Nucleic acid synthesizer

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 in 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 communicated with each other, the switching outlet is communicated with the liquid outlet, the liquid outlet can be communicated with the synthetic column inlet, and the switching piece is configured to rotate; the switching inlet is aligned with and communicated with any liquid inlet; in 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 used for introducing cleaning liquid, the liquid inlets used for introducing the various reaction reagents in the one-to-one correspondence manner are reagent liquid inlets, and the liquid inlets used for introducing the cleaning liquid are cleaning liquid inlets; the liquid inlet adjacent to at least one side of each reagent liquid inlet is a cleaning liquid inlet. 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

Technical Field

[0001] The present application relates to the field of bioengineering technology, and particularly to a nucleic acid synthesizer. Background Art

[0002] Artificial synthesis of nucleic acids is the only known way to directionally modify gene sequences, which is widely used in multiple fields such as protein modification and life sciences, such as nucleic acid drugs, enzyme engineering, gene detection, gene therapy, etc. During the synthesis process, various reaction reagents need to be injected into the synthesis column in sequence to react with the carrier in the synthesis column. Currently, a nucleic acid synthesizer is usually used to achieve the synthesis of nucleic acids. The nucleic acid synthesizer includes a multi-way switching valve, and various liquids are switched through the multi-way switching valve so that different reagents can be injected into the synthesis column in sequence. However, when various liquids are switched in the multi-way switching valve, it is easy to cause mutual contamination between reaction reagents, thereby affecting the synthesis effect. Summary of the Invention

[0003] Based on this, it is necessary to provide a nucleic acid synthesizer that can reduce the probability of mutual contamination between reaction reagents when various liquids are switched in the multi-way switching valve, so as to achieve a higher synthesis success rate.

[0004] A nucleic acid synthesizer, the nucleic acid synthesizer includes:

[0005] A synthesis column;

[0006] A multi-way switching valve having an outlet and a plurality of inlets. The plurality of inlets are arranged at intervals along the circumference of the multi-way switching valve. The multi-way switching valve includes a switching member having a mutually connected switching inlet and a switching outlet. The switching outlet is communicated with the outlet, and the outlet can be communicated with the inlet of the synthesis column. The switching member is configured to rotate so that the switching inlet is aligned with and communicated with any one of the inlets.

[0007] Among the plurality of inlets, some of the inlets are used to introduce various reaction reagents one by one, and some of the inlets are all used to introduce a cleaning solution. The inlets used to introduce various reaction reagents one by one are reagent inlets, and the inlets used to introduce the cleaning solution are cleaning solution inlets. Each of the reagent inlets has a cleaning solution inlet adjacent to at least one side of it.

[0008] In one embodiment, the inlet adjacent to one side of each reagent inlet is a cleaning solution inlet, and the inlet adjacent to the other side is another reagent inlet.

[0009] In one embodiment, the nucleic acid synthesizer includes a first flow path, a second flow path, and a sample mixer. The outlets of the first flow path and the second flow path are both connected to the inlet of the sample mixer. The outlet of the sample mixer can be connected to the inlet of the synthesis column. The first flow path and the second flow path are both provided with the multi-way switching valves, and the first flow path and the second flow path are respectively used to inject different liquids into the sample mixer.

[0010] In one embodiment, a plurality of the multi-way switching valves are arranged along the liquid flow direction on the first flow path. Among any two adjacent multi-way switching valves, one of the plurality of liquid inlets of the multi-way switching valve located downstream is connected to the liquid outlet of the multi-way switching valve located upstream.

[0011] In one embodiment, a two-stage switching valve group is arranged along the liquid flow direction on the second flow path. Among them, the switching valve group located downstream includes one multi-way switching valve, and the switching valve group located upstream includes a plurality of multi-way switching valves. The liquid outlets of the multi-way switching valves in the switching valve group located upstream are respectively connected to the plurality of liquid inlets of the multi-way switching valve in the switching valve group located downstream in a one-to-one correspondence.

[0012] In one embodiment, the nucleic acid synthesizer includes a three-way valve. One inlet of the three-way valve is used to connect to a cleaning solution storage bucket for storing the cleaning solution, and the other inlet is used to connect to a reagent storage bucket for storing the corresponding reaction reagent. The outlet of the three-way valve is connected to at least one of the liquid inlets of the corresponding multi-way switching valve.

[0013] In one embodiment, at least one of the liquid inlets of the plurality of multi-way switching valves is connected to the outlet of the three-way valve.

[0014] In one embodiment, the nucleic acid synthesizer includes a front-end selection valve connected between the synthesis column and the sample mixer, a rear-end selection valve connected downstream of the synthesis column, and a circulation flow path. The front-end selection valve, the synthesis column, and the rear-end selection valve are all located on the circulation flow path. The front-end selection valve and the rear-end selection valve both have different working positions. The front-end selection valve and the rear-end selection valve are configured to switch between different working positions so that the nucleic acid synthesizer is in a first state, a second state, a third state, or a fourth state;

[0015] In the first state, the liquid flowing out of the outlet of the sample mixer can sequentially flow through the front-end selection valve and the rear-end selection valve and then be discharged into a waste liquid bucket for collecting waste liquid; in the second state, the liquid flowing out of the outlet of the sample mixer can sequentially flow through the front-end selection valve, the synthesis column and the rear-end selection valve and then be discharged into the waste liquid bucket; 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 selection valve is configured to introduce the cleaning liquid, and the cleaning liquid introduced into the rear-end selection valve can flow through the circulation flow path to the front-end selection valve, and then flow through the front-end selection valve to the rear-end selection valve and then be discharged into the waste liquid bucket.

[0016] In one embodiment, both the front-end selection valve and the rear-end selection valve include a stator and a rotor rotatably connected. The stator includes a plurality of communication ports arranged at intervals along the circumferential direction of the rotor, and the rotor includes a plurality of arc-shaped channels arranged at intervals along the circumferential direction of the rotor. The rotor can rotate relative to the stator so that a plurality of adjacent communication ports coincide with corresponding arc-shaped channels to connect the plurality of adjacent communication ports.

[0017] 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 arranged at intervals in sequence along the circumferential direction of the rotor. The rotor includes three groups of arc-shaped channels, and two of the groups of arc-shaped channels can both cover the circumferential range of 3 communication ports, and the other group of arc-shaped channels can cover the circumferential range of 2 communication ports;

[0018] 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 bucket. The seventh communication port of the rear-end selection valve is communicated with the outlet of the synthesis column. The second communication port of the rear-end selection valve is used to introduce the cleaning liquid.

[0019] In the above nucleic acid synthesizer, the switching member of the multi-way switching valve can rotate, so that its switching inlet is aligned with and communicated with any one of the liquid inlets. Then, the liquid flowing in from this liquid inlet can flow through the switching inlet to the switching outlet communicated therewith, and then flow to the liquid outlet of the multi-way switching valve communicated with the switching outlet, and then flow into the synthesis column to react with the carrier in the synthesis column. Adjacent to at least one side of each reagent liquid inlet for introducing a reaction reagent is a cleaning liquid inlet for introducing a cleaning liquid. Then, after rotating the switching member to connect the switching inlet and this reagent liquid inlet to realize introducing this reaction reagent into the synthesis column for reaction, only by rotating the switching member to align the switching inlet with the cleaning liquid inlet adjacent to this reagent liquid inlet can the cleaning liquid be sent into the synthesis column for cleaning. During this process, since the switching member only needs to rotate to the cleaning liquid inlet adjacent to this reagent liquid inlet to realize the introduction of the cleaning liquid, and will not pass through other reagent liquid inlets during the rotation of the switching member, the probability of other reaction reagents at other reagent liquid inlets contaminating the switching inlet can be reduced, thereby reducing the probability of mutual contamination between various reaction reagents and making the synthesis success rate higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a schematic structural diagram of a multi-way switching valve in an embodiment of the present application.

[0021] Figure 2 It is a schematic flow path diagram of a nucleic acid synthesizer in an embodiment of the present application.

[0022] Figure 3 It is a schematic overall structural diagram of a nucleic acid synthesizer in an embodiment of the present application.

[0023] Figure 4 It is a schematic diagram of a circulation flow path in a first state in an embodiment of the present application.

[0024] Figure 5 It is a schematic diagram of a circulation flow path in a second state in an embodiment of the present application.

[0025] Figure 6 It is a schematic diagram of a circulation flow path in a third state in an embodiment of the present application.

[0026] Figure 7 It is a schematic diagram of a circulation flow path in a fourth state in an embodiment of the present application.

[0027] Figure 8 It is a schematic diagram of a front-end selection valve / rear-end selection valve in a first working position in an embodiment of the present application.

[0028] Figure 9 It is a schematic diagram of a front-end selection valve / rear-end selection valve in a second working position in an embodiment of the present application.

[0029] Figure 10Schematic diagram of the front-end selection valve / rear-end selection valve in the third working position in an embodiment of the present application.

[0030] Reference numerals:

[0031] 100, synthesis column; 200, multi-way switching valve; 210, liquid inlet; 220, liquid outlet; 200a, first multi-way switching valve; 200b, second multi-way switching valve; 200c, third multi-way switching valve; 200d, fourth multi-way switching valve; 200e, fifth multi-way switching valve; 200f, sixth multi-way switching valve; 310, first flow path; 311, first pressure sensor; 312, first liquid inlet pump; 313, first flowmeter; 320, second flow path; 321, second pressure sensor; 322, second liquid inlet pump; 323, second flowmeter; 330, sample mixer; 410, three-way valve; 420, reaction reagent supply pipe; 430, cleaning liquid supply pipe; 510, front-end selection valve; 511, communication port; 512, arc-shaped channel; 520, rear-end selection valve; 530, circulation pump; 540, circulation flow path; 5401, first circulation section; 5402, second circulation section; 541, third pressure sensor; 542, third flowmeter; 543, fourth pressure sensor; 550, waste liquid discharge flow path; 551, pH sensor; 552, conductivity sensor; 553, UV detector; 554, back pressure valve; 555, fourth flowmeter; 556, waste liquid valve; 557, waste liquid branch; 560, cleaning liquid branch. Detailed implementation manners

[0032] To make the above objects, features, and advantages of the present application more obvious and understandable, the following will describe the detailed implementation manners of the present application with reference to the accompanying drawings. Many specific details are set forth in the following description to fully understand the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present application. Therefore, the present application is not limited by the specific embodiments disclosed below.

[0033] In the description of the present application, it should be understood that if there appear 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., the orientation or positional relationship indicated by these terms is based on the orientation or positional relationship shown in the drawings, and is only for the convenience of describing the present application and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be construed as a limitation to the present application.

[0034] In addition, if the terms "first" and "second" appear, these terms are for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include at least one such feature. In the description of this application, if the term "a plurality" appears, the meaning of "a plurality" is at least two, such as two, three, etc., unless otherwise specifically defined.

[0035] In this application, unless otherwise clearly specified and defined, if terms such as "installed", "connected", "joined", "fixed", etc. appear, these terms shall be understood in a broad sense. For example, it may be a fixed connection, a detachable connection, or integrated; it may be a mechanical connection or an electrical connection; it may be directly connected or indirectly connected through an intermediate medium, and it may be the communication inside two elements or the interaction relationship between two elements, unless otherwise clearly defined. For those of ordinary skill in the art, the specific meanings of the above terms in this application can be understood according to specific circumstances.

[0036] In this application, unless otherwise clearly specified and defined, if there is a description such as a first feature being "on" or "under" a second feature, the meaning may be that the first and second features are in direct contact, or the first and second features are in indirect contact through an intermediate medium. Moreover, the first feature being "above", "over" and "on top of" the second feature may mean that the first feature is directly above or obliquely above the second feature, or merely indicates that the first feature has a higher horizontal height than the second feature. The first feature being "under", "beneath" and "underneath" the second feature may be that the first feature is directly below or obliquely below the second feature, or merely indicates that the first feature has a lower horizontal height than the second feature.

[0037] It should be noted that if an element is referred to as "fixed to" or "disposed on" another element, it may be directly on the other element or there may also be an intermediate element. If an element is considered to be "connected" to another element, it may be directly connected to the other element or there may be an intermediate element at the same time. If so, the terms "vertical", "horizontal", "up", "down", "left", "right" and similar expressions used in this application are only for the purpose of illustration and do not represent the only implementation.

[0038] Refer to Figures 1 to 3, a nucleic acid synthesizer provided by 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 circumferential direction of the multi-way switching valve 200. The multi-way switching valve 200 includes a switching member. The switching member has a switching inlet and a switching outlet that are connected to each other. The switching outlet is connected to the liquid outlet 220. The liquid outlet 220 can be connected to the inlet of the synthesis column 100. The switching member is configured to rotate so that the switching inlet is aligned with and connected to any one of the liquid inlets 210. Among the plurality of liquid inlets 210, some liquid inlets 210 are used to introduce various reaction reagents one by one, and some liquid inlets 210 are all used to introduce cleaning liquid. The liquid inlets 210 used to introduce various reaction reagents one by one are all denoted as reagent inlets, and the liquid inlets 210 used to introduce cleaning liquid are all denoted as cleaning liquid inlets. The adjacent liquid inlets 210 on at least one side of each reagent inlet are cleaning liquid inlets.

[0039] In the above nucleic acid synthesizer, the switching member of the multi-way switching valve 200 can rotate so that its switching inlet is aligned with and connected to any one of the liquid inlets 210. Then, the liquid flowing in from this liquid inlet 210 can flow through the switching inlet to the switching outlet connected thereto, and then flow to the liquid outlet 220 of the multi-way switching valve 200 connected to the switching outlet, and then flow into the synthesis column 100 to react with the carrier in the synthesis column 100. The adjacent liquid inlets 210 on at least one side of each reagent inlet for introducing reaction reagents are cleaning liquid inlets for introducing cleaning liquid. Then, after rotating the switching member to connect the switching inlet and this reagent inlet to realize introducing this reaction reagent into the synthesis column 100 for reaction, only need to rotate the switching member so that the switching inlet is aligned with the cleaning liquid inlet adjacent to this reagent inlet, and the cleaning liquid can be sent into the synthesis column 100 for cleaning. In this process, since the switching member only needs to rotate to the cleaning liquid inlet adjacent to this reagent inlet to realize the introduction of the cleaning liquid, and other reagent inlets will not be passed through during the rotation of the switching member, the probability of other reaction reagents at other reagent inlets contaminating the switching inlet can be reduced, thereby reducing the probability of mutual contamination between various reaction reagents and making the synthesis success rate higher. At the same time, the switching efficiency of the switching member can also be improved, thereby improving the synthesis efficiency.

[0040] Specifically, the switching member in the multi-way switching valve 200 can be arranged at the central position of the valve body. The switching outlet and the liquid outlet 220 of the multi-way switching valve 200 can be connected through a hose. The switching inlet is located on the outer peripheral surface of the switching member. When the switching member rotates, the orientation of the switching inlet will change, so as to align and communicate with different liquid inlets 210. A reaction reagent supply pipe 420 is connected to the reagent liquid inlet. The reaction reagent supply pipe 420 is communicated with the reagent storage barrel. The reagent in the reagent storage barrel can flow through the reaction reagent supply pipe 420 to the reagent liquid inlet. A cleaning liquid supply pipe 430 is connected to the cleaning liquid inlet. The cleaning liquid supply pipe 430 is communicated with the cleaning liquid storage barrel. The cleaning liquid in the cleaning liquid storage barrel can flow through the cleaning liquid supply pipe 430 to the cleaning liquid inlet. When the switching inlet aligns with the reagent liquid inlet, the introduction of the reaction reagent can be realized. When the switching inlet aligns with the cleaning liquid inlet, the introduction of the cleaning liquid can be realized. Each reagent liquid inlet can be used to introduce different reaction reagents. Just set the rotation angle of the switching member according to the reaction requirements, and make the switching inlet align with the reagent liquid inlet corresponding to the required reagent, then the introduction of this reagent can be realized. The specific structure inside the multi-way switching valve 200 is the prior art and will not be elaborated here.

[0041] In the embodiment shown in the drawings, the multi-way switching valve 200 is a ten-way switching valve, that is, it has 10 liquid inlets 210. The 10 liquid inlets 210 and one liquid outlet 220 are arranged at intervals along the circumferential direction of the multi-way switching valve 200. In other embodiments, the multi-way switching valve 200 can also be an eight-way switching valve, an eleven-way switching valve, etc. Just select the multi-way switching valve 200 with the corresponding number of liquid inlets 210 according to the reaction requirements.

[0042] Refer to Figures 1 to 3 , in some embodiments, the liquid inlet 210 adjacent to one side of each reagent liquid inlet is the cleaning liquid inlet, and the liquid inlet 210 adjacent to the other side is another reagent liquid inlet.

[0043] Specifically, two reagent liquid inlets are arranged continuously, and a cleaning liquid inlet is provided on each outer side of the whole of these two reagent liquid inlets. That is, the arrangement mode of the multiple liquid inlets 210 is: cleaning liquid inlet, reagent liquid inlet, reagent liquid inlet, cleaning liquid inlet, reagent liquid inlet, reagent liquid inlet, cleaning liquid inlet... After any one of the reagents is introduced, one of the adjacent liquid inlets 210 on both sides of the reagent liquid inlet corresponding to this reagent must be the cleaning liquid inlet. Just rotate the switching member to make its switching inlet align with the cleaning liquid inlet adjacent to this reagent liquid inlet, then the cleaning liquid can be sent into the synthesis column 100 for cleaning. In this way, it can be ensured that after any one of the reagents is selected to be introduced, the switching member can reach the cleaning liquid inlet with the shortest path, thereby reducing the probability of reagent contamination. At the same time, it can also improve the switching efficiency of the switching member, thereby improving the synthesis efficiency.

[0044] In other embodiments, the inlet 210 adjacent to one side of each reagent inlet is a cleaning liquid inlet, and the inlet 210 adjacent to the other side is also a cleaning liquid inlet. That is, the cleaning liquid inlets and the reagent inlets are arranged alternately at intervals.

[0045] Refer to Figures 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. 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 can be connected to the inlet of the synthesis column 100. Multi-way switching valves 200 are provided on both the first flow path 310 and the second flow path 320. The first flow path 310 and the second flow path 320 are respectively used to inject different liquids into the mixer 330.

[0046] Specifically, a first liquid inlet pump 312 is provided on the first flow path 310, which is used to pump the liquid into the mixer 330; a second liquid inlet pump 322 is provided on the second flow path 320, which is used to pump the liquid into the mixer 330. During the reaction process, some steps require different liquids to be sent into the synthesis column 100 for reaction at the same time. In this embodiment, by setting the first flow path 310 and the second flow path 320, different liquids can be sent into the synthesis column 100 at the same time. In addition, due to the presence of the mixer 330, the two liquids provided by the first flow path 310 and the second flow path 320 can be mixed evenly in the mixer 330 and then sent into the synthesis column 100 to react with the carrier, thereby improving the reaction uniformity and the synthesis quality. A multi-way switching valve 200 is provided on the first flow path 310. By switching the multi-way switching valve 200, a cleaning liquid or different reaction reagents can be provided for the first flow path 310, so as to meet the different reaction reagent requirements and cleaning requirements of each step of the reaction. Similarly, a multi-way switching valve 200 is provided on the second flow path 320. By switching the multi-way switching valve 200, a cleaning liquid or different reaction reagents can be provided for the second flow path 320, so as to meet the different reaction reagent requirements and cleaning requirements of each step of the reaction.

[0047] In the nucleic acid synthesis process, four common monomers T, G, C, and A, as well as 13 modified monomers are required. Some auxiliary reagents are also needed, such as ACT for monomer activation, and deprotection reagent DEB, capping reagents CAPA and CAPB, oxidation reagent OXI, and sulfurization reagent SUL, etc. Some of these reaction reagents can be selectively fed into the synthesis column 100 through the second flow path 320, and some can be selectively fed into the synthesis column 100 through the first flow path 310. Alternatively, some reaction reagents can be fed into the synthesis column 100 either through the first flow path 310 or through the second flow path 320. The reaction reagent supply tubes 420 corresponding to various reaction reagents are connected to the liquid inlet 210 in the multi-way switching valve 200 provided on the corresponding flow path in a one-to-one correspondence. Similarly, after each reaction reagent reacts in the synthesis column 100, a cleaning solution needs to be introduced for cleaning. The cleaning solution can be fed into the synthesis column 100 either through the first flow path 310 or through the second flow path 320. The cleaning solution supply tube 430 has multiple branch ports. Some of these branch ports are connected to the liquid inlet 210 in the multi-way switching valve 200 provided on the first flow path 310, and some are connected to the liquid inlet 210 in the multi-way switching valve 200 provided on the second flow path 320, so that the cleaning solution can be supplied to both flow paths.

[0048] In addition, some of the liquid inlets 210 in the multi-way switching valve 200 can be reserved and temporarily not connected to the reaction reagent supply tube 420 or the cleaning solution supply tube 430. According to the reaction requirements, the supply pipeline of the reagent to be fed into the synthesis column 100 is connected to these liquid inlets 210.

[0049] Refer to Figures 2 to 3 , in some embodiments, a plurality of multi-way switching valves 200 are provided on the first flow path 310 and arranged along the liquid flow direction. Among any two adjacent multi-way switching valves 200, one of the multiple liquid inlets 210 of the multi-way switching valve 200 located downstream is connected to the liquid outlet 220 of the multi-way switching valve 200 located upstream.

[0050] Specifically, multiple multi-way switching valves 200 on the first flow path 310 are arranged in series. In this way, the types of liquids supplied to the liquid inlet 210 of the multi-way switching valve 200 located downstream can be expanded. By switching the upstream multi-way switching valve 200, multiple liquids can be supplied to the corresponding liquid inlet 210 of the downstream multi-way switching valve 200. In the embodiment shown in the attached drawings, two multi-way switching valves 200 are arranged on the first flow path 310 in the liquid flow direction, namely the first multi-way switching valve 200a and the second multi-way switching valve 200b. One of the multiple liquid inlets 210 of the second multi-way switching valve 200b is communicated with the liquid outlet 220 of the first multi-way switching valve 200a. In this way, by switching the first multi-way switching valve 200a, multiple liquids (reaction reagents / washing liquids) can be provided to the corresponding liquid inlet 210 of the second multi-way switching valve 200b communicated with its liquid outlet 220. If both the first multi-way switching valve 200a and the second multi-way switching valve 200b are ten-way switching valves, through the above settings, 19 types of liquid supply can be realized for the ten liquid inlets 210 of the second multi-way switching valve 200b, greatly expanding the number of liquid supply types, so as to better meet the requirements of multiple liquids in the reaction.

[0051] In other embodiments, the number of multi-way switching valves 200 arranged in series can also be increased on the basis of the embodiment shown in the attached drawings to further expand the types of liquid supply.

[0052] Refer to Figures 2 to 3 , in some embodiments, a two-stage switching valve group is arranged on the second flow path 320 in the liquid flow direction. Among them, the switching valve group located downstream includes a multi-way switching valve 200, and the switching valve group located upstream includes multiple multi-way switching valves 200. Moreover, the liquid outlets 220 of the multi-way switching valves 200 in the upstream switching valve group are correspondingly communicated with the multiple liquid inlets 210 of the multi-way switching valve 200 in the downstream switching valve group one by one.

[0053] Specifically, the two switching valve groups are arranged in series. The second-stage (downstream) switching valve group includes the sixth multi-way switching valve 200f, and the first-stage (upstream) switching valve group includes the third multi-way switching valve 200c, the fourth multi-way switching valve 200d, and the fifth multi-way switching valve 200e arranged in parallel. 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 three liquid inlets 210 of the sixth multi-way switching valve 200f respectively to realize the expansion of the types of liquids entering these three liquid inlets 210. If ten-way switching valves are selected for all, through the above settings, 37 types of liquid supply can be realized for the ten liquid inlets 210 of the sixth multi-way switching valve 200f, greatly expanding the number of liquid supply types, so as to better meet the requirements of multiple liquids in the reaction.

[0054] In other embodiments, the number of series-connected multi-way switching valves 200 in the first-stage switching valve group can also be increased on the basis of the embodiments of the drawings to further expand the types of liquid supply thereof.

[0055] In other embodiments, the setting modes of the multi-way switching valves 200 in the first flow path 310 and the second flow path 320 can also be combined. For example, a three-stage switching valve group is provided. According to the current mode of the second-stage switching valve group, multiple mutually parallel second-stage switching valve groups are copied and set. A third-stage switching valve group is provided downstream of these mutually parallel second-stage switching valve groups. The liquid outlets of each second-stage switching valve group and the liquid inlets in the third-stage switching valve group are connected in one-to-one correspondence. In this way, a "tree-shaped" expansion structure is formed to achieve a greater degree of expansion of the types of liquid supply.

[0056] Refer to Figures 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 cleaning liquid storage barrel for storing cleaning liquid, and the other inlet is used to communicate with a reagent storage barrel for storing corresponding reaction reagents. The outlet of the three-way valve 410 is communicated with at least one liquid inlet 210 of the corresponding multi-way switching valve 200.

[0057] Specifically, as described above, the liquid inlet 210 in the multi-way switching valve 200 can be communicated with the reaction reagent supply pipe 420 to realize the supply of reaction reagents, or can be communicated with the cleaning liquid supply pipe 430 to realize the supply of cleaning liquid. In this embodiment, a three-way valve can be provided at at least one liquid inlet 210 of the multi-way switching valve 200. The outlet of the three-way valve is communicated with the liquid inlet 210. One inlet of the three-way valve is communicated with the cleaning liquid supply pipe 430 to communicate with the cleaning liquid storage barrel, and the other inlet of the three-way valve is communicated with the reaction reagent supply pipe 420 to communicate with the reagent storage barrel. In this way, each liquid inlet 210 can realize both the supply of reaction reagents and the supply of cleaning liquid. The switching of the types of liquid supply at the same liquid inlet 210 can be realized through the three-way valve to further expand the types of liquid supply.

[0058] Preferably, a three-way valve is provided at each liquid inlet 210 of the multi-way switching valve 200 to realize the switching of the types of liquid supply at each liquid inlet 210.

[0059] Refer to Figures 2 to 3 , in some embodiments, at least one liquid inlet 210 of multiple multi-way switching valves 200 is communicated with the outlet of the three-way valve 410.

[0060] Specifically, as described above, a plurality of multi-way switching valves 200 are provided on both the first flow path 310 and the second flow path 320. At least one liquid inlet of all the multi-way switching valves 200 is provided with a three-way valve 410 in the aforementioned manner. In this way, the plurality of multi-way switching valves 200 can all achieve the switching of the liquid supply type.

[0061] Refer to Figures 2 to 3 , in some embodiments, the nucleic acid synthesizer includes a front-end selection valve 510 connected between the synthesis column 100 and the sample mixer 330, a rear-end selection valve 520 connected downstream of the synthesis column 100, and a circulation flow path 540. The front-end selection valve 510, the synthesis column 100, and the rear-end selection valve 520 are all located on the circulation flow path 540. Also refer to Figures 8 to 10 , both the front-end selection valve 510 and the rear-end selection valve 520 have different working positions. The front-end selection valve 510 and the rear-end selection valve 520 are configured to switch between different working positions so that the nucleic acid synthesizer is in the first state, the second state, the third state, or the fourth state. Also refer to Figure 4 , in the first state, the liquid flowing out of the outlet of the sample mixer 330 can flow through the front-end selection valve 510 and the rear-end selection valve 520 in sequence and then be discharged into a waste liquid bucket for collecting waste liquid. Also refer to Figure 5 , in the second state, the liquid flowing out of the outlet of the sample mixer 330 can flow through the front-end selection valve 510, the synthesis column 100, and the rear-end selection valve 520 in sequence and then be discharged into the waste liquid bucket. Also refer to Figure 6 , 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. Also refer to Figure 7 , in the fourth state, the rear-end selection valve 520 is configured to introduce a cleaning liquid, and the cleaning liquid introduced into the rear-end selection valve 520 can flow through the circulation flow path 540 to the front-end selection valve 510, and then flow through the front-end selection valve 510 to the rear-end selection valve 520 and be discharged into the waste liquid bucket.

[0062] Specifically, the circulation flow path 540 includes a first circulation section 5401 and a second circulation section 5402 that are connected end to end to form a closed loop. The front-end selection valve 510, the synthesis column 100, and the rear-end selection valve 520 are all located on the first circulation section 5401. A circulation pump 530 is provided on the second circulation section 5402. The circulation pump 530 is used to drive the liquid to circulate clockwise or counterclockwise in the circulation flow path 540. A cleaning liquid branch 560 for introducing cleaning liquid is connected to the rear-end selection valve 520. In the first state, the liquid flowing out of the mixer 330 does not pass through the synthesis column 100, but directly flows through the front-end selection valve 510 and the rear-end selection valve 520 and then is discharged into the waste liquid bucket. When the synthesizer is just turned on, it can be switched to the first state to clean each liquid flow path, so as to avoid the adverse effects of the reagents remaining from the previous reaction on the current reaction. In the second state, if the liquid flowing out of the outlet of the mixer 330 is a reaction reagent, it can flow through the synthesis column 100 and react with the carrier; if the liquid flowing out of the outlet of the mixer 330 is a cleaning liquid, it can clean the synthesis column 100 after the previous reaction is completed to prepare for introducing other reaction reagents in the next step. 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 as to make the reaction more thorough and reduce the waste of reaction reagents. Therefore, after each time a reaction reagent is introduced into the synthesis column 100 for reaction, it can be switched to the third state for cyclic reaction. In the fourth state, the cleaning liquid is introduced from the rear-end selection valve 520, flows through the circulation flow path 540 to the front-end selection valve 510, and then flows through the front-end selection valve 510 to the rear-end selection valve 520 and is discharged into the waste liquid bucket. During this process, the cleaning liquid will flush out the reaction reagents circulating in the circulation flow path 540 in the third state into the waste liquid bucket to complete the cleaning of the circulation flow path 540, so that the reaction reagents are not easily cross-contaminated when circulating in the circulation flow path 540.

[0063] Refer to Figures 8 to 10 , in some embodiments, both the front-end selection valve 510 and the rear-end selection valve 520 include a stator and a rotor that are rotatably connected. The stator includes a plurality of communication ports 511 arranged at intervals along the circumference of the rotor. The rotor includes a plurality of arc-shaped channels 512 arranged at intervals along the circumference of the rotor. The rotor can rotate relative to the stator so that the adjacent plurality of communication ports 511 coincide with the corresponding arc-shaped channels 512 to connect the adjacent plurality of communication ports 511.

[0064] Specifically, the front-end selection valve 510 and the rear-end selection valve 520 have the same structure. By operating the rotation amplitude of their rotors, the positions of the respective arc-shaped channels 512 are made different, so as to connect different multiple communication ports 511, thereby realizing the switching of multiple states. When multiple communication ports 511 simultaneously fall within the range where an arc-shaped channel 512 is located, these communication ports 511 can be connected through this arc-shaped channel 512, enabling the liquid to flow from the communication port 511 at one end to the communication port 511 at the other end within the arc-shaped channel 512.

[0065] Further, referring to Figures 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 spaced apart along the circumferential direction of the rotor ( Figure 8 the numbers 1 to 8 spaced apart along the circumferential direction in Figures 4 to 7 represent the 8 communication ports 511). The rotor includes three groups of arc-shaped channels 512, where two groups of arc-shaped channels 512 can both cover the circumferential range of 3 communication ports 511, and the other group of arc-shaped channels 512 can cover the circumferential range of 2 communication ports 511. Also referring to

[0066] Specifically, the first communication port of the front-end selection valve 510 and the second communication port of the front-end selection valve 510 are connected through an external pipeline. The third communication port of the front-end selection valve 510 is connected to the first communication port of the rear-end selection valve 520 through the second circulation section 5402. The seventh communication port of the front-end selection valve 510 is connected to the fourth communication port of the rear-end selection valve 520 through an external pipeline. The fifth communication port of the rear-end selection valve 520 is connected to the waste liquid bucket through the waste liquid discharge flow path 550. A cleaning liquid branch 560 for introducing cleaning liquid is connected to the second communication port of the rear-end selection valve 520. In the first working position, among the front-end selection valve 510 and the rear-end selection valve 520, one arc-shaped channel 512 connects the first communication port, the seventh communication port, and the eighth communication port, another arc-shaped channel 512 connects the fourth communication port, the fifth communication port, and the sixth communication port, and another arc-shaped channel 512 connects the second communication port and the third communication port. In the second working position, among the front-end selection valve 510 and the rear-end selection valve 520, one arc-shaped channel 512 connects the sixth communication port, the seventh communication port, and the eighth communication port, another arc-shaped channel 512 connects the third communication port, the fourth communication port, and the fifth communication port, and another arc-shaped channel 512 connects the first communication port and the second communication port. In the third working position, among the front-end selection valve 510 and the rear-end selection valve 520, one arc-shaped channel 512 connects the fifth communication port, the sixth communication port, and the seventh communication port, another arc-shaped channel 512 connects the first communication port, the second communication port, and the eighth communication port, and another arc-shaped channel 512 connects the third communication port and the fourth communication port.

[0067] In the first state, the front-end selection valve 510 is in the third working position and the rear-end selection valve 520 is in the second working position. The liquid flowing out from the outlet of the mixer 330 flows into through the fifth communication port of the front-end selection valve 510, flows out from the seventh communication port of the front-end selection valve 510, and flows towards the fourth communication port of the rear-end selection valve 520, and then flows out from the fifth communication port of the rear-end selection valve 520 and is discharged into the waste liquid bucket through the waste liquid discharge flow path 550.

[0068] In the second state, the front-end selection valve 510 is in the first working position and the rear-end selection valve 520 is in the third working position. The liquid flowing out from the outlet of the mixer 330 flows into through the fifth communication port of the front-end selection valve 510, flows out from the fourth communication port of the front-end selection valve 510, and flows into the inlet of the synthesis column 100, and then flows out from the outlet of the synthesis column 100 to the seventh communication port of the rear-end selection valve 520, and then flows out from the fifth communication port of the rear-end selection valve 520 and is discharged into the waste liquid bucket through the waste liquid discharge flow path 550.

[0069] In the third state, the front-end selection valve 510 is in the third working position, and the rear-end selection valve 520 is in the first working position. The circulation pump 530 is started, and the liquid flowing out of the outlet of the synthesis column 100 is pumped into the seventh communication port of the rear-end selection valve 520, flows into the second circulation section 5402 from the first communication port of the rear-end selection valve 520, and then flows into the front-end selection valve 510 again from the third communication port of the front-end selection valve 510. After that, it flows into the inlet of the synthesis column 100 from the fourth communication port of the front-end selection valve 510. In this way, the liquid can be circulated in the circulation flow path 540, enabling it to react with the carrier in the synthesis column 100 multiple times.

[0070] In the fourth state, the front-end selection valve 510 is in the first working position, the rear-end selection valve 520 is in the second working position, and the circulation pump 530 is still started. The cleaning liquid flows into the second communication port of the rear-end selection valve 520 through the cleaning liquid branch 560, and then flows out of the first communication port of the rear-end selection valve 520 to the circulation flow path 540, then flows into the front-end selection valve 510 from the third communication port of the front-end selection valve 510, and then flows out of the seventh communication port of the front-end selection valve 510 to the fourth communication port of the rear-end selection valve 520, and then flows out of the fifth communication port of the rear-end selection valve 520 and is discharged into the waste liquid bucket through the waste liquid discharge flow path 550.

[0071] Refer to Figure 2 And Figure 3 , in some embodiments, pressure sensors for detecting pressure, flow meters for detecting flow rate, and other components are provided on each flow path. For example, a first pressure sensor 311 and a first flow meter 313 are provided on the first flow path 310, and a second pressure sensor 321 and a second flow meter 323 are provided on the second flow path 320. A third pressure sensor 541 and a third flow meter 542 are provided on the first circulation section 5401, and a fourth pressure sensor 543 is provided on the second circulation section 5402. 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, and a UV detector 553 and a back pressure valve 554 are also provided on the waste liquid discharge flow path 550. A waste liquid valve 556 is connected to the downstream of the waste liquid discharge flow path 550 for opening or closing the waste liquid discharge flow path 550. A plurality of waste liquid branches 557 are connected to the downstream of the waste liquid valve 556, and a waste liquid bucket is provided at the downstream of each waste liquid branch 557, and the waste liquid can be discharged into the corresponding waste liquid branch 557 according to the type of the waste liquid.

[0072] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0073] The above-described embodiments merely represent several implementation manners of the present application. The description thereof is relatively specific and detailed, but it should not be construed as a limitation to the scope of the patented application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all fall within the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A nucleic acid synthesizer, characterized in that, the nucleic acid synthesizer includes: a synthesis column; and a multi-way switching valve having a liquid outlet and a plurality of liquid inlets, the plurality of liquid inlets being arranged at intervals along the circumference of the multi-way switching valve, the multi-way switching valve including a switching member having a switching inlet and a switching outlet that communicate with each other, the switching outlet being communicated with the liquid outlet, the liquid outlet being capable of being communicated with the inlet of the synthesis column, and the switching member being configured to rotate so that the switching inlet is aligned with and communicated with any one of the liquid inlets; Among the plurality of liquid inlets, some of the liquid inlets are used to introduce various reaction reagents one by one, and some of the liquid inlets are all used to introduce a cleaning solution. The liquid inlets used to introduce various reaction reagents one by one are all reagent inlets, and the liquid inlets used to introduce the cleaning solution are all cleaning solution inlets. Each of the reagent inlets has a cleaning solution inlet adjacent to at least one side thereof.

2. The nucleic acid synthesizer according to claim 1, characterized in that, the liquid inlet adjacent to one side of each reagent inlet is the cleaning solution inlet, and the liquid inlet adjacent to the other side is another reagent inlet.

3. The nucleic acid synthesizer according to claim 1 or 2, characterized in that, the nucleic acid synthesizer includes a first flow path, a second flow path and a sample mixer, 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, multi-way switching valves are provided on both the first flow path and the second flow path, and the first flow path and the second flow path are respectively used to inject different liquids into the sample mixer.

4. The nucleic acid synthesizer according to claim 3, characterized in that, a plurality of the multi-way switching valves are arranged on the first flow path along the liquid flow direction, and in any two adjacent multi-way switching valves, one of the plurality of liquid inlets of the multi-way switching valve located downstream is communicated with the liquid outlet of the multi-way switching valve located upstream.

5. The nucleic acid synthesizer according to claim 3, characterized in that, a two-stage switching valve group is provided on the second flow path along the liquid flow direction, wherein the switching valve group located downstream includes one multi-way switching valve, the switching valve group located upstream includes a plurality of multi-way switching valves, and the liquid outlets of the multi-way switching valves in the switching valve group located upstream are respectively communicated with the plurality of liquid inlets of the multi-way switching valve in the switching valve group located downstream.

6. The nucleic acid synthesizer according to claim 4 or 5, characterized in that, the nucleic acid synthesizer includes a three-way valve, one inlet of the three-way valve is used to communicate with a cleaning solution storage barrel for storing the cleaning solution, the other inlet is used to communicate 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 of the liquid inlets of the corresponding multi-way switching valve.

7. The nucleic acid synthesizer according to claim 6, characterized in that, At least one of the liquid inlets of the plurality of multi-way switching valves is communicated with the outlet of the three-way valve.

8. The nucleic acid synthesizer according to claim 3, wherein, the nucleic acid synthesizer includes a front-end selection valve connected between the synthesis column and the sample mixer, a rear-end selection valve connected downstream of the synthesis column, and a circulation flow path. The front-end selection valve, the synthesis column and the rear-end selection valve are all located on the circulation flow path. The front-end selection valve and the rear-end selection valve both have different working positions, and the front-end selection valve and the rear-end selection valve are configured to switch between different working positions so that the nucleic acid synthesizer is in a first state, a second state, a third state or a fourth state; in the first state, the liquid flowing out of the outlet of the sample mixer can sequentially flow through the front-end selection valve and the rear-end selection valve and then be discharged into a waste liquid bucket for collecting waste liquid; in the second state, the liquid flowing out of the outlet of the sample mixer can sequentially flow through the front-end selection valve, the synthesis column and the rear-end selection valve and then be discharged into the waste liquid bucket; 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 selection valve is configured to introduce the cleaning liquid, and the cleaning liquid introduced into the rear-end selection valve can flow through the circulation flow path to the front-end selection valve, and then flow through the front-end selection valve to the rear-end selection valve and then be discharged into the waste liquid bucket.

9. The nucleic acid synthesizer according to claim 8, wherein, both the front-end selection valve and the rear-end selection valve include a stator and a rotor rotatably connected. The stator includes a plurality of communication ports arranged at intervals along the circumference of the rotor. The rotor includes a plurality of arc-shaped channels arranged at intervals along the circumference of the rotor. The rotor can rotate relative to the stator so that adjacent communication ports coincide with corresponding arc-shaped channels to connect adjacent 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 arranged at intervals in sequence along the circumference of the rotor. The rotor includes three groups of arc-shaped channels, and two of the groups of arc-shaped channels can both cover the circumferential range of 3 communication ports, and the other group of arc-shaped channels can cover the circumferential range of 2 communication ports; The first communication port of the front-end selection valve communicates with the second communication port of the front-end selection valve. The third communication port of the front-end selection valve communicates with the first communication port of the rear-end selection valve. The fourth communication port of the front-end selection valve communicates with the inlet of the synthesis column. The fifth communication port of the front-end selection valve communicates with the outlet of the sample mixer. The seventh communication port of the front-end selection valve communicates with the fourth communication port of the rear-end selection valve. The fifth communication port of the rear-end selection valve communicates with the waste liquid bucket. The seventh communication port of the rear-end selection valve communicates with the outlet of the synthesis column. The second communication port of the rear-end selection valve is used for introducing the cleaning liquid.

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