WO2025020046A1 - Integrated slide, liquid changing apparatus, and biochemical substance analysis system and analysis method - Google Patents

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 changing device, biochemical substance analysis system and analysis method Technical Field

The present application relates to the technical field of biochemical substance analysis, and in particular to an integrated slide, a liquid changing device, a biochemical substance analysis system and an analysis method.

Background Art

The second-generation gene sequencing technology is 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.

However, the sequencers used in the existing second-generation gene sequencing technology have a complex structure, cumbersome operation, and it is difficult to increase the throughput; moreover, the reagent loss during the sequencing process is high, and most of the reagents do not participate in the reaction (less than 1% of the reagent components participate in the reaction), resulting in a high sequencing cost. The second-generation gene sequencing technology mainly includes two forms: packaged carrier sequencing and open carrier sequencing, among which packaged carrier sequencing is the main form.

Summary of the invention

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

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 biochemical reactions 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 comprises 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.

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 discharging port; first The 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.

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 to enter the biochemical reaction chamber through the nozzle and is fixed by the array site.

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 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.

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 cavity into the drainage cavity.

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 used 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.

In some possible embodiments, 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, and the vacuum negative pressure device is connected to the liquid discharge cavity through the liquid suction port.

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.

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;

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.

In some possible embodiments, the liquid storage structure further includes at least one second storage structure connected to the liquid discharge cavity. The second liquid storage chamber is used to store the residual reagent.

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

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 in the dielectric layer, and along the stacking direction, a vertical projection of the metal wiring layer is located in the non-sensing region, 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.

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

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

In a second aspect, an embodiment of the present application provides a biochemical substance analysis system, comprising: a carrier and at least one of the aforementioned integrated carriers located on the carrier, the integrated carrier comprising a biochip and an inkjet chip encapsulated above the biochip, a biochemical reaction chamber being enclosed 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 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 comprises 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.

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 by using semiconductor packaging technology, so that the carrier liquid addition/exchange, biochemical reaction, and signal acquisition can be integrated on the same integrated carrier, which effectively simplifies the structure of the biochemical substance analysis system and the complexity of the liquid circuit system, reduces the volume of the overall biochemical substance analysis system, makes the system more compact, easy to assemble, easy to use, and can achieve ultra-high throughput detection, reducing equipment costs and detection costs; moreover, the integrated carrier can be discarded 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 liquid addition/exchange has high inkjet efficiency, small droplet volume, thin liquid film thickness and higher uniformity, which can reduce reagent loss and reduce detection costs.

In a third aspect, the present application provides a method for analyzing biochemical substances, comprising:

An integrated carrier is loaded on the carrier, the integrated carrier includes a biochip and an inkjet chip packaged 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 through a nozzle, and the biochip includes a biosensing layer facing the biochemical reaction chamber and a sensor layer, the biosensing layer comprising an array site for fixing a sample to be detected, the sensor layer being 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 via the nozzles, wherein 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 a signal generated by the reaction between the sample to be detected and the reagent through the sensor layer; and

The inkjet chip discharges the reacted residual reagent in the biochemical reaction chamber through the nozzle hole.

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 comprises 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.

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.

In some possible embodiments, the driving structure includes a deformation layer located on the first surface, and an electrode layer located on the deformation layer, and 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.

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.

In some possible embodiments, the inkjet chip includes a plurality of the liquid adding chambers, each of the liquid adding chambers is provided with a corresponding 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.

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.

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

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

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.

In some possible embodiments, the air knife includes an air knife cavity connected to the air supply structure, and a knife head connected to the air knife cavity, wherein the knife head is used to limit the airflow direction of the compressed gas.

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, and a blowing port is provided on the inclined surface.

In some possible embodiments, the liquid replacement device further includes a linkage structure, the liquid adding component and the liquid removing component are arranged on the linkage structure, and the linkage structure is used to enable the liquid adding component and the liquid removing component to be linked.

In some possible embodiments, the linkage structure includes a linkage shaft and a driving motor slidably disposed on the linkage shaft, and the liquid adding component and the liquid removing component are both mounted on the driving motor.

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, and the side of the carrier close to the liquid exchange device carries a biochip, and the biochip is an open carrier for fixing a sample to be detected; the liquid exchange device is configured to inkjet print a reagent layer of a preset thickness onto the biochip.

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

In some possible embodiments, the biochemical reaction device includes a heating cover, the heating cover includes a top wall and a side wall arranged at 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.

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, 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.

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

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 adopts the liquid replacement device described above.

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

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.

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.

In a sixth aspect, the present application provides another method for analyzing biochemical substances, comprising:

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; and

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.

In some possible embodiments, the biochip further includes a sensor layer stacked on a side of the biosensing layer close to the carrier, and 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.

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

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

(1) By integrating the biochemical reaction device, liquid replacement device and transfer device into one system, and cooperating with a biochip (or integrated imaging detection device) with in-situ imaging detection function, the integrated operation of sample addition, biochemical substance detection and analysis can be realized, which simplifies the system structure, is conducive to improving the detection efficiency, can realize ultra-high throughput detection, and reduce the equipment cost and detection cost. In addition, the volume of the overall biochemical substance analysis system is reduced, making the system more compact, easy to assemble and easy to use.

(2) The system integrates a liquid replacement device, 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 uses inkjet printing to add liquid, with a high printing frequency, small print droplets, and can 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 reagent loss can be roughly The detection cost can be further reduced by 50% to 80%. In addition, the liquid replacement device removes liquid by blowing or sucking liquid, which is simple and convenient. The liquid replacement process can be simple and fast when combined with the inkjet chip.

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

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

(5) An overflow tank is provided on the carrier to facilitate the collection of waste liquid during the liquid removal process.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments of the present application will be briefly introduced below. 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.

FIG. 1 is a schematic diagram of a biochemical substance analysis system in one embodiment of the present application.

FIG. 2 is a schematic diagram of the structure of an integrated carrier in one embodiment of the present application.

FIG. 3 is a schematic diagram of the structure of an inkjet chip adding reagents to a reaction chamber in one embodiment of the present application.

FIG. 4 is a schematic diagram of the structure of an inkjet chip adding reagents to a reaction chamber in another embodiment of the present application.

FIG. 5 is a schematic diagram of the structure of an inkjet chip in one embodiment of the present application discharging residual reagents in a biochip into a liquid discharge chamber

FIG. 6 is a schematic structural diagram of the integrated carrier arrangement liquid storage structure in FIG. 2 .

FIG. 7 is a top view of an inkjet chip in one embodiment of the present application.

FIG. 8 is a top view of an inkjet chip in another embodiment of the present application.

FIG. 9 is a top view of an inkjet chip in another embodiment of the present application.

FIG. 10 is a schematic diagram of the structure of a biochip in one embodiment of the present application.

FIG. 11 is a schematic diagram of the structure of a biochip in another embodiment of the present application.

FIG. 12 is a schematic diagram of the structure of a biochip in another embodiment of the present application.

FIG. 13 is a flow chart of a biochemical substance analysis method in one embodiment of the present application.

FIG. 14 is a schematic diagram of a biochemical substance analysis system in another embodiment of the present application.

FIG. 15 is a schematic diagram of the planar structure of a biochemical substance analysis system in another embodiment of the present application.

FIG. 16 is a schematic diagram of the three-dimensional structure of a biochemical substance analysis system in another embodiment of the present application.

FIG. 17 is a schematic diagram of the three-dimensional structure of the biochemical substance analysis system in another embodiment of the present application from another perspective.

FIG. 18 is a schematic structural diagram of the inkjet chip and liquid storage structure in FIG. 17 .

FIG. 19 is a cross-sectional view of an inkjet chip and a liquid storage structure in another embodiment of the present application.

FIG. 20 is a top view of an inkjet chip in another embodiment of the present application.

FIG. 21 is a top view of an inkjet chip in another embodiment of the present application.

FIG. 22 is a top view of an inkjet chip in another embodiment of the present application.

FIG. 23 is a schematic diagram of a liquid adding chamber 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.

FIG. 24 is a schematic diagram of an inkjet chip ejecting reagents in one embodiment of the present application.

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

FIG. 26 is a flow chart of a biochemical substance analysis method in another embodiment of the present application.

FIG. 27 is a flowchart of a biochemical substance analysis method in another embodiment of the present application.

Main component symbols

The following specific implementation methods will further illustrate the present application in conjunction with the above-mentioned drawings.

DETAILED DESCRIPTION

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

It should be noted that when a component is referred to as being "fixed to" or "mounted on" another component, it may be directly on the other component or there may be a central component. When a component is considered to be "set on" another component, it may be directly set on the other component or there may be a central component at the same time. The term "and/or" as used herein includes all and any combinations of one or more of the relevant listed items.

As shown in FIG2 , an embodiment of the present application provides an integrated carrier 200, which includes a biochip 210 and an inkjet chip 230 packaged above the biochip 210, and a biochemical reaction chamber 250 is formed between the biochip 210 and the inkjet chip 230. The inkjet chip 230 is connected to the biochemical reaction chamber 250 through a nozzle. Among them, the inkjet chip 230 is used to add the reagents required for the biochemical reaction into the biochemical reaction chamber 250 through the nozzle, or to discharge the residual reagents that have reacted in the biochemical reaction chamber 250 through the nozzle. That is, the inkjet chip 230 can realize the addition of the reagents required for the biochemical reaction into the biochemical reaction chamber 250, and can also realize the discharge of the residual reagents that have reacted in the biochemical reaction chamber 250. The biochip 210 includes a biosensing layer 219 and a sensor layer facing the biochemical reaction chamber 250, the biosensing layer 219 includes an array site 217 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. That is, the biochip 210 is used to make the sample to be detected located in the biochemical reaction chamber 250 react with the reagent, and can also realize in-situ signal detection of the reacted sample to be detected.

Referring to FIG. 1 and FIG. 2, the embodiment of the present application also provides a biochemical substance analysis system 1000, including: a carrier 100 and an integrated carrier located on the carrier 100. Optionally, the integrated carrier in the present embodiment is the above-mentioned integrated carrier 200. The biochemical substance analysis system 1000 also includes a main frame platform (not shown), and the carrier 100 is located on the main frame platform. The carrier 100 mainly includes a carrier seat 110 and a chip seat 120 located on the carrier seat 110, and the integrated carrier 200 is located on the chip seat 120. Specifically, the integrated carrier 200 can be adsorbed on the chip seat 120 by negative pressure adsorption. In addition, multiple integrated carriers 200 can be adsorbed on the chip seat 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 carrier 200 can be heated to achieve biochemical reactions.

Please refer to FIG. 2 and FIG. 3 , the inkjet chip 230 mainly includes an inkjet cavity layer 231 and a first driving 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 cavity 250 through the liquid outlet 235. The first driving structure 232 is superimposed on the first surface 2311 and covers the liquid adding cavity 233, that is, the first driving structure 232 can cover the opening of the liquid adding cavity 233 located on the first surface 2311. The first driving structure 232 can drive the reagent located in the liquid adding cavity 233 to enter the biochemical reaction cavity 250 through the liquid outlet 235. It is understandable that a negative pressure can be maintained in the liquid adding chamber 233 by adding a negative pressure air circuit (not shown) to communicate with the liquid adding chamber 233. When no liquid addition is needed, the reagent can be kept in the liquid adding chamber 233 without leaking out from the liquid outlet 235.

Please refer to FIG. 3 again. The first driving structure 232 can use piezoelectric inkjet printing technology to print the reagent in the liquid adding chamber 232 into the biochemical reaction chamber 250. The piezoelectric inkjet printing technology uses piezoelectric ceramics to deform due to the application of voltage, squeeze the liquid to generate high pressure and spray the liquid. In some embodiments, the first The driving 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 be deformed under the control of the first electrode layer 2323 to squeeze the reagent in the liquid adding chamber 233, so that the reagent flows out from the liquid outlet 235 and enters the biochemical reaction chamber 250. The liquid adding principle of the inkjet chip 230 is to apply a voltage to the first deformable layer 2321 through the first electrode layer 2323. Since the material of the first deformable layer 2321 can be piezoelectric ceramic, the first deformable layer 2321 will be affected by the voltage and produce instantaneous deformation. At this time, the first deformable layer 2321 can be controlled to bulge into the liquid adding chamber 233. Therefore, the reagent in the liquid adding chamber 233 is squeezed through this instantaneous deformation, and the reagent is ejected from the liquid outlet 235 at high pressure to form droplets, so as to be sprayed onto the corresponding position of the biochip 210. By using micro-piezoelectric technology to print reagent samples, the volume of the printed reagent droplets can be precisely controlled, thereby reducing reagent loss.

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. The heater will generate heat after power is turned on to heat the reagent in the liquid adding chamber 233, thereby generating bubbles. The bubbles squeeze the reagent droplets out of the liquid outlet 235 to achieve the purpose of printing.

Please refer to FIG. 2 again, and refer to FIG. 1 together. 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 nozzle can also be divided into a drainage port 236 located on the second surface 2312. The drainage cavity 234 is connected to the biochemical reaction chamber 250 through the drainage port 236. The inkjet chip 230 also includes a second driving structure 237 stacked on the first surface 2311. The second driving structure 237 covers the drainage cavity 234, that is, the second driving structure 237 covers the opening of the drainage cavity 234 located on the first surface 2311. The second driving structure 237 is used to form a negative pressure in the drainage cavity 234, so as to discharge the residual reagents after the reaction in the biochemical reaction chamber 250 is completed into the drainage cavity 234.

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 used to deform under the control of the second electrode layer 2373 to form a negative pressure in the drainage chamber 234, thereby allowing the residual reagent in 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 material of the second deformable layer 2371 is also piezoelectric ceramics, so the second deformable layer 2371 will be affected by the voltage and produce instantaneous deformation. At this time, the second deformable layer 2371 can be controlled to bulge in the direction away from the drainage chamber 234. Through this instantaneous deformation, the volume of the drainage chamber 234 can be enlarged, and a negative pressure is formed inside, so that the residual reagent in the biochemical reaction chamber 250 enters the drainage chamber 234 through the drainage port 236 under the adsorption of the negative pressure. It can be 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 FIG6, the inkjet chip 230 also has a liquid suction port 238 connected to the drainage chamber 234, and the residual reagent sucked into the drainage chamber 234 is discharged from the integrated carrier 200 through the liquid suction port 238. It can be understood that, in conjunction with FIG. 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 .

It can be understood that in other embodiments, the second driving structure can 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, negative pressure can be formed in the drainage chamber 234, thereby sucking away the residual reagents in the biochemical reaction chamber 250. In addition, the vacuum negative pressure device can also be connected to the waste liquid collection device 292 to collect waste liquid.

Please refer to FIG. 2 again. The inkjet cavity layer 231 may be a multi-layer structure. The inkjet cavity layer 231 includes 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 away from the resin layer 2314, wherein the surface of the resin layer 2314 away from the substrate 2313 constitutes a first surface 2311, and the surface of the nozzle plate 2315 away from the substrate 2313 constitutes a second surface 2312. It can be understood that the resin layer 2314 may be a single layer or a multi-layer. The portion of the liquid adding cavity 233 corresponding to the resin layer 2314 constitutes a first through hole 2316, the portion of the liquid adding cavity 233 corresponding to the substrate 2313 constitutes a second through hole 2317, the portion of the liquid adding cavity 233 corresponding to the nozzle plate 2315 constitutes a liquid outlet 235, and the portion of the liquid discharging cavity 234 corresponding to the nozzle plate 2315 constitutes a liquid discharging outlet 236.

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, that is, the liquid outlet 235 has the smallest caliber, which can better limit the outflow speed of the droplets to better control the volume of the droplets printed each time. In addition, the caliber of the liquid outlet 235 is small, and when the liquid is not added, under the action of negative pressure, the reagent can be better kept in the liquid addition cavity 233. In addition, the inner diameter of the first through hole 2316 is designed to be relatively large, so that more reagents can be carried.

In some embodiments, the nozzle plate 2315 located at the periphery of the drainage port 236 protrudes toward the biochemical reaction chamber 250, and the protrusion stretches the side wall of the drainage port 236 along the thickness direction. The setting of the protrusion is conducive to the residual reagent in the biochemical reaction chamber 250 entering the drainage chamber 234 during drainage.

In some embodiments, the material of the substrate 2313 may be silicon, and the material of the resin layer 2314 may be 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 formed into holes by etching, it is easier to form holes than the substrate 2313 made of silicon. Therefore, the inner diameter of the first through hole 2316 can be accurately controlled according to actual needs, thereby improving the accuracy of the volume control of the liquid adding chamber 233 and ensuring the accuracy of the reagent amount. In some embodiments, the volume of the liquid adding chamber 233 may be 9pL to 50pL. For example, the volume of the liquid adding chamber 233 may be 9pL, 10pL, 15pL, 20pL, 25pL, 30pL, 35pL, 40pL, 45pL or 50pL, etc.

Referring to FIG. 6 , the inkjet cavity layer 231 is further provided with at least one liquid inlet hole 239, which is in communication with the liquid adding cavity 233. In some embodiments, the opening of the liquid inlet hole 239 may be located on the first surface 2311 of the inkjet cavity layer 231, or may be located on the side surface of the inkjet cavity layer 231. In some embodiments, the liquid inlet hole 239 is opened On the resin layer 2314 , the opening of the liquid inlet hole 239 is located on the first surface 2311 .

Please refer to FIG. 6 again, and refer to FIG. 1 together. The integrated carrier 200 further 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 further 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 hole 239. In some embodiments, the first liquid storage cavity 271 is a closed cavity. When the liquid adding operation is not performed, the reagent in the first liquid storage cavity 271 and the liquid adding cavity 233 can be prevented from leaking out from the liquid outlet 235 through the negative pressure gas path.

The inkjet chip 230 further includes a sample chamber connected to the liquid adding chamber 233, and the sample chamber is used to accommodate the sample to be detected. Specifically, 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. It can be 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 storage chambers for reagents.

Please refer to FIG. 7, and refer to FIG. 1 and FIG. 2 together. The inkjet chip 230 includes a plurality of liquid adding chambers 233 arranged side by side, and each liquid adding chamber 233 is provided with a first driving structure 232 and a plurality of liquid outlets 235. At this time, a first driving structure 232 can squeeze the reagent in the liquid adding chamber 233 below the first driving structure 232, so that the reagent is ejected from the plurality of liquid outlets 235 at the same time. The plurality of first driving structures 232 can be electrically connected to the inkjet control circuit (not shown), so as to realize the independent control of the plurality of first driving structures 232, so as to realize the independent 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 driving 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 realized. The arrangement of the multiple liquid outlets 235 in each liquid adding cavity 233 can be designed according to the arrangement of the reaction sites on the biochip 210. For example, the multiple liquid outlets 235 in each liquid adding cavity 233 can be arranged in a straight line. It can be understood that the multiple liquid outlets 235 in each liquid adding cavity 233 can also be arranged in an array. In this way, the liquid outlets 235 in the multiple liquid adding cavities 233 arranged side by side form a micropore array, and the number of liquid outlets 235 can be adjusted according to the number of site arrays in the biochip 210. In order to improve the efficiency of the biochemical reaction, the flux of the biochip 210 is relatively high. At this time, the density of the liquid outlets 235 of the inkjet chip 230 can be designed to be relatively high, and the spacing between adjacent liquid outlets 235 can be set to be relatively small, for example, about 40 microns, thereby achieving high-density printing. In some embodiments, the liquid storage structure 270 is divided into a plurality of independent first liquid storage cavities 271, each of which corresponds to a liquid adding cavity 233 and is connected through a liquid inlet 239.

It can be understood that in other embodiments, as shown in Figure 8, the inkjet chip 230 includes a plurality of liquid adding chambers 233 arranged in an array, and each liquid adding chamber 233 is correspondingly provided with a first driving structure 232 and a liquid outlet 235, so as to realize independent control of inkjet of each liquid outlet 235, and then accurately control the volume of droplets discharged from each liquid outlet 235. At this time, the liquid storage structure 270 is divided into multiple independent first liquid storage chambers 271, each first liquid storage chamber 271 corresponds to a row of liquid adding chambers 233, and the same row of liquid adding chambers 233 are connected to the first liquid storage chamber 271 through a liquid inlet hole 239 respectively. Specifically, the types of reagents in the same row of liquid adding chambers 233 are the same.

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.

Please refer to Figures 6 to 9, and refer to Figure 1 together. The liquid storage structure 270 also includes at least one second liquid storage chamber 272 connected to the drainage chamber 234. The second liquid storage chamber 272 is used to store residual reagents. That is, the residual reagents entering the drainage chamber 234 from the biochemical reaction chamber 250 can further enter the second liquid storage chamber 272, thereby realizing the buffering of the residual reagents, and finally enter the waste liquid collection device 292 from the second liquid storage chamber 272. In some embodiments, all of the drainage chambers 234 are correspondingly provided with a second liquid storage chamber 272. Since various residual reagents can be treated as waste liquids, by providing a second liquid storage chamber 272, the collection of residual reagents can be facilitated, and the structural complexity of the integrated slide 200 can be further simplified.

Please refer to FIG. 10 , and refer to FIG. 2 together. The biochip 210 includes a biosensor layer and a sensor layer facing the biochemical reaction chamber 250. 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. The biochip 210 can be formed by integrating one or more biosensors 210a through a semiconductor packaging process, for example, it can be a semiconductor wafer containing one or more front-illuminated (FSI) image sensors. As shown in FIG. 10 , for example, the biochip 210 includes a biosensor 210a, wherein the sensor layer mainly includes: a semiconductor layer 211 having a light sensing area A and a non-sensing area B, a light sensing component 212 located in the light sensing area A, at least one dielectric layer 213 stacked on a surface of the semiconductor layer 211, and a metal wiring layer 214 located in the dielectric layer 213. The biosensor layer 219 includes a passivation layer 215 and an array site 217 located on the surface of the dielectric layer 213 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 the 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 at 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 base The biochip 210 of the semiconductor image sensor can be integrated in the packaging stage, supporting the packaging of a single biosensor 210a, and also supporting the array packaging of multiple biosensors 210a, which together constitute a biochip 210, so as to prepare a larger area of biochips to achieve ultra-high throughput detection. The biochip 210 can be used in non-excitation light imaging sequencing systems, such as semiconductor image sensor direct photosensing technology, and other sensing sequencing technologies such as capacitance, voltage, current, and ions, to achieve the sensing of intermediate products of biochemical reactions, the sensing of electrical signals generated by biochemical reactions, etc. In addition, local biochemical reactions and local sequencing can be carried out simultaneously on the biochip 210, and sequencing is more flexible.

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.

In some embodiments, the light sensing component 212 may be a photodiode, or other photosensitive components that can be used. 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 through 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, etc.

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

In some embodiments, the material of the array sites 217 may be at least one of Ta ₂ O ₅ , TiO ₂ , HfO ₂ , etc. The array sites 217 may be used to suppress dark current in the light sensing components 212 such as photodiodes.

In some embodiments, the passivation layer 215 can be deposited on the surface of the dielectric layer 213 by conventional semiconductor processing techniques (e.g., 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, silicon oxide, etc. 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.

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 to confine biological samples or chemical samples within the openings 216 constructed by the passivation layer 215 .

In other embodiments, as shown in FIG. 11 , the biosensor 210b may also be a semiconductor wafer including one or more back-illuminated (BSI) image sensors. The difference from the aforementioned biosensor 210a is that the passivation layer 215 and the array sites 217 in the biosensor 210b are both located on the surface of the semiconductor layer 211 away from the dielectric layer 214, the passivation layer 215 is formed with an opening 216 corresponding to the light sensing area A, the surface of the semiconductor layer 211 is exposed by the opening 216, and the array sites 217 are located in the opening 216. Compared with the front-illuminated (FSI) image sensor, the back-illuminated (BSI) image sensor has a larger surface area than the front-illuminated (FSI) image sensor. Like a sensor, the light sensing component 212 is closer to the array site 217, the transmission distance of the fluorescence after the reaction of the biological sample to the light sensing component 212 is shorter, and the light attenuation and loss are smaller.

In other embodiments, as shown in FIG. 12 , the biosensor 210c may also be a semiconductor chip including one or more back-illuminated (BSI) image sensors. The difference from the aforementioned biosensor 210b is that the dielectric layer 213 in the biosensor 210c 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, which can realize a larger array and more functional biochemical reactions.

Please refer to FIG. 2 again, the biochip 210 is packaged together with the inkjet chip 230 through the packaging layer 220. Specifically, the biochip 210 and the inkjet chip 230 are integrated into an integrated carrier 200 through a semiconductor process, which will greatly reduce the size and cost of the biochemical substance analysis equipment and improve ease of use. In the stacking technology, the biochip 210 and the inkjet chip 230 can be manufactured separately and then joined together through the packaging layer 220 in the 3-D stacking device.

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 at 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.

It can be understood that, as shown in FIG1 , the biochemical substance analysis system 1000 further includes a control platform 800 and necessary control circuits. The control circuits may include control circuits for controlling the operation of the integrated carrier 200, such as inkjet control circuits and liquid discharge control circuits, and may also include control circuits for controlling the heating of the carrier 100 and the adsorption of the integrated carrier 200. The control platform 800 may be used to control the operation of various parts of the biochemical substance analysis system 1000.

Please refer to FIG. 13 , and in combination with FIG. 2 , FIG. 3 and FIG. 5 , the method for performing biochemical substance analysis using the above biochemical substance analysis system 1000 includes the following steps:

Step S11, loading an integrated slide onto the stage. The integrated slide has a structure similar 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 sample to be detected fixed at the array site of the biosensing layer of the biochip includes but is not limited to at least one of a nucleic acid sequencing library, tissue protein, etc.

Step S12, adding reagents required for biochemical reactions into the biochemical reaction chamber through 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.

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.

Step S14, the reacted residual reagent in the biochemical reaction chamber is discharged through the inkjet chip.

Step S12 and step S13 can be repeated multiple times to load different reaction reagents on the biochip. Thus completing the biochemical reaction.

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

In the first step, the sample to be detected is loaded into the integrated slide 200, for example, DNB containing a DNA sequencing library, and the DNB is adsorbed on the reaction area of the biochip 210. It can be understood that the integrated biochip 200 can realize automatic loading of the sample to be detected.

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.

In the third step, the first deformation layer 2321 is deformed to squeeze the reagent in the liquid adding chamber 233 by controlling the first driving structure 232, and then the reagent is sprayed onto the corresponding reaction area in the biochemical reaction chamber 250. The type of reagent squeezed out of each liquid adding chamber 233, the size of the reagent droplet, the inkjet frequency, etc. can be independently controlled by the control circuit. Liquid is added by inkjet printing, the printing frequency is high (usually greater than 10Hz), and the printed droplets are small (usually 9pL to 50pL), which can effectively improve the printing efficiency, make the thickness of the liquid film more uniform, and reduce the loss of reagents and reduce costs.

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.

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

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

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.

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, so that the carrier liquid addition/exchange, biochemical reaction, and signal acquisition can be integrated on the same integrated carrier, 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 carrier 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 liquid addition/exchange has high inkjet efficiency, small droplet volume, thin liquid film thickness and higher uniformity, which can reduce reagent loss and reduce detection cost.

Referring to FIGS. 14 to 17 , the present embodiment provides another biochemical substance analysis system 2000 , which includes: a biochemical reaction device 300 , a carrier 100 , and a liquid replacement device 400 . The reaction device 300 is covered with the carrier 100 to form a reaction chamber 10, and the liquid replacement device 400 can be slidably disposed in the reaction chamber 10 and spaced from the carrier 100. The side of the carrier 100 close to the liquid replacement device 400 carries a biochip 700, and the biochip 700 is an open carrier for fixing the sample to be detected. The liquid replacement 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 of the sample to be detected and the reagent layer, thereby heating the biochip 700 so that the sample to be detected 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 achieve the addition of liquid to the biochip 700.

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, etc.

Please refer to Figures 14 to 17 again. A plurality of chip positions may be provided on the carrier 100, and each chip position is used to accommodate and fix a corresponding biochip 700. Specifically, the carrier 100 includes a carrier 110 and a chip holder 120 located on the carrier 110, and the biochip 700 is located on the chip holder 120. One or more biochips 700 may be loaded on the chip holder 120 according to the actual detection flux requirements, that is, at least one chip position may be provided on the chip holder 120 to fix the biochip 700.

In some embodiments, as shown in FIG. 17 , 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 .

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

Please refer to Figures 15 to 17. The biochemical reaction device 300 includes a heating cover 310, which includes a top wall 311 and a side wall 312 arranged at the periphery of the top wall 311. The side wall 312 forms an opening 313 at one end away from the top wall 311. The carrier 100 is used 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, the top wall 311 and the side wall 312 can be provided with a heating structure. The reaction chamber 10 is formed by covering the heating cover 310 with the carrier 100, which can play a role in heat preservation and can also slow down the evaporation of reagents during the liquid addition and reaction process.

In some embodiments, the top wall 311 includes a water storage cavity 314, and a portion of the water storage cavity 314 close to the reaction chamber 10 is provided with an ultrasonic element 315, which is used to atomize the water in the water storage cavity 314 and conduct the atomized water vapor to the reaction chamber 10. By burying the ultrasonic element 315, such as a piezoelectric atomization membrane, at 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, and 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.

In some embodiments, the side wall 312 has a vent hole 316, and the reaction chamber 10 is connected to the outside through the vent hole 316. A vent hole 316 is provided to allow the atomized water vapor to be guided out of the reaction chamber 10 through the air flow.

Please refer to FIG. 18 , and refer to FIG. 14 and FIG. 15 together, 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 a 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 a reagent reaction is completed, it is necessary to replace another reagent. At this time, it is necessary to use the liquid removal component 420 to remove the residual reagents after the previous step of the reaction, and then use the liquid 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.

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

Please refer to FIG. 18 and FIG. 19, and refer to FIG. 14 together. The inkjet chip 430 includes: a stacked inkjet cavity layer 431 and a driving structure 432, wherein the inkjet cavity layer 431 includes a first surface 4311 and a second surface 4312 arranged opposite to each other, the driving structure 432 is located on the first surface 4311, and the driving structure 432 is electrically connected to the inkjet control circuit 450. At least one liquid adding cavity 435 is formed through the first surface 4311 and the second surface 4312 of the inkjet cavity layer 431, and the liquid adding cavity 435 forms at least one liquid outlet 436 on the second surface 4312, and the liquid adding cavity 435 is used to accommodate the reagents required for the biochemical reaction. A negative pressure gas path (not shown) can be added to communicate with the liquid adding cavity 435, so that a certain negative pressure is maintained in the liquid adding cavity 435, so that the reagent is kept in the liquid adding cavity 435. The driving structure 432 is on the surface of the inkjet cavity layer 431 and covers the opening of the liquid adding cavity 435 opposite to the liquid outlet 436. The driving structure 432 can be deformed under the control of the inkjet control circuit 450, squeeze the reagent in the liquid adding cavity 435, discharge the reagent from the liquid outlet 436, and then print it on the biochip 700. The liquid addition method is adopted to accurately control the thickness of the liquid film, significantly reduce the loss of reagents, and further reduce the detection cost.

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 the smallest caliber, which can better limit the outflow speed of the droplets to better control the volume of the droplets printed each time. In addition, the liquid outlet 436 has a smaller caliber, and when the sample is not added, the sample can be better kept in the liquid adding chamber 435 under the action of negative pressure.

The inkjet cavity layer 431 may be a multi-layer structure, and the inkjet cavity layer 431 includes 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, wherein 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 can be understood that the resin layer 4314 may be a single layer or a multi-layer. The portion of the liquid cavity 435 corresponding to the resin layer 4314 constitutes the first through hole 4316, the portion of the liquid adding cavity 435 corresponding to the substrate 4313 constitutes the second through hole 4317, and the portion of the liquid adding cavity 435 corresponding to the nozzle plate 4315 constitutes the 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 no sample is added, the droplets of reagent in the liquid adding cavity 435 will not flow out of the liquid outlet 436 due to their own gravity under the action of surface tension at the small-diameter liquid outlet 436, thereby remaining in the liquid adding cavity 435. The inner diameter of the first through hole 4316 is designed to be relatively large, so that more reagents can be carried.

In some embodiments, the material of the substrate 4313 may be silicon, and the material of the resin layer 4314 may be polyimide. A second through hole 4317 with a smaller inner diameter may be formed on the substrate 4313, and a first through hole 4316 with a larger inner diameter may be formed on the resin layer 4314 by chemical etching. Since the resin layer 4314 can be formed into holes by etching, it is easier to form holes than the substrate 4313 made of silicon. Therefore, the inner diameter of the first through hole 4316 can be accurately controlled according to actual needs, thereby improving the accuracy of the volume control of the liquid adding chamber 435 and ensuring the accuracy of the reagent amount. In some embodiments, the volume of the liquid adding chamber 435 may be 9pL to 50pL. For example, the volume of the liquid adding chamber 435 may be 9pL, 10pL, 15pL, 20pL, 25pL, 30pL, 35pL, 40pL, 45pL or 50pL, etc.

The inkjet cavity layer 431 is further provided with at least one liquid inlet hole 437, which is communicated with the liquid adding cavity 435, and the liquid inlet hole 437 is communicated with the reagent storage box 440, so that the reagent in the reagent storage box 440 is added to the liquid adding cavity 435 through the liquid inlet hole 437. In some embodiments, the opening of the liquid inlet hole 437 can be located on the first surface 4311 of the inkjet cavity layer 431, or on the side surface of the inkjet cavity layer 431. In some embodiments, as shown in FIG. 7, the liquid inlet hole 437 is opened on the resin layer 4314, and the opening is located on the first surface 4311.

Please refer to Figures 18 and 19 again, and refer to Figure 14 together. The liquid adding component 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, and 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 hole 437. In some embodiments, the liquid storage cavity 471 is a closed cavity, and the reagent in the liquid storage cavity 471 and the liquid adding cavity 435 will not seep out from the liquid outlet 436 through a negative pressure gas circuit.

Please refer to Figure 20, and refer to Figures 14, 18 and 19 together. The inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged side by side, and each liquid adding chamber 435 is correspondingly provided with a driving structure 432 and a plurality of liquid outlets 436. The plurality of driving structures 432 can be electrically connected to an inkjet control circuit (not shown) to achieve independent control of the plurality of driving structures 432, so as 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 driving structure 432, and the droplet volumes discharged from the plurality of liquid outlets 436 are substantially the same. A reagent can be stored in each liquid adding chamber 435, so that the simultaneous printing of multiple reagents can be achieved. The arrangement of the plurality of liquid outlets 436 in each liquid adding chamber 435 can be designed according to the arrangement of the reaction sites on the biochip 700. For example, each liquid adding chamber 435 has a plurality of liquid outlets 436 arranged in a plurality of liquid outlets 436. The multiple liquid outlets 436 in 435 can be arranged in a straight line. It can be understood that the multiple liquid outlets 436 in each liquid adding chamber 435 can also be arranged in an array. In this way, the liquid outlets 436 in the multiple liquid adding chambers 435 arranged side by side form a micropore array, and the number of liquid outlets 436 can be adjusted according to the number of site arrays on the biochip 210. In order to improve the effect of the biochemical reaction, the flux of the biochip 700 is relatively high. At this time, the density of the liquid outlets 436 of the inkjet chip 430 can be designed to be relatively high. For example, the spacing between adjacent liquid outlets 436 can be about 40 microns, thereby achieving high-density printing. In some embodiments, the liquid storage structure 470 is divided into 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 437.

It can be understood that in other embodiments, as shown in FIG. 21 , the inkjet chip 430 includes a plurality of liquid adding chambers 435 arranged in an array, and each liquid adding chamber 435 is provided with a driving structure 432 and a liquid outlet 436, so as to realize the independent control of each liquid outlet 436, and then accurately control the volume of droplets discharged by each liquid outlet 436. At this time, the liquid storage structure 470 is divided into a plurality of independent liquid storage chambers 471, each liquid storage chamber 471 corresponds to a row of liquid adding chambers 435, and the same row of liquid adding chambers 435 are connected to the liquid storage chamber 471 through a liquid inlet hole 437, and specifically, the reagents in the same row of liquid adding chambers 435 are of the same type.

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.

Please refer to FIG. 23 and FIG. 24, and refer to FIG. 14 and FIG. 15 together. As shown above, the driving structure 432 can also use piezoelectric inkjet printing technology to realize the printing of the reagent in the liquid adding chamber 435 onto the biochip 700. In some embodiments, the driving structure 432 may include a deformation layer 4321 and an electrode layer 4322 located on the deformation layer 4321. As shown in FIG. 24, the operating principle of the inkjet chip 430 is to apply a voltage to the deformation layer 4321 through the electrode layer 4322. Since the material of the deformation layer 4321 can be piezoelectric ceramics, the deformation layer 4321 will be affected by the voltage and produce instantaneous deformation, and through this instantaneous deformation, the reagent in the liquid adding chamber 435 is squeezed, and the reagent is ejected at high pressure from the liquid outlet 436 to form droplets, thereby printing on the corresponding position of the biochip 700. By using a micro-piezoelectric method, the printing of the reagent can be realized, and the volume of the printed reagent droplets can be accurately controlled, thereby reducing the loss of the reagent.

In other embodiments, as shown in FIG. 25 , 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 powered on, the heater generates heat to heat the reagent in the liquid adding chamber 435, thereby generating bubbles. The bubbles squeeze the reagent droplets out of the liquid outlet 436 to achieve the purpose of printing.

Please refer to FIG. 14 again. The reagent storage box 440 can be connected to the liquid storage on the inkjet chip 430 through a set of liquid path connectors. The structure 470 is connected. It can be understood that the storage location of the reagent storage box 440 can selectively add a refrigeration module to maintain the environment required for storing biochemical reaction reagents.

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 achieve independent control of each liquid outlet 436 or each discharge liquid outlet 436 of the inkjet chip 430.

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

Please refer to Figures 14 and 15 again. The liquid removal component 420 uses airflow to remove the residual reagents that have reacted on the biochip 700. The liquid on the biochip 700 can be directly removed by blowing or sucking. The liquid removal component 420 includes an air knife 421 and an air supply structure 422, wherein the air knife 421 is connected to the air supply structure 422, and the air supply structure 422 can provide compressed gas or negative pressure to form an airflow, thereby blowing or sucking away the liquid on the surface of the biochip 700. The liquid removal is achieved by blowing or sucking, which is simple and convenient, and can be combined with the inkjet chip 430 to achieve a simple and fast liquid replacement process.

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

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.

Please refer to FIG. 15 and FIG. 16 again, and refer to FIG. 14 together. The liquid replacement device 400 also includes a linkage structure 460, which 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, and the liquid adding operation can be performed immediately after the liquid is removed, and the liquid replacement efficiency is high. In some embodiments, the linkage structure 460 may include a linkage shaft 461 and a driving motor 462 slidably arranged on the linkage shaft 461, and the inkjet chip 430 and the air knife 421 of the liquid removing component 420 are slidably arranged on the driving 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 of the traveling direction, so as to achieve the purpose of removing liquid first and then adding liquid.

The biochip 700 used in the biochemical substance analysis system 2000 can be a biochip integrating one or more biosensors. Specifically, the biochip 700 includes a biosensing layer facing the liquid replacement device 400 and a sensor layer stacked on the side of the biosensing layer close to the carrier 100, 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. After the biochemical reaction is completed, the sensor layer can directly collect the fluorescence signal of the reacted sample and perform signal analysis to complete the detection process. Specifically, the biosensor can adopt the structure of the aforementioned biosensor 210a (210b or 210c). Please refer to the above for the specific structure, and no further details will be given here.

Please refer to FIG. 14 again. The biochemical substance analysis system 2000 further includes a transfer device 600. The carrier 100 is located on the transfer device 600. The transfer device 600 is used to move the carrier 100 to or away from the biochemical reaction device 300 to load the biochip 700 and cover the carrier 100 with the heating cover 310 of the biochemical reaction device 300. It can be understood that the heating cover 310 of the biochemical reaction device 300 can also be controlled to move so that the heating cover 310 and the carrier 100 can be covered. Alternatively, the carrier 100 is first moved to the bottom of the heating cover 310 by the transfer device 600, and then the heating cover 310 is controlled to move so as to cover the carrier 100.

Please refer to FIG. 14 again. The biochemical substance analysis system 2000 further includes a control platform 800. The control platform 800 is used to control 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.

Please refer to FIG. 26 , the method for performing biochemical substance analysis using the aforementioned biochemical substance analysis system 2000 specifically includes the following steps:

Step S21 : loading the biochip 700 on the carrier 100 . The biochip 700 includes a biosensing layer, and samples to be detected are fixed on array sites of the biosensing layer.

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 .

Step S23 , inkjet printing a reagent layer of a preset thickness onto the array sites of the biochip 700 by using the liquid replacement device 400 .

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.

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:

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.

Wherein, step S23 and step S24 may be cycled for multiple times to achieve the loading of different reagents on the biochip 700 and different biochemical reaction processes until the biochemical reaction is completed.

As shown in FIG. 27 , in combination with FIG. 14 , FIG. 15 and FIG. 19 , the specific process of gene sequencing using the above method is given.

The first step is to load the sample to be tested into the biochip 700, such as DNB containing DNA sequencing library, DNB Adsorbed on the reaction area of the biochip 700.

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 with 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.

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

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.

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 the reagent is printed onto the corresponding reaction area of the biochip 700.

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, with a high printing frequency (usually greater than 10Hz) and small printed droplets (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 lowering costs.

The fifth step is to control the stage 100 to heat up, so as to 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.

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.

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

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.

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

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

(1) By integrating the biochemical reaction device 300, the liquid replacement device 400 and the transfer device 600 into one system, and cooperating with the biochip 700 with in-situ imaging detection function, the integrated operation of sample addition, biochemical substance analysis and imaging detection can be realized, which simplifies the system structure, is conducive to improving the detection efficiency, can realize ultra-high throughput detection, and reduces the equipment cost and detection cost. In addition, the volume of the overall biochemical substance analysis system 2000 is reduced, making the system more convenient. Small, easy to assemble, and easy to use.

(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 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 detection methods, the reagent loss can be reduced by about 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, and can be used with the inkjet chip 430 to simply and quickly perform the liquid replacement process.

(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.

(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 is conducive to improving the detection throughput.

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

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

Claims (50)

An integrated carrier, characterized in that it 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 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. 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. The integrated carrier as described in claim 2 is characterized in that the inkjet chip also 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. The integrated slide as claimed in claim 2 or 3, characterized in that the first driving structure comprises a first deformable layer located on the first surface, and a first electrode layer located on the first deformable layer, 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. The integrated carrier according to claim 2, characterized in that the inkjet chip further comprises: 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. The integrated carrier according to claim 5, characterized in that the second drive structure includes a A second deformable layer on the first surface, and a second electrode layer located on the second deformable layer, wherein 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. The integrated carrier as described in claim 5 is characterized in that the drainage chamber also has a liquid suction port located on the first surface, and the second driving structure is a vacuum negative pressure device, and the vacuum negative pressure device is connected to the drainage chamber through the liquid suction port. The integrated carrier as described in claim 5 is 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 cavity connected to the liquid adding cavity, and the first liquid storage cavity is used to store the reagent. 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 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. The integrated carrier as described in claim 8 is characterized in that the liquid storage structure also includes at least one second liquid storage cavity connected to the drainage cavity, and the second liquid storage cavity is used to store the residual reagent. The integrated carrier as described in claim 2 is characterized in that the volume of the liquid adding chamber is 9pL to 50pL. The integrated carrier according to claim 1, wherein 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. The integrated carrier as described in claim 12 is characterized in that, along the stacking direction, the thickness of the passivation layer is greater than the thickness of the array site. The integrated carrier as described in claim 13 is characterized in that the inkjet chip and the biochip are bonded together through a packaging layer. A biochemical substance analysis system, characterized in that it comprises: a carrier and at least one integrated carrier located on the carrier, the integrated carrier comprising a biochip and an inkjet chip packaged above the biochip, a biochemical reaction chamber being 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. 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. The biochemical substance analysis system as described in claim 16 is characterized in that the inkjet chamber layer also 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. The biochemical substance analysis system according to claim 15 or 16, characterized in that the first driving structure comprises a first deformable layer located on the first surface, and a first electrode layer located on the first deformable layer, the first deformable layer being 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. The biochemical substance analysis system according to claim 18, wherein the inkjet chip further comprises: 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. The biochemical substance analysis system according to claim 19, characterized in that the second driving structure comprises A second deformable layer is located on the first surface, and a second electrode layer is located on the second deformable layer, wherein 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. The biochemical substance analysis system as described in claim 19 is characterized in that the drainage chamber also has a liquid suction port located on the first surface, and the second driving structure is a vacuum negative pressure device, and the vacuum negative pressure device is connected to the drainage chamber through the liquid suction port. The biochemical substance analysis system as described in claim 19 is 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. 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 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. The biochemical substance analysis system as described in claim 15 is characterized in that the biochemical substance analysis system also includes a reagent storage box connected to the inkjet chip. A biochemical substance analysis method, characterized by comprising: Loading an integrated carrier on a carrier, the integrated carrier comprising a biochip and an inkjet chip packaged 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 through a nozzle, the biochip comprises a biosensing layer and a sensor layer facing the biochemical reaction chamber, the biosensing layer comprises 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; 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 a signal generated by the reaction between the sample to be detected and the reagent through the sensor layer; and The reacted residual reagent in the biochemical reaction chamber is discharged through the inkjet chip. A liquid replacement device, characterized in that it comprises: 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; and The liquid removal component is used to remove residual reagents after the reaction on the biochip is completed. The liquid 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 in the liquid adding cavity to be discharged from the liquid outlet. The liquid 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. The liquid replacement device as described in claim 27 is characterized in that the liquid adding component also includes a liquid storage structure stacked on the inkjet chip, the liquid storage structure includes at least one liquid storage cavity connected to the liquid adding cavity, and the liquid storage cavity is used to store the reagent. The liquid 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 corresponding 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. The liquid 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. The liquid replacement device as described in claim 26 is characterized in that the liquid adding component also includes a reagent storage box connected to the inkjet chip. The liquid replacement device as described in claim 26 is characterized in that the liquid removal component is used to provide positive pressure or negative pressure to blow away or suck away the residual reagent on the biochip. The liquid exchange device as described in claim 33 is characterized in that the liquid removal component 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. The liquid replacement device according to claim 34, characterized in that the air knife includes a The invention discloses an air knife cavity connected to the air knife cavity, and a cutter head connected to the air knife cavity, wherein the cutter head is used to limit the airflow direction of the compressed gas. The liquid exchange device as described in claim 35 is characterized in that 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, and an air blowing port is provided on the inclined surface. The fluid exchange device as described in claim 26 is characterized in that the fluid exchange device also includes a linkage structure, the fluid adding component and the fluid removing component are arranged on the linkage structure, and the linkage structure is used to link the fluid adding component and the fluid removing component. The fluid exchange device as described in claim 37 is characterized in that the linkage structure includes 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 installed on the driving motor. A biochemical substance analysis system, characterized in that it includes: 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. The biochemical substance analysis system as described in claim 39 is characterized in that the temperature in the reaction chamber is adjustable. The biochemical substance analysis system as described in claim 40 is characterized in that 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, the 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. The biochemical substance analysis system as described in claim 41 is characterized in that the top wall includes a water storage cavity, and the 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. The biochemical substance analysis system as described in claim 42 is characterized in that the side wall has a vent hole, and the reaction chamber is connected to the outside through the vent hole. The biochemical substance analysis system as described in claim 39 is 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. The biochemical substance analysis system as described in claim 44 is characterized in that the liquid replacement device is slidably arranged on the inner wall of the biochemical reaction device through a linkage structure. The biochemical substance analysis system according to claim 39, characterized in that the biochip includes a The biosensing layer of the liquid replacement device and the sensor layer stacked on the biosensing layer close to the carrier, 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. The biochemical substance analysis system as described in claim 39 is characterized in that the biochemical substance analysis system also 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. A biochemical substance analysis method, characterized by comprising: 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; and 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. The biochemical substance analysis method according to claim 48, characterized in that the biochip further comprises a sensor layer stacked on the side of the biosensing layer close to the carrier, and after the sample to be detected in the biochip reacts with the reagent layer, the method further comprises: 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. The biochemical substance analysis method as described in claim 48 is 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 biological chip.