CN109164157B - Detection system for biochemical detection - Google Patents
Detection system for biochemical detection Download PDFInfo
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- CN109164157B CN109164157B CN201811260375.6A CN201811260375A CN109164157B CN 109164157 B CN109164157 B CN 109164157B CN 201811260375 A CN201811260375 A CN 201811260375A CN 109164157 B CN109164157 B CN 109164157B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
- G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
- G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
- G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
- G01N27/4146—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS involving nanosized elements, e.g. nanotubes, nanowires
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
- G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
- G01N27/4148—Integrated circuits therefor, e.g. fabricated by CMOS processing
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Abstract
The invention provides a MOSFET type micro-film sensor for biochemical detection, a detection system and a detection method, wherein the MOSFET type micro-film sensor comprises a substrate, a hollow part arranged on the substrate, a micro-film positioned in the hollow part, four supporting micro-cantilevers and an MOSFET output structure on the supporting micro-cantilevers; the four supporting micro-cantilevers are symmetrically arranged, one end of each supporting micro-cantilever is connected with the micro-film, the other end of each supporting micro-cantilever is connected with the external substrate and then fixed, and the MOSEFET output structures on the four supporting micro-cantilevers are a pair of symmetrically arranged PMOS structures and a pair of symmetrically arranged NMOS structures. The invention has convenient use and strong anti-interference capability of the sensor, and can ensure the measurement precision; the sensor can be processed and manufactured by adopting MEMS, the cost is low, and the sensor can be ensured to have good consistency; the sensor and the corresponding detection system have strong universality and can be used for detection and monitoring in the fields of biomedicine, chemistry, food safety, environmental pollution and the like.
Description
Technical Field
The invention mainly relates to the technical field of sensors for micro-nano scale biochemical detection, in particular to a MOSFET type micro-film sensor, a detection system and a detection method. The sensor and the corresponding detection system can be used for detection and monitoring in the fields of biomedicine, chemistry, food safety, environmental pollution and the like.
Background
In the biochemical detection aspects, such as pathogen detection, early cancer diagnosis based on antibody-antigen and aptamer, gas detection, heavy metal detection and the like, a plurality of methods can be realized, and liquid chromatography, tandem mass spectrometry, enzyme-linked immunosorbent assay and the like are common. Such methods are time consuming, labor intensive, and expensive. For this reason, new methods such as surface plasmon resonance, quartz crystal microbalance, carbon nanotubes, microcantilever, etc. are emerging. The micro-cantilever beam does not need to be marked, and the detection sensitivity is higher than that of other detection methods, so that the micro-cantilever beam is widely regarded in the last decade. The common micro-cantilever adopts an optical detection method, namely, when the probe molecules on the gold surface of the micro-cantilever and the target molecules to be detected have specific reaction, the micro-cantilever can be bent and deformed, the light beams emitted to the gold surface of the micro-cantilever can be deflected after being reflected, and the deflection signals are detected by a PSD device, so that the real-time information of biochemical reaction can be obtained. However, the micro-cantilever detection system based on optical detection has many problems, such as bubbles or impurities in the solution, interference, inability to detect opaque liquid, etc. In addition, the micro-cantilever beam for optical reading requires complicated alignment adjustment before use, which is time-consuming and labor-consuming. In order to overcome the defects, the piezoresistive micro-cantilever beam is produced. However, the piezoresistive micro-cantilever is sensitive to the environmental temperature, and the sensitivity of the piezoresistive micro-cantilever cannot reach the micro-cantilever which is optically read.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides the MOSFET type micro-thin film sensor, the detection system and the detection method for biochemical detection by combining the prior art and starting from practical application.
The technical scheme of the invention is as follows:
the MOSFET type micro-film sensor for biochemical detection comprises a substrate, a hollow part arranged on the substrate, a micro-film positioned in the hollow part, four supporting micro-cantilevers and an MOSFET output structure on the supporting micro-cantilevers;
the four supporting micro-cantilevers are symmetrically arranged, one end of each supporting micro-cantilever is connected with the micro-film, the other end of each supporting micro-cantilever is connected with the external substrate and then fixed, and the MOSEFET output structures on the four supporting micro-cantilevers are a pair of symmetrically arranged PMOS structures and a pair of symmetrically arranged NMOS structures.
The micro-film component is silicon or silicon dioxide or silicon nitride, the thickness of the micro-film is less than 1.5 microns, and the micro-film is square or round.
The four supporting micro-cantilevers for supporting the micro-thin film are rectangular, the length, the width and the thickness of the four supporting micro-cantilevers are in a micron level, and the components of the supporting micro-cantilevers are silicon or silicon dioxide or silicon nitride.
And the MOSFET output metal electrodes on the four supporting micro-cantilevers are subjected to insulation packaging through silicon or silicon dioxide or silicon nitride.
The NMOS structure comprises a P-type silicon substrate, an N-type drain electrode D and a source electrode S, a grid electrode G formed by polycrystalline silicon, and metal electrodes led out of the drain electrode D, the source electrode S and the grid electrode G are made of aluminum or gold and are subjected to insulation treatment by SiO 2.
The PMOS output structure comprises an N-type silicon substrate, a P-type drain electrode D and a source electrode S, a grid electrode G formed by polycrystalline silicon doped WSix, metal electrodes led out of the drain electrode D, the source electrode S and the grid electrode G are made of aluminum or gold, and insulation treatment is conducted through SiO 2.
The MOSFET type micro-film sensor is manufactured by adopting an MEMS process.
A detection system using a MOSFET type micro-thin film sensor,
the supporting micro cantilever MOSFET of the micro-film sensor outputs NMOS1, PMOS1, NMOS2 and PMOS2, wherein the gate of the NMOS1 is connected with positive voltage Vg, the drain is connected with positive voltage VDD, the source is connected with the ground through a resistor R1, and the output voltage is VNMOS1(ii) a PMOS1 gate connected to negative voltage Vg, drain connected to negative voltage-VDD, source connected to ground via resistor R2, and output voltage VPMOS1；
NMOS2 has gate connected to positive voltage Vg, drain connected to positive voltage VDD, source connected to ground via resistor R4, and output voltage VNMOS2(ii) a PMOS1 gate connected to negative voltage Vg, drain connected to negative voltage-VDD, source connected to ground via resistor R3, and output voltage VPMOS2；
VNMOS1And VPMOS2The amplification factor of an access instrument amplifier IC1 and IC1 is determined by Rg and VPMOS1And VNMOS2An instrumentation amplifier IC2 is connected, the amplification factor of IC2 is determined by Rg, and the output of the instrumentation amplifier is formed by IC3The summation circuit performs summation to output a final signal Vout。
A detection method using MOSFET type micro-film sensor is characterized by that when the micro-film sensor is used, the biochemical modification is made on one surface of the micro-film to form specific probe molecule.
The biochemical molecules at least comprise an aptamer, an antibody, an antigen, DNA, biotin, gas and water.
The invention has the beneficial effects that:
according to the invention, the sensor micro-film is used as a contact surface for responding external information, when probe molecules on the biochemically modified micro-film and target molecules to be detected have specific reaction, the sensor micro-film can be deformed, namely convex or concave, so that four connecting micro-cantilevers supporting the sensor micro-film are bent, the output of an MOSFET (metal-oxide-semiconductor field effect transistor) is changed due to the bending of the micro-cantilevers, signals are acquired in real time through a subsequent processing circuit, the real-time monitoring of the biochemical information is realized, the whole use is convenient, the sensor has strong anti-interference capability, and the measurement precision can be ensured; the sensor can be processed and manufactured by adopting MEMS, the cost is low, and the sensor can be ensured to have good consistency; the sensor and the corresponding detection system have strong universality and can be used for detection and monitoring in the fields of biomedicine, chemistry, food safety, environmental pollution and the like.
Drawings
Fig. 1 is a schematic front view of a MOSFET type micro-thin film sensor.
FIG. 2 is a schematic diagram of an NMOS output structure.
FIG. 3 is a schematic diagram of a PMOS output structure.
FIG. 4 is a complementary NMOS and PMOS output circuit.
Fig. 5 is an NMOS output characteristic curve.
Fig. 6 is a PMOS output characteristic curve.
FIG. 7 is a diagram of a liquid biochemical detection device.
FIG. 8 is a liquid biochemical detection response curve.
Fig. 9 is a diagram of a gas detection device.
Fig. 10 is a graph of the real-time response of the sensor to VRLA battery gassing concentration.
Fig. 11 is a graph showing the relationship between the sensor output voltage and the VRLA battery off-gas concentration.
Detailed Description
The invention is further described with reference to the accompanying drawings and specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and these equivalents also fall within the scope of the present application.
As shown in fig. 1, the MOSFET type micro thin film sensor processed by the MEMS processing technology includes an SOI substrate 11, a hollow portion 12, a square micro thin film 13 (or a circular micro thin film 17), and four supporting micro cantilevers 15, which are symmetrical to each other, one end of each of the four supporting micro cantilevers 15 is connected to the micro thin film 13 or 17, the other end of each of the four supporting micro cantilevers is fixed to the external silicon substrate 11, and a MOSFET output PMOS structure 14 and an NMOS structure 16 on the supporting micro cantilevers 15 are paired and symmetrical.
The component of the micro-film 13 (or 17) is silicon or silicon dioxide or silicon nitride. The micro-film 13 has a thickness of less than 1.5 microns.
The four supporting micro-cantilevers 15 for supporting the micro-thin film 13 are rectangular, and the length, the width and the thickness are all in micron level. The supporting micro-cantilever 15 is made of silicon or silicon dioxide or silicon nitride.
The MOSFET output structures on the supporting micro-cantilever 15 are complementary structures, i.e. one pair is PMOS type and the other pair is NMOS type.
As shown in fig. 2, the NMOS output structure 16 includes a P-type silicon substrate, an N-type drain D and a source S, a gate G made of polysilicon, and a metal electrode led out of the drain D, the source S and the gate G is aluminum or gold, and is insulated by SiO 2.
As shown in fig. 3, the PMOS output structure 14 includes an N-type silicon substrate, a P-type drain D and a source S, a gate G made of polysilicon doped WSix, and a metal electrode led out from the drain D, the source S and the gate G is aluminum or gold, and is insulated by SiO 2.
The PMOS and NMOS internal structures include, but are not limited to, the structures shown in fig. 2 and 3.
As shown in fig. 4, the micro-cantilever MOSFET outputs NMOS1, PMOS1, NMOS2, PMOS2 are supported. NMOS1 has gate connected to positive voltage Vg, drain connected to positive voltage VDD, source connected to ground via resistor R1, and output voltage VNMOS1(ii) a PMOS1 gate connected to negative voltage Vg, drain connected to negative voltage-VDD, source connected to ground via resistor R2, and output voltage VPMOS1。
NMOS2 has gate connected to positive voltage Vg, drain connected to positive voltage VDD, source connected to ground via resistor R4, and output voltage VNMOS2(ii) a PMOS1 gate connected to negative voltage Vg, drain connected to negative voltage-VDD, source connected to ground via resistor R3, and output voltage VPMOS2。
VNMOS1And VPMOS2The amplification factor of an access instrument amplifier IC1 and IC1 is determined by Rg and VPMOS1And VNMOS2The meter amplifier IC2 is connected, the amplification factor of IC2 is determined by Rg, the output of the meter amplifier is summed by a summing circuit formed by IC3, and a final signal V is outputout。
Fig. 5 and 6 are NMOS and PMOS output characteristic curves, respectively.
When in use, the single side (front side or back side) of the micro-film is biochemically modified. For example, when the surface of the micro-thin film is silicon nitride, the surface of the micro-thin film is aminated with an APTES reagent, and biomolecules such as antibodies are bound thereto by means of self-assembly (SAM) to form specific probe molecules.
Such biomolecules include, but are not limited to, aptamers, antibodies, antigens, DNA, biotin, and the like.
The present invention will be further described with reference to the following examples, but is not limited to the examples.
Example 1: detection of botulinum toxin type A by MOSFET type micro-thin film sensor
As shown in FIG. 7, the MOSFET type micro thin film sensor 24 is connected to a circuit board 25, the circuit board 25 is connected to a PC 27, syringe pumps 21, 26 are connected to a container 22, and a thermostat 23 is attached to the bottom of the container 22.
Sequentially cleaning the surface of the sensor micro-film by using acetone, absolute ethyl alcohol and deionized water, then dripping a solution of H2O2/H2SO4 (1:3) on the surface of the sensor micro-film, sequentially cleaning for a plurality of times by using the absolute ethyl alcohol and the deionized water after 2 minutes, and drying by using nitrogen; injecting 3-Aminopropyltriethoxysilane (APTES) ethanol solution into a container, standing at room temperature for 3 hours for silanization treatment, and cleaning the container with deionized water for multiple times; the glutaraldehyde solution was poured into the vessel and left at room temperature for 3 hours, and the vessel was washed with deionized water several times.
Dropping Phosphate Buffer Solution (PBS) buffer solution of botulinum toxin type A antibody on the surface of the modified sensor micro-film, and placing the whole container in a constant temperature environment of 37 ℃ for 1 hour. The sensor and the entire container were washed with phosphate buffer (pH 7.4) to remove unreacted antibodies. Bovine serum albumin (BSA, 0.05% w/v) was purified from the non-reacted portion of the sensor for 1 hour.
Milk without botulinum toxin type A, milk with botulinum toxin type A contents of 10ng/ml and 20ng/ml, respectively, were separately injected into the vessel 22 under the same conditions using syringe pumps. The microfilm bulges to different degrees in the milk liquid of botulinum toxin type A at different depths, resulting in a change in the output signal.
As shown in FIG. 8, the three output voltage signal curves correspond to pure milk and milk containing 10ng/ml and 20ng/ml of botulinum toxin type A, i.e. the curves corresponding to different concentrations of botulinum toxin type A are different. Subtracting the output voltage signal curve of pure milk from the output voltage signal curve corresponding to the milk with the botulinum toxin type A content of 10ng/ml and 20ng/ml to obtain the change signal of the actual concentration.
Example 2: VRLA battery gassing detection
As shown in fig. 9, the MOSFET type micro thin film sensor 38 is connected to a circuit board 39 through a wire 36, the circuit board 39 is connected to a PC 310, and the sensor 38 is placed in a sealed container 37. The container 31 for storing pure air and the container 32 for storing the gas released from the VRLA battery are mixed by control valves 33 and 34, respectively, and sent into a sealed container 37 through a glass tube 35. By controlling the on-time of the valves 33, 34, the concentration of VRLA battery gassing in the sealed container 37 can be varied.
During the experiment, the valves 33 and 34 are controlled to adjust the proportion of the gas released by the VRLA battery in the container 37 to 20%, 30%, 40%, 70% and 80% respectively. Fig. 10 is a real-time response curve of different proportions, and fig. 11 is a fitting result according to the response curve of fig. 10, which still reflects a better linear relationship due to a certain error in adjusting the proportions by manually controlling the valves 33 and 34.
Claims (7)
1. Detection system for biochemical detection, using a micro-thin-film sensor of the MOSFET type, characterized in that: the micro-film type micro-cantilever structure comprises a substrate, a hollow part arranged on the substrate, a micro-film positioned in the hollow part, four supporting micro-cantilevers and an MOSFET output structure on the supporting micro-cantilevers; the four supporting micro-cantilevers are symmetrically arranged, one end of each supporting micro-cantilever is connected with the micro-film, the other end of each supporting micro-cantilever is connected with the external substrate and then fixed, and the MOSEFET output structures on the four supporting micro-cantilevers are a pair of symmetrically arranged PMOS structures and a pair of symmetrically arranged NMOS structures;
the MOSFET on the supporting micro cantilever beam of the micro-film sensor outputs NMOS1, PMOS1, NMOS2 and PMOS2, wherein the gate of the NMOS1 is connected with positive voltage Vg, the drain of the NMOS1 is connected with positive voltage VDD, the source of the NMOS is connected with the ground through a resistor R1, and the output voltage of the NMOS is VNMOS 1; the gate of the PMOS1 is connected with a negative voltage Vg, the drain is connected with a negative voltage-VDD, the source is connected with the ground through a resistor R2, and the output voltage is VPMOS 1;
the gate of the NMOS2 is connected with a positive voltage Vg, the drain is connected with a positive voltage VDD, the source is connected with the ground through a resistor R4, and the output voltage is VNMOS 2; the gate of the PMOS2 is connected with a negative voltage Vg, the drain is connected with a negative voltage-VDD, the source is connected with the ground through a resistor R3, and the output voltage is VPMOS 2;
VNMOS1 and VPMOS2 are connected to an instrument amplifier IC1, the amplification factor of the instrument amplifier IC1 is determined by a resistor Rg, VPMOS1 and VNMOS2 are connected to an instrument amplifier IC2, the amplification factor of the instrument amplifier IC2 is determined by a resistor Rg, the outputs of the instrument amplifier IC1 and the instrument amplifier IC2 are summed through a summing circuit formed by the instrument amplifier IC3, and a final signal Vout is output.
2. The detection system for biochemical detection according to claim 1, wherein: the micro-film component is silicon or silicon dioxide or silicon nitride, the thickness of the micro-film is less than 1.5 microns, and the micro-film is square or round.
3. The detection system for biochemical detection according to claim 1, wherein: the four supporting micro-cantilevers are rectangular, the length, the width and the thickness of the four supporting micro-cantilevers are in a micron level, and the components of the supporting micro-cantilevers are silicon or silicon dioxide or silicon nitride.
4. The detection system for biochemical detection according to claim 1, wherein: and the MOSFET output metal electrodes on the four supporting micro-cantilevers are subjected to insulation packaging through silicon or silicon dioxide or silicon nitride.
5. The detection system for biochemical detection according to claim 1, wherein: the NMOS structure comprises a P-type silicon substrate, an N-type drain D and a source S, a grid G formed by polycrystalline silicon, and a metal electrode led out from the drain D, the source S and the grid G is made of aluminum or gold and is made of SiO2And (5) performing insulation treatment.
6. The detection system for biochemical detection according to claim 1, wherein: the PMOS structure comprises an N-type silicon substrate, a P-type drain electrode D and a source electrode S, a grid electrode G formed by polycrystalline silicon doped with WSix, and a metal electrode led out from the drain electrode D, the source electrode S and the grid electrode G is made of aluminum or gold and is made of SiO2And (5) performing insulation treatment.
7. The detection system for biochemical detection according to claim 1, wherein: the MOSFET type micro-film sensor is manufactured by adopting an MEMS process.
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