CN114354722B - Multichannel field effect transistor nano biosensor and preparation method and application thereof - Google Patents
Multichannel field effect transistor nano biosensor and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a multichannel field effect transistor nano biosensor and a preparation method and application thereof, and belongs to the field of analysis and detection. According to the multichannel field effect transistor nano biosensor, the simultaneous and rapid detection of a plurality of bladder cancer markers in a urine sample is realized by establishing the corresponding relation between the concentration of the bladder cancer markers and the electric signal of an Indium Gallium Zinc Oxide (IGZO) field effect transistor sensing device. The field effect transistor nano biosensor can realize simultaneous and rapid detection of a plurality of cancer markers in a urine sample, and well overcomes the defects in the current bladder cancer diagnosis field. The sensor has the advantages of high detection flux, high sensitivity, good selectivity, high detection speed, good reproducibility and the like, and has wide clinical application prospect in the field of tumor marker detection.
Description
Technical Field
The invention relates to the field of analysis and detection, in particular to a multichannel field effect transistor nano biosensor, a preparation method and application thereof.
Technical Field
Bladder cancer is one of the most common malignant tumors of the urinary system, and has the characteristics of strong invasiveness, high recurrence rate and the like. About 75% of patients with new bladder cancer are non-myogenic invasive bladder cancer, and 25% progress to myogenic invasive stage. Early diagnosis is of great importance in preventing patients from developing myogenic invasive bladder cancer and improving survival rate of patients. Although the non-myogenic invasive bladder cancer does not endanger life, the recurrence rate of five years after local treatment is as high as 50% -70%. In order to prevent the disease from deteriorating, patients need to review periodically at any time and follow up for a long period. Currently, the means applied clinically to bladder cancer detection are mainly gold standard cystoscopy, tissue biopsy, and urine shed cytology. Gold standard cystoscopy and tissue biopsy are highly invasive and can cause great pain to the patient, and may also lead to urinary tract injuries, infections, etc., with poor patient compliance. Urine abscission cytology belongs to a noninvasive detection means, but has low sensitivity, and early canceration cannot be found. Therefore, there is a need to develop a noninvasive and sensitive detection technique for early screening and prognostic monitoring of bladder cancer.
The bladder is used as a urine storage organ, and the occurrence and development of bladder cancer can directly influence urine components. Therefore, the development of the urine-based liquid biopsy technology can provide convenience for early diagnosis and postoperative monitoring of bladder cancer, and urine monitoring also has the advantages of noninvasive and repeated sampling. Urine contains various bladder cancer markers, such as NMP22, miRNA, bladder tumor antigens, fibrinogen degradation products, and bladder cancer cells. In consideration of the differences among individuals and the heterogeneity of solid tumors, the complexity of the tumors is difficult to reflect by using only a single marker as a detection standard, and false positive or false negative results are easy to occur. The types and the contents of the markers expressed by the tumors at different stages are different, and the combined detection of the different tumor markers can improve the diagnosis accuracy, realize the stage and the grading of the tumors, and facilitate the adoption of different treatment means at different development stages of the tumors, so as to achieve the optimal treatment effect.
The field effect transistor sensor has the functions of signal conversion and signal amplification, realizes quantitative detection of a target substance through current signal change caused by combination of a target molecule and a semiconductor channel material, and has the advantages of high sensitivity, good selectivity, easiness in integration and the like. Field effect transistor sensors have been widely used in the fields of protein, nucleic acid and bacterial detection. By utilizing the advantage that the field effect transistor sensor is easy to integrate, the field effect transistor array is developed, the multichannel sensor is constructed, the simultaneous detection of various bladder cancer markers in urine is hopefully realized, the detection accuracy is improved, and the method has great clinical application value in the fields of cancer diagnosis, postoperative monitoring and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a multichannel field effect transistor nano-biosensor, and a preparation method and application thereof.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
In a first aspect, the present invention provides a method for preparing a multichannel field effect transistor nano-biosensor, which is characterized in that: preparing a gold electrode by ultraviolet lithography and a metal deposition method, growing an Indium Gallium Zinc Oxide (IGZO) channel material by a magnetron sputtering method, modifying recognition molecules by a chemical modification method, and finally assembling a Polydimethylsiloxane (PDMS) chamber with a device to realize the construction of a high-sensitivity, high-selectivity and high-flux multichannel IGZO field effect transistor sensor, wherein the method comprises the following steps:
S1: preparing a gold electrode:
s2: preparing an IGZO channel material:
S3: modifying the recognition molecule:
s4: the transistor and reservoir are assembled.
As a preferred scheme, the gold electrode is prepared in the step S1, specifically as follows:
s1.1: designing an electrode pattern consisting of 5 sources, 1 drain and 1 grid by adopting CAD software, and processing the electrode pattern into a corresponding mask for subsequent photoetching operation;
S1.2: selecting a p-type silicon wafer with a 300nm silicon oxide layer as a substrate, uniformly spin-coating a layer of positive photoresist AZ521 on the surface of the p-type silicon wafer, then placing the spin-coated silicon wafer on a heating plate, and heating at 115 ℃ for 4min to solidify the photoresist; then exposing the pattern on the mask plate by means of an ultraviolet photoetching machine, transferring the electrode pattern onto the spin-coated photoresist, and developing by using ZX-238 developing solution to expose the electrode position;
S1.3: uniformly depositing a 15nm Cr layer and a 50nm Au layer on the surface of the silicon wafer in the step S1.2 by adopting a thermal evaporation coating instrument, wherein the Cr layer is used for increasing the adhesive force of Au; and (3) soaking the silicon wafer after metal deposition in an acetone solution to strip photoresist, then flushing with isopropanol and deionized water respectively, and drying with nitrogen to expose the gold electrode, thereby completing the preparation of the gold electrode.
Further, the IGZO channel material is prepared in the step S2, specifically as follows:
S2.1: preparing an IGZO channel material by a magnetron sputtering method; when the vacuum degree in the cavity of the magnetron sputtering coating instrument meets the requirement, argon is introduced, the power of a radio frequency power supply is regulated to be 50W, the total pressure of the cavity is 0.65Pa, and the temperature of a substrate is 150 ℃; pre-sputtering for 10min, and removing an oxide layer or other pollutants on the surface of a ceramic target, wherein In 2O3:Ga2O3:ZnO=1:1:1 In the ceramic target; then opening a baffle plate, performing formal sputtering for 25min, and completing the preparation of the IGZO channel material;
s2.2: in order to prevent the field effect transistor from leaking, a layer of polymethyl methacrylate (PMMA) passivation gold electrode is coated on the surface of the IGZO transistor device prepared in the step S2.1 in a spin mode.
Further, the modification of the recognition molecule in the step S3 is as follows:
S3.1: in order to finish antibody modification of the device subsequently, silanization treatment is carried out on the surface of the IGZO material in S2.2;
S3.2: the silanized transistor is placed in 5% glutaraldehyde phosphate buffer solution (ph=7.4), the rotation speed is set at 180rpm, the temperature is 25 ℃, and the transistor is incubated in a constant temperature shaking table for 2 hours; finally, washing the rest glutaraldehyde with deionized water, and drying with nitrogen;
S3.3: in the step S3.2, different bladder cancer marker antibodies with concentration of 20mg mL –1 are respectively dripped into different channel regions of the transistor device, wherein the antibodies comprise nuclear matrix protein 22 (NMP 22), CA9 recombinant protein (CA 9), cytokeratin 8 (CK 8), cytokeratin 18 (CK 18) and recombinant human CD47 protein (CD 47), and then the transistor device is placed in a refrigerator at 4 ℃ for incubation for 12 hours, and antibody modification is completed through the reaction between aldehyde groups of glutaraldehyde serving as a crosslinking agent and amino groups of protein; finally, adopting phosphate buffer solution with pH=7.4, washing the unbound antibody molecules, and drying with nitrogen;
s3.4: to reduce non-specific adsorption, 0.01g of a Bovine Serum Albumin (BSA) solution of –1 was used to block the active sites of the unmodified antibody molecules in the IGZO channel region in step S3.2, and the procedure was incubated at 4℃for 1 hour in a refrigerator.
Further, the transistor and the liquid storage tank are assembled in the step S4, which is specifically as follows:
S4.1: firstly, preparing a liquid storage tank; weighing Sylgard 184 siloxane prepolymer and curing agent with the mass ratio of 10:1, fully and uniformly mixing the Sylgard 184 siloxane prepolymer and the curing agent, and completely removing bubbles in the mixture by vacuumizing; then the mixture is placed on a heating plate at 60 ℃ for heating for 2 hours, so that the bonding speed of the prepolymer and the curing agent is accelerated, and PDMS is formed; finally, the prepared PDMS is punched out of a required liquid storage tank by a puncher;
S4.2: treating the liquid storage tank for 3min by adopting oxygen plasma to enable the surface of the liquid storage tank to be provided with oxygen-containing functional groups; and tightly contacting the liquid storage tank after oxygen plasma treatment with the transistor to finally finish the preparation of the IGZO field effect transistor sensor.
Furthermore, in the step S2.2, in order to prevent the field effect transistor from leaking, a layer of PMMA passivation gold electrode is spin-coated on the surface of the IGZO transistor device prepared in the step S2.1; the method comprises the following specific steps:
Spin coating by using a spin coater, setting the rotating speed of the spin coater to be 500rpm, pre-spin coating for 5s, and then spin coating for 60s by increasing the rotating speed to 3000 rpm; placing the IGZO device subjected to spin coating on a heating plate and heating and baking for 5min; repeating the above operation once to achieve the aim of completely curing PMMA; finally, an electron beam exposure system (EBL) and development are used to expose the IGZO channel material covered by PMMA.
Furthermore, in the step S3.1, in order to finish antibody modification of the device later, the surface of the IGZO material in S2.2 is first subjected to silanization treatment, which specifically includes the following steps:
The IGZO field effect transistor prepared in S2.2 was rinsed with ethanol and subsequently immersed in a 5% ethanol solution of 3-aminopropyl triethoxysilane (APTES); setting the rotating speed to 180rpm, and incubating for 1 hour in a constant-temperature shaking table at the temperature of 25 ℃; and finally, placing the mixture in a 110 ℃ oven for 30min to finish the silanization treatment of the surface of the IGZO material.
In a second aspect, the present invention provides a multichannel field effect transistor nano-biosensor, characterized in that: the multichannel field effect transistor nano biosensor is prepared by the preparation method.
In a third aspect, the present invention provides an application of the multichannel field effect transistor nano-biosensor in simultaneous detection of a plurality of bladder cancer markers, which is characterized in that:
Firstly, testing a background signal of a sensor solution grid of a transistor; secondly, incubating a solution to be detected and a field effect transistor sensor for 30min by utilizing the antigen-antibody specific recognition effect, and respectively capturing corresponding antigen molecules in the solution through IGZO surface modified NMP22, CA9, CK8, CK18 and CD47 antibody molecules; subsequently, unbound antigen molecules are washed away, a current signal is tested by adopting a solution grid, and the captured antigen molecules influence the charge quantity on the surface of the IGZO channel material through electrostatic interaction, so that the carrier density of the IGZO is influenced, and the change of the current signal of the sensor is caused; the content of the marker can be analyzed by comparing the background signal with the signal change after incubation of the protein; different proteins have different amounts of charges and different influences on channel materials, so that analysis of different marker contents is realized.
The invention has the following advantages and effects:
(1) The IGZO field effect transistor sensor constructed by the invention has excellent electrical property and has the advantage of high sensitivity in bladder cancer marker monitoring.
(2) The IGZO field effect transistor sensor constructed by the invention can directly detect urine samples, and the samples do not need pretreatment, so that the detection steps are greatly simplified.
(3) The multi-marker simultaneous detection method improves the detection flux, greatly saves the time and labor cost and obviously improves the detection efficiency.
(4) The IGZO field effect transistor sensor has the advantage of miniaturization, can be further integrated into portable detection equipment, is applied to home medical treatment and instant diagnosis, and has great application prospect in the fields of cancer diagnosis and postoperative monitoring.
Drawings
Fig. 1 is a schematic diagram of a multi-channel IGZO fet sensor device fabricated in accordance with example 1 of the present invention.
Fig. 2 is a schematic diagram of a multi-channel IGZO fet sensor device for bladder cancer marker detection prepared in example 1 of the present invention.
FIG. 3 is a graph showing the transfer characteristics of the present invention for simultaneous detection of multiple bladder cancer markers according to application example 1.
FIG. 4 is a data statistical chart of simultaneous detection of 5 markers for 20 bladder cancer patients and 20 healthy human urine samples according to application example 2 of the present invention.
Detailed Description
For a better understanding of the present invention, the following examples are provided for further illustration of the invention, and the examples are set forth as preferred embodiments only, and not all. Other embodiments, which are obtained by those skilled in the art without making any inventive effort, are within the scope of the present invention. The present invention will be described in further detail with reference to specific embodiments and drawings.
Example 1:
Construction of a multichannel IGZO field effect transistor sensor:
s1, preparing a gold electrode:
And S1.1, designing an electrode pattern consisting of 5 sources, 1 drain and 1 grid by adopting CAD software, and processing the electrode pattern into a corresponding mask plate for subsequent photoetching operation.
S1.2, a p-type silicon wafer with a 300nm silicon oxide layer is selected as a substrate, a layer of positive photoresist AZ521 is uniformly spin-coated on the surface of the p-type silicon wafer, and then the spin-coated silicon wafer is placed on a heating plate and heated for 4min at 115 ℃ to solidify the photoresist. And then exposing the pattern on the mask plate by means of an ultraviolet photoetching machine, transferring the electrode pattern onto the spin-coated photoresist, and developing by using ZX-238 developing solution to expose the electrode position.
S1.3, a thermal evaporation coating instrument is adopted to sequentially and uniformly deposit a Cr layer with the thickness of 15nm and an Au layer with the thickness of 50nm on the surface of the silicon wafer in the S1, wherein the Cr layer is used for increasing the adhesive force of Au. And (3) soaking the silicon wafer after metal deposition in an acetone solution to strip photoresist, then flushing with isopropanol and deionized water respectively, and drying with nitrogen to expose the gold electrode, thereby completing the preparation of the gold electrode.
S2, preparing an IGZO channel material:
s2.1, preparing the IGZO channel material by adopting a magnetron sputtering method. When the vacuum degree in the cavity of the magnetron sputtering coating instrument meets the requirement, argon is introduced, the power of a radio frequency power supply is regulated to be 50W, the total pressure of the cavity is 0.65Pa, and the temperature of the substrate is 150 ℃. Pre-sputtering for 10min, removing oxide layer or other contaminants on the surface of the ceramic target (In 2O3:Ga2O3:ZnO=1:1:1). And then opening the baffle plate, performing formal sputtering for 25min, and completing the preparation of the IGZO channel material. The multichannel field effect transistor prepared at this time is shown in fig. 1. As shown in fig. 1, yellow is an electrode region consisting of 5 sources (sensing channels), 1 drain, 1 gate, and a blue region between the sources and the drains represents channel material.
S2.2, spin coating a PMMA passivation gold electrode on the surface of the IGZO transistor device prepared in S2.1 to prevent the field effect transistor from electric leakage. The method comprises the following specific steps: spin coating was performed using a spin coater, the spin speed of the spin coater was set to 500rpm, pre-spin coating was performed for 5s, and then the spin speed was increased to 3000rpm for spin coating for 60s. And placing the IGZO device subjected to spin coating on a heating plate and thermally drying for 5min. The above operation is repeated once to achieve the aim of completely curing PMMA. Finally, the IGZO channel material covered by PMMA is exposed using EBL and development.
To improve the stability of the grid electrode, ag/AgCl is used as a reference electrode. Firstly, uniformly coating a layer of Ag glue on a round grid, and heating at 70 ℃ for 20min to solidify the Ag glue. The FeCl 3 solution was then added dropwise onto the cured Ag gel and reacted for 4min to form AgCl. Finally, polyvinyl butyral (PVB) solution is dripped to form a PVB film, and the formed Ag/AgCl electrode is protected.
Construction of a multichannel IGZO field effect transistor sensing unit:
S3 modification recognition molecule:
S3.1 the prepared multichannel IGZO field effect transistor was rinsed with ethanol and subsequently immersed in a 5% APTES ethanol solution. The rotation speed was set at 180rpm, the temperature was 25℃and incubation was carried out in a thermostated shaker for 1 hour. And finally, placing the mixture in a 110 ℃ oven for 30min to finish the silanization treatment of the surface of the IGZO material. The silanized transistor was further placed in 5% glutaraldehyde phosphate buffer (ph=7.4), set at 180rpm, temperature 25 ℃, and incubated in a thermostated shaker for 2 hours. Finally, the remaining glutaraldehyde was rinsed out with phosphate buffer solution (ph=7.4) and dried with nitrogen.
S3.2, continuously dripping 30mL of different bladder cancer marker antibodies with the concentration of 20mg mL –1, including NMP22, CA9, CK8, CK18 and CD47, respectively into different channel regions of a transistor device, then placing the transistor device in a refrigerator at 4 ℃ for incubation for 12 hours, and finishing antibody modification through the reaction between aldehyde groups of a cross-linking agent glutaraldehyde and protein amino groups. Finally, unbound antibody molecules were rinsed clean with phosphate buffer (ph=7.4) and dried with nitrogen.
S3.3 to reduce non-specific adsorption, the active sites of the IGZO channel region unmodified antibody molecules in (3) ② were blocked with 0.01g of –1 BSA solution, and the procedure was incubated at 4℃for 1 hour in a refrigerator.
S4, assembling a transistor and a liquid storage tank:
S4.1, preparing a liquid storage tank firstly. Weighing Sylgard 184 siloxane prepolymer and curing agent with the mass ratio of 10:1, fully and uniformly mixing the prepolymer and the curing agent, and completely removing bubbles in the mixture by vacuumizing. And then the mixture is placed on a heating plate at 60 ℃ for heating for 2 hours to accelerate the bonding speed of the prepolymer and the curing agent, so as to form PDMS. Finally, the prepared PDMS is punched out of the required liquid storage tank by a puncher.
S4.2, treating the liquid storage tank for 3min by adopting oxygen plasma so that the surface of the liquid storage tank is provided with oxygen-containing functional groups. And tightly contacting the liquid storage tank after oxygen plasma treatment with the transistor to finally finish the preparation of the IGZO field effect transistor sensor.
Application example 1: simultaneous detection of multiple markers by IGZO field effect transistor sensors
The background signal of the non-antibody-bound field effect transistor sensor was first tested. And (3) dropwise adding a phosphate buffer solution (PB) into the liquid storage tank, setting the source-drain voltage V ds to be 0.2V, setting the grid voltage V g to be-0.6V-1.5V, and recording the transfer characteristic curve of the solution grid as a background signal.
10 –12g mL–1 Standard solutions of NMP22, CA9, CK8, CK18 and CD47 antigens were prepared. NMP22, CA9, CK8, CK18 and CD47 antigen standard solutions were added dropwise to the field effect transistor reservoirs prepared in example 2, respectively, and incubated for 30min to complete antigen-antibody binding. The remaining protein solution was then aspirated and washed 3 times with PB to wash away unbound protein molecules, and PB was added again for solution grid testing. And setting the test parameters same as the background signals, and recording transfer characteristic curves of different channels. Figure 3 shows transfer characteristics of background and incubation of different channels. It can be seen that the current is reduced due to the electrostatic shielding effect of antigen-antibody binding on the channel material. The degree of influence on the current is different due to different charges of different proteins.
Application example 2: detecting 5 markers in urine by using IGZO field effect transistor sensor
The morning urine of 20 patients with bladder cancer and 20 healthy people is stored in a refrigerator at-80 ℃ for testing. Firstly, setting the source-drain voltage V ds to be 0.2V, setting the grid voltage V g to be-0.6V to 1.5V, and recording the transfer characteristic curve of the field effect transistor solution grid background. And then dripping the thawed urine into a liquid storage tank, incubating for 30min, finishing the combination of various markers in the urine and corresponding antibodies, washing with PB for 3 times, washing away unbound protein molecules, and adding PB again for solution grid test. Under the same test conditions, transfer-specific curves of the markers were recorded. In order to realize accurate analysis of the content of the marker, the protein concentration is analyzed by adopting a relative value of current signal change when V g is 0.6V, namely the difference value of a background signal I 0 and a signal I after urine incubation is larger than that of a background signal I 0, and the larger the relative value of the current change is, the more the content of the marker is indicated. As fig. 4 shows the relative values of the change in current of the 5 markers for 20 patients with bladder cancer and 20 healthy people, it can be seen that the content of the 5 markers is significantly higher for bladder cancer patients than for healthy people. The multichannel field effect transistor constructed by the invention can sensitively detect the change of different marker contents, and has the advantage of high sensitivity. Through further integrated design, the multichannel IGZO field effect transistor is expected to develop into an instant detection technology for bladder cancer diagnosis and postoperative monitoring.
Claims (3)
1. A preparation method of a multichannel field effect transistor nano biosensor is characterized in that: preparing a gold electrode by ultraviolet lithography and a metal deposition method, growing an IGZO channel material by a magnetron sputtering method, modifying an identification molecule by a chemical modification method, and finally assembling Polydimethylsiloxane (PDMS) chambers and devices to realize the construction of a high-sensitivity, high-selectivity and high-flux multichannel IGZO field effect transistor sensor, wherein the method comprises the following steps:
S1: preparing a gold electrode: the gold electrode is prepared in the step S1, and the specific steps are as follows:
S1.1: designing an electrode pattern consisting of 5 sources, 1 drain and 1 grid by adopting CAD software, and processing the electrode pattern into a corresponding mask for subsequent photoetching operation;
s1.2: selecting a p-type silicon wafer with a 300 nm silicon oxide layer as a substrate, uniformly spin-coating a positive photoresist AZ521 on the surface of the p-type silicon wafer, then placing the spin-coated silicon wafer on a heating plate, and heating by 115 o C for 4 min to solidify the photoresist; then exposing the pattern on the mask plate by means of an ultraviolet photoetching machine, transferring the electrode pattern onto the spin-coated photoresist, and developing by using ZX-238 developing solution to expose the electrode position;
s1.3: uniformly depositing a Cr layer of 15 nm and an Au layer of 50 nm on the surface of the silicon wafer in the step S1.2 by adopting a thermal evaporation coating instrument, wherein the Cr layer is used for increasing the adhesive force of Au; soaking the silicon wafer after metal deposition in an acetone solution to strip photoresist, then flushing with isopropanol and deionized water respectively, and drying with nitrogen to expose a gold electrode, thereby completing the preparation of the gold electrode;
S2: preparing an IGZO channel material: in the step S2, IGZO channel materials are prepared, specifically as follows:
S2.1: preparing an IGZO channel material by a magnetron sputtering method; when the vacuum degree in the cavity of the magnetron sputtering coating instrument meets the requirement, argon is introduced, the power of a radio frequency power supply is regulated to be 50W, the total pressure of the cavity is 0.65 Pa, and the temperature of the substrate is 150 o ℃; pre-sputtering 10 min to remove oxide layers or other pollutants on the surface of a ceramic target, wherein In 2O3:Ga2O3:ZnO=1:1:1 In mass ratio; then opening a baffle plate, performing formal sputtering to 25 min, and completing the preparation of the IGZO channel material;
s2.2: in order to prevent the field effect transistor from leaking electricity, spin-coating a layer of polymethyl methacrylate (PMMA) passivation gold electrode on the surface of the IGZO transistor device prepared in the step S2.1; in the step S2.2, in order to prevent the field effect transistor from leaking electricity, a PMMA passivation gold electrode is spin-coated on the surface of the IGZO transistor device prepared in the step S2.1; the method comprises the following specific steps:
Spin coating by using a spin coater, setting the rotating speed of the spin coater to be 500 rpm, pre-spin coating to be 5 s, and then spin coating to be 60 s by increasing the rotating speed to 3000 rpm; placing the IGZO device subjected to spin coating on a heating plate, and heating and baking for 5 min; repeating the above operation once to achieve the aim of completely curing PMMA; finally, an electron beam exposure system, namely an EBL and development are adopted to expose the IGZO channel material covered by PMMA;
s3: modifying the recognition molecule: the modification recognition molecule in the step S3 comprises the following specific steps:
S3.1: in order to finish antibody modification of the device later, silanization treatment is carried out on the surface of the IGZO material prepared in the step S2.2; in the step S3.1, in order to finish antibody modification of the device later, the surface of the IGZO material in the step S2.2 is subjected to silanization treatment, which specifically comprises the following steps:
the IGZO field effect transistor prepared in S2.2 is rinsed with ethanol and then immersed in a 5% ethanol solution of 3-aminopropyl triethoxysilane, APTES; setting the rotating speed to 180 rpm, and incubating for 1 hour in a constant-temperature shaking table at the temperature of 25 o ℃; finally, placing the mixture in a 110 o C oven for 30 min to finish the silanization treatment of the surface of the IGZO material;
S3.2: the silanized transistor is continuously placed in 5% glutaraldehyde phosphate buffer solution pH=7.4, the rotating speed is set to be 180 rpm, the temperature is 25 o ℃, and the transistor is incubated for 2 hours in a constant temperature shaking table; finally, washing the rest glutaraldehyde with deionized water, and drying with nitrogen;
s3.3: in the step S3.2, different bladder cancer marker antibodies with the concentration of 20mg mL –1 of 30mL are respectively dripped into different channel regions of the transistor device, wherein the antibodies comprise nuclear matrix protein 22, namely NMP22, CA9 recombinant protein, namely CA9, cytokeratin 8, namely CK8, cytokeratin 18, namely CK18, recombinant human CD47 protein, namely CD47, and then the transistor device is placed in a 4 o C refrigerator for incubation for 12 hours, and antibody modification is completed through the reaction between aldehyde groups of glutaraldehyde serving as a crosslinking agent and amino groups of the protein; finally, adopting phosphate buffer solution with pH=7.4, washing the unbound antibody molecules, and drying with nitrogen;
S3.4: to reduce non-specific adsorption, the active sites of the IGZO channel region unmodified antibody molecules in step S3.2 were blocked with 0.01 g mL –1 bovine serum albumin, BSA solution, and the procedure was incubated under 4 o C refrigerator for 1 hour;
s4: assembling the transistor and the reservoir; in the step S4, the transistor and the liquid storage tank are assembled, specifically as follows:
S4.1: firstly, preparing a liquid storage tank; weighing Sylgard 184 siloxane prepolymer and curing agent with the mass ratio of 10:1, fully and uniformly mixing the Sylgard 184 siloxane prepolymer and the curing agent, and completely removing bubbles in the mixture by vacuumizing; then placing the mixture on a 60 o C heating plate to heat for 2 h to accelerate the bonding speed of the prepolymer and the curing agent and form PDMS; finally, the prepared PDMS is punched out of a required liquid storage tank by a puncher;
S4.2: treating the liquid storage tank 3 min by adopting oxygen plasma so that the surface of the liquid storage tank is provided with oxygen-containing functional groups; and tightly contacting the liquid storage tank after oxygen plasma treatment with the transistor to finally finish the preparation of the IGZO field effect transistor sensor.
2. A multichannel field effect transistor nano-biosensor, characterized in that: the multichannel field effect transistor nano-biosensor is manufactured by the manufacturing method of claim 1.
3. Use of the multichannel field effect transistor nano-biosensor according to claim 2 for simultaneous detection of multiple bladder cancer markers, characterized in that:
Firstly, testing a background signal of a sensor solution grid of a transistor; secondly, incubating a solution to be detected with a field effect transistor sensor for 30 min by utilizing the antigen-antibody specific recognition effect, and respectively capturing corresponding antigen molecules in the solution through IGZO surface modified NMP22, CA9, CK8, CK18 and CD47 antibody molecules; subsequently, unbound antigen molecules are washed away, a current signal is tested by adopting a solution grid, and the captured antigen molecules influence the charge quantity on the surface of the IGZO channel material through electrostatic interaction, so that the carrier density of the IGZO is influenced, and the change of the current signal of the sensor is caused; the content of the marker can be analyzed by comparing the background signal with the signal change after incubation of the protein; different proteins have different amounts of charges and different influences on channel materials, so that analysis of different marker contents is realized.
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