A multifunctional integrated device and synthesizer for high-throughput gene synthesis

Abstract

This application relates to the field of DNA synthesis technology, and in particular, to a multifunctional integrated device and a synthesizer for high-throughput gene synthesis. The integrated device includes a reaction well plate and a storage well plate, a liquid injection mechanism, a moving module, a reaction cover plate, and a multi-axis manipulator. The output end of the multi-axis manipulator is provided with a liquid discharge module, a cover plate clamping module, and a storage liquid addition module. Through the linkage between various devices, efficient and precise reagent injection, removal, and reagent rod storage operations are realized. Through the above structural design, this application eliminates the use of protective gases such as argon, reduces costs, and at the same time can ensure the normal progress of DNA synthesis. Moreover, combined with the use of the liquid discharge module, a round of DNA synthesis can be carried out quickly and efficiently, significantly improving the efficiency, precision, and stability in the process of high-throughput gene synthesis.

Description

Technical Field

[0001] The present application relates to the technical field of DNA synthesis, and in particular to a multifunctional integrated device and synthesizer for high-throughput gene synthesis. Background Art

[0002] Existing gene synthesizers include a synthesis cavity and a linear motion mechanism disposed within the synthesis cavity. A synthesis plate is mounted on the linear motion mechanism, and a liquid injection needle plate is disposed on the top wall of the synthesis cavity. The linear motion mechanism drives the synthesis column of the synthesis plate to move to a target liquid injection steel needle for injecting a target reagent.

[0003] In the related art, a patent with the publication number CN119161949A discloses a DNA synthesizer. The DNA synthesizer includes a housing assembly, a moving module, a synthesis unit, and a dispensing unit. The moving module is installed within the housing assembly. The synthesis unit includes a carrier and a synthesis plate disposed on the carrier. The carrier is disposed on the moving module and forms a synthesis cavity with the housing assembly. The carrier is provided with a protective gas inlet and a protective gas outlet, and a sealing structure that slides and rubs against the inner wall of the housing assembly is disposed on the carrier. An adjusting mechanism for driving the sealing structure away from or close to the housing assembly is disposed on the carrier. The moving module is used to drive the synthesis unit to move in at least one direction. The dispensing unit is disposed on the housing assembly and is used to inject a reagent into the synthesis plate. The present invention improves the structure of the DNA synthesizer, can synthesize a variety of genes, has a wide range of applications, the overall structure is compact, and the volume of the synthesis cavity is small, effectively reducing the loss of the protective gas for synthesizing the environment, and significantly reducing the synthesis cost.

[0004] In view of the above related art, in order to control the humidity within the synthesis cavity, it is necessary to precisely control the content of protective gases such as argon within the synthesis cavity. And in order to accurately control the content of protective gases such as argon, it is necessary to add sensors and corresponding gas path systems in the synthesizer. This design, on the one hand, leads to an increase in cost (consumption of argon), and on the other hand, due to the setting of the sensors and the gas path system, the structural complexity of the synthesizer is increased. Summary of the Invention

[0005] In order to simplify the structure and reduce the equipment usage cost, the present application provides a multifunctional integrated device and synthesizer for high-throughput gene synthesis.

[0006] In a first aspect, a multifunctional integrated device for high-throughput gene synthesis provided by the present application adopts the following technical solution:

[0007] A multifunctional integrated device for high-throughput gene synthesis, comprising:

[0008] A reaction well plate and a storage well plate, both of which have micro-wells on their surfaces and the micro-wells can accommodate reagents, and the micro-wells are connected with drainage channels;

[0009] A liquid injection mechanism for injecting reaction reagents into the micro-wells of a reaction well plate;

[0010] A moving module for driving the liquid injection mechanism to move in at least one direction;

[0011] A reaction cover plate provided with a reagent rod. The reaction cover plate can be hermetically sealed on the surface of the reaction well plate or the storage well plate, and the reagent rod can be placed in the micro-well;

[0012] A multi-axis manipulator has a liquid discharge module, a cover plate clamping module, and a storage liquid adding module at its output end. The liquid discharge module can be sealed on the surface of the reaction well plate or the storage well plate, and the liquid discharge module can push the reagent in the micro-well to the liquid discharge channel; the cover plate clamping module is used to clamp the reaction cover plate so that the reaction cover plate can be transferred between the reaction well plate and the storage well plate; the storage liquid adding module is used to inject a storage solution into the micro-wells of the storage well plate.

[0013] By adopting the above technical solution, after the liquid injection mechanism injects the reaction reagent into the micro-wells of the reaction well plate, the multi-axis manipulator uses the cover plate clamping module to clamp the reaction cover plate placed on the storage well plate to the upper surface of the reaction well plate. Then, the reagent rod of the reaction cover plate contacts and reacts with the reaction reagent in the micro-well. At the same time, the liquid discharge module is sealed on the upper surface of the storage well plate to drain the storage reagent in the micro-wells of the storage well plate. Then, the storage liquid adding module can re-inject the storage liquid into the micro-wells of the storage well plate. After the reaction between the reagent rod of the reaction cover plate and the reaction reagent is completed, the multi-axis manipulator uses the cover plate clamping module to clamp the reaction cover plate placed on the reaction well plate to the upper surface of the storage well plate, and uses the storage liquid in the storage well plate to isolate and protect the reagent rod. At the same time, the liquid discharge module drains the reaction reagent in the reaction well plate to carry out a new round of reaction process. The solution of the present application cancels the use of protective gases such as argon, reduces the cost, and can also ensure the normal progress of DNA synthesis. At the same time, combined with the use of the liquid discharge module, a round of DNA synthesis can be carried out quickly and efficiently, significantly improving the efficiency, accuracy, and stability in the high-throughput gene synthesis process. At the same time, compared with the solution of using a moving module that can move in multiple directions alone, the solution of combining the moving module that moves in at least one direction and the multi-axis manipulator has higher space utilization rate and further reduces the structural operation complexity.

[0014] Optionally, a switching turntable is provided at the output end of the multi-axis manipulator, and the liquid discharge module, the cover plate clamping module, and the storage liquid adding module are installed at intervals along the circumferential direction on the periphery of the switching turntable, and the liquid discharge module, the cover plate clamping module, and the storage liquid adding module extend outward in a direction away from the center of the switching turntable.

[0015] By adopting the above technical solutions, it is possible to further reduce the planar occupied space of the liquid discharging module, the cover plate clamping module, and the preservation liquid adding module on the upper surface of the reaction well plate or the preservation well plate, which helps to further improve the space utilization rate. Moreover, each functional module can quickly and accurately switch positions, improving the operation efficiency and flexibility.

[0016] Optionally, the liquid injection mechanism includes a liquid injection module and a liquid injection needle. A plurality of positioning holes are arranged in a crisscross pattern in the liquid injection module. The number of the positioning holes is less than the number of the micro holes. One liquid injection needle is installed in one positioning hole, and the liquid outlet end of the liquid injection needle can be placed above the micro hole.

[0017] By adopting the above technical solutions, the crisscross liquid injection needles move in one direction driven by the moving module. At this time, after a row of horizontal liquid injection needles inject reagents into the micro holes, another row of horizontally staggered liquid injection needles move to the same row of micro holes above and continue to inject reagents into the micro holes, so as to meet the addition of reagents to the micro holes in the same row of the well plate. This solution can reduce the number of liquid injection needles, reduce costs and improve the space utilization rate. In addition, it can also be applicable to the common 96-well plates and 384-well plates on the market.

[0018] Optionally, the liquid injection mechanism further includes a liquid injection bracket, a liquid injection solenoid valve, and a liquid injection pipe. The liquid injection bracket is installed at the output end of the moving module. The liquid injection module and the liquid injection solenoid valve are both installed on the liquid injection bracket. One end of the liquid injection pipe is connected to the liquid injection needle, and the other end is connected to the liquid injection solenoid valve.

[0019] By adopting the above technical solutions, the liquid injection process is made more accurate and controllable, improving the accuracy and stability of reagent injection. At the same time, this design also simplifies the equipment structure, facilitates maintenance and component replacement, and improves the overall operation convenience.

[0020] Optionally, the preservation liquid adding module includes a fixing block and a preservation liquid adding needle. The fixing block is detachably installed at the output end of the multi-axis manipulator, and the preservation liquid adding needle is installed on the fixing block.

[0021] By adopting the above technical solutions, when it is necessary to replace or clean the preservation liquid adding needle, there is no need to disassemble the whole device, which simplifies the operation process and improves the work efficiency. At the same time, this design also facilitates the quick adjustment and configuration of different preservation liquid adding needles under different experimental conditions, enhancing the adaptability and flexibility of the equipment.

[0022] Optionally, one preservation liquid adding needle is provided. When adding liquid to the micro holes of the preservation well plate, the multi-axis manipulator drives the preservation liquid adding needle to move in a serpentine trajectory.

[0023] By adopting the above technical solution, through the serpentine trajectory movement, a single liquid addition needle for the preservation solution can continuously and quickly inject liquid into multiple micro-wells, reducing the complexity and time cost brought by replacing or using a multi-channel liquid injection device; using a single liquid addition needle for the preservation solution and precisely moving it through a manipulator control after each liquid injection avoids the mutual interference between multiple needles and potential cross-contamination problems; compared with the multi-needle design, the design of the single liquid addition needle for the preservation solution is simpler, reducing the manufacturing and maintenance costs, while improving the reliability and stability of the system.

[0024] Optionally, the liquid discharge module includes a liquid discharge cover plate, a sealing groove is formed on the bottom side of the liquid discharge cover plate, the groove wall of the sealing groove can be hermetically connected to the peripheral side of the reaction well plate or the preservation well plate, a ventilation groove is formed in the center of the sealing groove, and the groove wall of the ventilation groove is externally connected to a gas supply system.

[0025] By adopting the above technical solution, a good sealing effect is achieved, thus effectively avoiding the problem of liquid leakage during the liquid discharge process. At the same time, a ventilation groove is formed in the center of the sealing groove, and the groove wall of the ventilation groove is externally connected to a gas supply system, which can provide a stable gas pressure during liquid discharge to ensure that the reagent in the micro-well is completely discharged, improving the liquid discharge efficiency and accuracy.

[0026] Optionally, a waste liquid tank is arranged at the liquid outlet end of the liquid discharge channel, and the waste liquid in the waste liquid tank contacts the liquid outlet end of the liquid discharge channel to form a liquid seal.

[0027] By adopting the above technical solution, the liquid seal can reduce the leakage of the reagent into the liquid discharge channel, enabling the reagent to be stored in the micro-well as much as possible when not discharging liquid, ensuring the normal progress of DNA synthesis.

[0028] Optionally, a pressurized liquid discharge structure for preventing the reagent from flowing into the liquid discharge channel under the action of gravity is arranged in the liquid discharge channel.

[0029] By adopting the above technical solution, the pressurized liquid discharge structure can effectively prevent the reagent from accidentally flowing into the liquid discharge channel under the action of gravity, ensuring the normal progress of DNA synthesis and the accuracy and reliability of the experimental results.

[0030] In a second aspect, a synthesizer provided by the present application adopts the following technical solution:

[0031] A synthesizer includes the above-mentioned multi-functional integrated device for high-throughput gene synthesis.

[0032] In summary, the present application includes at least one of the following beneficial technical effects:

[0033] 1. By integrating various functional modules such as reaction plates, storage plates, liquid injection mechanisms, moving modules, reaction covers, and multi-axis manipulators, the high-throughput gene synthesis process has been highly automated and integrated, significantly improving the experimental efficiency and reliability.

[0034] 2. The reagent rods on the reaction cover can be hermetically sealed in the micro-holes of the reaction plate or storage plate, effectively preventing reagent volatilization and contamination, and ensuring the stability and safety of the reaction environment.

[0035] 3. The liquid discharge module can push the reagent in the micro-hole into the liquid discharge channel and finally into the waste liquid tank, avoiding secondary pollution of waste. At the same time, the pressurized liquid discharge structure prevents the reagent from flowing into the liquid discharge channel under the action of gravity, ensuring the cleanliness and leak-free of the system. Description of the Drawings

[0036] Figure 1 It is a schematic diagram of the overall structure of the embodiment of the present application.

[0037] Figure 2 It is a schematic diagram of the structure of hiding the switching turntable and reaction cover in the embodiment of the present application.

[0038] Figure 3 It is a schematic diagram of mainly showing the bottom side of the reaction cover and the liquid discharge module in the embodiment of the present application.

[0039] Figure 4 is Figure 2 The enlarged schematic diagram of part A in

[0040] Description of the Reference Numerals:

[0041] 1, frame; 10, reaction plate; 11, storage plate; 13, micro-hole; 14, liquid discharge channel; 2, liquid injection mechanism; 21, liquid injection bracket; 22, liquid injection module; 221, positioning hole; 23, liquid injection needle; 24, liquid injection solenoid valve; 25, liquid injection tube; 3, moving module; 4, reaction cover; 41, reagent rod; 5, multi-axis manipulator; 51, switching turntable; 6, liquid discharge module; 61, liquid discharge cover; 62, sealing groove; 63, ventilation groove; 7, cover clamping module; 8, storage liquid adding module; 81, fixing block; 82, storage liquid adding needle; 9, waste liquid tank. Detailed Embodiments

[0042] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the attached Figures 1 - 4 , and the described embodiments are only possible technical implementations of the present invention, not all possible implementations. Those skilled in the art can fully combine the embodiments of the present invention to obtain other embodiments without creative labor, and these embodiments are also within the protection scope of the present invention.

[0043] The multi-functional integrated device for high-throughput gene synthesis provided by the embodiment of the present application, referring to Figure 1 and Figure 2 , includes a reaction well plate 10, a storage well plate 11, a liquid injection mechanism 2, a moving module 3, a reaction cover plate 4, and a multi-axis manipulator 5.

[0044] Referring to Figure 2 and Figure 3 , both the surfaces of the reaction well plate 10 and the storage well plate 11 are provided with micro-wells 13, and reagents can be accommodated in the micro-wells 13. The micro-wells 13 are connected with a liquid discharge channel 14; the liquid injection mechanism 2 is used to inject reaction reagents into the micro-wells 13 of the reaction well plate 10; the moving module 3 is used to drive the liquid injection mechanism 2 to move along at least one direction; the reaction cover plate 4 is provided with a reagent rod 41, the reaction cover plate 4 can be hermetically covered on the surface of the reaction well plate 10 or the storage well plate 11, and the reagent rod 41 can be placed in the micro-wells 13; the output end of the multi-axis manipulator 5 is provided with a liquid discharge module 6, a cover plate clamping module 7, and a storage liquid adding module 8. The liquid discharge module 6 can be covered on the surface of the reaction well plate 10 or the storage well plate 11, and the liquid discharge module 6 can push the reagents in the micro-wells 13 to the liquid discharge channel 14; the cover plate clamping module 7 is used to clamp the reaction cover plate 4 so that the reaction cover plate 4 can be transferred between the reaction well plate 10 and the storage well plate 11; the storage liquid adding module 8 is used to inject storage reagents into the micro-wells 13 of the storage well plate 11. This design realizes the effective combination of multiple functions on an integrated platform, significantly improving the experimental efficiency and reliability.

[0045] Referring to Figure 2 , in this embodiment, the integrated device further includes a frame 1. The reaction well plate 10 and the storage well plate 11 are both detachably connected to the inside of the frame 1, and the reaction well plate 10 and the storage well plate 11 can be quickly replaced according to requirements. Specifically, the reaction well plate 10 and the storage well plate 11 can be 96-well plates or 384-well plates on the market, or 192-well plates, etc., or can be customized into well plates with corresponding numbers of wells. The number of micro-wells 13 is not limited. In this application, a common 384-well plate on the market is used for illustration.

[0046] Preferably, the reaction well plate 10 and the storage well plate 11 can be made of metal materials. Reagents need to be accommodated in the micro-wells 13 of the reaction well plate 10 and the storage well plate 11, and the reaction temperature and storage temperature of the reagents both need to be maintained within a certain temperature range. Using reaction well plates 10 and storage well plates 11 made of metal materials is more conducive to quickly regulating the temperature and ensuring the normal progress of the reaction process. In this embodiment, there is one reaction well plate 10 and one storage well plate 11 each. In other embodiments, the number of reaction well plates 10 and storage well plates 11 can also be set to multiple.

[0047] Among them, the micro-holes 13 in the reaction well plate 10 are mainly used to accommodate reaction reagents, and the micro-holes 13 in the storage well plate 11 are mainly used to accommodate storage reagents. The reaction reagents mainly refer to various reagents in the process of synthesizing DNA, including deprotecting agents, activating agents, capping reagents, etc. The storage reagents mainly refer to the reagents used to store the reagent rod 41 to prevent the reagent rod 41 from reacting with air for a long time, mainly including DNA storage solution, phosphate solution, etc.

[0048] Referring to Figure 2 and Figure 4 In a preferred embodiment, the liquid injection mechanism 2 includes a liquid injection support 21, a liquid injection module 22, a liquid injection needle 23, a liquid injection solenoid valve 24, a liquid injection pipe 25, and a reagent bottle (not shown in the figure). The liquid injection support 21 is installed at the output end of the moving module 3. The liquid injection support 21 is provided with multiple layers in the height direction. The liquid injection module 22 is installed at the bottom layer of the liquid injection support 21, and under the movement of the moving module 3, the liquid injection module 22 can be disposed opposite to the reaction well plate 10.

[0049] Specifically, a plurality of criss-crossing positioning holes 221 are provided inside the liquid injection module 22. The number of these positioning holes 221 is less than the number of micro-holes 13. A liquid injection needle 23 is installed in one positioning hole 221. For example, for a 384-well plate, the number of its holes is 16×24. At this time, there are 8 positioning holes 221 in the same row in the horizontal direction, and the number of positioning holes 221 arranged alternately in the other row in the horizontal direction is also 8. The liquid injection needles 23 of the two rows of positioning holes 221 inject reagents into the micro-holes 13 of the same row of 16 holes in turn, so as to realize the replenishment of reagents in the micro-holes 13. This design can reduce the number of liquid injection needles 23 and reduce costs. In addition, it can also be adapted to the addition of reagents in 96-well plates, with a wider applicability.

[0050] Among them, one end of the liquid injection pipe 25 is connected to the liquid injection needle 23, and the other end is connected to the liquid injection solenoid valve 24. The liquid injection solenoid valve 24 is installed on the liquid injection support 21 and is located above the liquid injection needle 23, which is beneficial to the arrangement and sorting of the liquid injection pipe 25. The number of liquid injection solenoid valves 24 is set corresponding to the number of liquid injection needles 23, so that the liquid injection needles 23 can inject corresponding reagents. The reagent bottle is used to supply corresponding reagents and is also installed on the liquid injection support 21. The reagent bottle is connected to the liquid injection solenoid valve 24 through a pipeline. At the same time, an electric control system of the liquid injection solenoid valve 24 is also installed on the liquid injection support 21, and the electric control system is located above the liquid injection solenoid valve 24. When the moving module 3 moves, it can drive the entire liquid injection mechanism 2 to move. This design helps to enhance the overall stability of the liquid injection mechanism 2.

[0051] In a preferred embodiment, the moving module 3 is an X-axis moving module 3 or a Y-axis moving module 3. The moving module 3 is used to drive the liquid injection needle 23 to move unidirectionally, so that the liquid injection needle 23 can be quickly placed above the micro-holes 13 of the reaction well plate 10 to realize the addition of reagents.

[0052] Referring to Figure 2 and Figure 3 , the reagent rod 41 is fixed to the bottom side of the reaction cover plate 4. The surface of the reagent rod 41 is set as a hydrophobic surface. The number of reagent rods 41 corresponds one-to-one with the number of micro-holes 13. The reagent rod 41 can be inserted into the micro-hole 13 and contact with the reagent. Preferably, a clamping portion is provided on the top side of the reaction cover plate 4. The cover plate clamping module 7 can clamp the reaction cover plate 4 through the clamping portion and transfer it between the reaction well plate 10 and the storage well plate 11, so as to realize the reaction and storage of the reagent rod 41 and ensure the smooth progress of DNA synthesis. This solution eliminates the use of protective gases such as argon, and the equipment has lower usage costs and is easier to control.

[0053] Specifically, each module of the multi-axis manipulator 5 can be driven by a servo motor, and smooth and reliable movement can be achieved through a precision gear reducer. In one embodiment, the liquid discharge module 6, the cover plate clamping module 7, and the storage liquid adding module 8 are installed at intervals along the circumferential direction at the output end of the multi-axis manipulator 5. The extending directions of the liquid discharge module 6, the cover plate clamping module 7, and the storage liquid adding module 8 are the same as the central extending direction of the output end of the multi-axis manipulator 5. At this time, the output ends of the liquid discharge module 6, the cover plate clamping module 7, and the storage liquid adding module 8 are approximately located in the same plane, and function switching is realized by moving the multi-axis manipulator 5. However, this solution occupies a large area in the horizontal plane.

[0054] Referring to Figure 2 and Figure 3 , in a preferred embodiment, a switching turntable 51 is installed at the output end of the multi-axis manipulator 5. The multi-axis manipulator 5 can drive the switching turntable 51 to rotate. The liquid discharge module 6, the cover plate clamping module 7, and the storage liquid adding module 8 are installed at intervals along the circumferential direction on the switching turntable 51. The liquid discharge module 6, the cover plate clamping module 7, and the storage liquid adding module 8 extend outward in a direction away from the center of the switching turntable 51. It can further reduce the plane occupation space of the liquid discharge module 6, the cover plate clamping module 7, and the storage liquid adding module 8 on the upper surface of the reaction well plate 10 or the storage well plate 11, which helps to further improve the space utilization rate.

[0055] In a preferred embodiment, the liquid discharge module 6 includes a liquid discharge cover plate 61. A sealing groove 62 is opened on the bottom side of the liquid discharge cover plate 61. The groove wall of the sealing groove 62 can be hermetically connected to the peripheral side of the reaction well plate 10 or the storage well plate 11. An air vent groove 63 is opened at the center of the sealing groove 62, and the groove wall of the air vent groove 63 is externally connected to a gas supply system.

[0056] Optionally, a sealing ring is provided on the peripheral side of the sealing groove 62, and the sealing ring abuts against the peripheral side of the reaction or storage orifice plate 10 or 11, further enhancing the sealing effect. Further, an electromagnet control module may be provided between the liquid discharge cover plate 61 and the reaction or storage orifice plate 10 or 11 to further enhance the sealing performance between the liquid discharge cover plate 61 and the reaction or storage orifice plate 10 or 11 by using the electromagnet control module.

[0057] After the liquid discharge cover plate 61 is covered with the reaction or storage orifice plate 10 or 11, air is introduced into the ventilation groove 63 through the air supply system, and the reagent in the microhole 13 is pushed out by blowing, and the reagent is discharged into the liquid discharge channel 14 and discharged from the liquid discharge channel 14. Optionally, a waste liquid tank 9 is provided on the bottom side of the liquid discharge channel 14, and the reagent can be discharged into the waste liquid tank 9 for unified collection by the waste liquid tank 9.

[0058] The liquid outlet end of the liquid discharge channel 14 is placed in the waste liquid tank 9, and the liquid outlet end of the liquid discharge channel 14 contacts the waste liquid in the waste liquid tank 9 to form a liquid seal, so as to reduce the inflow of the reagent in the microhole 13 into the liquid discharge channel 14. Further, the aperture of the liquid discharge channel 14 can be designed to be smaller so that it is difficult for the reagent to flow into the liquid discharge channel 14 without external force. Further still, a pressurized liquid discharge structure (not shown in the figure) for preventing the reagent from flowing into the liquid discharge channel 14 under the action of gravity may be provided in the liquid discharge channel 14. The pressurized liquid discharge structure may be a small pump, which is controlled to be turned on and off by the small pump. In addition, the pressurized liquid discharge structure may also be other devices capable of preventing the reagent from flowing into the liquid discharge channel 14 under the action of gravity, and the structure is not specifically limited in this application.

[0059] In a preferred embodiment, the cover plate clamping module 7 is a finger cylinder, and the finger cylinder can clamp the clamping part of the reaction cover plate 4 to transfer the reaction cover plate 4 between the reaction orifice plate 10 and the storage orifice plate 11. In other embodiments, the cover plate clamping module 7 may also be a common clamping mechanism on the market.

[0060] In a preferred embodiment, the storage liquid adding module 8 includes a fixing block 81 and a storage liquid adding needle 82. The fixing block 81 can be detachably installed on the switching turntable 51 by bolts, and the storage liquid adding needle 82 is installed on the fixing block 81. Further, the storage liquid adding needle 82 is provided with one, and when adding liquid to the microholes 13 of the storage orifice plate 11, the multi-axis manipulator 5 drives the storage liquid adding needle 82 to move in a snake-like trajectory. Through the snake-like trajectory movement, a single storage liquid adding needle 82 can continuously and quickly inject liquid into a plurality of microholes 13, reducing the complexity and time cost brought by replacing or multi-channel liquid injection devices.

[0061] Preferably, the depth of the micro-holes 13 in the storage well plate 11 is less than that of the micro-holes 13 in the reaction well plate 10. The reason for such a design is that the requirements for the reagent rod 41 to contact the reaction reagent and the storage reagent are different. During the storage process of the reagent rod 41, it is only necessary for the end of the reagent rod 41 to contact the storage reagent. Therefore, such a design can reduce the usage amount of the storage reagent and lower the cost. Further, the micro-holes 13 in the storage well plate 11 can be connected through grooves, so that the amount of the storage reagent in each micro-hole 13 can be basically kept consistent, further enhancing the protection effect on the reagent rod 41. In other embodiments, the storage liquid adding needle 82 can also move in an involute trajectory driven by the multi-axis manipulator 5, etc.

[0062] The implementation principle of the embodiment of the present application is as follows: After the liquid injection mechanism 2 injects the reaction reagent into the micro-holes 13 of the reaction well plate 10, the moving module 3 controls the liquid injection mechanism 2 to move away. The multi-axis manipulator 5 uses the cover plate clamping module 7 to clamp the reaction cover plate 4 placed on the storage well plate 11 to the upper surface of the reaction well plate 10. Then, the reagent rod 41 of the reaction cover plate 4 contacts and reacts with the reaction reagent in the micro-hole 13. At the same time, the liquid discharge module 6 is covered on the upper surface of the storage well plate 11 to discharge the storage reagent in the micro-holes 13 of the storage well plate 11. Then, the storage liquid adding module 8 re-injects the storage liquid into the micro-holes 13 of the storage well plate 11. After the reaction between the reagent rod 41 of the reaction cover plate 4 and the reaction reagent is completed, the multi-axis manipulator 5 uses the cover plate clamping module 7 to clamp the reaction cover plate 4 placed on the reaction well plate 10 to the upper surface of the storage well plate 11, and uses the storage liquid in the storage well plate 11 to isolate and protect the reagent rod 41. At the same time, the liquid discharge module 6 discharges the reaction reagent in the reaction well plate 10 to carry out a new round of reaction process.

[0063] By integrating various functional modules such as the reaction well plate 10, the storage well plate 11, the liquid injection mechanism 2, the moving module 3, the reaction cover plate 4, and the multi-axis manipulator 5, the present application realizes the high degree of automation and integration of the high-throughput gene synthesis process, significantly improving the experimental efficiency and reliability.

[0064] The embodiment of the present application also discloses a synthesizer, which is mainly used for synthesizing DNA. Among them, the synthesizer includes the above-mentioned multi-functional integrated device for high-throughput gene synthesis. The synthesizer with the above integrated device not only simplifies the equipment structure, but also improves the reliability and repeatability of the experimental results, which is of great significance for promoting the development of high-throughput gene synthesis technology.

[0065] The above are all the preferred embodiments of the present application, and the protection scope of the present application is not limited by this. Therefore, all equivalent changes made according to the structure, shape, and principle of the present application should be covered within the protection scope of the present application.

Claims

1. A multifunctional integrated device for high-throughput gene synthesis, characterized in that: include: A reaction well plate (10) and a storage well plate (11), both of which have micropores (13) on their surfaces, and the micropores (13) are capable of accommodating reagents, and the micropores (13) are connected to drainage channels (14); A liquid injection mechanism (2) is used to inject the reaction reagent into the micropores (13) of the reaction well plate (10); A moving module (3) used for driving the liquid pumping mechanism (2) to move in at least one direction; A reaction cover plate (4) provided with a reagent stick (41); the reaction cover plate (4) can be sealed and covered on the surface of the reaction well plate (10) or the storage well plate (11), and the reagent stick (41) can be placed in the microwell (13); A multi-axis manipulator (5) is provided with a liquid discharge module (6), a cover plate clamping module (7) and a preservation solution adding module (8) at its output end. The liquid discharge module (6) can cover the surface of the reaction well plate (10) or the preservation well plate (11), and the liquid discharge module (6) can push the reagent in the microwell (13) to the liquid discharge channel (14); the cover plate clamping module (7) is used to clamp the reaction cover plate (4) so ​​that the reaction cover plate (4) can be transferred between the reaction well plate (10) and the preservation well plate (11); and the preservation solution adding module (8) is used to inject the preservation solution into the microwell (13) of the preservation well plate (11).

2. A multifunctional integrated device for high-throughput gene synthesis according to claim 1, characterized in that: The output end of the multi-axis manipulator (5) is provided with a switching turntable (51), and the liquid discharge module (6), the cover plate clamping module (7) and the preservation liquid adding module (8) are installed at intervals along the circumferential direction on the circumference of the switching turntable (51), and the liquid discharge module (6), the cover plate clamping module (7) and the preservation liquid adding module (8) extend outward in a direction away from the center of the switching turntable (51).

3. The multifunctional integrated device for high-throughput gene synthesis according to claim 1, characterized in that: The liquid injection mechanism (2) comprises a liquid injection module (22) and a liquid injection needle (23); a plurality of positioning holes (221) arranged in a crisscross pattern are provided in the liquid injection module (22); the number of the positioning holes (221) is less than the number of the micropores (13); one of the liquid injection needles (23) is installed in one of the positioning holes (221); and the liquid outlet end of the liquid injection needle (23) can be placed above the micropores (13).

4. A multifunctional integrated device for high-throughput gene synthesis according to claim 3, characterized in that: The liquid pumping mechanism (2) further comprises a liquid pumping bracket (21), a liquid pumping solenoid valve (24) and a liquid pumping tube (25); the liquid pumping bracket (21) is mounted on the output end of the movable module (3); the liquid pumping module (22) and the liquid pumping solenoid valve (24) are both mounted on the liquid pumping bracket (21); one end of the liquid pumping tube (25) is connected to the liquid pumping needle (23), and the other end is connected to the liquid pumping solenoid valve (24).

5. The multifunctional integrated device for high-throughput gene synthesis according to claim 1, characterized in that: The preservation solution adding module (8) comprises a fixed block (81) and a preservation solution adding needle (82); the fixed block (81) is detachably mounted on the output end of the multi-axis manipulator (5); and the preservation solution adding needle (82) is mounted on the fixed block (81).

6. A multifunctional integrated device for high-throughput gene synthesis according to claim 5, characterized in that: The preservation solution adding needle (82) is provided as one, and when adding liquid to the micropores (13) of the preservation well plate (11), the multi-axis manipulator (5) drives the preservation solution adding needle (82) to move in a serpentine trajectory.

7. The multifunctional integrated device for high-throughput gene synthesis according to claim 1, characterized in that: The drainage module (6) comprises a drainage cover plate (61), a sealing groove (62) is provided on the bottom side of the drainage cover plate (61), the groove wall of the sealing groove (62) can be sealed and connected to the peripheral side of the reaction well plate (10) or the storage well plate (11), a ventilation groove (63) is provided at the center of the sealing groove (62), and the groove wall of the ventilation groove (63) is externally connected to a gas supply system.

8. The multifunctional integrated device for high-throughput gene synthesis according to claim 1, characterized in that: A waste liquid tank (9) is provided at the liquid outlet end of the liquid discharge channel (14), and waste liquid in the waste liquid tank (9) contacts the liquid outlet end of the liquid discharge channel (14) to form a liquid seal.

9. A multifunctional integrated device for high-throughput gene synthesis according to claim 1 or 8, characterized in that: The drainage channel (14) is provided with a pressurized drainage structure for preventing the reagent from flowing into the drainage channel (14) under the action of gravity.

10. A synthesizer, characterized in that: A multifunctional integrated device for high-throughput gene synthesis comprising any one of claims 1 to 9.

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