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WO2020211306A1 - Biocapteur à résonance de points multifréquence, son procédé de préparation et son utilisation dans la détection de concentration cellulaire - Google Patents

Biocapteur à résonance de points multifréquence, son procédé de préparation et son utilisation dans la détection de concentration cellulaire Download PDF

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Publication number
WO2020211306A1
WO2020211306A1 PCT/CN2019/110653 CN2019110653W WO2020211306A1 WO 2020211306 A1 WO2020211306 A1 WO 2020211306A1 CN 2019110653 W CN2019110653 W CN 2019110653W WO 2020211306 A1 WO2020211306 A1 WO 2020211306A1
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WO
WIPO (PCT)
Prior art keywords
biosensor
frequency point
resonance
metal layer
frequency
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PCT/CN2019/110653
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English (en)
Inventor
Xin Yan
Yang MAOSHENG
Zhang Zhang
Liang LANJU
Wei DEQUAN
Wang MENG
Yao JIANQUAN
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Zaozhuang University
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Priority to CN201980005062.2A priority Critical patent/CN112292592A/zh
Publication of WO2020211306A1 publication Critical patent/WO2020211306A1/fr

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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

Definitions

  • the presented invention belongs to the overlap between terahertz technology and biotechnology fields which specially involves the metamaterial label-free biosensor with non-bianisotropy high-order Fano resonant multi-frequency point resonance in the terahertz frequency.
  • the biosensor method and applications in cell concentration test are also involved.
  • terahertz technology Due to its unique electric field response, terahertz technology is widely used in public security, communication, biomedical field and so on.
  • the methods of detecting cell concentration mainly include labeled fluorescence detection and labeled flow cytometry. These methods are of high sensitivity in practical applications, yet their detection cost is very high and most of them are used in conjunction with other chemicals, causing pollutions at a certain degree. For example, the detection sensitivity of CCK-8 method is high, but it comes at a high cost too.
  • CCK-8 reagent is similar to the color of culture medium, which might easily produce incorrect operations such as a shortage or extra addition in the experiment.
  • Another method is flow cell technology, which can quantitatively detect and analyze a single cell by using flow cytometer. It combines a series of techniques, such as monoclonal antibody and immunocy to chemistry, laser and computer science, etc., which bears the advantages of fast detection speed and high sensitivity, yet is unable to solve the problems of labeling, high cost, time-consuming and so on. At present, no cell detection scheme with low cost and label-free is available.
  • the presented invention aims to provide a multi-frequency point resonance biosensor, introduce its preparation method and its applications in testing cell concentrations.
  • the invented sensor can provide high sensitivity cell sensing and fast, multi-resonance label detection in terahertz wave at a low cost in comparison with other sensors.
  • the invention provides a multi-frequency point resonance biosensor, which includes a plurality of basic units.
  • the basic unit includes a metal layer and a dielectric layer
  • the metal layer is composed of an asymmetric U-shaped resonator and a rectangular antenna structure
  • the metal layer includes an upper metal layer and a lower metal layer; the upper metal layer is made of gold, and the lower metal layer is made of titanium;
  • the dielectric layer comprises a polyimide film.
  • the optimized number of basic units is smaller than 20 ⁇ 20.
  • the thickness of the metal upper layer is 150 ⁇ 230nm, and the thickness of the metal lower layer is 15 ⁇ 30nm.
  • the thickness of the dielectric layer is 5 ⁇ 15 ⁇ m.
  • both the inner and outer angles of the asymmetric U-shaped resonance are vertical angles.
  • the invention also provides a preparation method of the multi-frequency point resonance biosensor practical application.
  • the invention also provides a multi-frequency point resonance biosensor and the method for detecting cell concentration based on the technical proposal, including the following steps:
  • the terahertz beam is incident from the metal layer of the multi-frequency point resonance biosensor and emitted from the dielectric layer;
  • the shift refers to the shift of the resonance frequency measured by a multi-frequency point resonance biosensor inoculated with cells relative to the resonant frequency measured by the multi-frequency point resonance biosensor without cells;
  • step 2) Based on the deviation in step 2), plot the terahertz transmission spectrum curve along with the changes of cell concentration;
  • step 2) Detect the shift of the resonance frequency of the sample, and obtain the cell concentration of the sample based on the transmission spectrum curve obtained in step 3)
  • step 2) when the electric field is along the x direction, measure the quadrupolar Fano resonance frequency shift, octupolar Fano resonance frequency shift and hexadecapolar Fano resonance frequency shift respectively.
  • the cells mentioned include the adherent cells.
  • the adherent cell includes cancer cells; the cancer cells include oral scale cancer cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, normal keratinized cells HaCaT.
  • the cancer cells include oral scale cancer cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, normal keratinized cells HaCaT.
  • 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 is composed of an asymmetric U-shaped resonance and a rectangular antenna structure.
  • the metal layer comprises an upper metal layer and a lower metal layer; the metal upper layer is made of gold, and the metal lower layer is made of titanium; and the dielectric layer is a polyimide film.
  • a multi-frequency point resonance biosensor consists of an open asymmetric U-shaped structure and a rectangular antenna structure which can realize multi-frequency point resonance of high-order mode Fano resonance non-anisotropic electromagnetic response.
  • the loss at the resonance response frequency only relates to the material itself, and the detection information and the sensitivity of the sensor have been effectively improved.
  • the theoretical sensitivity of the hexadecapolar Fano resonance reaches up to 1000 GHz/RIU.
  • the multi-frequency resonance biosensor detects the cell concentration rapidly without labeling which realizes the high sensitivity cell sensing and the multi-resonance label-free detection in terahertz wave with high speed.
  • the experimental results reveal that a multi-frequency point resonance biosensor is capable of detecting the cell concentration within 30s without cell labeling.
  • the operation procedure is simple and the cost is greatly reduced while the sensitivity reaches up to 1000 GHz/RIU.
  • Fig.1 illustrates a schematic top view structure of the biosensor of the present invention
  • Fig.2 illustrates a schematic side view structure of the biosensor of the present invention
  • Fig.3 illustrates a schematic stereoscopic structure of the biosensor of the present invention
  • Fig.4 illustrates a microscope photograph of the biosensor of the present invention
  • Fig.5 illustrates a schematic periodic structure of the biosensor of the present invention
  • Fig6 illustrates a schematic view showing the detection of cell concentration in the present invention
  • Fig.7 illustrates a theoretical result transmission spectrum when an electric field of a terahertz wave is incident in the x and y directions according to the present invention
  • Fig.8 illustrates a transmission spectrum of an experimental result when an electric field of terahertz wave is incident in the x and y directions according to the present invention
  • Fig.9 illustrates a diagram of the resonance frequency shift of the electric field under different concentrations of A549 lung cancer cells along x direction tested by the biosensor
  • Fig.10 illustrates a diagram of the resonance frequency shift of the electric field under different concentrations of A549 lung cancer cells along y direction.
  • the present invention provides a multi-frequency point resonance biosensor, comprising a plurality of basic units
  • the present basic unit includes a metal layer and a dielectric layer
  • the present metal layer is composed of an asymmetric U-shaped structure and a rectangular antenna structure
  • the present metal layer comprises a metal upper layer and a metal lower layer: the metal upper layer is made of gold, and the metal lower layer is made of titanium;
  • the dielectric layer is a polyimide film.
  • the metal layer is a terahertz beam incident layer, and the dielectric layer is a terahertz beam output layer.
  • the thickness of the metal top layer is preferably 150 ⁇ 230nm, more preferably 200nm
  • the thickness of the metal bottom layer is preferably 15 ⁇ 30nm, more preferably 20nm
  • the thickness of the dielectric layer is preferably 5 ⁇ 15 ⁇ m, more preferably 10 ⁇ m.
  • the described inner and outer corners of open asymmetric U-shaped structure are both vertical angles.
  • the size of the basic unit is preferably 30 ⁇ m ⁇ 30 ⁇ m ⁇ 70 ⁇ m ⁇ 70 ⁇ m, more preferably 50X50 ⁇ m, and the number of the basic units is smaller than 20 ⁇ 20.
  • the metal layer is composed of an open asymmetrical U-shaped structure and a rectangular antenna structure.
  • the open asymmetric U-shaped structure and rectangular antenna structure can recognize multi-frequency point high order Fano resonance, the loss at resonance frequency only relates to the material itself, and the detection information and sensor sensitivity are improved.
  • the cell is inoculated on Fano resonance metamaterial through cell culture to detect its resonance frequency shift, and the theoretical sensitivity of hexadecapolar Fano resonance reaches up to 1000 GHz/RIU.
  • the preliminary detection of cancer cell concentration can be conducted rapidly and in the label-free way, and the concentration of cancer cells can be detected in 30s.
  • the open unsymmetrical U-shaped structure comprises a long arm and a short arm.
  • the long arm is preferably 18 ⁇ 23 ⁇ m, more preferably 20 ⁇ m, longer than the short arm.
  • the rectangular antenna structure is preferably located above the short arm; the rectangular antenna structure and the extension line of the outer side of the open asymmetrical U-shaped structure are preferably square; the center of the square is preferably located in the center of the basic unit.
  • the basic unit is preferably a square, and the side length of the basic unit is optimized to be 30 ⁇ 70 ⁇ m, more preferably 50 ⁇ m(p).
  • the outer edge of the open asymmetric U-type structure and the rectangular antenna structure is preferably 4 ⁇ 6 ⁇ m, more preferably 5 ⁇ m.
  • the length and width of the rectangular antenna structure are preferred to be 18 ⁇ 22 ⁇ m and 10 ⁇ 15 ⁇ m respectively, more preferably 20 ⁇ m and 12 ⁇ m.
  • the length of the long arm (d) of the open asymmetric U-type structure is preferred to be 25 ⁇ 60 ⁇ m, more preferably 40 ⁇ m, and the length of the short arm (1) of the asymmetric U-shaped structure is preferably 18 ⁇ 22 ⁇ m, more preferably 20 ⁇ m.
  • the width of the long arm and the short arm are the same, preferably 9 ⁇ 15 ⁇ m, more preferably 12 ⁇ m.
  • the width (n) of the bottom edge of the U-shaped structure with asymmetric is preferably 5 ⁇ 12 ⁇ m, more preferably 8 ⁇ m.
  • the biosensor of the present invention is a high-order mode Fano multi-resonant frequency metamaterial, specifically a high-order mode Fano resonance terahertz high-sensitivity cell multi-frequency point resonance biosensor based on a flexible substrate polyimide (PI).
  • PI flexible substrate polyimide
  • the overall structure of the sensor comprises two layers, an upper metal layer (1) and a lower dielectric layer (2).
  • the polyimide film is used as the flexible substrate to support the upper metal structure.
  • Fig.2 is a front elevational view of the biosensor of the present invention.
  • a schematic diagram of the three-dimensional structure of the biosensor is shown in Fig.3.
  • a micrograph of the biosensor is shown in Fig.4.
  • the periodic structure of the biosensor is shown in Fig.5; the cell concentration detection is shown in Fig.6.
  • the dielectric layer is a polyimide film.
  • the cells are preferably inoculated on the surface of the metal layer of the sensor, and the cell concentration is measured by detecting the resonance frequency shift of different order modes of the device.
  • the biosensor is a kind of multi-frequency point resonance based on high-order Fano metamaterial, in particular, the high-order Fano resonance terahertz highly sensitive cell multi-frequency point resonance biosensor based on flexible substrate polyimide (PI). By using its characteristics of enhancing electric field and high Q value response, a small change of external environment can cause obvious response of electric field intensity, corresponding to a sensitivity very high.
  • the invention also provides a preparation method of the multi-frequency point resonance biosensor according to the technical proposal, which includes the following steps:
  • the reverse photoresist such as reverse photoresist AZ5214
  • the reverse photoresist AZ5214 is rotated on the dielectric layer.
  • the UV exposure and development were carried out, preferably, on the hot plate which has been pre-baked at a temperature of 100°C, and for about 10 minutes.
  • ABM lithography machine is adopted for UV exposure of 15s, the development of 10s, thermal vapor the metal layer after UV exposure and development. If the metal film is deposited by controlled sputter and the vacuum plating condition is 5 ⁇ 10 -6 Pa; immerse the wafer in acetone solution after evaporating the metal layer, peel off and remove the metal evaporated on the reverse photoresist and the reverse photoresist and clean it with isopropanol and deionized water.
  • the sensor structure of silicon substrate and polyimide substrate was able to be peeled off.
  • the terahertz time domain spot is usually 5mm ⁇ 5mm, and the sensor of the invention is preferably prepared into 10mm ⁇ 10mm.
  • the multi-frequency point resonance biosensor has higher sensitivity and more resonance.
  • the theoretical sensitivity of hexadecapolar Fano resonance of the sensor reaches up to 1000GHz/RIU.
  • the present invention also provides a method for detecting cell concentration of a multi-frequency point resonance biosensor obtained by the multi-frequency point resonance biosensor according to the above technical solution or the preparation method, including the following steps:
  • the terahertz beam is incident from the metal layer of the multi-frequency point resonance biosensor and emitted from the dielectric layer;
  • the shift refers to the difference of resonances in frequency range of the multi-frequency point resonance biosensor of both with and without inoculating cells
  • step 2) Based on the deviation in step 2), plot the terahertz transmission spectrum curve along with the changes of cell concentration;
  • the cells include adherent cells; the adherent cell includes cancer cells; the cancer cells include oral scale cancer cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, normal keratinized cells HaCaT.
  • adherent cell includes cancer cells; the cancer cells include oral scale cancer cells HSC3 and SCC4, lung cancer cells A549 and H460, cervical cancer cells Hela and Siha, normal keratinized cells HaCaT.
  • different concentrations of cells were cultured on multi-frequency point resonance biosensor.
  • the vaccination is cultured on a metal layer of the sensor.
  • the purpose of the vaccination is to make the cells adhere to the wall and facilitate detection.
  • the vaccination method is optimized as follows: digest the cells from the petridish with trypsin; then blow the cells with the medium to form a single cell suspension; after sterilizing the sensor, place the sensor at the bottom of the culture plate and inoculate the single cell suspension in the culture plate, culture the cells growth in 37°C, 5 ⁇ 10% carbon dioxide cell incubators to the cell wall. After the cell adheres to the wall, the biosensor is preferably dried before the cell concentration is tested.
  • the terahertz time-domain spectral device is preferably a terahertz time-domain spectral tester.
  • a terahertz time domain spectrometer of the ADVANTEST TAS7500SU model is preferably used, with a spectrum range of 0.5 ⁇ 7THz, with a resolution of 7.6 GHz.
  • the terahertz beam is incident from the metal layer of the multi-frequency point resonance biosensor and emitted from the dielectric layer.
  • the resonance frequency shift of transmission line refers to the difference between the resonance frequencies measured by the multi-frequency point resonance biosensor inoculated with the cell relative to the resonance frequency measured by the multi-frequency point resonance biosensor without inoculated cells.
  • the electric field extend along the x direction to test the resonance frequency shift of the polarized quadrupolar Fano; the octupolar Fano resonance frequency shift and the hexadecapolar Fano resonance frequency shift; the electric field extends along the y direction to test the polarized quadrupolar Fano resonance frequency shift and the octupolar Fano resonance frequency is tested respectively.
  • the transmission spectrum curve of the test terahertz with the change of cell concentration is plotted.
  • the invention preferably uses terahertz time domain spectrum tester to test the resonant frequency of transmission spectrum of A549 lung cancer cells with concentrations of 0.1 ⁇ 10 5 cell/ml, 0.3 ⁇ 10 5 cell/ml, 0.5 ⁇ 10 5 cell/ml, 1 ⁇ 10 5 cell/ml, 3 ⁇ 10 5 cell/ml and 5 ⁇ 10 5 cell/ml compared with the resonant frequency in the absence of A549 lung cancer culture.
  • the beam first incident from the metal layer of the sensor, then the detection was carried out from the dielectric layer, and the concentration detection curve of A549 lung cancer cells was plotted.
  • the terahertz time domain spectrometer is used to detect the deviation of the sample, and the cell concentration of the sample is obtained by combining the above transmission spectrum curve.
  • the shift of the sensor is mainly the analysis of the shift of these resonant frequencies. Cultivate different concentrations of lung cancer cells on the surface of the metamaterial, and test the curves terahertz time domain spectroscopy. By comparing the terahertz time domain curve of each concentration of lung cancer cell metamaterial with that of metamaterial terahertz time domain curve without cancer cells, the resonance point is shifted. The beam is first incident from the metal layer of the metamaterial and then emitted from the dielectric layer for detection. Finally, the concentration detection curve of A549 lung cancer cells is plotted, as shown in Fig.9 and Fig.10.
  • A549 lung cancer cells with concentrations of 0.1 ⁇ 10 5 cell/ml, 0.3 ⁇ 10 5 cell/ml, 0.5 ⁇ 10 5 cell/ml, 1 ⁇ 10 5 cell/ml, 3 ⁇ 10 5 cell/ml and 5 ⁇ 10 5 cell/ml multi-frequency point resonance biosensor under the condition of 37°C constant temperature and 10% carbon dioxide concentration. After 24 hours’ cultivation, remove from the medium and remove the surface moisture with filter paper. Then detect the shift in resonance frequency of the biosensor compared with the cell-free one by terahertz time-domain spectrometer after drying up.
  • Fig.9 and Fig.10 illustrate the transmission lines of cultured A549 lung cancer cells measured by terahertz time domain spectroscopy in dry nitrogen environment at room temperature, indoor humidity is less than 4%.
  • Fig.9 illustrates the shift in the resonance frequency of the electric field tested by the source sensor of the invention along the concentration of different A549 lung cancer cells in the x direction; that is, different cancer cell concentrations frequency shift in quadrupolar resonance the (Q), octupolar resonance (O), hexadecapolar resonance (H) when the electric field direction of the terahertz wave is incident in the x direction.
  • Fig.10 is a diagram of the resonance frequency shift of an electric field measured by the source biosensor under different concentrations of A549 lung cancer cells in the y direction; that is, the shift of different cancer cell concentration frequency in the quadrupolar resonances and octupolar resonances when the electric field direction of the terahertz wave is incident in the y direction.
  • the 6 different cell concentrations under 6 different cancer cell concentrations are respectively: 0.1 ⁇ 10 5 cell/mL, 5 cell/mL, 0.5 ⁇ 10 5 cell/mL, 1 ⁇ 10 5 cell/mL, 3 ⁇ 10 5 cell/mL and 5 ⁇ 10 5 cell/mL.
  • the quadrupolar Fano resonant frequency shift of the electric field in the x direction are 22.6GHz 28.87GHz, 97.5GHz, 15.8GHz, 28.2GHz, and 67.4GHz respectively.
  • the octupolar Fano resonance frequency shift is 6GHz, 50.9GHz, 63.3GHz, 108.87GHz, 108.5GHz and 120.2GHz respectively; the hexadecapolar Fano resonance frequency shift are 3.56GHz, 59.2GHz, 81.66GHz, 90.03GHz, 97.1GHz and 117.56GHz respectively.
  • the quadrupolar Fano resonant frequency shift of the electric field in the y direction under the same conditions are 0GHz, 49.7GHz, 45.3GHz, 126.27GHz, 36.7GHz, and8.75GHz respectively.
  • the resonance frequency shift of the octupolar Fano are -0.5GHz, 48.23GHz, 60.1GHz, 107.43GHz, 17.23GHz and 32.56GHz respectively.
  • the samples were detected by terahertz time domain spectra.
  • the theoretical sensitivity of the terahertz high-order Fano resonance biosensor of the present invention attains 1000 GHz/RIU.
  • the biosensor provided by the invention is designed and produced at a flexible high-molecular material substrate, and the biosensor provided with the terahertz high-order mode Fano resonance metamaterial. It can be used for pure electric field response, high sensitivity and label-free detection of multiple resonances, and can be widely applied to the field of terahertz cell sensing and identification.
  • the existing method for detecting cell concentrations needs to consume fluorescent labeled antibody; the cost of each test is as high as 2000RMB.
  • the high detection cost exerts economic pressure to the patient.
  • the usual test takes about 2 hours, and consumes more quantity of the sample, in addition that the materials used are disposable and cannot be recycled.
  • the invention not only has higher sensitivity, but also greatly reduces the cost and greatly reduces the test time.

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Abstract

La présente invention porte sur un biocapteur à résonance de points multifréquence, son procédé de préparation et un procédé de détection de concentration de cellule avec le biocapteur. Le biocapteur à résonance de points multifréquence comprend une pluralité d'unités de base. L'unité de base comprend une couche métallique et une couche diélectrique : la couche métallique est composée d'une structure asymétrique en forme de U et d'une structure d'antenne rectangulaire. La couche métallique comprend une couche supérieure métallique et une couche inférieure métallique, la couche supérieure métallique étant en or et la couche inférieure métallique étant en titane. La couche diélectrique comprend un film de polyimide. Le biocapteur de l'invention peut réaliser une détection cellulaire à haute sensibilité avec une détection rapide et sans marqueur à résonance multiple dans la fréquence du térahertz.
PCT/CN2019/110653 2019-04-15 2019-10-11 Biocapteur à résonance de points multifréquence, son procédé de préparation et son utilisation dans la détection de concentration cellulaire WO2020211306A1 (fr)

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