CN110146463A - A kind of method of multifrequency point resonant biosensor and preparation method thereof and test cell concentration - Google Patents
A kind of method of multifrequency point resonant biosensor and preparation method thereof and test cell concentration Download PDFInfo
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- 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
- G01N21/3581—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
- 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]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- 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
- G01N21/3581—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
Abstract
The present invention relates to the methods of a kind of multifrequency point resonant biosensor and preparation method thereof and test cell concentration, belong to Terahertz Technology and biotechnology crossing domain.Multifrequency point resonant biosensor provided by the invention includes multiple basic units；The basic unit includes metal layer and dielectric layer；The metal layer is by an asymmetrical U-shaped structure of opening and a rectangular antenna structure composition；The metal layer includes metal top layer and metal back layer, and the material of the metal top layer is gold, and the material of the metal back layer is titanium；The dielectric layer includes polyimide film.Sensor of the present invention can be realized terahertz wave band high sensitivity cell and sense quick, multi-resonant markless detection.
Description
Technical field
The present invention relates to Terahertz Technologies and biotechnology crossing domain, and in particular to a kind of non-double anisotropy of Terahertz
High-order mode Fano resonance unmarked biosensor of multifrequency point resonance metamaterial and preparation method thereof and test cell concentration
Method.
Background technique
The development of Terahertz Technology is highly visible, becomes new century mostly important one of core technology.Many country's handles
Terahertz Technology is classified as emphasis development project.Due to unique electric field response, Terahertz Technology be widely applied to public safety,
Communication and biologic medical etc..The method of current detecting cell concentration mainly includes fluorescence detection and the label of label
FCM analysis technology, although in practical applications these have it is very highly sensitive, their testing cost is very
Height, and most of other chemical substances of cooperation use, and then will cause a degree of pollution.Such as: its detection of CCK-8 method
Sensitivity, but CCK-8 is expensive, in addition, the color of CCK-8 reagent is pale red, it is close with culture medium color, it is testing
In be easy to produce leakage plus or the incorrect operation such as add；There are also Flow Cytometries, can be to list using flow cytometer
One cell carries out quantitative detection and analytical technology, combines monoclonal antibody and immunocytochemical technique, laser and electronics
A series of technologies such as computer science have detection speed fast, high sensitivity, but cannot equally avoid the need for label, cost
High, the problems such as time-consuming.There is no a kind of cell detection schemes at low cost, without label at present.
Summary of the invention
The purpose of the present invention is to provide a kind of multifrequency point resonant biosensor and preparation method thereof and test cell are dense
The method of degree.Sensor of the present invention can be realized terahertz wave band high sensitivity cell sensing quickly, multi-resonant it is unmarked
Detection, and it is at low cost.
The present invention provides a kind of multifrequency point resonant biosensor, the sensor includes multiple basic units；
The basic unit includes metal layer and dielectric layer；
The metal layer is by an asymmetrical U-shaped structure of opening and a rectangular antenna structure composition；The metal
Layer includes metal top layer and metal back layer, and the material of the metal top layer is gold, and the material of the metal back layer is titanium；
The dielectric layer includes polyimide film.
Preferably, the number of the basic unit is not less than 20 × 20.
Preferably, the metal top layer with a thickness of 150~230nm, the metal back layer with a thickness of 15~30nm.
Preferably, the dielectric layer with a thickness of 5~15 μm.
Preferably, the interior angle of the asymmetrical U-shaped structure of opening and exterior angle are right angle.
The present invention also provides the preparation method of multifrequency point resonant biosensor described in above-mentioned technical proposal, including it is following
Step:
(1) the spin-on polyimide film on silicon wafer, obtains dielectric layer；
(2) the spin coating reversal photoresist on dielectric layer；
(3) uv-exposure and development；
(4) evaporated metal layer；
(5) it is impregnated in acetone soln, the metal being deposited on removing removal reversal photoresist and the reversal photoresist is used
Isopropanol and deionized water cleaning；
(6) silicon base is removed.
The present invention also provides the multifrequency point resonant biosensor or above-mentioned technical proposals based on the above-mentioned technical proposal
The method of the detection cell concentration for the multifrequency point resonant biosensor that the preparation method obtains, comprising the following steps:
1) cell of various concentration is seeded in respectively on multifrequency point resonant biosensor；
2) the transmission spectral line in terahertz time-domain spectroscopy test device test electric field the difference in the x-direction upper and direction y is utilized
The drift condition of resonant frequency；
In the test, the metal layer of terahertz wave beam from multifrequency point resonant biosensor is incident, projects from dielectric layer；
The offset refers to resonance frequency that the multifrequency point resonant biosensor for being vaccinated with cell is measured relative to not connecing
The offset for the resonance frequency that the multifrequency point resonant biosensor of kind cell is measured；
3) drift condition obtained according to step 2) draws the transmission spectral curve of the test Terahertz changed with cell concentration；
4) drift condition for detecting sample to be tested, obtains the cell of sample to be tested in conjunction with the transmission spectral curve that step 3) obtains
Concentration.
Preferably, in step 2), electric field is along the four dipole Fano resonance resonance on the direction x, distinguishing tests polarization
Frequency offset；Eight dipole Fano resonance resonance frequency shift amount and 16 dipole Fano resonance resonance frequency shift amount；
Electric field in the y-direction on, the four dipole Fano resonance resonance frequency shift amount and eight dipoles of tests polarization respectively
Fano resonance resonance frequency shift amount.
Preferably, the cell includes attached cell.
Preferably, the attached cell includes cancer cell；The cancer cell include oral cavity squamous cancer cell HSC3 and
SCC4, lung cell A549 and H460, cervical cancer cell Hela and Siha, normal keratinocyte HaCaT.
The present invention provides a kind of multifrequency point resonant biosensors.Multifrequency point resonant biosensor packet of the present invention
Include multiple basic units；The basic unit includes metal layer and dielectric layer；The metal layer is asymmetrical U-shaped by an opening
Structure and a rectangular antenna structure composition；The metal layer includes metal top layer and metal back layer, the metal top layer
Material is gold, and the material of the metal back layer is titanium；The dielectric layer includes polyimide film.Sensor of the present invention is by one
A asymmetrical U-shaped structure of opening and a rectangular antenna structure are constituted, and it is non-double every to can be realized high-order mode Fano resonance
The multifrequency point resonance of anisotropic electromagnetic response, loss is only related with material itself at resonance response frequency, and detection information amount with
The sensitivity of sensor greatly promotes, and by inoculating cell, detects its resonant frequency shift, 16 dipole theories are sensitive
Degree is up to 1000GHz/RIU, and the quick unmarked preliminary detection cell concentration in ground of energy, i.e., biosensor of the present invention can be real
Existing terahertz wave band high sensitivity cell senses quick, multi-resonant markless detection.Test result shows sensing of the present invention
The detection of cell concentration can be realized in device 30s, and without carrying out cell marking, easy to operate, cost is greatly lowered, sensitivity
Up to 1000GHz/RIU.
Detailed description of the invention
Fig. 1 is the overlooking structure diagram of biosensor provided by the invention；
Fig. 2 is the side structure schematic diagram of biosensor provided by the invention；
Fig. 3 is the schematic perspective view of biosensor provided by the invention；
Fig. 4 is the microscope photo of biosensor provided by the invention；
Fig. 5 is the periodic structure figure of biosensor provided by the invention；
Fig. 6 is cell concentration detection schematic diagram provided by the invention；
Fig. 7 is the notional result transmission spectrum provided by the invention when the electric field of THz wave is with the incidence of the direction x and y；
Fig. 8 is the experimental result transmission spectrum provided by the invention when the electric field of THz wave is with the incidence of the direction x and y；
Fig. 9 is the electric field of biosensor test provided by the invention along under the difference A549 lung carcinoma cell concentration of the direction x
Resonant frequency shift diagram；
Figure 10 is the electric field of biosensor test provided by the invention along under the difference A549 lung carcinoma cell concentration of the direction y
Resonant frequency shift diagram.
Specific embodiment
The present invention provides a kind of multifrequency point resonant biosensor, the sensor includes multiple basic units；
The basic unit includes metal layer and dielectric layer；
The metal layer is by an asymmetrical U-shaped structure of opening and a rectangular antenna structure composition；The metal
Layer includes metal top layer and metal back layer, and the material of the metal top layer is gold, and the material of the metal back layer is titanium；
The dielectric layer includes polyimide film.
When using THz wave detection cell concentration, the metal layer is terahertz wave beam incident layer, the dielectric layer
For terahertz wave beam exit layer.
In the present invention, the thickness of the metal top layer is preferably 150~230nm, more preferably 200nm, the metal
The thickness of bottom is preferably 15~30nm, more preferably 20nm.In the present invention, the thickness of the dielectric layer is preferably 5~15 μ
M, more preferably 10 μm.In the present invention, the interior angle of the asymmetrical U-shaped structure of opening and exterior angle are right angle.
In the present invention, the basic unit is preferably dimensioned to be 70 μm of 30 μ m, 30 μm~70 μ m, more preferably 50 μ
m×50μm.In the present invention, the number of the basic unit is not less than 20 × 20.
When sensor of the present invention is overlooked, the metal layer is by the asymmetrical U-shaped structure of an opening and one
Rectangular antenna structure composition.The present invention does not have the size of the asymmetrical U-shaped structure of the opening and rectangular antenna structure
Particular determination can generate multifrequency point method promise resonance.In the present invention, the asymmetrical U-shaped structure of the opening and rectangular
Multifrequency point high price mould Fano resonance may be implemented in shape antenna structure, and loss is only related with material itself at resonance response frequency, and
And the sensitivity of detection information amount and sensor greatly promotes, by cell culture, inoculation is thin on Fano resonance metamaterial
Born of the same parents detect its resonant frequency shift, and 16 dipole theory high sensitivities reach 1000GHz/RIU, and energy is quickly at the beginning of unmarked ground
The detection of cell concentration can be realized in step detection cancer cell concentration, 30s.As shown in Figure 1, in the present invention, the opening is non-right
The U-shaped structure of title includes long-armed and galianconism.In the present invention, described long-armed 18~23 μm preferably longer than galianconism, more preferably 20 μ
m.In the present invention, the rectangular antenna structure is preferably placed above galianconism, and the rectangular antenna structure is opened with described
The extended line of the outer side edges of the asymmetric U-shaped structure of mouth is preferably square, and the center of the square is preferably placed at described basic
The center of unit.In the present invention, the basic unit is preferably square, and the side length of the basic unit is preferably 30~70
μm, more preferably 50 μm (p).In the present invention, the outer ledge of the opening asymmetric U-shaped structure and rectangular antenna structure
It is preferred that 4~6 μm away from basic unit edge, it is 5 μm more preferable.In the present invention, the length of the rectangular antenna structure and width are preferred
Respectively 18~22 μm and 10~15 μm, be more preferably respectively 20 μm and 12 μm.In the present invention, the asymmetrical U of opening
Long-armed (d) of type structure is preferably 25~60 μm, and more preferably 40 μm, the galianconism (l) of the asymmetrical U-shaped structure of opening is excellent
It is selected as 18~22 μm, more preferably 20 μm.In the present invention, described long-armed and galianconism width is preferably identical and is 9~15 μ
M, more preferably 12 μm.In the present invention, the width (n) on the asymmetrical U-shaped structure bottom edge of opening is preferably 5~12 μm.
Cell inoculation when in use, is preferably passed through inspection in the sensor layer on surface of metal by sensor of the present invention
The resonant frequency shift for surveying device not same order mould carries out the concentration determination of cell.Biosensor of the present invention is a kind of base
In high-order mode Fano multifrequency point resonance metamaterial, specially the high-order mode Fano based on flexible substrates polyimides (PI) resonates
The highly sensitive cell multifrequency point resonant transducer of Terahertz enhances the characteristic of electric field and high q-factor response, small extraneous ring using it
Border variation can cause electric field strength to obvious response to, its corresponding sensing sensitivity is very high.Biosensor of the present invention
Plan structure as shown in Figure 1, the sensor overall structure include two layers, be top metal layer (1) and lower part medium
Layer (2), polyimides support upper layer metal structure as flexible substrates.Fig. 2 is the main view of biosensor of the present invention.
The schematic perspective view of biosensor is as shown in Figure 3.The microscope photo of biosensor is as shown in Figure 4.Bio-sensing
The periodic structure figure of device is as shown in Figure 5；Cell concentration detection schematic diagram is as shown in Figure 6.
The present invention also provides the preparation method of multifrequency point resonant biosensor described in above-mentioned technical proposal, including it is following
Step:
(1) the spin-on polyimide film on silicon wafer, obtains dielectric layer；
(2) the spin coating reversal photoresist on dielectric layer；
(3) uv-exposure and development；
(4) evaporated metal layer；
(5) it is impregnated in acetone soln, the metal being deposited on removing removal reversal photoresist and the reversal photoresist is used
Isopropanol and deionized water cleaning；
(6) silicon base is removed.
Present invention spin-on polyimide film on silicon wafer, obtains dielectric layer.The present invention is not special to the spin coating method
It limits, is operated using spin coating technique well known to those skilled in the art.
After obtaining dielectric layer, present invention spin coating reversal photoresist on dielectric layer.The present invention is to the reversal photoresist
Source and model are not particularly limited, and using the conventional use of reversal photoresist of those skilled in the art, such as invert photoetching
Glue AZ5214.The present invention is not particularly limited the spin coating method, using conventional spin-on process, is such as opening yellow fluorescent lamp
Clean room in, with Special suction pipe draw reversal photoresist AZ5214, then dripped on the dielectric layer on 500 microns of thick silicon wafers
One layer of AZ5214, using spin coater on dielectric layer spin coating reversal photoresist AZ5214.
After the complete reversal photoresist of spin coating, the present invention carries out front baking preferably by hot plate at a temperature of 100 DEG C, and front baking 10 minutes
Left and right, then carry out uv-exposure and development.The present invention is not particularly limited the operating method of the uv-exposure and development, adopts
With Conventional UV exposure and imaging method well known to those skilled in the art, uv-exposure is such as carried out using ABM litho machine
15s, develop 10s.
After carrying out uv-exposure and development, the present invention carries out evaporated metal layer.Vapor deposition side of the present invention to the metal layer
Method does not have special restriction, using the method for conventional evaporation metal well known to those skilled in the art.Such as utilize control sputtering
Metal-coated films, the condition of vacuum degree are preferably 5 × 10-6Pa。
After metal layer has been deposited, the present invention impregnates in acetone soln, removing removal reversal photoresist and the reversion light
The metal being deposited in photoresist, is cleaned with isopropanol and deionized water.
After cleaning, the present invention removes silicon base, obtains sensor as shown in Figure 4.The present invention removes the silicon base
Method is not particularly limited, using conventional silicon base stripping means well known to those skilled in the art, such as in pure hydrofluoric acid
It in solution, impregnates about 15 minutes, realizes silicon base and polyimides is the sensor structure removing of substrate.The present invention is to described
The size of sensor does not have special limitation, size required for being prepared into.Terahertz time-domain hot spot be usually 5mm ×
5mm, sensor of the present invention are preferably prepared to 10mm × 10mm.Sensor of the present invention compares previous structure, sensitivity
Higher, resonance is more, and 16 dipole theory high sensitivities of the sensor reach 1000GHz/RIU.
The present invention also provides the multifrequency point resonant biosensor or above-mentioned technical proposals based on the above-mentioned technical proposal
The method of the detection cell concentration for the multifrequency point resonant biosensor that the preparation method obtains, comprising the following steps:
1) cell of various concentration is seeded in respectively on multifrequency point resonant biosensor；
2) the transmission spectral line in terahertz time-domain spectroscopy test device test electric field the difference in the x-direction upper and direction y is utilized
The drift condition of resonant frequency；
In the test, the metal layer of terahertz wave beam from multifrequency point resonant biosensor is incident, projects from dielectric layer；
The offset refers to resonance frequency that the multifrequency point resonant biosensor for being vaccinated with cell is measured relative to not connecing
The offset for the resonance frequency that the multifrequency point resonant biosensor of kind cell is measured；
3) drift condition obtained according to step 2) draws the transmission spectral curve of the test Terahertz changed with cell concentration；
4) drift condition for detecting sample to be tested, obtains the cell of sample to be tested in conjunction with the transmission spectral curve that step 3) obtains
Concentration.
The present invention preferably first carries out the preparation of transmission spectrum curve when detecting to cell concentration, and then foundation obtains
Transmission spectral curve realize sample to be tested in cell concentration detection.In the present invention, the cell includes attached cell.At this
In invention, the attached cell includes cancer cell；The cancer cell includes oral cavity squamous cancer cell HSC3 and SCC4, lung carcinoma cell
A549 and H460, cervical cancer cell Hela and Siha, normal keratinocyte HaCaT.The present invention is first by the cell of various concentration point
It is not seeded on multifrequency point resonant biosensor.In the present invention, the inoculation is to be seeded on the metal layer of sensor.?
In the present invention, the purpose of the inoculation is to keep cell adherent, convenient for detection.The present invention does not have special limit to the inoculation method
It is fixed, using traditional vaccination method.Specifically, the inoculation method is preferred are as follows: cell is disappeared from culture dish with trypsase
Change is got off；Even cell is blown with culture medium again, forms single cell suspension；After sensor is sterilized, it is placed in culture plate bottom and single
Cell suspension inoculation is cultivated adherent to cell into culture plate in 37 DEG C, 5~10% carbon dioxide cell incubators.This hair
It is bright after cell is adherent, the detection of cell concentration is carried out after preferably biosensor is dried again.
After various concentration cell is adherent, the present invention is using terahertz time-domain spectroscopy test device test electric field respectively along the side x
The drift condition of transmission spectral line resonant frequency upwards and on the direction y.In the present invention, the terahertz time-domain spectroscopy test dress
Set preferably terahertz time-domain spectroscopy tester.The present invention does not have special limit to the model of the terahertz time-domain spectroscopy tester
It is fixed.Specifically, in embodiments of the present invention preferably by the terahertz time-domain spectroscopy of this model of ADVANTEST TAS7500SU
Instrument, spectral range are 0.5~7THz, resolution ratio 7.6GHz.Frequency spectrum model of the present invention to the terahertz time-domain spectroscopy instrument
It encloses and is not specifically limited with resolution ratio.In the test, metal layer of the terahertz wave beam from multifrequency point resonant biosensor
Incidence is projected from dielectric layer.In the present invention, the offset refers to what the multifrequency point resonant biosensor for being vaccinated with cell was measured
The offset for the resonance frequency that resonance frequency is measured relative to the multifrequency point resonant biosensor of not inoculating cell.In this hair
In bright, electric field is along the four dipole Fano resonance resonance frequency shift amount on the direction x, distinguishing tests polarization；Eight dipoles
Fano resonance resonance frequency shift amount and 16 dipole Fano resonance resonance frequency shift amount；Electric field in the y-direction on, survey respectively
The four dipole Fano resonance resonance frequency shift amount and eight dipole Fano resonance resonance frequency shift amount of examination polarization.
The present invention draws the transmission spectral curve of the test Terahertz changed with cell concentration according to above-mentioned drift condition.At this
In invention specific embodiment, the present invention preferably by terahertz time-domain spectroscopy tester test cultures concentration be 0.1 ×
105cell/ml、0.3×105cell/ml、0.5×105cell/ml、1×105cell/ml、3×105Cell/ml and 5 ×
105In the case of the resonance frequency of the transmission spectrum of the A549 lung carcinoma cell of cell/ml concentration is relative to no culture A549 lung cancer
The drift condition of resonance frequency, wave beam is incident from the metal layer of sensor first, then is detected from dielectric layer injection, finally draws
The Concentration Testing curve of A549 lung carcinoma cell processed.
Finally, the present invention detects the drift condition of sample to be tested, the present invention combines above-mentioned transmission spectral curve to obtain to test sample
The cell concentration of product.
Combined with specific embodiments below to a kind of multifrequency point resonant biosensor of the present invention and preparation method thereof
It is further described in detail with the method for test cell concentration, technical solution of the present invention includes but is not limited to following implements
Example.
Embodiment 1
Lung carcinoma cell concentration determination.
1) A549 lung carcinoma cell is seeded on biosensor of the present invention, i.e., the novel non-double anisotropy high-orders of Terahertz
On the metal layer of mould Fano resonance multifrequency point resonance metamaterial.
2) there is the resonance of the transmission spectrum of the A549 sample of various concentration using terahertz time-domain spectroscopy tester test cultures
Drift condition (concrete operations are as follows: first with terahertz of the frequency relative to the resonance frequency in the case of no culture A549 lung cancer
Meta Materials curve (the metamaterial biology of design that Fig. 7 and Fig. 8 mainly characterize of the hereby time-domain spectroscopy test without culture cell
There are four dipoles when the electric field of THz wave is with the incidence of the direction x in terahertz time-domain spectroscopy curve when sensor is cell-free
Son, eight dipoles, 16 dipole resonances.When the electric field of THz wave is with the incidence of the direction y, there are four dipoles, eight dipoles
Sub- resonance.The offset of sensor is mainly to analyze the offset of these resonance frequencies), then cultivated not on metamaterial surface
With the lung carcinoma cell of concentration, terahertz time-domain spectroscopy is recycled to test its curve respectively.Then the lung carcinoma cell of each concentration
Meta Materials terahertz time-domain curve and the Meta Materials terahertz time-domain curve of not cancer cell compare, and can obtain resonance point hair
Raw offset), wave beam is incident from the metal layer of Meta Materials first, then is detected from dielectric layer injection, and A549 lung cancer is finally drawn
The Concentration Testing curve of cell, as shown in Figure 9 and Figure 10.
3) inoculated and cultured concentration is 0.1 × 10 on multifrequency point resonant biosensor5cell/mL、0.3×105cell/
mL、0.5×105cell/mL、1×105cell/mL、3×105Cell/mL and 5 × 105The A549 lung cancer of cell/mL concentration
Cell cultivates (condition of culture is 37 DEG C of constant temperature, 10% carbon dioxide) and takes out from culture medium after 24 hours and removed with filter paper
Surface moisture is to be dried sufficiently rear dense compared to cell-free using terahertz time-domain spectroscopy instrument detection biosensor resonant frequency
Resonant frequency shift amount under degree, Fig. 9 and Figure 10 are to use Terahertz under the nitrogen environment of drying at room temperature (humidity is less than 4%)
Time-domain spectroscopy apparatus measures culture has the transmission spectral line of A549 lung carcinoma cell.Wherein, Fig. 9 is biosensor provided by the invention
The electric field of test along the resonant frequency shift under the difference A549 lung carcinoma cell concentration of the direction x diagram；That is the electricity of THz wave
When field direction is with the incidence of the direction x, in four dipole photons (Q), eight dipole photons (O), 16 dipole photons (H) Shi Butong
Cancer cell concentration frequency offset.Figure 10 is the electric field of biosensor test provided by the invention along the direction y difference A549
The diagram of resonant frequency shift under lung carcinoma cell concentration；When i.e. the direction of an electric field of THz wave is with the incidence of the direction y, in four dipoles
Sub-resonance, resonate when eight dipole photons different carcinoma cell concentration frequency offset.It is from Fig. 9 and Figure 10 it is found that dense in 6 differences
Under the cancer cell of degree, compared to cell-free metamaterial, (0.1 × 10 under 6 different cell concentrations5cell/mL、0.3×
105cell/mL、0.5×105cell/mL、1×105cell/mL、3×105Cell/mL and 5 × 105Cell/mL), electric field edge
The direction x polarization four dipole Fano resonance resonance frequency shift be respectively 22.6GHz, 28.87GHz, 97.5GHz,
15.8GHz,28.2GHz,67.4GHz；Eight dipole Fano resonance resonance frequency shift be respectively 6GHz, 50.9GHz,
63.3GHz, 108.87GHz, 108.5GHz and 120.2GHz；16 dipole Fano resonance resonance frequency shift be respectively
3.56GHz, 59.2GHz, 81.66GHz, 90.03GHz, 97.1GHz and 117.56GHz；Meanwhile in 6 differences of same case
Electric field is polarized along the direction y under cell concentration four dipole Fano resonance resonance frequency shift be respectively 0GHz, 49.7GHz,
45.3GHz, 126.27GHz, 36.7GHz and -8.75GHz；Eight dipole Fano resonate resonance frequency shift be respectively-
0.5GHz, 48.23GHz, 60.13GHz, 107.43GHz, 17.23GHz and 32.56GHz.
The detection of sample is carried out using terahertz time-domain spectroscopy.
It is high to obtain Terahertz of the invention by calculating for the test result for emulating the sample to be tested of different refractivity parameter
Valence mould Fano resonance biological sensor theoretical sensitivity reaches 1000GHz/RIU.The present invention designs on flexible polyimide substrate
The biosensor with the Terahertz high-order mode Fano resonance unmarked characteristic of metamaterial of production can be with pure electric field response, spirit
Sensitivity height, multi-resonant markless detection can be widely applied for Terahertz cell sensing and identification field.
The method of existing detection cell concentration needs to consume the antibody of fluorescent marker, testing cost height (cost each time
Need about 2000 yuan or so), relatively time consuming (about 2 hours of testing time), sample size needs are more, and are disposable, nothings
Method recycles, and compared with the existing detection method, not only high sensitivity, and cost substantially reduces, the time greatly shortens the present invention.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of multifrequency point resonant biosensor, which is characterized in that the sensor includes multiple basic units；
The basic unit includes metal layer and dielectric layer；
The metal layer is by an asymmetrical U-shaped structure of opening and a rectangular antenna structure composition；The metal layer packet
Metal top layer and metal back layer are included, the material of the metal top layer is gold, and the material of the metal back layer is titanium；
The dielectric layer includes polyimide film.
2. biosensor according to claim 1, which is characterized in that the number of the basic unit not less than 20 ×
20。
3. biosensor according to claim 1, which is characterized in that the metal top layer with a thickness of 150~
230nm, the metal back layer with a thickness of 15~30nm.
4. biosensor according to claim 1, which is characterized in that the dielectric layer with a thickness of 5~15 μm.
5. biosensor according to claim 1, which is characterized in that the interior angle of the asymmetrical U-shaped structure of opening
It is right angle with exterior angle.
6. the preparation method of any one of Claims 1 to 5 multifrequency point resonant biosensor, comprising the following steps:
(1) the spin-on polyimide film on silicon wafer, obtains dielectric layer；
(2) the spin coating reversal photoresist on dielectric layer；
(3) uv-exposure and development；
(4) evaporated metal layer；
(5) it is impregnated in acetone soln, the metal being deposited on removing removal reversal photoresist and the reversal photoresist uses isopropyl
Pure and mild deionized water cleaning；
(6) silicon base is removed.
7. being obtained based on preparation method described in any one of the Claims 1 to 5 multifrequency point resonant biosensor or claim 6
The method of the detection cell concentration of the multifrequency point resonant biosensor arrived, comprising the following steps:
1) cell of various concentration is seeded in respectively on multifrequency point resonant biosensor；
2) using terahertz time-domain spectroscopy test device test electric field, the transmission spectral line above and on the direction y resonates in the x-direction respectively
The drift condition of frequency；
In the test, the metal layer of terahertz wave beam from multifrequency point resonant biosensor is incident, projects from dielectric layer；
The offset refers to that the resonance frequency that the multifrequency point resonant biosensor for being vaccinated with cell is measured is thin relative to no inoculation
The offset for the resonance frequency that the multifrequency point resonant biosensor of born of the same parents is measured；
3) drift condition obtained according to step 2) draws the transmission spectral curve of the test Terahertz changed with cell concentration；
4) drift condition of sample to be tested is detected, the cell for obtaining sample to be tested in conjunction with the transmission spectral curve that step 3) obtains is dense
Degree.
8. the method according to the description of claim 7 is characterized in that electric field is along on the direction x, and test is inclined respectively in step 2)
The four dipole Fano resonance resonance frequency shift amount of vibration；Eight dipole Fano resonance resonance frequency shift amount and 16 dipoles
Fano resonance resonance frequency shift amount；
Electric field in the y-direction on, the four dipole Fano resonance resonance frequency shift amount and eight dipole Fano of tests polarization respectively
Resonate resonance frequency shift amount.
9. the method according to the description of claim 7 is characterized in that the cell includes attached cell.
10. according to the method described in claim 9, it is characterized in that, the attached cell includes cancer cell；The cancer cell packet
It is thin to include oral cavity squamous cancer cell HSC3 and SCC4, lung cell A549 and H460, cervical cancer cell Hela and Siha, normal angling
Born of the same parents HaCaT.
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