Polarization-insensitive terahertz metasurface biosensor and application thereof

Abstract

The invention discloses a polarization-insensitive terahertz metasurface biosensor and application thereof. The sensor comprises a substrate layer and a resonance layer arranged on the substrate layer, the resonance layer is a unit structure array formed by an annular ring dipole and split resonance rings which are in central rotational symmetry in four directions, and the unit structure array is arranged according to a square period; wherein the internal current of the annular ring dipole has the characteristic of annular flow, the consistency of electromagnetic field distribution can be kept for incident electric fields in any polarization direction, the split-ring resonators in four-direction center rotation symmetry enable different electromagnetic modes to generate a coupling effect at the same frequency point, and symmetrical response performance is formed. Therefore, the polarization insensitive characteristic is realized. According to the invention, the contribution of the ring shape of the ring dipole is similar to that of the electric dipole moment in a far field, so that scattering loss is inhibited; while the local field effect is enhanced, the stable response to the change of an incident angle is realized, and the sensitivity of a traditional sensor to the polarization direction is effectively overcome.

Description

Technical Field

[0001] The invention belongs to the technical field of terahertz and biosensing, and in particular relates to a polarization-insensitive terahertz supersurface biosensor and an application thereof. Background Art

[0002] Because terahertz waves have the characteristics of being label-free, non-ionizing, and having high temporal resolution, and can penetrate many non-metallic and non-water molecular materials, they exhibit unique sensing capabilities for biological tissues and biological molecules, making them an ideal tool for sensing the internal structure and dynamic changes of biological cells.

[0003] The terahertz band is located between microwaves and infrared light. It has non-ionizing and low photon energy characteristics and will not cause damage to biological tissues. It has wide application potential in the biomedical field, especially for detecting the vibration mode and structural changes of biomolecules. However, due to the small absorption cross-section of biomolecules in the terahertz band, the signal change is weak, which increases the difficulty of detection. In order to overcome this challenge, researchers have developed a variety of terahertz sensors based on metasurfaces, which can enhance electromagnetic field resonance and thus improve detection sensitivity. However, existing terahertz metasurface biosensors still face many technical bottlenecks. First, traditional metasurface structures usually rely on electric and magnetic multipolar resonance modes, but these resonance modes have large losses in high-frequency transmission, resulting in a decrease in overall sensing sensitivity. In addition, many terahertz metasurfaces are highly sensitive to polarization angles, which means that the polarization direction of the incident light needs to be precisely controlled during the detection process, which increases the complexity of the measurement and the difficulty of operation. This polarization dependence severely limits the versatility and flexibility of sensors in practical biosensing applications. In addition, for the early diagnosis and treatment monitoring of cancer in practical applications, high-sensitivity and high-specificity detection of cancer cells in circulating tumor cells (CTCs) or tissue biopsy samples in patients is essential. However, clinical samples are usually highly heterogeneous, including a variety of normal cell types and other potential interfering substances in addition to target cancer cells, which increases the difficulty of detection. Therefore, it is necessary to deeply design terahertz metasurface biosensing methods for two or more mixed cells.

[0004] Traditional terahertz metasurface biosensors are sensitive to the polarization direction of the incident electromagnetic wave, which means that the signal response under different polarization states will be different, which not only reduces the consistency and reliability of the sensor, but also limits its applicability in various application scenarios. At the same time, when dealing with complex mixed samples, such as clinical samples containing multiple cell types, the presence of non-target components will lead to increased background noise, reduce the detection limit and accuracy, and thus affect the reliability and specificity of the test results. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a polarization-insensitive terahertz metasurface biosensor and its application.

[0006] A first aspect of an embodiment of the present invention provides a polarization-insensitive terahertz metasurface biosensor, comprising:

[0007] Basal layer,

[0008] and a resonance layer disposed on the base layer;

[0009] The resonant layer is a unit structure array composed of annular ring dipoles and open resonant rings with four-way central rotational symmetry, and the unit structure array is arranged in a square period;

[0010] Among them, the internal current of the annular ring dipole presents the characteristics of circular flow, and can maintain the consistency of electromagnetic field distribution for the incident electric field of any polarization direction. The open resonant ring with four-way central rotational symmetry enables different electromagnetic modes to couple at the same frequency, forming a symmetrical response performance, thereby achieving polarization-insensitive characteristics.

[0011] A second aspect of the embodiments of the present invention provides an application of a polarization-insensitive terahertz metasurface biosensor in biological detection. The biological detection method based on the polarization-insensitive terahertz metasurface biosensor includes:

[0012] preparing normal cell samples and tumor cell samples at different cell concentrations, and mixing normal cell samples and tumor cell samples at the same cell concentration in different proportions to form several groups of biological cell suspensions;

[0013] The incident terahertz wave passes through the biological cell suspension and the polarization-insensitive terahertz metasurface biosensor to obtain the terahertz transmission spectrum corresponding to each biological cell suspension;

[0014] The partial least squares regression method is used to extract features from the terahertz transmission spectrum;

[0015] The features are input into the support vector regression model for optimization to obtain the nonlinear relationship between cell concentration and cell type; the biological cell samples to be tested are tested using the optimized support vector regression model to obtain the cell concentration in the biological cell samples to be tested and the proportion of tumor cell samples.

[0016] According to a third aspect of an embodiment of the present invention, an electronic device is provided, comprising a memory and a processor, wherein the memory is coupled to the processor; wherein the memory is used to store program data, and the processor is used to execute the program data to implement the above-mentioned biological detection method based on the polarization-insensitive terahertz metasurface biosensor.

[0017] According to a fourth aspect of an embodiment of the present invention, a computer-readable storage medium is provided, on which a computer program is stored. When the program is executed by a processor, the biological detection method based on the polarization-insensitive terahertz metasurface biosensor is implemented.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention provides a polarization-insensitive terahertz metasurface biosensor, the sensor comprising: a substrate layer, and a resonance layer arranged on the substrate layer; the resonance layer is a unit structure array composed of annular ring dipoles and four-way central rotationally symmetrical open resonant rings, and the unit structure array is arranged in a square period; wherein the internal current of the annular ring dipole presents the characteristics of annular flow, and the electromagnetic field distribution can be kept consistent for the incident electric field of any polarization direction, and the four-way central rotationally symmetrical open resonant ring enables different electromagnetic modes to couple at the same frequency point, forming a symmetrical response performance, thereby realizing polarization-insensitive characteristics. The present invention utilizes the similar contributions of the annular and electric dipole moments of the ring dipole in the far field, thereby suppressing scattering losses and realizing high-quality factor and high-sensitivity biosensing; while enhancing the local field effect, a stable response to changes in the incident angle is achieved, effectively overcoming the sensitivity of traditional sensors to polarization direction.

[0020] At the same time, the present invention provides an application of a polarization-insensitive terahertz metasurface biosensor in biological detection, which can obtain the cell concentration in the biological cell sample to be tested and the proportion of tumor cell samples. The present invention can solve the problems of low sensitivity and polarization dependence of the terahertz metasurface, and consider the complex mixed sample situation faced in the actual tumor cell detection application, introduce the partial least squares-support vector regression method, extract the characteristic information related to the target cell from the complex frequency domain signal, and then establish a high-precision prediction model. The solution provided by the invention can not only accurately distinguish and quantify the target cancer cells, but also show excellent stability and reliability in the face of complex backgrounds. This technology is suitable for the detection of cancer cells in complex mixed samples, and can be widely used in biomedical research, clinical diagnosis, personalized medicine and other fields, providing a new tool and technical means for early cancer screening and treatment monitoring. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative labor.

[0022] Figure 1is a schematic diagram of polarization-insensitive terahertz metasurface biosensing;

[0023] Figure 2 is the dimension diagram of the unit structure of polarization-insensitive terahertz metasurface biosensor;

[0024] Figure 3 The present invention proposes a polarization-insensitive terahertz metasurface biosensing method;

[0025] Figure 4 is the transmission diagram of polarization-insensitive terahertz metasurface and the transmission coefficient at different polarization angles;

[0026] Figure 5 is the current distribution diagram of the ring dipole and the split resonant ring in mode 1 and mode 2;

[0027] Figure 6 is a sensitivity simulation diagram of the polarization-insensitive terahertz metasurface;

[0028] Figure 7 It is the transmission spectrum and sensitivity simulation diagram of polarization-insensitive terahertz metasurface under different sample thicknesses;

[0029] Figure 8 is a graph of biological cell transmission coefficient at different concentrations in the embodiment;

[0030] Fig. 9 It is a diagram of quantitative analysis of biological cells and optimization of SVR parameters at different mixing ratios in the embodiment. DETAILED DESCRIPTION

[0031] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] It should be noted that, in the absence of conflict, the features in the following embodiments and implementations may be combined with each other.

[0033] like Figure 1 and Figure 2 As shown, the present invention provides a polarization-insensitive terahertz metasurface biosensor, comprising:

[0034] Basal layer,

[0035] and a resonance layer disposed on the base layer;

[0036] The resonant layer is a unit structure array composed of annular ring dipoles and open resonant rings with four-way central rotational symmetry, and the unit structure array is arranged in a square period;

[0037] Among them, the internal current of the annular ring dipole presents the characteristics of circular flow, and can maintain the consistency of electromagnetic field distribution for the incident electric field of any polarization direction. The open resonant ring with four-way central rotational symmetry enables different electromagnetic modes to couple at the same frequency, forming a symmetrical response performance, thereby achieving polarization-insensitive characteristics.

[0038] It should be noted that the present invention achieves a uniform response to any polarization incident angle through a ring-shaped and four-way central rotationally symmetrical structure, maintaining consistent high-performance sensing at different polarization angles; utilizes the similar contributions of the ring and electric dipole moments of the ring dipole in the far field to suppress scattering losses and achieve high-quality factor and high-sensitivity biosensing; while enhancing the local field effect, it achieves a stable response to changes in the incident angle, effectively overcoming the sensitivity of traditional sensors to polarization direction.

[0039] Furthermore, the outer radius of the annular ring dipole R1=23 μm, the outer radius of the open resonant ring R2=7 μm, the ring width W=4 μm, the spacing between the centers of the open resonant ring g=17 μm, and the opening size s=4 μm.

[0040] Furthermore, the base layer adopts a 75μm thick polyimide base, and the resonance layer adopts a 0.2μm thick gold; a 10nm thick titanium is also provided between the base layer and the resonance layer as an adhesive; the cross-section of each unit structure array element in the resonance layer is a square with a side length of 50μm.

[0041] Furthermore, the resonance frequency caused by the annular ring dipole is near 1.52 THz, the quality factor is 40.67, and the sensitivity is 342 GHz / RIU; when the annular ring dipole is irradiated by the incident electromagnetic wave, a ring current is induced in the ring, and in the lowest-order resonance mode, the current in the ring is symmetrically distributed, and a dipole radiation field is formed around the ring; the resonance frequency generated by the four-way central rotationally symmetrical open resonant ring is near 3.00 THz, the quality factor is 46.39, and the sensitivity is 721 GHz / RIU.

[0042] Furthermore, the terahertz metasurface biosensor exhibits consistent and stable transmission performance within the range of incident polarization angles of -45° to 45°; the terahertz metasurface biosensor maintains consistent and stable transmission performance within the range of thickness of the biological cell suspension of 10 to 50 μm.

[0043] It should be noted that the polarization-insensitive terahertz metasurface biosensor based on ring dipole exhibits consistent and stable transmission performance within the incident polarization angle range of -45° to 45° (or equivalently 0° to 90°). The structure has the characteristic of four-way central rotational symmetry, which enables it to have polarization-insensitive characteristics of 0 to 360° in practical applications.

[0044] Figure 4 (a) shows the transmission characteristics of the sensor between 0.5THz and 3.2THz, generating the resonance frequency point f1 of mode 1 and the resonance frequency point f2 of mode 2 at 1.52THz and 3.00THz. Figure 4 (b) shows that the sensor maintains good transmission performance when the incident polarization angle is in the range of -45° to 45°; Figure 5 (a) and Figure 5 (b) shows the current distribution of the ring dipole and the open resonant ring in mode 1 and mode 2, revealing the ring dipole principle. When an electromagnetic wave is incident on the ring structure, a ring current is induced in the ring. In the lowest-order resonance mode, the current in the ring is symmetrically distributed, and a dipole radiation field is formed around the ring. Figure 6 (a) shows the change of transmission coefficient of different refractive indices (corresponding to different biological cell types and different mixed ratio cells). Figure 6 (b) shows the linear fitting results at the corresponding resonance frequencies f1 and f2, indicating that the sensor has a sensitivity of 342 GHz / RIU and 721 GHz / RIU in mode 1 and mode 2; Figure 7 (a) shows the transmission image of biological samples with a thickness of 10 to 50 μm between 0.5 THz and 3.5 THz. Figure 7 (a) shows the sensitivity of the sensor for biological samples with a thickness between 10 and 50 μm, exhibiting consistent and stable transmission performance.

[0045] On the other hand, Figure 3 As shown, the present invention provides an application of a polarization-insensitive terahertz metasurface biosensor in biological detection; specifically, a biological detection method based on the polarization-insensitive terahertz metasurface biosensor includes:

[0046] Step S1, preparing normal cell samples and tumor cell samples at different cell concentrations, and mixing normal cell samples and tumor cell samples at the same cell concentration in different proportions to form several groups of biological cell suspensions.

[0047] Step S2, incident terahertz waves, passing through the biological cell suspension and the polarization-insensitive terahertz metasurface biosensor to obtain a terahertz transmission spectrum corresponding to each biological cell suspension.

[0048] Step S3, using the partial least squares regression (PLS) method to extract features from the terahertz transmission spectrum, optimize the number of components in the dimensionality reduction process, and extract the main characteristic components related to the concentration change of the target sample. In addition, by introducing a nonlinear characteristic enhancement module into the PLS model, the model's ability to analyze complex mixed ratio samples is further improved, so that the model can better capture complex data structures.

[0049] Step S4, input the features into a support vector regression model based on a radial basis kernel function for optimization to obtain the nonlinear relationship between cell concentration and cell type; the biological cell sample to be tested is tested by the optimized support vector regression model to obtain the cell concentration in the biological cell sample to be tested and the proportion of tumor cell samples.

[0050] Furthermore, the process of optimizing the support vector regression model includes:

[0051] Initialize the parameters of the support vector regression model: Generate a parameter grid containing all combinations of penalty coefficients γ and kernel function parameters C according to the set logarithmic range;

[0052] For each group (γ, C), the support vector regression model is trained using the cross-validation technique and the corresponding mean square error is recorded;

[0053] Compare the mean square errors under all combinations, and select the (γ, C) combination corresponding to the minimum mean square error as the parameters of the final optimal support vector regression model.

[0054] Step S5, performing model error analysis in combination with experimental results, including evaluation of the signal-to-noise ratio (SNR) and comparative analysis, verifying the detection sensitivity and prediction ability of the sensor, and evaluating its performance stability and applicability in actual biosensing applications.

[0055] Example 1

[0056] This embodiment uses two biological cell suspensions, Miha and HepG2, as examples for high-sensitivity sensing and quantitative detection, where Miha and HepG2 are normal human liver cells and liver cancer tumor cells, and the cell concentrations configured in this embodiment are 5×10 3 cells / mL、2.5×10 4 cells / mL、5×10 4 cells / mL、2.5×10 5 cells / mL、5×10 5 cells / mL, the measured transmission spectrum results are as follows Figure 8As shown in the figure, DMEM is a blank culture medium without any biological cells. The experimentally measured sensitivity of the polarization-insensitive terahertz metasurface biosensor to Miha and HepG2 biological cells is 380kHz / (cell·mL -1 ) and 1000kHz / (cell·mL -1 ).

[0057] This embodiment accurately identifies and quantitatively analyzes the content of the target component of the above-mentioned Miha and HepG2 biological cells mixed in different proportions. The ratios of Miha to HepG2 are 0:10, 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, 9:1, and 10:0, respectively. The partial least squares model is used to extract the features, and the optimal principal component is selected. The square term and cubic term of the most principal component are then added to increase the nonlinear characteristics of the model. The support vector regression model is input for quantitative analysis. In order to obtain better consistency and accuracy, multiple experiments are performed on cells of different types and concentration gradients. This embodiment performs 156 groups of experiments on each group of mixed biological cells of different proportions, and a total of 1716 groups of transmission spectrum frequency domain data are obtained. 80% of the data set is used as a training set and 20% as a test set. The kernel scale and box constraint parameters of the support vector regression are optimized and reversed with the mean square error as an indicator. The optimal kernel scale parameter is 0.1, the box constraint parameter is 10, and the final mean square error is 0.083. Fig. 9 (a) shows the results of quantitative prediction. Fig. 9 (b) in FIG. 5 shows the optimization diagram of the kernel scale parameter.

[0058] Those skilled in the art will appreciate that the embodiments of the present application may be provided as methods, systems, or computer program products. Therefore, the present application may adopt the form of a complete hardware embodiment, a complete software embodiment, or an embodiment in combination with software and hardware. Moreover, the present application may adopt the form of a computer program product implemented in one or more computer-usable storage media (including but not limited to disk storage, CD-ROM, optical storage, etc.) that include computer-usable program code.

[0059] The present application is described with reference to the flowcharts and / or block diagrams of the methods, devices (systems), and computer program products according to the embodiments of the present application. It should be understood that each process and / or box in the flowchart and / or block diagram, as well as the combination of the processes and / or boxes in the flowchart and / or block diagram, can be implemented by computer program instructions. These computer program instructions can be provided to a processor of a general-purpose computer, a special-purpose computer, an embedded processor, or other programmable data processing device to generate a machine, so that the instructions executed by the processor of the computer or other programmable data processing device generate instructions for implementing the processes in the flowchart and / or block diagram. Figure 1A process or multiple processes and / or boxes Figure 1 A device that provides the functions specified in a block or multiple blocks.

[0060] These computer program instructions may also be stored in a computer-readable memory capable of directing a computer or other programmable data processing device to operate in a specific manner, so that the instructions stored in the computer-readable memory produce an article of manufacture comprising an instruction device, which implements the process Figure 1 A process or multiple processes and / or boxes Figure 1 A function specified in one or more boxes.

[0061] These computer program instructions can also be loaded onto a computer or other programmable data processing device so that a series of operating steps are executed on the computer or other programmable device to produce a computer-implemented process, thereby providing instructions for implementing the process. Figure 1 A process or multiple processes and / or boxes Figure 1 The steps for the functions specified in one or more boxes.

[0062] The above embodiments are only used to illustrate the design ideas and features of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. The protection scope of the present invention is not limited to the above embodiments. Therefore, any equivalent changes or modifications made based on the principles and design ideas disclosed by the present invention are within the protection scope of the present invention.

Claims

1. A polarization-insensitive terahertz metasurface biosensor, characterized in that: include: Basal layer, and a resonance layer disposed on the base layer; The resonant layer is a unit structure array composed of annular ring dipoles and open resonant rings with four-way central rotational symmetry, and the unit structure array is arranged in a square period; Among them, the internal current of the annular ring dipole presents the characteristics of circular flow, and can maintain the consistency of electromagnetic field distribution for the incident electric field of any polarization direction. The open resonant ring with four-way central rotational symmetry enables different electromagnetic modes to couple at the same frequency, forming a symmetrical response performance, thereby achieving polarization-insensitive characteristics.

2. The polarization-insensitive terahertz metasurface biosensor according to claim 1, characterized in that: The outer radius of the annular ring dipole is R1=23 μm, the outer radius of the open resonant ring is R2=7 μm, the ring width is W=4 μm, the spacing between the centers of the open resonant ring is g=17 μm, and the opening size is s=4 μm.

3. The polarization-insensitive terahertz metasurface biosensor according to claim 1, characterized in that: The resonance frequency caused by the annular ring dipole is around 1.52 THz, the quality factor is 40.67, and the sensitivity is 342 GHz / RIU; The resonance frequency point generated by the four-way central rotationally symmetrical open resonant ring is near 3.00 THz, the quality factor is 46.39, and the sensitivity is 721 GHz / RIU.

4. The polarization-insensitive terahertz metasurface biosensor according to claim 1, characterized in that: The terahertz metasurface biosensor exhibits consistent and stable transmission performance within the range of incident polarization angles of -45° to 45°; The terahertz supersurface biosensor maintains consistent and stable transmission performance within the range of 10 to 50 μm thickness of the biological cell suspension.

5. The polarization-insensitive terahertz metasurface biosensor according to claim 1, characterized in that: The base layer is a 75 μm thick polyimide base, and the resonance layer is a 0.2 μm thick gold. A 10 nm thick titanium is provided between the base layer and the resonance layer as an adhesive. The cross section of each unit structure array element in the resonance layer is a square with a side length of 50 μm.

6. Application of a polarization-insensitive terahertz metasurface biosensor in biological detection.

7. The use according to claim 1, characterized in that: Biological detection methods based on polarization-insensitive terahertz metasurface biosensors include: preparing normal cell samples and tumor cell samples at different cell concentrations, and mixing normal cell samples and tumor cell samples at the same cell concentration in different proportions to form several groups of biological cell suspensions; The incident terahertz wave passes through the biological cell suspension and the polarization-insensitive terahertz metasurface biosensor to obtain the terahertz transmission spectrum corresponding to each biological cell suspension; The partial least squares regression method is used to extract features from the terahertz transmission spectrum; The features are input into the support vector regression model for optimization to obtain the nonlinear relationship between cell concentration and cell type; the biological cell samples to be tested are tested using the optimized support vector regression model to obtain the cell concentration in the biological cell samples to be tested and the proportion of tumor cell samples.

8. The use according to claim 7, characterized in that: The process of optimizing a support vector regression model involves: Initialize the parameters of the support vector regression model: Generate a parameter grid containing all combinations of penalty coefficients γ and kernel function parameters C according to the set logarithmic range; For each group (γ, C), the support vector regression model is trained using the cross-validation technique and the corresponding mean square error is recorded; Compare the mean square errors under all combinations, and select the (γ, C) combination corresponding to the minimum mean square error as the parameters of the final optimal support vector regression model.

9. An electronic device, comprising a memory and a processor, characterized in that: The memory is coupled to the processor; wherein the memory is used to store program data, and the processor is used to execute the program data to implement the biological detection method based on the polarization-insensitive terahertz metasurface biosensor as described in any one of claims 7-8.

10. A computer-readable storage medium having a computer program stored thereon, characterized in that: When the program is executed by a processor, the biological detection method based on the polarization-insensitive terahertz metasurface biosensor as described in any one of claims 7 to 8 is implemented.

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