CN112292592A - Multi-frequency-point resonance biosensor, preparation method thereof and method for testing cell concentration - Google Patents
Multi-frequency-point resonance biosensor, preparation method thereof and method for testing cell concentration Download PDFInfo
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
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- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
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- G01N21/3586—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using far infrared light; using Terahertz radiation by Terahertz time domain spectroscopy [THz-TDS]
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
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Abstract
The invention relates to a multi-frequency-point resonance biosensor, a preparation method thereof and a method for testing cell concentration, and belongs to the crossing field of terahertz technology and biotechnology. The invention provides a multi-frequency point resonance biosensor, which comprises a plurality of basic units; the basic unit comprises a metal layer and a dielectric layer; the metal layer consists of a U-shaped structure with an asymmetric opening and a rectangular antenna structure; the metal layer comprises a metal top layer and a metal bottom layer, the metal top layer is made of gold, and the metal bottom layer is made of titanium; the dielectric layer comprises a polymer flexible film. The sensor can realize rapid multi-resonance label-free detection of terahertz waveband high-sensitivity cell sensing.
Description
Technical Field
The invention relates to the crossing field of terahertz technology and biotechnology, in particular to a terahertz non-bi-anisotropic high-order mode Fano resonance multi-frequency point resonance metamaterial label-free biosensor, a preparation method thereof and a method for testing cell concentration.
Background
The development of the terahertz technology has attracted attention and becomes one of the most important core technologies in the new century. Many countries have terahertz technology as a key research and development project. Due to unique electric field response, the terahertz technology is widely applied to the aspects of public safety, communication, biomedical treatment and the like. The current methods for detecting cell concentration mainly comprise labeled fluorescence detection and labeled flow cytometry detection technologies, and although the labeled fluorescence detection and labeled flow cytometry detection technologies have very high sensitivity in practical application, the detection cost of the labeled fluorescence detection and labeled flow cytometry detection technologies is very high, and most of the labeled flow cytometry detection and labeled flow cytometry detection technologies are matched with other chemical substances to be used, so that certain pollution is caused. For example: the detection sensitivity of the CCK-8 method is high, but the CCK-8 is expensive, in addition, the color of the CCK-8 reagent is light red, the color is similar to that of a culture medium, and incorrect operations such as addition omission or addition excess and the like are easy to generate in experiments; the flow cytometry technology is also used for carrying out quantitative detection and analysis on single cells by utilizing a flow cytometer, integrates a series of technologies such as monoclonal antibody and immunocytochemistry technology, laser and electronic computer science, and has the advantages of high detection speed and high sensitivity, but the problems of marking, high cost, long time consumption and the like cannot be avoided. At present, no cell detection scheme which is low in cost and does not need to be marked exists.
Disclosure of Invention
The invention aims to provide a multi-frequency-point resonance biosensor, a preparation method thereof and a method for testing cell concentration. The sensor can realize rapid multi-resonance unmarked detection of terahertz waveband high-sensitivity cell sensing and has low cost.
The invention provides a multi-frequency point resonance biosensor, which comprises a plurality of basic units;
the basic unit comprises a metal layer and a dielectric layer.
The metal layer consists of a U-shaped structure with an asymmetric opening and a rectangular antenna structure; the metal layer comprises a metal top layer and a metal bottom layer, the metal top layer is made of gold, and the metal bottom layer is made of titanium.
The dielectric layer includes a polyimide film.
Preferably, the number of the basic units is not less than 20 × 20.
Preferably, the thickness of the metal top layer is 150-230 nm, and the thickness of the metal bottom layer is 15-30 nm.
Preferably, the thickness of the dielectric layer is 5-15 μm.
Preferably, the inner and outer corners of the asymmetric U-shaped structure of the opening are both right angles.
The invention also provides a preparation method of the multi-frequency point resonance biosensor, which comprises the following steps:
(1) and spin-coating a polyimide film on the silicon wafer to obtain the dielectric layer.
(2) And spin-coating reverse photoresist on the dielectric layer.
(3) Ultraviolet exposure and development.
(4) And evaporating the metal layer.
(5) Soaking in acetone solution, stripping to remove the reverse photoresist and the metal evaporated on the reverse photoresist, and cleaning with isopropanol and deionized water.
(6) And stripping the silicon substrate.
The invention also provides a method for detecting the cell concentration of the multi-frequency point resonance biosensor based on the technical scheme or the preparation method of the technical scheme, which comprises the following steps:
1) cells with different concentrations are respectively inoculated on the multi-frequency point resonance biosensor.
2) And testing the shift conditions of the resonance frequency of the transmission spectral line of the electric field along the x direction and the y direction respectively by using a terahertz time-domain spectroscopy testing device.
In the test, the terahertz wave beam is incident from the metal layer of the multi-frequency point resonance biosensor and is emitted from the dielectric layer.
The offset refers to an offset of a resonance frequency measured by the multi-frequency point resonance biosensor inoculated with cells relative to a resonance frequency measured by the multi-frequency point resonance biosensor not inoculated with cells.
3) And (3) drawing a transmission spectrum curve of the test terahertz changing along with the cell concentration according to the deviation condition obtained in the step 2).
4) Detecting the deviation condition of the sample to be detected, and combining the transmission spectrum curve obtained in the step 3) to obtain the cell concentration of the sample to be detected.
Preferably, in the step 2), the polarized four-dipole Fano resonance frequency offsets are respectively tested along the x direction by the electric field; an eight dipole Fano resonance frequency offset and a sixteen dipole Fano resonance frequency offset.
And respectively testing the polarized four-dipole Fano resonance frequency offset and eight-dipole Fano resonance frequency offset of the electric field along the y direction.
Preferably, the cells comprise adherent cells.
Preferably, the adherent cells comprise cancer cells; the cancer cells comprise oral squamous carcinoma cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, and normal keratinocyte HaCaT.
The invention provides a multi-frequency point resonance biosensor. The multi-frequency point resonance biosensor comprises a plurality of basic units; the basic unit comprises a metal layer and a dielectric layer; the metal layer consists of a U-shaped structure with an asymmetric opening and a rectangular antenna structure; the metal layer comprises a metal top layer and a metal bottom layer, the metal top layer is made of gold, and the metal bottom layer is made of titanium; the dielectric layer includes a polyimide film. The sensor is composed of an asymmetric U-shaped structure with an opening and a rectangular antenna structure, multi-frequency point resonance of high-order mode Fano resonance non-double anisotropic electromagnetic response can be realized, the loss at the resonance response frequency is only related to the material, the detection information quantity and the sensitivity of the sensor are greatly improved, the resonance frequency offset of the sensor is detected by inoculating cells, the sixteen dipole theoretical sensitivity of the sensor is up to 1000 GHz/RIU, and the cell concentration can be rapidly and preliminarily detected without a label, namely the biosensor can realize rapid multi-resonance label-free detection of terahertz waveband high-sensitivity cell sensing. Test results show that the sensor can realize the detection of cell concentration in 30s, does not need to carry out cell marking, has simple operation, greatly reduces the cost and has the sensitivity as high as 1000 GHz/RIU.
Drawings
Fig. 1 is a schematic top view of a biosensor according to the present invention.
FIG. 2 is a schematic side view of a biosensor according to the present invention.
Fig. 3 is a schematic perspective view of a biosensor according to the present invention.
FIG. 4 is a photomicrograph of a biosensor provided in accordance with the present invention.
FIG. 5 is a schematic view of a biosensor according to the present invention.
FIG. 6 is a schematic diagram of the detection of cell concentration according to the present invention.
Fig. 7 is a transmission spectrum of a theoretical result when an electric field of a terahertz wave is incident in x and y directions, which is provided by the present invention.
Fig. 8 is an experimental result transmission spectrum when an electric field of a terahertz wave is incident in x and y directions, provided by the present invention.
FIG. 9 is a graphical representation of the shift in resonance frequency of the electric field of the biosensor test provided by the present invention along the x-direction at different A549 lung cancer cell concentrations.
FIG. 10 is a graphical representation of the shift in resonance frequency of the electric field of the biosensor test provided by the present invention along the y-direction for different A549 lung cancer cell concentrations.
Detailed Description
The invention provides a multi-frequency point resonance biosensor, which comprises a plurality of basic units.
The basic unit comprises a metal layer and a dielectric layer.
The metal layer consists of a U-shaped structure with an asymmetric opening and a rectangular antenna structure; the metal layer comprises a metal top layer and a metal bottom layer, the metal top layer is made of gold, and the metal bottom layer is made of titanium.
The dielectric layer includes a polyimide film.
When the cell concentration is detected by using terahertz waves, the metal layer is a terahertz wave beam incident layer, and the dielectric layer is a terahertz wave beam emergent layer.
In the invention, the thickness of the metal top layer is preferably 150-230 nm, more preferably 200 nm, and the thickness of the metal bottom layer is preferably 15-30 nm, more preferably 20 nm. In the invention, the thickness of the dielectric layer is preferably 5-15 μm, and more preferably 10 μm. In the invention, the inner angle and the outer angle of the U-shaped structure with asymmetric openings are right angles.
In the present invention, the size of the basic unit is preferably 30 μm × 30 μm to 70 μm × 70 μm, and more preferably 50 μm × 50 μm. In the present invention, the number of the basic units is not less than 20 × 20.
When the sensor is viewed from the top, the metal layer consists of a U-shaped structure with an asymmetric opening and a rectangular antenna structure. The sizes of the U-shaped structure with the asymmetric opening and the rectangular antenna structure are not particularly limited, and multi-frequency Fano resonance can be generated. In the invention, the U-shaped structure with asymmetric openings and the rectangular antenna structure can realize multi-frequency high-valence mode Fano resonance, the loss at the resonance response frequency is only related to the material, the detection information quantity and the sensitivity of the sensor are greatly improved, cells are inoculated on the Fano resonance metamaterial through cell culture to detect the resonance frequency deviation, the sixteen dipole theoretical sensitivity is up to 1000 GHz/RIU, the cancer cell concentration can be rapidly and primarily detected without marks, and the cell concentration can be detected within 30 s. In the present invention, as shown in fig. 1, the open asymmetric U-shaped structure includes a long arm and a short arm. In the present invention, the long arm is preferably 18 to 23 μm longer than the short arm, and more preferably 20 μm. In the present invention, the rectangular antenna structure is preferably located above the short arm, and an extension line of an outer side of the U-shaped structure in which the rectangular antenna structure is asymmetric to the opening is preferably a square, and a center of the square is preferably located at a center of the base unit. In the invention, the basic unit is preferably square, and the side length of the basic unit is preferably 30-70 μm, and more preferably 50 μm (p). In the invention, the outer edges of the open asymmetric U-shaped structure and the rectangular antenna structure are preferably 4-6 μm, and more preferably 5 μm away from the edge of the basic unit. In the present invention, the length and width of the rectangular antenna structure are preferably 18 to 22 μm and 10 to 15 μm, respectively, and more preferably 20 μm and 12 μm, respectively. In the present invention, the long arm (d) of the U-shaped structure having an asymmetric opening is preferably 25 to 60 μm, and the short arm (l) of the U-shaped structure having an asymmetric opening is preferably 18 to 22 μm, and more preferably 20 μm. In the invention, the widths of the long arm and the short arm are preferably the same and are both 9-15 μm, and more preferably 12 μm. In the present invention, the width (n) of the bottom side of the U-shaped structure having an asymmetric opening is preferably 5 to 12 μm.
When the sensor is used, cells are preferably inoculated on the surface of the metal layer of the sensor, and the concentration of the cells is tested by detecting the shift of the resonance frequency of different order modes of the device. The biosensor is a high-order mode Fano multi-frequency point resonance metamaterial, in particular to a high-order mode Fano resonance terahertz high-sensitivity cell multi-frequency point resonance sensor based on flexible substrate Polyimide (PI), and by utilizing the characteristics of the sensor for enhancing the response of an electric field and a high Q value, the electric field intensity can be obviously responded due to small external environment changes, and the sensing sensitivity is very high correspondingly. The top view structure of the biosensor is shown in fig. 1, the overall structure of the biosensor comprises two layers, namely an upper metal layer (1) and a lower dielectric layer (2), and polyimide is used as a flexible substrate to support the upper metal structure. FIG. 2 is a front view of the biosensor according to the present invention. The schematic perspective structure of the biosensor is shown in fig. 3.
The photomicrograph of the biosensor is shown in FIG. 4. The periodic structure of the biosensor is shown in FIG. 5; a schematic of the cell concentration assay is shown in FIG. 6.
The invention also provides a preparation method of the multi-frequency point resonance biosensor, which comprises the following steps:
(1) and spin-coating a polyimide film on the silicon wafer to obtain the dielectric layer.
(2) And spin-coating reverse photoresist on the dielectric layer.
(3) Ultraviolet exposure and development.
(4) And evaporating the metal layer.
(5) Soaking in acetone solution, stripping to remove the reverse photoresist and the metal evaporated on the reverse photoresist, and cleaning with isopropanol and deionized water.
(6) And stripping the silicon substrate.
The invention spin-coats polyimide film on silicon chip to obtain dielectric layer. The spin coating method is not particularly limited in the present invention, and the spin coating technique known to those skilled in the art may be used.
After the dielectric layer is obtained, reverse photoresist is spin-coated on the dielectric layer. The source and model of the reverse photoresist are not particularly limited in the invention, and the reverse photoresist conventionally used by a person skilled in the art, such as the reverse photoresist AZ5214, can be adopted. The spin coating method is not particularly limited, and a conventional spin coating method can be adopted, for example, in an ultra-clean room with a yellow light lamp, a special suction tube is used for sucking the reverse photoresist AZ5214, then a layer of AZ5214 is dripped on a dielectric layer on a silicon wafer with the thickness of 500 micrometers, and a spin coater is used for spin coating the reverse photoresist AZ5214 on the dielectric layer.
After the reverse photoresist is spin-coated, the invention preferably uses a hot plate to perform prebaking at the temperature of 100 ℃ for about 10 minutes, and then performs ultraviolet exposure and development. The operation method of the ultraviolet exposure and development is not particularly limited in the present invention, and conventional ultraviolet exposure and development methods well known to those skilled in the art can be adopted, for example, ultraviolet exposure is carried out for 15s and development is carried out for 10s by using an ABM photoetching machine.
After ultraviolet exposure and development, the invention carries out vapor plating of the metal layer. The method for evaporating the metal layer is not particularly limited in the present invention, and a conventional method for evaporating metal, which is well known to those skilled in the art, may be used. If the metal film is plated by sputtering, the vacuum degree is preferably 5X 10-6 Pa。
After the metal layer is evaporated, the reverse photoresist and the metal evaporated on the reverse photoresist are stripped and removed, and the metal is cleaned by isopropanol and deionized water.
After cleaning, the invention peels off the silicon substrate to obtain the sensor shown in fig. 4. The method for peeling the silicon substrate is not particularly limited, and a conventional method for peeling the silicon substrate, which is well known to those skilled in the art, can be adopted, for example, the silicon substrate and the polyimide-based sensor structure are peeled by soaking in a pure hydrofluoric acid solution for about 15 minutes. The size of the sensor is not particularly limited, and the sensor can be prepared into the required size. The terahertz time-domain light spot is usually 5mm multiplied by 5mm, and the sensor of the invention is preferably prepared to be 10 mm multiplied by 10 mm. Compared with the prior structure, the sensor has higher sensitivity and more resonance, and the sixteen dipole theoretical sensitivity of the sensor is as high as 1000 GHz/RIU.
The invention also provides a method for detecting the cell concentration of the multi-frequency point resonance biosensor based on the technical scheme or the preparation method of the technical scheme, which comprises the following steps:
1) cells with different concentrations are respectively inoculated on the multi-frequency point resonance biosensor.
2) And testing the shift conditions of the resonance frequency of the transmission spectral line of the electric field along the x direction and the y direction respectively by using a terahertz time-domain spectroscopy testing device.
In the test, the terahertz wave beam is incident from the metal layer of the multi-frequency point resonance biosensor and is emitted from the dielectric layer.
The offset refers to an offset of a resonance frequency measured by the multi-frequency point resonance biosensor inoculated with cells relative to a resonance frequency measured by the multi-frequency point resonance biosensor not inoculated with cells.
3) And (3) drawing a transmission spectrum curve of the test terahertz changing along with the cell concentration according to the deviation condition obtained in the step 2).
4) Detecting the deviation condition of the sample to be detected, and combining the transmission spectrum curve obtained in the step 3) to obtain the cell concentration of the sample to be detected.
When the cell concentration is detected, the preparation of the transmission spectrum curve is preferably carried out, and then the detection of the cell concentration in the sample to be detected is realized according to the obtained transmission spectrum curve. In the present invention, the cells include adherent cells. In the present invention, the adherent cells include cancer cells; the cancer cells comprise oral squamous carcinoma cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, and normal keratinocyte HaCaT. The invention firstly inoculates cells with different concentrations on the multi-frequency point resonance biosensor. In the present invention, the seeding is seeded on the metal layer of the sensor. In the present invention, the purpose of the seeding is to allow the cells to adhere to the wall for ease of detection. The inoculation method is not particularly limited, and a conventional inoculation method can be adopted. Specifically, the inoculation method is preferably: digesting the cells from the culture dish with trypsin; then blowing the uniform cells by using a culture medium to form a single cell suspension; and (3) sterilizing the sensor, placing the sensor at the bottom of a culture plate, inoculating the single cell suspension into the culture plate, and culturing in a 5-10% carbon dioxide cell culture box at 37 ℃ until the cells adhere to the wall. According to the invention, after the cells are attached to the wall, the biosensor is preferably dried and then the cell concentration is detected.
After cells with different concentrations adhere to the wall, the terahertz time-domain spectroscopy testing device is used for testing the shift conditions of the resonance frequencies of the transmission spectral lines of the electric field along the x direction and the y direction respectively. In the invention, the terahertz time-domain spectroscopy testing device is preferably a terahertz time-domain spectroscopy tester. The terahertz time-domain spectroscopy tester is not specially limited in model. Specifically, in the embodiment of the invention, a terahertz time-domain spectrometer of model ADVANTEST TAS7500SU is preferably used, the spectrum range is 0.5-7 THz, and the resolution is 7.6 GHz. The invention has no specific limitation on the frequency spectrum range and the resolution of the terahertz time-domain spectrograph. In the test, the terahertz wave beam is incident from the metal layer of the multi-frequency point resonance biosensor and is emitted from the dielectric layer. In the present invention, the offset refers to an offset of a resonance frequency measured by the multi-frequency resonance biosensor inoculated with cells with respect to a resonance frequency measured by the multi-frequency resonance biosensor not inoculated with cells. In the invention, the electric field is respectively tested for the offset of the resonance frequency of the polarized four-dipole Fano resonance along the x direction; eight-dipole Fano resonance frequency offset and sixteen-dipole Fano resonance frequency offset; and respectively testing the polarized four-dipole Fano resonance frequency offset and eight-dipole Fano resonance frequency offset of the electric field along the y direction.
According to the invention, a transmission spectrum curve of the test terahertz, which changes with the cell concentration, is drawn according to the deviation condition. In the embodiment of the invention, the culture concentration is preferably measured to be 0.1 multiplied by 10 by using the terahertz time-domain spectroscopy tester5cell/ml、0.3×105cell/ml、0.5×105cell/ml、1×105cell/ml、3×105cell/ml and 5X 105The resonance frequency of the transmission spectrum of the A549 lung cancer cell with the cell/ml concentration is shifted relative to the resonance frequency under the condition that the A549 lung cancer is not cultured, the wave beam firstly enters from the metal layer of the sensor and then exits from the medium layer for detection, and finally the concentration of the A549 lung cancer cell is drawnAnd (5) measuring a curve.
And finally, detecting the offset condition of the sample to be detected, and combining the transmission spectrum curve to obtain the cell concentration of the sample to be detected.
The multi-frequency resonance biosensor, the method for manufacturing the same, and the method for measuring cell concentration according to the present invention will be described in further detail with reference to the following embodiments, which are not intended to be limiting.
Example 1
Lung cancer cell concentration test
1) A549 lung cancer cells are inoculated on the biosensor, namely a metal layer of the novel terahertz non-bi-anisotropic high-order mode Fano resonance multi-frequency point resonance metamaterial.
2) The shift of the resonance frequency of the transmission spectrum of a549 sample cultured with different concentrations relative to the resonance frequency of the sample cultured without the a549 lung cancer was tested by using a terahertz time-domain spectroscopy tester (specific operations are: firstly, a terahertz time-domain spectroscopy is used for testing a metamaterial curve without cultured cells (fig. 7 and 8 mainly represent terahertz time-domain spectroscopy curves when a designed metamaterial biosensor is free of cells, when an electric field of terahertz waves is incident in the x direction, four-dipole, eight-dipole and sixteen-dipole resonance occur, when the electric field of terahertz waves is incident in the y direction, four-dipole and eight-dipole resonance occur, the offset of the sensor is mainly used for analyzing the offset of the resonance frequencies), then lung cancer cells with different concentrations are cultured on the surface of the metamaterial, and the terahertz time-domain spectroscopy is used for testing the curves respectively. Then comparing the lung cancer cell metamaterial terahertz time-domain curve with each concentration with the metamaterial terahertz time-domain curve without cancer cells, the resonance point can be shifted), the wave beam firstly enters from the metal layer of the metamaterial, then exits from the dielectric layer for detection, and finally, a concentration detection curve of the A549 lung cancer cells is drawn, as shown in fig. 9 and fig. 10.
3) Inoculating culture concentration of 0.1 × 10 on multi-frequency resonance biosensor5cell/mL、0.3×105cell/mL、0.5×105cell/mL、1×105cell/mL、3×105cell/mL and 5X 105A549 lung cancer cells with cell/mL concentration are cultured (the culture condition is constant temperature at 37 ℃ and 10% carbon dioxide) for 24 hours, then are taken out from the culture medium, surface moisture is removed by using filter paper, after the cells are fully dried, a terahertz time-domain spectrometer is used for detecting the resonance frequency offset of the biosensor compared with the resonance frequency offset under the cell-free concentration, and FIGS. 9 and 10 show the transmission line of the A549 lung cancer cells cultured by the terahertz time-domain spectrometer under the nitrogen environment dried at room temperature (the humidity is less than 4%). FIG. 9 is a graph of resonance frequency shift of the electric field of the biosensor test provided by the present invention along the x-direction at different A549 lung cancer cell concentrations; that is, when the electric field direction of the terahertz wave is incident in the x direction, the frequency shift amount of the cancer cell concentration is different in the four-dipole resonance (Q), the eight-dipole resonance (O), and the sixteen-dipole resonance (H). FIG. 10 is a graphical representation of the shift in resonance frequency of the electric field of the biosensor test provided by the present invention along the y-direction at different A549 lung cancer cell concentrations; that is, when the electric field direction of the terahertz wave is incident in the y direction, the terahertz wave resonates at four dipoles and at eight dipoles with a different cancer cell concentration frequency shift. As is clear from FIGS. 9 and 10, the cancer cells at 6 different concentrations were at 6 different cell concentrations (0.1X 10) compared to the cell-free metamaterial5cell/mL、0.3×105cell/mL、0.5×105cell/mL、1×105cell/mL、3×105cell/mL and 5X 105cell/mL), the frequency shifts of resonance frequencies of four-dipole Fano resonance polarized along the x direction of the electric field are respectively 22.6 GHz, 28.87 GHz, 97.5 GHz, 15.8 GHz, 28.2 GHz and 67.4 GHz; the frequency deviation of the eight-dipole Fano resonance is respectively 6 GHz, 50.9 GHz, 63.3 GHz, 108.87 GHz, 108.5GHz and 120.2 GHz; the resonance frequency shifts of the sixteen-dipole Fano resonance are respectively 3.56 GHz, 59.2 GHz, 81.66 GHz, 90.03 GHz, 97.1 GHz and 117.56 GHz; meanwhile, under the same condition, under 6 different cell concentrations, the resonance frequency shifts of four-dipole Fano resonance polarized by an electric field along the y direction are respectively 0 GHz, 49.7 GHz, 45.3 GHz, 126.27 GHz, 36.7 GHz and-8.75 GHz; the eight dipole Fano resonance frequency shifts are-0, respectively.5GHz, 48.23 GHz, 60.13 GHz, 107.43 GHz, 17.23GHz and 32.56 GHz.
And detecting the sample by utilizing the terahertz time-domain spectroscopy.
Simulating the test results of samples to be tested with different refractive index parameters, and calculating to obtain the theoretical sensitivity of the terahertz high-valence Fano resonance biosensor of the invention reaching 1000 GHz/RIU. The biosensor with the non-label characteristic of the terahertz high-order mode Fano resonance metamaterial designed and manufactured on the flexible polyimide substrate can be used for pure electric field response, high in sensitivity and multi-resonance non-label detection, and can be widely applied to the field of terahertz cell sensing and identification.
The existing method for detecting the cell concentration needs to consume the fluorescence labeled antibody, has high detection cost (the cost of each time needs about 2000 yuan), is time-consuming (the testing time is about 2 hours), needs more samples, is disposable and cannot be recycled.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A multi-frequency point resonant biosensor, comprising a plurality of base units;
the basic unit comprises a metal layer and a dielectric layer;
the metal layer consists of a U-shaped structure with an asymmetric opening and a rectangular antenna structure; the metal layer comprises a metal top layer and a metal bottom layer, the metal top layer is made of gold, and the metal bottom layer is made of titanium;
the dielectric layer includes a polyimide film.
2. The biosensor according to claim 1, wherein the number of the base units is not less than 20 x 20.
3. The biosensor as claimed in claim 1, wherein the top metal layer has a thickness of 150 to 230nm and the bottom metal layer has a thickness of 15 to 30 nm.
4. The biosensor of claim 1, wherein the dielectric layer has a thickness of 5-15 μm.
5. The biosensor of claim 1, wherein the asymmetric U-shaped structure of the opening has both inner and outer corners that are right angles.
6. The method for preparing a multi-frequency resonance biosensor as claimed in any one of claims 1 to 5, comprising the steps of:
(1) spin-coating a polyimide film on a silicon wafer to obtain a dielectric layer;
(2) spin-coating a reverse photoresist on the dielectric layer;
(3) ultraviolet exposure and development;
(4) evaporating a metal layer;
(5) soaking in acetone solution, stripping to remove the reverse photoresist and the metal evaporated on the reverse photoresist, and cleaning with isopropanol and deionized water;
(6) and stripping the silicon substrate.
7. The method for detecting cell concentration based on the multi-frequency resonance biosensor of any one of claims 1 to 5 or the multi-frequency resonance biosensor obtained by the preparation method of claim 6, comprising the steps of:
1) respectively inoculating cells with different concentrations on a multi-frequency point resonance biosensor;
2) testing the shift conditions of the resonance frequency of the transmission spectral line of the electric field along the x direction and the y direction respectively by using a terahertz time-domain spectroscopy testing device;
in the test, a terahertz wave beam is incident from a metal layer of the multi-frequency point resonance biosensor and is emitted from a dielectric layer;
the offset refers to the offset of the resonance frequency measured by the multi-frequency point resonance biosensor inoculated with cells relative to the resonance frequency measured by the multi-frequency point resonance biosensor not inoculated with cells;
3) drawing a transmission spectrum curve of the test terahertz changing along with the cell concentration according to the deviation condition obtained in the step 2);
4) detecting the deviation condition of the sample to be detected, and combining the transmission spectrum curve obtained in the step 3) to obtain the cell concentration of the sample to be detected.
8. The method according to claim 7, wherein in step 2), the electric field is respectively tested for the polarized four-dipole Fano resonance frequency offset along the x direction; eight-dipole Fano resonance frequency offset and sixteen-dipole Fano resonance frequency offset;
and respectively testing the polarized four-dipole Fano resonance frequency offset and eight-dipole Fano resonance frequency offset of the electric field along the y direction.
9. The method of claim 7, wherein the cells comprise adherent cells.
10. The method of claim 9, wherein the adherent cells comprise cancer cells; the cancer cells comprise oral squamous carcinoma cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, and normal keratinocyte HaCaT.
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