Terahertz biosensor for hydroxyproline detection in lung lavage fluid

Abstract

This invention discloses a dual-resonance terahertz biosensor for detecting hydroxyproline in bronchoalveolar lavage fluid. The sensor comprises a dielectric substrate and a periodic metasurface array. Each metasurface unit includes a first and a second dielectric pillar forming an asymmetric coupling structure, which generate two resolvable dielectric Mie resonant modes under terahertz wave excitation. The two resonant modes are frequency-matched to the two terahertz characteristic absorption bands of hydroxyproline, and the local field enhancement regions overlap with the sample loading region. During detection, the frequency and amplitude changes of the two resonant characteristics before and after sample loading are compared to construct a dual-channel response vector. The hydroxyproline content is calculated based on a pre-established calibration relationship, and response consistency is verified. The hydroxyproline content in the sample is determined based on the correspondence between hydroxyproline concentration and frequency shift. This invention forms a closed loop by combining dual-mode structure enhancement, molecular fingerprint frequency matching, and dual-channel joint determination, which can significantly improve the sensitivity and reliability of complex sample detection. Simultaneously, it provides new ideas for the design of sensors for detecting other disease biomarkers.

Description

Technical Field

[0001] This invention relates to the field of terahertz biomedical detection technology, specifically to a terahertz biosensor for the detection of hydroxyproline in bronchoalveolar lavage fluid. Background Technology

[0002] Bronchoalveolar lavage fluid (BALF) can reflect some physiological and pathological changes in the alveolar and pulmonary interstitial microenvironment and can be used for the detection and research of lung disease-related indicators. Hydroxyproline (HYP) is an important component of collagen, and its content changes are closely related to collagen metabolism and tissue fibrosis processes, and can be used as one of the indicators for fibrosis-related research and evaluation.

[0003] Existing methods for detecting hydroxyproline mainly include chromatography, mass spectrometry, immunoassay, and fluorescence analysis. While each method has its own advantages, some suffer from drawbacks such as complex sample pretreatment, long detection times, high instrument costs, or reliance on chemical reagents, thus limiting their effectiveness in rapid detection.

[0004] Terahertz waves typically refer to electromagnetic waves with frequencies ranging from 0.1 to 10.0 THz. Terahertz spectroscopy is characterized by low photon energy, no need for labeling, and high sensitivity to low-frequency molecular vibrations and intermolecular interactions, making it suitable for obtaining spectral information related to molecular composition and structure. Hydroxyproline exhibits a recognizable characteristic absorption response in the terahertz band, thus providing a basis for its detection using terahertz spectroscopy.

[0005] However, directly detecting hydroxyproline in bronchoalveolar lavage fluid using terahertz spectroscopy still presents certain challenges. On the one hand, when the hydroxyproline content in the sample is low, its interaction with terahertz waves is weak; on the other hand, salts, proteins, and other components in the bronchoalveolar lavage fluid may cause background absorption, scattering, and changes in the local dielectric environment. Furthermore, changes in sample loading conditions and measurement conditions can also cause variations in the terahertz spectrum, affecting the detection results.

[0006] To enhance the interaction between terahertz waves and the sample under test, metasurface structures can be used to modulate the local electromagnetic field. Compared with metallic resonant structures, dielectric metasurfaces can reduce the influence of ohmic losses in metals and support dielectric Mie resonances, generating a strong electromagnetic field in a localized region. By changing structural parameters such as the size, relative position, and inter-pillar gaps of the dielectric units, the frequency and field distribution of the resonant modes can also be adjusted.

[0007] For analytes with multiple terahertz characteristic absorption bands, the characteristic spectral information available from a single resonant mode is limited. Therefore, it is necessary to design a terahertz biosensor with two resolvable dielectric Mie resonant modes, such that the two resonant modes are frequency-matched to the two target terahertz characteristic absorption bands of hydroxyproline. The local field enhancement regions of both resonant modes overlap with the sample loading region, allowing for the detection of hydroxyproline by measuring the frequency and amplitude changes of the two resonant modes before and after sample loading. Summary of the Invention

[0008] To address the problems of low hydroxyproline content, weak direct terahertz response, limited characteristic spectral information available from a single resonant mode, and susceptibility to sample matrix and loading conditions in bronchoalveolar lavage fluid (BALF), this invention provides a terahertz biosensor for the detection of hydroxyproline in BLF. This sensor employs an asymmetric dielectric metasurface structure composed of a first and second dielectric pillar. Under terahertz wave excitation, it forms two resolvable dielectric Mie resonant modes, which are frequency-matched to the two target terahertz characteristic absorption bands of hydroxyproline. The detection of hydroxyproline is achieved by comparing the frequency and amplitude changes of the two resonant modes before and after sample loading.

[0009] The technical solution of this invention is as follows: This invention provides a terahertz biosensor for the detection of hydroxyproline in bronchoalveolar lavage fluid, comprising a dielectric substrate and a periodic metasurface array disposed on the dielectric substrate. Each metasurface unit of the periodic metasurface array includes a first dielectric pillar and a second dielectric pillar, which differ in at least one of the following: length, width, height, relative position, or inter-pillar spacing, to form an asymmetric coupling structure. Under terahertz wave excitation, the asymmetric coupling structure forms a first dielectric Mie resonant mode and a second dielectric Mie resonant mode. The two resonant modes respectively form frequency matches with the two target terahertz characteristic absorption bands of hydroxyproline, and the local field enhancement regions of the two resonant modes overlap with the sample loading region.

[0010] Furthermore, near-field coupling occurs between the first dielectric pillar and the second dielectric pillar. The first dielectric Mie resonance mode and the second dielectric Mie resonance mode have different field distributions and can be tuned by changing at least one structural parameter among the dimensions of the first dielectric pillar, the second dielectric pillar, and the inter-pillar gap.

[0011] Furthermore, the two terahertz characteristic absorption bands include 1.80 THz and 2.34 THz, respectively.

[0012] Furthermore, the dimensional differences include differences in column width, column length, or column height, and the relative positional differences include the positional offset of the two dielectric columns within the metasurface unit.

[0013] Furthermore, the first dielectric post and the second dielectric post differ in at least one of the following: post length, post width, post height, lateral offset, and relative spacing.

[0014] Furthermore, the center frequencies of the two Mie resonant channels are located in the first target response frequency band and the second target response frequency band of hydroxyproline, respectively.

[0015] Furthermore, the first dielectric post and the second dielectric post are respectively one of a cylindrical post, a rectangular post, an elliptical post, or a polygonal post.

[0016] Furthermore, the materials of the first dielectric pillar and the second dielectric pillar include, but are not limited to, high-resistivity silicon, silicon, quartz, alumina, or polyimide.

[0017] Furthermore, the dielectric substrate includes, but is not limited to, quartz, silicon, sapphire, polyimide, or polytetrafluoroethylene.

[0018] Furthermore, the sample loading area includes a first dielectric pillar, a second dielectric pillar, a gap between the two dielectric pillars, and their adjacent areas, for bearing the sample residue film formed after quantitative dripping and drying.

[0019] The beneficial effects of this invention are as follows: This invention sets up a periodic metasurface array composed of asymmetric dielectric pillars on a dielectric substrate, forming two resolvable dielectric Mie resonant modes under terahertz wave excitation. This reduces the influence of ohmic losses in the metal resonant structure and creates local field enhancement in the sample loading region, thereby enhancing the interaction between the terahertz wave and the sample under test. The two resonant modes are frequency-matched to the two target terahertz characteristic absorption bands of hydroxyproline, allowing simultaneous utilization of the spectral information of different characteristic bands of hydroxyproline. After sample loading, changes in the local dielectric environment cause changes in the frequency and amplitude of the two resonant modes. By comparing the frequency and amplitude changes before and after sample loading, a dual-channel response is constructed, and the hydroxyproline content is determined based on the calibration relationship established using standard samples. Simultaneously, consistency verification of the responses of the two resonant channels helps reduce the impact of measurement fluctuations in a single resonant channel on the detection results, improving the sensitivity and reliability of complex sample detection. Furthermore, by changing structural parameters such as the size of the dielectric pillars, their relative positions, the gaps between the pillars, and the array period, the center frequency and field distribution of the dielectric Mie resonance mode can be adjusted, enabling the sensor to be designed according to different target characteristic frequency bands, thus possessing a certain degree of scalability. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the unit structure of the terahertz biosensor for detecting hydroxyproline in bronchoalveolar lavage fluid according to the present invention. Figure 2This is a schematic diagram of the array structure of the terahertz biosensor for detecting hydroxyproline in bronchoalveolar lavage fluid according to the present invention. Figure 3 The image shows the terahertz characteristic absorption spectrum of hydroxyproline. Figure 4 Terahertz transmission spectra of the terahertz biosensor of the present invention before and after loading with hydroxyproline. Detailed Implementation

[0021] The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings. It should be noted that the drawings are all in a very simplified form and use non-precise ratios, and are only used to facilitate and clarify the explanation of the embodiments of the present invention.

[0022] Figure 1 shows a schematic diagram of the unit structure of the terahertz biosensor for detecting hydroxyproline in bronchoalveolar lavage fluid according to the present invention. The terahertz biosensor of the present invention includes a dielectric substrate 2-1 and a first dielectric pillar 2-2 and a second dielectric pillar 2-3 disposed on the dielectric substrate 2-1. The first dielectric pillar 2-2 and the second dielectric pillar 2-3 constitute an asymmetric coupling structure, and the two differ in at least one of the pillar length, pillar width, pillar height, relative position, or inter-pillar spacing. Under terahertz wave excitation, this asymmetric coupling structure forms a first dielectric Mie resonant mode and a second dielectric Mie resonant mode, and the two resonant modes are mutually distinguishable in the spectrum.

[0023] Figure 2 shows a schematic diagram of the array structure of the terahertz biosensor for detecting hydroxyproline in bronchoalveolar lavage fluid according to the present invention. The metasurface array structure of the sensor of the present invention consists of multiple identical metasurface units constructed on the surface of a substrate material and arranged periodically at equal intervals in the transverse and longitudinal directions. The periodic arrangement enables the metasurface to generate a stable electromagnetic response in the terahertz band, ensuring consistent sensor performance under different operating conditions.

[0024] like Figure 3 The image shows the terahertz characteristic absorption spectrum of hydroxyproline. Hydroxyproline exhibits characteristic absorption responses around 1.80 THz and 2.34 THz. Therefore, two characteristic absorption bands encompassing 1.80 THz and 2.34 THz were selected as the target response frequency bands. The metasurface structure and material parameters were adjusted to achieve frequency matching between the first and second dielectric Mie resonance modes and the aforementioned two target characteristic absorption bands, thereby enhancing the terahertz response signal of the target molecule. Frequency matching refers to the resonance center frequency being located within the corresponding target characteristic absorption band, or the resonance linewidth covering the corresponding characteristic absorption center, without requiring the resonance center frequency to be exactly the same as the value of the characteristic absorption center.

[0025] like Figure 4As shown, after loading with hydroxyproline, the resonant frequencies and transmission amplitudes of both the first and second dielectric Michaelis resonant modes changed. By comparing the terahertz transmission spectra before and after sample loading, the frequency and amplitude changes of the two resonant modes were obtained, and the responses of the first and second resonant channels were derived accordingly. The two channels together constitute a dual-channel response vector. A calibration relationship between hydroxyproline concentration and the dual-channel response was established using hydroxyproline samples of different concentrations. The correspondence between concentration and frequency shift was used for hydroxyproline content analysis, and the responses of the two resonant channels were used for response consistency verification.

[0026] In the specific embodiments below, the dielectric substrate of the terahertz biosensor is made of quartz material with a thickness of 300 µm. The periodic metasurface array disposed on the dielectric substrate is made of high-resistivity silicon material with a height of 90 µm. The array structure is fabricated by photolithography. Each metasurface unit is a rectangle with a side length of 98 µm × 84 µm. The overall side length of the terahertz biosensor is 10 mm, containing approximately 10,000 metasurface units. Both the dielectric substrate and the dielectric metasurface array can be replaced with other dielectric materials. All the above parameters can be designed and fabricated according to the characteristics of the sample to be tested.

[0027] In the specific embodiment, the terahertz characteristic absorption spectrum of hydroxyproline and the terahertz transmission spectrum before and after loading the hydroxyproline sample onto the sensor were measured. The terahertz characteristic absorption spectrum of hydroxyproline was tested using a pure sample pellet, and a hydroxyproline solution was used as the sample for sensor detection. Each time, 20 μL of sample was quantitatively added to the first dielectric column, the second dielectric column, the gap between the two dielectric columns, and their adjacent areas, and then rapidly dried to remove the solvent, forming a residual film on the metasurface. Samples of different concentrations were subjected to the same addition volume, drying method, and drying time. All the above spectral measurements were performed under the same testing environment, with a spectral resolution of approximately 7.6 GHz, a testing temperature of 23 ℃, and a relative humidity below 3%. Each sample was measured repeatedly, and the frequency domain spectrum was obtained by Fourier transform.

[0028] The contents not described in detail in this specification are prior art known to those skilled in the art. It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A dual-resonance terahertz biosensor for detecting hydroxyproline in bronchoalveolar lavage fluid, characterized in that, The system includes a dielectric substrate and a periodic metasurface array disposed on the dielectric substrate. Each metasurface unit of the periodic metasurface array includes a first dielectric pillar and a second dielectric pillar, which differ in at least one of the following: length, width, height, relative position, or inter-pillar spacing, to form an asymmetric coupling structure. The asymmetric coupling structure forms a first dielectric Mie resonance mode and a second dielectric Mie resonance mode under terahertz wave excitation. The two resonance modes respectively form frequency matching with the two target terahertz characteristic absorption bands of hydroxyproline, and the local field enhancement regions of the two resonance modes overlap with the sample loading region.

2. The biosensor according to claim 1, characterized in that, Near-field coupling occurs between the first dielectric pillar and the second dielectric pillar. The first dielectric Mie resonance mode and the second dielectric Mie resonance mode have different field distributions and can be tuned by changing at least one structural parameter among the dimensions of the first dielectric pillar, the second dielectric pillar, and the gap between the pillars.

3. The biosensor according to claim 1, characterized in that, The two terahertz characteristic absorption bands include 1.80 THz and 2.34 THz, respectively.

4. The biosensor according to claim 1, characterized in that, The dimensional differences include differences in column width, column length, or column height, and the relative positional differences include the positional offset of the two dielectric columns within the metasurface unit.

5. The biosensor according to claim 1, characterized in that, The first dielectric post and the second dielectric post differ in at least one of the following: post length, post width, post height, lateral offset, and relative spacing.

6. The biosensor according to claim 1, characterized in that, The center frequencies of the two Mie resonant channels are located in the first target response band and the second target response band of hydroxyproline, respectively.

7. The biosensor according to claim 1, characterized in that, The first dielectric post and the second dielectric post are respectively one of a cylindrical post, a rectangular post, an elliptical post, or a polygonal post.

8. The biosensor according to claim 1, characterized in that, The materials of the first dielectric post and the second dielectric post include, but are not limited to, high-resistivity silicon, silicon, quartz, alumina, or polyimide.

9. The biosensor according to claim 1, characterized in that, The dielectric substrate includes, but is not limited to, quartz, silicon, sapphire, polyimide, or polytetrafluoroethylene.

10. The biosensor according to claim 1, characterized in that, The sample loading area includes a first dielectric column, a second dielectric column, the gap between the two dielectric columns, and their adjacent areas, which are used to support the sample residue film formed after quantitative addition and drying.

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