，机柜212，到位感应器213；
进出料机构220，第一承载件221，第二承载件222，第一移载组件223，第二移载组件224，第一容纳槽225，第二容纳槽226，第一位置227，第二位置228，第三位置229，第四位置230，存储机构240；
检测装置30；
图像采集仪310，采图平台320，吸附盘321，真空管路322，排废管路323，隔离腔体324，排废泵325，真空泵326；
转移装置40；
行走机构410，机械臂420，末端抓手430，手指驱动组件431，手指432，压缩气源433，调压过滤器434，二位五通阀435，调速器436，消声器437；
主控机50。
具体实施方式
以下将结合实施例对本申请的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本申请的目的、特征和效果。显然，所描述的实施例只是本申请的一部分实施例，而不是全部实施例，基于本申请的实施例，本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例，均属于本申请保护的范围。
在本申请实施例的描述中，如果涉及到方位描述，例如“上”、“下”、“前”、 “后”、“左”、“右”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本申请和简化描述，而不是指示或暗示所指的装置或器件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本申请的限制。
在本申请实施例的描述中，如果某一特征被称为“设置”、“固定”、“连接”、“安装”在另一个特征，它可以直接设置、固定、连接在另一个特征上，也可以间接地设置、固定、连接、安装在另一个特征上。在本申请实施例的描述中，如果涉及到“若干”，其含义是一个以上，如果涉及到“多个”，其含义是两个以上，如果涉及到“大于”、“小于”、“超过”，均应理解为不包括本数，如果涉及到“以上”、“以下”、“以内”，均应理解为包括本数。如果涉及到“第一”、“第二”，应当理解为用于区分技术特征，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量或者隐含指明所指示的技术特征的先后关系。
核酸测序中，采用开放的流体系统实现，通过将待测芯片反复浸泡多种试剂实现开放式的生化反应，在反应过程中需要试剂种类多，以及需要将芯片在多种试剂中转移以便进行相应的反应，与目前常用的二代测序方法相比，能够重复利用试剂，减少了测序成本，并且开放式反应系统能够满足测序要求以及时空组学研究需求。但目前的检测设备对试剂的添加方式复杂，导致操作较为繁杂，难以对多种试剂进行多次灌注和补液，完成设定反应和成像检测的芯片无法及时移出，影响后续芯片的反应及检测，难以进行操作节拍的优化，从而影响检测效率。本申请实施例提供了一种核酸测序系统及测序控制方法，能够采用开放式的生化反应方式，实现试剂的进液和排液，以及测试芯片的转移，从而便于芯片的上料、反应、检测和下料，有助于提高检测效率。
参考图1和图2，根据本申请第一方面实施例的核酸测序系统，包括生化反应装置10、上样装置20、检测装置30和转移装置40，其中，生化反应装置10用于为芯片提供生化反应的场所，上样装置20用芯片的进样、出样和试剂进液、排液，检测装置30用于承接从生化反应装置10转移出的芯片并对芯片进行成像检测分析。转移装置40用于于将芯片在生化反应装置10、上样装置20和检测装置30之间转移，实现芯片在整个测序流程中的转移。
参考图3，生化反应装置10包括反应容器100、移动机构150、进液机构120和排液机构。反应容器100设置有多个具有开口的试剂槽101，试剂槽101用于 盛放试剂并且浸泡待测的芯片，实现芯片的开放式浸泡。移动机构150用于将芯片在设定的试剂槽101之间转移，芯片能够进行相应的生化反应，单个试剂槽101能够先后浸泡多个芯片，实现试剂的重复实用。进液机构120连通于试剂槽101，用于移取设定试剂并向设定的试剂槽101进液。排液机构连通于试剂槽101，用于排出试剂槽101内的试剂，从而能够对试剂槽101进液和排液。由此可便于反应前试剂的灌注、反应过程中试剂的补液以及整个测序完成后试剂的排出，
参考图1和图2，上样装置20包括进出料机构220，进出料机构220包括若干承载件和移动机构150，承载件用于承载芯片，移动机构150连接于承载件，并用于驱使承载件靠近或远离反应容器100，以对芯片进样或出样。通过上样装置20实现测试芯片向生化反应装置10的进样和出样，保证反应和测试的连续性。
参考图1和图2，在一些实施例中，转移装置40包括行走机构410和机械臂420，行走机构410连接于机械臂420，用于承载并驱使机械臂420沿设定方向移动，机械臂420的执行端设置有末端抓手430，用于取放芯片；行走机构410和机械臂420配合能够驱使末端抓手430在上样装置20、生化反应装置10和检测装置30之间移动，从而在各装置进行相关的操作、反应或检测，保证测序流程的进行。
并且，本申请实施例的核酸测序系统中，上样装置20、生化反应装置10和检测装置30之间由转移装置40衔接，各装置的数量分别可根据具体的节拍进行合理配置，组合方式较为灵活，从而可通过调整流程或各装置的增减、替换进一步开发系统的测序能力，无需系统整体升级迭代，由此能够节省成本。例如，在一些实施例中，每1台生化反应装置10可对应设置1台或多台检测装置30，图1和图2中示出的是1台生化反应装置10对应设置2台检测装置30的方案。
其中，机械臂420可采用常用的六轴机械臂420，行走机构410可以采用常用的直线运动机构，从而实现机械臂420运动空间的拓展，使得末端抓手430能够到在更大的范围内活动，适用于各装置之间位置较为分散的情况，或者装置数量较多、芯片需要移动的范围较大的情况。当然，在机械臂420的活动范围可以覆盖各个装置的设定位置，从而覆盖芯片所需移动的范围的方案中，也可以省去行走机构410。
上述各装置可采用对称的布局放置，例如，以配置2台检测装置30的方案 为例，生化反应装置10和上样装置20分别设置于转移装置40的两侧，2台检测装置30分别对应于生化反应装置10和上样装置20对称设置于转移装置40的两侧，由此，在中部形成活动通道，转移装置40可通过行走机构410带动机械臂420在该通道中移动，从而能够到达各装置的对应位置以便于芯片的取放和转移。
参考图4至图8，在一些实施例中，反应容器100的各试剂槽101分别连通有进液孔102和出液孔103；进液机构120包括进液组件121和进液管路122，各进液孔102分别连接进液管路122，进液组件121用于移取设定试剂，并通过设定的进液管路122向试剂槽101进液。排液机构包括排液组件和排液管路，各出液孔103分别连接排液管路，排液组件用于将试剂槽101内的试剂通过排液管路排出。由此，通过进液孔102、出液孔103、进液机构120和排液机构能够对试剂槽101进行进液和排液，从而便于试剂的灌注、补液和更新，以便于芯片多次浸泡操作的持续进行，有助于提高反应效率，进而提高核酸测序的效率。
与现有的二代测序方法相比，避免了封闭流体系统的使用，同一试剂槽101可依次浸泡多个芯片，避免试剂浪费。由此，测序系统具备一定的柔性，可根据需要调整芯片上料浸泡和浸泡完成后下料的节拍，并依此配置前、后工序的工作节拍，例如可调整搭配上样装置20的数量、进样操作、出样操作等，以及调整搭配检测装置30的数量、检测时间等等，形成支持多种柔性组合方案的系统，便于进一步挖掘测序系统的测序效率，调整方便，无需整体升级迭代，从而节约升级成本。
参考图1至图3，在一些实施例中，生化反应装置10还包括移动机构150，其中，移动机构150包括移动组件151和夹持组件152，夹持组件152适于持取芯片，移动机构150连接于夹持组件152，用于驱使夹持组件152相对反应容器100移动以置入设定的试剂槽101中进行浸泡。通过移动机构150实现芯片在不同试剂槽101之间的移动，以便于芯片多次浸泡操作的持续进行，有助于提高反应效率，进而提高核酸测序的效率。
其中，移动组件151可采用机械设备中常用的多轴机械手实现，夹持组件152可采用气缸驱动的抓手，包括两个手指和一个气缸，气缸驱动手指相向或相离运动从而闭合或打开，可实现芯片的抓取和释放。夹持组件152还可设置多个 传感器，包括为抓取传感器、释放传感器和芯片有无检测传感器。抓取传感器用于感测两个手指是否正确闭合，可通过距离传感器或在闭合位置设置光电传感器实现该检测。释放传感器用于感测两个手指是否正确打开，可通过距离传感器或在打开位置设置光电传感器实现该检测。芯片有无检测传感器用于在开始抓取时感测抓手对应位置上是否有芯片，以及用于在转移过程中感测抓手上是否持有芯片，并且用于在释放是感测抓手上是否有芯片，由此保证抓取前能够顺利抓取芯片，抓取时能够识别芯片跌落，释放后确保芯片顺利释放。可通过接触式或非接触式的传感器实现芯片的检测。多个传感器实现芯片取放和转移操作过程的相关检测，从而提高操作的安全性，便于识别异常情况从而提高芯片抓取转移效率。
在一些实施例的测序系统中，生化反应装置10还可以包括主控机50和多个感测单元，各试剂槽101分别设置有一感测单元，感测单元用于感测对应的试剂槽101内是否容纳有芯片，并将感测信号发送至主控机50；主控机50通讯连接于移动机构150，用于控制移动组件151的对夹持组件152的移动操作以及控制夹持组件152对芯片的取放操作。主控机50能够根据感测信号控制移动机构150按设定程序取放和移动至少一个芯片。例如，设定程序可以设定每个芯片浸泡不同类型试剂的顺序和浸泡时间等等，以及，可在芯片上设置识别码，通过读取模块读取识别码获取每个芯片的样本信息，从而通过预设程序进行芯片的浸泡和转移。
主控机50是一个在工业控制应用中广泛使用的反馈回路部件，例如可编程的存储器，在其内部存储执行逻辑运算、顺序控制、定时、计数和算术运算等操作的指令，通过数字式或模拟式的输入输出来控制各种类型的机械设备或生产过程。由此可知，本申请实施例通过设定程序和感测信号实现移动组件151的对夹持组件152的移动操作以及控制夹持组件152对芯片的取放操作为本领域技术人员根据现有的控制器功能可轻易实现的，其原理及控制方法在此不做赘述。
具体而言，反应容器100可以采用一体式结构，也可以采用由多个结构件装形成的分体式结构，试剂槽101、进液孔102和出液孔103可以采用多种方式实现。例如：参考图2至图4，在一些实施例的生化反应装置10中，反应容器100包括承托件104和多个反应池107，多个反应池107按设定方式排布，并连接于承托件104，各反应池107内部设有试剂槽101，试剂槽101贯通反应池107的 顶部表面形成开口，以供芯片进出，进液孔102和出液孔103设置于反应池107的壁体上并连通于试剂槽101。由此，承托件104和多个反应池107可单独加工，并且，试剂槽101具有设定的深度以便于容纳芯片，可根据试剂槽101所需的尺寸配置反应池107的尺寸，而承托件104只需能够连接并承托反应池107即可，由此能够减轻反应容器100整体重量和材料用量。
其中，生化反应过程中的一些试剂具有一定的温度要求，为满足温度要求，目前一些采用开放式测序方法的系统中，通过设置升降装置和水浴锅，在进行具有温控需求的反应时，通过升降装置将装载有芯片和试剂的容器放入水浴锅中，实现反应温度的控制，虽然与传统的二代测序方案相比，温控方案更为简易，省去了精确的温控系统，节约了成本，但整个测序过程需要对容器进行多次升降移动，增加了机构的复杂度和控制难度。本申请一些实施例的测序系统中，反应容器100的至少部分反应池107上还可设置第一温控模块，用于调节试剂槽101内的试剂的温度，以便于进行具有一定温度要求的反应，无需移动反应容器100。其中，第一温控模块可包括温控器、加热器、温度传感器和温度保护开关，加热器可连接于反应池107的外壁，通过对反应池107加热实现试剂槽101内试剂的温度调节，加热器可选用贴片形式的加热贴，可贴附于反应池107的外壁，也可以通过内嵌的方式成型于反应池107的壁体上。
温度保护开关可作为安全器件，用于限制试剂槽101的最大温度。温度传感器和温度保护开关通讯连接于温控器，可通过温度传感器感测反应池107的温度形成温度信号，温控器接收该温度信号并指示加热器工作，在温度超过设定值时还可通过温度保护开关切换加热器的启停从而停止加热。与现有的二代测序方法相比，无需对整个生化反应装置10配置精准的温控系统，能够有效降低成本，且针对性地对部分试剂槽101实现温度控制，可便于反应温度的管理，避免出现反应的不均衡的现象。
参考图6，在一些实施例中，至少部分反应池107的壁体上还设若干安装部108，温度传感器和/或温度保护开关连接于安装部108，该部分反应池107可用于进行具有设定温度要求的浸泡反应，安装部108可便于温度传感器和/或温度保护开关的安装，安装部108可以是设置于反应池107外壁的孔状或槽状结构，温度传感器和/或温度保护开关可设置于该孔状或槽状结构内部，可避免凸出于 反应池107外壁或减少凸出于反应池107外壁的部分，从而避免碰撞损伤。
参考图4至图8，在一些实施例中，承托件104包括托盘105和侧壁106，托盘105连接于侧壁106的顶部，托盘105设置有多个贯通的安装口111，反应池107设置于安装口111内并抵持于托盘105的顶部，由此实现反应池107的承托。另外，承托件104的侧壁106支撑于托盘105的底部，从而能够将托盘105抬起，可通过侧壁106与工作台的安装实现反应容器100的定位固定，以便于通过机械手进行芯片的取放和转移。其中，托盘105的顶部还可以设置有集液槽109，用于承接收集芯片转移过程中的滴液，托盘105还开设有若干排废孔110，排废孔110连接于集液槽109，排废孔110还连接有排液管路，排液组件用于通过排液管路排出集液槽109内的液体，避免液体溢出而污染台面或其他电器件。
在一些实施例中，反应容器100也可以采用一体式的结构，例如，反应容器100包括本体，该本体上多个位置设置有试剂槽101，试剂槽101贯通该本体的顶部形成供芯片进出的开口，本体的底部封闭试剂槽101，从而能够盛放试剂；本体的侧部或底部设置连通试剂槽101的进液孔102和出液孔103，实现进液和排液的需求。该本体可以设置为一体式结构，可简化装配。
参考图9和图10，在一些实施例的测序系统中，进液组件121包括进液泵123、第一控制阀124和第二控制阀125，第一控制阀124适于通过进液管路122引入测试设定的试剂，第二控制阀125通过进液管路122连接于试剂槽101的进液孔102，进液泵123通过进液管路122连接于第一控制阀124和第二控制阀125之间，用于将所需试剂通过进液管路122、第一控制阀124和第二控制阀125通入试剂槽101中，第一控制阀124用于选择通入设定试剂，第二控制阀125用于选择设定的试剂槽101。其中，进液泵123可采用注射泵或柱塞泵，实现试剂的泵送，控制阀可选用旋转阀或三通阀，实现相应的进液管路122的通断切换。图7和图8以第一控制阀124和第二控制阀125采用旋转阀为例示出了其连接关系，本申请实施例不限于图示的连接方式。
参考图9和图10，在一些实施例的生化反应装置10中，第一控制阀124包括多个第一阀门，第一阀门用于通过进液管路122连接用于储存试剂的容器，由此可通过多个第一控制阀124中多个第一阀门的通断选择所需通入的试剂。第二控制阀125包括多个第二阀门，第二阀门用于连接试剂槽101的进液孔102，由 此可通过第二控制阀125中多个第二阀门的通断选择设定的试剂槽101注入由第一控制阀124通入的试剂。
参考图9，进液机构120包括多组进液组件121，多个第二控制阀125的第二阀门的数量之和不小于试剂槽101的数量，各试剂槽101通过进液孔102和进液管路122与各第二阀门一一对应连接，从而每个试剂槽101都可以通过第一控制阀124和第二控制阀125选择所需注入的试剂种类。
图11为本申请实施例中排液机构的部分连接示意图，参考图9和图11，在一些实施例中，排液组件包括排液泵和第三控制阀，第三控制阀通过排液管路连接于试剂槽101的出液孔103，排液泵通过排液管路连接于第三控制阀，用于将设定的试剂槽101中的试剂排出，第三控制阀用于选择设定的试剂槽101。排液机构还可包括废液容器135，用于收集排液机构排出的液体。其中，第三控制阀可以选用旋转阀或三通阀，图7和图9以第三控制阀选用旋转阀为例示意出了其连接关系，本申请实施例不限于图示的连接方式。
参考图9和图11，第三控制阀可包括多个第三阀门，第三阀门用于连接试剂槽101的出液孔103，进液机构120包括多组排液组件，多个第三控制阀的第三阀门的数量之和不小于试剂槽101的数量，各试剂槽101通过出液孔103和排液管路与各第三阀门一一对应连接。从而每个试剂槽101都可以通过第三控制阀选择所需排液的试剂槽101进行排液。
图12为本申请实施例中排液机构的另一部分连接示意图，参考图12，对于托盘105上设置有集液槽109的反应容器100，排液机构还可以设置废液泵136和废液管路137，用于连接托盘105上的排废孔110，以将集液槽109内的液体排出，从而清除芯片转移过程产生的滴液。
参考图3，在上述实施例中，生化反应装置10还包括控制箱140，控制箱140通讯连接于进液组件121，用于控制进液组件121的进液操作；控制箱140还通讯连接于排液组件，用于控制排液组件的排液操作，例如控制各控制阀选择各阀门的通断，以及控制进液泵123和排液泵的。通过控制箱140实现泵阀控制是本领域的成熟技术，其原理及控制方法在此不做赘述。
在一些实施例中，控制箱140还通讯连接于排液组件，用于控制排液组件的排液操作；主控机50还用于根据设定的试剂槽101状态指示控制箱140控制进 液组件121进液或控制排液组件排液。试剂槽101状态可包括通过计数器反馈的已进行浸泡的芯片数量，或通过计时器或设定程序反馈的已进行反应的时长，或通过液位传感器感测的液面位置。
参考图3至图5，以及图13，在一些实施例中，反应容器100的多个试剂槽101以设定方式分布形成多个反应区112，各反应区112分别具有多个试剂槽101，并且，对应于各反应区112的位置分别设置有移动机构150，各移动机构150用于在对应的反应区112内取放和移动芯片。另外，反应容器100中，还可包括缓冲区113(图中采用虚线框进行示意)，缓冲区113具有若干试剂槽101，缓冲区113位于相邻反应区112之间，相邻的移动机构150能够在缓冲区113内取放和移动芯片。由此，可实现相邻移动机构150的协作，芯片在相邻的反应区112之间转移时，可先通过一个反应区112的移动机构150将芯片放置于缓冲区113的试剂槽101，再通过另一反应区112的移动机构150抓取缓冲区113内的芯片从而转移至另一反应区112进行浸泡，避免时空交集而发生干涉。缓冲区113的还可以用于暂存反应完成等待转到光学装置进行图像采集的芯片。
在一些实施例中，各反应区112中的设定位置还可以预留部分试剂槽101作为上料位或下料位，例如，以图13示出的布局方式为例，两个反应区112分别位于缓冲区113的左右两侧，左侧反应区112远离移动机构150的一侧预留多个(图中为3个)试剂槽101作为上料位，用于接收从上样装置20的第一承载件221转移而来的待测芯片，转移装置40将芯片上料至该上料位，以便移动机构150获取芯片并进行后续的浸泡反应。反应区112远离移动机构150的一侧预留多个(图中为3个)试剂槽101作为下料位，用于存放反应完成后等待移出反应容器100的芯片，移动机构150将反应完成的芯片放置于该下料位，以便转移装置40在该下料位获取芯片并移出反应容器100。
参考图14和图15，上样装置20包括机架210、进出料机构220和存储机构240，进出料机构220包括第一承载件221、第二承载件222和移载机构，移载机构连接于机架210，用于驱使第一承载件221和第二承载件222沿进出料方向往复移动，第一承载件221用于承载待测序的芯片，第二承载件222用于承载测序完成后的芯片。存储机构240连接于机架210，包括第一存储区和第二存储区，第一存储区配置为在常温下存储试剂，可用于存储没有额外的温度要求的试剂， 例如检测过程中使用到的一些中间缓冲液和清洗液等。第二存储区设置有第二温控模块，第二温控模块用于使第二存储区的温度保持在设定温度范围内，以便在相应的温度范围内存储试剂，该温度范围低于常温，因此可以储存具有低温要求的试剂，例如一些含有酶，或者样本的试剂。
因此，本申请实施例的核酸测序系统在工作时，可通过进出样机构的第一承载件221实现待测芯片的承载，并通过移载机构进样，以便于后续转移装置40对待测芯片进行上料至反应容器100，通过转移装置40将生化反应装置10已检测完成的芯片进行下料并承载于第二承载件222，并通过移载机构移出实现出样。通过存储机构240的第一存储区和第二存储区实现具有不同温度要求的试剂的存储和供给。上样装置20实现芯片的进样和出样，并且满足不同温度要求的多种试剂的存储和供给，从而便于核酸测序系统中的芯片和试剂的对外交互，实现芯片和试剂的有序管理，以便核酸测序的有序进行。
参考图14和图16，本申请的一些实施例，移载机构包括第一移载组件223和第二移载组件224。第一移载组件223连接于第一承载件221，用于驱使第一承载件221沿进出料方向往复移动至第一位置227或第二位置228，从而可将承载有待测芯片的第一承载件221放置于第一位置227，并通过第一移载组件223移动至第二位置228实现芯片的进样，便于后续芯片的上料检测。第二移载组件224连接于第二承载件222，用于驱使第二承载件222沿进出料方向往复移动至第三位置229或第四位置230，从而将第二承载件222移动至第三位置229，用于承载检测完成后的芯片，并通过第二移载组件224移出至第四位置230，实现芯片的出料。第二位置228与第三位置229相对应，便于对同一生化反应装置10进行进料和出料。
其中，机架210上对应于第二位置228设置有到位感应器213，用于感测第一承载件221移动到第二位置228，以便于芯片上料。机架210上对应于第三位置229也设置有到位感应器213，用于感测第二承载件222移动到第三位置229，以便于芯片下料至第二承载件222上。
上述实施例中，第一移载组件223和第二移载组件224可相互独立，从而实现进样和出样的分别操作，有助于优化节拍。第一移载组件223和第二移载组件224可采用步进电机、伺服电机或直线电机实现。
图17为本申请实施例中上样装置20的进出样机构的部分结构示意图，其中示出了第一承载件221及第一移载组件223，参考图14和图17，在一些实施例中，第一承载件221设置有若干第一容纳槽225，第一容纳槽225适于收容待测序的芯片，例如，第一容纳槽225可设置为与芯片外形相适配的窄缝结构，能够收容芯片并可实现芯片的有效定位，从而便于机械化的上料操作。其中，第一容纳槽225的数量可以是1个或多个，例如2个、3个、4个、5个、6个或更多，多个第一容纳槽225沿第一设定方向间隔排布设置，从而实现待测芯片的有序进料，该第一设定方向可以与第一承载件221的进料方向一致，或者垂直于该进料方向，具体的排布方向可根据后续工序的结构进行合理配置。
在一些实施例中，第一容纳槽225内设置有第一传感器，用于检测第一容纳槽225内芯片的有无，第一传感器可选用工业生产中常用的有无检测传感器，例如限位开关或光电传感器等，由此便于后续检测工序准确获取第一承载件221上的芯片，例如通过机械手抓取芯片时，避免机械手空抓，从而确保抓取的准确性和安全性。
在一些实施例中，第二承载件222设置有若干第二容纳槽226，第二容纳槽226适于收容测序完成后的芯片，例如，第二容纳槽226可设置为与芯片外形相适配的窄缝结构，能够收容芯片。其中，第二容纳槽226的数量可以是1个或多个，例如2个、3个、4个、5个、6个或更多，多个第二容纳槽226沿第二设定方向间隔排布设置，实现芯片的有序回收和出料。其中，第二容纳槽226内还可以设置第二传感器，用于检测第二容纳槽226内芯片的有无，第二传感器选用工业生产中常用的有无检测传感器，例如限位开关或光电传感器等，由此可避免芯片重叠放置于同一第二容纳槽226而发生碰撞风险，保证安全性。需要说明的是，在一些实施例中，第二承载件222的结构与第一承载件221的结构可以相同，也可以不同。采用相同结构的第一承载件221和第二承载件222时，由于芯片进料时需要保持一定的位置精度以便于被后续工序准确获取，第一承载件221需要时常清洁维护，以保持第一容纳槽225对芯片的定位的准确性，而出料时，对芯片的定位要求低，因此第二承载件222的维护要求低于第一承载件221。
在一些实施例中，对于无需对检测完成后的芯片有序摆放的情况，第二承载件222也可以不设置上述的多个第二容纳槽226，而只需具有用于承载芯片的承 载部即可，从而可避免芯片回收时的对位放置，能够有效简化结构和操作控制。
参考图14和图15，第二温控模块可采用半导体制冷或压缩制冷的方式，以冷却第二存储区中的试剂。例如，第二温控模块包括半导体制冷器或压缩式制冷器，半导体制冷器或压缩式制冷器用于对第二存储区内的试剂制冷以维持在所需温度范围内，例如，在一些实施例中，第二温控模块用于使第二存储区的试剂保持在4℃至8℃之间，该温度适于保存一些含有酶或者样本的试剂，可采用常用的温控器实现温度的反馈和半导体制冷器或压缩式制冷器的工作状态的调节，从而维持所需的温度范围。半导体制冷器不需制冷剂、具有体积小、无噪音，重量轻等特点，且工作可靠，操作简便。压缩式制冷器主要包括压缩机、冷凝器、节流阀和蒸发器，通过压缩机的抽吸压缩、冷凝器的放热冷凝、节流阀的节流降压、蒸发器的吸热汽化的不停循环过程，达到使被冷对象温度下降目的，具有较高的制冷系数。两种制冷方式均能够实现第二存储区的有效制冷，具体实施时可根据实际的制冷和安装需求进行合理选择配置。
在一些实施例中，存储机构240还包括试剂针和第三移载组件，第三移载组件连接于试剂针，用于驱使试剂针相对第一存储区和第二存储区移动，通过试剂针抽取所需的试剂以便灌注和补液。
移液器是实验设备中通常用来准确移取一定体积的溶液的量器，因此，存储机构240也可根据试剂的体积和灌注或补液要求选择合适规格的移液器，以实现各试剂的定量移取，从而进行灌注或补液。
参考图14和图15，在一些实施例中，机架210包括平台211和机柜212，平台211位于机柜212的顶部，进出料机构220设置于平台211上，存储机构240设置于机柜212的内部，由此形成上下布局的结构，整体较为紧凑，可减少占用面积。
参考图18，转移装置40可用于在第一承载件221、生化反应装置10和第二承载件222之间移动转移芯片。转移装置40可位于第一承载件221和第二承载件222的同一侧，第一承载件221和第二承载件222可沿进样方向靠近或远离转移机构，从而便于芯片的进料和出料。其中，转移装置40可以采用多轴机械臂420，实现夹持机构的位置转移，夹持机构可以采用机械抓手或吸盘，实现芯片的持取。
进料时，可将装载有待测芯片的第一承载件221放置于第一移载组件223，通过第一移载组件223将第一承载件221朝向生化反应装置10方向移动，实现芯片的进料，转移装置40相对于上样装置20移动至第一承载件221处获取承载于第一承载件221上的待测芯片，并转移至生化反应装置10，从而将待测芯片上料至生化反应装置10。
检测完成后，芯片出料时，可通过转移装置40在生化反应装置10处获取通过生化反应装置10检测完成的芯片，再移动至第二承载件222处放置，通过第一移载组件223驱使第二承载件222移动以将收集的芯片送出，实现出料。
由上述可知，核酸测序系统工作时，通过上样装置20向生化反应装置10的试剂容器提供试剂，以及向生化反应装置10提供待测芯片以及回收测试完成的芯片，实现芯片和试剂的对外交互，并且便于检测过程中所需的试剂的灌注和补液，有助于加快处理节拍，提高测序效率。
参考图19，在一些实施例中，检测装置30包括采图平台320和图像采集仪310，采图平台320用于定位从生化反应装置10移出的芯片，图像采集仪310对应于采图平台320设置，用于对置于采图平台320上的芯片采集图像。可通过转移装置40将芯片从生化反应装置10移出以及放置于采图平台320上进行图像采集，另外，检测装置30还可包括配置有图像处理模块的工作站，工作站用于接收图像采集仪310生成的图像并通过图像处理模块处理，从而分析获取核酸序列信息。可采用本领域中常用的图像处理模块实现上述的处理和分析，其原理和算法在此不做赘述。
参考图19和图20在一些实施例中，采图平台320包括吸附盘321、真空管路322和排废管路323，真空管路322用于连接真空气源并连通于吸附盘321，用于在吸附盘321形成负压以吸附芯片，排废管路323连通于真空管路322的设定位置，用于收集和排除从吸附盘321进入真空管路322的废液，并设置隔离腔体324，液体会首先进入到隔离腔体324内，通过排废泵325抽离，从而避免废液进入真空气源，进而大大提高了真空泵326的使用寿命。真空气源可以是场地布设的真空管路322，将真空管路322通过管线接入从而实现吸附盘321的真空吸附功能，也可以是自带真空泵326，将真空泵326通过真空管路322连接从而实现吸附盘321的真空吸附功能。在一些实施例中，采图平台320还设置破真空 阀，可以很好的破真空，使得芯片的释放更快，有助于加快处理节拍。
参考图21和图22，在一些实施例中，转移装置40的末端抓手430包括手指驱动组件431和手指432，手指驱动组件431连接于手指432并用于驱动手指432张开或闭合；末端抓手430上还设置有抓取传感器、释放传感器和芯片有无传感器，其作用与前文实施例中生化反应装置10的夹持组件152相似，在此不做赘述。手指驱动组件431可以采用双向气缸实现，通过气缸驱动手指432的张合运动控制是本领域的习知技术，在此不做赘述，仅做简单介绍，其控制原理图参考图22，气缸接入压缩气源433，通过调压过滤器434、二位五通阀435和两个调速器436连接于手指432，其中还可以在二位五通阀435处设置两个消声器437，减少噪音。调压过滤器434用于调整从压缩气源433进入气缸的气压。生化反应装置10中的夹持组件152也可以采用与该末端抓手430相似的结构及控制方式。
参考图23，在一些实施例中，生化反应装置10设置上述的主控机50，并且上样装置20、转移装置40和检测装置30通讯连接于主控机50，主控机50可通过TCP/IP协议控制上样装置20、转移装置40和检测装置30，例如，主控机50用于控制上样装置20对芯片的进样和出样操作、生化反应装置10对芯片的浸泡操作、检测装置对芯片的成像检测分析操作，以及控制转移装置40件将芯片在上样装置20、生化反应装置10和检测装置30之间转移。
参考图1、图2、图23和图23，本申请第二方面实施例的测序控制方法，包括反应及检测以及进液和排液的控制，其中：
反应及检测：对试剂槽101内是否置有芯片进行感测并形成感测信号，根据感测信号并按预设的测序模式控制移动机构150将芯片移动至相应的试剂槽101中进行浸泡反应，以及控制转移装置40将已完成设定反应过程的芯片转移至检测装置30进行成像检测；
进液和排液：在反应及检测前，控制进液机构按预设程序向多个试剂槽101分别灌注设定的试剂；在反应及检测的过程中，响应于设定的反应参数信号控制进液机构对设定的试剂槽101补液；在反应及检测结束后，响应于芯片总数处理完成信号控制排液机构对试剂槽101排液。
其中，上述的反应参数信号可包括在反应及检测过程中对芯片进行计数生成 的数量信号，或者，对反应进行的时间进行感测生成的时间信号，或者，对试剂槽101的液位进行感测生成的液位信号。例如，可通过计数器实现反应芯片的计数，当该计数达到设定数量时生成数量信号，感应与该数量信号控制进液机构对设定的试剂槽101补液；或者通过计时器进行反应时间的计时，当反应时间达到设定时长时生成时间信号，响应于该时间信号控制进液机构对设定的试剂槽101补液；或者通过液位传感器感测试剂槽101的液位，感测试剂槽101的液位低于设定液位时生成液位信号，响应于该液位信号控制进液机构对设定的试剂槽101补液。上述方式仅为列举的可行的实施方式，具体实施时，还可以采用其他方式控制进液机构进行补液。
由上述的控制方法可知，通过对多个试剂槽101灌注试剂，从而能够支持通过浸泡的方式进行生化反应，通过将芯片移动至像一个的试剂槽101中进行浸泡反应，同一试剂槽101能够先后浸泡多个芯片，实现试剂的重复使用，并且，通过在反应及检测的过程中对相应的试剂槽101补液，能够保证生化反应的持续进行，芯片可持续上料、浸泡反应和成像检测，能够有效提高反应效率，从而提高测序通量。另外，与现有测序系统和测序方法针对建立文库之后的测序流程相比，本申请实施例核酸测序系统基于开放式的生化反应、柔性的装置组合和流程控制，使得随机序列的合成与测序成为可能。本申请实施例的核酸测序系统及测序控制方法也适用于进行时空组学的研究。
在一些实施例中，测序控制方法还包括芯片上下料：根据感测信号并按预设程序控制进出样机构驱使承载件靠近反应容器100，并控制转移装置40将待测芯片转移至反应容器100实现上料，或将反应及检测完成后的芯片转移至承载件实现下料。参考图23，测序过程如下：
开始测序时，通过上述芯片上下料方法将上样装置20上的待测芯片上料至生化反应装置10的反应容器100；
通过上述反应及检测方法依次进行杂交扩增和第一步合成反应，反应完成后转移至检测装置30(光机模块)进行拍照成像以及检测分析；
判断是否达到需要的轮数，若否，则切除反应后进行第二步合成反应，应完成后转移至检测装置30(光机模块)进行拍照成像以及检测分析，重复该过程直至判断达到所需轮数；若是，则下料至上样装置20，结束测序流程。
可以理解的是，核酸测序所需的生化反应需要使用多种试剂，芯片在不同的试剂中浸泡从而进行相应的生化反应，一些反应需要在设定的温度下进行，因此，在一些实施例中，测序控制方法还包括温度控制：根据预设程序控制盛放有设定试剂的试剂槽101的温度，以将设定的浸泡反应所需的试剂温度控制在所需的温度范围内。可通过第一温控模块实现相应试剂槽101的温度控制，可通过设定程序控制第一温控模块的开启、工作时长和关闭等。反应容器100设置多个试剂槽101实现多种试剂的盛放，试剂槽101的排布方式可根据生化反应的流程、试剂槽101的加热需求、循环反应的方式等等进行合理配置。
参考图24，作为一种示例，图24示出了反应容器100试剂槽101的一种布局方式，其中反应容器100包括39个试剂槽101，以每行13个的方式排成三排，为便于说明，三排试剂槽101分别标记为A、B、C，并通过数字从一侧向另一侧对应标记13列，可以通过排号和列号组合表达相应位置的试剂槽101(或试剂)，例如A1表示位于A排第1列的试剂槽101。在本实施例中，包括多种试剂：重扩增试剂、样品试剂、扩增试剂、变性试剂、消化试剂、U试剂、阻断试剂、测序引物1、测序引物2、标签引物1、标签引物2、G试剂、CLEAVE试剂、合成试剂A、合成试剂B、清洗试剂、预清洗试剂等等。
本示例中，位于中部的A7、B7、C7三个试剂槽101用于盛放清洗试剂和预清洗试剂，作为缓冲区，缓冲区将试剂槽101分为两个反应区，两个反应区的试剂槽101分别设置相应试剂，且均具有清洗试剂，各反应区中均包括具有第一温控模块的试剂槽101和常温的试剂槽101。对应于两个反应区的位置分别设置移动机构150，实现各反应区芯片的分别转移，需要芯片跨越两个反应区时，可先将芯片放置于缓冲区，再通过另一移动机构150将芯片移动到设定的试剂槽101中，避免时空间的干涉。由此，可根据试剂槽101和试剂的分别进行反应的控制。
各反应区中的设定位置还可以预留部分试剂槽101作为上料位或下料位，例如，C1、C2、C3为上料位，C11、C12、C13为下料位，转移装置40将芯片上料至该上料位，以便移动机构150获取芯片并进行后续的浸泡反应。移动机构150将反应完成的芯片放置于该下料位，以便转移装置40在该下料位获取芯片并移出反应容器100。
所有的生化反应都在上述试剂槽101中进行浸泡完成，开始反应时，先对需 要温度控制的试剂槽101开启温度设置，然后开始前清洗并清理处理的芯片次数计数，然后开始对试剂槽101灌注全部的新鲜试剂，并进行芯片的浸泡反应，当结束后将芯片移出并将芯片计数加一，然后查看是否处理完所有的芯片，如果处理完成所有的芯片，则进行试剂槽101后清洗然后结束流程。如果没有处理完成所有的芯片，则判断是否达到设定的需要补液的芯片数，如果是，则从前清洗试剂槽101开始并全部灌注新鲜试剂，否则就补损失试剂并等待下一个芯片进入浸泡反应。例如，反应区的试剂槽101的工作流程参考图25，试剂槽101的控制可按如下流程进行：
S1，开始反应时，对相应试剂槽101开启第一温控模块；
S2，进行试剂槽101前清洗，并清零芯片计数；
S3，进行试剂槽101的灌注；
S4，按预设程序将芯片浸泡至设定试剂槽101中进行反应；
S5，反应完成后将芯片移出反应容器100并对芯片计数加一；
S6，判断是否处理完所有的芯片，若是，则进行S8；若否，则进行S7；
S7，判断是否达到设定的芯片数量，若是，则进行S2至S6；若否，则继续S4至S6，并补液；
S8，进行试剂槽101后清洗操作，结束反应流程。
具体的，参考图24，本申请提供一种示例，采用的试剂包括：重扩增试剂、样品试剂、扩增试剂、变性试剂、消化试剂、U试剂、阻断试剂、测序引物1、测序引物2、标签引物1、标签引物2、G试剂、CLEAVE试剂、合成试剂A、合成试剂B、清洗试剂、预清洗试剂。试剂种类的选择以及各试剂槽101内的试剂可根据具体的反应需求和芯片的移动方式进行合理分布，本示例中各试剂槽101及其试剂采用如下分布：
A1：重扩增试剂(温控)  A7：清洗试剂           A13：清洗试剂
A2：样品试剂(温控)    A8：消化试剂(温控)     B1：清洗试剂
A3：扩增试剂(温控)    A9：扩增试剂(温控)     B2：U试剂(温控)
A4：变性试剂          A10：变性试剂          B3：阻断试剂(温控)
A5：清洗试剂          A11：清洗试剂          B4：测序引物1(温控)
A6：清洗试剂(温控)    A12：清洗试剂(温控)    B5：标签引物1(温控)
B6：清洗试剂           B13：清洗试剂          C7：预清洗试剂
B7：清洗试剂           C1：上料位             C8：合成试剂A(温控)
B8：清洗试剂           C2：上料位             C9：清洗试剂
B9：标签引物2(温控)    C3：上料位             C10：合成试剂B(温控)
B10：测序引物2(温控)   C4：CLEAVE(温控)       C11：下料位
B11：G试剂(温控)       C5：清洗试剂           C12：下料位
B12：清洗试剂          C6：预清洗试剂         C13：下料位
需要说明的是，上述分布仅作为一种可实施的方式的参考示例，不是固定的分布方式，各试剂槽101及其试剂可根据实际情况调整布置。
上述方法中，根据设定的测序模式进行反应及检测控制，参考图26，示出了双端测序模式，包括：PCR过程、一链测序过程、BARCODE1测序过程、BARCODE2测序过程和二链测序过程。其中，PCR过程在其余各过程之前，一链测序过程在二链测序过程之前。参考图24至图26，具体过程如下：
PCR过程：
开始测序时，芯片被放置到上样装置20(例如放置于第一承载件上)并通过上样装置20进料，通过转移装置40将芯片转移到反应容器100的上料位C1至C3，然后进行PCR过程1或PCR过程2。结合上述试剂槽101分布示例，PCR过程1或PCR过程2具体如下：
PCR过程1：
C1(C2,C3)-A2-(A5-A6-A3-A4)-A5-A6-A7-A8-A11-B7-B2-A5-B3-A5-B4-A5。其中，(A5-A6-A3-A4)表示该部分进行多次循环。
PCR过程2：
C1(C2,C3)-A2-A7-(A11-A12-A9-A10)-A11-A8-A11-A10-B7-B2-A5-B3-A5-B4-A5。其中，(A11-A12-A9-A10)表示该部分继续进行多次循环。
一链测序过程：
PCR过程结束后，进行FIRST过程，且在FIRST过程反应完成后，控制移动机构150将芯片转移到下料位C11至C13；结合上述试剂槽101分布示例，FIRST过程可为：C5-C6-C7-C8-C9-C10-C11(C12，C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后进行SEQENCE过程，在SEQENCE过程反应完成后，控制移动机构150将芯片转移到下料位C11至C13；结合上述试剂槽101分布示例，SEQENCE过程可以为：C1(C2,C3)-C4-C5-C6-C7-C8-C9-C10-C11(C12,C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后，控制转移装置40将芯片转移回反应容器100，判断是否完成指定轮数，若否，则返回SEQENCE过程开始继续进行反应；若是，则进入BARCODE1测序过程。
BARCODE1测序过程：
控制转移装置40将芯片转移到上料位C1至C3，进行BARCODE1过程；BARCODE1过程可以是：C1(C2,C3)-A4-A5-A7-C8-C9-C10-C11(C12,C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后进行SEQENCE过程，在SEQENCE过程反应完成后，控制移动机构150将芯片转移到下料位C11至C13；结合上述试剂槽101分布示例，SEQENCE过程可以为：C1(C2,C3)-C4-C5-C6-C7-C8-C9-C10-C11(C12,C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后，控制转移装置40将芯片转移回反应容器100，判断是否完成指定轮数，若否，则返回SEQENCE过程开始继续进行反应；若是，则进入BARCODE2测序过程。
BARCODE2测序过程：
控制转移装置40将芯片转移到上料位C1至C3，进行BARCODE2过程；BARCODE2过程可以是：C1(C2,C3)-A7-A10-B10-C8-C9-C10-C11(C12,C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后进行SEQENCE过程，在SEQENCE过程反应完成后，控制移动机构150将芯片转移到下料位C11至C13；结合上述试剂槽101分布示例，SEQENCE过程可以为：C1(C2,C3)-C4-C5-C6-C7-C8-C9-C10-C11(C12,C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测， 当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后，控制转移装置40将芯片转移回反应容器100，判断是否完成指定轮数，若否，则返回SEQENCE过程开始继续进行反应；若是，则进入二链测序过程。
二链测序过程：
后续芯片被放置到上样装置20(例如放置于第一承载件上)并通过上样装置20进料，通过转移装置40将芯片转移到反应容器100的上料位C1至C3；
进行PE过程1或PE过程2。结合上述试剂槽101分布示例，PE过程1或PE过程2具体如下：
PE过程1：
C1(C2,C3)-A1-(A4-A5-A6-A3)-A5-A4-A5-A7-B11-A7-A4-A5-B3-B7-B9-B7-A5。其中，(A4-A5-A6-A3)表示该部分进行多次循环；
PE过程2：
C1(C2,C3)-A1-A7-(A10-A11-A12-A9)-A11-A10-A11-B11-A7-A4-B3-B7-B9-B7-A5。其中，(A10-A11-A12-A9)表示该部分进行多次循环；
PE过程1或PE过程2结束后，进行FIRST过程，且在FIRST过程反应完成后，控制移动机构150将芯片转移到下料位C11至C13；结合上述试剂槽101分布示例，FIRST过程可为：C5-C6-C7-C8-C9-C10-C11(C12，C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后进行SEQENCE过程，在SEQENCE过程反应完成后，控制移动机构150将芯片转移到下料位C11至C13；结合上述试剂槽101分布示例，SEQENCE过程可以为：C1(C2,C3)-C4-C5-C6-C7-C8-C9-C10-C11(C12,C13)；
控制转移装置40将下料位C11至C13的芯片转移到检测装置30进行拍照成像检测，当检测装置30为多个时，可通过感测选择转移至空余的检测装置30；
成像检测完成后，控制转移装置40将芯片转移回反应容器100，判断是否完成指定轮数，若否，则返回SEQENCE过程开始继续进行反应；若是，控制转移装置40将下料位C11至C13的芯片转移到上样装置20(例如第二承载件)进行出样，结束测序过程。
由上述可知，本申请实施例的核酸测序系统和测序控制方法，可用于进行核酸检测，能够完成：研究者样本的杂交、扩增、单端或者双端核酸检测、生物标签的检测功能。并可配备有服务器进行fastQ文件的输出。同时由于其开放性的反应系统和流体设计，还能够用于时空组学研究，除了完成整个测序的过程外，还能完成时空组学研究需要的全部生化 过程。
上面结合附图对本申请实施例作了详细说明，但是本申请不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本申请宗旨的前提下作出各种变化。此外，在不冲突的情况下，本申请的实施例及实施例中的特征可以相互组合。

Claims (22)

  1. 核酸测序系统，其特征在于，包括：
    生化反应装置，包括反应容器、移动机构、进液机构和排液机构，所述反应容器设置有多个具有开口的试剂槽，所述试剂槽用于盛放试剂并且浸泡待测的芯片，所述移动机构用于将所述芯片在设定的所述试剂槽之间转移；所述进液机构连通于所述试剂槽，用于移取设定试剂并向设定的所述试剂槽进液，所述排液机构连通于所述试剂槽，用于排出所述试剂槽内的试剂；
    上样装置，包括进出料机构，所述进出料机构包括若干承载件和移动机构，所述承载件用于承载芯片，所述移动机构连接于所述承载件，并用于驱使所述承载件靠近或远离所述反应容器，以对芯片进样或出样；
    检测装置，用于承接从所述生化反应装置转移出的芯片并对所述芯片进行成像检测分析；
    转移装置，用于获取芯片并用于所述芯片在所述上样装置、所述生化反应装置或所述检测装置之间的相互转移。
  2. 根据权利要求1所述的核酸测序系统，其特征在于，所述反应容器包括承托件和多个反应池，多个所述反应池按设定方式排布，并连接于承托件，各所述反应池内部设有所述试剂槽，所述试剂槽贯通所述反应池的顶部表面形成所述开口，以供所述芯片进出，所述反应池的壁体上设置有连通于所述试剂槽的进液孔和出液孔；所述进液机构包括进液组件和进液管路，各所述进液孔分别连接所述进液管路，所述进液组件用于移取设定试剂，并通过设定的所述进液管路向所述试剂槽进液；所述排液机构包括排液组件和排液管路，各所述出液孔分别连接所述排液管路，所述排液组件用于将所述试剂槽内的试剂通过所述排液管路排出。
  3. 根据权利要求1所述的核酸测序系统，其特征在于，所述生化反应装置中，至少部分所述反应池上还设置有第一温控模块，用于对相应的所述试剂槽内的试剂进行温度控制，所述第一温控模块包括温度保护开关，所述温度保护开关用于限制所述试剂槽的最大温度。
  4. 根据权利要求1所述的核酸测序系统，其特征在于，所述移动机构包括移动组件和夹持组件，所述夹持组件适于持取所述芯片，所述移动机构连接于所述夹持组件，用于驱使所述夹持组件相对所述反应容器移动以将所述芯片在设定的所述试剂槽之间转移。
  5. 根据权利要求4所述的核酸测序系统，其特征在于，所述反应容器中，多个所述试剂槽以设定方式分布形成多个反应区，各所述反应区分别具有多个所述试剂槽，对应于各所述反应区的位置分别设置有所述移动机构，各所述移动机构用于在对应的所述反应区内取放和移动所述芯片，所述转移机构能够在各所述反应区取放和移动所述芯片。
  6. 根据权利要求5所述的核酸测序系统，其特征在于，所述反应容器中，还包括缓冲区，所述缓冲区具有若干所述试剂槽，所述缓冲区位于相邻所述反应区之间，相邻的所述移动机构能够在所述缓 冲区内取放和移动所述芯片，所述转移机构能够在所述缓冲区取放和移动所述芯片。
  7. 根据权利要求2所述的核酸测序系统，其特征在于，所述上样装置还包括存储机构，所述存储机构包括若干存储区，所述存储区用于存储核酸测序所需的试剂，所述进液机构还包括移液器，所述移液器通过所述进液管路连接于所述进液组件，所述移液器用于获取存储于所述存储区的试剂。
  8. 根据权利要求7所述的核酸测序系统，其特征在于，所述存储机构包括第一存储区和第二存储区，所述第一存储区配置为在常温下存储试剂，所述第二存储区设置有第二温控模块，所述第二温控模块用于使所述第二存储区的温度维持在设定温度范围内，以便在所述温度范围内存储试剂，所述温度范围低于常温。
  9. 根据权利要求1所述的核酸测序系统，其特征在于，所述检测装置包括采图平台和图像采集仪，所述采图平台用于定位从所述生化反应装置移出的芯片，所述图像采集仪对应于所述采图平台设置，用于对置于所述采图平台上的芯片采集图像。
  10. 根据权利要求9所述的核酸测序系统，其特征在于，所述检测装置还包括配置有图像处理模块的工作站，所述工作站用于接收所述图像采集仪生成的图像并通过图像处理模块处理获取核酸序列信息。
  11. 根据权利要求9所述的核酸测序系统，其特征在于，所述采图平台包括吸附盘、真空管路和排废管路，所述真空管路用于连接真空气源并连通于所述吸附盘，用于在所述吸附盘形成负压以吸附芯片，所述排废管路连通于所述真空管路的设定位置，用于收集和排除从吸附盘进入所述真空管路的废液。
  12. 根据权利要求1所述的核酸测序系统，其特征在于，所述转移装置包括行走机构和机械臂，所述行走机构连接于所述机械臂，用于承载并驱使所述机械臂沿设定方向移动，所述机械臂的执行端设置有末端抓手，用于取放芯片；所述行走机构和所述机械臂配合能够驱使所述末端抓手在所述上样装置、所述生化反应装置和所述检测装置之间移动。
  13. 根据权利要求12所述的核酸测序系统，其特征在于，所述末端抓手包括手指驱动组件和手指，所述手指驱动组件连接于所述手指并用于驱动所述手指张开或闭合；所述末端抓手上还设置有抓取传感器、释放传感器和芯片有无传感器。
  14. 根据权利要求1所述的核酸测序系统，其特征在于，所述核酸测序系统中，1台所述生化反应装置对应设置1台或多台所述检测装置。
  15. 根据权利要求1至14中任一项所述的核酸测序系统，其特征在于，所述生化反应装置还包括主控机和多个感测单元，各所述试剂槽分别设置有一感测单元，所述感测单元用于感测对应的所述试剂槽内是否容纳有芯片，并将感测信号发送至所述主控机；所述主控机能够根据所述感测信号控制所述移动机构按设定程序取放和移动至少一个芯片。
  16. 根据权利要求15所述的核酸测序系统，其特征在于，所述生化反应装置还包括控制箱，所述 控制箱通讯连接于所述进液组件，用于控制所述进液组件的进液操作；所述控制箱还通讯连接于所述排液组件，用于控制所述排液组件的排液操作；所述主控机还用于根据设定的试剂槽状态指示所述控制箱控制所述进液组件进液或控制所述排液组件排液。
  17. 根据权利要求15所述的核酸测序系统，其特征在于，所述上样装置、所述转移装置和所述检测装置通讯连接于所述主控机，所述主控机用于控制所述上样装置对芯片的进样和出样操作、所述生化反应装置对芯片的浸泡操作、所述检测装置对芯片的成像检测分析操作，以及控制所述转移装置件将芯片在所述上样装置、所述生化反应装置和所述检测装置之间转移。
  18. 测序控制方法，其特征在于，包括：
    反应及检测：对所述试剂槽内是否置有芯片进行感测并形成感测信号，根据感测信号并按预设的测序模式控制移动机构将芯片移动至相应的试剂槽中进行浸泡反应，以及控制转移装置将已完成设定反应过程的芯片转移至检测装置进行成像检测；
    进液和排液：在反应及检测前，控制进液机构按预设程序向多个试剂槽分别灌注设定的试剂；在反应及检测的过程中，响应于设定的反应参数信号控制进液机构对设定的试剂槽补液；在反应及检测结束后，响应于芯片总数处理完成信号控制排液机构对试剂槽排液。
  19. 根据权利要求18所述的测序控制方法，其特征在于，所述测序模式包括：PCR过程、一链测序过程、BARCODE1测序过程、BARCODE2测序过程和二链测序过程，其中，PCR过程在其余各过程之前，一链测序过程在二链测序过程之前。
  20. 根据权利要求18所述的测序控制方法，其特征在于，所述反应参数信号包括在反应及检测过程中对芯片进行计数生成的数量信号，或者，对反应进行的时间进行感测生成的时间信号，或者，对试剂槽的液位进行感测生成的液位信号。
  21. 根据权利要求18所述的测序控制方法，其特征在于，所述方法还包括温度控制：根据预设程序控制盛放有设定试剂的所述试剂槽的温度，以将设定的浸泡反应所需的试剂温度控制在所需的温度范围内。
  22. 根据权利要求18所述的测序控制方法，其特征在于，所述方法还包括芯片上下料：根据所述感测信号并按预设程序控制进出样机构驱使承载件靠近所述反应容器，并控制所述转移装置将待测芯片转移至所述反应容器实现上料，或将反应及检测完成后的芯片转移至所述承载件实现下料。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019023951A1 (zh) * 2017-08-01 2019-02-07 深圳华大智造科技有限公司 核酸测序方法
WO2019023948A1 (zh) * 2017-08-01 2019-02-07 深圳华大智造科技有限公司 基因测序反应设备、基因测序系统和基因测序反应方法
WO2019061353A1 (zh) * 2017-09-29 2019-04-04 深圳华大智造科技有限公司 基因测序反应设备和基因测序系统
WO2020103126A1 (zh) * 2018-11-23 2020-05-28 深圳华大智造科技有限公司 基因测序反应平台、测序芯片及相关方法、系统
WO2021128214A1 (zh) * 2019-12-26 2021-07-01 深圳华大智造科技股份有限公司 液体转移装置与方法、生化物质反应装置及生化物质分析装置与方法
CN115433667A (zh) * 2022-08-03 2022-12-06 深圳赛陆医疗科技有限公司 生化反应装置及核酸测序设备
CN115433675A (zh) * 2022-08-03 2022-12-06 深圳赛陆医疗科技有限公司 核酸测序系统及测序控制方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3342878B1 (en) * 2016-12-30 2020-07-15 GeneMind Biosciences Company Limited Method for controlling base sequence determination reaction, base sequence determination system and control device

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019023951A1 (zh) * 2017-08-01 2019-02-07 深圳华大智造科技有限公司 核酸测序方法
WO2019023948A1 (zh) * 2017-08-01 2019-02-07 深圳华大智造科技有限公司 基因测序反应设备、基因测序系统和基因测序反应方法
WO2019061353A1 (zh) * 2017-09-29 2019-04-04 深圳华大智造科技有限公司 基因测序反应设备和基因测序系统
WO2020103126A1 (zh) * 2018-11-23 2020-05-28 深圳华大智造科技有限公司 基因测序反应平台、测序芯片及相关方法、系统
WO2021128214A1 (zh) * 2019-12-26 2021-07-01 深圳华大智造科技股份有限公司 液体转移装置与方法、生化物质反应装置及生化物质分析装置与方法
CN115433667A (zh) * 2022-08-03 2022-12-06 深圳赛陆医疗科技有限公司 生化反应装置及核酸测序设备
CN115433675A (zh) * 2022-08-03 2022-12-06 深圳赛陆医疗科技有限公司 核酸测序系统及测序控制方法

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