CN115704800A - Virus detection device, preparation method and virus detection method - Google Patents
Virus detection device, preparation method and virus detection method Download PDFInfo
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Abstract
According to the virus detection device, the preparation method and the virus detection method provided by the embodiment of the invention, a nucleic acid probe or a virus antibody or a virus antigen for virus detection can be directly modified on the grid metal in the top metal material layer in the metal-oxide semiconductor field effect transistor chip layer.
Description
Technical Field
The invention relates to the technical field of biological detection, in particular to a virus detection device, a preparation method and a virus detection method.
Background
At present, the common way of detecting viruses is to use an electrochemical biosensor for detection. The basic principle of virus detection by electrochemical biosensors is: the fixed electrode is used as a basic electrode, the electrochemical active recognition substance is fixed on the surface of the electrode, then the target molecule is captured to the surface of the electrode through the specific recognition function among biological molecules, and the basic electrode converts a concentration signal into an electric signal as a response signal, thereby realizing the quantitative or qualitative analysis of the target substance (such as virus).
However, the existing electrochemical biosensor needs not only to introduce an electrochemical active identifier, but also needs a special preparation process for preparation, and the compatibility of the preparation process is poor.
Disclosure of Invention
The embodiment of the invention aims to provide a virus detection device, a preparation method and a virus detection method, so as to improve the compatibility of the prepared virus detection device.
To achieve the object of the embodiments of the present invention, an embodiment of the present invention provides a virus detection device, including: a metal-oxide semiconductor field effect transistor die slice layer and a micro-channel layer;
the metal-oxide semiconductor field effect tube core sheet layer comprises a field effect tube functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is internally provided with a grid metal, a source metal and a drain metal which are correspondingly connected with the grid, the source and the drain, and the grid metal is modified with a nucleic acid probe or a virus antibody or a virus antigen for virus detection;
the micro-flow channel layer is arranged on the top metal material layer; the micro-channel layer is internally provided with a micro-channel reactor positioned on the grid metal, and the micro-channel reactor is used for reacting a detected sample with a nucleic acid probe or a virus antibody or a virus antigen modified on the top metal material layer.
Preferably, the metal material of the top metal material layer is aluminum or gold.
Preferably, when the metal material of the top metal material layer is aluminum, the metal gate is modified with a nucleic acid probe or a virus antibody or a virus antigen through an amide bond constructed by the reaction of a bridging molecule loaded on the surface of the aluminum metal and the nucleic acid probe or the virus antibody or the virus antigen modified with carboxyl at the end group;
the bridging molecule comprises: a siloxane-based molecule; 3-aminopropyltriethoxysilane is preferred.
Preferably, when the metal material of the top metal material layer is gold, the nucleic acid probe is modified on the gate metal through a gold-sulfur bond constructed by the reaction of the gold metal and the nucleic acid probe modified with a sulfur group at the end group; or the grid metal is modified with a virus antibody or a virus antigen through a gold-sulfur bond which is constructed by the reaction of gold metal and the virus antibody or the virus antigen with sulfur radicals;
in order to achieve the purpose of the embodiment of the present invention, the embodiment of the present invention further provides two methods for manufacturing the virus detection device.
A method of making a first virus detection device, comprising:
preparing a metal-oxide semiconductor field effect tube core sheet layer, wherein the metal-oxide semiconductor field effect tube core sheet layer comprises a field effect tube functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is internally provided with grid metal, source metal and drain metal which are correspondingly connected with the grid, the source and the drain;
the metal material of the top metal material layer is aluminum;
a micro-channel layer is arranged on the top metal material layer; the micro-channel layer is internally provided with a micro-channel reactor positioned on the grid metal, and the micro-channel reactor is used for reacting a detected sample with a nucleic acid probe or a virus antibody or a virus antigen modified on the top metal material layer;
attaching a bridging molecule to the aluminum metal surface;
reacting the bridging molecule with the nucleic acid probe modified with carboxyl at the end group or the virus antibody or the virus antigen to construct an amido bond, so that the nucleic acid probe or the virus antibody or the virus antigen is modified on the grid metal;
the bridging molecule comprises: a siloxane-based molecule; 3-aminopropyltriethoxysilane is preferred.
A second method of manufacturing a virus detection device, comprising:
preparing a metal-oxide semiconductor field effect tube core sheet layer, wherein the metal-oxide semiconductor field effect tube core sheet layer comprises a field effect tube functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is internally provided with grid metal, source metal and drain metal which are correspondingly connected with the grid, the source and the drain;
the metal material of the top metal material layer is aluminum;
replacing the grid metal with gold metal;
a micro-channel layer is arranged on the top metal material layer; the micro-channel layer is internally provided with a micro-channel reactor positioned on the grid metal, and the micro-channel reactor is used for reacting a detected sample with a nucleic acid probe or a virus antibody or a virus antigen modified on the top metal material layer;
reacting gold metal with a nucleic acid probe modified with a sulfenyl group at an end group to construct a gold-sulfur bond, so that the metal of the grid electrode is modified with the nucleic acid probe;
or the like, or, alternatively,
the gold metal reacts with the virus antibody or antigen with sulfur radicals to construct gold-sulfur bonds, so that the virus antibody or antigen is modified on the grid metal.
In order to achieve the object of the embodiment of the present invention, an embodiment of the present invention further provides a virus detection method using the above virus detection device, including:
applying test voltages between a source metal and a drain metal, and between the source metal and a gate metal of the virus detection device;
adding a detected sample into a micro-channel reactor of a virus detection device;
detecting the change of an electric signal of a conductive channel between the source metal and the drain metal before and after the conductive channel is added into a detected sample;
and determining whether the detected sample contains the target virus or not based on the change of the electric signal and the nucleic acid probe or virus antibody or virus antigen modified on the grid metal and used for virus detection.
The embodiment of the invention has the following beneficial effects:
according to the virus detection device, the preparation method and the virus detection method provided by the embodiment of the invention, a nucleic acid probe or a virus antibody or a virus antigen for virus detection can be directly modified on the gate metal in the top metal material layer in the metal-oxide semiconductor field effect transistor chip layer, and the virus detection can be realized without introducing an electrochemical activity identifier as a marker.
Meanwhile, because the commercial metal-oxide semiconductor field effect transistor chip at present usually has a top metal material layer, the metal-oxide semiconductor field effect transistor chip layer of the virus detection device provided by the embodiment of the application can be prepared without particularly complicated modification of the commercial metal-oxide semiconductor field effect transistor chip, and the metal-oxide semiconductor field effect transistor chip layer can be compatible with the current mainstream MOSFET processing technology, so that a deep foundation is laid for realizing large-scale commercial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a schematic structural diagram of a virus detection device according to an embodiment of the present invention;
FIG. 2a is a diagram illustrating an exemplary structure of a virus detection device according to an embodiment of the present invention;
FIG. 2b is a diagram showing an example of the structure of a micro-channel micro-reactor;
FIG. 2c is a top view of the metal-oxide semiconductor field effect die slice 100 of the virus detection device of FIG. 2 a;
FIG. 3a is a schematic diagram of a nucleic acid probe modified on a gate metal when the gate metal is aluminum;
FIG. 3b is a schematic diagram of the modification of virus antigen on the gate metal when the gate metal is aluminum;
FIG. 3c is a schematic diagram of the modification of virus antibodies on the gate metal when the gate metal is aluminum;
FIG. 4 is a schematic diagram of a nucleic acid probe modified on a gate metal when the gate metal is gold;
fig. 5 is a schematic flowchart of a method for manufacturing a virus detection device with aluminum gate metal according to an embodiment of the present invention;
fig. 6 is a schematic flow chart of a method for manufacturing a virus detection device with gold gate metal according to an embodiment of the present invention;
FIG. 7 is a schematic flow chart of a virus detection method according to an embodiment of the present invention;
FIG. 8 is a schematic diagram illustrating a virus detection method according to an embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In order to reduce the process complexity of preparing a virus detection device, embodiments of the present invention provide a virus detection device, a preparation method thereof, and a virus detection method, which are described in detail below.
Referring to fig. 1, fig. 1 is a schematic structural diagram of a virus detection device according to an embodiment of the present invention. The virus detection device includes: a metal-oxide semiconductor field effect die paddle 120 and a micro-channel layer 110.
As shown in fig. 1, the mosfet die paddle 120 includes: a field effect transistor functional layer 121 and a top metal material layer 122 which are arranged from bottom to top in sequence; the fet functional layer 121 includes a gate, a source, and a drain (not shown in fig. 1); the top metal material layer 122 is provided with a gate metal, a source metal and a drain metal which are correspondingly connected with the gate, the source and the drain, and the gate metal is modified with a nucleic acid probe or a virus antibody or a virus antigen for virus detection;
the micro-channel layer 110 is disposed on the top metal material layer 122; the micro-channel layer 110 is provided with a micro-channel reactor on the gate metal, and the micro-channel reactor is used for reacting the detected sample with the nucleic acid probe or the virus antibody or the virus antigen modified on the top metal material layer.
As can be seen from the virus detection device shown in fig. 1, the virus detection device provided in the embodiment of the present invention can directly modify a nucleic acid probe or a virus antibody or a virus antigen for virus detection on the gate metal in the top metal material layer in the metal-oxide semiconductor field effect transistor die sheet, and can realize virus detection without introducing an electrochemically active identifier as a marker.
Meanwhile, because the current commercial Metal-Oxide Semiconductor Field Effect Transistor chip, which is abbreviated as MOSFET (Metal-Oxide-Semiconductor Field-Effect-Transistor) in english, usually has a top Metal material layer, the Metal-Oxide Semiconductor Field Effect Transistor chip layer of the virus detection device provided by the embodiment of the application can be prepared without particularly complicated modification of the commercial Metal-Oxide Semiconductor Field Effect Transistor chip, and the Metal-Oxide Semiconductor Field Effect Transistor chip layer can be compatible with the current mainstream MOSFET processing technology, so that a deep foundation is laid for realizing large-scale commercial production.
In practical application, a metal-oxide semiconductor field effect transistor chip with a top metal layer can be purchased from a chip manufacturer, and then a micro-channel layer is prepared on the chip, so that the virus detection device provided by the embodiment of the invention is obtained.
Referring to fig. 2a, fig. 2a is a diagram illustrating a specific structure of a virus detection device according to an embodiment of the present invention.
The virus detection device shown in fig. 2a is a simple schematic diagram of a device based on an NMOS structure in a six-layer silicon-based MOSFET process. The virus detection device includes: a metal-oxide semiconductor field effect die slice and a micro-channel layer 110. Wherein, (1), (5) and (6) are 1 layer, 5 layers and 6 layers of metal, the layer where (6) is located is called a top metal material layer, and the main component of the material is aluminum. One (6) is an extended gate metal, and the two (6) are a source terminal and a drain terminal, respectively. (2) Is a polysilicon gate, i.e., a gate. (3) Is the connection hole between the layers. (4) Is an insulating silicon dioxide isolation layer, i.e., an oxide layer. (7) Is a P-type doped silicon substrate. (8) And (9) N-doped source and drain. And r is the P-doped substrate extraction.
Is a microchannel reactor in the microchannel layer 110 manufactured in the next step.
In the virus detector of the present embodiment, the metal-oxide-semiconductor field effect transistor is of an insulated gate type. It is mainly characterized by an insulating layer between the gate and the channel, such as: a silicon dioxide insulating layer.
Referring to fig. 2b, fig. 2b is a diagram illustrating a structure of a micro-channel micro-reactor. The micro-channel reactor is internally provided with a reaction cavity of a sample to be detected, which penetrates through the micro-channel micro-reactor from top to bottom and is used for reacting the sample to be detected with a nucleic acid probe or a virus antibody or a virus antigen modified on the top metal material layer.
The virus detection device provided by the embodiment of the invention can be finally made into a chip form, and the grid electrode, the source electrode and the drain electrode of the virus detection device can be led out of the chip through the top metal layer to form a grid end, a source end and a drain end on the chip.
Referring to fig. 2c, fig. 2c is a top view of the mosfet die slice 120 of the virus detection device of fig. 2 a. As shown in fig. 2c, the top metal layer of the slice layer of the mosfet comprises: a source metal, a drain metal and an extended gate; the other position of the top metal layer is insulated silicon dioxide. Wherein the source metal and the drain metal lead out a source terminal and a drain terminal, respectively. The metal of the extended gate is modified with a nucleic acid probe or a virus antibody or a virus antigen, and the micro-channel reactor in the micro-channel layer 110 is disposed on the extended gate.
In the micro-channel microreactor in this embodiment, silica insulated in the top metal layer is mounted on the top metal layer. The reaction cavity of the sample to be detected of the micro-channel micro-reactor is positioned at the position of the extension grid metal in the top metal layer and is used for the reaction of the sample to be detected and the nucleic acid probe or the virus antibody or the virus antigen modified on the top metal material layer.
The virus detection device provided by the embodiment of the invention can be used for detecting various viruses such as influenza virus, new coronavirus and the like. For example: the gate metal is modified with a nucleic acid probe for detecting influenza viruses or an influenza virus antibody or an influenza virus antigen, so that the detection of the influenza viruses can be realized; the detection of the new coronavirus can be realized by modifying a nucleic acid probe or a new coronavirus antibody or a new coronavirus antigen for detecting the new coronavirus on the grid metal.
For example: when detecting the new coronavirus, the metal of the grid electrode can be modified with a new coronavirus (SARS-CoV-2) antigen, or a SARS-CoV-2 antibody, or a nucleic acid probe for detecting SARS-CoV-2.
Specifically, the SARS-CoV-2 antigen is: igM and IgG antigen fragments;
the IgM and IgG antigen fragments consist of the S protein and the N protein 1:1, mixing;
wherein, the S protein is: S1-RBD, the amino acid sequence of which is as follows:
RVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNF；
the amino acid sequence of the N protein is as follows:
MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA ；
the SARS-CoV-2 antibody is: igM and IgG antibody fragments;
the nucleic acid probe for detecting the novel coronavirus can be one of the following nucleic acid probes: (wherein each probe is 5' -3',5' -modified SH-C6 from left to right)
ORF1ab probe:
a first probe: TTAAGTGTAAAACCCACAGGG
And a second probe: ACGATTGTGCATCAGCTGA
N protein probe:
a first probe: ATTCTAGCAGGAGAAGTTCCCC
And a second probe: CAGACATTTTGCTCTCAAGCTG.
The main component of the material of the top metallic material layer of the virus detection device shown in fig. 2c is aluminum, i.e. the extended gate metal is aluminum. In other embodiments of the virus detection device, the extended gate metal may be gold.
In practical application, when the metal material of the top metal material layer is aluminum, the metal gate may be modified with a nucleic acid probe or a virus antibody or a virus antigen by an amide bond constructed by a reaction between a bridging molecule loaded on the surface of the aluminum metal and the nucleic acid probe or the virus antibody or the virus antigen modified with a carboxyl group at an end group.
The bridging molecule may include: a siloxane-based molecule; 3-aminopropyltriethoxysilane is preferred.
Specifically, as shown in fig. 3a to 3c, 3-aminopropyl silicon is loaded on the surface of metal aluminum, an amide bond is constructed by using a condensation reaction between a carboxyl group and a nucleic acid probe or a virus antibody or a virus antigen amino group modified with a carboxyl group at an end group, and the nucleic acid probe or the virus antibody or the virus antigen is modified on the gate metal aluminum.
In practical application, when the metal material of the top metal material layer is gold, the gold can directly react with the nucleic acid probe modified with the sulfur group at the end group or the virus antibody or virus antigen with the sulfur group to construct a gold-sulfur bond, so as to modify the nucleic acid probe.
Specifically, as shown in fig. 4, gold directly reacts with the nucleic acid probe or the virus antibody or the virus antigen modified with a sulfur group at the end group to construct a gold-sulfur bond, thereby modifying the nucleic acid probe.
As can be seen from the above embodiments, compared with the existing electrochemical biosensor, the virus detection device provided by the embodiments of the present invention does not need to introduce an electrochemical activity identifier as a marker, and is compatible with the current mainstream MOSFET processing technology, thereby laying a deep foundation for realizing large-scale commercial production. In other words, the embodiment of the invention can combine mature MOSFET processing technology, chemical/biological modification and microfluidic technology, and has the advantages of miniaturization, low cost, easy integration, high-throughput detection, on-site rapid detection and the like.
The embodiment of the invention provides two preparation methods of a virus detection device, which are respectively used for preparing the virus detection device with aluminum grid metal and the virus detection device with gold grid metal. The following are detailed below.
Referring to fig. 5, fig. 5 is a schematic flow chart of a method for manufacturing a virus detection device with aluminum gate metal according to an embodiment of the present invention, where the method includes the following steps:
In practical application, a chip manufacturer can adopt a mature MOSFET processing technology to prepare the metal-oxide semiconductor field effect tube core sheet layer.
As shown in fig. 2c, the top metal layer of the metal-oxide semiconductor field effect transistor die slice layer comprises: a source metal, a drain metal and an extended gate metal; the other position of the top metal layer is insulated silicon dioxide.
Thus, the micro-channel microreactor in the present embodiment can be mounted on the top metal layer through the silica insulated in the top metal layer. The reaction cavity of the sample to be detected of the micro-channel micro-reactor is positioned at the position of the extension grid metal in the top metal layer and is used for the reaction of the sample to be detected and the nucleic acid probe or the virus antibody or the virus antigen modified on the top metal material layer.
In fig. 5, steps 503 to 504 are processes of modifying nucleic acid probes or virus antibodies or virus antigens on the extension gate metal, as shown in fig. 3a to 3c.
The process of modifying a nucleic acid probe on gate aluminum will be described in detail with reference to FIG. 3a as an example.
Step one, a metal-oxide MOSFET chip with the grid metal being aluminum is placed in a solution of 3-aminopropyl triethoxysilane with the concentration of 0.2 mol/L.
And step two, heating to more than 100 ℃ and reacting for 12 hours.
And step three, washing with an organic solvent (such as ethanol) to obtain the chip with the 3-aminopropyl silicon loaded on the surface of the metal aluminum.
And step four, continuously placing the chip in a single-chain DNA probe solution (in other embodiments, the single-chain DNA probe solution can be an antibody probe or an antigen probe) modified by the terminal carboxyl, adding a condensing agent (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and N-hydroxysuccinimide), and constructing an amido bond by utilizing the condensation reaction between the carboxyl and the amino.
And step five, washing with organic solvent (such as ethanol) and water to prepare the aluminum metal-oxide MOSFET chip with the nucleic acid probe modified on the grid metal aluminum.
It can be seen from the above embodiments that, the method for manufacturing a virus detection device with aluminum gate metal according to the embodiments of the present invention can directly modify a nucleic acid probe or a virus antibody or a virus antigen for virus detection on the gate metal aluminum in the top metal material layer in the metal-oxide semiconductor field effect die sheet layer, compared with the existing electrochemical biosensor, does not need to introduce an electrochemically active identifier as a marker, and is compatible with the currently mainstream MOSFET processing technology, thereby laying a deep foundation for large-scale commercial production.
Referring to fig. 6, fig. 6 is a schematic flow chart of a method for manufacturing a virus detection device with gold gate metal according to an embodiment of the present invention, where the method includes the following steps:
601, preparing a metal-oxide semiconductor field effect transistor core sheet layer, wherein the metal-oxide semiconductor field effect transistor core sheet layer comprises a field effect transistor functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is internally provided with grid metal, source metal and drain metal which are correspondingly connected with the grid, the source and the drain; the metal material of the top metal material layer is aluminum;
in practical application, a chip manufacturer can adopt a mature MOSFET processing technology to prepare a metal-oxide semiconductor field effect transistor core lamella with a top metal layer of aluminum, and then replace the aluminum metal of the grid metal with the gold metal.
For example: the extended gate in figure 2c can be replaced with gold metal.
Due to the limitation of the MOSFET processing technology, the main component of the top metal material of the device gate is aluminum, and in order to implement the diversification of the modification means, the aluminum metal material may be replaced by gold in this embodiment.
The method comprises the following specific steps:
first, a metal-oxide MOSFET chip is uniformly spin-coated with a photoresist, followed by a patterned exposure, and the exposed photoresist is developed to remove the exposed photoresist, so that the portion of the extended gate metal in fig. 2c is exposed.
The exposed extension gate aluminum metal is then etched completely with an aluminum etchant.
And then, plating gold on the positions where the grid metal is extended by using an electron beam evaporation instrument or a thermal evaporation instrument.
Finally, the remaining photoresist is stripped together with the above film formation, and the aluminum metal extending the gate metal portion is replaced with gold metal.
step 604a, reacting the gold metal with a nucleic acid probe modified with a sulfur group at an end group to construct a gold-sulfur bond, so that the nucleic acid probe is modified on the gate metal;
or the like, or, alternatively,
In FIG. 6, step 603 is a process of directly modifying metal gold on a grid (e.g., an extension grid) with a nucleic acid probe or a virus antibody or a virus antigen.
The process of modifying the gold gate with a nucleic acid probe will be described in detail with reference to fig. 4 as an example.
Step one, soaking a metal-oxide MOSFET chip with a gold grid metal in a single-stranded DNA probe solution modified by end-group sulfydryl for 24 hours, wherein the sulfydryl and the gold can directly form a gold-sulfur bond, so that the DNA probe can be self-assembled on the surface of the gold, and the DNA probe molecules are connected to the gold grid.
And step two, soaking the chip in an aqueous solution of 6-mercaptohexanol with the concentration of 1mmol/L for 1 hour, flushing with deionized water, and drying with nitrogen. Or soaking in 200mmol/L sodium bromide buffer solution for half an hour, flushing with buffer solution, and blowing with nitrogen.
As can be seen from the foregoing embodiments, the method for manufacturing a virus detection device with gold as gate metal according to the embodiments of the present invention can replace gold as gate metal aluminum in the top metal material layer of the metal-oxide semiconductor field effect transistor die sheet, and directly modify nucleic acid probes or virus antibodies or virus antigens for virus detection on the gate metal gold.
Finally, referring to fig. 7, fig. 7 is a schematic flow chart of a virus detection method according to an embodiment of the present invention. The method can be used for detecting any virus detection device, and comprises the following steps:
and step 704, determining whether the detected sample contains the target virus or not based on the change of the electric signal and the nucleic acid probe or the virus antibody or the virus antigen which is modified on the grid metal and used for virus detection.
For example: if the voltage reaches a threshold voltage, it is determined whether the detected sample contains the target virus.
Specifically, the basic principle of virus detection of the virus detection device provided by the embodiment of the present invention as shown in fig. 2a is shown in fig. 8:
when virus detection is carried out, the virus is detected in a micro-channel reactor
A reference electrode is arranged in the tested sample liquid.
When a voltage is applied between the N-doped source and drain terminals and between the source terminal and the reference electrode (i.e. between the source and gate), the conduction channel under the gate (2) generates a current which is determined by the resistance of the conduction channel, and the voltage at the gate (2) affects the resistance of the channel. If the base complementary pairing or antibody antigen combination aiming at the nucleic acid probe occurs at the end of the expanded grid metal (6), electron gain or loss or potential difference is generated, the equivalent effect is that the grid voltage or the threshold voltage of the transistor is changed at the end of the grid (2), so that the resistance of the channel is changed, the current flowing through the channel is further changed, and whether the corresponding reaction occurs or not can be determined by detecting whether the current changes or not.
Therefore, in the actual use process, a test voltage is applied between the source terminal and the gate terminal, and between the source terminal and the reference electrode in fig. 2b, and then a sample to be tested (nucleic acid, blood sample, throat swab, etc.) of a patient is added into the micro flow channel reactor, and whether the patient is infected with a virus is determined by the change of current signals before and after the addition.
The effect of the test data on the virus detection method is described below:
firstly, the virus detection is carried out by the following devices: the virus detection device with gold as grid metal directly modifies the N protein probe I (5 ' -3',5' modified SH-C6 from left to right) on gold through a gold-sulfur bond:
ATTCTAGCAGGAGAAGTTCCCC
dropping probe complementary strand of different concentration
Then, dripping probe complementary strands (5 '-3' from left to right) with different concentrations on the surface of the chip (namely, a micro-flow channel layer of the virus detection device) to perform hybridization reaction:
GGGGAACTTCTCCTGCTAGAAT
the result shows that the lowest concentration which can be detected by the chip is 0.1fg/mL, the detection time is less than ten minutes, and the accuracy rate reaches more than 99.9 percent.
18 cases of clinical samples are detected in total, and are respectively checked by using an RT-qPCR detection method and the virus detection device provided by the embodiment of the invention, 9 cases of results obtained by using the RT-qPCR detection method are negative, 9 cases of results are positive, and the results are all consistent with the detection results of the virus detection device provided by the embodiment of the invention. Specifically, the experimental data are as follows:
| numbering | RT-qPCR detection results | Detection result of virus detection device | Consistency |
| 1 | Negative of | Negative of | Is that |
| 2 | Negative of | Negative of | Is that |
| 3 | Negative of | Negative of | Is that |
| 4 | Negative of | Negative of | Is that |
| 5 | Negative of | Negative of | Is that |
| 6 | Negative of | Negative of | Is that |
| 7 | Negative of | Negative of | Is that |
| 8 | Negative of | Negative of | Is that |
| 9 | Negative of | Negative of | Is that |
| 10 | Positive for | Positive for | Is that |
| 11 | Positive for | Positive for | Is that |
| 12 | Positive for | Positive for | Is that |
| 13 | Positive for | Positive for | Is that |
| 14 | Positive for | Positive for | Is that |
| 15 | Positive for | Positive for | Is that |
| 16 | Positive for | Positive for | Is that |
| 17 | Positive for | Positive for | Is that |
| 18 | Positive for | Positive for | Is that |
The embodiments of the present invention can show that the virus detection method provided by the embodiments of the present invention has the advantages of short virus detection time, high sensitivity, strong specificity and high accuracy. In addition, the embodiment of the invention combines mature MOSFET processing technology, chemical/biological modification and microfluidic technology, and has the advantages of miniaturization, low cost, easy integration, high-throughput detection, on-site rapid detection and the like.
The above description is only for the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (7)
1. A virus detection device, comprising: a metal-oxide semiconductor field effect transistor die slice layer and a micro-channel layer;
the metal-oxide semiconductor field effect tube core sheet layer comprises a field effect tube functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is internally provided with a grid metal, a source metal and a drain metal which are correspondingly connected with the grid, the source and the drain, and the grid metal is modified with a nucleic acid probe or a virus antibody or a virus antigen for virus detection;
the micro-flow channel layer is arranged on the top metal material layer; the micro-channel layer is internally provided with a micro-channel reactor positioned on the grid metal, and the micro-channel reactor is used for reacting a sample to be detected with the nucleic acid probe or the virus antibody or the virus antigen modified on the top metal material layer.
2. The virus detection device of claim 1, wherein the metal material of the top metal material layer is aluminum or gold.
3. The virus detection device according to claim 2,
when the metal material of the top metal material layer is aluminum, the metal of the grid electrode is modified with a nucleic acid probe or a virus antibody or a virus antigen through an amido bond constructed by the reaction of a bridging molecule loaded on the surface of the aluminum metal and the nucleic acid probe or the virus antibody or the virus antigen modified with carboxyl at the end group;
the bridging molecule comprises: a siloxane-based molecule; 3-aminopropyltriethoxysilane is preferred.
4. The virus detection device according to claim 1,
when the metal material of the top metal material layer is gold, the nucleic acid probe is modified through a gold-sulfur bond which is constructed by the reaction of the gold metal and the nucleic acid probe modified with sulfur on the end group; or the like, or, alternatively,
the grid metal is modified with virus antibody or virus antigen through gold-sulfur bond constructed by reaction of gold metal and virus antibody or antigen with sulfur radical.
5. A method of making a virus detection device, comprising:
preparing a metal-oxide semiconductor field effect tube core sheet layer, wherein the metal-oxide semiconductor field effect tube core sheet layer comprises a field effect tube functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is internally provided with grid metal, source metal and drain metal which are correspondingly connected with the grid, the source and the drain;
the metal material of the top metal material layer is aluminum;
a micro-channel layer is arranged on the top metal material layer; the micro-channel layer is internally provided with a micro-channel reactor positioned on the grid metal, and the micro-channel reactor is used for reacting a detected sample with a nucleic acid probe or a virus antibody or a virus antigen modified on the top metal material layer;
attaching a bridging molecule to the aluminum metal surface;
reacting the bridging molecule with the nucleic acid probe modified with carboxyl at the end group or the virus antibody or the virus antigen to construct an amido bond, so that the nucleic acid probe or the virus antibody or the virus antigen is modified on the grid metal;
the bridging molecule comprises: a siloxane-based molecule; 3-aminopropyltriethoxysilane is preferred.
6. A method of making a virus detection device, comprising:
preparing a metal-oxide semiconductor field effect tube core sheet layer, wherein the metal-oxide semiconductor field effect tube core sheet layer comprises a field effect tube functional layer and a top metal material layer which are sequentially arranged from bottom to top; the field effect transistor functional layer comprises a grid electrode, a source electrode and a drain electrode; the top metal material layer is provided with a grid metal, a source metal and a drain metal which are correspondingly connected with the grid, the source and the drain;
the metal material of the top metal material layer is aluminum;
replacing the grid metal with gold metal;
a micro-channel layer is arranged on the top metal material layer; the micro-channel layer is internally provided with a micro-channel reactor positioned on the grid metal, and the micro-channel reactor is used for reacting a detected sample with a nucleic acid probe or a virus antibody or a virus antigen modified on the top metal material layer;
reacting gold metal with a nucleic acid probe modified with a sulfur group at an end group to construct a gold-sulfur bond, so that the nucleic acid probe is modified on the grid metal;
or the like, or, alternatively,
the gold metal reacts with the virus antibody or antigen with sulfur radicals to construct gold-sulfur bonds, so that the virus antibody or antigen is modified on the grid metal.
7. A virus detection method using the virus detection device according to any one of claims 1 to 4, comprising:
applying test voltages between a source metal and a drain metal, and between the source metal and a gate metal of the virus detection device;
adding a detected sample into a micro-channel reactor of a virus detection device;
detecting the change of an electric signal of a conductive channel between the source metal and the drain metal before and after the conductive channel is added into a detected sample;
and determining whether the detected sample contains the target virus or not based on the change of the electric signal and the nucleic acid probe or virus antibody or virus antigen modified on the grid metal and used for virus detection.
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