A MEMS detection sensor and detection method

Abstract

The present invention belongs to the technical field of sensors for biomolecule detection, and specifically relates to a MEMS sensor with detection function and a detection method, which can assemble a molecular layer membrane on the surface of the sensor sensitive unit to specifically bind to the substance to be detected, and convert the signal changes before and after the specific binding of the two into electrical signal output for detection, thereby solving the technical problems of complex operation and low detection efficiency caused by the use of fluorescent labels in traditional PCR and ELISA detection methods.

Description

Technical Field

[0001] The present invention relates to the technical field of sensors for biomolecule detection, and specifically to a MEMS sensor with detection function and a detection method, which can assemble a molecular layer membrane on the surface of the sensor sensitive unit to specifically bind to the substance to be detected, and convert the signal changes before and after the specific binding of the two into electrical signal output, thereby realizing a new sensor and detection method with detection function. Background Art

[0002] Molecular testing refers to the technology of using molecular biological methods to detect changes in the structure or expression level of genetic material in the patient's body to make a diagnosis. Molecular testing is the main method of predictive diagnosis. It can be used to diagnose individual genetic diseases and prenatal diagnosis. Molecular diagnosis mainly refers to the detection of genes encoding various structural proteins, enzymes, antigens and antibodies, and immune-active molecules related to the disease.

[0003] At present, the commonly used detection methods of traditional molecular detection include PCR, ELISA, electron microscopy technology, gene chips and other types. PCR, also known as polymerase chain reaction, is a method for rapid amplification of gene fragments in vitro. It can amplify specific gene fragments in a small amount of genomic DNA or RNA samples by millions of times in just a few hours, with high specificity and accuracy. ELISA, also known as enzyme-linked immunosorbent assay, refers to a qualitative and quantitative detection method that combines soluble antigens or antibodies with solid phase carriers such as polystyrene and uses the specific binding of antigens and antibodies to perform immune reactions.

[0004] PCR and ELISA are currently the most commonly used methods for rapid detection of food pathogens. However, because both require the use of fluorescent labeling methods and a series of complex biochemical processing processes to achieve detection functions, the operation is cumbersome and the hybridization time is long, often taking several hours or even days. The expensive probe labeling and modification have not fundamentally reduced the detection time of pathogens and increased the detection speed, making it difficult to meet the actual requirements of rapid detection.

[0005] Therefore, in view of the technical problems in the current molecular detection field that the sensor needs fluorescent labeling during the detection process, the detection time is long, and the sensitivity is low, a solution is needed to solve the problems in the existing technology.

[0006] MEMS sensor, or micro-electromechanical system, is a new type of sensor manufactured using microelectronics and micromachining technology. Compared with traditional sensors, it has the characteristics of small size, light weight, low cost, low power consumption, high reliability, suitable for mass production, easy integration and intelligentization. At the same time, the characteristic size of the micron level enables it to complete certain functions that traditional mechanical sensors cannot achieve. As a new detection technology, MEMS sensor has the characteristics of fast detection speed, high sensitivity, strong practicality and low-cost detection. It has gradually become the focus of attention in various fields such as molecular detection, biomedicine, chemistry, and environmental engineering, and has received more and more attention and research. Summary of the invention

[0007] The present invention provides a MEMS detection sensor, which can at least solve some of the problems existing in the prior art.

[0008] To solve the above technical problems, according to one aspect of the present invention, the present invention provides the following technical solutions:

[0009] A MEMS detection sensor comprises a sensor unit and a piezoelectric module, wherein the piezoelectric module is arranged on one side of the sensor unit;

[0010] The sensor unit includes an upper conductive plate, a lower conductive plate and a supporting structure. The upper conductive plate of the sensor unit is in a suspended state under the support of the supporting structure. An aptamer molecule layer membrane for specific binding is provided on the surface of the upper conductive plate. After the aptamer molecule layer membrane specifically binds to the substance to be detected, the relative area and / or relative distance between the upper conductive plate and the lower conductive plate changes.

[0011] As a preferred solution of a MEMS detection sensor described in the present invention, wherein: the sensor unit is arranged above the substrate and arranged in an array structure, the sensor unit includes a detection unit and a reference unit, and the detection unit and the reference unit are arranged adjacent to each other on the substrate.

[0012] As a preferred solution of a MEMS detection sensor described in the present invention, the supporting structure includes a pillar structure and a serpentine beam structure which are connected to each other, wherein the two ends of the serpentine beam structure are respectively connected to an upper conductive plate and the pillar structure, the lower conductive plate is arranged on the surface of the substrate, the pillar structure is arranged at the outer edge of the lower conductive plate, and the two sides of the upper conductive plate are respectively connected to the serpentine beam structure.

[0013] As a preferred solution of the MEMS detection sensor described in the present invention, wherein: the piezoelectric module is connected to the alternating electric field.

[0014] As a preferred solution of a MEMS detection sensor described in the present invention, the connecting line between the two ends of the serpentine beam structure and the connecting line between the centers of the upper conductive plate and the lower conductive plate are the same straight line.

[0015] As a preferred solution of the MEMS detection sensor described in the present invention, a sensitive layer is also provided on the surface of the upper conductive plate.

[0016] As a preferred solution of the MEMS detection sensor described in the present invention, the sensitive layer is made of any one of metal and two-dimensional material.

[0017] As a preferred solution of the MEMS detection sensor described in the present invention, the surface of the upper conductive plate of the reference unit is provided with an anti-fouling molecular layer for preventing non-specific binding.

[0018] To solve the above technical problem, according to another aspect of the present invention, the present invention provides the following technical solution:

[0019] A detection method for a MEMS detection sensor comprises the following steps:

[0020] Apply an alternating electric field to the piezoelectric module of the MEMS detection sensor, and then immerse it in a test solution containing the substance to be detected;

[0021] Set the detection temperature and detection time to allow the sensor unit to fully combine with the substance to be detected;

[0022] According to the test results of the detection unit and the reference unit, the detection limit of the substance to be detected is obtained.

[0023] As a preferred embodiment of the detection method of a MEMS detection sensor described in the present invention, the detection limit of the substance to be detected is obtained according to the detection results of the detection unit and the reference unit, which includes the following steps:

[0024] The concentration of the substance to be detected in the test solution is gradually increased from zero, and the test solution is added to the surface area of ​​the sensitive membrane of the detection unit. The color change and degree on the surface of the detection unit and the reference unit are compared, and the detection limit of the detection unit for the substance to be detected is obtained by calculation.

[0025] The beneficial effects of the present invention are as follows:

[0026] 1. The present invention provides a novel MEMS detection sensor structure, which utilizes the aptamer molecular layer membrane on the surface of the sensor to specifically bind to the substance to be detected, and converts the signal changes before and after the detection into electrical signals for output. It does not require the use of fluorescent labeling operations in traditional PCR and ELISA detection methods, which can greatly reduce the detection operation and detection time, greatly improve the detection efficiency and detection sensitivity, and the sensitivity can reach ng / ml.

[0027] 2. The MEMS detection sensor provided by the present invention includes a detection unit and a reference unit. A sensitive layer metal film and an adapter molecular layer membrane are arranged on the surface of the detection unit, which can specifically bind to the substance to be detected. The surface of the reference unit is modified with an anti-fouling molecular layer to prevent non-specific binding of the substance to be detected. The detection signal of the reference unit can be used as noise. The detection limit of the substance to be detected can be calculated through the detection difference between the detection unit and the reference unit. The detection operation is simple, and the detection efficiency and detection accuracy are significantly improved.

[0028] 3. The present invention adopts a piezoelectric module to drive the sensor array. Compared with other driving methods, the piezoelectric driving method has the advantages of simple structure, low power consumption, fast response speed, high temperature resistance and strong anti-interference ability.

[0029] 4. By applying an alternating electric field to the piezoelectric module, the piezoelectric crystal lattice changes under the action of the electric field, causing overall mechanical vibration, thereby generating shear force in the XY direction on the sensor array. The shear force in the XY direction has no component in the Z-axis direction, so the sound wave energy will not be dissipated vertically into the liquid, ensuring that the sound wave energy is limited to the chip surface, and the minimum energy attenuation can be maintained in the liquid phase detection environment to achieve the detection of the target substance. When the substance to be detected is added to the sensor array, the shear force can also effectively remove non-specific binding substances, thereby improving the authenticity and accuracy of the detection. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0031] Figure 1 A schematic diagram showing the structure of the MEMS sensor array of the present invention;

[0032] Figure 2 It is a schematic diagram of the structure of the MEMS detection sensor unit of the present invention;

[0033] Figure 3 It is a schematic diagram of the structure of the detection unit and the reference unit of the MEMS detection sensor unit of the present invention;

[0034] Figure 4 It is a schematic diagram of the detection principle of the MEMS detection sensor of the present invention.

[0035] Description of Figure Numbers:

[0036] 1-sensor unit, 2-piezoelectric module, 3-detection unit, 4-reference unit, 5-substrate, 6-upper conductive plate, 7-lower conductive plate, 8-pillar structure, 9-serpentine beam structure, 10-aptamer molecular layer membrane, 11-antifouling molecular layer, 12-specific binding substance, 13-sensitive layer.

[0037] The realization of the purpose, functional features and advantages of the present invention will be further explained in conjunction with embodiments and with reference to the accompanying drawings. DETAILED DESCRIPTION

[0038] The following will be described clearly and completely in conjunction with the technical solutions in the embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] It should be noted that if the embodiments of the present invention involve directional indications (such as up, down, left, right, front, back, etc.), the directional indications are only used to explain the relative position relationship, movement status, etc. between the components under a certain specific posture (as shown in the accompanying drawings). If the specific posture changes, the directional indication will also change accordingly.

[0040] In addition, if there are descriptions involving "first", "second", etc. in the embodiments of the present invention, the descriptions of "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or suggesting their relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0041] The present invention provides a MEMS detection sensor and a detection method, which can conveniently and quickly realize the concentration detection of a substance to be detected. The detection method is simple to operate and has excellent detection sensitivity and accuracy.

[0042] A MEMS detection sensor comprises a sensor unit and a piezoelectric module, wherein the piezoelectric module is arranged on one side of the sensor unit;

[0043] The sensor unit includes an upper conductive plate, a lower conductive plate and a supporting structure. The upper conductive plate of the sensor unit is in a suspended state under the support of the supporting structure. An aptamer molecule layer membrane for specific binding is provided on the surface of the upper conductive plate. After the aptamer molecule layer membrane specifically binds to the substance to be detected, the relative area and / or relative distance between the upper conductive plate and the lower conductive plate changes.

[0044] The sensor units are disposed above the substrate and arranged in an array structure. The sensor units include detection units and reference units. The detection units and reference units are arranged adjacent to each other on the substrate.

[0045] The support structure includes a pillar structure and a serpentine beam structure that are interconnected, wherein: the two ends of the serpentine beam structure are respectively connected to an upper conductive plate and the pillar structure, the lower conductive plate is arranged on the surface of the substrate, the pillar structure is arranged at the outer edge of the lower conductive plate, and the two sides of the upper conductive plate are respectively connected to the serpentine beam structure. The piezoelectric module is connected to an alternating electric field. The line between the two ends of the serpentine beam structure is the same straight line as the center line between the upper conductive plate and the lower conductive plate. A sensitive layer is also provided on the surface of the upper conductive plate. The sensitive layer is made of any one of metal and two-dimensional material; specifically, the sensitive layer is a metal film, and the metal film of the sensitive layer can be a gold film. An anti-fouling molecular layer is provided on the surface of the upper conductive plate of the reference unit to prevent nonspecific binding.

[0046] The upper conductive plate is suspended in the air through a supporting structure to form a certain distance between it and the lower conductive plate. When the substance to be detected specifically binds to the aptamer molecular layer membrane, the mass load on the surface of the detection unit changes, the relative area between the upper conductive plate and the lower conductive plate changes, and then the capacitance changes. The concentration of the substance to be detected can be calculated based on the difference in change before and after the loading of the substance to be detected.

[0047] The detection sensor is equipped with a piezoelectric module, which is used to drive the entire sensor array. By applying an alternating electric field to the piezoelectric module, the piezoelectric crystal lattice changes under the action of the electric field, causing overall mechanical vibration, thereby generating shear force in the XY direction on the sensor array, which can maintain minimal energy attenuation in the liquid phase detection environment. When the substance to be detected is added to the sensor array, the shear force can also effectively remove non-specific binding substances, thereby improving the authenticity and accuracy of the detection.

[0048] According to another aspect of the present invention, the present invention also provides a detection method for a detection sensor.

[0049] A detection method for a MEMS detection sensor comprises the following steps:

[0050] Apply an alternating electric field to the piezoelectric module of the MEMS detection sensor, and then immerse it in a test solution containing the substance to be detected;

[0051] Set the detection temperature and detection time to allow the sensor unit to fully combine with the substance to be detected;

[0052] According to the test results of the detection unit and the reference unit, the detection limit of the substance to be detected is obtained.

[0053] The method of obtaining the detection limit of the substance to be detected based on the detection results of the detection unit and the reference unit comprises the following steps:

[0054] The concentration of the substance to be detected in the test solution is gradually increased from zero, and the test solution is added to the surface area of ​​the sensitive membrane of the detection unit. The color change and degree on the surface of the detection unit and the reference unit are compared, and the detection limit of the detection unit for the substance to be detected is obtained by calculation.

[0055] A sensitive layer of metal film or two-dimensional material layer, such as a gold film, is also provided on the upper conductive plate to enhance the surface activity of the upper conductive plate.

[0056] Example 1

[0057] Embodiment 1 of the present invention provides a MEMS detection sensor, such as Figure 1-4 shown.

[0058] A MEMS detection sensor comprises a sensor unit 1 and a piezoelectric module 2, wherein the piezoelectric module 2 is arranged on one side of the sensor unit 1;

[0059] The sensor unit 1 includes an upper conductive plate 6, a lower conductive plate 7 and a supporting structure. The upper conductive plate 6 of the sensor unit 1 is in a suspended state under the support of the supporting structure. An aptamer molecule layer membrane 10 for specific binding is provided on the surface of the upper conductive plate 6. After the aptamer molecule layer membrane 10 specifically binds to the substance to be detected, the relative area and / or relative distance between the upper conductive plate 6 and the lower conductive plate 7 changes.

[0060] The sensor unit 1 is disposed above the substrate 5 and arranged in an array structure. The sensor unit 1 includes a detection unit 3 and a reference unit 4 . The detection unit 3 and the reference unit 4 are arranged adjacent to each other on the substrate 5 .

[0061] The supporting structure includes a pillar structure 8 and a serpentine beam structure 9 which are connected to each other, wherein: the two ends of the serpentine beam structure 9 are respectively connected to the upper conductive plate 6 and the pillar structure 8, the lower conductive plate 7 is arranged on the surface of the substrate 5, the pillar structure 8 is arranged at the outer edge of the lower conductive plate 7, and the two sides of the upper conductive plate 6 are respectively connected to the serpentine beam structure 9.

[0062] The piezoelectric module 2 is connected to an alternating electric field. The line between the two ends of the serpentine beam structure 9 and the center line of the upper conductive plate 6 and the lower conductive plate 7 are the same straight line. A sensitive layer 13 is also provided on the surface of the upper conductive plate 6, and the sensitive layer 13 is a gold film. An anti-fouling molecular layer 11 is provided on the surface of the upper conductive plate 6 of the reference unit 4 to prevent nonspecific binding.

[0063] Example 2

[0064] Embodiment 2 of the present invention provides a detection method for a MEMS detection sensor.

[0065] A detection method for a MEMS detection sensor comprises the following steps:

[0066] Apply an alternating electric field to the piezoelectric module of the MEMS detection sensor, and then immerse it in a test solution containing the substance to be detected;

[0067] Set the detection temperature and detection time to allow the sensor unit to fully combine with the substance to be detected;

[0068] According to the test results of the detection unit and the reference unit, the detection limit of the substance to be detected is obtained.

[0069] The method of obtaining the detection limit of the substance to be detected based on the detection results of the detection unit and the reference unit comprises the following steps:

[0070] The concentration of the substance to be detected in the test solution is gradually increased from zero, and the test solution is added to the surface area of ​​the sensitive membrane of the detection unit. The color change and degree on the surface of the detection unit and the reference unit are compared, and the detection limit of the detection unit for the substance to be detected is obtained by calculation.

[0071] An aptamer molecular layer membrane is arranged on the surface of the detection unit. The aptamer molecular layer membrane contains magnetic balls that capture cancer cell antibodies and can specifically bind to the cancer cells of the substance to be detected. The surface of the reference unit is modified with an anti-fouling molecular layer. The anti-fouling molecular layer is serum protein, which can prevent the non-specific binding of the substance to be detected. The measurement value of the reference electrode is used as noise. The concentration of the substance to be detected can be calculated through the detection difference between the detection unit and the reference unit. The detection operation is simple, and the detection efficiency and detection accuracy are significantly improved. The detection sensitivity can reach ng / ml.

[0072] By applying an alternating electric field to the piezoelectric module, the piezoelectric crystal lattice changes under the action of the electric field, causing overall mechanical vibration, thereby generating shear force in the XY direction on the sensor array, which can maintain minimal energy attenuation in the liquid phase detection environment. When the substance to be detected is added to the sensor array, the shear force can also effectively remove non-specific binding substances, thereby improving the authenticity and accuracy of the detection.

[0073] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent structural changes made by using the contents of the present invention specification under the inventive concept of the present invention, or directly / indirectly applied in other related technical fields are included in the patent protection scope of the present invention.

Claims

1. A MEMS detection sensor, characterized in that: It comprises a sensor unit (1) and a piezoelectric module (2), wherein the piezoelectric module (2) is arranged on one side of the sensor unit (1); The sensor unit (1) comprises an upper conductive plate (6), a lower conductive plate (7) and a support structure. The upper conductive plate (6) of the sensor unit (1) is in a suspended state under the support of the support structure. An aptamer molecule layer membrane (10) for specific binding is arranged on the surface of the upper conductive plate (6). After the aptamer molecule layer membrane (10) specifically binds to a substance to be detected, the relative area and / or relative distance between the upper conductive plate (6) and the lower conductive plate (7) changes.

2. A MEMS detection sensor according to claim 1, characterized in that: The sensor unit (1) is disposed above the substrate (5) and arranged in an array structure. The sensor unit (1) comprises a detection unit (3) and a reference unit (4). The detection unit (3) and the reference unit (4) are arranged adjacent to each other on the substrate (5).

3. A MEMS detection sensor according to claim 2, characterized in that: The support structure comprises a pillar structure (8) and a serpentine beam structure (9) which are connected to each other, wherein: the two ends of the serpentine beam structure (9) are respectively connected to an upper conductive plate (6) and the pillar structure (8); the lower conductive plate (7) is arranged on the surface of the substrate (5); the pillar structure (8) is arranged at the outer edge of the lower conductive plate (7); and the two sides of the upper conductive plate (6) are respectively connected to the serpentine beam structure (9).

4. A MEMS detection sensor according to claim 1, characterized in that: The piezoelectric module (2) is connected to an alternating electric field.

5. A MEMS detection sensor according to claim 3, characterized in that: The line connecting the two ends of the serpentine beam structure (9) and the line connecting the centers of the upper conductive plate (6) and the lower conductive plate (7) are the same straight line.

6. A MEMS detection sensor according to claim 1, characterized in that: A sensitive layer (13) is also provided on the surface of the upper conductive plate (6).

7. A MEMS detection sensor according to claim 6, characterized in that: The sensitive layer (13) is made of any one of metal and two-dimensional material.

8. A MEMS detection sensor according to claim 2, characterized in that: The surface of the upper conductive plate (6) of the reference unit (4) is provided with an anti-fouling molecular layer (11) for preventing non-specific binding.

9. The detection method of the MEMS detection sensor according to any one of claims 1 to 8, comprising the following steps: Apply an alternating electric field to the piezoelectric module of the MEMS detection sensor, and then immerse it in a test solution containing the substance to be detected; Set the detection temperature and detection time to allow the sensor unit to fully combine with the substance to be detected; According to the test results of the detection unit and the reference unit, the detection limit of the substance to be detected is obtained.

10. According to the detection method of the MEMS detection sensor as claimed in claim 9, the step of obtaining the detection limit of the substance to be detected based on the detection results of the detection unit and the reference unit comprises the following steps: The concentration of the substance to be detected in the test solution is gradually increased from zero, and the test solution is added to the surface area of ​​the sensitive membrane of the detection unit. The color change and degree on the surface of the detection unit and the reference unit are compared, and the detection limit of the detection unit for the substance to be detected is obtained by calculation.

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