Biochemical substance analysis system and biochemical substance analysis method

Abstract

A biochemical substance analysis system and a biochemical substance analysis method, the biochemical substance analysis system comprises a biochemical reaction module, a liquid change module, an imaging detection module, a transfer module and a stage, a biochip is located on the stage, and the transfer module drives the stage to be movably arranged relative to the biochemical reaction module, the liquid change module and the imaging detection module; the liquid changing module can print a reaction layer with a preset thickness on the biological chip; a reaction control device in the biochemical reaction module and the carrying table can form a reaction chamber for reaction of a sample to be detected and a reagent; and the imaging detection module can perform imaging acquisition on the reacted sample to be detected. The biochemical reaction module, the liquid change module, the imaging detection module and the transfer module are integrated in one system, so that the integrated operation of sample adding, biochemical substance analysis and imaging can be realized, the system structure is simplified, the reagent loss is reduced, the biochemical detection efficiency is improved, and the biochemical detection cost is reduced.

Description

Technical Field

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

[0002] Current biochemical material analysis equipment, such as sequencers, has the characteristics of low cost, high throughput, and high degree of automation, which has greatly promoted the development of the biochemical material analysis industry.

[0003] However, existing sequencers have complex structures, are difficult to assemble, are complex to operate, and have high equipment costs. In addition, during the sequencing process, existing sequencers have high reagent loss, 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. Summary of the invention

[0004] In order to solve at least one of the above defects, it is necessary to propose a biochemical substance analysis system and a biochemical substance analysis method.

[0005] In a first aspect, a biochemical substance analysis system is provided, comprising: a biochemical reaction module, a liquid exchange module, an imaging detection module, a transfer module and a carrier, wherein the carrier is used to carry a biochip, and the biochip is an open substrate for fixing a sample to be detected; the carrier is supported by the transfer module and is movably arranged relative to the biochemical reaction module, the liquid exchange module, and the imaging detection module; the liquid exchange module comprises a liquid adding device for printing a reaction layer of a predetermined thickness on the biochip, and the reaction layer comprises a reagent for reacting with the sample to be detected; the biochemical reaction module comprises a reaction control device, and the reaction control device is movably arranged relative to the carrier to form a reaction chamber with the carrier for the sample to be detected to react with the reagent; the imaging detection module has a lens assembly for imaging and collecting the sample to be detected after the reaction.

[0006] In some possible embodiments, the liquid replacement module further includes a liquid removal device for removing residual reagents that have reacted on the biochip.

[0007] In some possible embodiments, the liquid adding device prints the reaction layer onto the biochip by inkjet printing.

[0008] In some possible embodiments, the liquid adding device includes an inkjet chip, and the inkjet chip includes:

[0009] 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;

[0010] A driving layer is stacked on the first surface and covers the liquid adding cavity, and the driving layer is used to drive the reagent in the liquid adding cavity to be discharged from the liquid outlet.

[0011] In some possible embodiments, the volume of the liquid adding chamber is 9 pL to 50 pL; and the printing frequency of the inkjet chip is greater than or equal to 10 kHz.

[0012] In some possible embodiments, the inkjet chip further includes a liquid storage structure disposed on the first surface, 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.

[0013] In some possible embodiments, the inkjet chip includes a plurality of the liquid adding chambers, each of the liquid adding chambers corresponds to a liquid storage chamber, and each of the liquid adding chambers corresponds to a drive layer and at least one liquid outlet; or, the inkjet chip includes a plurality of the liquid adding chambers arranged in an array, each of the liquid adding chambers corresponds to a drive layer and a liquid outlet, and a liquid storage chamber is provided above the liquid adding chambers in the same row.

[0014] In some possible embodiments, the driving layer adopts piezoelectric inkjet printing technology or thermal bubble inkjet printing technology, so that the reagent located in the liquid adding chamber is ejected from the liquid outlet.

[0015] In some possible embodiments, the liquid removal device includes an air supply structure and an air knife connected to the air supply structure, wherein the air supply structure is used to provide an air flow to the air knife, and the air flow is used to remove the residual reagent located on the biochip.

[0016] In some possible embodiments, the imaging detection module further includes a detection device signal-connected to the lens assembly.

[0017] In some possible embodiments, the reaction control device includes a movable heating cover, and the heating cover is used to cover the biochip to form the closed reaction chamber.

[0018] In some possible embodiments, the height of the reaction chamber is 200 μm to 500 μm.

[0019] In some possible embodiments, the transfer module includes a first axis 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, and the carrier 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.

[0020] In a second aspect, a biochemical substance analysis method using the biochemical substance analysis system as described above is provided, comprising:

[0021] Loading the biochip onto the carrier;

[0022] The transfer module drives the carrier to transfer the biochip to a liquid replacement site, and the liquid adding device in the liquid replacement module prints a reaction layer of a predetermined thickness on the biochip;

[0023] The transfer module drives the carrier to transfer the biochip printed with the reaction layer to a reaction site, and moves the reaction control device in the biochemical reaction module to form a reaction chamber with the carrier, and controls the reaction control device and the carrier to make the sample to be detected on the biochip react with the reagent; and

[0024] The transfer module drives the carrier to transfer the biochip on which the reaction has occurred to an imaging site, and the lens assembly in the imaging detection module collects an image of the biochip.

[0025] In some possible embodiments, before the step of printing a reaction layer of predetermined thickness on the biochip by the liquid adding device in the liquid replacement module, the biochemical substance analysis method further includes:

[0026] The liquid removal device in the liquid replacement module is used to remove the residual reagents on the biochip after the reaction.

[0027] In some possible embodiments, after the step of moving the reaction control device in the biochemical reaction module to form a reaction chamber with the carrier, the biochemical substance analysis method further includes:

[0028] The atmosphere inside the reaction chamber is controlled to be different from the atmosphere outside the reaction chamber.

[0029] The above-mentioned biochemical substance analysis system provided in the embodiment of the present application can realize the integrated operation of sample addition, biochemical substance analysis and imaging by integrating the biochemical reaction module, liquid exchange module, imaging detection module and transfer module into one system, simplifying the system structure, easy to assemble and operate, and conducive to improving detection efficiency and reducing detection costs. The liquid exchange module is added to the system, and there is no need to add a liquid circuit control structure on the carrier, which reduces the structural complexity of the carrier, is conducive to the transfer of the carrier at different sites, and reduces the overall detection cost. Moreover, the liquid exchange module adopts inkjet printing to achieve liquid addition, with high printing frequency, small printing droplets, and can accurately control the thickness of the liquid film, improve the uniformity of the liquid film thickness, can accurately control the thickness of the liquid film, significantly reduce the loss of reagents, and further reduce the detection cost; the liquid exchange module adopts blowing or liquid suction to achieve liquid removal, which is simple and convenient, and can be used with the inkjet chip to achieve a simple and fast liquid exchange process. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments of the present invention will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0031] Figure 1 It is a schematic diagram of a biochemical substance analysis system in one embodiment of the present application.

[0032] Figure 2 It is a schematic diagram of the three-dimensional structure of a biochemical substance analysis system in one embodiment of the present application.

[0033] Figure 3 yes Figure 2 Top view after removing the top platform.

[0034] Figure 4 It is a schematic diagram of the arrangement of the biochemical reaction module, the liquid replacement module and the imaging detection module in another embodiment.

[0035] Figure 5 yes Figure 2 Schematic diagram of the structure of the fluid exchange module.

[0036] Figure 6 yes Figure 5 Schematic diagram of the inkjet chip and liquid storage structure.

[0037] Figure 7 It is a cross-sectional view of an inkjet chip and a liquid storage structure in one embodiment of the present application.

[0038] Figure 8 1 is a top view of an inkjet chip in one embodiment of the present application.

[0039] Fig. 9 It is a top view of an inkjet chip in another embodiment of the present application.

[0040] Fig.10 It is a top view of an inkjet chip in another embodiment of the present application.

[0041] Fig.11 It is a schematic diagram of an inkjet chip without adding liquid in one embodiment of the present application.

[0042] Fig.12 It is a schematic diagram of an inkjet chip ejecting reagents in one embodiment of the present application.

[0043] Fig.13 It is a schematic diagram of the structure of an inkjet chip ejecting reagents in another embodiment of the present application.

[0044] Fig.14 It is a flow chart of a biochemical substance analysis method in one embodiment of the present application.

[0045] Fig.15 It is a flowchart of a biochemical substance analysis method in one embodiment of the present application.

[0046] Main component symbols

[0047]

[0048]

[0049] The following specific implementation manner will further illustrate the present invention in conjunction with the above-mentioned drawings. DETAILED DESCRIPTION

[0050] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0051] 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 be a central component. When a component is considered to be "set on" another component, it may be directly set 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 combinations of one or more of the relevant listed items.

[0052] See also Figure 1 and Figure 2As shown, the embodiment of the present application provides a biochemical substance analysis system 1000, which includes a transfer module 100, a carrier 200, a biochemical reaction module 300, a liquid replacement module 400, an imaging detection module 500, and a control platform 600. The carrier 200 is used to carry a biochip 700. For example, the carrier 200 can adsorb the biochip 700 by negative pressure adsorption, and the biochip 700 is an open substrate for fixing a sample to be detected. The sample to be detected can be, for example, a DNA sample (in this embodiment, a DNA nanoball, referred to as "DNB"). The carrier 200 is supported by the transfer module 100 and is movably arranged relative to the biochemical reaction module 300, the liquid exchange module 400, and the imaging detection module 500, that is, the transfer module 100 can move the carrier 200 between different sites, which include the reaction sites corresponding to the biochemical reaction module 300, the liquid exchange sites corresponding to the liquid exchange module 400, and the imaging sites corresponding to the imaging detection module 500, so that the biochip 700 can smoothly complete the entire detection process. The liquid exchange module 400 can add liquid to the biochip 700. Specifically, the liquid exchange module 400 includes a liquid adding device 410 for printing a reaction layer of a predetermined thickness on the biochip 700, and the reaction layer includes a reagent for reacting with the sample to be detected. The biochemical reaction module 300 includes a reaction control device 340, which is movably arranged relative to the carrier 200 to form a reaction chamber 900 with the carrier 200 for the sample to be detected to react with the reagent. The imaging detection module 500 is used to perform imaging detection analysis on the sample to be detected after the reaction. Specifically, the imaging detection module 500 has a lens assembly 510 for imaging and collecting the sample to be detected after the reaction. The control platform 600 is used to control the coordinated operation of the transfer module 100, the stage 200, the biochemical reaction module 300, the liquid replacement module 400 and the imaging detection module 500.

[0053] See also Figure 2 , the biochemical substance analysis system 1000 also includes a main structure platform 800, wherein the main structure platform 800 is used to arrange the transfer module 100, the carrier 200, the biochemical reaction module 300, the liquid exchange module 400 and the imaging detection module 500. The main structure platform 800 includes a main platform 810, an upper frame 820 disposed on the main platform 810, and a top platform 830 disposed on the upper frame 820. In some embodiments, the biochemical reaction module 300 is disposed on the upper frame 820, and the liquid exchange module 400 and the imaging detection module 500 are both disposed on the top platform 830. In some embodiments, the transfer module 100 is disposed on the main platform 810, and the carrier 200 is disposed on the transfer module 100, and the reaction site, the liquid exchange site and the imaging site are provided within the travel range of the transfer module 100, wherein, as Figure 3As shown, the reaction site is located below the biochemical reaction module 300, the liquid replacement site is located below the liquid replacement module 400, and the imaging site is located below the imaging detection module 500. The three sites are roughly arranged in a "pin" shape. It can be understood that the "site" described in the embodiments of the present application refers to an area with a certain area. It can be understood that in other embodiments, as Figure 4 shown, the reaction site, the liquid replacement site, and the imaging site can also be arranged in a straight line. Therefore, the biochemical reaction module 300, the liquid replacement module 400, and the imaging detection module 500 are roughly arranged in a straight line. The transfer module 100 can drive the stage 200 to transfer the biochip 700 to below the liquid replacement module 400 for sample addition, and then transfer the stage 200 connected to the biochip 700 after sample addition to below the biochemical reaction module 300 for biochemical reaction. After the biochemical reaction is completed, the stage 200 connected to the biochip 700 is transferred to below the imaging detection module 500 for imaging detection and analysis to complete the entire process of biochemical reaction.

[0054] Please refer to Figure 2 , the transfer module 100 includes a first axis 110 provided on the main platform 810 and extending along the first direction x, a second axis 120 slidably provided on the first axis 110 and extending along the second direction y, and a third axis 130 slidably provided on the second axis 120 and extending along the third direction z. The stage 200 is provided on the third axis 130. Among them, the first direction x, the second direction y, and the third direction z are perpendicular to each other and form a three-dimensional coordinate system. In some embodiments, the first axis 110 is fixed to the main platform 810 through a fixing block 140, the second axis 120 is slidably provided on the first axis 110 through a first slider 150, and the third axis 130 is slidably provided on the second axis 120 through a second slider 160. The second axis 120 can move along the first axis 110 to drive the stage 200 to move along the first direction x, thereby adjusting the position of the biochip 700 in the first direction x. The third axis 130 can move along the second axis 120 to drive the stage 200 to move along the second direction y, thereby adjusting the position of the biochip 700 in the second direction y. The third axis 130 can also drive the stage 200 to move along the third direction z, thereby adjusting the position of the biochip 700 in the third direction z. Through the transfer module 100, the transfer of the biochip 700 at different sites can be realized. The structure of the transfer module 100 is simple, and there is no need to separately set up a complex robot to transfer the biochip, which reduces the structural complexity of the biochemical substance analysis system 1000. Moreover, the transfer efficiency of the biochip 700 is high, the accuracy of displacement control is high, and it is beneficial to reduce the overall detection cost.

[0055] Please refer to Figure 5 , and refer to Figure 1 in combination with Figure 2The liquid adding device 410 of the liquid changing module 400 can print the reagents required for the biochemical reaction onto the biochip 700 to form a reaction layer with a predetermined thickness. The liquid adding device 410 can use inkjet printing to spray the reagents (usually liquid) required for the biochemical reaction onto the open biochip 700. The liquid adding device 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 biochip 700.

[0056] See also Figure 6 and Figure 7 , and refer to Figure 1 , the inkjet chip 430 includes: a stacked inkjet cavity layer 431 and a driving layer 432, wherein the inkjet cavity layer 431 includes a first surface 433 and a second surface 434 arranged opposite to each other, the driving layer 432 is located on the first surface 433, and the driving layer 432 is electrically connected to the inkjet control circuit 450. At least one liquid adding cavity 435 is formed through the first surface 433 and the second surface 434 of the inkjet cavity layer 431, and the liquid adding cavity 435 forms at least one liquid outlet 436 on the second surface 434, and the liquid adding cavity 435 is used to accommodate the sample or reagent described in the biochemical reaction. A negative pressure gas path (not shown) can be added to communicate with the liquid adding cavity 435, so that a certain negative pressure is maintained in the liquid adding cavity 435, so that the reagent is kept in the liquid adding cavity 435. The driving layer 432 is on the surface of the inkjet cavity layer 431 and covers the opening of the liquid adding cavity 435 relative to the liquid outlet 436. The driving layer 432 can generate, under the control of the inkjet control circuit 450, a reagent in the liquid adding chamber 435 to be discharged from the liquid outlet 436, and then printed on the biochip 700. Specifically, the thickness of the reaction layer printed on the biochip 700 can be precisely controlled by controlling the volume of the printed droplets, the printing frequency, and the printing layer. The liquid addition by inkjet printing can precisely control the thickness of the liquid film, significantly reduce the loss of reagents, and further reduce the detection cost.

[0057] In some embodiments, along the extension direction a perpendicular to the inkjet chip 430, the diameter L1 of the liquid outlet 436 is smaller than the minimum inner diameter L2 of the liquid adding chamber 435, that is, the diameter of the liquid outlet 436 is the smallest, which can better limit the outflow speed of the droplets to better control the volume of the droplets printed each time. In addition, the diameter of the liquid outlet 436 is small, and when the sample is not added, the sample can be better kept in the liquid adding chamber 435 under the action of negative pressure.

[0058] The inkjet cavity layer 431 may be a multi-layer structure, and the inkjet cavity layer 431 includes a substrate 4311, a resin layer 4312 stacked on the substrate 4311, and a nozzle plate 4313 stacked on the surface of the substrate 4311 facing away from the resin layer 4312, wherein the surface of the resin layer 4312 facing away from the substrate 4311 constitutes a first surface 433, and the surface of the nozzle plate 4313 facing away from the substrate 4311 constitutes a second surface 434. It can be understood that the resin layer 4312 may be a single layer or a multi-layer structure. The portion of the liquid adding cavity 435 corresponding to the resin layer 4312 constitutes a first through hole 4314, the portion of the liquid adding cavity 435 corresponding to the substrate 4311 constitutes a second through hole 4315, and the portion of the liquid adding cavity 435 corresponding to the nozzle plate 4313 constitutes a liquid outlet 436. In some embodiments, the inner diameters of the first through hole 4314, the second through hole 4315, 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 4314 is designed to be relatively large so as to carry more reagents.

[0059] In some embodiments, the material of the substrate 4311 may be silicon, and the material of the resin layer 4312 may be polyimide. A second through hole 4315 with a smaller inner diameter may be formed on the substrate 4311, and a first through hole 4314 with a larger inner diameter may be formed on the resin layer 4312 by chemical etching. Since the resin layer 4312 can be formed into holes by etching, it is easier to form holes than the substrate 4311 made of silicon. Therefore, the inner diameter of the first through hole 4315 can be accurately controlled according to actual needs, thereby improving the accuracy of the volume control of the liquid adding chamber 435 and ensuring the accuracy of the reagent amount. In some embodiments, the volume of the liquid adding chamber 435 may be 9pL to 50pL. For example, the volume of the liquid adding chamber 435 may be 9pL, 10pL, 15pL, 20pL, 25pL, 30pL, 35pL, 40pL, 45pL or 50pL, etc.

[0060] The inkjet cavity layer 431 is further provided with at least one liquid inlet hole 437, which is in communication with the liquid adding cavity 435, and is in communication with the reagent storage box 440, so that the reagent in the reagent storage box 440 is added to the liquid adding cavity 435 via the liquid inlet hole 437. In some embodiments, the opening of the liquid inlet hole 437 may be located on the first surface 433 of the inkjet cavity layer 431, or may be located on the side surface of the inkjet cavity layer 431. In some embodiments, as Figure 7 As shown, the liquid inlet hole 437 is opened on the resin layer 4312 , and the opening is located on the first surface 433 .

[0061] Please refer again Figure 6 and Figure 7 , and refer to Figure 1 The liquid adding device 410 further includes a liquid storage structure 470 located on the inkjet chip 430, and 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, and the liquid storage cavity 471 is connected to the reagent storage box 440, and the reagent in the reagent storage box 440 can flow into the liquid storage cavity 471 by gravity, and then further enter the liquid adding cavity 435 through the liquid inlet hole 437. In some embodiments, the liquid storage cavity 471 is a closed cavity, and the reagent in the liquid storage cavity 471 and the liquid adding cavity 435 will not leak out from the liquid outlet 436 through a negative pressure gas path.

[0062] See also Figure 8 , and refer to Figure 1 and Figure 2 , the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged side by side, and each liquid adding chamber 435 is correspondingly provided with a driving layer 432 and a plurality of liquid outlets 436. The plurality of driving layers 432 can be electrically connected to the inkjet control circuit 450, so as to realize the independent control of the plurality of driving layers 432, so as to realize the independent sample addition of the plurality of liquid adding chambers 435. At this time, the reagent in the same liquid adding chamber 435 is driven by the driving layer 432, and the volume of the droplets discharged from the plurality of liquid outlets 436 is substantially the same. A reagent can be stored in each liquid adding chamber 435, so that the simultaneous printing of multiple reagents can be realized. The arrangement of the plurality of liquid outlets 436 in each liquid adding chamber 435 can be designed according to the arrangement form of the reaction sites on the biochip 700. For example, the plurality of liquid outlets 436 in each liquid adding chamber 435 can be arranged in a straight line. It can be understood that the plurality of 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 micropore array, and the number of the liquid outlets 436 can be adjusted according to the number of the site arrays on the biochip 700. In order to improve the effect of the biochemical reaction, the flux of the biochip 700 is relatively high. At this time, the density of the liquid outlets 436 of the inkjet chip 430 can be designed to be relatively high, 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.

[0063] It can be understood that in other embodiments, such as Fig. 9As shown, the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged in an array, and each liquid adding chamber 435 is provided with a driving layer 432 and a liquid outlet 436, so as to realize the independent control of each liquid outlet 436, and then accurately control the volume of the droplets discharged by each liquid outlet 436. At this time, the liquid storage structure 470 is divided into a plurality of independent liquid storage chambers 471, and each liquid storage chamber 471 corresponds to a row of liquid adding chambers 435. The same row of liquid adding chambers 435 are connected to the liquid storage chamber 471 through a liquid inlet hole 437. Specifically, the reagents in the same row of liquid adding chambers 435 are of the same type.

[0064] It can also be understood that in other embodiments, such as Fig.10 As shown, 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 layer 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.

[0065] See also Fig.11 and Fig.12 , and refer to Figures 5 to 7 The driving layer 432 can use piezoelectric inkjet printing technology to print the reagent in the liquid adding chamber 435 onto the biochip 700. The piezoelectric inkjet printing technology uses piezoelectric ceramics (piezoelectric ceramics) to deform due to the application of voltage, squeeze the liquid to generate high pressure and spray the liquid. In some embodiments, the driving layer 432 may include a piezoelectric layer 4321 and an electrode layer 4322 located on the piezoelectric layer 4321. Fig.12 As shown, the operating principle of the inkjet chip 430 is to apply voltage to the piezoelectric layer 4321 through the electrode layer 4322. Since the material of the piezoelectric layer 4321 can be piezoelectric ceramics, the piezoelectric layer 4321 will be affected by the voltage and produce instantaneous deformation, and through this instantaneous deformation, the reagent in the liquid adding cavity 435 is squeezed, and the reagent is ejected from the liquid outlet 436 at high pressure to form droplets, which are then printed on the corresponding position of the biochip 700. By using micro-piezoelectric means to realize the printing of the reagent, the volume of the printed reagent droplets can be accurately controlled, thereby reducing the reagent loss.

[0066] In other embodiments, Fig.13 As shown, the driving layer 432 can also use thermal bubble inkjet printing technology to achieve liquid spraying. The driving layer 432 can also include a heater. The heater will generate heat after being powered on to heat the reagent in the liquid adding chamber 435, thereby generating bubbles. The bubbles squeeze the reagent droplets out of the liquid outlet 436 to achieve the purpose of printing.

[0067] Please refer again Figure 1 The reagent storage box 440 can be connected to the liquid storage structure 470 on the inkjet chip 430 through a set of liquid path connectors. It can be understood that the storage location of the reagent storage box 440 can selectively add a refrigeration module to maintain the environment required for storing the biochemical reaction reagents.

[0068] 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 layer 432 and can independently control each liquid outlet 436 or each discharge liquid outlet 436 of the inkjet chip 430.

[0069] In some embodiments, the printing frequency of the inkjet chip 430 may be greater than or equal to 10 kHz. The higher the printing frequency, the better the printing uniformity, thereby improving the sample loading efficiency of the biochip 700 and the uniformity of the liquid film thickness.

[0070] Please refer again Figure 1 , Figure 2 and Figure 5 The liquid replacement device 400 also includes a liquid removal device 420, which can remove the residual reagents on the biochip 700 after the reaction. Usually, after the reaction of one reagent is completed, another reagent needs to be replaced. At this time, the liquid removal device 420 needs to be used to remove the residual reagents after the previous step of reaction, and then the liquid adding device 410 is used to add another reagent. Through the cooperation of the liquid adding device 410 and the liquid removal device 420, liquid addition and liquid removal on the biochip 700 can be achieved.

[0071] Among them, the liquid removal device 420 uses airflow to remove the residual reagents that have reacted on the biochip 700. Specifically, the liquid existing on the biochip 700 can be directly removed by blowing or absorbing liquid. In some embodiments, the liquid removal device 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 absorbing the liquid on the surface of the biochip 700. Liquid removal is achieved by blowing or absorbing liquid, which is simple and convenient, and the liquid replacement process can be simple and fast in conjunction with the inkjet chip 430. It can be understood that an overflow tank (not shown) is provided on the carrier 200 to collect the residual reagents blown off the biochip 700.

[0072] In some embodiments, the gas supply structure 422 can be a gas compressor that can provide compressed gas, such as compressed air or compressed nitrogen. The compressed gas enters the gas knife 421 through the gas path. The gas knife 421 limits the blown gas to the surface of the biochip 700, thereby removing the liquid on the surface of the biochip 700. The gas knife is used to blow or inhale to form the airflow. In some embodiments, the biochip 700 is maintained at a low temperature, such as 10°C to 15°C, when blowing.

[0073] 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 biochip 700.

[0074] Please refer again Figure 5 , and refer to Figure 1 and Figure 2 The liquid replacement module 400 further includes a linkage structure 460, which is disposed on the top platform 830. The linkage structure 460 can drive the liquid adding device 410 and the liquid removing device 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, and the inkjet chip 430 of the liquid adding device 410 and the air knife 421 of the liquid removing device 420 are slidably disposed on the linkage shaft 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 traveling direction, so as to achieve the purpose of removing liquid first and then adding liquid.

[0075] Please refer again Figure 1 and Figure 2 The reaction control device 340 in the biochemical reaction module 300 includes a support 310 located on the main platform 810 and a heating cover 320 movably arranged on the support 310. When the biochip 700 moves to the reaction site, the heating cover 320 can move up and down, left and right, and then cover the biochip 700, so that the heating cover 320 and the biochip 700 form a closed reaction chamber 900. The heating cover 320 can heat the top of the biochip 700, and the carrier 200 can heat the bottom of the biochip 700, thereby providing a specific temperature for the biochemical reaction in the reaction chamber 900, so that the heating in the reaction chamber 900 is more uniform.

[0076] In some embodiments, depending on the actual volume of the reagent, after the heating cover 320 is covered on the biochip 700, the height of the reaction chamber 900 formed can be 200 μm to 500 μm to meet different volume requirements.

[0077] In some embodiments, a sealing ring 330 is provided at the periphery of one end of the heating cover 320 close to the biochip 700 , so that the sealing performance of the reaction chamber 900 can be improved after the heating cover 320 and the biochip 700 are covered.

[0078] Please refer again Figure 1 and Figure 2 The imaging detection module 500 also includes a detection device 520 signal-connected to the lens assembly 510. After the biochip 700 completes the reaction, the biochip 700 cools down and moves to the liquid replacement module 400 to replace the photographic reagent, and then moves to the bottom of the lens assembly 510 of the imaging detection module 500 to complete the fluorescent imaging of the entire biochip 700. After that, the lens assembly 510 transmits the fluorescent image to the detection device 520 for imaging analysis.

[0079] In some embodiments, lens assembly 510 includes an objective lens.

[0080] The following focuses on the functions of each of the above devices and the methods for executing them.

[0081] See also Fig.14 , and refer to Figure 1 and Figure 2 The present application also provides a method for performing biochemical substance analysis using the aforementioned biochemical substance analysis system 1000, the method comprising the following steps:

[0082] Step S1 , loading the biochip 700 : loading the biochip 700 onto the carrier 200 .

[0083] The biochip 700 is in a non-packaged form, specifically an open substrate for fixing the sample to be detected, which is convenient for adding and replacing liquid.

[0084] Step S2, adding or replacing liquid of the biochip 700: the transfer module 100 drives the carrier 200 to transfer the biochip 700 to the liquid replacement site, and the liquid adding device 410 in the liquid replacement module 400 prints a reaction layer of a predetermined thickness on the biochip 700.

[0085] The transfer module 100 is moved by the control of the control platform 600. In this embodiment, the control platform 600 may include a main control computer, a display, a keyboard, a mouse, a touch screen, and a LAN switch, etc. The control platform 600 is used to control and operate the entire process of the biochemical reaction. In addition, a sensing unit (the sensing unit may include a detection switch and a sensor, etc.) may be set at the reaction site, the liquid replacement site, and the imaging site. The sensing unit may sense whether the carrier 200 is moved into place, and the control platform 600 controls the corresponding program to start executing according to the sensing signal sent by the sensing switch and the preset program.

[0086] Specifically, the control platform 600 controls the transfer module 100 to drive the carrier 200 to move, and then moves the biochip 700 to the liquid replacement site. The movement of the biochip 700 is sensed by the sensing unit. The control platform 600 controls the heating device 410 in the liquid replacement module 400 to add liquid to the biochip 700 according to the sensing signal and the preset liquid adding program.

[0087] In some embodiments, before step S2 , the biochemical substance analysis method further includes: using the liquid removal device 420 in the liquid replacement module 400 to remove the residual reagents on the biochip 700 after the reaction.

[0088] Specifically, during the first liquid addition, the reaction layer of a predetermined thickness is directly printed on the biochip 700 according to step S2. In the subsequent liquid addition process, residual reagents after the reaction already exist on the biochip 700, and the liquid needs to be removed first, and then another reagent is added to the biochip 700 to realize the liquid replacement process.

[0089] Specifically, during the liquid adding process: when liquid is added, the control platform 600 controls the inkjet chip 430 in the liquid adding device 410 to print a reaction layer of a predetermined thickness onto the biochip 700 .

[0090] Liquid replacement process: Before adding liquid for the second, third or more times, the control platform 600 controls the linkage structure 460 to drive the air knife 421 and the inkjet chip 430 to move, and 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 biochip 700 after the reaction; at the same time, the inkjet chip 430 is controlled to add another reagent to the biochip 700 from which the residual reagent has been removed to form a reaction layer of a predetermined thickness, thereby completing the liquid replacement process.

[0091] Step S3, biochemical substance analysis: the transfer module 100 drives the carrier 200 to transfer the biochip 700 printed with the reaction layer to the reaction site, and moves the reaction control device 340 in the biochemical reaction module 300 to form a reaction chamber 900 with the carrier 200, and controls the reaction control device 340 and the carrier 200 to make the sample to be detected located on the biochip 700 react with the reagent.

[0092] Specifically, the control platform 600 controls the transfer module 100 to drive the carrier 200 to move, and then moves the biochip 700 to the reaction site. The movement of the biochip 700 into position is sensed by the sensing unit. The control platform 600 controls the movement of the heating cover 320 of the reaction control device 340 according to the sensing signal and the preset reaction program, so that the heating cover 320 is covered on the biochip 700, and the biochemical substance analysis program is started.

[0093] In some embodiments, before performing biochemical substance analysis, it is necessary to start a heating program to heat the cover 320 and the carrier 200 to a target temperature, and then start the biochemical reaction program.

[0094] In some embodiments, the biochemical reaction module 300 can start the heating process during the process of adding or removing liquid from the biochip 700, so that the heating cover 320 is preheated to the target temperature, which can improve the reaction efficiency and shorten the reaction cycle. The heating of the carrier 200 can be turned on after the biochip 700 moves to the reaction site. The specific steps include:

[0095] Step S31 , heating the heating cover 320 of the reaction control device 340 to a target temperature.

[0096] In step S32 , the transfer module 100 drives the carrier 200 to transfer the biochip 700 after adding liquid to the reaction site.

[0097] Step S33 , covering the heating cover 320 onto the biochip 700 .

[0098] Step S34 , heating the carrier 200 to a target temperature so that the sample to be detected in the biochip 700 reacts with the reagent.

[0099] The above steps S2 and S3 can be repeated multiple times to add different chemical reagents for biochemical reactions to the biochip 700 and complete biochemical substance analysis. After each step S3, the biochip 700 needs to be cooled to about 15°C and the liquid is replaced.

[0100] Step S4, imaging detection: the transfer module 100 drives the carrier 200 to transfer the reacted biochip 700 to the imaging site, and the lens assembly 510 in the imaging detection module 500 collects the image of the biochip 700.

[0101] Before the imaging detection step, it is necessary to replace the imaging reagent on the biochip 700, which specifically includes the following steps: the transfer module 100 drives the carrier to transfer the reacted biochip 700 to the liquid replacement site, the liquid replacement module 400 removes the residual sample on the biochip 700, and adds the imaging reagent.

[0102] Specifically, after the biochemical reaction is completed, the biochip 700 is cooled to about 15°C, and the control platform 600 controls the transfer module 100 to move the carrier 200 to move the biochip 700 to the liquid replacement site, and controls the liquid replacement module 400 to remove the residual sample on the biochip 700 and add the imaging reagent; then the carrier 200 is moved to move the biochip 700 to the imaging site, and the lens assembly 510 in the imaging detection module 500 is controlled to complete the acquisition of the entire biochip 700 image, and the fluorescent image of the sample to be detected after the reaction in the acquired image is analyzed by the detection device 520 to obtain the detection result; finally, after the imaging is completed, the transfer module 100 drives the carrier 200 to reset, removes the biochip 700 that has completed the biochemical reaction, and replaces it with another biochip 700 to carry out the next biochemical reaction.

[0103] See also Fig.15 , and refer to Figure 1 , the specific process of gene sequencing using the above method is given below.

[0104] In the first step, a biological sample, such as DNB containing a DNA sequencing library, is loaded into the biochip 700 , and the DNB is adsorbed on the reaction area of ​​the biochip 700 .

[0105] In the second step, the biochip 700 loaded with the biological sample is placed on the carrier 200, the biochip 700 is adsorbed by negative pressure, the carrier 200 is transferred to the liquid replacement site by the transfer module 100, and liquid is added to the biochip 700 by the liquid replacement module 400. At the same time, the heating cover 320 of the biochemical reaction module 300 is opened to heat the heating cover 320 to the target temperature.

[0106] The third step is to control the driving layer 432 to deform and squeeze the reagent in the liquid adding chamber 435 , thereby printing the reagent in the liquid adding chamber 435 of the inkjet chip 430 onto the corresponding reaction area of ​​the biochip 700 .

[0107] In the fourth step, the transfer module 100 is controlled to transfer the carrier 200 to the reaction site, and the heating cover 320 is covered on the biochip 700 .

[0108] The fifth step is to control the heating of the carrier 200 to heat the biochip 700 to a target temperature so that the biological sample in the biochip 700 undergoes the first step reaction.

[0109] In the sixth step, after the reaction is completed, the transfer module 100 is controlled to transfer the carrier 200 to the liquid replacement module 400 , and the residual reagent on the biochip 700 is blown away by the air knife 421 .

[0110] Step 7: Repeat steps 3 to 6 until the biochemical reaction is completed.

[0111] In the eighth step, the transfer module 100 is controlled to transfer the carrier 200 to the imaging detection site, and the imaging detection module 500 is used to collect the fluorescent image of the biochip 700 that has completed the reaction, so as to complete the sequencing.

[0112] In summary, the above-mentioned biochemical substance analysis system 1000 provided in the embodiment of the present application adds a liquid exchange module 400 to the system, and there is no need to add a liquid circuit control structure to the carrier 200, which reduces the structural complexity of the carrier, is conducive to the transfer of the carrier 200 at different sites, and reduces the overall detection cost. Moreover, the liquid exchange module 400 adopts inkjet printing to achieve liquid addition, with high printing frequency, small printing droplets, and can accurately control the thickness of the liquid film, improve the uniformity of the thickness of the liquid film, and significantly reduce the loss of reagents, so as to further reduce the detection cost; the liquid exchange module 400 adopts blowing or liquid suction to achieve liquid removal, which is simple and convenient, and can be used in conjunction with the inkjet chip 430 to achieve a simple and fast liquid exchange process. In addition, the biochemical substance analysis system 1000 integrates the biochemical reaction module 300, the liquid exchange module 400, the imaging detection module 500 and the transfer module 100 into one system, which can realize the integrated operation of sample addition, biochemical substance analysis and imaging, simplifies the system structure, is conducive to improving detection efficiency, and reduces detection costs.

[0113] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. A biochemical substance analysis system, characterized in that: include: A biochemical reaction module, a liquid replacement module, an imaging detection module, a transfer module and a carrier, wherein the carrier is used to carry a biochip, and the biochip is an open substrate for fixing a sample to be detected; The carrier is supported by the transfer module and is movably arranged relative to the biochemical reaction module, the liquid replacement module, and the imaging detection module; The liquid replacement module includes a liquid adding device for printing a reaction layer of a predetermined thickness on the biochip, wherein the reaction layer includes a reagent for reacting with the sample to be detected; The biochemical reaction module comprises a reaction control device, which is movably arranged relative to the carrier to form a reaction chamber with the carrier for the sample to be detected to react with the reagent; The imaging detection module has a lens assembly for performing imaging acquisition on the sample to be detected after the reaction.

2. The biochemical substance analysis system according to claim 1, characterized in that: The liquid replacement module also includes a liquid removal device for removing residual reagents that have reacted on the biochip.

3. The biochemical substance analysis system according to claim 2, characterized in that: The liquid adding device prints the reaction layer on the biochip in an inkjet printing manner.

4. The biochemical substance analysis system according to claim 3, characterized in that: The liquid adding device comprises an inkjet chip, and 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 layer is stacked on the first surface and covers the liquid adding cavity, and the driving layer is used to drive the reagent in the liquid adding cavity to be discharged from the liquid outlet.

5. The biochemical substance analysis system according to claim 4, characterized in that: The volume of the liquid adding chamber is 9pL to 50pL; The printing frequency of the inkjet chip is greater than or equal to 10 kHz.

6. The biochemical substance analysis system according to claim 4, characterized in that: The inkjet chip further comprises a liquid storage structure disposed on the first surface, 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.

7. The biochemical substance analysis system according to claim 6, characterized in that: The inkjet chip comprises a plurality of the liquid adding chambers, each of the liquid adding chambers corresponds to one of the liquid storage chambers, and each of the liquid adding chambers corresponds to one of the driving layers and at least one of the liquid outlets; Alternatively, the inkjet chip comprises a plurality of the liquid adding chambers arranged in an array, each of the liquid adding chambers is provided with a driving layer and a liquid outlet, and a liquid storage chamber is provided above the liquid adding chambers in the same row.

8. The biochemical substance analysis system according to claim 4, characterized in that: The driving layer adopts piezoelectric inkjet printing technology or thermal foaming inkjet printing technology to make the reagent in the liquid adding cavity spray out from the liquid outlet.

9. The biochemical substance analysis system according to any one of claims 2 to 7, characterized in that: The liquid removal device comprises an air supply structure and an air knife connected to the air supply structure, wherein the air supply structure is used to provide an air flow to the air knife, and the air flow is used to remove the residual reagent located on the biochip.

10. The biochemical substance analysis system according to claim 1, characterized in that: The imaging detection module also includes a detection device connected to the lens assembly signal.

11. The biochemical substance analysis system according to claim 1, characterized in that: The reaction control device comprises a movable heating cover, and the heating cover is used to cover the biochip to form the closed reaction chamber.

12. The biochemical substance analysis system according to claim 1, characterized in that: The height of the reaction chamber is 200 μm to 500 μm.

13. The biochemical substance analysis system according to claim 1, characterized in that: The transfer module includes a first axis extending along a first direction, a second axis slidably arranged on the first axis and extending along a second direction, and a third axis slidably arranged on the second axis and extending along a third direction, and the carrier 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.

14. A biochemical substance analysis method using the biochemical substance analysis system according to any one of claims 1 to 13, characterized in that: include: Loading the biochip onto the carrier; The transfer module drives the carrier to transfer the biochip to a liquid replacement site, and the liquid adding device in the liquid replacement module prints a reaction layer of a predetermined thickness on the biochip; The transfer module drives the carrier to transfer the biochip printed with the reaction layer to a reaction site, and moves the reaction control device in the biochemical reaction module to form a reaction chamber with the carrier, and controls the reaction control device and the carrier to make the sample to be detected on the biochip react with the reagent; as well as The transfer module drives the carrier to transfer the biochip on which the reaction has occurred to an imaging site, and the lens assembly in the imaging detection module collects an image of the biochip.

15. The biochemical substance analysis method according to claim 14, characterized in that: Before the step of printing a reaction layer of a predetermined thickness on the biochip by the liquid adding device in the liquid replacement module, the biochemical substance analysis method further includes: The liquid removal device in the liquid replacement module is used to remove the residual reagents on the biochip after the reaction.

16. The biochemical substance analysis method according to claim 14, characterized in that: After the step of moving the reaction control device in the biochemical reaction module to form a reaction chamber with the carrier, the biochemical substance analysis method further includes: The atmosphere inside the reaction chamber is controlled to be different from the atmosphere outside the reaction chamber.

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