CN117844624A

CN117844624A - Biomolecule detection device

Info

Publication number: CN117844624A
Application number: CN202410037559.5A
Authority: CN
Inventors: 林德泉; 汪源; 宋璐; 夏晓翔
Original assignee: Qitan Technology Ltd Beijing
Current assignee: Qitan Technology Ltd Beijing
Priority date: 2024-01-10
Filing date: 2024-01-10
Publication date: 2024-04-09

Abstract

The embodiment of the specification discloses a biomolecule detection device. The detection device comprises a detection unit array, wherein the detection unit array consists of one or more detection units; the detection unit comprises a nanopore, a film, a detection electrode and a sampling resistor; the film is provided with the nano holes, and the nano holes provide unique passages for polar solutions at two sides of the film; the sampling resistor is made of solid materials and is used for converting current signals of the nanopores in the process into voltage signals; the detection electrode is used for sensing the voltage signal converted by the sampling resistor.

Description

Biomolecule detection device

Technical Field

The present disclosure relates to the field of biomolecule detection technologies, and in particular, to a biomolecule detection device.

Background

Micromachining technology has played an important role in the advancement of biomolecular detection technology. The micro-machining technology can realize the flow channel unit, the detection unit and even the data transmission unit in a micro-scale range, thereby greatly improving the detection efficiency and the detection precision of the molecular detection device and even realizing a new detection function.

The molecular detection device represented by the nanopore detection device can be provided with a plurality of detection units on substrates such as monocrystalline silicon, glass and the like by utilizing a micromachining technology, each detection unit has an independent detection function, and the detection units jointly form a detection array so as to realize molecular detection. In actual detection, all detection units in the detection array detect simultaneously, so that the detection efficiency is greatly improved. With the deep application, various fields put forward further requirements on the nanopore detection device, and requirements of high-flux and even ultra-high-flux detection are met.

In the prior art, a method for improving the detection flux of a molecular detection device comprises the following steps: simultaneously detecting by using a plurality of detection devices; or more detection units are integrated on the detection device. The method for detecting by using a plurality of detection devices simultaneously has lower implementation difficulty, but the method can greatly increase the cost. Therefore, the integration of more detection units on a detection device has become an important development for improving the detection throughput of a molecular detection device.

Integrating more detection units on the detection device, i.e. increasing the number of detection units on a single detection device, if the current detection unit size is not changed, but only the number of detection units, the area of the detection device needs to be increased to accommodate the larger number of detection units, which will lead to an increase in cost. Therefore, it can be achieved only by a method of downsizing the detecting unit, that is, increasing the density of the detecting unit. However, since each detection unit is connected to the corresponding electric signal reading circuit by a chip packaging technology (such as stitching), increasing the number of detection units means that more chip packages and electric signal reading circuits are required, which also causes a significant increase in cost. Therefore, in order to solve the problem, the current solution is to integrate the electric signal reading circuit on a substrate, the substrate is generally an ASIC (Application Specific Integrated Circuit ) substrate, and then a detection unit is disposed on the ASIC substrate, and each detection unit corresponding to the ASIC substrate is provided with an independent electric signal reading circuit, so that the chip packaging process can be simplified, and no additional manufacturing of a current reading circuit chip is required, thereby not only reducing the cost, but also greatly improving the detection flux. In the prior art, the area of the existing electric signal reading circuit is difficult to be further reduced, and each detection unit correspondingly has an independent electric signal reading circuit, so that the size of the detection unit cannot be further reduced, and the detection unit becomes a bottleneck for limiting the ultra-high flux detection device.

Based on this, a new biomolecule detection device is needed to achieve ultra high throughput detection.

Disclosure of Invention

The embodiment of the specification provides a biomolecule detection device for solving the following technical problems: in the prior art, in order to improve the detection flux of the molecular detection device, the current reading circuit is generally integrated on the substrate, the substrate is generally an ASIC substrate, then the detection units are arranged on the ASIC substrate, and each detection unit corresponding to the ASIC substrate is provided with an independent current reading circuit, so that the chip packaging process can be simplified, and the current reading circuit chip is not required to be additionally manufactured, so that the cost can be reduced, and the detection flux can be greatly improved. In the prior art, the area of the current reading circuit is difficult to be further reduced, and thus the current reading circuit becomes a bottleneck for limiting the ultra-high flux detection device.

In order to solve the above technical problems, the embodiments of the present specification are implemented as follows:

the embodiment of the specification provides a biomolecule detection device, which comprises a detection unit array, wherein the detection unit array consists of one or more detection units;

the detection unit comprises a nanopore, a film, a detection electrode and a sampling resistor;

the thin film is provided with a nano hole, and the nano hole provides a unique passage for polar solutions at two sides of the thin film;

the sampling resistor is made of solid material and is used for converting a current signal flowing through the nanopore into a voltage signal;

the detection electrode is used for sensing the voltage signal converted by the sampling resistor.

The above-mentioned at least one technical scheme that this description embodiment adopted can reach following beneficial effect: according to the biomolecule detection device provided by the embodiment of the specification, the current signal flowing through the nanopore is converted into the voltage signal through the sampling resistor, and the voltage signal is further collected by the signal processing module and the voltage reading module, so that a current reading circuit is not required to be arranged for each detection unit, the occupied area of the current reading circuit can be removed, the purpose of improving the density of the detection units is achieved, the purpose of high-flux even ultra-high-flux detection is achieved, and the production cost is not required to be increased.

Drawings

In order to more clearly illustrate the embodiments of the present description or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described below, it being obvious that the drawings in the following description are only some of the embodiments described in the present description, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 (a) is a schematic diagram of a prior art detecting unit array according to an embodiment of the present disclosure;

fig. 1 (b) is a schematic diagram of the working principle of a detection unit in the prior art according to the embodiment of the present disclosure;

FIG. 2 (a) is a schematic cross-sectional view of a nanopore detection device with detection cells disposed on an ASIC substrate according to the prior art provided in the embodiments of the present disclosure;

FIG. 2 (b) is a system frame diagram of a prior art arrangement of a detection unit on an ASIC substrate provided by embodiments of the present disclosure;

FIG. 3 is a schematic diagram of a resistor voltage division method according to an embodiment of the present disclosure;

FIG. 4 (a) is a schematic cross-sectional view of a single detection unit provided in an embodiment of the present disclosure;

FIG. 4 (b) is a block diagram of a single detection unit system provided in an embodiment of the present disclosure;

FIG. 5 is a schematic diagram of a device for detecting biomolecules according to an embodiment of the present disclosure;

FIG. 6 (a) is a schematic diagram of a layout of a snake-type sampling resistor;

FIG. 6 (b) is a schematic diagram of the layout of the loop-type sampling resistor;

fig. 7 is a schematic cross-sectional view of a detection unit according to a first embodiment of the present disclosure;

fig. 8 is a schematic diagram of a process flow for preparing a detection unit according to an embodiment of the present disclosure;

fig. 9 is a schematic cross-sectional view of a detection unit according to a second embodiment of the present disclosure;

fig. 10 is a schematic diagram of a process flow for preparing a detection unit according to a second embodiment of the present disclosure;

fig. 11 is a schematic cross-sectional view of a detection unit according to a third embodiment of the present disclosure;

fig. 12 is a schematic diagram of a process flow for preparing a detection unit according to a third embodiment of the present disclosure;

fig. 13 is a schematic layout design diagram of a loop-type sampling resistor according to the second and third embodiments of the present disclosure;

fig. 14 (a) and 14 (b) are schematic diagrams of two detection units sharing one sampling resistor according to the embodiments of the present disclosure;

fig. 14 (c) is a schematic diagram of the two detection units according to the embodiment of the present disclosure sharing one sampling resistor;

fig. 14 (d) is a schematic diagram of n sampling resistors shared by m detection units according to the embodiment of the present disclosure.

Detailed Description

In order to make the technical solutions in the present specification better understood by those skilled in the art, the technical solutions in the embodiments of the present specification will be clearly and completely described below with reference to the drawings in the embodiments of the present specification, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments herein without making any inventive effort, shall fall within the scope of the present application.

In order to understand the technical problems to be solved by the embodiments of the present specification, the following description will be made with reference to specific schematic diagrams.

The existing mature nanopore detection device consists of single detection units with independent detection functions, the detection units jointly form a detection unit array, and as shown in fig. 1 (a), a plurality of detection units are arranged in the detection unit array. The detection of the nanopore detection device is realized by detecting a current signal, and fig. 1 (b) is a schematic diagram of the working principle of a detection unit in the prior art provided in the embodiment of the present specification. As shown in fig. 1 (b), each detection unit is filled with a polar solution, a detection electrode is arranged at the bottom of the detection unit, a layer of film is arranged above the detection electrode, and a nanopore is arranged on the film and is the only passage of the polar solution at two sides of the film. In practice, the analyte (e.g. DNA) to be detected is added near the detection unit, and by applying a constant voltage between the outside of the detection unit and the detection electrode, ions in the solution are driven to pass through the nanopore under the action of the electric field force, and the directional flow of such ions generates a relatively stable current and is detected by the current reading circuit at the detection electrode. In addition, the analyte to be measured also passes through the nanopore under the influence of the electric field force. The analyte to be measured, when passing through the nanopore, can cause a "plug" of the nanopore, impeding the passage of ions in the polar solution through the nanopore, thereby reducing the current. The degree of "blockage" caused by the different types of bases on the analyte to be measured is different, so that the current will change continuously during the passage of the analyte to be measured through the nanopore. Therefore, the function of sequencing the analyte to be detected can be realized by detecting and analyzing the continuously-changing current signal.

Hundreds of detection units are integrated in the mature nanopore detection device. The volume of the detection device is similar to that of a pen, and Gb-level detection data can be obtained in a short time. At present, the detection device has been widely applied in the fields of protein detection, gene sequencing, nanoparticle characterization and the like.

With the deep application, various fields also put further demands on nanopore detection devices, among which the most important is the demand for high-throughput and even ultra-high-throughput detection. The existing high-flux nanopore detection device is integrated with thousands of detection units, and the detection flux is improved by nearly 10 times compared with that of the conventional nanopore detection device. In addition, by simultaneously operating 48 high-flux detection devices, detection data exceeding 10Tb can be acquired within 72 hours, and ultra-high-flux detection can be realized.

At present, the integration of more detection units on the detection device is a main method for improving the detection flux, and the adopted solution is to integrate the electric signal reading circuit on the substrate in order to solve the problems of increasing the number of the detection units and not increasing the chip package and the electric signal reading circuit, and also not causing significant increase of the cost.

Fig. 2 (a) is a schematic cross-sectional view of a nanopore detection device of the prior art provided in the embodiments of the present disclosure, where a detection cell is disposed on an ASIC substrate. As shown in fig. 2 (a), each corresponding cell on the ASIC (Application Specific Integrated Circuit ) substrate is provided with a separate electrical signal reading circuit, including a current conversion module, a signal processing module, a voltage reading module, and corresponding interconnect leads. The detection electrode is connected with the electric signal reading circuit through the lead wire, so that the electric signal flowing through the detection electrode is transmitted to the current conversion module of the electric signal reading circuit through the lead wire.

To further understand the principle of providing a detection unit on an ASIC substrate, fig. 2 (b) is a system frame diagram provided in the embodiment of the present specification for providing a detection unit on an ASIC substrate. As shown in fig. 2 (b), the current signal flowing through the nanopore is firstly converted into a voltage signal by the current conversion module, then noise reduction processing is performed by the signal processing module, and finally the voltage signal is collected by the voltage reading module.

The high-flux detection device described above uses a current conversion module to realize the function of converting a current signal into a voltage signal, and an operational amplifier is usually manufactured in an ASIC substrate using CMOS technology as the current conversion module. In addition to converting a current signal into a voltage signal using a current conversion module, a method of converting a current signal into a voltage signal using a voltage division resistance method is also contemplated.

Fig. 3 is a schematic diagram of a resistor voltage division method according to an embodiment of the present disclosure. Voltage V _in The resistance between the two is mainly composed of an equivalent resistance R embedded with a nano hole _f And a sampling resistor R, wherein the DNA molecules pass through the nanopore during the sequencing process, and the DNA base combinations passing through the nanopore at different moments are different, so that the equivalent resistance R of the nanopore is caused _f Will change with time, i.e. the nanopore equivalent resistance R _f Can be regarded as a variable resistor. Thus, the voltage V is divided by the sampling voltage at a given moment _out Can determine the equivalent resistance R of the nano-pore _f And then, a deep learning algorithm is adopted to calculate and obtain the DNA molecular base sequence passing through the nanopore.

The reason why the above-mentioned resistive voltage dividing method has not been used in the high-flux detection device yet is that the resistance of the nanopore equivalent resistor is on the order of gΩ, and to achieve effective voltage division, the resistance of the sampling resistor needs to be at least 100mΩ, and the area occupied by implementing a large-resistance resistor such as 100mΩ by the substrate process is much larger than the area of one current conversion module. At present, the prior art proposes that a liquid resistor can be used for realizing a large-resistance resistor, but no precedent for realizing the large-resistance resistor based on a solid high-resistance material through a substrate process in a biological molecule detection device exists.

Based on this, the present inventors have conceived that if a large-resistance sampling resistor of a small size can be realized on an ASIC substrate, as shown in fig. 4 (a), the sampling resistor does not occupy the area of the electric signal reading circuit in the substrate, it is possible to omit the current conversion module from the electric signal reading circuit, thereby reducing the area of the electric signal reading circuit.

As shown in fig. 4 (b), the current signal flowing through the nanopore simultaneously flows through the sampling resistor, and a potential difference, i.e., a voltage signal, is formed across the sampling resistor, and the voltage signal is collected by the signal processing module and the voltage reading module. The design of the electric signal reading circuit does not need to use a current conversion module, so that the area of the electric signal reading circuit can be effectively reduced, and the density of the detection unit can be increased.

The embodiment of the specification provides a biomolecule detection device, which utilizes a solid sampling resistor to convert a current signal into a voltage signal, and the voltage signal is further collected by a signal processing module and a voltage reading module, so that the aim of improving the density of a detection unit is fulfilled, and the aim of high-flux or even ultra-high-flux detection is fulfilled.

Fig. 5 is a schematic diagram of a biomolecule detection device according to an embodiment of the present disclosure. In fig. 5, only one detection unit is given by way of example. As shown in fig. 5, the detection device includes a detection unit array, where the detection unit array is composed of one or more detection units;

the film is provided with the nano holes, and the nano holes provide unique passages for polar solutions at two sides of the film;

In the embodiments of the present disclosure, the film may be an amphiphilic film whose main component is amphiphilic molecules dissolved in a nonpolar solution, such as a lipid bilayer, a block polymer, or a solid film formed of an organic or inorganic material, such as an insulating material (e.g., si ₃ N ₄ 、A1 ₂ O ₃ And SiO), organic and inorganic polymers (such as polyamides), graphene, and the like;

in the present embodiments, the nanopore may be a transmembrane protein pore, including but not limited to P-toxins, such as hemolysin, anthrax toxin, and leukomodulin, and outer membrane proteins/porins of bacteria, such as mycobacterium smegmatis porins (Msp), such as MspA, hemolysin, outer membrane porin F (OmpF). The pores may be derived from CsgG. The nanopores may also be holes etched in a solid state film, which may be referred to as solid state holes;

the biomolecule detecting device provided in the embodiments of the present disclosure may be used for proteins, enzymes, DNA, RNA, or other biomolecules.

In the embodiment of the present specification, the nanopore is a pore with a size of a nanometer order, and functions as a detector of a molecule to be detected, and performs detection of the molecule to be detected.

In the embodiment of the present specification, the detection electrode is disposed at the bottom of the detection unit. In a specific embodiment, the diameter of the detection electrode is, for example, 15 μm. The detection electrode is a low-resistance material, and specifically, the detection electrode is preferably aluminum, gold, silver, or platinum.

The main component of the film is an amphiphilic molecule dissolved in nonpolar solution, the amphiphilic molecule can be phospholipid or block polymer, and the film has the characteristic of electric insulation. In this embodiment of the present disclosure, the film separates an upper cavity and a lower cavity, the upper cavity is located above the detection unit, the lower cavity is located inside the detection unit, and both the upper cavity and the lower cavity are filled with a conductive polar solution.

In the embodiments of the present disclosure, the detection unit is located on a substrate, which is monocrystalline silicon, glass, or quartz, and the substrate is preferably an ASIC substrate.

In this embodiment of the present disclosure, an insulating medium layer is further disposed between the substrate and the detection unit. In a specific embodiment, the insulating medium is an electrical insulating material, and may be silicon oxide, silicon nitride, or aluminum oxide.

In the embodiment of the specification, the head end and the tail end of the sampling resistor are respectively provided with a detection electrode through hole and a substrate through hole, the detection electrode through holes are used for connecting the sampling resistor with the detection electrode, and the substrate through holes are used for connecting the sampling resistor with the substrate.

The sampling resistor converts a part of current or voltage in the circuit into a signal which can be measured in a mode of dividing the voltage in the circuit by the resistor. By introducing a measurable resistance in the circuit, the current or voltage is converted into a corresponding voltage signal. In the embodiment of the present specification, the sampling resistor is capable of converting a current signal into a voltage signal, and the sampling resistor is a high-resistance material, and specifically, the sampling resistor is preferably polysilicon, indium Gallium Zinc Oxide (IGZO), titanium oxide, titanium nitride, or tin oxide. In particular embodiments, the design of the sampling resistor may be, for example, a serpentine or "back" type layout.

FIG. 6 (a) is a schematic diagram of a layout of a snake-type sampling resistor; fig. 6 (b) is a schematic layout diagram of the loop-type sampling resistor. As shown in fig. 6 (a), the sampling resistors are laid out in a serpentine shape, and as shown in fig. 6 (b), the sampling resistors are laid out in a loop shape. Whether the sampling resistor is laid out in a serpentine shape or in a loop shape, the sampling resistor should be located inside the detection channel wall, i.e. inside the detection channel wall edge.

In the embodiment of the present disclosure, the implementation manner of the sampling resistor includes, but is not limited to, the two modes.

In this embodiment of the present disclosure, the first and second ends of the sampling resistor are respectively provided with a detection electrode through hole and a substrate through hole, and the substrate through hole is an ASIC substrate through hole. Fig. 7 is a schematic cross-sectional view of a detection unit according to an embodiment of the present disclosure. As shown in fig. 7, the detection unit includes a detection electrode, a sampling resistor, an ASIC substrate, an insulating medium, and a detection channel wall. It is understood that the cavity formed by the walls of the detection channel to be filled with the electrically conductive polar solution serves as the detection channel. The sampling resistor is located below the detection electrode, and the total area of the sampling resistor is not larger than the bottom area of the detection unit, specifically, the bottom area of the detection unit can be the range defined by the edge of the detection channel wall.

In the embodiment of the present specification, the sampling resistor satisfies the following condition:

R＝R _s ·L/W

wherein,

r is the resistance value required to be reached by the sampling resistor;

R _s a square resistor which is the sampling resistor;

l is the length of the sampling resistor;

w is the width of the sampling resistor.

In a specific embodiment, the thickness of the sampling resistor is typically no more than, for example, 200nm.

In the first embodiment, the sampling resistor may be in a snake-shaped layout or a loop-shaped layout. It should be noted that, when the single-layer sampling resistor cannot reach the resistance value, the sampling resistor may be a multi-layer sampling resistor, and the multi-layer sampling resistor adopts a stacked structure.

Fig. 8 is a schematic diagram of a process flow for preparing a detection unit according to an embodiment of the present disclosure. As shown in fig. 8, the preparation process flow of the detection unit provided in the first embodiment includes:

etching a plurality of holes comprising substrate through holes on the insulating medium on the top surface of the substrate;

depositing a high-resistance material on the top surface of the substrate, and forming a sampling resistor by etching;

growing or depositing an insulating medium layer on the top surface of the substrate;

etching a plurality of holes comprising electrode through holes on the insulating dielectric layer on the top surface of the substrate;

depositing metal on the top surface of the substrate, and forming a detection electrode by etching, wherein the sampling resistor is arranged below the detection electrode;

and covering a structural layer on the top surface of the substrate, and forming detection channel walls by photoetching or etching, wherein the detection channel walls are used for forming a cavity to be filled with conductive polar solution.

Fig. 9 is a schematic cross-sectional view of a detection unit according to a second embodiment of the present disclosure. As shown in fig. 9, the detection unit includes a detection electrode, a sampling resistor, an ASIC substrate, an insulating medium, and a detection channel wall. The difference from the first embodiment is that the sampling resistor is transformed from a varistor material.

Fig. 10 is a schematic diagram of a process flow of manufacturing a detection unit according to a second embodiment of the present disclosure. As shown in fig. 10, the preparation process flow of the detection unit provided in the second embodiment includes:

etching a plurality of holes in an insulating medium on the top surface of the substrate;

depositing a resistance variable material on the top surface of the substrate, and patterning by etching;

etching a plurality of holes in the insulating dielectric layer on the top surface of the substrate;

depositing metal on the top surface of the substrate, and forming a detection electrode through patterning, wherein the detection electrode is partially overlapped with the varistor material;

some insulating materials, such as silicon oxide, have relatively sparse textures, oxygen or nitrogen can penetrate, and through oxidation or nitridation treatment of the substrate, the varistor material outside the area overlapped by the detection electrode can be oxidized or nitrided, so as to form the sampling resistor, and the varistor material overlapped by the detection electrode is not oxidized or nitrided due to the blocking effect of the detection electrode and is used for realizing electrical connection between the detection electrode and the sampling resistor;

and covering a structural layer on the top surface of the substrate, and forming a detection channel wall by photoetching or etching.

Fig. 11 is a schematic cross-sectional view of a detection unit according to a third embodiment of the present disclosure. As shown in fig. 11, the detection unit includes a detection electrode, a low-resistance intermediate layer made of a varistor material, a sampling resistor, an ASIC substrate, an insulating medium, and a detection channel wall formed.

In the third embodiment of the present disclosure, the difference between the second embodiment and the third embodiment is that the low-resistance intermediate layer made of a varistor material, the sampling resistor and the detection electrode are disposed on the insulating medium layer together, the sampling resistor is located outside the detection electrode, and the total area of the sampling resistor and the detection electrode is not greater than the bottom area of the detection unit.

Fig. 12 is a schematic diagram of a process flow for preparing a detection unit according to a third embodiment of the present disclosure, where, as shown in fig. 12, the process flow for preparing a detection unit according to the third embodiment includes:

oxidizing or nitriding the substrate, oxidizing or nitriding the varistor material outside the area overlapped with the detection electrode to form the sampling resistor, wherein the varistor material overlapped with the detection electrode is not oxidized or nitrided due to the blocking effect of the detection electrode and becomes a low-resistance intermediate layer, and the low-resistance intermediate layer is used for realizing the electric connection between the detection electrode and the substrate and the sampling resistor;

In the embodiment of the present disclosure, the varistor material is a material with a relatively low resistivity, and preferably, the varistor material is titanium or tin. And then forming high resistivity materials such as titanium oxide, titanium nitride, or tin oxide by oxidation or nitridation.

It should be noted that, in the preparation process of the detection unit in either the first embodiment or the second embodiment, the etching may be dry etching or wet etching.

The dry etching comprises the following steps: deep reactive ions of silicon, reactive ions, and gaseous xenon difluoride etching and reactive ions of silicon oxide, plasma, and gaseous hydrogen fluoride etching.

The etchant for wet etching the silicon layer is one or a combination of more of the following etchants: potassium hydroxide, tetramethylammonium hydroxide, or ethylenediamine catechol etching solution. The etchant for wet etching the silicon oxide layer is one or a combination of a plurality of the following etchants: hydrofluoric acid and buffered hydrofluoric acid.

In the second embodiment and the third embodiment of the present disclosure, the sampling resistor may adopt a layout of a loop type, and fig. 13 is a schematic layout design diagram of the loop type sampling resistor provided in the second embodiment and the third embodiment of the present disclosure.

In the present embodiment, in the foregoing embodiments, one sampling resistor and one electric signal reading circuit are provided for each detection unit.

In a specific embodiment, one or several pairs of the sampling resistors and the electric signal reading circuits may be shared by the plurality of detection units, where the number of the pairs of the sampling resistors and the electric signal reading circuits is smaller than the number of the plurality of detection units. In this embodiment of the present disclosure, when the plurality of detection units share a plurality of pairs of sampling resistors, a gating circuit is disposed between the nanopore and the sampling resistor, and connection between the nanopore and the sampling resistor is alternately implemented based on the gating circuit.

For further understanding of the embodiments of the present disclosure, the detection unit is provided with one or more pairs of sampling resistors and one or more detection circuits, which will be described below with reference to specific embodiments.

Fig. 14 (a) and 14 (b) are schematic diagrams of two detection units sharing one sampling resistor according to the embodiment of the present disclosure, as shown in fig. 14 (a) and 14 (b).

Fig. 14 (c) is a schematic diagram of the principle that two detection units provided in the embodiment of the present disclosure share one sampling resistor, and as shown in fig. 14 (c), a gating circuit is disposed between the nanopore a and the sampling resistor, and the gating circuit alternately connects the nanopore a and the nanopore B to the electric signal reading circuit.

Fig. 14 (d) is a schematic diagram of n sampling resistors shared by m detection units according to the embodiment of the present disclosure. As shown in fig. 14 (d), a gate circuit is provided between m nanopores and n sampling resistors, and the m nanopores are alternately connected to the electric signal reading circuit by the gate circuit.

The mode that the nanopore is connected with the detection circuit is realized based on the gating circuit, the number of sampling resistors and electric signal reading circuits can be reduced, a pair of sampling resistors and electric signal reading circuits are shared by a plurality of detection units, the density of the detection units can be further improved, and the use efficiency of the electric signal reading circuits can be improved.

By adopting the biomolecule detection device provided by the embodiment of the specification, the current signal is converted into the voltage signal through the sampling resistor, and the voltage signal is further collected by the signal processing module and the voltage reading module, so that the purpose of improving the density of the detection unit is realized, the purpose of high-flux even ultra-high-flux detection is realized, and the production cost does not need to be increased.

The foregoing describes specific embodiments of the present disclosure. Other embodiments are within the scope of the following claims. In some cases, the actions or steps recited in the claims can be performed in a different order than in the embodiments and still achieve desirable results. In addition, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In some embodiments, multitasking and parallel processing are also possible or may be advantageous.

In this specification, each embodiment is described in a progressive manner, and identical and similar parts of each embodiment are all referred to each other, and each embodiment mainly describes differences from other embodiments. In particular, for system embodiments, since they are substantially similar to method embodiments, the description is relatively simple, as relevant to see a section of the description of method embodiments.

The foregoing is merely exemplary embodiments of the present disclosure and is not intended to limit the present disclosure. Various modifications and changes may be made to the present application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc. which are within the spirit and principles of the present application are intended to be included within the scope of the claims of the present application.

Claims

1. A biomolecule detection device, wherein the detection device comprises an array of detection units, the array of detection units comprising one or more detection units;

2. The biomolecule detection device of claim 1, wherein the membrane separates an upper chamber and a lower chamber, the upper chamber being located above the detection unit, the lower chamber being located inside the detection unit, the upper chamber and the lower chamber each being filled with a conductive polar solution.

3. The biomolecule detection device according to claim 1, wherein the detection unit is located on a substrate, preferably an ASIC substrate, which is monocrystalline silicon, glass, or quartz.

4. A biomolecule detection device according to claim 3, wherein an insulating medium layer is provided between the substrate and the detection unit.

5. The molecular detection device according to claim 4, wherein the detection electrode is disposed on the insulating medium layer.

6. The biomolecule detection device of claim 1, wherein the sampling resistor is in a serpentine or "back" type arrangement or a multi-layer stack arrangement.

7. The biomolecule detection device according to claim 1, wherein the sampling resistor is a high-resistance material, preferably polysilicon, indium gallium zinc oxide, titanium nitride or tin oxide.

8. The biomolecule detection device of claim 5, wherein the sampling resistor is disposed in the insulating medium layer and below the detection electrode, and wherein a total area of the sampling resistor is not greater than a bottom area of the detection unit.

9. The biomolecule detection device of claim 5, wherein the sampling resistor is disposed in the insulating medium layer and is located outside the detection electrode, and a total area of the sampling resistor is not greater than a bottom area of the detection unit.

10. The biomolecule detecting device according to claim 8, wherein in the insulating medium layer, detecting electrode through holes and substrate through holes are respectively provided at the end-to-end ends of the sampling resistor, the detecting electrode through holes are used for connecting the sampling resistor with the detecting electrode, and the substrate through holes are used for connecting the sampling resistor with the substrate.

11. The biomolecule detection device of claim 1, wherein the sampling resistance satisfies the following condition:

R＝R _s ·L/W

wherein,

r is the resistance value required to be reached by the sampling resistor;

R _s a square resistor which is the sampling resistor;

l is the length of the sampling resistor;

w is the width of the sampling resistor.

12. The biomolecule detection device of claim 5, wherein the sampling resistor is disposed on the insulating medium layer and is located outside the detection electrode, and a total area of the sampling resistor and the detection electrode is not greater than a bottom area of the detection unit.

13. The biomolecule detection device of claim 12, further comprising a low resistance intermediate layer, wherein the detection electrode is connected to the substrate and the sampling resistor by the low resistance intermediate layer located thereunder.

14. The biomolecule detection device of claim 12, wherein a substrate via is provided in the insulating medium layer at a tail end of the sampling resistor, the substrate via being for connecting the sampling resistor to the substrate.

15. The biomolecule detection device of claim 1, wherein each of the detection units is provided with a sampling resistor and a detection circuit, or wherein a plurality of the detection units share one of the sampling resistors and one of the detection circuits.

16. The biomolecule detecting device according to claim 15, wherein when the plurality of detecting units share one sampling resistor and one detecting circuit, the biomolecule detecting device further has a gating circuit based on which connection of the plurality of detecting units to the sampling resistor and the one detecting circuit is alternately achieved.

17. The biomolecule detection device of claim 8, wherein the preparation of the detection device comprises:

18. The biomolecule detection device of claim 12, wherein the preparation of the detection device comprises:

oxidizing or nitriding the substrate, oxidizing or nitriding the varistor material outside the area overlapped with the detection electrode, and forming the sampling resistor;

19. The biomolecule detection device of claim 9, wherein the preparation of the detection device comprises:

oxidizing or nitriding the substrate, oxidizing or nitriding the varistor material outside the area overlapped by the detection electrode, thereby forming the sampling resistor;

20. A biomolecule detection device according to claims 17 to 19, wherein the etching is a dry etching or a wet etching.