Integrated slide, liquid changing apparatus, and biochemical substance analysis system and analysis method

Abstract

An integrated slide, a liquid changing apparatus, and a biochemical substance analysis system and analysis method. The integrated slide comprises a biochip and an ink-jet chip packaged above the biochip, the biochip and the ink-jet chip defining a biochemical reaction chamber; the ink-jet chip is communicated with the biochemical reaction chamber and is capable of adding into the biochemical reaction chamber a reagent needed by a biochemical reaction, or discharging from the biochemical reaction chamber a residual reagent which has undergone a reaction; the biological chip can implement in-situ signal detection. In the present application, the biochemical substance analysis system using the integrated slide can implement an integrated operation of sample addition, biochemical substance analysis and imaging, thereby simplifying the system structure, reducing reagent losses, helping to improve detection efficiency and reducing detection costs.

Description

Integrated slide, liquid exchange device, biochemical substance analysis system and analysis method Technical Field

[0001] The present application relates to the technical field of biochemical substance analysis, and in particular to an integrated slide, a liquid exchange device, a biochemical substance analysis system, and an analysis method. Background Art

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

[0003] However, the sequencers used in existing second-generation gene sequencing technologies have complex structures, cumbersome operations, and difficulty in increasing throughput. Moreover, the reagent loss during sequencing is high, and most of the reagents do not participate in the reaction (less than 1% of the reagent components participate in the reaction), resulting in high sequencing costs. Second-generation gene sequencing technologies mainly include packaged slide sequencing and open slide sequencing, among which packaged slide sequencing is the main form.

[0004] Summary of the Invention

[0005] In order to solve at least one of the above-mentioned defects, it is necessary to propose an integrated slide, liquid changing device, biochemical substance analysis system and biochemical substance analysis method.

[0006] In a first aspect, an embodiment of the present application provides an integrated carrier, comprising: a biochip and an inkjet chip encapsulated above the biochip, wherein a biochemical reaction chamber is enclosed between the biochip and the inkjet chip; wherein the inkjet chip is connected to the biochemical reaction chamber through a nozzle; the inkjet chip is used to add reagents required for the biochemical reaction into the biochemical reaction chamber through the nozzle, or to discharge residual reagents that have reacted in the biochemical reaction chamber through the nozzle; the biochip comprises a biosensing layer and a sensor layer facing the biochemical reaction chamber, the biosensing layer comprising array sites for fixing a sample to be detected, and the sensor layer is configured to identify a signal generated after the sample to be detected reacts with the reagent.

[0007] In some possible embodiments, the inkjet chip includes: an inkjet cavity layer and a first driving structure, the inkjet cavity layer includes a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity and at least one liquid discharging cavity are formed through the first surface and the second surface, the nozzle is divided into a liquid outlet located on the second surface and connected to the liquid adding cavity, and a liquid discharging port located on the second surface and connected to the liquid discharging cavity, the liquid adding cavity is connected to the biochemical reaction cavity through the liquid outlet, and the liquid discharging cavity is connected to the biochemical reaction cavity through the liquid outlet; the first driving structure is superimposed on the first surface and covers the liquid adding cavity, and the first driving structure is used to drive the liquid in the liquid adding cavity into the biochemical reaction cavity through the liquid outlet.

[0008] In some possible embodiments, the inkjet chamber layer further includes a sample chamber connected to the liquid adding chamber, the sample chamber is used to accommodate the sample to be detected, and the sample to be detected is driven by the first driving structure through the nozzle into the biochemical reaction chamber and is fixed by the array site.

[0009] In some possible embodiments, the first driving structure includes a first deformable layer located on the first surface, and a first electrode layer located on the first deformable layer, wherein the first deformable layer is configured to deform under the control of the first electrode layer to squeeze the reagent located in the liquid adding chamber, so that the reagent enters the biochemical reaction chamber through the liquid outlet;

[0010] Alternatively, the first driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent so that the reagent enters the biochemical reaction chamber through the liquid outlet.

[0011] In some possible embodiments, the inkjet chip further includes: a second driving structure, superimposed on the first surface and covering the drainage cavity, the second driving structure being used to form a negative pressure in the drainage cavity to discharge the residual reagent in the biochemical reaction chamber into the drainage cavity.

[0012] In some possible embodiments, the second driving structure includes a second deformable layer located on the first surface, and a second electrode layer located on the second deformable layer, and the second deformable layer is configured to deform under the control of the second electrode layer to form a negative pressure in the drainage chamber, thereby allowing the residual reagent in the biochemical reaction chamber to enter the drainage chamber.

[0013] In some possible embodiments, the drainage cavity further has a liquid suction port located on the first surface, and the second driving structure is a vacuum negative pressure device, which is connected to the drainage cavity through the liquid suction port.

[0014] In some possible embodiments, the integrated carrier further includes a liquid storage structure stacked on the inkjet chip, the liquid storage structure includes at least one first liquid storage cavity connected to the liquid adding cavity, and the first liquid storage cavity is used to store the reagent.

[0015] In some possible embodiments, the inkjet chip includes a plurality of the liquid adding chambers, each of the liquid adding chambers is correspondingly provided with a first driving structure and at least one liquid outlet, and a first liquid storage chamber is provided above each of the liquid adding chambers;

[0016] Alternatively, the inkjet chip includes a plurality of liquid adding chambers arranged in an array, each of the liquid adding chambers is correspondingly provided with a first driving structure and a liquid outlet, and a first liquid storage chamber is provided above the liquid adding chambers in the same row.

[0017] In some possible embodiments, the liquid storage structure further includes at least one second liquid storage cavity communicated with the drainage cavity, and the second liquid storage cavity is used to store the residual reagent.

[0018] In some possible embodiments, the volume of the liquid adding chamber is 9 pL to 50 pL.

[0019] In some possible embodiments, the sensor layer includes: a semiconductor layer having a light sensing region and a non-sensing region, a light sensing component located in the light sensing region, at least one dielectric layer stacked on a surface of the semiconductor layer, and a metal wiring layer located within the dielectric layer, wherein a vertical projection of the metal wiring layer is located in the non-sensing region along a stacking direction, and the metal wiring layer is electrically connected to the light sensing component;

[0020] The biosensing layer includes: a passivation layer located on a surface of the dielectric layer facing away from the semiconductor layer, or located on a surface of the semiconductor layer facing away from the dielectric layer, wherein the passivation layer has an opening corresponding to the light sensing area; and the functionalized array site located in the opening.

[0021] In some possible embodiments, along the stacking direction, the thickness of the passivation layer is greater than the thickness of the array site.

[0022] In some possible embodiments, the inkjet chip and the biochip are bonded together via a packaging layer.

[0023] In a second aspect, an embodiment of the present application provides a biochemical substance analysis system, comprising: a carrier and at least one aforementioned integrated carrier located on the carrier, the integrated carrier comprising a biochip and an inkjet chip encapsulated above the biochip, a biochemical reaction chamber being formed between the biochip and the inkjet chip; the inkjet chip is connected to the biochemical reaction chamber through a nozzle; the inkjet chip is used to add reagents required for biochemical reactions into the biochemical reaction chamber through the nozzle, or to discharge residual reacted reagents in the biochemical reaction chamber through the nozzle; the biochip comprises a biosensing layer and a sensor layer facing the biochemical reaction chamber, the biosensing layer comprising an array site for fixing a sample to be detected, and the sensor layer is configured to identify a signal generated after the sample to be detected reacts with the reagent.

[0024] The biochemical substance analysis system provided in the second aspect of the present application integrates the inkjet chip and the biochip into an integrated structure using semiconductor packaging technology, so that the slide adding / changing liquid, biochemical reactions, and signal acquisition can be integrated on the same integrated slide, effectively simplifying the structure of the biochemical substance analysis system and the complexity of the liquid path system, reducing the volume of the overall biochemical substance analysis system, making the system more compact, easy to assemble, easy to use, and capable of achieving ultra-high throughput detection, reducing equipment costs and detection costs; moreover, the integrated slide is disposable as a whole, and there is no need to be equipped with a load cleaning device, further simplifying the complexity of the system; in addition, the use of inkjet chip for adding / changing liquid has high inkjet efficiency, small droplet volume, thinner liquid film thickness and higher uniformity, which can reduce reagent loss and reduce detection costs.

[0025] In a third aspect, the present invention provides a method for analyzing biochemical substances, comprising:

[0026] An integrated slide is loaded onto a stage. The integrated slide includes a biochip and an inkjet chip encapsulated above the biochip. A biochemical reaction chamber is formed between the biochip and the inkjet chip. The inkjet chip is connected to the biochemical reaction chamber via a nozzle. The biochip includes a biosensing layer and a sensor layer facing the biochemical reaction chamber. The biosensing layer includes array sites for fixing a sample to be detected. The sensor layer is configured to identify a signal generated after the sample to be detected reacts.

[0027] adding reagents required for biochemical reaction into the biochemical reaction chamber via the inkjet chip through the nozzles, wherein the reagents are attached to the array sites;

[0028] heating the carrier to allow the reagent in the biochemical reaction chamber to react with the sample to be detected, and identifying a signal generated by the reaction between the sample to be detected and the reagent through the sensor layer; and

[0029] The inkjet chip is used to discharge the reacted residual reagent in the biochemical reaction chamber through the nozzle holes.

[0030] In a fourth aspect, an embodiment of the present application provides a liquid replacement device, comprising: a liquid adding component and a liquid removal component, the liquid adding component includes an inkjet chip, the inkjet chip is used to load reagents for a biochip by inkjet printing, and the biochip is an open semiconductor biochip; the liquid removal component is used to remove residual reagents on the biochip after the reaction is completed.

[0031] In some possible embodiments, the inkjet chip includes: an inkjet cavity layer and a driving structure, the inkjet cavity layer includes a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity is formed through the first surface and the second surface, the liquid adding cavity is used to accommodate the reagent, and the liquid adding cavity has at least one liquid outlet located on the second surface; the driving structure is superimposed on the first surface and covers the liquid adding cavity, and the driving structure is used to drive the reagent located in the liquid adding cavity to be discharged from the liquid outlet.

[0032] In some possible embodiments, the driving structure includes a deformable layer located on the first surface, and an electrode layer located on the deformable layer, wherein the deformable layer is configured to deform under the action of a voltage to squeeze the reagent located in the liquid adding chamber;

[0033] Alternatively, the driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent.

[0034] In some possible embodiments, the liquid adding assembly further includes a liquid storage structure stacked on the inkjet chip, the liquid storage structure includes at least one liquid storage cavity connected to the liquid adding cavity, and the liquid storage cavity is used to store the reagent.

[0035] In some possible embodiments, the inkjet chip includes a plurality of the liquid adding chambers, each of the liquid adding chambers is correspondingly provided with a driving structure and at least one liquid outlet, and a liquid storage chamber is provided above each of the liquid adding chambers;

[0036] Alternatively, the inkjet chip includes a plurality of liquid adding chambers arranged in an array, each of the liquid adding chambers is correspondingly provided with a driving structure and a liquid outlet, and a liquid storage chamber is provided above the liquid adding chambers in the same row.

[0037] 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.

[0038] In some possible embodiments, the liquid adding assembly further includes a reagent storage box connected to the inkjet chip.

[0039] In some possible embodiments, the liquid removal component is configured to provide positive pressure or negative pressure to blow or suck away the residual reagent on the biochip.

[0040] In some possible embodiments, the liquid removal assembly includes an air supply structure and an air knife connected to the air supply structure, and the air supply structure is used to provide compressed gas to the air knife.

[0041] In some possible embodiments, the air knife includes an air knife cavity communicated with the air supply structure, and a cutter head communicated with the air knife cavity, wherein the cutter head is used to limit the airflow direction of the compressed gas.

[0042] In some possible embodiments, the cutter head includes a cutter head body connected to the air knife cavity, and at least one inclined surface located at one end of the cutter head body away from the air knife cavity, wherein an air blowing port is provided on the inclined surface.

[0043] In some possible embodiments, the liquid exchanging device further includes a linkage structure, the liquid adding component and the liquid removing component are provided on the linkage structure, and the linkage structure is used to enable the liquid adding component and the liquid removing component to be linked.

[0044] In some possible embodiments, the linkage structure includes a linkage shaft and a drive motor slidably disposed on the linkage shaft, and the liquid adding assembly and the liquid removing assembly are both mounted on the drive motor.

[0045] In a fifth aspect, an embodiment of the present application provides another biochemical substance analysis system, comprising: a biochemical reaction device, a carrier, and a liquid exchange device, wherein the biochemical reaction device is covered with the carrier to form a reaction chamber, the liquid exchange device can be slidably disposed in the reaction chamber and is spaced apart from the carrier, the side of the carrier close to the liquid exchange device carries a biochip, and the biochip is an open carrier for fixing the sample to be tested; the liquid exchange device is configured to inkjet print a reagent layer of a preset thickness on the biochip.

[0046] In some possible embodiments, the temperature in the reaction chamber is adjustable.

[0047] In some possible embodiments, the biochemical reaction device includes a heating cover, the heating cover includes a top wall and a side wall arranged on the periphery of the top wall, an opening is formed at one end of the side wall away from the top wall, and the carrier is used to seal the opening to form the reaction chamber.

[0048] In some possible embodiments, the top wall includes a water storage cavity, and a portion of the water storage cavity close to the reaction chamber is provided with an ultrasonic element, which is used to atomize the water in the water storage cavity and conduct the atomized water vapor to the reaction chamber.

[0049] In some possible embodiments, the side wall has a vent hole, and the reaction chamber is connected to the outside through the vent hole.

[0050] In some possible embodiments, the liquid replacement device is further configured to remove residual reagents on the surface of the biochip after the reaction, and the liquid replacement device is the liquid replacement device described above.

[0051] In some possible embodiments, the liquid replacement device is slidably disposed on the inner wall of the biochemical reaction device through a linkage structure.

[0052] In some possible embodiments, the biochip includes a biosensing layer facing the fluid exchange device and a sensor layer stacked on the biosensing layer near the carrier side, the biosensing layer includes array sites for fixing the sample to be detected, and the sensor layer is configured to identify the signal generated after the sample to be detected reacts with the reagent.

[0053] In some possible embodiments, the biochemical substance analysis system further includes a transfer device, the carrier is located on the transfer device, and the transfer device is used to move the carrier to or away from the biochemical reaction device.

[0054] In a sixth aspect, the present invention provides another method for analyzing biochemical substances, comprising:

[0055] Loading a biochip on a carrier, the biochip comprising a biosensing layer, with samples to be detected fixed on array sites of the biosensing layer;

[0056] Covering the biochemical reaction device with the carrier to form a reaction chamber, wherein the biochip is located in the reaction chamber;

[0057] inkjet printing a reagent layer of a preset thickness onto the array site using a liquid replacement device; and

[0058] The reaction chamber is heated by the biochemical reaction device and the carrier, so that the sample to be detected in the biochip reacts with the reagent layer.

[0059] In some possible embodiments, the biochip further includes a sensor layer stacked on a side of the biosensing layer close to the carrier. After the sample to be detected in the biochip reacts with the reagent layer, the method further includes:

[0060] The sensor layer identifies the signal generated after the sample to be detected reacts with the reagent layer and performs in-situ signal detection and analysis.

[0061] In some possible embodiments, a plurality of chip positions are provided on the carrier, and each chip position is used to accommodate and fix a corresponding biochip.

[0062] The biochemical substance analysis system provided in the fifth aspect of the present application has the following beneficial effects:

[0063] (1) By integrating the biochemical reaction device, liquid exchange device, and transfer device into a single system, and simultaneously coordinating with a biochip (or integrated imaging detection device) with in situ imaging detection capabilities, it is possible to achieve integrated operations for sample addition, biochemical substance detection, and analysis. This simplifies the system structure, improves detection efficiency, enables ultra-high throughput detection, and reduces equipment and detection costs. Furthermore, the overall size of the biochemical substance analysis system is reduced, making the system more compact, easier to assemble, and easier to use.

[0064] (2) A liquid exchange device is integrated into the system, which simplifies the complexity of the liquid circuit system for adding reagents, reduces the structural complexity of the overall system, is easy to assemble and operate, and reduces the overall detection cost. In addition, the liquid exchange device uses inkjet printing to add liquid, with a high printing frequency and small print droplets. It can also accurately control the thickness of the liquid film, improve the uniformity of the liquid film thickness, and significantly reduce reagent loss (compared to the current conventional sequencing method, the amount of reagent loss can be reduced by approximately 50% to 80%), thereby further reducing the detection cost. In addition, the liquid exchange device uses blowing or suction to remove liquid, which is simple and convenient. In combination with the inkjet chip, the liquid exchange process can be simple and fast.

[0065] (3) By combining the heating cover and the carrier cover to form a reaction chamber, and arranging an ultrasonic element on the heating cover that can generate high-temperature mist, a stable reaction atmosphere can be constructed and the evaporation rate of the reagent during the inkjet printing process can be slowed down.

[0066] (4) Multiple biochips can be loaded onto the carrier, and the liquid addition and replacement processes can be completed sequentially through the liquid replacement device, which is easy to operate and helps to improve the detection throughput.

[0067] (5) An overflow trough is provided on the carrier to facilitate the collection of waste liquid during the liquid removal process. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments of the present application. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0069] FIG1 is a schematic diagram of a biochemical substance analysis system in one embodiment of the present application.

[0070] FIG2 is a schematic structural diagram of an integrated slide in one embodiment of the present application.

[0071] FIG3 is a schematic structural diagram of an inkjet chip adding reagents to a reaction chamber in one embodiment of the present application.

[0072] FIG4 is a schematic structural diagram of an inkjet chip adding reagents to a reaction chamber in another embodiment of the present application.

[0073] FIG5 is a schematic diagram of the structure of an inkjet chip in one embodiment of the present application for discharging residual reagents in a biochip into a drainage chamber.

[0074] FIG6 is a schematic structural diagram of the integrated slide-mounted liquid storage structure in FIG2 .

[0075] FIG7 is a top view of an inkjet chip in one embodiment of the present application.

[0076] FIG8 is a top view of an inkjet chip in another embodiment of the present application.

[0077] FIG9 is a top view of an inkjet chip in another embodiment of the present application.

[0078] FIG10 is a schematic structural diagram of a biochip in one embodiment of the present application.

[0079] FIG11 is a schematic structural diagram of a biochip in another embodiment of the present application.

[0080] FIG12 is a schematic structural diagram of a biochip in another embodiment of the present application.

[0081] FIG13 is a flow chart of a biochemical substance analysis method according to an embodiment of the present application.

[0082] FIG14 is a schematic diagram of a biochemical substance analysis system in another embodiment of the present application.

[0083] FIG15 is a schematic plan view of the structure of a biochemical substance analysis system in another embodiment of the present application.

[0084] FIG16 is a schematic diagram of the three-dimensional structure of a biochemical substance analysis system in another embodiment of the present application.

[0085] FIG17 is a schematic diagram of the three-dimensional structure of a biochemical substance analysis system in another embodiment of the present application from another perspective.

[0086] FIG18 is a schematic structural diagram of the inkjet chip and liquid storage structure in FIG17 .

[0087] FIG19 is a cross-sectional view of an inkjet chip and a liquid storage structure in another embodiment of the present application.

[0088] FIG20 is a top view of an inkjet chip in another embodiment of the present application.

[0089] FIG21 is a top view of an inkjet chip in another embodiment of the present application.

[0090] FIG22 is a top view of an inkjet chip in another embodiment of the present application.

[0091] FIG23 is a schematic diagram of an inkjet chip in an embodiment of the present application when the liquid adding chamber is filled with reagent and no liquid is added.

[0092] FIG24 is a schematic diagram of an inkjet chip ejecting reagents in one embodiment of the present application.

[0093] Figure 25 is a schematic diagram of the structure of the inkjet chip ejecting reagents in another embodiment of the present application.

[0094] FIG. 26 is a flow chart of a biochemical substance analysis method according to another embodiment of the present application.

[0095] FIG. 27 is a flowchart of a biochemical substance analysis method according to another embodiment of the present application.

[0096] Description of main component symbols

[0097] The following specific implementation methods will further illustrate this application in conjunction with the above-mentioned drawings. DETAILED DESCRIPTION

[0098] The following will be combined with the drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0099] 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 referred to as being "disposed on" another component, it may be directly on the other component or there may be a central component. As used herein, the term "and / or" includes all and any combinations of one or more of the relevant listed items.

[0100] As shown in FIG2 , an embodiment of the present application provides an integrated slide 200. The integrated slide 200 includes a biochip 210 and an inkjet chip 230 encapsulated above the biochip 210. A biochemical reaction chamber 250 is formed between the biochip 210 and the inkjet chip 230. The inkjet chip 230 communicates with the biochemical reaction chamber 250 via nozzles. The inkjet chip 230 is used to add reagents required for a biochemical reaction into the biochemical reaction chamber 250 through the nozzles, or to discharge residual reagents from the biochemical reaction chamber 250 after reacting through the nozzles. In other words, the inkjet chip 230 can both add reagents required for a biochemical reaction into the biochemical reaction chamber 250 and discharge residual reagents from the biochemical reaction chamber 250 after reacting. The biochip 210 includes a biosensing layer 219 facing the biochemical reaction chamber 250 and a sensor layer. The biosensing layer 219 includes array sites 217 for fixing a sample to be detected. The sensor layer is configured to recognize signals generated by the reaction between the sample to be detected and the reagents. That is, the biochip 210 is used to allow the sample to be detected located in the biochemical reaction chamber 250 to react with the reagent, and can also perform in-situ signal detection on the reacted sample to be detected.

[0101] Referring to Figures 1 and 2, an embodiment of the present application further provides a biochemical substance analysis system 1000, comprising: a carrier 100 and an integrated slide positioned on the carrier 100. Optionally, the integrated slide in the present embodiment is the above-mentioned integrated slide 200. The biochemical substance analysis system 1000 also includes a main architecture platform (not shown), on which the carrier 100 is positioned. The carrier 100 mainly comprises a carrier seat 110 and a chip holder 120 positioned on the carrier seat 110, and the integrated slide 200 is positioned on the chip holder 120. Specifically, the integrated slide 200 can be adsorbed on the chip holder 120 by negative pressure adsorption. In addition, multiple integrated slides 200 can be adsorbed on the chip holder 120 at the same time to achieve high-throughput detection. A heating device (not shown) is also provided in the carrier 100 so that the integrated slide 200 can be heated to achieve biochemical reactions.

[0102] Referring to Figures 2 and 3, the inkjet chip 230 mainly includes an inkjet cavity layer 231 and a first drive structure 232. The inkjet cavity layer 231 includes a first surface 2311 and a second surface 2312 arranged opposite to each other, and at least one liquid adding cavity 233 is formed through the first surface 2311 and the second surface 2312. Specifically, the nozzle can be divided into a liquid outlet 235 located on the second surface 2312, and the liquid adding cavity 233 is connected to the biochemical reaction chamber 250 through the liquid outlet 235. The first drive structure 232 is superimposed on the first surface 2311 and covers the liquid adding cavity 233, that is, the first drive structure 232 can cover the opening of the liquid adding cavity 233 located on the first surface 2311. The first drive structure 232 can drive the reagent located in the liquid adding cavity 233 to enter the biochemical reaction chamber 250 through the liquid outlet 235. It is understandable that a certain negative pressure can be maintained in the liquid adding chamber 233 by adding a negative pressure air circuit (not shown) to connect it to the liquid adding chamber 233. When no liquid is needed, the reagent can be kept in the liquid adding chamber 233 and will not leak out from the liquid outlet 235.

[0103] Referring again to FIG. 3 , the first drive structure 232 can utilize piezoelectric inkjet printing technology to print the reagent within the liquid addition chamber 232 into the biochemical reaction chamber 250. Piezoelectric inkjet printing utilizes piezoelectric ceramics to deform due to applied voltage, squeezing liquid to generate high pressure and eject the liquid. In some embodiments, the first drive structure 232 includes a first deformable layer 2321 located on the first surface 2311 and a first electrode layer 2323 located on the first deformable layer 2321. The first deformable layer 2321 can deform under the control of the first electrode layer 2323 to squeeze the reagent within the liquid addition chamber 233, thereby causing the reagent to flow out of the liquid outlet 235 and into the biochemical reaction chamber 250. The inkjet chip 230's liquid addition principle involves applying a voltage to the first deformable layer 2321 via the first electrode layer 2323. Since the first deformable layer 2321 can be made of piezoelectric ceramic, it undergoes a momentary deformation under the influence of the voltage. This momentary deformation can then be controlled to bulge into the liquid addition chamber 233. This momentary deformation squeezes the reagent within the liquid addition chamber 233, and the reagent is ejected from the liquid outlet 235 at high pressure to form droplets, which are then printed onto corresponding locations on the biochip 210. By using micro-piezoelectric technology to achieve reagent sample printing, the volume of the printed reagent droplets can be precisely controlled, thereby reducing reagent loss.

[0104] It can be understood that in other embodiments, as shown in Figure 4, the first driving structure 232 can also use thermal bubble inkjet printing technology to achieve liquid spraying. The first driving structure 232 can also include a heater. When the heater is powered on, it will generate heat to heat the reagent in the liquid adding chamber 233, thereby generating bubbles. The bubbles squeeze out the reagent droplets from the liquid outlet 235 to achieve the purpose of printing.

[0105] Referring again to FIG. 2 and in conjunction with FIG. 1 , at least one drainage cavity 234 is formed through the first surface 2311 and the second surface 2312 of the inkjet cavity layer 231. Specifically, the nozzles can be further divided into drainage ports 236 located on the second surface 2312. The drainage cavity 234 communicates with the biochemical reaction chamber 250 through the drainage ports 236. The inkjet chip 230 also includes a second drive structure 237 superimposed on the first surface 2311. The second drive structure 237 covers the drainage cavity 234, that is, it covers the opening of the drainage cavity 234 located on the first surface 2311. The second drive structure 237 is used to create a negative pressure within the drainage cavity 234, thereby draining residual reagents from the biochemical reaction chamber 250 into the drainage cavity 234 after the reaction is completed.

[0106] In some embodiments, as shown in FIG5 , the second driving structure 237 may include a second deformable layer 2371 located on the first surface 2311 and a second electrode layer 2373 located on the second deformable layer 2371. The second deformable layer 2371 is configured to deform under the control of the second electrode layer 2373 to create a negative pressure within the drainage chamber 234, thereby allowing residual reagents within the biochemical reaction chamber 250 to enter the drainage chamber 234 through the drainage port 236 under the action of the negative pressure. In some embodiments, the second deformable layer 2371 is also made of piezoelectric ceramic. Therefore, the second deformable layer 2371 is subject to instantaneous deformation under the influence of voltage. At this time, the second deformable layer 2371 can be controlled to bulge in a direction away from the drainage chamber 234. This instantaneous deformation increases the volume of the drainage chamber 234, creating a negative pressure therein. Consequently, residual reagents within the biochemical reaction chamber 250 are attracted by the negative pressure and enter the drainage chamber 234 through the drainage port 236. It is understood that the drainage chamber 234 is also connected to the waste liquid collection device 292, so that the residual reagent discharged into the drainage chamber 234 is discharged into the waste liquid collection device 292. In some embodiments, as shown in Figure 6, the inkjet chip 230 further has a liquid suction port 238 connected to the drainage chamber 234. The residual reagent sucked into the drainage chamber 234 is discharged from the integrated slide 200 through the liquid suction port 238. It is understood that, in conjunction with Figure 1, the liquid suction port 238 can be connected to the waste liquid collection device 292 to further discharge the residual reagent into the waste liquid collection device 292.

[0107] It is understood that in other embodiments, the second driving structure may also be a vacuum negative pressure device (not shown), which is connected to the drainage chamber 234. Under the action of the vacuum negative pressure device, a negative pressure is formed in the drainage chamber 234, thereby absorbing the residual reagent in the biochemical reaction chamber 250. In addition, the vacuum negative pressure device may also be connected to the waste liquid collection device 292 to collect waste liquid.

[0108] Referring again to Figure 2 , the inkjet cavity layer 231 can be a multi-layer structure, comprising a substrate 2313, a resin layer 2314 stacked on the substrate 2313, and a nozzle plate 2315 stacked on the surface of the substrate 2313 facing away from the resin layer 2314. The surface of the resin layer 2314 facing away from the substrate 2313 constitutes a first surface 2311, and the surface of the nozzle plate 2315 facing away from the substrate 2313 constitutes a second surface 2312. It will be appreciated that the resin layer 2314 can be a single layer or multiple layers. The portion of the liquid adding chamber 233 corresponding to the resin layer 2314 constitutes a first through hole 2316, the portion of the liquid adding chamber 233 corresponding to the substrate 2313 constitutes a second through hole 2317, the portion of the liquid adding chamber 233 corresponding to the nozzle plate 2315 constitutes a liquid outlet 235, and the portion of the liquid drain chamber 234 corresponding to the nozzle plate 2315 constitutes a liquid drain outlet 236.

[0109] In some embodiments, along the extension direction a of the inkjet cavity layer 231, the inner diameters of the first through hole 2316, the second through hole 2317, and the liquid outlet 235 decrease in sequence, i.e., the liquid outlet 235 has the smallest diameter, which can better limit the outflow rate of the droplets and better control the volume of the droplets printed each time. In addition, the small diameter of the liquid outlet 235 can better maintain the reagent within the liquid addition chamber 233 under the action of negative pressure when liquid addition is not being performed. In addition, the relatively large inner diameter of the first through hole 2316 can accommodate a larger amount of reagent.

[0110] In some embodiments, the nozzle plate 2315 located at the periphery of the drainage port 236 protrudes toward the biochemical reaction chamber 250. The protrusion stretches the sidewall of the drainage port 236 along the thickness direction. The provision of the protrusion facilitates the flow of residual reagents in the biochemical reaction chamber 250 into the drainage chamber 234 during drainage.

[0111] In some embodiments, the substrate 2313 may be made of silicon, and the resin layer 2314 may be made of polyimide. A second through-hole 2317 with a smaller inner diameter may be formed on the substrate 2313, and a first through-hole 2316 with a larger inner diameter may be formed on the resin layer 2314 by chemical etching. Since the resin layer 2314 can be etched to form holes, compared to the silicon substrate 2313, the inner diameter of the first through-hole 2316 can be precisely controlled according to actual needs, thereby improving the accuracy of the volume control of the liquid addition chamber 233 and ensuring the accuracy of the reagent amount. In some embodiments, the volume of the liquid addition chamber 233 may be 9 pL to 50 pL. For example, the volume of the liquid addition chamber 233 may be 9 pL, 10 pL, 15 pL, 20 pL, 25 pL, 30 pL, 35 pL, 40 pL, 45 pL, or 50 pL, etc.

[0112] Referring to Figure 6 , the inkjet cavity layer 231 further defines at least one liquid inlet 239, which communicates with the liquid adding cavity 233. In some embodiments, the opening of the liquid inlet 239 may be located on the first surface 2311 of the inkjet cavity layer 231, or on a side surface of the inkjet cavity layer 231. In some embodiments, the liquid inlet 239 is formed on the resin layer 2314, with the opening of the liquid inlet 239 located on the first surface 2311.

[0113] Please refer to Figure 6 again, and in conjunction with Figure 1, the integrated slide 200 also includes a liquid storage structure 270 located on the inkjet chip 230. The liquid storage structure 270 includes at least one first liquid storage cavity 271, and each first liquid storage cavity 271 is connected to at least one liquid adding cavity 233. In addition, the biochemical substance analysis system 1000 also includes a reagent storage box 291. The first liquid storage cavity 271 is connected to the reagent storage box 291. The reagent in the reagent storage box 291 can flow into the first liquid storage cavity 271 by gravity and then further enter the liquid adding cavity 233 through the liquid inlet 239. In some embodiments, the first liquid storage cavity 271 is a sealed cavity. When liquid addition is not being performed, a negative pressure air circuit can be used to prevent the reagent in the first liquid storage cavity 271 and the liquid adding cavity 233 from leaking out of the liquid outlet 235.

[0114] The inkjet chip 230 further includes a sample chamber connected to the liquid adding chamber 233. The sample chamber is used to accommodate a sample to be tested. Specifically, the sample to be tested is driven by the first driving structure through the nozzle into the biochemical reaction chamber and is fixed by the array site. It is understood that when the liquid storage structure 270 has multiple first liquid storage chambers 271, one first liquid storage chamber 271 can be used as a sample chamber, and the other first liquid storage chambers 271 can be used as reagent storage chambers.

[0115] Refer to Figure 7, and refer to Figure 1 and Figure 2 together. The inkjet chip 230 includes a plurality of liquid-adding chambers 233 arranged side by side. Each liquid-adding chamber 233 is correspondingly provided with a first drive structure 232 and a plurality of liquid outlets 235. At this time, a first drive structure 232 can squeeze the reagent in the liquid-adding chamber 233 below the first drive structure 232 so that the reagent is ejected simultaneously from the plurality of liquid outlets 235. The plurality of first drive structures 232 can be electrically connected to an inkjet control circuit (not shown) to achieve independent control of the plurality of first drive structures 232 so as to achieve independent sample addition of the plurality of liquid-adding chambers 233. At this time, the reagent in the same liquid-adding chamber 233 is driven by the first drive structure 232, and the droplet volume discharged from the plurality of liquid outlets 235 is substantially the same. A reagent can be stored in each liquid-adding chamber 233, so that the simultaneous printing of multiple reagents can be achieved. The arrangement of the multiple liquid outlets 235 within each liquid addition chamber 233 can be designed based on the arrangement of the reaction sites on the biochip 210. For example, the multiple liquid outlets 235 within each liquid addition chamber 233 can be arranged in a straight line. It is understood that the multiple liquid outlets 235 within each liquid addition chamber 233 can also be arranged in an array. In this way, the liquid outlets 235 within the multiple liquid addition chambers 233 arranged side by side form a microwell array, and the number of liquid outlets 235 can be adjusted based on the number of site arrays in the biochip 210. To improve the efficiency of biochemical reactions and achieve a high throughput on the biochip 210, the density of the liquid outlets 235 of the inkjet chip 230 can be designed to be high, and the spacing between adjacent liquid outlets 235 can be set to be small, for example, approximately 40 microns, thereby achieving high-density printing. In some embodiments, the liquid storage structure 270 is divided into multiple independent first liquid storage chambers 271, each of which corresponds to a liquid addition chamber 233 and is connected via a liquid inlet 239.

[0116] It is understood that in other embodiments, as shown in FIG8 , the inkjet chip 230 includes a plurality of liquid addition chambers 233 arranged in an array, each liquid addition chamber 233 correspondingly provided with a first drive structure 232 and a liquid outlet 235, thereby achieving independent control of inkjet from each liquid outlet 235 and thereby precisely controlling the volume of droplets discharged from each liquid outlet 235. In this case, the liquid storage structure 270 is divided into a plurality of independent first liquid storage chambers 271, each first liquid storage chamber 271 corresponding to a row of liquid addition chambers 233, and the liquid addition chambers 233 in the same row are connected to the first liquid storage chamber 271 via a liquid inlet 239. Specifically, the reagents in the liquid addition chambers 233 in the same row are of the same type.

[0117] It can also be understood that in other embodiments, as shown in Figure 9, the inkjet chip 230 includes a plurality of liquid adding chambers 233 arranged in an array, each liquid adding chamber 233 corresponds to a first driving structure 232 and a liquid outlet 235, and at this time, the liquid storage structure 270 is divided into a plurality of independent first liquid storage chambers 271, each first liquid storage chamber 271 corresponds to a liquid adding chamber 233, and is connected through a liquid inlet hole 239, so that the type of reagent in each liquid adding chamber 233 and the volume of the sample droplet can be flexibly set.

[0118] Referring to Figures 6 to 9 , and in conjunction with Figure 1 , the liquid storage structure 270 further includes at least one second liquid storage chamber 272 in communication with the drainage chamber 234. The second liquid storage chamber 272 is used to store residual reagents. Specifically, residual reagents entering the drainage chamber 234 from the biochemical reaction chamber 250 can further enter the second liquid storage chamber 272, thereby buffering the residual reagents and ultimately enter the waste liquid collection device 292 from the second liquid storage chamber 272. In some embodiments, each of the drainage chambers 234 is provided with a corresponding second liquid storage chamber 272. Since various residual reagents can be treated as waste liquid, providing a second liquid storage chamber 272 facilitates the collection of residual reagents and further simplifies the structural complexity of the integrated slide 200.

[0119] Referring to Figure 10 , in conjunction with Figure 2 , a biochip 210 includes a biosensor layer and a sensor layer facing a biochemical reaction chamber 250. The biosensor layer includes array sites for securing a sample to be tested, and the sensor layer is configured to detect signals generated by the reaction between the sample to be tested and the reagent. Biochip 210 can be formed by integrating one or more biosensors 210a through a semiconductor packaging process, for example, a semiconductor wafer containing one or more front-side illuminated (FSI) image sensors. As shown in Figure 10 , for example, biochip 210 includes a biosensor 210a. The sensor layer primarily comprises: a semiconductor layer 211 having a light-sensing region A and a non-sensing region B; a light-sensing element 212 located in the light-sensing region A; at least one dielectric layer 213 disposed on a surface of the semiconductor layer 211; and a metal wiring layer 214 located within the dielectric layer 213. The biosensor layer 219 includes a passivation layer 215 and array sites 217 located on the surface of the dielectric layer 213 facing away from the semiconductor layer 211. The passivation layer 215 is formed with an opening 216 corresponding to the light sensing area A, the surface of the dielectric layer 213 is exposed by the opening 216, and the array site 217 is located in the opening 216. Along the stacking direction b, the vertical projection of the metal wiring layer 214 is located in the non-sensing area B, the metal wiring layer 214 is electrically connected to the light sensing component 212, and the metal wiring layer 215 can also be used for interconnection of integrated circuit materials and external electrical connections. Along the stacking direction b, the vertical projection of the array site 217 is located in the light sensing area A, and chemical or biological samples can be placed on the array site 217 for analysis. Generally, for DNA sequencing, the biological sample contains a DNA sequencing library, wherein the DNA sequencing library is mainly DNA nanoballs, referred to as DNBs, which are adsorbed on the array site 217 for biochemical reactions before gene sequencing. This semiconductor image sensor-based biochip 210 can be integrated during the packaging phase, supporting both the packaging of a single biosensor 210a and the arrayed packaging of multiple biosensors 210a, which together constitute a biochip 210, thereby enabling the preparation of larger biochips for ultra-high throughput detection. This biochip 210 can be used in non-excitation light imaging sequencing systems, such as direct light-sensing technology using semiconductor image sensors, as well as other sensing sequencing technologies such as capacitance, voltage, current, and ions, to achieve sensing of intermediate products of biochemical reactions and sensing of electrical signals generated by biochemical reactions. Furthermore, local biochemical reactions and local sequencing can be performed simultaneously on the biochip 210, making sequencing more flexible.

[0120] In some embodiments, the semiconductor layer 211 may be made of any suitable material, and the material of the semiconductor layer 211 may be silicon.

[0121] In some embodiments, the light sensing component 212 may be a photodiode or other usable photosensitive component. The photodiode may convert the measured light into a current. The photodiode may include a source and a drain of a MOS transistor (not shown), and the converted current may be transmitted to other components via the MOS transistor. The other components may include a reset transistor, a current source follower, or a row selector for converting the current into a digital signal.

[0122] In some embodiments, the dielectric layer 213 may be made of a transparent electrically insulating material, such as silicon dioxide.

[0123] In some embodiments, the material of the array sites 217 may be at least one of Ta2O5, TiO2, HfO2, etc. The array sites 217 may be used to suppress dark current in the light sensing component 212 such as a photodiode.

[0124] In some embodiments, the passivation layer 215 can be deposited on the surface of the dielectric layer 213 by conventional semiconductor processing technology (for example, low temperature plasma chemical vapor deposition, PECVD, sputtering, ALD, spin coating, dip coating, etc.), and then the passivation layer 215 can be patterned by an etching process to form an opening 216 corresponding to the light sensing area A. The passivation layer 215 can include any suitable protective material. For example, the passivation layer 215 can include dielectric materials such as silicon nitride and silicon oxide. The passivation layer 215 can be used to construct different reaction areas, has a reflective effect on light, and can improve the light collection efficiency. In some embodiments, as shown in the cross-sectional view of Figure 10, the cross-sectional shape of the opening 216 etched on the passivation layer 215 is roughly rectangular. It can be understood that the cross-sectional shape of the opening 216 can also be roughly V-shaped, circular, elliptical, etc. By controlling the shape and size of the opening 216, the efficiency of light collection can be improved.

[0125] In some embodiments, along the stacking direction b, the thickness of the passivation layer 215 is greater than the thickness of the array site 217 , so that different reaction areas can be constructed by the passivation layer 215 and biological samples or chemical samples can be confined within the opening 216 constructed by the passivation layer 215 .

[0126] In other embodiments, as shown in FIG11 , biosensor 210b may also be a semiconductor wafer comprising one or more backside-illuminated (BSI) image sensors. Unlike biosensor 210a described above, in biosensor 210b, both the passivation layer 215 and array sites 217 are located on the surface of semiconductor layer 211 facing away from dielectric layer 214. Passivation layer 215 has an opening 216 corresponding to the light-sensing region A, exposing the surface of semiconductor layer 211 through opening 216. Array sites 217 are located within opening 216. Compared to frontside-illuminated (FSI) image sensors, light-sensing elements 212 in backside-illuminated (BSI) image sensors are closer to array sites 217. This shortens the distance that fluorescence from a biological sample reacts to reach light-sensing elements 212, resulting in less light attenuation and loss.

[0127] In other embodiments, as shown in FIG12 , the biosensor 210 c may also be a semiconductor wafer comprising one or more backside-illuminated (BSI) image sensors. The difference from the aforementioned biosensor 210 b is that the dielectric layer 213 in the biosensor 210 c is multi-layered, each dielectric layer 213 is embedded with a metal wiring layer 214, and the multi-layer dielectric layer 213 is formed on a base layer 218, thereby enabling larger arrays and more functional biochemical reactions.

[0128] Referring again to Figure 2 , biochip 210 is encapsulated with inkjet chip 230 via encapsulation layer 220. Specifically, biochip 210 and inkjet chip 230 are integrated into a single slide 200 using semiconductor technology. This significantly reduces the size and cost of biochemical analysis equipment, while improving ease of use. In stacking technology, biochip 210 and inkjet chip 230 can be manufactured separately and then bonded together via encapsulation layer 220 in a 3D stacking device.

[0129] In some embodiments, the biochip 210 includes a reaction area C and a connection area D located at the periphery of the reaction area C. The encapsulation layer 220 is located in the connection area D. The connection area D of the biochip 210 is connected to the periphery of the inkjet chip 230 through the encapsulation layer 220, thereby constructing the reaction area C into a sealed biochemical reaction chamber 250 to provide a place for biochemical reactions.

[0130] As will be appreciated, as shown in FIG1 , the biochemical substance analysis system 1000 also includes a control platform 800 and necessary control circuits. The control circuits may include control circuits for controlling the operation of the integrated slide 200, such as inkjet control circuits and liquid discharge control circuits. They may also include control circuits for controlling the heating of the stage 100 and the adsorption of the integrated slide 200. The control platform 800 can be used to control the operation of various components of the biochemical substance analysis system 1000.

[0131] Referring to FIG. 13 , and in conjunction with FIG. 2 , FIG. 3 , and FIG. 5 , the method for performing biochemical substance analysis using the biochemical substance analysis system 1000 includes the following steps:

[0132] Step S11: Loading an integrated slide onto the stage. The integrated slide has a similar structure to the aforementioned integrated slide, including a biochip and an inkjet chip encapsulated above the biochip. The biochip is similar in structure to the aforementioned biochip, except that the samples to be detected, including but not limited to at least one of a nucleic acid sequencing library and tissue proteins, are fixed to the array sites of the biosensor layer of the biochip.

[0133] Step S12: adding reagents required for biochemical reactions into the biochemical reaction chamber via the inkjet chip, and the reagents are attached to the array sites. The biochemical reactions include but are not limited to nucleic acid sequencing reactions, specific binding reactions, etc.

[0134] Step S13: heating the carrier to make the reagent in the biochemical reaction chamber react with the sample to be detected, and identifying the signal generated by the reaction between the sample to be detected and the reagent through the sensor layer. The signal may be an optical signal.

[0135] Step S14: Expelling the reacted residual reagents in the biochemical reaction chamber through the inkjet chip.

[0136] Step S12 and step S13 may be cycled multiple times to load different reaction reagents into the biochip, thereby completing the biochemical reaction.

[0137] The specific process of gene sequencing using the above method is given below.

[0138] In the first step, the sample to be tested, such as DNB containing a DNA sequencing library, is loaded into the integrated slide 200, and the DNB is adsorbed on the reaction area of ​​the biochip 210. It is understood that the integrated biochip 200 can realize automatic loading of the sample to be tested.

[0139] In the second step, the integrated carrier 200 loaded with the sample to be tested is placed on the carrier 100, and the integrated carrier 200 is adsorbed by negative pressure. At the same time, the reagent storage box 291 is connected to the first liquid storage chamber 271 of the inkjet chip 230. Under the action of gravity, the reagent stored in the reagent storage box 291 flows into the first liquid storage chamber 271 and further enters the liquid adding chamber 233.

[0140] In the third step, by controlling the first drive structure 232, the first deformable layer 2321 is deformed to squeeze the reagents within the liquid-adding chambers 233, thereby printing the reagents onto the corresponding reaction areas within the biochemical reaction chamber 250. The control circuit can independently control the type of reagent, droplet size, and inkjet frequency extruded from each liquid-adding chamber 233. Inkjet printing allows for high printing frequencies (typically greater than 10 Hz) and small droplets (typically between 9 and 50 pL), effectively improving printing efficiency and achieving a more uniform liquid film thickness. This reduces reagent loss and lowers costs.

[0141] The fourth step is to control the heating of the carrier 100 to heat the integrated carrier 200 to a target temperature, so that the sample to be detected in the biochemical reaction chamber 250 reacts with the reagent in the first step.

[0142] In the fifth step, negative pressure is formed in the drainage chamber 234 by controlling the second driving structure 237 , so that the residual reagents after the first step reaction in the biochemical reaction chamber 250 are discharged into the drainage chamber 234 , and the integrated slide 200 is further discharged.

[0143] Step 6: Repeat steps 3 to 5 until the biochemical reaction is completed.

[0144] In the seventh step, the image sensor in the biochip 210 can sense the fluorescence emitted by the sample to be detected that has completed the reaction in real time, and perform signal recognition to complete the sequencing.

[0145] The biochemical substance analysis system 1000 provided in the embodiment of the present application integrates an inkjet chip (for example, inkjet chip 230) and a biochip (for example, biochip 210) into an integrated structure using semiconductor packaging technology. The slide adding / exchanging liquid, biochemical reactions, and signal acquisition are integrated on the same integrated slide, which effectively simplifies the structure of the biochemical substance analysis system 1000 and the complexity of the liquid circuit system, reduces the volume of the overall biochemical substance analysis system 1000, makes the system more compact, easy to assemble, easy to use, and can achieve ultra-high throughput detection, reducing equipment cost and detection cost; moreover, the integrated integrated slide is disposable as a whole, and there is no need to be equipped with a load cleaning device, which further simplifies the complexity of the system; in addition, the use of inkjet chip for adding / exchanging liquid has high inkjet efficiency, small droplet volume, thin liquid film thickness and higher uniformity, which can reduce reagent loss and reduce detection cost.

[0146] Referring to Figures 14 to 17, an embodiment of the present application provides another biochemical substance analysis system 2000, which includes: a biochemical reaction device 300, a carrier 100, and a liquid exchange device 400. The biochemical reaction device 300 and the carrier 100 are covered to form a reaction chamber 10, and the liquid exchange device 400 can be slidably arranged in the reaction chamber 10 and is spaced apart from the carrier 100. The side of the carrier 100 close to the liquid exchange device 400 carries a biochip 700, which is an open slide that fixes the sample to be tested. The liquid exchange device 400 is configured to inkjet print a reagent layer of a preset thickness on the biochip 700. Among them, the biochemical reaction device 300 can heat the reaction chamber 10, and the temperature in the reaction chamber 10 can be adjusted according to the biochemical reaction between the sample to be tested and the reagent layer, thereby heating the biochip 700 so that the sample to be tested in the biochip 700 reacts with the reagent layer. Specifically, the liquid replacement device 400 can be slidably disposed on the top of the biochemical reaction device 300 to add liquid to the biochip 700 .

[0147] Please refer to FIG. 14 again. The biochemical substance analysis system 2000 further includes a main structure platform (not shown), wherein the main structure platform is used to arrange the carrier 100, the biochemical reaction device 300, the liquid replacement device 400, and the transfer device 600.

[0148] Referring again to Figures 14 to 17 , the carrier 100 can be provided with multiple chip positions, each of which is used to accommodate and secure a corresponding biochip 700. Specifically, the carrier 100 includes a carrier 110 and a chip holder 120 located on the carrier 110, with the biochip 700 located on the chip holder 120. Depending on the actual detection throughput requirements, one or more biochips 700 can be loaded onto the chip holder 120. Specifically, the chip holder 120 can be provided with at least one chip position for securing a biochip 700.

[0149] In some embodiments, as shown in FIG17 , there are three chip positions on the chip holder 120 , which can be loaded with three biochips 700 , and the three biochips 700 are arranged in sequence along the moving direction of the liquid replacement device 400 , so that the liquid replacement device 400 can pass over the three biochips 700 in sequence to add or remove liquid for each biochip 700 .

[0150] In some embodiments, as shown in FIG. 17 , the chip holder 120 is further provided with an overflow groove 130 . During the liquid addition process of the biochip 700 , the overflow groove 130 can collect overflowed reagents.

[0151] Referring to Figures 15 to 17 , the biochemical reaction device 300 includes a heating cover 310. The heating cover 310 includes a top wall 311 and side walls 312 disposed around the periphery of the top wall 311. An opening 313 is formed at one end of the side wall 312 facing away from the top wall 311. The carrier 100 is configured to cooperate with the heating cover 310 to seal the opening 313 to form a reaction chamber 10. The heating cover 310 can heat the reaction chamber 10. For example, both the top wall 311 and the side walls 312 can be provided with heating structures. The heating cover 310 and the carrier 100 together form the reaction chamber 10, which can provide insulation and slow down the evaporation of reagents during the addition and reaction processes.

[0152] In some embodiments, the top wall 311 includes a water storage cavity 314. The portion of the water storage cavity 314 near the reaction chamber 10 is provided with an ultrasonic element 315. The ultrasonic element 315 is used to atomize the water in the water storage cavity 314 and conduct the atomized water vapor to the reaction chamber 10. By embedding the ultrasonic element 315, such as a piezoelectric atomization membrane, in the lower portion of the water storage cavity 314 of the top wall 311, the pure water in the water storage cavity 314 can be atomized. The atomized water vapor can penetrate the piezoelectric atomization membrane and further enter the reaction chamber 10, thereby reducing the evaporation rate of the reagent during the inkjet process.

[0153] In some embodiments, the sidewall 312 has a vent 316 , and the reaction chamber 10 is connected to the outside through the vent 316 . The vent 316 is provided to allow the atomized water vapor to be discharged from the reaction chamber 10 through air flow.

[0154] Please refer to Figure 18, and refer to Figure 14 and Figure 15 in combination. The liquid replacement device 400 includes a liquid adding component 410. Among them, the liquid adding component 410 can print the reagents used for the biochemical reaction onto the biochip 700 to form a reagent layer of predetermined thickness. In addition, the liquid replacement device 400 is also configured to remove the residual reagents after the reaction on the surface of the biochip 700, that is, the liquid replacement device 400 also includes a liquid removal component 420 that can remove the residual reagents of the completed reaction on the biochip 700. Usually after one reagent reaction is completed, it is necessary to replace another reagent. At this time, it is necessary to use the liquid removal component 420 to remove the residual reagents after the previous step of reaction, and then use the liquid addition component 410 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.

[0155] The liquid adding assembly 410 can use inkjet printing to spray reagents (typically liquid reagents) required for biochemical reactions onto the open biochip 700. The liquid adding assembly 410 includes an inkjet chip 430, a reagent storage box 440 connected to the inkjet chip 430, and an inkjet control circuit 450. The inkjet control circuit 450 is electrically connected to the inkjet chip 430 to control the inkjet chip 430 to spray the reagent sample onto the biochip 700.

[0156] Referring to Figures 18 and 19 , and in conjunction with Figure 14 , the inkjet chip 430 includes a stacked inkjet chamber layer 431 and a drive structure 432. The inkjet chamber layer 431 includes a first surface 4311 and a second surface 4312 disposed opposite each other. The drive structure 432 is located on the first surface 4311 and is electrically connected to the inkjet control circuit 450. At least one liquid addition chamber 435 is formed through the first and second surfaces 4311 and 4312 of the inkjet chamber layer 431. The liquid addition chamber 435 defines at least one liquid outlet 436 on the second surface 4312. The liquid addition chamber 435 is used to hold reagents required for biochemical reactions. A negative pressure gas line (not shown) can be added to communicate with the liquid addition chamber 435 to maintain a certain negative pressure within the liquid addition chamber 435, thereby retaining the reagents within the chamber. The drive structure 432 is located on the surface of the inkjet cavity layer 431 and covers the opening between the liquid addition cavity 435 and the liquid outlet 436. Under the control of the inkjet control circuit 450, the drive structure 432 can deform, squeezing the reagent in the liquid addition cavity 435, causing it to be discharged through the liquid outlet 436 and then printed onto the biochip 700. Using inkjet printing to add liquid allows for precise control of liquid film thickness, significantly reducing reagent loss, and further lowering testing costs.

[0157] In some embodiments, along the extension direction a of the inkjet chip 430, the inner diameter of the liquid outlet 436 is smaller than the minimum inner diameter of the liquid adding chamber 435. That is, the liquid outlet 436 has a minimum diameter, which can better limit the outflow rate of the droplets and better control the volume of the droplets printed each time. Furthermore, the smaller diameter of the liquid outlet 436 can better maintain the sample within the liquid adding chamber 435 under the action of negative pressure when the sample is not being added.

[0158] The inkjet cavity layer 431 can be a multi-layer structure, comprising a substrate 4313, a resin layer 4314 stacked on the substrate 4313, and a nozzle plate 4315 stacked on the surface of the substrate 4313 facing away from the resin layer 4314. The surface of the resin layer 4314 facing away from the substrate 4313 constitutes a first surface 4311, and the surface of the nozzle plate 4315 facing away from the substrate 4313 constitutes a second surface 4312. It is understood that the resin layer 4314 can be a single layer or multiple layers. The portion of the liquid adding chamber 435 corresponding to the resin layer 4314 constitutes a first through-hole 4316, the portion of the liquid adding chamber 435 corresponding to the substrate 4313 constitutes a second through-hole 4317, and the portion of the liquid adding chamber 435 corresponding to the nozzle plate 4315 constitutes a liquid outlet 436. In some embodiments, the inner diameters of the first through-hole 4316, the second through-hole 4317, and the liquid outlet 436 decrease in sequence. Here, the inner diameter of the liquid outlet 436 is designed to be the smallest. When sample addition is not required, the reagent in the liquid adding chamber 435 will not flow out of the liquid outlet 436 due to its own gravity under the action of surface tension at the small-diameter liquid outlet 436, and will remain in the liquid adding chamber 435. The inner diameter of the first through hole 4316 is designed to be relatively large so that it can carry more reagents.

[0159] In some embodiments, the material of substrate 4313 can be silicon, and the material of resin layer 4314 can be polyimide. A second through-hole 4317 with a smaller inner diameter can be formed on substrate 4313, and a first through-hole 4316 with a larger inner diameter can be formed on resin layer 4314 by chemical etching. Because the resin layer 4314 can be etched to form holes, which is easier to form holes than the silicon substrate 4313, the inner diameter of first through-hole 4316 can be precisely controlled according to actual needs, thereby improving the accuracy of volume control of liquid addition chamber 435 and ensuring the accuracy of reagent dosage. In some embodiments, the volume of liquid addition chamber 435 can be 9pL to 50pL. For example, the volume of liquid addition chamber 435 can be 9pL, 10pL, 15pL, 20pL, 25pL, 30pL, 35pL, 40pL, 45pL, or 50pL, etc.

[0160] The inkjet cavity layer 431 also has at least one liquid inlet 437, which communicates with the liquid adding cavity 435 and the reagent storage box 440, allowing the reagent in the reagent storage box 440 to be added to the liquid adding cavity 435 via the liquid inlet 437. In some embodiments, the opening of the liquid inlet 437 can be located on the first surface 4311 of the inkjet cavity layer 431 or on a side surface of the inkjet cavity layer 431. In some embodiments, as shown in FIG7 , the liquid inlet 437 is provided in the resin layer 4314, with the opening located on the first surface 4311.

[0161] Please refer again to Figures 18 and 19, and in conjunction with Figure 14, the liquid adding assembly 410 also includes a liquid storage structure 470 located on the inkjet chip 430. The liquid storage structure 470 includes at least one liquid storage cavity 471. Each liquid storage cavity 471 is connected to at least one liquid adding cavity 435. The liquid storage cavity 471 is connected to the reagent storage box 440. The reagent in the reagent storage box 440 can flow into the liquid storage cavity 471 by gravity and then further enter the liquid adding cavity 435 through the liquid inlet 437. In some embodiments, the liquid storage cavity 471 is a sealed cavity, and a negative pressure air circuit can be used to prevent the reagent in the liquid storage cavity 471 and the liquid adding cavity 435 from leaking out of the liquid outlet 436.

[0162] Please refer to Figure 20, and refer to Figures 14, 18 and 19 in combination. The inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged side by side, and each liquid adding chamber 435 is provided with a drive structure 432 and a plurality of liquid outlets 436. The plurality of drive structures 432 can be electrically connected to an inkjet control circuit (not shown) to achieve independent control of the plurality of drive structures 432 to achieve independent sample addition of the plurality of liquid adding chambers 435. At this time, the reagents in the same liquid adding chamber 435 are driven by the drive structure 432, and the droplet volumes discharged from the plurality of liquid outlets 436 are substantially the same. One reagent can be stored in each liquid adding chamber 435, so that simultaneous printing of multiple reagents can be achieved. The arrangement of the multiple liquid outlets 436 within each liquid addition chamber 435 can be designed based on the arrangement of the reaction sites on the biochip 700. For example, the multiple liquid outlets 436 within each liquid addition chamber 435 can be arranged in a straight line. It is understood that the multiple liquid outlets 436 within each liquid addition chamber 435 can also be arranged in an array. In this way, the liquid outlets 436 within the multiple liquid addition chambers 435 arranged side by side form a microwell array, and the number of liquid outlets 436 can be adjusted based on the number of site arrays on the biochip 210. To improve the effectiveness of biochemical reactions, the biochip 700 has a higher throughput. In this case, the density of the liquid outlets 436 of the inkjet chip 430 can be designed to be higher. For example, the spacing between adjacent liquid outlets 436 can be approximately 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 of which corresponds to a liquid addition chamber 435 and is connected through a liquid inlet 437.

[0163] It is understood that in other embodiments, as shown in FIG21 , the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged in an array, each liquid adding chamber 435 correspondingly provided with a drive structure 432 and a liquid outlet 436, thereby achieving independent control of each liquid outlet 436, and further precisely controlling the volume of droplets discharged from each liquid outlet 436. In this case, the liquid storage structure 470 is divided into a plurality of independent liquid storage chambers 471, each liquid storage chamber 471 corresponding to a row of liquid adding chambers 435, and the liquid adding chambers 435 in the same row are connected to the liquid storage chamber 471 via a liquid inlet 437. Specifically, the reagents in the liquid adding chambers 435 in the same row are of the same type.

[0164] It can also be understood that in other embodiments, as shown in Figure 22, the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged in an array, each liquid adding chamber 435 corresponds to a driving structure 432 and a liquid outlet 436, and at this time, the liquid storage structure 470 is divided into a plurality of independent liquid storage chambers 471, each liquid storage chamber 471 corresponds to a liquid adding chamber 435, and is connected through a liquid inlet hole 437, so that the type of reagent in each liquid adding chamber 435 and the volume of the sample droplet can be flexibly set.

[0165] Referring to Figures 23 and 24 , and in conjunction with Figures 14 and 15 , as previously described, the drive structure 432 can also utilize piezoelectric inkjet printing technology to achieve printing of the reagent within the liquid addition chamber 435 onto the biochip 700. In some embodiments, the drive structure 432 can include a deformable layer 4321 and an electrode layer 4322 positioned on the deformable layer 4321. As shown in Figure 24 , the inkjet chip 430 operates by applying a voltage to the deformable layer 4321 via the electrode layer 4322. Since the deformable layer 4321 can be made of piezoelectric ceramic, the deformable layer 4321 undergoes instantaneous deformation under the influence of the voltage. This instantaneous deformation squeezes the reagent within the liquid addition chamber 435 and ejects the reagent at high pressure from the liquid outlet 436 to form droplets, which are then printed onto corresponding locations on the biochip 700. By utilizing micro-piezoelectric technology to achieve reagent printing, the volume of the printed reagent droplets can be precisely controlled, thereby reducing reagent loss.

[0166] In other embodiments, as shown in FIG25 , the driving structure 432 can also use thermal bubble inkjet printing technology to achieve liquid spraying. The driving structure 432 can also include a heater. When the heater is powered on, it will generate heat to heat the reagent in the liquid adding chamber 435, thereby generating bubbles. The bubbles squeeze out the reagent droplets from the liquid outlet 436 to achieve the purpose of printing.

[0167] 14 again, the reagent storage box 440 can be connected to the liquid storage structure 470 on the inkjet chip 430 through a set of liquid connectors. It is understood that the storage location of the reagent storage box 440 can be optionally equipped with a refrigeration module to maintain the required environment for storing biochemical reaction reagents.

[0168] The inkjet control circuit 450 is mainly used to control the movement position, reagent type and reagent amount of the inkjet chip 430. It is electrically connected to each driving structure 432 and can realize independent control of each liquid outlet 436 or each discharge liquid outlet 436 of the inkjet chip 430.

[0169] In some embodiments, the printing frequency of the inkjet chip 430 may be greater than or equal to 10 kHz. A high printing frequency and good printing uniformity can improve the sample loading efficiency of the biochip 700 and the uniformity of the liquid film thickness.

[0170] Referring again to Figures 14 and 15 , the liquid removal assembly 420 uses airflow to remove residual reacted reagents from the biochip 700. Liquid existing on the biochip 700 can be directly removed by blowing air or aspirating liquid. The liquid removal assembly 420 includes an air knife 421 and an air supply structure 422. The air knife 421 is connected to the air supply structure 422, which can provide compressed air or negative pressure to form an airflow, thereby blowing or aspirating liquid away from the surface of the biochip 700. Liquid removal using air blowing or aspirating liquid is simple and convenient, and when used with the inkjet chip 430, liquid replacement can be simple and rapid.

[0171] In some embodiments, the gas supply structure 422 can be a gas compressor capable of providing compressed gas, such as compressed air or compressed nitrogen. The compressed gas enters the air knife 421 through the air path. The air knife 421 confines the blown gas to the surface of the biochip 700, thereby removing the liquid on the surface of the biochip 700. The air knife is used to blow or suck air to form the airflow. In some embodiments, the temperature on the biochip 700 is maintained at a low temperature, for example, 10°C to 15°C, during the blowing process.

[0172] 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.

[0173] Please refer to Figures 15 and 16 again, and in conjunction with Figure 14, the liquid replacement device 400 also includes a linkage structure 460. The linkage structure 460 is arranged on the inner wall of the biochemical reaction device 300. Specifically, the linkage structure 460 is arranged on the top wall 311 of the heating cover 310. 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, thereby improving the liquid replacement efficiency. In some embodiments, the linkage structure 460 can include a linkage shaft 461 and a drive motor 462 slidably arranged on the linkage shaft 461. The inkjet chip 430 and the air knife 421 of the liquid removing component 420 are slidably arranged on the drive motor 462 of the linkage structure 460, wherein the inkjet chip 430 and the air knife 421 are arranged side by side along the extension direction of the linkage shaft 461, and the air knife 421 is located at the front end in the direction of travel, so as to achieve the purpose of removing liquid first and then adding liquid.

[0174] The biochip 700 used in the biochemical substance analysis system 2000 can be a biochip that integrates one or more biosensors. Specifically, the biochip 700 includes a biosensor layer facing the liquid exchange device 400 and a sensor layer stacked on the side of the biosensor layer close to the carrier 100. The biosensor layer includes an array site for fixing the sample to be detected, and the sensor layer is configured to identify the signal generated after the sample to be detected reacts with the reagent. After the biochemical reaction is completed, the fluorescent signal of the reacted sample can be directly collected through the sensor layer, and the signal analysis is performed to complete the detection process. Specifically, the biosensor can adopt the structure of the aforementioned biosensor 210a (210b or 210c). For the specific structure, please refer to the above and we will not go into details here.

[0175] Referring again to FIG. 14 , the biochemical substance analysis system 2000 further includes a transfer device 600, on which the carrier 100 is located. The transfer device 600 is used to move the carrier 100 to or from the biochemical reaction apparatus 300 to facilitate loading of the biochip 700 and to secure the carrier 100 to the heating cover 310 of the biochemical reaction apparatus 300. It will be appreciated that the heating cover 310 of the biochemical reaction apparatus 300 can also be controlled to move so as to secure the carrier 100 to the heating cover 310. Alternatively, the carrier 100 can be first moved below the heating cover 310 by the transfer device 600, and then the heating cover 310 can be controlled to move to secure the carrier 100 to the heating cover 310.

[0176] Please refer to FIG. 14 again. The biochemical substance analysis system 2000 further includes a control platform 800 for controlling the coordinated operation of the transfer device 600, the carrier 100, the biochemical reaction device 300, the liquid replacement device 400, and the biochip 700.

[0177] Referring to FIG. 26 , a method for performing biochemical substance analysis using the aforementioned biochemical substance analysis system 2000 specifically includes the following steps:

[0178] In step S21 , a biochip 700 is loaded onto the carrier 100 . The biochip 700 includes a biosensing layer, and samples to be detected are fixed on array sites of the biosensing layer.

[0179] In step S22 , the biochemical reaction device 300 and the carrier 100 are covered to form a reaction chamber 10 , and the biochip 700 is located in the reaction chamber 10 .

[0180] In step S23 , a reagent layer of a preset thickness is inkjet printed onto the array sites of the biochip 700 by the liquid replacement device 400 .

[0181] In step S24 , the biochip 700 is heated by the biochemical reaction device 300 and the carrier 100 so that the sample to be detected in the biochip 700 reacts with the reagent layer.

[0182] The biochip 700 further includes a sensor layer stacked on a side of the biosensing layer close to the carrier 100. After the sample to be detected in the biochip 700 reacts with the reagent layer, the method further includes:

[0183] Step S25 , identifying the signal generated by the reaction between the sample to be detected and the reagent layer through the sensor layer and performing in-situ signal detection and analysis.

[0184] Step S23 and step S24 may be cycled multiple times to achieve the loading of different reagents on the biochip 700 and different biochemical reaction processes until the biochemical reaction is completed.

[0185] As shown in FIG27 , in combination with FIG14 , FIG15 and FIG19 , the specific process of gene sequencing using the above method is given.

[0186] In the first step, a sample to be detected, 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 .

[0187] In the second step, the biochip 700 loaded with the sample to be tested is placed on the carrier 100, and the biochip 700 is adsorbed by negative pressure. At the same time, the reagent storage box 440 is connected to the liquid storage chamber 471 of the inkjet chip 430. Under the action of gravity, the reagent stored in the reagent storage box 440 flows into the liquid storage chamber 471 and further enters the liquid adding chamber 435.

[0188] After loading the biochip 700 , the temperature of the biochip 700 may be adjusted to about 15° C.

[0189] In the third step, the carrier 100 is moved to the bottom of the biochemical reaction device 300 by the transfer device 600, and the heating cover 310 is controlled to cover the carrier 100 to enclose the reaction chamber 10. At the same time, the heating cover 310 is started to heat to the target temperature.

[0190] In the fourth step, the atomization on the heating cover 310 is started, and air is introduced into the reaction chamber 10. At the same time, the inkjet chip 430 and the air knife 421 are moved to the top of the biochip 700 by controlling the linkage structure 460, and the driving structure 432 is controlled to deform the deformation layer 4321 to squeeze the reagent in the liquid adding chamber 435, and then print the reagent onto the corresponding reaction area of ​​the biochip 700.

[0191] The inkjet control circuit 450 can independently control the type of reagent squeezed out of each liquid adding chamber 435, the size of the reagent droplets, the inkjet frequency, etc., and the liquid is added by inkjet printing, the printing frequency is high (usually greater than 10Hz), and the printed droplets are small (usually between 9pL and 50pL), which can effectively improve the printing efficiency and make the thickness of the liquid film more uniform, while reducing the loss of reagents and reducing costs.

[0192] The fifth step is to control the stage 100 to heat up and heat the biochip 700 to the target temperature, so that the sample to be detected in the biochip 700 reacts with the reagent in the first step.

[0193] In the sixth step, the residual reagents on the biochip 700 that have completed the reaction are blown into the overflow tank 130 of the carrier 100 by controlling the liquid removal component 420 to blow air, and the residual reagents are further collected.

[0194] Step 7: Repeat steps 4 to 6 until the biochemical reaction is completed.

[0195] In the eighth step, the residual reagents on the biochip 700 that have completed the reaction are blown into the overflow tank 130 of the carrier 100 by controlling the liquid removal component 420 to blow air, and the inkjet chip 430 is turned on to replace the imaging reagents for the biochip 700.

[0196] In the ninth step, the image sensor in the biochip 700 can sense the fluorescence emitted by the sample after the reaction is completed in real time, and perform in situ signal detection and analysis to complete the sequencing.

[0197] The biochemical substance analysis system 2000 provided in the embodiment of the present application has the following beneficial effects:

[0198] (1) By integrating the biochemical reaction device 300, the liquid exchange device 400, and the transfer device 600 into a single system, and simultaneously cooperating with the biochip 700 having in-situ imaging detection capabilities, the integrated operations of sample addition, biochemical substance analysis, and imaging detection can be achieved. This simplifies the system structure, improves detection efficiency, enables ultra-high throughput detection, and reduces equipment and detection costs. Furthermore, the overall size of the biochemical substance analysis system 2000 is reduced, making the system more compact, easier to assemble, and easier to use.

[0199] (2) The liquid replacement device 400 is integrated into the system, which simplifies the complexity of the liquid circuit system for adding reagents, reduces the structural complexity of the overall system, is easy to assemble and operate, and reduces the overall detection cost. In addition, the liquid replacement device 400 uses inkjet printing to achieve liquid addition, with a high printing frequency and small printed droplets. It can also accurately control the thickness of the liquid film, improve the uniformity of the liquid film thickness, and significantly reduce reagent loss (compared to the current conventional detection methods, the amount of reagent loss can be reduced by approximately 50% to 80%), thereby further reducing the detection cost. In addition, the liquid replacement device 400 uses blowing or suction to achieve liquid removal, which is simple and convenient. In conjunction with the inkjet chip 430, the liquid replacement process can be simple and fast.

[0200] (3) By covering the heating cover 310 with the carrier 100 to form the reaction chamber 10, and arranging an ultrasonic element 315 capable of generating high-temperature mist on the heating cover 310, a stable reaction atmosphere can be constructed and the evaporation rate of the reagent during the inkjet printing process can be slowed down.

[0201] (4) Multiple biochips 700 can be loaded on the carrier 100, and the liquid adding and liquid changing processes can be completed in sequence through the liquid changing device 400, which is easy to operate and helps to improve the detection throughput.

[0202] (5) An overflow trough 130 is provided on the carrier 100 to facilitate the collection of waste liquid during the liquid removal process.

[0203] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application and are not intended to limit the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application.

Claims

1. An integrated carrier, characterized in that: include: A biochip and an inkjet chip packaged above the biochip, wherein a biochemical reaction chamber is enclosed between the biochip and the inkjet chip; wherein, The inkjet chip is connected to the biochemical reaction chamber through a nozzle hole; the inkjet chip is used to add reagents required for biochemical reaction into the biochemical reaction chamber through the nozzle hole, or to discharge the residual reagents that have reacted in the biochemical reaction chamber through the nozzle hole; The biochip comprises a biosensing layer and a sensor layer facing the biochemical reaction chamber, the biosensing layer comprises array sites for fixing samples to be detected, and the sensor layer is configured to identify signals generated after the samples to be detected react with the reagents.

2. The integrated carrier according to claim 1, characterized in that: The inkjet chip comprises: The inkjet cavity layer comprises a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity and at least one liquid discharging cavity are formed through the first surface and the second surface, the nozzle hole is divided into a liquid outlet and a liquid discharging port, the liquid adding cavity is connected with the biochemical reaction chamber through the liquid outlet, and the liquid discharging cavity is connected with the biochemical reaction chamber through the liquid discharging port; The first driving structure is stacked on the first surface and covers the liquid adding cavity. The first driving structure is used to drive the liquid in the liquid adding cavity to enter the biochemical reaction cavity through the liquid outlet.

3. The integrated carrier according to claim 2, characterized in that: The inkjet chip further comprises a sample chamber connected to the liquid adding chamber, wherein the sample chamber is used to contain the sample to be detected. The sample to be detected is driven by the first driving structure to enter the biochemical reaction chamber through the nozzle and is fixed by the array site.

4. The integrated carrier according to claim 2 or 3, characterized in that: The first driving structure includes a first deformable layer located on the first surface, and a first electrode layer located on the first deformable layer, wherein the first deformable layer is used to deform under the control of the first electrode layer to squeeze the reagent located in the liquid adding chamber, so that the reagent enters the biochemical reaction chamber through the liquid outlet; Alternatively, the first driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent so that the reagent enters the biochemical reaction chamber through the liquid outlet.

5. The integrated carrier according to claim 2, characterized in that: The inkjet chip also includes: The second driving structure is stacked on the first surface and covers the drainage cavity. The second driving structure is used to form a negative pressure in the drainage cavity to discharge the residual reagent in the biochemical reaction cavity into the drainage cavity.

6. The integrated carrier according to claim 5, characterized in that: The second driving structure includes a second deformable layer located on the first surface, and a second electrode layer located on the second deformable layer. The second deformable layer is used to deform under the control of the second electrode layer to form a negative pressure in the drainage cavity, thereby allowing the residual reagent in the biochemical reaction cavity to enter the drainage cavity.

7. The integrated carrier according to claim 5, characterized in that: The liquid discharge cavity further has a liquid suction port located on the first surface, and the second driving structure is a vacuum negative pressure device, which is connected to the liquid discharge cavity through the liquid suction port.

8. The integrated carrier according to claim 5, characterized in that: The integrated carrier sheet further comprises a liquid storage structure stacked on the inkjet chip, wherein the liquid storage structure comprises at least one first liquid storage cavity connected to the liquid adding cavity, and the first liquid storage cavity is used to store the reagent.

9. The integrated carrier according to claim 8, characterized in that: The inkjet chip comprises a plurality of the liquid adding chambers, each of the liquid adding chambers is correspondingly provided with a first driving structure and at least one liquid outlet, and a first liquid storage chamber is provided above each of the liquid adding chambers; Alternatively, the inkjet chip includes a plurality of the liquid adding chambers arranged in an array, each of the liquid adding chambers is correspondingly provided with a first driving structure and a liquid outlet, and a first liquid storage chamber is provided above the liquid adding chambers in the same row.

10. The integrated carrier according to claim 8, characterized in that: The liquid storage structure further comprises at least one second liquid storage cavity communicated with the liquid drainage cavity, and the second liquid storage cavity is used for storing the residual reagent.

11. The integrated carrier according to claim 2, characterized in that: The volume of the liquid adding chamber is 9pL to 50pL.

12. The integrated carrier according to claim 1, characterized in that: The sensor layer comprises: A semiconductor layer having a light sensing region and a non-sensing region; A light sensing component, located in the light sensing area; At least one dielectric layer is stacked on a surface of the semiconductor layer; A metal wiring layer, located in the dielectric layer, and along the stacking direction, a vertical projection of the metal wiring layer is located in the non-sensing area, and the metal wiring layer is electrically connected to the light sensing component; The biosensing layer includes: a passivation layer located on the surface of the dielectric layer facing away from the semiconductor layer, or located on the surface of the semiconductor layer facing away from the dielectric layer, the passivation layer has an opening corresponding to the light sensing area; and the functionalized array site located in the opening.

13. The integrated carrier according to claim 12, characterized in that: Along the stacking direction, the thickness of the passivation layer is greater than the thickness of the array site.

14. The integrated carrier according to claim 13, characterized in that: The inkjet chip and the biochip are bonded together via a packaging layer.

15. A biochemical substance analysis system, characterized in that: include: A carrier and at least one integrated carrier located on the carrier, wherein the integrated carrier comprises a biochip and an inkjet chip packaged above the biochip, and a biochemical reaction chamber is enclosed between the biochip and the inkjet chip; The inkjet chip is connected to the biochemical reaction chamber through a nozzle hole; the inkjet chip is used to add reagents required for biochemical reaction into the biochemical reaction chamber through the nozzle hole, or to discharge the residual reagents that have reacted in the biochemical reaction chamber through the nozzle hole; The biochip comprises a biosensing layer and a sensor layer facing the biochemical reaction chamber, the biosensing layer comprises array sites for fixing samples to be detected, and the sensor layer is configured to identify signals generated after the samples to be detected react with the reagents.

16. The biochemical substance analysis system according to claim 15, characterized in that: The inkjet chip comprises: The inkjet cavity layer comprises a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity and at least one liquid discharging cavity are formed through the first surface and the second surface, the nozzle hole is divided into a liquid outlet located on the second surface and connected to the liquid adding cavity, and a liquid discharging port located on the second surface and connected to the liquid discharging cavity, the liquid adding cavity is connected to the biochemical reaction cavity through the liquid outlet, and the liquid discharging cavity is connected to the biochemical reaction cavity through the liquid discharging port; The first driving structure is stacked on the first surface and covers the liquid adding cavity. The first driving structure is used to drive the liquid in the liquid adding cavity to enter the biochemical reaction cavity through the liquid outlet.

17. The biochemical substance analysis system according to claim 16, characterized in that: The inkjet cavity layer further comprises a sample cavity communicated with the liquid adding cavity, the sample cavity is used to contain the sample to be detected, the sample to be detected is driven by the first driving structure to enter the biochemical reaction cavity through the nozzle and is fixed by the array site.

18. The biochemical substance analysis system according to claim 15 or 16, characterized in that: The first driving structure includes a first deformable layer located on the first surface, and a first electrode layer located on the first deformable layer, wherein the first deformable layer is used to deform under the control of the first electrode layer to squeeze the reagent located in the liquid adding chamber, so that the reagent enters the biochemical reaction chamber through the liquid outlet; Alternatively, the first driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent so that the reagent enters the biochemical reaction chamber through the liquid outlet.

19. The biochemical substance analysis system according to claim 18, characterized in that: The inkjet chip also includes: The second driving structure is stacked on the first surface and covers the drainage cavity. The second driving structure is used to form a negative pressure in the drainage cavity to discharge the residual reagent in the biochemical reaction cavity into the drainage cavity.

20. The biochemical substance analysis system according to claim 19, characterized in that: The second driving structure includes a second deformable layer located on the first surface, and a second electrode layer located on the second deformable layer. The second deformable layer is used to deform under the control of the second electrode layer to form a negative pressure in the drainage cavity, thereby allowing the residual reagent in the biochemical reaction cavity to enter the drainage cavity.

21. The biochemical substance analysis system according to claim 19, characterized in that: The liquid discharge cavity further has a liquid suction port located on the first surface, and the second driving structure is a vacuum negative pressure device, which is connected to the liquid discharge cavity through the liquid suction port.

22. The biochemical substance analysis system according to claim 19, characterized in that: The integrated carrier also includes a liquid storage structure stacked on the inkjet chip, the liquid storage structure includes at least one first liquid storage chamber connected to the liquid adding chamber, and at least one second liquid storage chamber connected to the liquid discharging chamber, the first liquid storage chamber is used to store the reagent, and the second liquid storage chamber is used to store the residual reagent.

23. The biochemical substance analysis system according to claim 22, characterized in that: The inkjet chip comprises a plurality of the liquid adding chambers, each of the liquid adding chambers is correspondingly provided with a first driving structure and at least one liquid outlet, and a first liquid storage chamber is provided above each of the liquid adding chambers; Alternatively, the inkjet chip includes a plurality of the liquid adding chambers arranged in an array, each of the liquid adding chambers is correspondingly provided with a first driving structure and a liquid outlet, and a first liquid storage chamber is provided above the liquid adding chambers in the same row.

24. The biochemical substance analysis system according to claim 15, characterized in that: The biochemical substance analysis system also includes a reagent storage box connected to the inkjet chip.

25. A method for analyzing biochemical substances, characterized in that: include: An integrated carrier is loaded on the carrier, wherein the integrated carrier comprises a biochip and an inkjet chip packaged above the biochip, wherein a biochemical reaction chamber is enclosed between the biochip and the inkjet chip, wherein the inkjet chip is connected to the biochemical reaction chamber through a nozzle, wherein the biochip comprises a biosensing layer and a sensor layer facing the biochemical reaction chamber, wherein the biosensing layer comprises an array site for fixing a sample to be detected, and wherein the sensor layer is configured to identify a signal generated after the sample to be detected reacts; Adding reagents required for biochemical reaction into the biochemical reaction chamber through the inkjet chip, and the reagents are attached to the array sites; Heating the carrier to make the reagent in the biochemical reaction chamber react with the sample to be detected, and identifying the signal generated by the reaction between the sample to be detected and the reagent through the sensor layer; as well as The reacted residual reagent in the biochemical reaction chamber is discharged through the inkjet chip.

26. A liquid replacement device, characterized in that: include: A liquid adding component, wherein the liquid adding component includes an inkjet chip, and the inkjet chip is used for printing by inkjet. loading reagents on a biochip, wherein the biochip is an open semiconductor biochip; as well as The liquid removal component is used to remove residual reagents after the reaction on the biochip is completed.

27. The fluid replacement device according to claim 26, characterized in that: The inkjet chip comprises: An inkjet cavity layer, comprising a first surface and a second surface arranged opposite to each other, at least one liquid adding cavity is formed through the first surface and the second surface, the liquid adding cavity is used to accommodate the reagent, and the liquid adding cavity has at least one liquid outlet located on the second surface; A driving structure is stacked on the first surface and covers the liquid adding cavity, and the driving structure is used to drive the reagent located in the liquid adding cavity to be discharged from the liquid outlet.

28. The fluid replacement device according to claim 27, characterized in that: The driving structure comprises a deformation layer located on the first surface and an electrode layer located on the deformation layer, wherein the deformation layer is used to deform under the action of voltage to squeeze the reagent located in the liquid adding chamber; Alternatively, the driving structure includes a heater located on the first surface, the heater is used to heat the reagent located in the liquid adding chamber to generate bubbles, and the bubbles are used to squeeze the reagent.

29. The fluid replacement device according to claim 27, characterized in that: The liquid adding assembly further comprises a liquid storage structure stacked on the inkjet chip, wherein the liquid storage structure comprises at least one liquid storage cavity communicated with the liquid adding cavity, and the liquid storage cavity is used to store the reagent.

30. The fluid replacement device according to claim 29, characterized in that: The inkjet chip comprises a plurality of the liquid adding chambers, each of the liquid adding chambers is provided with a driving structure and at least one liquid outlet, and a liquid storage chamber is provided above each of the liquid adding chambers; Alternatively, the inkjet chip includes a plurality of the liquid adding chambers arranged in an array, each of the liquid adding chambers is provided with a driving structure and a liquid outlet, and a liquid storage chamber is provided above the liquid adding chambers in the same row.

31. The fluid replacement device according to claim 27, 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.

32. The fluid replacement device according to claim 26, characterized in that: The liquid adding assembly also includes a reagent storage box communicated with the inkjet chip.

33. The fluid replacement device according to claim 26, characterized in that: The liquid removal component is used to provide positive pressure or negative pressure to blow or suck away the residual reagent on the biochip.

34. The fluid replacement device according to claim 33, characterized in that: The liquid removal assembly comprises an air supply structure and an air knife communicated with the air supply structure, wherein the air supply structure is used to provide compressed gas to the air knife.

35. The fluid replacement device according to claim 34, characterized in that: The air knife comprises an air knife cavity communicated with the air supply structure, and a cutter head communicated with the air knife cavity, wherein the cutter head is used for limiting the airflow direction of the compressed gas.

36. The fluid replacement device according to claim 35, characterized in that: The cutter head comprises a cutter head body connected to the air knife cavity, and at least one inclined surface located at one end of the cutter head body away from the air knife cavity, wherein an air blowing port is provided on the inclined surface.

37. The fluid replacement device according to claim 26, characterized in that: The liquid replacement device further comprises a linkage structure, the liquid adding component and the liquid removing component are arranged on the linkage structure, and the linkage structure is used to make the liquid adding component and the liquid removing component linked.

38. The fluid replacement device according to claim 37, characterized in that: The linkage structure comprises a linkage shaft and a driving motor slidably arranged on the linkage shaft, and the liquid adding component and the liquid removing component are both mounted on the driving motor.

39. A biochemical substance analysis system, characterized in that: include: A biochemical reaction device, a carrier and a liquid changing device, wherein the biochemical reaction device is covered with the carrier to form a reaction chamber, the liquid changing device can be slidably arranged in the reaction chamber and is spaced apart from the carrier, the side of the carrier close to the liquid changing device carries a biochip, and the biochip is an open carrier for fixing a sample to be detected; the liquid changing device is configured to inkjet print a reagent layer of a preset thickness on the biochip.

40. The biochemical substance analysis system according to claim 39, characterized in that: The temperature in the reaction chamber is adjustable.

41. The biochemical substance analysis system according to claim 40, characterized in that: The biochemical reaction device comprises a heating cover, which comprises a top wall and a side wall arranged at the periphery of the top wall. An end of the side wall facing away from the top wall forms an opening, and the carrier is used to seal the opening to form the reaction chamber.

42. The biochemical substance analysis system according to claim 41, characterized in that: The top wall includes a water storage cavity, and a portion of the water storage cavity close to the reaction chamber is provided with an ultrasonic element, and the ultrasonic element is used to atomize the water in the water storage cavity and conduct the atomized water vapor to the reaction chamber.

43. The biochemical substance analysis system according to claim 42, characterized in that: The side wall has a vent hole, and the reaction chamber is connected with the outside through the vent hole.

44. The biochemical substance analysis system according to claim 39, characterized in that: The liquid replacement device is also configured to remove residual reagents on the surface of the biochip after the reaction, and the liquid replacement device adopts the liquid replacement device as described in any one of claims 26 to 38.

45. The biochemical substance analysis system according to claim 44, characterized in that: The liquid replacement device is slidably arranged on the inner wall of the biochemical reaction device through a linkage structure.

46. ​​The biochemical substance analysis system according to claim 39, characterized in that: The biochip includes a biosensing layer facing the fluid exchange device and a sensor layer stacked on the biosensing layer near the carrier side, the biosensing layer includes array sites for fixing the sample to be detected, and the sensor layer is configured to identify the signal generated after the sample to be detected reacts with the reagent.

47. The biochemical substance analysis system according to claim 39, characterized in that: The biochemical substance analysis system further comprises a transfer device, the carrier is located on the transfer device, and the transfer device is used to move the carrier to or away from the biochemical reaction device.

48. A method for analyzing biochemical substances, characterized in that: include: Loading a biochip on a carrier, wherein the biochip comprises a biosensing layer, and samples to be detected are fixed on array sites of the biosensing layer; Covering the biochemical reaction device with the carrier to form a reaction chamber, wherein the biochip is located in the reaction chamber; inkjet printing a reagent layer of a preset thickness onto the array site by a liquid replacement device; as well as The reaction chamber is heated by the biochemical reaction device and the carrier, so that the sample to be detected in the biochip reacts with the reagent layer.

49. The biochemical substance analysis method according to claim 48, characterized in that: The biochip further includes a sensor layer stacked on the biological sensing layer near the carrier. After the sample to be detected in the biochip reacts with the reagent layer, the method further includes: The sensor layer identifies the signal generated after the sample to be detected reacts with the reagent layer and performs in-situ signal detection and analysis.

50. The biochemical substance analysis method according to claim 48, characterized in that: A plurality of chip positions are arranged on the carrier, and each of the chip positions is used to accommodate and fix a corresponding biochip.

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