Uric acid detection system based on BIC metasurface enhanced Raman spectroscopy

Abstract

The invention provides a uric acid detection system based on BIC metasurface enhanced Raman spectroscopy. The system comprises a Raman excitation module, a resonance metasurface, an SERS functional layer, a signal acquisition module and a data processing module. The resonance metasurface is composed of asymmetrical medium nanorod arrays which are periodically arranged, the filtering wavelength is matched with the excitation wavelength of a Raman spectroscopy method of uric acid, and the resonance metasurface is used for exciting a high-Q-value quasi-BIC mode to enhance an optical signal; the SERS functional layer is a noble metal nanoparticle array modified on the surface of the resonance metasurface and is used for synergistically enhancing a Raman signal through an electromagnetic field and chemical enhancement. The system supports direct detection of saliva or sweat samples without pretreatment, has high sensitivity, high specificity and portability, and can be expanded to be used for non-invasive rapid detection of various biochemical indexes.

Description

Technical Field

[0001] The present invention relates to the field of micro-nano optical technologies, and particularly to a uric acid detection system based on BIC metasurface-enhanced Raman spectroscopy. Background Art

[0002] Uric acid is the final product of purine metabolism in the human body, and its concentration in the blood is one of the important indicators for evaluating human health status. The detection of uric acid concentration in the blood plays an important role in the early detection of hyperuricemia, prevention of gout attacks, monitoring of renal function status, and assessment of cardiovascular disease risk.

[0003] Traditional uric acid detection methods, such as the uricase-peroxidase coupling method, the uricase-ultraviolet spectrophotometry method, etc., although can meet the clinical detection needs to a certain extent, still have some limitations, such as relying on biochemical reactions, high equipment complexity, inability to perform non-invasive detection, being easily interfered, and the sensitivity needs to be improved, etc.

[0004] Due to the advantage of molecular fingerprint recognition, Raman spectroscopy has high specificity, and does not require complex sample pretreatment, can quickly and accurately detect uric acid concentration, and the detection reliability is high, having good prospects in the detection of uric acid concentration. However, it is limited by weak Raman signals and is difficult to detect uric acid in low-concentration samples. In this regard, some researchers have adopted the Surface-Enhanced Raman Scattering (SERS) technology to enhance Raman signals through metal nanoparticles, but there are still problems such as random distribution of hot spots and poor repeatability.

[0005] Therefore, there is an urgent need for a uric acid detection system with high detection sensitivity to achieve efficient and accurate detection of uric acid concentration and provide a powerful tool for clinical disease diagnosis and treatment. Summary of the Invention

[0006] To solve the above problems, the present invention provides a uric acid detection system based on BIC metasurface-enhanced Raman spectroscopy, including: A resonant metasurface for enhancing optical signals; the resonant metasurface is composed of an array of asymmetric dielectric nanocolumns arranged periodically, and the filtering wavelength of the resonant metasurface matches the excitation wavelength of the Raman spectroscopy of uric acid; The resonant metasurface includes a plurality of metasurface units arranged periodically; each metasurface unit includes four nanocolumns; the nanocolumns are cuboids with a square bottom surface; the nanocolumns are sub-wavelength structures; the material of the nanocolumns is a high refractive index material with a refractive index greater than 1.3; SERS functional layer for enhancing Raman signals; the SERS functional layer is an array of noble metal nanoparticles modified on the surface of the resonant metasurface; the diameter of the noble metal nanoparticles is 20–50 nm, and the spacing between the noble metal nanoparticles in the array is ≤5 nm; Raman excitation module for emitting a laser to irradiate the resonant metasurface and the sample to be measured thereon, so as to excite uric acid molecules in the sample to be measured to generate Raman signals on the resonant metasurface, and the wavelength of the laser is consistent with the filter wavelength; Signal acquisition module for collecting the Raman signals through a semiconductor photodetector or a photomultiplier tube and converting them into electrical signals for transmission to the data processing module; Data processing module for calculating the uric acid concentration in the sample to be measured according to the Raman signals provided by the signal acquisition module.

[0007] In some embodiments, the material of the nanocolumns is silicon, titanium dioxide, or silicon nitride.

[0008] In some embodiments, the filter wavelength of the resonant metasurface is 785 nm.

[0009] In some more specific embodiments, the period length of the metasurface unit is 680 nm, the height of the nanocolumns is 140 nm, and the side length of the bottom surface is 220 nm; among the four nanocolumns in the metasurface unit, they move closer to the center position, and the moving distances in the horizontal and vertical directions are both 40 nm.

[0010] In some embodiments, the method of modifying the noble metal nanoparticles on the resonant metasurface is any one of electron beam sputtering, self-assembly, chemical bonding, and nanosphere lithography.

[0011] In some embodiments, the noble metal is gold, silver, or a gold-silver alloy.

[0012] In some embodiments, the Raman excitation module includes a semiconductor laser, a collimating lens, an objective lens, a reflector, and a polarization controller; the polarization controller includes a linear polarizer and a quarter-wave plate.

[0013] In some embodiments, calculating the uric acid concentration in the sample according to the Raman signals provided by the signal acquisition module is realized through a Raman spectroscopy analysis algorithm, and the Raman spectroscopy analysis algorithm includes: Baseline correction algorithm for removing the fluorescence background through adaptive iterative weighted penalized least squares; Noise reduction algorithm for filtering out high-frequency noise by wavelet transform; Smoothing algorithm for smoothing the spectrum based on a Savitzky-Golay filter; Feature peak extraction algorithm for determining uric acid at 1330 cm based on the second derivative after smoothing by Savitzky-Golay filter -1 and 640 cm -1 Integrated intensity of the characteristic peak; Convolutional neural network concentration inversion algorithm for determining uric acid concentration according to the integrated intensity of the characteristic peak.

[0014] In some more specific embodiments, the convolutional neural network concentration inversion algorithm is trained based on the ResNet-18 architecture, and the training sample features are the integrated intensity matrices of the characteristic peaks at 1330 cm -1 and 640 cm -1 with the label being the uric acid concentration value.

[0015] In some embodiments, the sample to be measured is unpretreated saliva or sweat.

[0016] The uric acid detection system provided by the present invention can significantly enhance the Raman scattering efficiency and signal reproducibility in uric acid detection by combining the BIC metasurface with the SERS substrate, realizing efficient and accurate detection of uric acid concentration. This system has high sensitivity, high specificity and portability, can overcome many limitations of existing uric acid detection technologies, and promote the development of the uric acid detection field. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for description in the embodiments. Obviously, the following drawings are only some embodiments of the present invention, and those of ordinary skill in the art can also obtain other drawings without creative efforts based on these drawings.

[0018] Figure 1 Schematic diagram of the structure of the uric acid detection system provided by the present invention; Figure 2 Optical path diagram of a Raman excitation module provided by the present invention; Figure 3 Schematic diagram of the structure of a metasurface unit provided by the present invention; Figure 4 Top view of a metasurface unit plane provided by the present invention; Figure 5 Schematic diagram of the BIC position of a resonant metasurface provided by the present invention; Symbol description: 1 - metasurface unit, 2 - nanorod. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0019] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be described below with reference to the accompanying drawings.

[0020] When light waves interact with some dielectric subwavelength structures that meet certain size conditions, electrical or magnetic resonance phenomena will occur (it is also possible that electromagnetic resonance exists simultaneously). Common resonance types include Mie resonance, Fano resonance, Bound State in the Continuum (BIC), and so on.

[0021] An optical metasurface is a highly sensitive optical biosensor based on the BIC principle. As a new form of material with a two-dimensional artificial periodic structure, it has feature sizes at the subwavelength level and can be designed to regulate information such as the phase, amplitude, and polarization of light waves. When the resonance spectrum overlaps with the absorption fingerprint, the enhanced molecule-resonator coupling will cause changes in the resonance frequency or intensity, so that the molecular fingerprint can be extracted. And this overlap can be achieved by changing the structural parameters and displacement parameters of the metasurface, thereby realizing a significant enhancement of the spectral signal. Compared with traditional optical devices, the metasurface has a smaller size, higher resolution, and thinner thickness, and is compatible with microelectronic manufacturing technology, making it easier to be integrated on miniaturized optoelectronic devices. In recent years, with the development of nanotechnology and micro-nano optics, the metasurface, as an artificial micro-nano structure with unique electromagnetic properties, provides new ideas and methods for biological detection, shows great potential in various applications such as biological science, clinical medicine, and environmental monitoring, and brings new possibilities for breaking through the bottlenecks in biological detection and other industries.

[0022] The applicant found that by breaking the symmetry structure of the metasurface unit, a symmetry-protected quasi-BIC mode with a high quality factor (Q value) resonance can be generated. Combining the BIC metasurface with the SERS substrate and using the high-Q local field enhancement of BIC to improve the Raman scattering efficiency, and at the same time realizing the improvement of signal repeatability through an ordered nanostructure, non-invasive detection of uric acid with a detection sensitivity at the pM level can be achieved. Based on this, the present invention uses the high-Q value characteristics of the quasi-BIC mode metasurface to cooperate with an ordered noble metal array to improve the repeatability of Raman signals and realize non-invasive detection of uric acid with high sensitivity.

[0023] Based on the above concept, the present invention designs a uric acid detection system based on enhancing Raman spectral signals with a BIC metasurface. Below, with reference to the accompanying drawings, the functions and structures of each part of the uric acid detection system provided by the present invention will be specifically described. As Figure 1As shown in the figure, the uric acid detection system provided by the present invention includes a Raman excitation module, a resonant metasurface, a SERS functional layer, a signal acquisition module, and a data processing module. When using this system to detect uric acid, just place the sample to be tested on the resonant metasurface, put it into the detection area of the system and turn on the switch, then the detection of the uric acid concentration in the sample to be tested can be completed. Moreover, this system supports the direct detection of saliva or sweat samples without pretreatment, which is very convenient.

[0024] The uric acid detection system provided by the present invention detects the uric acid concentration based on the Raman spectroscopy detection method. Therefore, this system uses the excitation wavelength of the Raman spectroscopy of uric acid as the working wavelength. The excitation wavelength of the Raman spectroscopy of uric acid is 532 nm or 785 nm. For the convenience of description, 785 nm is selected as the working wavelength subsequently.

[0025] First, the Raman excitation module is introduced. The Raman excitation module is used to emit laser light to irradiate the resonant metasurface and the sample to be tested thereon, so as to excite the uric acid molecules in the sample to be tested to generate Raman signals on the resonant metasurface.

[0026] The optical path diagram of the Raman laser module is as Figure 2 shown, including a semiconductor laser, a collimating lens, an objective lens, a reflector, and a polarization controller. Among them, the output wavelength of the semiconductor laser is 785 nm; the collimating lens is a parabolic mirror or an aspherical lens, and its function is to compress the laser beam diameter to 2 nm; the reflector is used to adjust and optimize the optical path direction, and the number is 2; the polarization controller includes a linear polarizer and a quarter-wave plate, which are used to match the requirements of the BIC mode TE polarization.

[0027] The above introduced the Raman excitation module. Next, the resonant metasurface is introduced. The resonant metasurface is used to amplify the optical signal of the target wavelength.

[0028] The resonant metasurface includes a plurality of periodically arranged metasurface units 1. The structure of each metasurface unit 1 is the same. The structure of the metasurface unit 1 is as Figure 2 and Figure 3 shown; each metasurface unit 1 includes four nanocolumns 2, which are arranged in a 2×2 array. The structure of each nanocolumn 2 is a cuboid with a square bottom surface and the same structural parameters; the nanocolumn 2 is a sub-wavelength structure, and its specific size and spacing are used to adjust the filtering wavelength. The filtering wavelength of the resonant metasurface is 785 nm. The material of the nanocolumn 2 is a high refractive index material with a refractive index greater than 1.3, such as silicon, titanium dioxide, and silicon nitride. The nanocolumn 2 is made of a dielectric material with a high refractive index and low loss in the working band, which is convenient for processing and is conducive to generating resonance modes inside the nanostructure with a sufficiently low aspect ratio.

[0029] The above introduced the resonant metasurface. Next, the SERS functional layer is introduced. The SERS functional layer is used to enhance the Raman signal.

[0030] The SERS functional layer is an array of noble metal nanoparticles modified on the surface of the resonant metasurface. These modified gold nanoparticles form ordered SERS hotspots on the resonant metasurface, playing the role of enhancing Raman signals. The noble metal can be gold or silver or a gold-silver alloy; the diameter of the noble metal nanoparticles is 20–50 nm, and the spacing between the noble metal nanoparticles in the array is ≤5 nm. The method of modifying the noble metal nanoparticles on the resonant metasurface can be any one of electron beam sputtering, self-assembly, chemical bonding, and nanosphere lithography.

[0031] The above introduced the SERS functional layer. Next, briefly introduce how the resonant metasurface and the SERS functional layer cooperate to enhance Raman signals. When the metasurface unit 1 of the metasurface acts on the incident light wave of 785 nm output by the Raman excitation module, the resonant peak position corresponds to a lower transmittance, and the transmittance on both sides of the resonant peak is higher, thereby realizing the amplification of the optical signal of the target wavelength; and when a SERS functional layer is formed by modifying gold nanoparticles on the surface of the metasurface, surface-enhanced Raman scattering can be realized, making the Raman signal excited by the incident light stronger.

[0032] The above introduced the Raman excitation module, the resonant metasurface and the SERS functional layer. Next, introduce the signal acquisition module.

[0033] The signal acquisition module is used to collect the Raman signal after the light source passes through the reaction system of the BIC+SERS metasurface, and convert it into an electrical signal and transmit it to the data processing module. The signal acquisition module includes a semiconductor photodetector or a photomultiplier tube, and a narrowband bandpass filter.

[0034] The above introduced the signal acquisition module. Next, introduce the data processing module.

[0035] The data processing module is used to calculate the uric acid concentration in the sample to be measured according to the Raman signal provided by the signal acquisition module.

[0036] The data processing module uses Raman spectroscopy analysis algorithms to calculate the uric acid concentration in the sample to be measured. The Raman spectroscopy analysis algorithms include: A baseline correction algorithm, which is used to remove the fluorescence background by adaptive iterative weighted penalized least squares method; A noise reduction algorithm, which is used to filter out high-frequency noise by wavelet transform (Daubechies 4 basis function); A smoothing algorithm, which is used to smooth the spectrum based on the Savitzky-Golay filter; A characteristic peak extraction algorithm, which is used to determine the 1330 cm of uric acid based on the second derivative after smoothing by the Savitzky-Golay filter -1(C-N bond) and 640 cm -1 Integral intensity of the characteristic peak ( -1 purine ring deformation); A convolutional neural network concentration inversion algorithm is used to determine the uric acid concentration based on the integral intensity of the characteristic peak. The convolutional neural network concentration inversion algorithm is a deep learning algorithm, trained based on the ResNet-18 architecture, and the training sample features are the integral intensity matrices of the characteristic peaks at 1330 cm -1 and 640 cm -1 with the label being the uric acid concentration value.

[0037] To make the specific implementation and effects of the present invention clearer, a specific example of the resonant metasurface in a uric acid detection system in actual application is provided below.

[0038] In this embodiment, the device operates in the near-infrared band, 785 nm is selected as the working wavelength, and the incident light is linearly polarized light along the x direction. The height H of the metasurface is set to 140 nm. The metasurface unit 1 is composed of four cuboid nanorods 2 of the same size. As Figure 4 shown, the period length of the metasurface unit is denoted as P, and the side lengths of the cross-section of the nanorod 2 are denoted as a and b.

[0039] The four nanorods 2 in the metasurface unit 1 move closer to the center position, with the lateral movement distance being g1 and the longitudinal movement distance being g2. The displacement parameter , and the purpose of introducing the displacement parameter is to break the symmetry of the metasurface unit structure, so that the incident light wave can excite the symmetry-protected bound states in the continuum, namely BICs, therein. The magnitude of the displacement parameter Δg determines the quality factor, i.e., Q value, of the electromagnetic BICs resonance generated when the light wave interacts with the metasurface. The asymmetry parameter α = Δg / g, and the asymmetry parameter α and Q satisfy the following relationship: Q ∝ α -2 From this relationship, it can be seen that the smaller the value of Δg, the larger the Q value. To make the resonance peak of the metasurface overlap with the sensitive wavelength of uric acid and blood sugar, in this embodiment, g1 = g2 = 40 nm is taken.

[0040] In this embodiment, single-crystalline silicon is selected as the material of the nanorods 2, and its refractive index at the working wavelength is 3. When using an electromagnetic simulation software to scan and optimize the size parameters of the metasurface unit, it is necessary to adjust the structural parameters and displacement parameters to shift the position of the resonance peak towards the excitation wavelength of the Raman spectroscopy method for uric acid. During the simulation process, it is observed that changes in the parameters P, a, b, H, and Δg will all cause the shift of the resonance wavelengths of the electric and magnetic BICs. By optimizing the nanorod size to achieve resonance wavelength matching, the size parameters of the BICs-based resonant metasurface are finally adjusted to H = 140 nm, P = 680 nm, a = 220 nm, b = 220 nm, g1 = 40 nm, and g2 = 40 nm when the resonance peak position is 785 nm.

[0041] Finally, through electromagnetic simulation, the effect of the metasurface system designed in this embodiment for enhancing the detection of uric acid concentration by Raman spectroscopy signal is as Figure 5 shown. Figure 5 It is a schematic diagram of the optical wave transmission coefficient of the metasurface varying with wavelength. It can be seen from the results that the position of the resonance peak is at 785 nm, and the transmission coefficients are all lower than 0.01. This shows that the metasurface system designed in this embodiment can be used to enhance the spectral signal at 785 nm.

[0042] It can be seen that compared with the prior art, the uric acid detection system provided by the present invention has the following beneficial effects: (1) The high-q resonance of the metasurface system designed by the present invention for uric acid concentration detection is spectrally clean without additional resonance background, and it allows highly spectral-selective enhancement of the uric acid concentration signal with rich spectra.

[0043] (2) The size of the metasurface unit of the present invention is of sub-wavelength order, with a smaller volume and lighter weight. When applied to uric acid concentration detection, it has the advantage of high integration compared with the existing uric acid detection methods.

[0044] (3) By cleverly combining the designed BIC metasurface and the SERS substrate, the present invention can significantly enhance the Raman scattering efficiency and signal repeatability in uric acid detection, making it easier for the detection device to detect signal changes, greatly improving the detection sensitivity, and contributing to the early detection of abnormal fluctuations in uric acid levels.

[0045] The uric acid detection system provided by the present invention combines high sensitivity, high specificity, and portability, can overcome many limitations of the existing uric acid detection technologies, and achieve efficient and accurate detection of uric acid concentration, thus promoting the development of the uric acid detection field.

[0046] In the description of the embodiments of the present application, words such as "exemplary", "for example", or "for illustration purposes" are used to denote examples, illustrations, or explanations. Any embodiment or design solution described as "exemplary", "for example", or "for illustration purposes" in the embodiments of the present application should not be construed as being more preferred or having more advantages than other embodiments or design solutions. Rather, the use of words such as "exemplary", "for example", or "for illustration purposes" is intended to present the relevant concepts in a specific manner.

[0047] In the description of the embodiments of the present application, the term "and / or" is merely a description of the association relationship between associated objects, indicating that three relationships may exist. For example, A and / or B may represent three situations: A exists alone, B exists alone, and A and B exist simultaneously. Additionally, unless otherwise specified, the term "plural" means two or more.

[0048] Furthermore, the terms "first" and "second" are only used for descriptive purposes and should not be construed as indicating or implying relative importance or implicitly specifying the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. The terms "comprise", "include", "have", and their variants all mean "including but not limited to", unless otherwise specifically emphasized in another way.

[0049] The specific embodiments described above further elaborate on the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only for the specific embodiments of the present invention and is not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made based on the technical solution of the present invention should be included within the protection scope of the present invention.

Claims

1. A uric acid detection system, characterized in that, Including: A resonant metasurface for enhancing optical signals; the resonant metasurface is composed of an array of asymmetric dielectric nanocolumns arranged periodically, and the filtering wavelength of the resonant metasurface matches the excitation wavelength of the Raman spectroscopy of uric acid; The resonant metasurface includes a plurality of metasurface units arranged periodically; each metasurface unit includes four nanocolumns; the nanocolumns are cuboids with a square bottom surface; the nanocolumns are sub-wavelength structures; the material of the nanocolumns is a high refractive index material with a refractive index greater than 1.3; A SERS functional layer for enhancing Raman signals; the SERS functional layer is an array of noble metal nanoparticles modified on the surface of the resonant metasurface; the diameter of the noble metal nanoparticles is 20–50 nm, and the spacing between the noble metal nanoparticles in the array ≤5 nm; A Raman excitation module for emitting a laser to irradiate the resonant metasurface and the sample to be measured thereon, so as to excite uric acid molecules in the sample to be measured to generate Raman signals on the resonant metasurface, and the wavelength of the laser is consistent with the filtering wavelength; A signal acquisition module for collecting the Raman signals through a semiconductor photodetector or a photomultiplier tube and converting them into electrical signals for transmission to a data processing module; A data processing module for calculating the uric acid concentration in the sample to be measured according to the Raman signals provided by the signal acquisition module.

2. The uric acid detection system according to claim 1, wherein The material of the nanocolumns is silicon or titanium dioxide or silicon nitride.

3. The uric acid detection system according to claim 1, wherein The filtering wavelength of the resonant metasurface is 785 nm.

4. The uric acid detection system according to claim 1 or 3, characterized in that, The period length of the metasurface unit is 680 nm, the height of the nanocolumns is 140 nm, and the side length of the bottom surface is 220 nm; the four nanocolumns in the metasurface unit move closer to the central position, and the moving distances in the horizontal and vertical directions are both 40 nm.

5. The uric acid detection system according to claim 1, wherein The method of modifying the noble metal nanoparticles on the resonant metasurface is any one of electron beam sputtering method, self-assembly method, chemical bonding method, and nanosphere lithography method.

6. The uric acid detection system according to claim 1, wherein The noble metal is gold or silver or a gold-silver alloy.

7. The uric acid detection system according to claim 1, characterized in that The Raman excitation module includes a semiconductor laser, a collimating lens, an objective lens, a reflector, and a polarization controller; the polarization controller includes a linear polarizer and a quarter-wave plate.

8. The uric acid detection system according to claim 1, characterized in that, The calculation of the uric acid concentration in the sample according to the Raman signals provided by the signal acquisition module is realized through a Raman spectroscopy analysis algorithm, and the Raman spectroscopy analysis algorithm includes: A baseline correction algorithm for removing the fluorescence background through adaptive iterative weighted penalized least squares method; A noise reduction algorithm for filtering high-frequency noise by wavelet transform; A smoothing algorithm for smoothing the spectrum based on a Savitzky-Golay filter; Characteristic peak extraction algorithm, used to determine the uric acid at 1330 cm based on the second derivative after smoothing by Savitzky-Golay filter -1 and 640 cm -1 Integral intensity of characteristic peak; A convolutional neural network concentration inversion algorithm for determining the uric acid concentration according to the integrated intensity of the characteristic peaks.

9. The uric acid detection system according to claim 8, characterized in that, The convolutional neural network concentration inversion algorithm is trained based on the ResNet-18 architecture, and the training sample features are the integrated intensity matrices of the characteristic peaks at 1330 cm -1 and 640 cm -1 , with the label being the uric acid concentration value.

10. The uric acid detection system according to claim 1, wherein, The sample to be measured is untreated saliva or sweat.

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