CN221310575U

CN221310575U - Nucleic acid synthesizer

Info

Publication number: CN221310575U
Application number: CN202323251469.6U
Authority: CN
Inventors: 杜军; 朱强; 李彤; 崔树琴; 李俊杰
Original assignee: Tsingke Biotechnology Co Ltd
Current assignee: Tsingke Biotechnology Co Ltd
Priority date: 2023-11-30
Filing date: 2023-11-30
Publication date: 2024-07-12
Anticipated expiration: 2033-11-30

Abstract

The present application relates to a nucleic acid synthesizer comprising: a synthesis column; the multi-way switching valve is provided with a liquid outlet and a plurality of liquid inlets, the liquid inlets are distributed at intervals along the circumferential direction of the multi-way switching valve, the multi-way switching valve comprises a switching piece, the switching piece is provided with a switching inlet and a switching outlet which are mutually communicated, the switching outlet is communicated with the liquid outlet, the liquid outlet can be communicated with the inlet of the synthesis column, and the switching piece is configured to rotate so that the switching inlet is aligned with and communicated with any liquid inlet; among the plurality of liquid inlets, part of the liquid inlets are used for introducing various reaction reagents in a one-to-one correspondence manner, part of the liquid inlets are all used for introducing cleaning liquid, the liquid inlets used for introducing various reaction reagents in a one-to-one correspondence manner are all reagent liquid inlets, the liquid inlets used for introducing cleaning liquid are all cleaning liquid inlets, and the liquid inlets adjacent to at least one side of each reagent liquid inlet are cleaning liquid inlets. The nucleic acid synthesizer can reduce the probability of mutual pollution among reaction reagents when various liquids are switched in the multi-way switching valve.

Description

Nucleic acid synthesizer

Technical Field

The application relates to the technical field of bioengineering, in particular to a nucleic acid synthesizer.

Background

Artificially synthesized nucleic acid is the only way for the known directional modification of gene sequences, and is widely applied to various fields of protein modification, life science and the like, such as nucleic acid medicine, enzyme engineering, gene detection, gene therapy and the like. In the synthesis process, various reagents are required to be sequentially injected into the synthesis column to react with the carrier in the synthesis column. At present, a nucleic acid synthesizer is generally used for synthesizing nucleic acid, the nucleic acid synthesizer comprises a multi-way switching valve, and various liquids are switched through the multi-way switching valve, so that different reagents can be sequentially injected into a synthesis column. However, when various liquids are switched in the multi-way switching valve, mutual pollution among the reactants is easily caused, and the synthesis effect is further affected.

Disclosure of utility model

Accordingly, there is a need for a nucleic acid synthesizer that reduces the probability of mutual contamination between reagents when switching between various liquids in a multi-way switching valve, thereby increasing the success rate of synthesis.

A nucleic acid synthesizer, the nucleic acid synthesizer comprising:

A synthesis column;

The multi-way switching valve is provided with a liquid outlet and a plurality of liquid inlets, the liquid inlets are arranged at intervals along the circumferential direction of the multi-way switching valve, the multi-way switching valve comprises a switching piece, the switching piece is provided with a switching inlet and a switching outlet which are mutually communicated, the switching outlet is communicated with the liquid outlet, the liquid outlet can be communicated with the inlet of the synthesis column, and the switching piece is configured to rotate so that the switching inlet is aligned with and communicated with any liquid inlet;

Among the liquid inlets, part of the liquid inlets are used for introducing various reaction reagents in a one-to-one correspondence manner, part of the liquid inlets are used for introducing cleaning liquid, all the liquid inlets used for introducing various reaction reagents in a one-to-one correspondence manner are reagent liquid inlets, all the liquid inlets used for introducing cleaning liquid are cleaning liquid inlets, and each adjacent liquid inlet on at least one side of each reagent liquid inlet is a cleaning liquid inlet.

In one embodiment, the liquid inlet adjacent to one side of each reagent liquid inlet is the cleaning liquid inlet, and the liquid inlet adjacent to the other side is the other reagent liquid inlet.

In one embodiment, the nucleic acid synthesizer comprises a first flow path, a second flow path and a sample mixer, wherein the outlets of the first flow path and the second flow path are both communicated with the inlet of the sample mixer, the outlet of the sample mixer can be communicated with the inlet of the synthesis column, the first flow path and the second flow path are both provided with the multi-way switching valve, and the first flow path and the second flow path are respectively used for injecting different liquids into the sample mixer.

In one embodiment, the first flow path is provided with a plurality of multi-way switching valves arranged along the flowing direction of the liquid, and one of the liquid inlets of the multi-way switching valves positioned at the downstream is communicated with the liquid outlet of the multi-way switching valve positioned at the upstream in any two adjacent multi-way switching valves.

In one embodiment, the second flow path is provided with two-stage switching valve groups arranged along the flowing direction of the liquid, wherein the downstream switching valve group comprises one multi-way switching valve, the upstream switching valve group comprises a plurality of multi-way switching valves, the liquid outlets of the multi-way switching valves in the upstream switching valve group are correspondingly communicated with the liquid inlets of the multi-way switching valves in the downstream switching valve group one by one.

In one embodiment, the nucleic acid synthesizer comprises a three-way valve, one inlet of the three-way valve is used for being communicated with a cleaning solution storage barrel for storing the cleaning solution, the other inlet of the three-way valve is used for being communicated with a reagent storage barrel for storing the corresponding reaction reagent, and the outlet of the three-way valve is communicated with at least one liquid inlet of the corresponding multi-way switching valve.

In one embodiment, at least one of the liquid inlets of the multiple multi-way switching valves is communicated with the outlet of the three-way valve.

In one embodiment, the nucleic acid synthesizer includes a front end selector valve connected between the synthesis column and the sample mixer, a back end selector valve connected downstream of the synthesis column, and a circulation flow path, the front end selector valve, the synthesis column, and the back end selector valve each being on the circulation flow path, the front end selector valve and the back end selector valve each having different stations, the front end selector valve and the back end selector valve being configured to switch between the different stations to place the nucleic acid synthesizer in a first state, a second state, a third state, or a fourth state;

In the first state, the liquid flowing out from the outlet of the sample mixer can flow through the front end selection valve and the rear end selection valve in sequence and then is discharged into a waste liquid barrel for collecting waste liquid; in the second state, the liquid flowing out of the outlet of the sample mixer can flow through the front end selection valve, the synthesis column and the rear end selection valve in sequence and then be discharged into the waste liquid barrel; in the third state, the liquid flowing out of the outlet of the synthesis column can flow into the inlet of the synthesis column through the circulation flow path; in the fourth state, the rear end selector valve is configured to be opened with the cleaning liquid, and the cleaning liquid opened with the rear end selector valve can flow to the front end selector valve through the circulation flow path, and can flow to the rear end selector valve through the front end selector valve and then be discharged into the waste liquid tank.

In one embodiment, the front end selector valve and the rear end selector valve each comprise a stator and a rotor which are rotationally connected, the stator comprises a plurality of communication ports arranged at intervals along the circumferential direction of the rotor, the rotor comprises a plurality of arc-shaped channels arranged at intervals along the circumferential direction of the rotor, and the rotor can rotate relative to the stator so that adjacent communication ports are overlapped with the corresponding arc-shaped channels in position to communicate the adjacent communication ports.

In one embodiment, the stator includes a first communication port, a second communication port, a third communication port, a fourth communication port, a fifth communication port, a sixth communication port, a seventh communication port and an eighth communication port that are sequentially arranged at intervals along the circumferential direction of the rotor, and the rotor includes three groups of arc-shaped channels, wherein two groups of arc-shaped channels can each cover the circumferential ranges of 3 communication ports, and the other group of arc-shaped channels can cover the circumferential ranges of 2 communication ports;

The first communication port of the front end selection valve is communicated with the second communication port of the front end selection valve, the third communication port of the front end selection valve is communicated with the first communication port of the rear end selection valve, the fourth communication port of the front end selection valve is communicated with the inlet of the synthesis column, the fifth communication port of the front end selection valve is communicated with the outlet of the sample mixer, the seventh communication port of the front end selection valve is communicated with the fourth communication port of the rear end selection valve, the fifth communication port of the rear end selection valve is communicated with the waste liquid barrel, the seventh communication port of the rear end selection valve is communicated with the outlet of the synthesis column, and the second communication port of the rear end selection valve is used for introducing the cleaning liquid.

According to the nucleic acid synthesizer, the switching piece of the multi-way switching valve can rotate, so that the switching inlet is aligned with and communicated with any liquid inlet, and then liquid flowing in from the liquid inlet can flow to the switching outlet communicated with the liquid inlet through the switching inlet, further flows to the liquid outlet of the multi-way switching valve communicated with the switching outlet, flows into the synthesis column and reacts with the carrier in the synthesis column. The adjacent liquid inlet on at least one side of each reagent liquid inlet for introducing the reaction reagent is a cleaning liquid inlet for introducing cleaning liquid, so that after the reaction reagent is introduced into the synthesis column for reaction, the switching part is rotated to enable the switching inlet to be communicated with the reagent liquid inlet, and the cleaning liquid can be introduced into the synthesis column for cleaning only by rotating the switching part to enable the switching inlet to be aligned with the cleaning liquid inlet adjacent to the reagent liquid inlet. In the process, the switching piece can realize the feeding of the cleaning liquid only by rotating the cleaning liquid inlet positioned at the adjacent position of the reagent inlet, and the probability that other reaction reagents at the positions of the other reagent inlets pollute the switching inlet can be reduced without passing through the other reagent inlets in the rotating process of the switching piece, so that the probability of mutual pollution among the reaction reagents is reduced, and the success rate of synthesis is higher.

Drawings

Fig. 1 is a schematic structural diagram of a multi-way switching valve according to an embodiment of the application.

FIG. 2 is a schematic flow chart of a nucleic acid synthesizer according to an embodiment of the present application.

FIG. 3 is a schematic diagram showing the overall structure of a nucleic acid synthesizer according to an embodiment of the present application.

FIG. 4 is a schematic view of a circulation flow path in a first state according to an embodiment of the application.

FIG. 5 is a schematic view of a circulation flow path in a second state according to an embodiment of the application.

FIG. 6 is a schematic view of a circulation flow path in a third state according to an embodiment of the present application.

FIG. 7 is a schematic view of a circulation flow path in a fourth state according to an embodiment of the application.

FIG. 8 is a schematic view of a front end selector valve/rear end selector valve in a first position according to an embodiment of the present application.

FIG. 9 is a schematic diagram of the front end selector valve/rear end selector valve in a second position according to an embodiment of the present application.

FIG. 10 is a schematic view of the front end selector valve/rear end selector valve in a third position according to an embodiment of the present application.

Reference numerals:

100. A synthesis column; 200. a multi-way switching valve; 210. a liquid inlet; 220. a liquid outlet; 200a, a first multi-way switching valve; 200b, a second multi-way switching valve; 200c, a third multi-way switching valve; 200d, a fourth multi-way switching valve; 200e, a fifth multi-way switching valve; 200f, a sixth multi-way switching valve; 310. a first flow path; 311. a first pressure sensor; 312. a first liquid inlet pump; 313. a first flowmeter; 320. a second flow path; 321. a second pressure sensor; 322. a second liquid inlet pump; 323. a second flowmeter; 330. a sample mixer; 410. a three-way valve; 420. a reactant supply tube; 430. a cleaning liquid supply pipe; 510. a front end selection valve; 511. a communication port; 512. an arcuate channel; 520. a rear end selection valve; 530. a circulation pump; 540. a circulation flow path; 5401 first circulation section; 5402. a second circulation section; 541. a third pressure sensor; 542. a third flowmeter; 543. a fourth pressure sensor; 550. a waste liquid discharge channel; 551. a PH sensor; 552. a conductivity sensor; 553. a UV detector; 554. a back pressure valve; 555. a fourth flow meter; 556. a waste liquid valve; 557. a waste liquid branch; 560. a cleaning liquid branch.

Detailed Description

In order that the above objects, features and advantages of the application will be readily understood, a more particular description of the application will be rendered by reference to the appended drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. The present application may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit of the application, whereby the application is not limited to the specific embodiments disclosed below.

In the description of the present application, it should be understood that, if any, these terms "center", "longitudinal", "transverse", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", "axial", "radial", "circumferential", etc., are used herein with respect to the orientation or positional relationship shown in the drawings, these terms refer to the orientation or positional relationship for convenience of description and simplicity of description only, and do not indicate or imply that the apparatus or element referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore should not be construed as limiting the application.

Furthermore, the terms "first," "second," and the like, if any, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the present application, the terms "plurality" and "a plurality" if any, mean at least two, such as two, three, etc., unless specifically defined otherwise.

In the present application, unless explicitly stated and limited otherwise, the terms "mounted," "connected," "secured," and the like are to be construed broadly. For example, the two parts can be fixedly connected, detachably connected or integrated; can be mechanically or electrically connected; either directly or indirectly, through intermediaries, or both, may be in communication with each other or in interaction with each other, unless expressly defined otherwise. The specific meaning of the above terms in the present application can be understood by those of ordinary skill in the art according to the specific circumstances.

In the present application, unless expressly stated or limited otherwise, the meaning of a first feature being "on" or "off" a second feature, and the like, is that the first and second features are either in direct contact or in indirect contact through an intervening medium. Moreover, a first feature being "above," "over" and "on" a second feature may be a first feature being directly above or obliquely above the second feature, or simply indicating that the first feature is level higher than the second feature. The first feature being "under", "below" and "beneath" the second feature may be the first feature being directly under or obliquely below the second feature, or simply indicating that the first feature is less level than the second feature.

It will be understood that if an element is referred to as being "fixed" or "disposed" on another element, it can be directly on the other element or intervening elements may also be present. If an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present. The terms "vertical," "horizontal," "upper," "lower," "left," "right," and the like as used herein, if any, are for descriptive purposes only and do not represent a unique embodiment.

Referring to fig. 1 to 3, a nucleic acid synthesizer according to an embodiment of the present application includes a synthesis column 100 and a multi-way switching valve 200. The multi-way switching valve 200 has a liquid outlet 220 and a plurality of liquid inlets 210, the plurality of liquid inlets 210 are arranged at intervals along the circumference of the multi-way switching valve 200, the multi-way switching valve 200 comprises a switching member having a switching inlet and a switching outlet which are communicated with each other, the switching outlet is communicated with the liquid outlet 220, the liquid outlet 220 can be communicated with the inlet of the synthesis column 100, and the switching member is configured to rotate so that the switching inlet is aligned with and communicated with any one of the liquid inlets 210. Among the plurality of liquid inlets 210, part of the liquid inlets 210 are used for introducing various reaction reagents in a one-to-one correspondence manner, part of the liquid inlets 210 are all used for introducing cleaning liquid, the liquid inlets 210 used for introducing various reaction reagents in a one-to-one correspondence manner are all marked as reagent liquid inlets, the liquid inlets 210 used for introducing cleaning liquid are all marked as cleaning liquid inlets, and the adjacent liquid inlet 210 on at least one side of each reagent liquid inlet is a cleaning liquid inlet.

In the nucleic acid synthesizer, the switching member of the multi-way switching valve 200 can be rotated so that the switching inlet is aligned with and connected to any one of the liquid inlets 210, and the liquid flowing in from the liquid inlet 210 can flow through the switching inlet to the switching outlet connected thereto, further to the liquid outlet 220 of the multi-way switching valve 200 connected to the switching outlet, further to the synthesis column 100, and react with the carrier in the synthesis column 100. The adjacent liquid inlet 210 on at least one side of each reagent liquid inlet for introducing the reaction reagent is a cleaning liquid inlet for introducing the cleaning liquid, so after the switching member is rotated to enable the switching inlet to be communicated with the reagent liquid inlet so as to realize the reaction of introducing the reaction reagent into the synthesis column 100, the switching member is only rotated to enable the switching inlet to be aligned with the cleaning liquid inlet adjacent to the reagent liquid inlet, and then the cleaning liquid can be fed into the synthesis column 100 for cleaning. In the process, the switching piece can realize the feeding of the cleaning liquid only by rotating the cleaning liquid inlet positioned at the adjacent position of the reagent inlet, and the probability that other reaction reagents at the positions of the other reagent inlets pollute the switching inlet can be reduced without passing through the other reagent inlets in the rotating process of the switching piece, so that the probability of mutual pollution among the reaction reagents is reduced, and the success rate of synthesis is higher. Meanwhile, the switching efficiency of the switching piece can be improved, so that the synthesis efficiency is improved.

Specifically, the switching member in the multi-way switching valve 200 may be disposed at a central position of the valve body, and the switching outlet thereof may be communicated with the liquid outlet 220 of the multi-way switching valve 200 through a hose, and the switching inlet is disposed on an outer peripheral surface of the switching member, and when the switching member rotates, the direction of the switching inlet may be changed, thereby aligning with and communicating with different liquid inlets 210. The reagent inlet is connected with a reagent supply pipe 420, the reagent supply pipe 420 is communicated with a reagent storage barrel, and the reagent in the reagent storage barrel can flow to the reagent inlet through the reagent supply pipe 420. The cleaning liquid inlet is connected with a cleaning liquid supply pipe 430, the cleaning liquid supply pipe 430 is communicated with a cleaning liquid storage barrel, and cleaning liquid in the cleaning liquid storage barrel can flow to the cleaning liquid inlet through the cleaning liquid supply pipe 430. When the switching inlet is aligned with the reagent inlet, the reaction reagent can be introduced, and when the switching inlet is aligned with the cleaning liquid inlet, the cleaning liquid can be introduced. Each reagent inlet can be used for introducing different reaction reagents, and the reagent can be introduced only by setting the rotation angle of the switching piece according to the reaction requirement and enabling the switching inlet to be aligned with the reagent inlet corresponding to the required reagent. The specific structure of the inside of the multi-way switching valve 200 is the prior art, and will not be described herein.

In the embodiment shown in the drawings, the multi-way switching valve 200 is a ten-way switching valve, that is, 10 liquid inlets 210 are provided, and 10 liquid inlets 210 and one liquid outlet 220 are arranged at intervals along the circumference of the multi-way switching valve 200. In other embodiments, the multi-way switching valve 200 may be an eight-way switching valve, an eleven-way switching valve, or the like, and the multi-way switching valve 200 with a corresponding number of liquid inlets 210 may be selected according to the reaction requirement.

Referring to fig. 1-3, in some embodiments, each reagent inlet is adjacent to one side of the inlet 210 for cleaning fluid and adjacent to the other side of the inlet 210 for another reagent.

Specifically, the two reagent liquid inlets are continuously arranged, and a cleaning liquid inlet is respectively arranged at the outer sides of the whole of the two reagent liquid inlets, namely, the arrangement mode of the plurality of liquid inlets 210 is as follows: after one of the reagents is arbitrarily selected from the cleaning liquid inlet, the reagent inlet, the cleaning liquid inlet, the reagent inlet and the cleaning liquid inlet … …, one of the adjacent inlets 210 on both sides of the reagent inlet corresponding to the reagent is necessarily the cleaning liquid inlet, and the switching member is only required to be rotated to align the switching inlet with the cleaning liquid inlet adjacent to the reagent inlet, so that the cleaning liquid can be sent into the synthesis column 100 for cleaning. Therefore, after any reagent is selected to be introduced, the switching piece can reach the cleaning liquid inlet in the shortest path, so that the pollution probability of the reagent is reduced, and meanwhile, the switching efficiency of the switching piece can be improved, and the synthesis efficiency is improved.

In other embodiments, the adjacent inlet 210 on one side of each reagent inlet is a cleaning fluid inlet, and the adjacent inlet 210 on the other side is a cleaning fluid inlet. Namely, the cleaning liquid inlet and the reagent inlet are alternately arranged at intervals.

Referring to fig. 2 to 3, in some embodiments, the nucleic acid synthesizer includes a first flow path 310, a second flow path 320 and a mixer 330, wherein the outlets of the first flow path 310 and the second flow path 320 are both connected to the inlet of the mixer 330, the outlet of the mixer 330 is capable of being connected to the inlet of the synthesis column 100, the first flow path 310 and the second flow path 320 are both provided with a multi-way switching valve 200, and the first flow path 310 and the second flow path 320 are respectively used for injecting different liquids into the mixer 330.

Specifically, a first liquid inlet pump 312 is provided in the first flow path 310 for drawing liquid into the sample mixer 330; a second liquid inlet pump 322 is provided in the second flow path 320 for drawing liquid into the sample mixer 330. During the reaction, some steps require that different liquids be fed simultaneously to the synthesis column 100 for the reaction. In this embodiment, by providing the first flow path 310 and the second flow path 320, different liquids can be simultaneously fed to the synthesis column 100. In addition, since the sample mixer 330 is provided, the two liquids provided by the first flow path 310 and the second flow path 320 can be mixed uniformly in the sample mixer 330 and then fed into the synthesis column 100 to react with the carrier, thereby improving the reaction uniformity and the synthesis quality. The first flow path 310 is provided with the multi-way switching valve 200, and the cleaning liquid or different reagents can be provided for the first flow path 310 through the switching of the multi-way switching valve 200, so that different reagent requirements and cleaning requirements of each step of the reaction are met. Similarly, the second flow path 320 is provided with a multi-way switching valve 200, and by switching the multi-way switching valve 200, the second flow path 320 can be provided with cleaning liquid or different reagents, so as to meet different reagent requirements and cleaning requirements of each step of the reaction.

In the process of nucleic acid synthesis, four common monomers of T, G, C and A and 13 modified monomers are needed, and auxiliary reagents such as ACT used for monomer activation, deprotection reagents DEB, capping reagents CAPA and CAPB, oxidation reagents OXI and a thio reagent SUL are needed. Some of these reagents may be selectively fed to the synthesis column 100 via the second flow path 320, and some may be selectively fed to the synthesis column 100 via the first flow path 310. Or a portion of the reactants may be fed to the synthesis column 100 via the first flow path 310 or the synthesis column 100 via the second flow path 320. The reactant supply pipes 420 corresponding to the various types of reactants are communicated with the liquid inlets 210 in the multi-way switching valve 200 arranged on the corresponding flow path in a one-to-one correspondence. Similarly, after each reactant is reacted in the synthesis column 100, a cleaning solution is introduced to clean the synthesis column 100, and the cleaning solution can be introduced into the synthesis column 100 through the first flow path 310 or the second flow path 320. The cleaning solution supply pipe 430 has a plurality of branch ports, and part of the branch ports are communicated with the liquid inlet 210 in the multi-way switching valve 200 provided on the first flow path 310, and part of the branch ports are communicated with the liquid inlet 210 in the multi-way switching valve 200 provided on the second flow path 320, so that both flow paths can realize the supply of cleaning solution.

In addition, some of the liquid inlets 210 of the multi-way switching valve 200 may be reserved so as not to communicate with the reagent supply pipe 420 or the cleaning liquid supply pipe 430, and the supply line of the reagent to be fed into the synthesis column 100 may communicate with these liquid inlets 210 according to the reaction requirement.

Referring to fig. 2 to 3, in some embodiments, the first flow path 310 is provided with a plurality of multi-way switching valves 200 arranged along the flow direction of the liquid, and one of the plurality of liquid inlets 210 of any two adjacent multi-way switching valves 200 positioned at the downstream multi-way switching valve 200 is communicated with the liquid outlet 220 of the multi-way switching valve 200 positioned at the upstream.

Specifically, the plurality of multi-way switching valves 200 in the first flow path 310 are arranged in series, so that the type of liquid supplied to the liquid inlet 210 of the downstream multi-way switching valve 200 can be expanded, and a plurality of liquids can be supplied to the corresponding liquid inlet 210 of the downstream multi-way switching valve 200 by switching the upstream multi-way switching valve 200. In the embodiment shown in the drawings, two multi-way switching valves 200, which are a first multi-way switching valve 200a and a second multi-way switching valve 200b, are disposed on the first flow path 310 along the flow direction of the liquid. One of the plurality of liquid inlets 210 of the second multi-way switching valve 200b communicates with the liquid outlet 220 of the first multi-way switching valve 200 a. Thus, by switching the first multi-way switching valve 200a, a plurality of liquids (reagents/cleaning solutions) can be supplied to the corresponding liquid inlet 210 of the second multi-way switching valve 200b, which is connected to the liquid outlet 220. If the first multi-way switching valve 200a and the second multi-way switching valve 200b are all ten-way switching valves, by the above arrangement, the ten liquid inlets 210 of the second multi-way switching valve 200b can realize the supply of the liquid in 19, and the number of liquid supply types is greatly expanded, so as to better meet the requirements of multiple liquids in the reaction.

In other embodiments, the number of series connections of the multi-way switching valve 200 may be increased on the basis of the embodiment of the drawings to further expand the liquid supply type thereof.

Referring to fig. 2 to 3, in some embodiments, a two-stage switching valve group arranged along the flow direction of the liquid is disposed on the second flow path 320, where the downstream switching valve group includes one multi-way switching valve 200, the upstream switching valve group includes a plurality of multi-way switching valves 200, and the liquid outlets 220 of the respective multi-way switching valves 200 in the upstream switching valve group are in one-to-one correspondence with the plurality of liquid inlets 210 of the multi-way switching valves 200 in the downstream switching valve group.

Specifically, two switching valve banks are arranged in series, the second stage (downstream) switching valve bank includes a sixth multi-way switching valve 200f, and the first stage (upstream) switching valve bank includes a third multi-way switching valve 200c, a fourth multi-way switching valve 200d, and a fifth multi-way switching valve 200e that are parallel to each other. The third multi-way switching valve 200c, the fourth multi-way switching valve 200d and the fifth multi-way switching valve 200e are correspondingly communicated with the three liquid inlets 210 of the sixth multi-way switching valve 200f one by one, so as to realize the expansion of the liquid inlet types of the three liquid inlets 210. If ten-way switching valves are selected, the above arrangement can enable ten liquid inlets 210 of the sixth multi-way switching valve 200f to realize the supply of liquid in 37, and greatly expand the number of liquid supply types, thereby better meeting the requirements of various liquids in the reaction.

In other embodiments, the number of series connection of the multi-way switching valves 200 in the first-stage switching valve group can be increased on the basis of the embodiment of the drawings, so as to further expand the liquid supply type thereof.

In other embodiments, the arrangement modes of the multi-way switching valve 200 in the first flow path 310 and the second flow path 320 may be combined, for example, three-stage switching valve groups are provided, a plurality of second-stage switching valve groups connected in parallel are duplicated and provided according to the current second-stage switching valve group mode, a third-stage switching valve group is provided at the downstream of the second-stage switching valve groups connected in parallel, and the liquid outlets of the second-stage switching valve groups and the liquid inlets in the third-stage switching valve groups are correspondingly communicated one by one. In this way, a "tree" expansion structure is formed, enabling a greater expansion of the liquid supply type.

Referring to fig. 2 to 3, in some embodiments, the nucleic acid synthesizer includes a three-way valve 410, one inlet of the three-way valve 410 is used to communicate with a washing liquid storage tank storing washing liquid, the other inlet is used to communicate with a reagent storage tank storing a corresponding reaction reagent, and an outlet of the three-way valve 410 is communicated with at least one liquid inlet 210 of a corresponding multi-way switching valve 200.

Specifically, as previously described, the liquid inlet 210 in the multi-way switching valve 200 may be in communication with the reactant supply pipe 420 to effect the supply of the reactant, or may be in communication with the cleaning liquid supply pipe 430 to effect the supply of the cleaning liquid. In this embodiment, a three-way valve may be provided at least one liquid inlet 210 of the multi-way switching valve 200, with an outlet of the three-way valve being communicated with the liquid inlet 210, one inlet of the three-way valve being communicated with the cleaning liquid supply pipe 430 to be communicated with the cleaning liquid storage tub, and the other inlet of the three-way valve being communicated with the reaction reagent supply pipe 420 to be communicated with the reagent storage tub. Thus, each liquid inlet 210 can supply both the reaction reagent and the cleaning liquid, and the liquid supply type can be switched at the same liquid inlet 210 by the three-way valve, so as to further expand the liquid supply type.

Preferably, a three-way valve is disposed at each liquid inlet 210 of the multi-way switching valve 200, so as to switch the liquid supply type at each liquid inlet 210.

Referring to fig. 2-3, in some embodiments, at least one fluid inlet 210 of the multiple-way switching valves 200 is in communication with an outlet of the three-way valve 410.

Specifically, as described above, the first flow path 310 and the second flow path 320 are each provided with the multiple-way switching valves 200, and at least one liquid inlet of each of the multiple-way switching valves 200 is provided with the three-way valve 410 in the manner described above, so that the multiple-way switching valves 200 can switch the liquid supply types.

Referring to fig. 2 to 3, in some embodiments, the nucleic acid synthesizer includes a front end selector valve 510 connected between the synthesis column 100 and the sample mixer 330, a rear end selector valve 520 connected downstream of the synthesis column 100, and a circulation flow path 540, and the front end selector valve 510, the synthesis column 100, and the rear end selector valve 520 are all located on the circulation flow path 540. Referring also to fig. 8 to 10, the front end selector valve 510 and the rear end selector valve 520 each have different stations, and the front end selector valve 510 and the rear end selector valve 520 are configured to switch between the different stations to place the nucleic acid synthesizer in the first state, the second state, the third state, or the fourth state. Referring also to fig. 4, in the first state, the liquid flowing out from the outlet of the mixer 330 can flow through the front end selector valve 510 and the rear end selector valve 520 in sequence and then be discharged into the waste liquid tank for collecting waste liquid. Referring also to fig. 5, in the second state, the liquid flowing out of the outlet of the mixer 330 can flow through the front end selector valve 510, the synthesis column 100 and the rear end selector valve 520 in this order and then be discharged into the waste liquid tank. Referring also to fig. 6, in the third state, liquid flowing out of the outlet of the synthesis column 100 can flow into the inlet of the synthesis column 100 via the circulation flow path 540. Referring also to fig. 7, in the fourth state, the rear end selector valve 520 is configured to be supplied with cleaning liquid, and the cleaning liquid supplied to the rear end selector valve 520 can flow to the front end selector valve 510 through the circulation flow path 540, and can flow to the rear end selector valve 520 through the front end selector valve 510 and then be discharged into the waste liquid tank.

Specifically, the circulation flow path 540 includes a first circulation section 5401 and a second circulation section 5402 that are connected end to form a closed loop, the front end selector valve 510, the synthesis column 100 and the rear end selector valve 520 are all located on the first circulation section 5401, and the second circulation section 5402 is provided with a circulation pump 530, where the circulation pump 530 is used to drive the liquid to circulate clockwise or counterclockwise in the circulation flow path 540. The rear end selector valve 520 is connected with a cleaning liquid branch 560 for introducing cleaning liquid. In the first state, the liquid flowing out of the mixer 330 is discharged into the waste liquid tank through the front end selector valve 510 and the rear end selector valve 520 without passing through the synthesis column 100. When the synthesizer is just started, the synthesizer can be switched to the first state, and each liquid flow path is cleaned, so that the reagent remained in the last reaction does not cause adverse effect on the reaction. In the second state, if the liquid flowing out from the outlet of the sample mixer 330 is a reaction reagent, the reaction can be performed between the synthesis column 100 and the carrier; if the liquid flowing out from the outlet of the sample mixer 330 is a cleaning liquid, the synthetic column 100 after the completion of the previous reaction step can be cleaned, and preparation is made for the next step of introducing other reaction reagents. In the third state, the liquid flowing out of the outlet of the synthesis column 100 can flow into the inlet of the synthesis column 100 through the circulation flow path 540, and react with the carrier in the synthesis column 100 again, so that the reaction is more thorough, and the waste of the reaction reagent is reduced. Therefore, each time the reaction reagent is introduced into the synthesis column 100 to react, the reaction may be switched to the third state to perform the cyclic reaction. In the fourth state, the cleaning solution is introduced from the rear end selector valve 520, flows to the front end selector valve 510 through the circulation flow path 540, flows to the rear end selector valve 520 through the front end selector valve 510, and is discharged into the waste liquid barrel, and in this process, the cleaning solution washes out the reactant flowing in the circulation flow path 540 in the third state to the waste liquid barrel, so as to complete cleaning of the circulation flow path 540, and the reactant is not easy to cause cross contamination when flowing in the circulation flow path 540.

Referring to fig. 8 to 10, in some embodiments, the front end selector valve 510 and the rear end selector valve 520 each include a rotatably coupled stator and a rotor, the stator includes a plurality of communication ports 511 arranged at intervals along a circumferential direction of the rotor, the rotor includes a plurality of arc-shaped passages 512 arranged at intervals along the circumferential direction of the rotor, and the rotor is rotatable relative to the stator such that adjacent communication ports 511 are aligned with corresponding arc-shaped passages 512 to communicate the adjacent communication ports 511.

Specifically, the front end selector valve 510 and the rear end selector valve 520 have the same structure, and by operating the rotor rotation amplitudes of the front end selector valve and the rear end selector valve, the positions of the arc-shaped channels 512 are different, so that the different communication ports 511 are communicated, and the switching of multiple states is realized. When a plurality of communication ports 511 are simultaneously located within the range of one arc-shaped passage 512, the communication ports 511 can communicate through the arc-shaped passage 512, so that liquid can flow from the communication port 511 at one end to the communication port 511 at the other end in the arc-shaped passage 512.

Further, referring to fig. 8 to 10, in some embodiments, the stator includes a first communication port, a second communication port, a third communication port, a fourth communication port, a fifth communication port, a sixth communication port, a seventh communication port, and an eighth communication port that are sequentially arranged at intervals along the circumferential direction of the rotor (numerals 1 to 8 in fig. 8, which represent 8 communication ports 511). The rotor comprises three sets of arcuate channels 512, wherein two sets of arcuate channels 512 can each cover the circumferential extent of 3 communication ports 511, and another set of arcuate channels 512 can cover the circumferential extent of 2 communication ports 511. Referring to fig. 4 to 7, the first communication port of the front end selector valve 510 is communicated with the second communication port of the front end selector valve 510, the third communication port of the front end selector valve 510 is communicated with the first communication port of the rear end selector valve 520, the fourth communication port of the front end selector valve 510 is communicated with the inlet of the synthesis column 100, the fifth communication port of the front end selector valve 510 is communicated with the outlet of the sample mixer 330, the seventh communication port of the front end selector valve 510 is communicated with the fourth communication port of the rear end selector valve 520, the fifth communication port of the rear end selector valve 520 is communicated with the waste liquid tank, the seventh communication port of the rear end selector valve 520 is communicated with the outlet of the synthesis column 100, and the second communication port of the rear end selector valve 520 is used for introducing cleaning liquid.

Specifically, the first communication port of the front-end selector valve 510 and the second communication port of the front-end selector valve 510 communicate through an externally connected pipe. The third communication port of the front end selector valve 510 communicates with the first communication port of the rear end selector valve 520 through the second circulation section 5402. The seventh communication port of the front end selector valve 510 communicates with the fourth communication port of the rear end selector valve 520 through an externally connected pipe. The fifth communication port of the rear end selector valve 520 communicates with the waste liquid tank through the waste liquid discharge flow path 550. A second communication port of the rear end selector valve 520 is connected with a cleaning liquid branch 560 for introducing cleaning liquid. In the first station, in the front end selector valve 510 and the rear end selector valve 520, one of the arc-shaped channels 512 communicates the first communication port, the seventh communication port and the eighth communication port, the other arc-shaped channel 512 communicates the fourth communication port, the fifth communication port and the sixth communication port, and the other arc-shaped channel 512 communicates the second communication port and the third communication port. In the second station, in the front end selector valve 510 and the rear end selector valve 520, one of the arc-shaped channels 512 communicates the sixth communication port, the seventh communication port and the eighth communication port, the other arc-shaped channel 512 communicates the third communication port, the fourth communication port and the fifth communication port, and the other arc-shaped channel 512 communicates the first communication port and the second communication port. In the third station, in the front end selector valve 510 and the rear end selector valve 520, one of the arc-shaped channels 512 communicates the fifth communication port, the sixth communication port and the seventh communication port, the other arc-shaped channel 512 communicates the first communication port, the second communication port and the eighth communication port, and the other arc-shaped channel 512 communicates the third communication port and the fourth communication port.

In the first state, the front end selector valve 510 is in the third position and the rear end selector valve 520 is in the second position. The liquid flowing out of the outlet of the sample mixer 330 flows in through the fifth communication port of the front end selector valve 510, flows out of the seventh communication port of the front end selector valve 510, flows out to the fourth communication port of the rear end selector valve 520, flows out of the fifth communication port of the rear end selector valve 520, and is discharged into the waste liquid tank through the waste liquid discharge flow path 550.

In the second state, the front end selector valve 510 is in the first position and the rear end selector valve 520 is in the third position. The liquid flowing out of the outlet of the sample mixer 330 flows in through the fifth communication port of the front end selector valve 510, flows out of the fourth communication port of the front end selector valve 510, flows into the inlet of the synthesis column 100, flows out of the outlet of the synthesis column 100 to the seventh communication port of the rear end selector valve 520, flows out of the fifth communication port of the rear end selector valve 520, and is discharged into the waste liquid tank through the waste liquid discharge flow path 550.

In the third state, the front end selector valve 510 is in the third position and the rear end selector valve 520 is in the first position. The circulation pump 530 is activated to draw the liquid flowing out of the outlet of the synthesis column 100 into the seventh communication port of the rear end selector valve 520, and flows into the second circulation section 5402 from the first communication port of the rear end selector valve 520, and flows into the front end selector valve 510 again from the third communication port of the front end selector valve 510, and then flows into the inlet of the synthesis column 100 from the fourth communication port of the front end selector valve 510. Thus, the liquid can circulate in the circulation flow path 540, and can react with the carrier in the synthesis column 100 a plurality of times.

In the fourth state, the front end selector valve 510 is in the first position, the rear end selector valve 520 is in the second position, and the circulation pump 530 is still activated. The cleaning liquid flows into the second communication port of the rear end selector valve 520 through the cleaning liquid branch 560, flows out from the first communication port of the rear end selector valve 520 to the circulation flow path 540, flows into the front end selector valve 510 from the third communication port of the front end selector valve 510, flows out from the seventh communication port of the front end selector valve 510 to the fourth communication port of the rear end selector valve 520, flows out from the fifth communication port of the rear end selector valve 520, and is discharged into the waste liquid tank through the waste liquid discharge flow path 550.

Referring to fig. 2 and 3, in some embodiments, pressure sensors for detecting pressure, flow meters for detecting flow, and the like are provided on each flow path. For example, the first flow path 310 is provided with a first pressure sensor 311 and a first flow meter 313, and the second flow path 320 is provided with a second pressure sensor 321 and a second flow meter 323. The first circulation section 5401 is provided with a third pressure sensor 541 and a third flowmeter 542, and the second circulation section 5402 is provided with a fourth pressure sensor 543. The waste liquid discharge channel 550 is provided with a PH sensor 551 for detecting the PH value of the waste liquid, a conductivity sensor 552 for detecting the conductivity of the waste liquid, a fourth flow meter 555 for detecting the flow rate of the waste liquid, a UV detector 553, a back pressure valve 554, and the like. A waste liquid valve 556 is connected downstream of the waste liquid discharge flow path 550 for opening or closing the waste liquid discharge flow path 550. The downstream of the waste liquid valve 556 is connected with a plurality of waste liquid branches 557, and each waste liquid branch 557 downstream is provided with a waste liquid barrel, which can be discharged into the corresponding waste liquid branch 557 according to the type of waste liquid.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The above examples illustrate only a few embodiments of the application, which are described in detail and are not to be construed as limiting the scope of the claims. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the application, which are all within the scope of the application. Accordingly, the scope of protection of the present application is to be determined by the appended claims.

Claims

1. A nucleic acid synthesizer, the nucleic acid synthesizer comprising:

A synthesis column; and

2. The nucleic acid synthesizer of claim 1 wherein each of said reagent inlets is adjacent to one side of said inlet for said wash solution and adjacent to the other side of said inlet for said reagent.

3. The nucleic acid synthesizer according to claim 1 or 2, comprising a first flow path, a second flow path and a sample mixer, wherein the outlets of the first flow path and the second flow path are both communicated with the inlet of the sample mixer, the outlet of the sample mixer is capable of being communicated with the inlet of the synthesis column, the first flow path and the second flow path are both provided with the multi-way switching valve, and the first flow path and the second flow path are respectively used for injecting different liquids into the sample mixer.

4. The nucleic acid synthesizer according to claim 3, wherein a plurality of the multi-way switching valves arranged in a liquid flow direction are provided in the first flow path, and one of the liquid inlets of the downstream multi-way switching valve and the liquid outlet of the upstream multi-way switching valve are in communication with each other in any adjacent two of the multi-way switching valves.

5. The nucleic acid synthesizer according to claim 3, wherein two-stage switching valve groups arranged along the flow direction of the liquid are provided on the second flow path, wherein the downstream switching valve group comprises one of the multi-way switching valves, the upstream switching valve group comprises a plurality of the multi-way switching valves, and the liquid outlets of the multi-way switching valves in the upstream switching valve group are in one-to-one communication with the liquid inlets of the multi-way switching valves in the downstream switching valve group.

6. The nucleic acid synthesizer of claim 4 or 5, comprising a three-way valve having one inlet for communicating with a wash solution storage tank storing the wash solution and the other inlet for communicating with a reagent storage tank storing the corresponding reagent, and an outlet for communicating with at least one of the liquid inlets of the corresponding multi-way switching valve.

7. The nucleic acid synthesizer according to claim 6, wherein at least one of the liquid inlets of the multiple-way switching valves is connected to an outlet of the three-way valve.

8. The nucleic acid synthesizer of claim 3, comprising a front end selector valve connected between the synthesis column and the sample mixer, a back end selector valve connected downstream of the synthesis column, and a circulation flow path, the front end selector valve, the synthesis column, and the back end selector valve each being located on the circulation flow path, the front end selector valve and the back end selector valve each having different stations, the front end selector valve and the back end selector valve being configured to switch between the different stations to place the nucleic acid synthesizer in a first state, a second state, a third state, or a fourth state;

9. The nucleic acid synthesizer of claim 8 wherein said front end selector valve and said rear end selector valve each include a stator and a rotor rotatably connected, said stator including a plurality of communication ports circumferentially spaced along said rotor, said rotor including a plurality of arcuate channels circumferentially spaced along said rotor, said rotor being rotatable relative to said stator to position adjacent ones of said communication ports in registry with corresponding ones of said arcuate channels to communicate adjacent ones of said communication ports.

10. The nucleic acid synthesizer according to claim 9, wherein the stator includes a first communication port, a second communication port, a third communication port, a fourth communication port, a fifth communication port, a sixth communication port, a seventh communication port, and an eighth communication port that are sequentially arranged at intervals in the circumferential direction of the rotor, the rotor includes three sets of the arc-shaped passages, wherein two sets of the arc-shaped passages can each cover the circumferential ranges of 3 of the communication ports, and the other set of the arc-shaped passages can cover the circumferential ranges of 2 of the communication ports;