Biochemical substance analysis system, biochemical substance analysis method, sequencing system and sequencing method

Abstract

A biochemical substance analysis system, a biochemical substance analysis method, a sequencing system and a sequencing method. The biochemical substance analysis system comprises a biochemical substance analysis platform and a transfer device. The biochemical substance analysis platform comprises a liquid change device, an imaging detection device and at least one biochemical reaction device. The transfer device transfers a test chip between different sites, the sites comprising a reaction site, a liquid change site and an imaging site. The test chip comprises an open-type slide capable of immobilizing a sample to be tested, and the liquid change device is used for adding a liquid to the test chip. The biochemical reaction device is used for enabling the sample in the test chip to react. The imaging detection device is used for executing imaging detection analysis on the test chip which has undergone a reaction. The biochemical substance analysis system provided by the present application can achieve integrated operation of sample adding, biochemical substance analysis and imaging, thus simplifying the system structure, reducing reagent loss, improving test efficiency and reducing test costs.

Description

Biochemical substance analysis system and biochemical substance analysis method, sequencing system and sequencing method Technical Field

[0001] The present application relates to the technical field of biochemical substance analysis, and in particular to a biochemical substance analysis system and method, a sequencing system and method. Background Art

[0002] The second-generation gene sequencing technology was developed based on the first-generation Sanger sequencing technology. It has the characteristics of low cost, high throughput, and automation, which has greatly promoted the development of the gene sequencing industry.

[0003] However, the sequencers used in existing second-generation gene sequencing technologies have complex structures, cumbersome operations, and low operational flexibility. Moreover, the reagent loss during the sequencing process is high, and most of the reagents do not participate in the reaction (less than 1% of the reagent components participate in the reaction), resulting in high sequencing costs.

[0004] Summary of the Invention

[0005] In order to solve at least one of the above defects, it is necessary to propose a biochemical substance analysis system and biochemical substance analysis method, a sequencing system and sequencing method.

[0006] In a first aspect, an embodiment of the present application provides a biochemical substance analysis system, comprising: a biochemical substance analysis platform and a transfer device, wherein the biochemical substance analysis platform comprises: a fluid exchange device, an imaging detection device, and at least one biochemical reaction device; wherein the transfer device is used to detachably support a detection chip and drive the detection chip to transfer along a preset path at different sites, wherein the sites include reaction sites corresponding to the biochemical reaction device, fluid exchange sites corresponding to the fluid exchange device, and imaging sites corresponding to the imaging detection device; the detection chip is an open slide for fixing a sample to be detected, and the fluid exchange device comprises a liquid adding component for printing a layer to be reacted of a preset thickness on the detection chip, wherein the layer to be reacted comprises a reagent; the biochemical reaction device comprises a reaction chamber, and the detection chip after printing the layer to be reacted is transferred to the reaction chamber by the transfer device and the reaction between the sample and the reagent is performed in the reaction chamber; the imaging detection device is used to perform imaging detection analysis on the detection chip after the reaction.

[0007] In some possible embodiments, the transfer device includes a mounting seat, a robotic arm disposed on the mounting seat, and a robotic arm disposed at an end of the robotic arm away from the mounting seat, wherein the robotic arm is used to detachably clamp the detection chip.

[0008] In some possible embodiments, the open slide fixes the samples to be detected arranged in an array; at the liquid exchange site, the manipulator clamps the detection chip and moves horizontally relative to the liquid exchange device, so that the liquid adding component adds liquid to the detection chip.

[0009] In some possible embodiments, a liquid exchange platform is provided below the liquid exchange device and is spaced apart from the liquid exchange device; the liquid exchange site is located between the liquid exchange platform and the liquid exchange device; the liquid exchange platform has a cold air release structure toward the liquid exchange site to cool the detection chip located above the liquid exchange site.

[0010] In some possible embodiments, the biochemical reaction device includes a stacked reaction platform and a heating cover, the heating cover and the reaction platform form a reaction chamber, the reaction chamber has a chip inlet, and the transfer device is used to insert the detection chip into the reaction chamber through the chip inlet so that the detection chip is adsorbed on the reaction platform.

[0011] In some possible embodiments, the reaction platform includes a bottom wall, a side wall arranged on the periphery of the bottom wall, and an adsorption platform arranged on the bottom wall and located in the reaction chamber, the adsorption platform is used to adsorb the detection chip, the heating cover is arranged at one end of the side wall away from the bottom wall, and the chip inlet is located on the side wall.

[0012] In some possible embodiments, the heating cover includes a reaction area, a first connection area connected to the periphery of the reaction area, and a second connection area connected to the first connection area away from the periphery of the reaction area, and the side wall is connected to the second connection area; along the stacking direction, the vertical projection of the reaction area on the bottom wall is located on the adsorption platform; the reaction area has a groove opening toward the adsorption platform, and when the detection chip is adsorbed on the adsorption platform, the groove and the reaction area of ​​the detection chip form a closed reaction space.

[0013] In some possible embodiments, a sealing ring is provided on a periphery of the first connection region close to the groove, and the sealing ring is used to support the detection chip.

[0014] In some possible embodiments, an imaging platform is provided under the imaging detection device, and the imaging platform includes a carrier platform, a movable component provided on the carrier platform, and a chip carrier provided on the movable component. The chip carrier is used to carry the detection chip, and the movable component is used to adjust the position of the detection chip.

[0015] In some possible embodiments, a temperature regulating component is provided on the chip carrier, and the temperature regulating component is used to heat or cool the detection chip.

[0016] In some possible embodiments, the moving component includes a first axis provided on the imaging platform and extending along a first direction, a second axis slidably provided on the first axis and extending along a second direction, and a third axis slidably provided on the second axis and extending along a third direction, and the platform is located on the third axis, wherein the first direction, the second direction and the third direction are perpendicular to each other and constitute a three-dimensional coordinate system.

[0017] In some possible embodiments, the liquid adding component includes an inkjet chip, which is used to load reagents for the detection chip by inkjet printing; the liquid changing device also includes a liquid removal component for removing residual reagents on the detection chip after the reaction is completed.

[0018] In some possible embodiments, the inkjet chip includes: an inkjet cavity layer and a driving structure, the inkjet cavity layer includes a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity is formed through the first surface and the second surface, the liquid adding cavity is used to accommodate the reagent, and the liquid adding cavity has at least one liquid outlet located on the second surface; the driving structure is superimposed on the first surface and covers the liquid adding cavity, and the driving structure is used to drive the reagent located in the liquid adding cavity to be discharged from the liquid outlet.

[0019] In some possible embodiments, the driving structure includes a deformable layer located on the first surface, and an electrode layer located on the deformable layer, wherein the deformable layer is configured to deform under the action of a voltage to squeeze the reagent located in the liquid adding chamber;

[0020] Alternatively, the driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent.

[0021] In some possible embodiments, the liquid adding assembly further includes a liquid storage structure stacked on the inkjet chip, the liquid storage structure includes at least one liquid storage cavity connected to the liquid adding cavity, and the liquid storage cavity is used to store the reagent.

[0022] In some possible embodiments, the liquid removal component is used to provide positive pressure or negative pressure to blow away or absorb the residual reagent on the detection chip.

[0023] In some possible embodiments, the liquid removal assembly includes an air supply structure and an air knife connected to the air supply structure, and the air supply structure is used to provide compressed gas to the air knife.

[0024] In some possible embodiments, the liquid replacement device further includes a linkage structure, the liquid adding component and the liquid removing component are arranged on the linkage structure, and the linkage structure is used to link the liquid adding component and the liquid removing component to add liquid or replace liquid for the detection chip.

[0025] In some possible embodiments, the biochemical reaction platform includes a plurality of the biochemical reaction devices, one liquid replacement device, and one imaging detection device.

[0026] In a second aspect, an embodiment of the present application provides a method for analyzing biochemical substances, the method comprising:

[0027] Liquid adding step: transferring the detection chip to the liquid replacement site by a transfer device, and printing a reaction layer of a preset thickness on the detection chip by a liquid adding component in the liquid replacement device, wherein the reaction layer includes a reagent, and the detection chip includes an open slide for fixing the sample to be detected;

[0028] Reaction step: transferring the detection chip printed with the layer to be reacted to a reaction site by the transfer device, and causing the sample to be detected in the detection chip to react with the reagent by a biochemical reaction device;

[0029] Detection step: transferring the detection chip after the reaction to an imaging site by the transfer device, acquiring the detectable signal of the detection chip by the imaging detection device and performing imaging detection analysis; and

[0030] Circulation step: moving the detection chip back and forth between the liquid exchange site and the reaction site and imaging site according to a preset path to achieve multiple liquid addition steps and multiple reaction steps; and between two adjacent liquid addition steps, the method also includes a liquid removal step of removing the reacted residual reagent on the surface of the detection chip through the liquid removal component in the liquid exchange device.

[0031] In some possible embodiments, during the liquid adding step and the liquid removing step, the transfer device drives the detection chip to move below the liquid replacing device, so that the liquid adding component adds liquid to or replaces liquid for the detection chip.

[0032] In some possible embodiments, in the liquid adding step or the liquid removing step, the method further includes:

[0033] Cold air is blown toward the detection chip through a liquid replacement platform located below the liquid replacement device to cool the detection chip.

[0034] In some possible embodiments, the method includes at least two liquid-adding steps, and the reagent printed in at least one of the liquid-adding steps is different from the reagent printed in the other liquid-adding steps.

[0035] In some possible embodiments, the liquid adding step includes: adding the reagent to the detection chip by inkjet printing;

[0036] The liquid replacement step includes: removing the residual reagent on the detection chip by blowing or inhaling.

[0037] In some possible embodiments, before the detecting step, the method further includes:

[0038] The temperature of the detection chip is lowered to a photographing temperature through an imaging stage located below the imaging detection device.

[0039] In some possible embodiments, the biochemical reaction in the reaction step is a nucleic acid sequencing reaction, and the sample to be detected is a nucleic acid sequencing library.

[0040] In some possible embodiments, the detectable signal is an optical signal.

[0041] In some possible embodiments, the sample to be detected is a tissue sample, and the biochemical reaction in the reaction step is a specific binding reaction.

[0042] In a third aspect, the present invention further provides a sequencing method, comprising:

[0043] Moving an open slide fixed with a sequence sample array to be detected between a liquid exchange site and a reaction site according to a preset reaction sequence; printing a reagent layer with a preset thickness on the slide at the liquid exchange site; transferring the slide printed with the reagent layer to a reaction chamber at the reaction site, allowing the sequence sample array to be detected and the reagent layer to react in the reaction chamber;

[0044] The slide after the reaction is transferred to a detection site, and image recognition is performed on the fluorescent signal of the sequence sample array to be detected after the reaction.

[0045] In some possible embodiments, at the liquid exchange site, the reagent layer is printed onto the carrier slide by inkjet printing.

[0046] In some possible embodiments, during the process of printing the reagent layer at the liquid replacement site, the slide moves horizontally along the arrangement direction of the array of sequence samples to be detected.

[0047] In some possible embodiments, before transferring the carrier slide after the reaction to the detection site, the method further includes: moving the carrier slide after the reaction to the liquid exchange site, removing the residual reaction reagents on the carrier slide, and printing a photographic reagent layer on the surface of the carrier slide.

[0048] In some possible embodiments, during the process of the carrier moving back and forth between the liquid exchange site and the reaction site, before printing a reagent layer different from the previously printed reagent on the carrier, the method further includes: clearing the residual reagent from the previous reaction on the carrier.

[0049] In a fourth aspect, the present application also provides a sequencing method, comprising: fixing a sample to be detected to an open slide having a site array, wherein the sample to be detected includes a nucleic acid sequencing library; printing a reaction reagent onto the open slide to form a reaction reagent layer having a preset thickness; adjusting the reaction temperature of the reaction reagent and the sample to be detected to perform a reaction between the sample to be detected and the reaction reagent; and detecting a detectable signal on the open slide and identifying the base sequence information of the sample to be detected based on the detectable signal.

[0050] In a fifth aspect, the present application also provides a sequencing system, comprising: an open slide having a site array, the site array being used to fix a sample to be detected, the sample to be detected comprising a nucleic acid sequencing library; a liquid adding component, the liquid adding component being spaced apart from the open slide and movable relative to the open slide, the liquid adding component being used to print a reaction reagent onto the open slide to form a reaction reagent layer having a preset thickness; a biochemical reaction device, the biochemical reaction device being configured to correspondingly adjust the reaction temperature of the reaction reagent layer and the sample to be detected to perform a reaction between the sample to be detected and the reaction reagent; and a detection device, the detection device being configured to detect a detectable signal on the open slide and identify the base sequence information of the sample to be detected based on the detectable signal.

[0051] The biochemical substance analysis system provided in the embodiments of the present application has the following beneficial effects:

[0052] (1) By integrating the biochemical reaction device, liquid exchange device and imaging detection device into a biochemical substance analysis platform, and coordinating with a transfer device set up independently of the biochemical substance analysis platform, the integrated operation of sample addition, biochemical substance analysis and imaging detection can be realized, which simplifies the system structure, is conducive to improving the detection efficiency, can realize ultra-high throughput detection, and reduce the equipment cost and detection cost.

[0053] (2) By setting up an independent transfer device, there is no need to set up a transfer device in the biochemical substance analysis platform, which is conducive to reducing the volume of the biochemical substance analysis platform, making the biochemical substance analysis platform more compact, easy to assemble, and easy to use; moreover, the space for installing the transfer device can be saved to set up multiple groups of biochemical reaction devices to further improve the detection throughput; in addition, the use of a transfer device such as a robot to transfer the detection chip reduces the requirements for the spatial layout between the various structures of the biochemical substance analysis system.

[0054] (3) The transfer device drives the detection chip to move under the liquid exchange device to add or exchange liquid, which is more flexible and does not require an additional carrier at the liquid exchange site, simplifying the system structure.

[0055] (4) A liquid exchange device is integrated into the system, which simplifies the complexity of the liquid circuit system for adding reagents, reduces the structural complexity of the overall system, is easy to assemble and operate, and reduces the overall detection cost. In addition, the liquid exchange device uses inkjet printing to add liquid, with a high printing frequency and small print droplets. It can also accurately control the thickness of the liquid film, improve the uniformity of the liquid film thickness, and significantly reduce reagent loss (compared to the current conventional sequencing method, the amount of reagent loss can be reduced by approximately 50% to 80%), thereby further reducing the detection cost. In addition, the liquid exchange device uses blowing or suction to remove liquid, which is simple and convenient. In combination with the inkjet chip, the liquid exchange process can be simple and fast.

[0056] (5) Multiple biochemical reaction devices can be integrated into the same biochemical substance analysis platform, and equipped with a liquid exchange device and an imaging detection device, which can further improve the detection throughput and increase the utilization rate of the liquid exchange device and the imaging detection device. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments of the present application. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0058] FIG1 is a schematic diagram of a biochemical substance analysis system in one embodiment of the present application.

[0059] FIG2 is a schematic diagram of the three-dimensional structure of a biochemical substance analysis system in one embodiment of the present application.

[0060] FIG3 is a schematic structural diagram of the biochemical substance analysis platform in FIG2 .

[0061] FIG4 is a schematic structural diagram of the biochemical reaction device in FIG3 .

[0062] Figure 5 is an exploded view of Figure 4.

[0063] FIG6 is a cross-sectional view along line VI-VI in FIG4 .

[0064] FIG7 is a schematic structural diagram of an inkjet chip and a liquid storage structure in one embodiment of the present application.

[0065] FIG8 is a cross-sectional view of an inkjet chip and a liquid storage structure in one embodiment of the present application.

[0066] FIG9 is a top view of an inkjet chip in one embodiment of the present application.

[0067] FIG10 is a top view of an inkjet chip in another embodiment of the present application.

[0068] Figure 11 is a top view of the inkjet chip in another embodiment of the present application.

[0069] FIG12 is a schematic diagram of an inkjet chip in an embodiment of the present application when the liquid adding chamber is filled with reagent and no liquid is added.

[0070] FIG13 is a schematic diagram of an inkjet chip ejecting reagents in one embodiment of the present application.

[0071] FIG14 is a schematic diagram of the structure of an inkjet chip ejecting reagents in another embodiment of the present application.

[0072] FIG15 is a schematic diagram of a biochemical substance analysis system in another embodiment of the present application.

[0073] FIG16 is a schematic structural diagram of a liquid replacement device in another embodiment of the present application.

[0074] FIG17 is a flow chart of a biochemical substance analysis method according to an embodiment of the present application.

[0075] FIG18 is a flow chart of a biochemical substance analysis method according to another embodiment of the present application.

[0076] FIG19 is a flowchart of a biochemical substance analysis method according to an embodiment of the present application.

[0077] FIG20 is a schematic flow chart of a sequencing method according to an embodiment of the present application.

[0078] Figure 21 is a schematic diagram of a sequencing system according to an embodiment of the present application.

[0079] Figure 22 is a schematic structural diagram of an open slide according to an embodiment of the present application.

[0080] Figure 23 is a structural schematic diagram of an open slide according to another embodiment of the present application.

[0081] Description of main component symbols

[0082] The following specific implementation methods will further illustrate this application in conjunction with the above-mentioned drawings. DETAILED DESCRIPTION

[0083] The following will be combined with the drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0084] It should be noted that when a component is referred to as being "fixed to" or "mounted on" another component, it may be directly on the other component or there may also be a central component. When a component is considered to be "disposed on" another component, it may be directly on the other component or there may be a central component at the same time. The term "and / or" as used herein includes all and any combination of one or more related listed items. "Printing", "inkjet printing", etc. described in this application refer to the operation of spraying substances required for biochemical reactions onto a slide.

[0085] Referring to Figures 1 and 2, an embodiment of the present application provides a biochemical substance analysis system 1000, comprising: a biochemical substance analysis platform 100 and a transfer device 200. The biochemical substance analysis platform 100 comprises a biochemical reaction device 300, a liquid exchange device 400, and an imaging detection device 500. The transfer device 200 is used to detachably support the detection chip 700 for transfer between different sites, so that the detection chip 700 can smoothly complete the entire process of biochemical substance analysis. The detection chip 700 is an open slide for fixing the sample to be detected. The detection chip 700 can be a sequencing chip used for gene sequencing, and the biochemical substance analysis can be a gene sequencing process. The sites include reaction sites corresponding to the biochemical reaction device 300, liquid exchange sites corresponding to the liquid exchange device 400, and imaging sites corresponding to the imaging detection device 500. The liquid exchange device 400 includes a liquid adding component 410 for printing a predetermined thickness of a reaction layer on the detection chip 700, and the reaction layer includes a reagent. The reaction layer of the preset thickness can, for example, be evenly spread on the surface of the detection chip, or it can be a patterned layer covering a specified position of the detection chip. The biochemical reaction device 300 includes a reaction chamber 330, and the detection chip 700 after printing the reaction layer is transferred to the reaction chamber 330 by the transfer device 200 and performs the reaction of the sample to be detected with the reagent in the reaction chamber 330, for example, in the gene sequencing reaction, the DNA sample on the sequencing chip (for example, DNA nanoballs, referred to as "DNB") is subjected to a chemical reaction before gene sequencing. The imaging detection device 500 is used to perform imaging detection analysis on the detection chip 700 after the reaction. In addition, the biochemical substance analysis system 1000 also includes a control platform 800, which is used to control the collaborative operation of the transfer device 200, the biochemical reaction device 300, the liquid exchange device 400 and the imaging detection device 500.

[0086] Referring to FIG. 2 , the biochemical substance analysis platform 100 further includes a main platform 600, which is used to house the biochemical reaction apparatus 300, the fluid exchange apparatus 400, and the imaging detection apparatus 500. The main platform 600 includes a main platform 610 and a top platform 630 disposed on the main platform 610. In some embodiments, the biochemical reaction apparatus 300 is disposed on the main platform 610, and the fluid exchange apparatus 400 and the imaging detection apparatus 500 are both disposed on the top platform 630.

[0087] Please refer to Figure 2 again. The transfer device 200 can be a robot independently provided with the biochemical substance analysis platform 100, specifically including a mounting seat 210, a robotic arm 220 provided on the mounting seat 210, and a robotic arm 230 provided at one end of the robotic arm 220 away from the mounting seat 210. Among them, the robotic arm 230 is used to take and place the detection chip 700, and the specific taking and placing method can adopt a detachable clamping or adsorption method. In some embodiments, the open slide is fixed with an array of samples to be tested, and the detection chip 700 is clamped by the transfer device 200 and moved to the liquid exchange site. At the liquid exchange site, the transfer device 200 drives the detection chip 700 to move relative to the liquid exchange device 400, so that the liquid adding component 410 in the liquid exchange device 400 can add liquid to the detection chip 700. The detection chip 700 is clamped by the transfer device 200 and moved under the liquid exchange device 400 to achieve liquid addition, which is more flexible.

[0088] In some embodiments, the robotic arm 220 includes a plurality of rotating mechanisms 221 that are rotatably connected, and can achieve rotation in multiple directions, thereby flexibly taking and placing the detection chip 700 .

[0089] Referring to Figures 3 to 5 , and in conjunction with Figure 2 , the biochemical reaction device 300 includes a reaction platform 310 and a heating cover 320. The heating cover 320 and the reaction platform 310 can enclose a reaction chamber 330. The reaction chamber 330 has a chip inlet 340. The transfer device 200 is used to insert the detection chip 700 into the reaction chamber 330 through the chip inlet 340 so that the detection chip 700 is adsorbed on the reaction platform 310. Specifically, the reaction platform 310 and the heating cover 320 both have temperature control functions and can heat or cool the detection chip 700. Since the detection chip 700 adopts the form of an open slide, the reaction chamber 330 formed by the reaction platform 310 and the heating cover 320 can provide a relatively closed place for the biochemical reaction of the detection chip 700, which can better control the reaction temperature and effectively reduce the evaporation of reagents on the detection chip 700.

[0090] In some embodiments, the reaction platform 310 and the heating cover 320 are detachably connected to facilitate maintenance of the reaction platform 310 and the heating cover 320 .

[0091] In some embodiments, the reaction platform 310 includes a bottom wall 311, a side wall 312 provided on the periphery of the bottom wall 311, and an adsorption platform 313 provided on the bottom wall 311. The heating cover 320 is provided at one end of the side wall 312 away from the bottom wall 311. The adsorption platform 313 is located in the reaction chamber 330, and specifically detects the chip 700 by negative pressure adsorption. Among them, the chip inlet 340 is opened on the side wall 312. In some embodiments, the end surface 314 of the side wall 312 facing away from the bottom wall 311 is recessed toward the bottom wall 311 to form the chip inlet 340. Specifically, the end surface 314 of the chip inlet 340 close to the bottom wall 311 (i.e., the bottom surface of the chip inlet 340) is flush with the surface of the adsorption platform 313 close to the heating cover 320, so that the detection chip 700 can be inserted into the chip inlet 340 and smoothly reach the adsorption platform 313 and be adsorbed by the adsorption platform 313. At the same time, it is also convenient for the detection chip 700 to be taken out.

[0092] In some embodiments, the heating cover 320 includes a reaction zone 321 corresponding to the adsorption platform 313, a first connection zone 322 connected to the periphery of the reaction zone 321, and a second connection zone 323 connected to the periphery of the first connection zone 322 away from the reaction zone 321. The end surface 314 of the sidewall 312 abuts the second connection zone 323, so that the heating cover 320 and the reaction platform 310 form a reaction chamber 330. The reaction zone 321 has a groove 326 that opens toward the adsorption platform 313. Specifically, the heating cover 320 has a first surface 324 adjacent to the reaction platform 310 and a second surface 325 opposite the first surface 324. The first surface 324 located in the reaction zone 321 is recessed toward the second surface 325 to form the groove 326. When the detection chip 700 is attached to the adsorption platform 313, the groove 326 is used to enclose the reaction area of ​​the detection chip 700 to form a sealed reaction space. Specifically, when the detection chip 700 is attached to the adsorption platform 313, the peripheral edge of the detection chip 700 abuts against the first connection area 322. At this time, the reaction area of ​​the detection chip 700 is exactly located at the opening of the groove 326, thereby forming a sealed reaction space between the detection chip 700 and the groove 326. In some embodiments, the first surface 324 of the heating cover 320 is provided with a sealing ring 360. The sealing ring 360 is located between the first connection area 322 and the detection chip 700, thereby enhancing the sealing of the reaction space between the groove 326 and the detection chip 700. In some embodiments, the depth of the groove 326 is approximately 500 μm. When the detection chip 700 is attached to the adsorption platform 313, the distance between the surface of the detection chip 700 close to the heating cover 320 and the bottom of the groove 326 is approximately 500 μm, thereby forming a sufficient reaction space.

[0093] In some embodiments, the biochemical reaction device 300 further includes a support structure 350 disposed on the main platform 610, with the reaction platform 310 and the heating cover 320 both located on the support structure 350. It is understood that the support structure 350 can adjust the positions of the reaction platform 310 and the heating cover 320 to better cooperate with the transfer device 200 in taking and placing the detection chip 700.

[0094] It is understood that in other embodiments, the heating cover 320 is movable. Specifically, a lifting mechanism is provided on the support structure 350, and the heating cover 320 is mounted on the lifting mechanism. When the detection chip 700 is placed on the reaction platform 310, the lifting mechanism drives the heating cover 320 to close onto the reaction platform 310, thereby forming a sealed reaction space between the heating cover 320 and the detection chip 700. In this embodiment, the chip inlet 340 is not required on the reaction platform 310.

[0095] Please refer to Figures 3 and 7, and refer to Figures 1 and 2 in combination. The liquid changing device 400 also includes a liquid removal component 420. Specifically, the liquid adding component 410 and the liquid removal component 420 are installed on the top platform 630 through a mounting plate. Among them, the liquid adding component 410 can load the reagents used for the biochemical reaction onto the detection chip 700. The liquid removal component 420 can remove the residual reagents of the completed reaction on the detection chip 700. Usually after one reagent reaction is completed, it is necessary to replace another reagent. At this time, it is necessary to use the liquid removal component 420 to remove the residual reagents after the previous step of the reaction, and then use the liquid adding component 410 to add another reagent. Through the cooperation of the liquid adding component 410 and the liquid removal component 420, the liquid addition and liquid removal on the detection chip 700 can be achieved respectively.

[0096] The liquid adding assembly 410 can use inkjet printing to spray the reagents (typically liquid reagents) required for the biochemical reaction onto the open detection chip 700 to form a reaction layer containing the sample to be detected. The liquid adding assembly 410 includes: an inkjet chip 430, a reagent storage box 440 connected to the inkjet chip 430, and an inkjet control circuit 450. The inkjet control circuit 450 is electrically connected to the inkjet chip 430 to control the inkjet chip 430 to spray the reagents onto the detection chip 700.

[0097] Referring to Figures 7 and 8 , and in conjunction with Figure 1 , the inkjet chip 430 includes a stacked inkjet chamber layer 431 and a drive structure 432. The inkjet chamber layer 431 includes a first surface 4311 and a second surface 4312 disposed opposite each other. The drive structure 432 is located on the first surface 4311 and is electrically connected to an inkjet control circuit 450. At least one liquid addition chamber 435 is formed through the first and second surfaces 4311 and 4312 of the inkjet chamber layer 431. The liquid addition chamber 435 defines at least one liquid outlet 436 on the second surface 4312. The liquid addition chamber 435 is used to accommodate reagents required for biochemical analysis. A negative pressure air path (not shown) can be added to communicate with the liquid addition chamber 435 to maintain a certain negative pressure within the liquid addition chamber 435, thereby retaining the reagents within the chamber. The drive structure 432 is located on the surface of the inkjet cavity layer 431 and covers the opening between the liquid addition cavity 435 and the liquid outlet 436. Under the control of the inkjet control circuit 450, the drive structure 432 can deform, squeezing the reagent in the liquid addition cavity 435, causing it to be discharged through the liquid outlet 436 and then printed onto the detection chip 700 to form a layer to be reacted. Using inkjet printing to add liquid to the detection chip 700 allows for precise control of liquid film thickness, significantly reducing reagent loss, and further lowering detection costs.

[0098] In some embodiments, along the extension direction a of the inkjet chip 430, the inner diameter of the liquid outlet 436 is smaller than the minimum inner diameter of the liquid adding chamber 435. That is, the liquid outlet 436 has a minimum diameter, which can better limit the outflow rate of the droplets and better control the volume of the droplets printed each time. Furthermore, the smaller diameter of the liquid outlet 436 can better maintain the sample within the liquid adding chamber 435 under the action of negative pressure when the sample is not being added.

[0099] The inkjet cavity layer 431 can be a multi-layer structure, comprising a substrate 4313, a resin layer 4314 stacked on the substrate 4313, and a nozzle plate 4315 stacked on the surface of the substrate 4313 facing away from the resin layer 4314. The surface of the resin layer 4314 facing away from the substrate 4313 constitutes a first surface 4311, and the surface of the nozzle plate 4315 facing away from the substrate 4313 constitutes a second surface 4312. It is understood that the resin layer 4314 can be a single layer or multiple layers. The portion of the liquid adding chamber 435 corresponding to the resin layer 4314 constitutes a first through-hole 4316, the portion of the liquid adding chamber 435 corresponding to the substrate 4313 constitutes a second through-hole 4317, and the portion of the liquid adding chamber 435 corresponding to the nozzle plate 4315 constitutes a liquid outlet 436. In some embodiments, the inner diameters of the first through-hole 4316, the second through-hole 4317, and the liquid outlet 436 decrease in sequence. Here, the inner diameter of the liquid outlet 436 is designed to be the smallest. When sample addition is not required, the reagent in the liquid adding chamber 435 will not flow out of the liquid outlet 436 due to its own gravity under the action of surface tension at the small-diameter liquid outlet 436, and will remain in the liquid adding chamber 435. The inner diameter of the first through hole 4316 is designed to be relatively large so that it can carry more reagents.

[0100] In some embodiments, the material of substrate 4313 can be silicon, and the material of resin layer 4314 can be polyimide. A second through-hole 4317 with a smaller inner diameter can be formed on substrate 4313, and a first through-hole 4316 with a larger inner diameter can be formed on resin layer 4314 by chemical etching. Because the resin layer 4314 can be etched to form holes, which is easier to form holes than the silicon substrate 4313, the inner diameter of first through-hole 4316 can be precisely controlled according to actual needs, thereby improving the accuracy of volume control of liquid addition chamber 435 and ensuring the accuracy of reagent dosage. In some embodiments, the volume of liquid addition chamber 435 can be 9pL to 50pL. For example, the volume of liquid addition chamber 435 can be 9pL, 10pL, 15pL, 20pL, 25pL, 30pL, 35pL, 40pL, 45pL, or 50pL, etc.

[0101] The inkjet cavity layer 431 also has at least one liquid inlet 437, which communicates with the liquid adding cavity 435 and the reagent storage box 440, allowing the reagent in the reagent storage box 440 to be added to the liquid adding cavity 435 via the liquid inlet 437. In some embodiments, the opening of the liquid inlet 437 can be located on the first surface 4311 of the inkjet cavity layer 431 or on a side surface of the inkjet cavity layer 431. In some embodiments, as shown in FIG7 , the liquid inlet 437 is provided in the resin layer 4314, with the opening located on the first surface 4311.

[0102] Please refer again to Figures 7 and 8, and in conjunction with Figure 1, the liquid adding assembly 410 also includes a liquid storage structure 470 located on the inkjet chip 430. The liquid storage structure 470 includes at least one liquid storage cavity 471. Each liquid storage cavity 471 is connected to at least one liquid adding cavity 435. The liquid storage cavity 471 is connected to the reagent storage box 440. The reagent in the reagent storage box 440 can flow into the liquid storage cavity 471 by gravity and then further into the liquid adding cavity 435 through the liquid inlet 437. In some embodiments, the liquid storage cavity 471 is a sealed cavity, and a negative pressure air circuit can be used to prevent the reagent in the liquid storage cavity 471 and the liquid adding cavity 435 from leaking out of the liquid outlet 436.

[0103] Please refer to Figure 9, and refer to Figures 1, 7, and 8 in combination. The inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged side by side, and each liquid adding chamber 435 is provided with a drive structure 432 and a plurality of liquid outlets 436. The plurality of drive structures 432 can be electrically connected to an inkjet control circuit (not shown) to achieve independent control of the plurality of drive structures 432 to achieve independent sample addition of the plurality of liquid adding chambers 435. At this time, the reagents in the same liquid adding chamber 435 are driven by the drive structure 432, and the droplet volumes discharged from the plurality of liquid outlets 436 are substantially the same. One reagent can be stored in each liquid adding chamber 435, so that simultaneous printing of multiple reagents can be achieved. The arrangement of the multiple liquid outlets 436 in each liquid adding chamber 435 can be designed according to the arrangement of the reaction sites on the detection chip 700. For example, the multiple liquid outlets 436 in each liquid adding chamber 435 can be arranged in a straight line. It is understandable that the multiple liquid outlets 436 in each liquid adding chamber 435 can also be arranged in an array. In this way, the liquid outlets 436 in the multiple liquid adding chambers 435 arranged side by side form a microwell array, and the number of liquid outlets 436 can be adjusted according to the number of site arrays on the detection chip 700 (for example, it can be a sequencing chip). In order to improve the effect of the biochemical reaction, the flux of the detection chip 700 is higher. In this case, the density of the liquid outlets 436 of the inkjet chip 430 can be designed to be higher. For example, the spacing between adjacent liquid outlets 436 can be about 40 microns, thereby achieving high-density printing. In some embodiments, the liquid storage structure 470 is divided into multiple independent liquid storage chambers 471, each liquid storage chamber 471 corresponds to a liquid adding chamber 435 and is connected through a liquid inlet 437.

[0104] It is understood that in other embodiments, as shown in FIG10 , the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged in an array, each liquid adding chamber 435 correspondingly provided with a drive structure 432 and a liquid outlet 436, thereby achieving independent control of each liquid outlet 436, and further precisely controlling the volume of droplets discharged from each liquid outlet 436. In this case, the liquid storage structure 470 is divided into a plurality of independent liquid storage chambers 471, each liquid storage chamber 471 corresponding to a row of liquid adding chambers 435, and the same row of liquid adding chambers 435 are connected to the liquid storage chamber 471 via a liquid inlet 437. Specifically, the reagents in the same row of liquid adding chambers 435 are of the same type.

[0105] It can also be understood that in other embodiments, as shown in Figure 11, the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged in an array, each liquid adding chamber 435 corresponds to a driving structure 432 and a liquid outlet 436, and at this time, the liquid storage structure 470 is divided into a plurality of independent liquid storage chambers 471, each liquid storage chamber 471 corresponds to a liquid adding chamber 435, and is connected through a liquid inlet hole 437, so that the type of reagent in each liquid adding chamber 435 and the volume of the sample droplet can be flexibly set.

[0106] Referring to Figures 12 and 13, and in conjunction with Figure 1, the drive structure 432 can use piezoelectric inkjet printing technology to print the reagent in the liquid addition chamber 435 onto the detection chip 700. Piezoelectric inkjet printing technology uses piezoelectric ceramics to deform due to the application of voltage, squeezing the liquid to generate high pressure and ejecting the liquid. In some embodiments, the drive structure 432 may include a piezoelectric layer 4321 and an electrode layer 4322 located on the piezoelectric layer 4321. As shown in Figure 12, the operating principle of the inkjet chip 430 is to apply a voltage to the piezoelectric layer 4321 through the electrode layer 4322. Since the material of the piezoelectric layer 4321 can be piezoelectric ceramic, the piezoelectric layer 4321 will be affected by the voltage and produce a transient deformation. This transient deformation squeezes the reagent in the liquid addition chamber 435 and ejects the reagent at high pressure from the liquid outlet 436 to form droplets, thereby printing them onto the corresponding position of the detection chip 700. By using micro-piezoelectric technology to achieve reagent printing, the volume of the printed reagent droplets can be precisely controlled, thereby reducing reagent loss.

[0107] In other embodiments, as shown in FIG14 , the driving structure 432 may also employ thermal bubble inkjet printing technology to achieve liquid spraying. The driving structure 432 may also include a heater, which generates heat when energized to heat the reagent in the liquid adding chamber 435 , thereby generating bubbles. The bubbles squeeze out the reagent droplets from the liquid outlet 436 to achieve the purpose of printing.

[0108] 1 again, the reagent storage box 440 can be connected to the liquid storage structure 470 on the inkjet chip 430 through a set of liquid connectors. It is understood that the storage location of the reagent storage box 440 can be selectively equipped with a refrigeration module to maintain the required environment for the reaction reagents.

[0109] The inkjet control circuit 450 is mainly used to control the movement position, reagent type and reagent amount of the inkjet chip 430. It is electrically connected to each driving structure 432 and can realize independent control of each liquid outlet 436 or each discharge liquid outlet 436 of the inkjet chip 430.

[0110] In some embodiments, the printing frequency of the inkjet chip 430 may be greater than or equal to 10 kHz. A high printing frequency and good printing uniformity can improve the sample loading efficiency of the detection chip 700 and the uniformity of the liquid film thickness.

[0111] Please refer to Figures 1 and 2 again. The liquid removal component 420 uses airflow to remove residual reagents that have reacted on the detection chip 700. The liquid existing on the detection chip 700 can be directly removed by blowing air or sucking liquid. The liquid removal component 420 includes an air knife 421 and an air supply structure 422, wherein the air knife 421 is connected to the air supply structure 422, and the air supply structure 422 can provide compressed gas or provide negative pressure to form an airflow, thereby blowing or sucking away the liquid on the surface of the detection chip 700. The use of air blowing or liquid suction to achieve liquid removal is simple and convenient, and combined with the inkjet chip 430, a simple and fast liquid replacement process can be achieved.

[0112] In some embodiments, the air supply structure 422 can be a gas compressor capable of providing compressed gas, such as compressed air or compressed nitrogen. The compressed gas enters the air knife 421 through the air path. The air knife 421 confines the blown gas to the surface of the detection chip 700, thereby removing the liquid on the surface of the detection chip 700. The air knife is used to blow or suck air to form the airflow. In some embodiments, the temperature on the detection chip 700 is maintained at a low temperature, for example, 10°C to 15°C, during the blowing process.

[0113] It is understandable that in other embodiments, the air supply structure 422 may also be a vacuum pump, which can use vacuum negative pressure to absorb the liquid on the surface of the detection chip 700.

[0114] Please refer to Figure 15. The biochemical substance analysis platform 100 also includes a liquid exchange platform 910 located below the liquid exchange device 400 and spaced apart from the liquid exchange device 400. During the liquid addition and removal process, the liquid exchange site is located between the liquid exchange device 400 and the liquid exchange platform 910. The liquid exchange platform 910 has a cold air release structure toward the liquid exchange site to cool the detection chip 700 located at the liquid exchange site.

[0115] Please refer to Figure 16. It can be understood that in other embodiments, the liquid replacement device 400 also includes a linkage structure 460, which is arranged on the top platform 630. The linkage structure 460 can drive the liquid adding component 410 and the liquid removing component 420 to be linked, so that the liquid adding operation can be performed immediately after the liquid is removed, and the liquid replacement efficiency is high. In some embodiments, the linkage structure 460 may include a linkage shaft 461 and a drive motor 462. The inkjet chip 430 of the liquid adding component 410 and the air knife 421 of the liquid removing component 420 are slidably arranged on the drive motor 462 of the linkage structure 460, wherein the inkjet chip 430 and the air knife 421 are arranged side by side along the extension direction of the linkage shaft, and the air knife 421 is located at the front end of the travel direction to achieve the purpose of removing liquid first and then adding liquid. In this embodiment, during the process of adding and removing liquid, the detection chip 700 can be fixed, and the addition and removal of liquid of the detection chip 700 can be achieved by controlling the movement of the liquid adding component 410 and the liquid removing component 420.

[0116] Referring again to Figures 2 and 3, the imaging detection device 500 includes a lens assembly 510 and a detection assembly 520. The lens assembly 510 is disposed on a top platform 630 and is signal-connected to the detection assembly 520. The lens assembly 510 can capture an image of the detection chip 700 that is reacting to a biochemical reaction and transmit the image to the detection assembly 520 for analysis of the detection results.

[0117] Please refer to Figures 2 and 3 again. The biochemical substance analysis platform 100 also includes an imaging stage 920 located below the imaging detection device 500. When the detection chip 700 is placed on the imaging stage 920, the imaging stage 920 can adjust the position of the detection chip 700, so that the lens assembly 510 can better capture a complete image of the detection chip 700.

[0118] In some embodiments, the imaging platform 920 includes a carrier 921, a movable component 922 disposed on the carrier 921, and a chip carrier 923 disposed on the movable component 922. The carrier 921 is disposed on the main platform 610, the chip carrier 923 is used to carry the detection chip 700, and the movable component 922 is used to adjust the position of the detection chip 700.

[0119] In some embodiments, the moving assembly 922 is a multi-axis moving mechanism, specifically including a first axis 924 disposed on the carrier 921 and extending along a first direction x, a second axis 925 slidably disposed on the first axis 924 and extending along a second direction y, and a third axis 926 slidably disposed on the second axis 925 and extending along a third direction z. The chip carrier 923 is disposed on the third axis 926. The first direction x, second direction y, and third direction z are mutually perpendicular and form a three-dimensional coordinate system. The second axis 925 can move along the first axis 924 to drive the chip carrier 923 to move along the first direction x, thereby adjusting the position of the detection chip 700 in the first direction x. The third axis 926 can move along the second axis 925 to drive the chip carrier 923 to move along the second direction y, thereby adjusting the position of the detection chip 700 in the second direction y. The third axis 926 can also drive the chip carrier 923 to move along the third direction z, thereby adjusting the position of the detection chip 700 in the third direction z.

[0120] In some embodiments, the chip carrier 923 is provided with a temperature adjustment component (not shown) for heating or cooling the detection chip. Specifically, the chip carrier 923 is a temperature-variable (heating and cooling) chip carrier with a temperature adjustment function, thereby ensuring that the detection chip 700 reaches the temperature required for imaging.

[0121] It can be understood that the biochemical substance analysis platform 100 can include multiple biochemical reaction devices 300, a liquid exchange device 400 and an imaging detection device 500. A biochemical reaction device 300 can realize the biochemical reaction of a group of detection chips 700. A group of detection chips 700 can be one or more. By setting multiple biochemical reaction devices 300, the biochemical reactions of multiple groups of detection chips 700 can be realized simultaneously. By setting the timing of multiple biochemical reaction devices 300 through the control platform 800, the reaction steps of multiple biochemical reaction devices 300 can be staggered. In this way, the liquid exchange device 400 and the imaging detection device 500 can be fully utilized and the operating efficiency can be improved. By combining multiple biochemical reaction devices 300 with a liquid exchange device 400 and an imaging detection device 500, and combining the reasonable scheduling of a transfer device 200, it is beneficial to improve the detection throughput, improve the detection efficiency, and at the same time improve the utilization rate of the liquid exchange device 400 and the imaging detection device 500.

[0122] The aforementioned biochemical substance analysis system 1000 may specifically be a floor-standing / distributed sequencing system based on fluorescence imaging, and the size of the sequencing chip may be, for example, larger than 60 mm.

[0123] As shown in Figure 21, the application also provides a sequencing system 2000, which includes an open slide 700 with a site array, a liquid adding assembly 410, a biochemical reaction device 300, and a detection device 500. The site array is used to fix the sample to be detected, and the sample to be detected includes a nucleic acid sequencing library. The liquid adding assembly 410 is spaced apart from the open slide 700 and can move relative to the open slide 700. The liquid adding assembly 410 is used to print reaction reagents to the open slide 700 to form a reaction reagent layer with a preset thickness. The biochemical reaction device 300 is configured to perform the reaction of the sample to be detected with the reaction reagent layer in response to the reaction temperature of the reaction reagent layer and the sample to be detected. The detection device 500 is configured to detect a detectable signal on the open slide 700 and identify the base sequence information of the sample to be detected based on the detectable signal. Alternatively, as shown in Figures 22-23, an open slide 700 includes a substrate 701 and a site array 702 arranged on the surface of the substrate, each of which has a derivatization structure for fixing the sample to be detected. The open slide 700 can be square or circular, or any other regular or irregular shape. The derivatization structure can include a nucleic acid template molecule. For example, the derivatization structure can be a surface chemistry arranged at the site, which is used to bind nucleic acid template molecules (e.g., DNB), and the surface chemistry includes, for example, (3-aminopropyl) trimethoxysilane (APTMS). The relevant structures of the liquid addition component and the biochemical reaction device in this embodiment are similar to the liquid addition component and the biochemical reaction device described in other embodiments above and are not described in detail. In addition, the detection device in this embodiment can, for example, include a camera for collecting images, and its relevant structure is similar to the image detection device described above. It should be understood that the detection device in the sequencing system of the present application can also be other sensing structures that collect other detectable signals (e.g., electrical signals, etc.) in addition to optical signals. Please refer to FIG. 17 , and refer to FIG. 1 and FIG. 2 together, for a method of performing biochemical substance analysis using the aforementioned biochemical substance analysis system 1000 , which specifically includes the following steps:

[0124] Step S11, liquid adding step: the detection chip 700 is transferred to the liquid replacement site by the transfer device 200, and a reaction layer of a preset thickness is printed on the detection chip 700 by the liquid adding component 410 in the liquid replacement device 400. The reaction layer includes reagents, and the detection chip 700 includes an open carrier for fixing the sample to be detected.

[0125] Specifically, the open carrier of the detection chip 700 is fixed with the samples to be detected arranged in an array. The detection chip 700 is moved under the liquid replacement device 400 by the transfer device 200, so that the liquid addition component 410 prints the reagents onto the detection chip 700 to form a layer to be reacted, thereby completing the liquid addition process. The liquid addition component 410 prints the reagents onto the detection chip 700 by inkjet printing.

[0126] In some embodiments, a liquid exchange platform 910 is provided below the liquid exchange device 400 and is spaced apart from the liquid exchange device 400. During the liquid adding process, the transfer device 200 clamps the detection chip 700 and moves it to the liquid exchange position between the liquid exchange platform 910 and the liquid exchange device 400. At this time, the cold air release structure 930 on the liquid exchange platform 910 can blow out cold air to cool the detection chip 700.

[0127] In some embodiments, a collection tank (not shown) is provided on the liquid exchange carrier 910 to collect residual reagents blown away from the detection chip 700 .

[0128] It is understandable that before adding liquid to the detection chip 700 , a biological sample (such as a nucleic acid molecule) needs to be added into the detection chip 700 in advance.

[0129] Step S12, reaction step: the detection chip 700 printed with the layer to be reacted is transferred to the reaction site by the transfer device 200, and the sample to be detected in the detection chip 700 reacts with the reagent by the biochemical reaction device 300.

[0130] Step S13, detection step: The detection chip 700 after the reaction is transferred to the imaging site by the transfer device 200, and the detectable signal of the detection chip 700 is obtained by the imaging detection device 500 and imaging detection analysis is performed. In some embodiments, before the imaging detection, the imaging stage 920 located below the imaging detection device 500 can be used to adjust the position of the detection chip 700 and reduce the temperature of the detection chip 700 to a photographic temperature.

[0131] Step S14, a loop step: moving the detection chip 700 back and forth between the liquid exchange site and the reaction site and imaging site according to a preset path to achieve multiple liquid addition steps and reaction steps; and between two adjacent liquid addition steps, the method also includes a liquid removal step of removing the reacted residual reagent on the surface of the detection chip 700 through the liquid removal component 420 in the liquid exchange device 400.

[0132] In the first liquid adding step, the transfer device 200 drives the detection chip 700 to move below the inkjet chip 430 , and the control platform 800 controls the inkjet chip 430 to add liquid to the detection chip 700 .

[0133] In the subsequent liquid adding step (i.e., liquid replacement), a liquid removal step must be performed first. The transfer device 200 drives the detection chip 700 to move under the liquid replacement device 400. The control platform 800 controls the gas supply structure 422 to provide compressed gas. The compressed gas flows through the air knife 421 and removes the residual reagent on the detection chip 700 after the reaction; then the liquid adding step is performed, and at the same time, the inkjet chip 430 is controlled to add another reagent to the detection chip 700 from which the residual reagent has been removed, thereby completing the liquid replacement process.

[0134] Among them, the cycle step of step S14 can be performed multiple times. For example, the method can include at least two of the aforementioned liquid adding steps, and the reagent printed in at least one of the liquid adding steps is different from the reagent printed in other liquid adding steps, so as to realize the loading of different reagents on the detection chip 700 and different biochemical reaction processes until the biochemical reaction is completed.

[0135] As shown in Figures 18 and 19, in combination with Figures 1 and 2, the specific process of gene sequencing using the above method is given. The detection chip 700 can be an open carrier for sequencing, the biochemical reaction in the reaction step is a nucleic acid sequencing reaction, the sample to be detected is a nucleic acid sequencing library, and the detectable signal is an optical signal; alternatively, the sample to be detected is a tissue sample, and the biochemical reaction in the reaction step is a specific binding reaction.

[0136] In step S21, the sequence sample array to be detected is fixed to an open slide, wherein the sequence sample array to be detected, for example, comprises DNBs of a DNA sequencing library, and the DNBs are adsorbed on the reaction area of ​​the slide.

[0137] In step S22, the slide is moved between the liquid exchange site and the reaction site according to a preset reaction sequence; a reagent layer having a preset thickness is printed on the slide at the liquid exchange site; and at the reaction site, the slide printed with the reagent layer is transferred to the reaction chamber 330, so that the sequence sample array to be detected reacts with the reagent layer in the reaction chamber 330.

[0138] Specifically, in the first step, a transfer device 200 (e.g., a robot) grips a slide loaded with a biological sample and moves it beneath the liquid exchange device 400. The liquid addition assembly 410 is activated to perform inkjet printing, while the cooling air on the liquid exchange platform 910 is simultaneously activated to add liquid to the slide. The cooling air temperature from the liquid exchange platform 910 can be controlled to approximately 15°C, thereby adjusting the slide temperature to approximately 15°C. During the printing of the reagent layer at the liquid exchange site, the slide moves horizontally along the arrangement direction of the array of samples of the sequence to be detected.

[0139] In the second step, the robot transfers the slide to the reaction site and inserts the slide into the reaction chamber 330 from the chip inlet 340 . The heating cover 320 and the reaction platform 310 are controlled to heat to the target temperature for incubation.

[0140] In the third step, the temperature of the reaction platform 310 at the reaction site is lowered to about 15° C., and the robot takes the slide out of the reaction chamber 330 .

[0141] The fourth step is to control the liquid removal component 420 to blow air to blow away the residual reagents on the slide that have completed the reaction.

[0142] Step S23 , transferring the post-reaction slide to a detection site, and performing image recognition on the post-reaction fluorescence signals of the sequence sample array to be detected.

[0143] Specifically, first, the robot transfers the slide to the liquid exchange site, controls the liquid removal component 420 to blow air to remove the residual reagents that have completed the reaction on the slide, and turns on the inkjet chip 430 to print a photographic reagent layer on the surface of the slide.

[0144] Afterwards, the robot transfers the slide to the imaging stage 920 and controls the imaging stage 920 to heat up to room temperature. The imaging detection device 500 takes pictures of the slide that has completed the reaction and performs analysis to complete the sequencing process.

[0145] Similarly, as shown in FIG20 , the present application also provides a sequencing method using the above-mentioned sequencing system, which specifically includes the following steps.

[0146] S31, fixing the sample to be detected to an open slide having a site array.

[0147] S32, printing a reaction reagent layer with a preset thickness onto the open slide.

[0148] S33, adjusting the reaction temperature of the reagent layer and the sample to be detected to perform the reaction between the sample to be detected and the reaction reagent layer.

[0149] S34, detecting the detectable signal on the open slide and identifying the base sequence information of the sample to be detected based on the detectable signal.

[0150] The sample to be detected is a DNB molecule comprising a nucleic acid sequencing library. In step S31 , the sample to be detected is adsorbed and fixed on the open slide by utilizing the derivatization structure and binding at site 702 in the open slide 700 .

[0151] In step S32, inkjet printing is performed using the liquid adding assembly 410 at a position corresponding to the open slide 700 to print the reaction reagent to a predetermined thickness on the open slide, thereby achieving precise control of the amount of reaction reagent and avoiding reagent waste. Similar to the above-mentioned method for biochemical substance analysis, the slide temperature can also be adjusted by providing a low-temperature gas (e.g., 15°C cold air) toward the open slide 700 (e.g., the back side) to prevent evaporation of the reaction reagent layer and reduce reagent loss.

[0152] In step S33, similar to the above-mentioned method of biochemical substance analysis, the above-mentioned heating cover and reaction chamber structure can also be used to control the reaction temperature and other reaction environments of the open slide. The specific control process is similar to the above-mentioned method of biochemical substance analysis. To avoid repetition, it will not be described here.

[0153] Furthermore, the sequencing reaction involves reactions between different reagents and the sample to be detected. Therefore, the sequencing method includes printing the reaction reagent layers containing different reaction reagents onto the open slide in batches. Between printing two adjacent reaction reagent layers, the sequencing method also includes a liquid removal step to remove residual reaction reagents on the open slide. Specifically, the liquid removal assembly 420 is controlled to blow air to remove residual reagents from the slide after the reaction has completed.

[0154] In step S34, the detection tool 500 including a camera can be used to take pictures of the open slide after the reaction and perform analysis to complete the sequencing process.

[0155] The biochemical substance analysis system 1000 provided in the embodiment of the present application has the following beneficial effects:

[0156] (1) By integrating the biochemical reaction device 300, the liquid exchange device 400, and the imaging detection device 500 into a biochemical substance analysis platform 100, and cooperating with the transfer device 200 independently provided on the biochemical substance analysis platform 100, the integrated operation of sample addition, biochemical substance analysis, and imaging detection can be realized, thereby simplifying the system structure, improving the detection efficiency, realizing ultra-high throughput detection, and reducing the equipment cost and the detection cost.

[0157] (2) By providing an independent transfer device 200, there is no need to provide a transfer device in the regenerative biochemical substance analysis platform 100, which is beneficial to reducing the volume of the biochemical substance analysis platform 100, making the biochemical substance analysis platform 100 more compact, easier to assemble, and easier to use; moreover, the space for installing the transfer device can be saved to set up multiple groups of biochemical reaction devices 300, thereby further improving the detection throughput; in addition, the transfer device 200 such as a robot is used to transfer the detection chip 700, which reduces the requirements for the spatial layout between the various structures of the biochemical substance analysis system 1000.

[0158] (3) The transfer device 200 drives the detection chip 700 to move under the liquid replacement device 400 to add or replace liquid, which is more flexible and does not require an additional carrier at the liquid replacement site, thereby simplifying the system structure.

[0159] (4) The system integrates a liquid replacement device 400, which simplifies the complexity of the liquid circuit system for adding reagents, reduces the structural complexity of the overall system, is easy to assemble and operate, and reduces the overall detection cost. In addition, the liquid replacement device 400 uses inkjet printing to achieve liquid addition, with a high printing frequency and small printed droplets. It can also accurately control the thickness of the liquid film, improve the uniformity of the liquid film thickness, and significantly reduce reagent loss (compared to the current conventional sequencing method, the amount of reagent loss can be reduced by approximately 50% to 80%), thereby further reducing the detection cost. In addition, the liquid replacement device 400 uses blowing or liquid suction to achieve liquid removal, which is simple and convenient. In conjunction with the inkjet chip 430, the liquid replacement process can be simple and fast.

[0160] (5) A plurality of biochemical reaction devices 300 can be integrated into the same biochemical substance analysis platform 100, and a liquid exchange device 400 and an imaging detection device 500 can be equipped at the same time, which can further improve the detection throughput and improve the utilization rate of the liquid exchange device 400 and the imaging detection device 500.

[0161] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application and are not intended to limit the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application.

Claims

1. A biochemical substance analysis system, characterized in that: include: A biochemical substance analysis platform and a transfer device, wherein the biochemical substance analysis platform comprises: a liquid replacement device, an imaging detection device, and at least one biochemical reaction device; The transfer device is used to detachably support the detection chip and drive the detection chip to transfer along a preset path to different sites, wherein the sites include a reaction site corresponding to the biochemical reaction device, a liquid replacement site corresponding to the liquid replacement device, and an imaging site corresponding to the imaging detection device; the detection chip is an open slide for fixing the sample to be detected; The liquid replacement device comprises a liquid adding component for printing a layer to be reacted of a preset thickness onto the detection chip, wherein the layer to be reacted comprises a reagent; The biochemical reaction device comprises a reaction chamber, the detection chip after printing the reaction layer is transferred to the reaction chamber by the transfer device and the reaction between the sample to be detected and the reagent is performed in the reaction chamber; The imaging detection device is used to perform imaging detection analysis on the detection chip after the reaction.

2. The biochemical substance analysis system according to claim 1, characterized in that: The transfer device comprises a mounting seat, a mechanical arm arranged on the mounting seat, and a mechanical hand arranged at one end of the mechanical arm away from the mounting seat, wherein the mechanical hand is used for detachably clamping the detection chip.

3. The biochemical substance analysis system according to claim 2, characterized in that: The open slide is fixed with the samples to be detected arranged in an array; At the liquid replacement site, the manipulator clamps the detection chip and moves horizontally relative to the liquid replacement device, so that the liquid adding component adds liquid to the detection chip.

4. The biochemical substance analysis system according to any one of claims 1 to 3, characterized in that: A liquid replacement platform is provided below the liquid replacement device and is spaced apart from the liquid replacement device; The liquid replacement site is located between the liquid replacement platform and the liquid replacement device; The liquid exchange platform has a cold air release structure toward the liquid exchange site to cool the detection chip located at the liquid exchange site.

5. The biochemical substance analysis system according to claim 1, characterized in that: The biochemical reaction device comprises a stacked reaction platform and a heating cover, wherein the heating cover and the reaction platform form a reaction chamber, and the reaction chamber has a chip inlet. The transfer device is used to insert the detection chip into the reaction chamber through the chip inlet so that the detection chip is adsorbed on the reaction platform.

6. The biochemical substance analysis system according to claim 5, characterized in that: The reaction platform includes a bottom wall, a side wall arranged at the periphery of the bottom wall, and an adsorption platform arranged on the bottom wall and located in the reaction chamber, the adsorption platform is used to adsorb the detection chip, the heating cover is arranged at one end of the side wall away from the bottom wall, and the chip inlet is located on the side wall.

7. The biochemical substance analysis system according to claim 6, characterized in that: The heating cover comprises a reaction zone, a first connection zone connected to the periphery of the reaction zone, and a second connection zone connected to the first connection zone and away from the periphery of the reaction zone, and the side wall is connected to the second connection zone; along the stacking direction, the vertical projection of the reaction zone on the bottom wall is located on the adsorption platform; The reaction area has a groove with an opening facing the adsorption platform. When the detection chip is adsorbed on the adsorption platform, the groove and the reaction area of ​​the detection chip form a closed reaction space.

8. The biochemical substance analysis system according to claim 7, characterized in that: A sealing ring is provided at the periphery of the first connection area close to the groove, and the sealing ring is used to support the detection chip.

9. The biochemical substance analysis system according to claim 1, characterized in that: An imaging stage is provided below the imaging detection device, and the imaging stage includes a carrier, a moving component provided on the carrier, and a chip carrier provided on the moving component. The chip carrier is used to carry the detection chip, and the moving component is used to adjust the position of the detection chip.

10. The biochemical substance analysis system according to claim 9, characterized in that: The chip carrier is provided with a temperature regulating component, and the temperature regulating component is used to heat or cool the detection chip.

11. The biochemical substance analysis system according to claim 9, characterized in that: The moving component includes a first axis disposed on the imaging stage and extending along a first direction, a second axis slidably disposed on the first axis and extending along a second direction, and a third axis slidably disposed on the second axis and extending along a third direction, wherein the stage is located on the third axis, wherein the first direction, the second direction and the third direction are perpendicular to each other and constitute a three-dimensional coordinate system.

12. The biochemical substance analysis system according to claim 1, characterized in that: The liquid adding component includes an inkjet chip, and the inkjet chip is used to load reagents for the detection chip by inkjet printing; The liquid replacement device also includes a liquid removal component, which is used to remove residual reagents on the detection chip after the reaction is completed.

13. The biochemical substance analysis system according to claim 12, characterized in that: The inkjet chip comprises: An inkjet cavity layer, comprising a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity is formed through the first surface and the second surface, the liquid adding cavity is used to accommodate the reagent, and the liquid adding cavity has at least one liquid outlet located on the second surface; A driving structure is stacked on the first surface and covers the liquid adding cavity, and the driving structure is used to drive the reagent in the liquid adding cavity to be discharged from the liquid outlet.

14. The biochemical substance analysis system according to claim 13, characterized in that: The driving structure comprises a deformation layer located on the first surface and an electrode layer located on the deformation layer, wherein the deformation layer is used to deform under the action of voltage to squeeze the reagent located in the liquid adding chamber; Alternatively, the driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent.

15. The biochemical substance analysis system according to claim 13, characterized in that: The liquid adding assembly further comprises a liquid storage structure stacked on the inkjet chip, wherein the liquid storage structure comprises at least one liquid storage cavity communicated with the liquid adding cavity, and the liquid storage cavity is used to store the reagent.

16. The biochemical substance analysis system according to claim 12, characterized in that: The liquid removal component is used to provide positive pressure or negative pressure to blow away or absorb the residual reagent on the detection chip.

17. The biochemical substance analysis system according to claim 16, characterized in that: The liquid removal assembly comprises an air supply structure and an air knife communicated with the air supply structure, wherein the air supply structure is used to provide compressed gas to the air knife.

18. The biochemical substance analysis system according to claim 12, characterized in that: The liquid replacement device further comprises a linkage structure, the liquid adding component and the liquid removing component are arranged on the linkage structure, and the linkage structure is used to make the liquid adding component and the liquid removing component linked to each other so as to add liquid to or replace liquid for the detection chip.

19. The biochemical substance analysis system according to claim 1, characterized in that: The biochemical reaction platform includes a plurality of the biochemical reaction devices, a liquid replacement device, and an imaging detection device.

20. A method for analyzing biochemical substances, characterized in that: include: Liquid adding step: transferring the detection chip to the liquid replacement site by means of a transfer device, and printing a reaction layer of a preset thickness on the detection chip by means of a liquid adding component in the liquid replacement device, wherein the reaction layer includes a reagent, and the detection chip includes an open slide for fixing the sample to be detected; Reaction step: transferring the detection chip printed with the layer to be reacted to a reaction site by the transfer device, and causing the sample to be detected in the detection chip to react with the reagent by a biochemical reaction device; Detection step: transferring the detection chip after the reaction to the imaging site by the transfer device, acquiring the detectable signal of the detection chip by the imaging detection device and performing imaging detection analysis; Circulation step: moving the detection chip back and forth between the liquid replacement site and the reaction site and the imaging site according to a preset path to achieve multiple liquid addition steps and multiple reaction steps; and between two adjacent liquid addition steps, the method also includes a liquid removal step of removing the reacted residual reagent on the surface of the detection chip by a liquid removal component in the liquid replacement device.

21. The biochemical substance analysis method according to claim 20, characterized in that: In the liquid adding step and the liquid removing step, the transfer device drives the detection chip to move horizontally relative to the bottom of the liquid replacing device, so that the liquid replacing device adds liquid to or replaces liquid for the detection chip.

22. The biochemical substance analysis method according to claim 20, characterized in that: In the liquid adding step or the liquid removing step, the method further comprises: Cold air is blown toward the detection chip through a liquid replacement platform located below the liquid replacement device to cool the detection chip.

23. The biochemical substance analysis method according to claim 20, characterized in that: The method comprises at least two liquid adding steps, and the reagent printed in at least one of the liquid adding steps is different from the reagent printed in the other liquid adding steps.

24. The biochemical substance analysis method according to claim 23, characterized in that: The liquid adding step comprises: adding the reagent to the detection chip by inkjet printing; The liquid replacement step includes: removing the residual reagent on the detection chip by blowing or inhaling.

25. The biochemical substance analysis method according to claim 20, characterized in that: Before the detecting step, the method further comprises: The temperature of the detection chip is lowered to a photographing temperature through an imaging stage located below the imaging detection device.

26. The biochemical substance analysis method according to claim 20, characterized in that: The biochemical reaction in the reaction step is a nucleic acid sequencing reaction, and the sample to be detected is a nucleic acid sequencing library.

27. The biochemical substance analysis method according to claim 20, characterized in that: The detectable signal is an optical signal.

28. The biochemical substance analysis method according to claim 20, characterized in that: The sample to be detected is a tissue sample, and the biochemical reaction in the reaction step is a specific binding reaction.

29. A sequencing method, characterized in that: include: Move the open slide fixed with the array of sequence samples to be detected between the liquid replacement site and the reaction site according to the preset reaction order; Printing a reagent layer with a preset thickness on the carrier at the liquid replacement site; transferring the carrier with the reagent layer printed thereon to a reaction chamber at the reaction site, so that the array of sequence samples to be detected reacts with the reagent layer in the reaction chamber; The carrier sheet after the reaction is transferred to the detection site, and image recognition is performed on the fluorescent signal of the sequence sample array to be detected after the reaction.

30. The sequencing method according to claim 29, wherein: At the liquid replacement site, the reagent layer is printed onto the carrier sheet by inkjet printing.

31. The sequencing method according to claim 29, wherein: During the process of printing the reagent layer at the liquid replacement site, the carrier moves horizontally along the arrangement direction of the array of sequence samples to be detected.

32. The sequencing method according to claim 29, wherein: Before transferring the carrier slide after the reaction to the detection site, the method further includes: moving the carrier slide after the reaction to the liquid replacement site, removing the residual reaction reagent on the carrier slide, and printing a photographic reagent layer on the surface of the carrier slide.

33. The sequencing method according to claim 29, wherein: During the process of the carrier moving back and forth between the liquid replacement site and the reaction site, before printing a reagent layer different from the reagent printed last time on the carrier, the method further includes: removing residual reagents from the last reaction on the carrier.

34. A sequencing method, characterized in that: include: Fixing a sample to be detected to an open slide having a site array, wherein the sample to be detected includes a nucleic acid sequencing library; Printing a reaction reagent toward the open carrier to form a reaction reagent layer having a preset thickness; Adjusting the reaction temperature of the reaction reagent and the sample to be detected to perform the reaction between the sample to be detected and the reaction reagent; as well as The detectable signal on the open slide is detected and the base sequence information of the sample to be detected is identified based on the detectable signal.

35. The sequencing method according to claim 34, wherein: Printing reaction reagents onto the open carrier to form the reaction reagent layer having a preset thickness includes: printing the reaction reagent layers including different reaction reagents onto the open carrier in batches; wherein, between two adjacent printings of the reaction reagent layers, the sequencing method further includes a liquid removal step of removing the reaction reagents remaining on the open carrier.

36. The sequencing method according to claim 34, wherein: Printing a reaction reagent onto the open carrier to form the reaction reagent layer having a preset thickness comprises: printing the reaction reagent layer onto the open carrier by inkjet printing.

37. The sequencing method according to claim 35, characterized in that In the liquid removal step, the reaction reagent remaining on the open slide is removed by blowing or sucking.

38. The sequencing method according to claim 35, characterized in that The open slide comprises a substrate and a site array arranged on the surface of the substrate, each of the sites having a derivatization structure for fixing the sample to be detected.

39. The sequencing method according to claim 38, wherein: Each of the sites is formed by being recessed from the surface of the substrate.

40. A sequencing system, characterized in that include: An open slide having a site array, wherein the site array is used to fix a sample to be detected, wherein the sample to be detected includes a nucleic acid sequencing library; A liquid adding component, the liquid adding component is spaced apart from the open slide and can move relative to the open slide, and the liquid adding component is used to print a reaction reagent onto the open slide to form a reaction reagent layer with a preset thickness; A biochemical reaction device, wherein the biochemical reaction device is configured to correspondingly adjust the reaction temperature of the reaction reagent layer and the sample to be detected to perform a reaction between the sample to be detected and the reaction reagent; as well as A detection device is configured to detect the detectable signal on the open slide and identify the base sequence information of the sample to be detected based on the detectable signal.

41. The sequencing system of claim 40, wherein: It also includes a liquid removal component, which removes the reaction reagent remaining on the open carrier.

42. The sequencing system of claim 41, wherein: The liquid removal assembly comprises an air supply structure and an air knife communicated with the air supply structure, wherein the air supply structure is used to provide compressed gas to the air knife.

43. The sequencing system of claim 41, wherein: The liquid adding component comprises an inkjet chip, and the inkjet chip is used to print the reaction reagent layer onto the open carrier by inkjet printing.

44. The sequencing system of claim 43, wherein: The inkjet chip comprises: An inkjet cavity layer, comprising a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity is formed through the first surface and the second surface, the liquid adding cavity is used to accommodate the reaction reagent, and the liquid adding cavity has at least one liquid outlet located on the second surface; A driving structure is stacked on the first surface and covers the liquid adding cavity, and the driving structure is used to drive the reaction reagent located in the liquid adding cavity to be discharged from the liquid outlet.

45. The sequencing system of claim 44, wherein: The driving structure comprises a deformation layer located on the first surface and an electrode layer located on the deformation layer, wherein the deformation layer is used to deform under the action of voltage to squeeze the reaction reagent located in the liquid adding chamber; Alternatively, the driving structure includes a heater located on the first surface, the heater is used to heat the reaction reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reaction reagent.

46. ​​The sequencing system of claim 45, wherein: The liquid adding component also includes a liquid storage structure stacked on the inkjet chip, the liquid storage structure includes at least one liquid storage cavity connected to the liquid adding cavity, and the liquid storage cavity is used to store the reaction reagent.

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