Biochemical substance analysis system and biochemical substance analysis method

Abstract

The invention relates to a biochemical substance analysis system and a biochemical substance analysis method, the biochemical substance analysis system comprises a biochemical reaction module, a liquid changing device, an imaging detection device, a transfer device and a carrying platform, the carrying platform is used for carrying a biochip, and the transfer device is used for transferring the carrying platform at different sites; the liquid changing device is used for adding liquid to the biochip; the biochemical reaction module is used for enabling an analyte to be detected in the biochip to react; and the imaging detection device is used for executing imaging detection analysis on the reacted analyte to be detected. The liquid changing device, the imaging detection device, the transferring device and the at least two groups of biochemical reaction modules 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 detection flux and the detection efficiency are improved, and the detection cost is reduced.

Description

Technical Field

[0001] The present invention relates to the technical 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 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 biochemical substance analysis equipment (such as sequencers) has a complex structure, is difficult to assemble, is complicated to operate, has a high equipment cost, and is difficult to increase throughput; in addition, during the biochemical substance analysis process, the existing biochemical substance analysis equipment has a 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), making it difficult to reduce 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 transfer device, at least two groups of biochemical reaction modules, and an imaging detection device, wherein the biochemical substance analysis system has an imaging area and at least two reaction areas, each of the reaction areas is provided with a group of the biochemical reaction modules, the imaging area is provided with the imaging detection device, each group of the biochemical reaction modules comprises: a carrier, a biochemical reaction device and a liquid replacement device, the carrier is used to carry a biochip, the biochip is an open substrate for fixing an analyte to be detected; wherein the transfer device is used to transport the carrier along a preset path, the preset path at least includes a distribution site located in each of the reaction areas The distribution site corresponds to the liquid replacement device, and the reaction site corresponds to the biochemical reaction device; at the distribution site, the liquid replacement device has a liquid adding component that sprays a solution layer of a predetermined thickness onto the biochip, and the solution layer at least includes a reaction reagent that reacts with the analyte to be detected; at the reaction site, the biochemical reaction device is combined with the carrier to control the reaction between the analyte to be detected in the biochip and the reaction reagent; at the detection site, the imaging detection device has a lens component for collecting a fluorescent image of the analyte to be detected after the reaction.

[0006] In some possible embodiments, the biochemical substance analysis system includes two groups of biochemical reaction modules arranged opposite to each other, the imaging detection device is located between the two groups of biochemical reaction modules, and the liquid replacement device in each group of biochemical reaction modules is arranged close to the imaging detection device.

[0007] In some possible embodiments, the transfer device includes a first transfer mechanism and at least two second transfer mechanisms slidably disposed on the first transfer mechanism, and each of the second transfer mechanisms is provided with a carrier.

[0008] In some possible embodiments, the first transfer mechanism includes a guide rail extending along a first direction, and the first direction is an arrangement direction of the two groups of biochemical reaction modules;

[0009] The second transfer mechanism includes a first axis slidably disposed on the guide rail and extending along the first direction, a second axis slidably disposed on the first axis and extending along the second direction, and a third axis slidably disposed on the second axis and extending along the 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.

[0010] In some possible embodiments, the liquid adding component includes an inkjet chip, a liquid storage structure located on the inkjet chip and connected to the inkjet chip, and a reagent storage box connected to the liquid storage structure. The inkjet chip uses piezoelectric inkjet printing technology or thermal bubble inkjet printing technology to spray reagents.

[0011] In some possible embodiments, the liquid replacement device further includes a liquid removal component, and the liquid removal component is used to remove residual reagents after the reaction on the biochip.

[0012] In some possible embodiments, the liquid removal component 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.

[0013] In some possible embodiments, the biochemical reaction device includes a heating cover, and the heating cover is used to cover the biochip to form a reaction chamber for the analyte to be detected to react with the reaction reagent.

[0014] In a second aspect, the present application provides a biochemical substance analysis method using the biochemical substance analysis system as described above, comprising:

[0015] Loading the biochip on each of the carriers in at least two of the reaction areas;

[0016] In a single reaction area, the carrier is driven to move along the preset path by the transfer device to transfer the biochip to the distribution site, and the solution layer of a predetermined thickness is sprayed on the biochip by the liquid adding component in the liquid replacement device;

[0017] In a single reaction area, the carrier is driven by the transfer device to move along the preset path to transfer the biochip sprayed with the solution layer to the reaction site, and the biochemical reaction device is combined with the carrier to control the analyte to be detected in the biochip to react with the reaction reagent; and

[0018] The carriers located in different reaction areas are sequentially transferred to the detection sites by the transfer device, and the fluorescent image of the analyte to be detected after the reaction is completed is collected by the lens assembly in the imaging detection device.

[0019] In some possible embodiments, before the step of spraying the solution layer of a predetermined thickness on the biochip by the liquid adding component in the liquid replacement device, the biochemical substance analysis method further includes:

[0020] The residual reagent on the surface of the biochip is removed by using the liquid removal component in the liquid replacement device.

[0021] The above-mentioned biochemical substance analysis system provided by the embodiment of the present application can simultaneously carry out the detection reaction of at least two biochips by integrating at least two sets of biochemical reaction modules, which is conducive to realizing ultra-high throughput detection and improving detection efficiency. At the same time, the biochemical substance analysis system has a high degree of integration, which effectively reduces the size of the biochemical substance analysis system; and multiple sets of biochemical reaction modules integrate a set of imaging detection devices, which can improve the utilization rate of the imaging detection device, simplify the structural complexity of the system, and reduce the difficulty of assembly and operation. A liquid replacement device 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 realizing the transfer of the carrier at different sites, and reduces the overall detection cost. Moreover, the liquid replacement device adopts inkjet printing to realize 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 replacement device is also equipped with a liquid removal component, which adopts the method of blowing or sucking liquid to realize the actual removal of the residue on the biochip, which is simple and convenient, and can be used with the inkjet chip to achieve a simple and fast liquid replacement process. In addition, the biochemical substance analysis system can realize the integrated operation of sample addition, biochemical substance analysis and imaging by integrating at least two groups of biochemical reaction modules, a liquid changing device, an imaging detection device and a transfer device into one system, further simplifying the system structure, which is conducive to improving the detection efficiency and reducing the detection cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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.

[0023] Figure 1 It is a schematic diagram of a biochemical substance analysis system in one embodiment of the present application.

[0024] 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.

[0025] Figure 3 yes Figure 2 Top view after removing the top platform.

[0026] Figure 4 yes Figure 2 Schematic diagram of the structure of the liquid exchange device.

[0027] Figure 5 yes Figure 4 Schematic diagram of the inkjet chip and liquid storage structure.

[0028] Figure 6 It is a cross-sectional view of an inkjet chip and a liquid storage structure in one embodiment of the present application.

[0029] Figure 7 1 is a top view of an inkjet chip in one embodiment of the present application.

[0030] Figure 8 It is a top view of an inkjet chip in another embodiment of the present application.

[0031] Fig. 9 It is a top view of an inkjet chip in another embodiment of the present application.

[0032] Fig.10 It is a schematic diagram of an inkjet chip without adding liquid in one embodiment of the present application.

[0033] Fig.11 It is a schematic diagram of an inkjet chip ejecting reagents in one embodiment of the present application.

[0034] Fig.12 It is a schematic diagram of the structure of an inkjet chip ejecting reagents in another embodiment of the present application.

[0035] Fig.13 Flow chart of a biochemical substance analysis method in one embodiment of the present application.

[0036] Fig.14 It is a flowchart of a biochemical substance analysis method in one embodiment of the present application.

[0037] Main component symbols

[0038]

[0039]

[0040] The following specific implementation manner will further illustrate the present invention in conjunction with the above-mentioned drawings. DETAILED DESCRIPTION

[0041] 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.

[0042] 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.

[0043] See also Figure 1 and Figure 2As shown, the embodiment of the present application provides a biochemical substance analysis system 1000, the biochemical substance analysis system 1000 includes: at least two groups of biochemical reaction modules 10, a transfer device 100, an imaging detection device 500, and a control platform 600. Each group of biochemical reaction modules includes: a carrier 200, a biochemical reaction device 300 and a liquid replacement device 400, the carrier 200 is used to carry a biochip 700, for example, the carrier 200 can use a negative pressure adsorption method to adsorb at least one biochip 700, and the biochip 700 adopts a non-encapsulated form, specifically an open substrate for fixing an analyte to be detected, for example, the biochip can be a sequencing chip, and the analyte to be detected can be a DNA sample (in this embodiment, a DNA nanoball, referred to as "DNB"). The biochemical substance analysis system 1000 has an imaging area and at least two reaction areas, each reaction area is provided with a group of biochemical reaction modules 10, and the imaging area is provided with an imaging detection device 500. The transfer device 100 is used to transport the carrier 200 along a preset path, and the preset path includes at least a distribution site and a reaction site located in each reaction area, and a detection site corresponding to the imaging detection device 500, wherein the distribution site corresponds to the liquid replacement device 400, and the reaction site corresponds to the biochemical reaction device 300. Driven by the transfer device 100, the carrier 200 moves along the preset path so that the biochip 700 can successfully complete the entire detection process. At the distribution site, the liquid replacement device 400 has a liquid adding component 410 for spraying a solution layer of a predetermined thickness on the biochip 700, and the solution layer at least includes a reaction reagent that reacts with the analyte to be detected. At the reaction site, the biochemical reaction device 300 and the carrier 200 are combined to control the reaction between the analyte to be detected in the biochip 700 and the reaction reagent. At the detection site, the imaging detection device 500 has a lens component 510 for performing imaging detection and analysis on the biochip 700 after the reaction. The control platform 600 is used to control the coordinated operation of the transfer device 100 , at least two groups of biochemical reaction modules 10 , and the imaging detection device 500 .

[0044] See also Figure 2 The biochemical substance analysis system 1000 includes a main structure platform 800 , wherein the main structure platform 800 is used to arrange the transfer device 100 , the carrier 200 , the biochemical reaction device 300 , the liquid replacement device 400 and the imaging detection device 500 .

[0045] 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. The transfer device 100 is disposed on the main platform 810, and each carrier 200 is disposed on the transfer device 100. The transfer device 100 can move according to a preset path. For example, the type of reagent required for each reaction step in a single cycle reaction determines the number of liquid additions (i.e., the number of times the reaction site and the distribution site are returned). The preset path is designed according to the number of liquid additions, so as to control the transfer device 100 to drive the carrier 200 to cycle back and forth between the distribution site and the reaction site in a single reaction area until the reaction is completed, and finally drive the biochip 700 that has completed the reaction to the detection site for imaging detection. In some embodiments, the biochemical substance analysis system 1000 includes two groups of biochemical reaction modules 10, which share an imaging detection device 500, and the imaging detection device 500 is located between the two groups of biochemical reaction modules 10. As Figure 3 As shown, the detection sites and the reaction sites and distribution sites in each reaction area can be arranged in a straight line, that is, the two biochemical reaction devices 300, the two liquid exchange devices 400 and the lens assembly 510 in the imaging detection device 500 are arranged roughly in a straight line. The transfer device 100 can drive each carrier 200 to transfer the biochip 700 located on the carrier 200 to the bottom of the liquid exchange device 400 for sample loading, and then transfer it to the bottom of the biochemical reaction device 300 for detection reaction, and then transfer the biochip 700 that has completed the biochemical reaction to the bottom of the imaging detection device 500 for imaging detection analysis to complete the entire detection process. It can be understood that the two groups of biochemical reaction modules 10 share one imaging detection device 500. When the detection reaction in the two reaction areas is set in the program, the steps of biochemical reaction, liquid distribution, imaging detection, etc. can be staggered, so that the two biochips 700 are alternately imaged and detected without waiting, thereby improving the utilization rate and detection efficiency of the imaging detection device 500.

[0046] See also Figure 2 The transfer device 100 includes a first transfer mechanism 110 and at least two second transfer mechanisms 120 slidably disposed on the first transfer mechanism 110, and each first transfer mechanism 110 carries a carrier 200. The first transfer mechanism 110 includes a fixed block 111 disposed on the main platform 810, and a guide rail 112 disposed on the fixed block 111 and extending along a first direction x, and the second transfer mechanism 120 is slidably disposed on the guide rail 112. The first direction x is the arrangement direction of at least two groups of biochemical reaction modules 10. Each second transfer mechanism 120 is used to drive the carrier 200, and then drive the biochip 700 located on the carrier 200 to transfer the reaction sites and distribution sites in the same reaction area, and the detection sites located in the detection area.

[0047] Each second transfer mechanism 120 includes a first axis 121 slidably disposed on the guide rail 112 and extending along a first direction x, a second axis 122 slidably disposed on the first axis 121 and extending along a second direction y, and a third axis 123 slidably disposed on the second axis 122 and extending along a third direction z, and the carrier 200 is disposed on the third axis 123. The first direction x, the second direction y, and the third direction z are perpendicular to each other and constitute a three-dimensional coordinate system. In some embodiments, a first slider 124 is disposed on the guide rail 112, a mounting seat 125 is disposed on the first slider 124, and the first axis 121 is disposed on the mounting seat 125; the second axis 122 is slidably disposed on the first axis 121 through a second slider 126; and the third axis 123 is slidably disposed on the second axis 122 through a third slider 127. On each second transfer mechanism 120, the second axis 122 can move along the first axis 121 to drive the carrier 200 to move along the first direction x, thereby adjusting the position of the biochip 700 in the first direction x; the third axis 123 can move along the second axis 122 to drive the carrier 200 to move along the second direction y, thereby adjusting the position of the biochip 700 in the second direction y; the third axis 123 can also drive the carrier 200 to move along the third direction z, thereby adjusting the position of the biochip 700 in the third direction z. The transfer device 100 can realize the transfer of multiple groups of biochips 700 at different locations. The transfer device 100 has a simple structure and high integration. There is no need to set up a complex robot to transfer the biochips separately. In addition, by setting an independent second transfer mechanism 120 on the transfer device 100, different biochips 700 can be independently controlled, which reduces the structural complexity of the biochemical substance analysis system 1000, improves the transfer efficiency and the accuracy of displacement control, and is conducive to reducing the overall detection cost.

[0048] See also Figure 4 , and refer to Figure 1 and Figure 2 The liquid adding component 410 in the liquid changing device 400 can use inkjet printing to spray the reaction reagent (usually a liquid sample) required for biochemical substance analysis onto the open biochip 700 to form a solution layer of a predetermined thickness. The liquid adding component 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 reagent onto the biochip 700.

[0049] See also Figure 5 and Figure 6 , 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 reaction reagents required for biochemical substance analysis. 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 reaction reagents are 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 a reaction reagent in the liquid adding chamber 435 to be discharged from the liquid outlet 436 under the control of the inkjet control circuit 450, and then printed on the biochip 700 to form a solution layer. The liquid addition is realized by inkjet printing, and the liquid film thickness can be accurately controlled by controlling the droplet volume, printing frequency and printing times, which significantly reduces the reagent loss and further reduces the detection cost.

[0050] 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.

[0051] 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.

[0052] 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 4314 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.

[0053] 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 .

[0054] Please refer again Figure 5 and Figure 6 , and refer to Figure 1 The liquid adding component 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 circuit.

[0055] See also Figure 7 , 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 droplet volume 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 mode 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 detection sites. In order to improve the effect of the detection reaction, the throughput 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 around 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.

[0056] It can be understood that in other embodiments, such as Figure 8As 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.

[0057] It is also understandable that in other embodiments, such as Fig. 9 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.

[0058] See also Fig.10 and Fig.11 , and refer to Figures 4 to 6 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.11 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.

[0059] In other embodiments, Fig.12 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.

[0060] 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 the storage of the detection reagent.

[0061] 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.

[0062] 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.

[0063] Please refer again Figure 1 , Figure 2 and Figure 4 The liquid replacement device 400 also includes a liquid removal component 420, wherein the liquid removal component 420 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 component 420 needs to be used to remove the residual reagents after the previous step of the reaction, and then the liquid addition component 410 is used to add another reagent. Through the cooperation of the liquid addition component 410 and the liquid removal component 420, liquid addition and liquid removal on the biochip 700 can be achieved.

[0064] The liquid removal component 420 uses airflow to remove the residual reagents that have reacted on the biochip 700. Specifically, the liquid on the biochip 700 can be directly removed by blowing or sucking. 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 negative pressure to form an airflow, thereby blowing or sucking away the liquid on the surface of the biochip 700. The liquid removal is achieved by blowing or sucking, which is simple and convenient, and can be combined with the inkjet chip 430 to achieve a simple and fast liquid replacement process.

[0065] 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.

[0066] 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.

[0067] Please refer again Figure 4 , and refer to Figure 1 and Figure 2 The liquid replacement device 400 also includes a linkage structure 460, which is arranged on the top platform 830. 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, and 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 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.

[0068] Please refer again Figure 1 and Figure 2 The biochemical reaction device 300 includes a support 310 located on the main platform 810 and a heating cover 320 movably disposed 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 for the analyte to be detected to react with the reaction reagent. 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 detection reaction in the reaction chamber 900, so that the heating in the reaction chamber 900 is more uniform.

[0069] 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.

[0070] 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.

[0071] Please refer again Figure 1 and Figure 2The imaging detection device 500 also includes a detection component 520 signal-connected to the lens component 510. After the biochip 700 completes the reaction, the biochip 700 is cooled down and moved to the liquid replacement device 400 to replace the photographic reagent, and then moved to the bottom of the lens component 510 of the imaging detection device 500 to complete the fluorescent imaging of the entire biochip 700. After that, the lens component 510 transmits the fluorescent image to the detection component 520 for imaging analysis.

[0072] In some embodiments, lens assembly 510 includes an objective lens.

[0073] The following focuses on the functions of each of the above devices and the methods for executing them.

[0074] See also Fig.13 and Fig.14 , and refer to Figure 1 and Figure 2 The embodiment of the present application also provides a method for performing biochemical substance analysis using the aforementioned biochemical substance analysis system 1000. The biochemical substance analysis system 1000 can load at least two biochips 700 at the same time. The specific method for performing biochemical substance analysis includes the following steps:

[0075] Step S1, loading of biochip 700: loading a biochip 700 on each carrier 200 in at least two of the reaction areas. The biochip 700 is an open substrate for fixing the analyte to be detected, which is convenient for adding and replacing liquid.

[0076] Step S2, adding liquid to the biochip 700: In a single reaction area, the carrier 200 is driven by the transfer device 100 to move along the preset path to transfer the biochip 700 to the distribution site, and the liquid adding component 410 in the liquid changing device 400 is used to spray a solution layer of a predetermined thickness on the biochip 700.

[0077] The transfer device 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 biochemical detection (for example, gene sequencing). In addition, by setting a sensing unit (the sensing unit may include a detection switch and a sensor, etc.) at the reaction site, the distribution site, and the detection site, the sensing unit can sense whether the carrier 200 is moved into place, and the control platform 600 controls the corresponding program to start execution according to the sensing signal sent by the sensing switch and the preset program.

[0078] Specifically, the control platform 600 controls the transfer device 100 to drive the carrier 200 to move, and then moves the biochip 700 to the distribution site. The movement of the biochip 700 is sensed by the sensing unit. The control platform 600 controls the liquid adding component 410 in the liquid replacement device 400 to add liquid to the biochip 700 according to the sensing signal and the preset liquid adding program.

[0079] In some embodiments, before step S2, the biochemical substance analysis method further includes: using the liquid removal component 420 in the liquid replacement device 400 to remove the residual substances on the biochip 700 after the reaction.

[0080] Specifically, during the first liquid addition, the solution layer of a predetermined thickness is directly printed on the biochip 700 according to step S2. In the subsequent liquid addition process, since there are residual reagents that have reacted on the biochip 700, it is necessary to remove the liquid first, and then add another reagent to the biochip 700 to achieve the liquid replacement process.

[0081] Specifically, during the liquid adding process: when adding liquid, the control platform 600 controls the inkjet chip 430 in the liquid adding component 410 to print a solution layer of a predetermined thickness onto the biochip 700 .

[0082] 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 is removed to form a solution layer of a predetermined thickness, thereby completing the liquid replacement process.

[0083] Step S3, biochemical reaction: In a single reaction area, the carrier 200 is driven by the transfer device 100 to move along the preset path to transfer the biochip 700 sprayed with the solution layer to the reaction site, and the biochemical reaction device 300 is combined with the carrier 200 to control the reaction between the analyte to be detected in the biochip 700 and the reaction reagent.

[0084] Specifically, the control platform 600 controls the transfer device 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 biochemical reaction device 300 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.

[0085] In some embodiments, before performing biochemical substance analysis, a heating program needs to be started first to heat the biochemical reaction device 300 and the carrier 200 to a target temperature, and then a detection reaction program is started.

[0086] In some embodiments, the biochemical reaction device 300 can start the heating process during the process of adding liquid 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 detection cycle. The heating of the carrier 200 can be turned on after the biochip 700 moves to the reaction site. The specific steps include:

[0087] Step S31 , heating the heating cover 320 of the biochemical reaction device 300 to a target temperature.

[0088] In step S32 , the carrier 200 is driven by the transfer device 100 to transfer the biochip 700 after adding liquid to the reaction site.

[0089] Step S33 , covering the heating cover 320 onto the biochip 700 .

[0090] Step S34 , heating the carrier 200 to a target temperature so that the analyte to be detected in the biochip 700 reacts with the reaction reagent.

[0091] The above steps S2 and S3 can be repeated multiple times to add different chemical reagents for detection reactions and complete biochemical substance analysis on the biochip 700. After each step S3, the biochip 700 needs to be cooled to about 15°C and the liquid is replaced.

[0092] Step S4, imaging detection: the carriers 200 located in different reaction areas are sequentially transferred to the detection sites by the transfer device 100, and the fluorescent image of the analyte to be detected after the reaction is completed is collected by the lens assembly 510 in the imaging detection device 500.

[0093] Before the imaging detection step, it is necessary to replace the imaging reagent on the biochip 700, which specifically includes the following steps: the carrier 200 is driven by the transfer device 100 to transfer the reacted biochip 700 to the distribution site, the residual sample on the biochip 700 is removed by the liquid replacement device 400, and the imaging reagent is added.

[0094] Specifically, after the detection reaction is completed, the biochip 700 is cooled to about 15°C, and the control platform 600 controls the transfer device 100 to move the carrier 200 to move the biochip 700 to the distribution site, and controls the liquid replacement device 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 area, and the lens assembly 510 in the imaging detection device 500 is controlled to complete the fluorescence imaging of the entire biochip 700, and the collected fluorescence image is imaged, detected and analyzed by the detection assembly 520 to obtain the detection result; finally, after the imaging is completed, the transfer device 100 drives the carrier 200 to reset, removes the biochip 700 that has completed the reaction, and replaces it with another biochip 700 to carry out the next detection reaction.

[0095] In the embodiment of the present application, since multiple groups of biochemical reaction modules 10 share one imaging detection device 500, for different biochemical reaction modules 10, there are certain alternating rules in the timing of the above steps when the program is set, so that the biochips 700 in different reaction areas are alternately transferred to the imaging area for the detection process, so as to improve the utilization rate and detection efficiency of the imaging detection device 500.

[0096] In summary, the above-mentioned biochemical substance analysis system 1000 provided in the embodiment of the present application can simultaneously perform detection reactions of at least two biochips 700 by integrating at least two sets of biochemical reaction modules 10, which is conducive to realizing ultra-high throughput detection and improving detection efficiency. At the same time, the biochemical substance analysis system 1000 has a high degree of integration, which effectively reduces the size of the system; and multiple sets of biochemical reaction modules 10 integrate a set of imaging detection devices 500, which can improve the utilization rate of the imaging detection device 500, simplify the structural complexity of the system, and reduce the difficulty of assembly and operation. By adding a liquid replacement device 400, the liquid circuit control structure can be simplified, the structural complexity of the system is reduced, and it is conducive to realizing the transfer of the biochip 700 at different sites, reducing the overall detection cost. Moreover, the liquid replacement device 400 uses inkjet printing to achieve liquid addition, with high printing frequency, small print droplets, and can accurately control the thickness of the liquid film, improve the uniformity of the liquid film thickness, significantly reduce reagent loss, and further reduce the detection cost; the liquid replacement device 400 is also equipped with a liquid removal component, which uses blowing or suction to achieve the actual removal of residues on the biochip, which is simple and convenient, and can be used with the inkjet chip 430 to achieve a simple and fast liquid replacement process. In addition, the biochemical substance analysis system 1000 integrates multiple groups of biochemical reaction devices 300, multiple groups of liquid replacement devices 400, imaging detection devices 500 and transfer devices 100 into one system, which can realize the integrated operation of sample addition, biochemical substance analysis and imaging, simplify the system structure, and is conducive to improving the detection throughput, improving the detection efficiency, and reducing the detection cost.

[0097] 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 transfer device, at least two groups of biochemical reaction modules, and an imaging detection device. The biochemical substance analysis system has an imaging area and at least two reaction areas. Each reaction area is provided with a group of biochemical reaction modules. The imaging area is provided with the imaging detection device. Each group of biochemical reaction modules includes: a carrier, a biochemical reaction device, and a liquid replacement device. The carrier is used to carry a biochip, and the biochip is an open substrate for fixing an analyte to be detected. The transfer device is used to transport the carrier along a preset path, and the preset path at least includes a distribution site and a reaction site located in each of the reaction areas, and a detection site corresponding to the imaging detection device, the distribution site corresponds to the liquid replacement device, and the reaction site corresponds to the biochemical reaction device; At the distribution site, the liquid replacement device has a liquid adding component for spraying a solution layer of a predetermined thickness onto the biochip, wherein the solution layer at least includes a reaction reagent that reacts with the analyte to be detected; at the reaction site, the biochemical reaction device is combined with the carrier to control the reaction between the analyte to be detected in the biochip and the reaction reagent; at the detection site, the imaging detection device has a lens component for capturing a fluorescent image of the analyte to be detected after the reaction.

2. The biochemical substance analysis system according to claim 1, characterized in that: The biochemical substance analysis system comprises two groups of biochemical reaction modules arranged opposite to each other, the imaging detection device is located between the two groups of biochemical reaction modules, and the liquid replacement device in each group of biochemical reaction modules is arranged close to the imaging detection device.

3. The biochemical substance analysis system according to claim 2, characterized in that: The transfer device comprises a first transfer mechanism and at least two second transfer mechanisms slidably arranged on the first transfer mechanism, and each of the second transfer mechanisms is provided with a carrier.

4. The biochemical substance analysis system according to claim 3, characterized in that: The first transfer mechanism comprises a guide rail extending along a first direction, and the first direction is the arrangement direction of the two groups of biochemical reaction modules; The second transfer mechanism includes a first axis slidably disposed on the guide rail and extending along the first direction, a second axis slidably disposed on the first axis and extending along the second direction, and a third axis slidably disposed on the second axis and extending along the 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.

5. The biochemical substance analysis system according to claim 1, characterized in that: The liquid adding component includes an inkjet chip, a liquid storage structure located on the inkjet chip and connected to the inkjet chip, and a reagent storage box connected to the liquid storage structure. The inkjet chip uses piezoelectric inkjet printing technology or thermal bubble inkjet printing technology to spray reagents.

6. The biochemical substance analysis system according to claim 1, characterized in that: The liquid replacement device also includes a liquid removal component, which is used to remove residual reagents after the reaction on the biochip.

7. The biochemical substance analysis system according to claim 6, characterized in that: The liquid removal component 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.

8. The biochemical substance analysis system according to claim 1, characterized in that: The biochemical reaction device comprises a heating cover, and the heating cover is used to cover the biochip to form a reaction chamber for the analyte to be detected to react with the reaction reagent.

9. A biochemical substance analysis method using the biochemical substance analysis system according to any one of claims 1 to 8, characterized in that: include: Loading the biochip on each of the carriers in at least two of the reaction areas; In a single reaction area, the carrier is driven to move along the preset path by the transfer device to transfer the biochip to the distribution site, and the solution layer of a predetermined thickness is sprayed on the biochip by the liquid adding component in the liquid replacement device; In a single reaction area, the carrier is driven by the transfer device to move along the preset path to transfer the biochip sprayed with the solution layer to the reaction site, and the biochemical reaction device is combined with the carrier to control the analyte to be detected in the biochip to react with the reaction reagent; as well as The carriers located in different reaction areas are sequentially transferred to the detection sites by the transfer device, and the fluorescent image of the analyte to be detected after the reaction is completed is collected by the lens assembly in the imaging detection device.

10. The biochemical substance analysis method according to claim 9, characterized in that: Before the step of spraying the solution layer of a predetermined thickness on the biochip by the liquid adding component in the liquid replacement device, the biochemical substance analysis method further includes: The residual reagent on the surface of the biochip is removed by using the liquid removal component in the liquid replacement device.

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