A method for enhancing molecular surface photoacoustic signals based on high refractive index dielectrics

Abstract

This invention provides a method for enhancing molecular surface photoacoustic signals using high-refractive-index dielectrics. This method leverages the ultra-low loss of GaP dimers in the near-infrared region, achieving photoacoustic enhancement of molecular signals. The invention effectively enhances molecular photoacoustic signals while preserving their specificity, while also reducing signal interference from contrast agents, thereby avoiding false-positive diagnostic results.

Description

Technical Field

[0001] The present invention relates to photoacoustic imaging, and in particular to a method for enhancing molecular surface photoacoustic signals based on a high-refractive-index dielectric. Background Art

[0002] Photoacoustic imaging is a rapidly developing non-invasive biomedical imaging modality for biomolecular sensing and disease diagnosis. Due to the limited light absorption capacity and light scattering of biological tissues, endogenous contrast agents such as hemoglobin, lipids, and melanin cannot generate sufficient photoacoustic signals using lasers. To overcome this obstacle, more sensitive and efficient contrast agents are urgently needed to provide sufficiently high contrast-to-noise (CNR) to achieve high-resolution PA imaging. PA contrast agents significantly enhance photoacoustic imaging in the near-infrared (NIR) range (650-900 nm) by modifying local optical and acoustic properties.

[0003] Currently, photoacoustic contrast agents have become a cutting-edge research area in molecular imaging. For example, organic dye molecules can be combined with targeting molecules (such as antibodies) to achieve high-contrast imaging of mouse tumors and dynamic monitoring of ion concentrations in vivo. To enhance the intensity of the photoacoustic signal and achieve higher imaging quality, molecular probes are often modified using nanotechnology. For example, ICG dye molecules loaded onto MoS2 nanosheets and gold nanorod-melanotan hybrids (GNR-melaninnanohybrids) exploit the high absorption characteristics of metals to achieve tunable photoacoustic signal enhancement [15-17] and photothermal therapy. The enhanced imaging is achieved thanks to the contrast agent, but the photoacoustic signal generated by the contrast agent is different from the background signal. Although metal probes provide strong localized electric field enhancement for the interaction between molecules and nearby materials, they inherently suffer from high-loss absorption. This results in the contrast agent generating a stronger signal than the molecule, masking the signal characteristics of the molecule itself, easily leading to "false-positive" diagnostic results and causing problems in pathological detection. Summary of the Invention

[0004] In order to solve the problems in the prior art, the present invention provides a method for enhancing molecular surface photoacoustic signals based on a high refractive index dielectric.

[0005] The present invention provides a method for enhancing molecular surface photoacoustic signals based on high-refractive-index dielectrics, which realizes photoacoustic signal enhancement of molecular signals through the ultra-low loss of GaP dimers made of high-refractive-index dielectrics in the near-infrared region.

[0006] As a further improvement of the present invention, the signal of the molecular probe is enhanced by the GaP dimer.

[0007] As a further improvement of the present invention, molecules are placed in the gaps of the GaP dimers, so that the molecules have greater light absorption capability.

[0008] As a further improvement to the present invention, the analyte or absorber is Au or C, but this is not limited to these. The invention can be applied to photoacoustic signal amplification of any light-absorbing molecule. The GaP dimer can enhance the photoacoustic signal intensity not only of Au and C but also of any light-absorbing substance, such as aggregated melanin and the organic dye molecule ICG. This invention can be applied to enhance the signal of any substance with a weak photoacoustic signal intensity.

[0009] As a further improvement of the present invention, the GaP dimer made of a high-refractive-index dielectric has zero light absorption and does not generate a photoacoustic signal.

[0010] The beneficial effects of the present invention are as follows: through the above scheme, a new concept - molecular surface photoacoustic enhancement of high-refractive-index dielectrics is proposed. The ultra-low loss of GaP dimers made of high-refractive-index dielectrics in the near-infrared region is used as a new method to achieve photoacoustic signal enhancement of molecular signals. This method can not only effectively enhance the photoacoustic signal of the molecules and retain the specificity of the molecular photoacoustic signal; it can also reduce the signal interference of the contrast agent and avoid "false positive" diagnostic results. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other solutions can be obtained based on these drawings without paying any creative work.

[0012] Figure 1 This is a schematic diagram of the structure of GaP dimer enhancing molecular photoacoustic signals.

[0013] Figure 2 It is a flowchart of Comsol simulation.

[0014] Figure 3 It is the characteristics of GaP, absorption and scattering spectra, electric field strength and temperature distribution.

[0015] Figure 4 This is a picture of the photoacoustic signal detection of two different analytes, Au and C, by GaP dimer.

[0016] Figure 5 It is the enhanced photoacoustic spectrum, the enhancement factor of photoacoustic signals at different wavelengths, and the photoacoustic signal diagram.

[0017] Figure 6This is a structural diagram of a system for enhancing molecular surface photoacoustic signals based on a high-refractive-index dielectric probe according to the present invention. DETAILED DESCRIPTION

[0018] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0019] In the description of the present invention, it should be understood that the terms "center", "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside" and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the scope of protection of the present invention. In addition, the terms "first", "second" and the like are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, features defined as "first", "second" and the like may explicitly or implicitly include one or more of the features. In the description of the present invention, unless otherwise specified, "multiple" means two or more.

[0020] In the description of the present invention, it should be noted that, unless otherwise expressly specified or limited, the terms "mounted," "connected," and "connected" should be understood broadly. For example, they may refer to fixed connections, detachable connections, or integral connections; they may refer to direct connections, indirect connections through an intermediate medium, or internal communication between two components. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0021] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0022] A method for enhancing molecular surface photoacoustic signals using high-refractive-index dielectrics proposes a novel concept: molecular surface photoacoustic enhancement using high-refractive-index dielectrics. The ultra-low loss of GaP dimers made from high-refractive-index dielectrics in the near-infrared region serves as a novel approach for photoacoustic enhancement of molecular signals. Photoacoustic imaging has entered the era of molecular probes, where targeted binding of molecular probes to antibodies enhances photoacoustic signals. However, given the insufficient signal intensity, loading with metal nanomaterials is often required. The present invention opts for enhancing the signal of molecular probes using high-refractive-index dielectric GaP dimers. In principle, improving the sensitivity of photoacoustic signals generally involves enhancing light absorption and thermoacoustic conversion efficiency, thereby achieving a stronger photoacoustic signal. First, the gaps between high-refractive-index dielectric dimers enhance the electromagnetic field. Placing molecules within the gaps between GaP dimers maximizes their light absorption capacity. Second, the molecular photoacoustic effect also involves the process of acoustic transmission. The dielectric GaP dimer particles should also have a radiation-enhancing effect on the generated acoustic waves, further enhancing the overall surface-enhanced photoacoustic effect.

[0023] The present invention is characterized by improving the molecular light absorption capacity and heat conversion efficiency, which can greatly enhance the molecular photoacoustic signal without interfering with the photoacoustic response of the evaluated target.

[0024] Currently, the enhancement of photoacoustic signals mainly focuses on the effect of metal nanoparticles on tumor cancer cells, which will face an important problem. The metal nanoparticles themselves have strong light absorption capabilities and produce large photoacoustic signals, which completely cover up the photoacoustic signals of the object to be tested itself, which will interfere with the diagnosis of pathology to a certain extent.

[0025] What the present invention aims to achieve is to utilize the properties of both surface electromagnetic field enhancement and low light absorption of high-refractive index dielectric particles in the near-infrared band, which can not only effectively enhance the photoacoustic signal of the object to be tested; at the same time, the light absorption capacity of the high-refractive dielectric GaP dimer is low, no background photoacoustic signal is generated, and the specificity of the molecule is retained. By using this method to enhance the photoacoustic signal of molecular probes, an optional and effective method is contributed to the expansion of biomedical photoacoustic molecular functional imaging applications. The application that best reflects the advantages of this method should be the improvement of the photoacoustic signal of multiple photoacoustic molecular probes that exist simultaneously in biological tissues, and the further enhancement of the photoacoustic signal of genetically encoded chromophore molecules that are difficult to associate with other contrast substances. This method can not only effectively enhance the photoacoustic signal of the molecule and retain the specificity of the molecular photoacoustic signal; it can also reduce the signal interference of the contrast agent.

[0026] The present invention has been verified to be feasible through theoretical simulation and has achieved the design objectives. The following is the design and results:

[0027] like Figure 1Figure 2 shows the structure of GaP dimers enhancing molecular photoacoustic signals. The principle of photoacoustic imaging is that when a laser pulse strikes a molecule, a portion of the light energy is absorbed and converted into heat, causing the surrounding temperature to rise rapidly and elastic expansion to occur, thus generating sound waves that propagate through the medium.

[0028] First, a theoretical simulation experiment is conducted: the simulation geometry is set according to the structure of the sample, and the grid is divided appropriately. Then, the equations used in the theoretical derivation are used to establish a multi-physics field joint solution physical model.

[0029] Comsol numerical simulation analysis research technology route is as follows Figure 2 As shown, each module corresponds to solving the physical process of photoacoustic wave generation and transmission. In the process of establishing the computational model, the convergence and accuracy of the solution depend not only on the mesh but also on the boundary conditions between each module. This simulation method is designed with four modules: the optical module, the heat transfer module, the structural mechanics module, and the acoustic module. The optical module mainly calculates the surface electromagnetic field of nanoparticles and analyzes the light absorption capacity of molecules. The absorbed light energy is converted into thermal energy of the molecules, which rapidly heats up and causes changes in the temperature of the surrounding solution. The surrounding tissue expands due to heat, generating pressure waves, which finally propagate outward in the form of sound waves.

[0030] The characteristics of gallium phosphide (GaP) are as follows Figure 3 As shown in Figure 2, the absorption cross section of GaP decreases rapidly and disappears at 600nm. This indicates that within the transparent region of GaP (λ>600nm), the refractive index of GaP is real and large enough to exhibit electromagnetic resonance. More importantly, GaP has a large scattering, which gives GaP a competitive advantage in electric field enhancement. The electromagnetic field enhancement at the center of the GaP dimer is shown in Figure 2. Figure 3 As shown in (b), the maximum dipole electromagnetic field enhancement reaches more than 3 times. It can also be seen that GaP has greater light absorption and higher temperatures at low wavelengths. As the wavelength increases, the temperature decreases rapidly, and at 600nm, due to the lack of light absorption, the temperature approaches the initial temperature of 293K.

[0031] These results demonstrate that GaP, as an exogenous probe, enhances molecular photoacoustic signals without generating background photoacoustic signals. GaP is a low-loss dielectric material that does not absorb light energy under the action of lasers, thus generating no heat and no photoacoustic signal. This probe achieves zero loss and no interference from photoacoustic signals. More notably, GaP exhibits significant scattering, giving it a competitive advantage in electric field enhancement.

[0032] In order to verify the photoacoustic enhancement effect of GaP on different molecules, Au and C were used as analytes to observe the signal enhancement effect and molecular specificity of the analytes at a specific wavelength of 620 nm.

[0033] In this work, the present invention selected GaP dimers to detect the photoacoustic signals of two different analytes, Au and C. First, the photoacoustic response of Au and C immersed in water and the photoacoustic signal at 620nm under GaP enhancement were demonstrated. The intensities of the Au and C photoacoustic signals differ, which is mainly due to the different light absorption capabilities of the different analytes. Looking at the Au and C signals and the signals after response enhancement, it can be found that the photoacoustic signal of the analytes has been significantly improved under the action of GaP.

[0034] In addition, the absorption cross sections and photoacoustic spectra of Au and C as well as the enhanced photoacoustic spectra of GaP dimers are shown here ( Figure 5 (ab) in the figure). For ease of comparison, the results at 620nm are normalized to their maximum values. The figure shows that the absorption cross sections of Au and C agree well with the photoacoustic spectra. This is primarily due to the fact that the intensity of the photoacoustic signal depends on the light absorption capacity of the molecules themselves. In other words, the strength of the light absorption of the molecules determines the intensity of the photoacoustic signal. In the presence of GaP dimers, the photoacoustic spectrum still agrees well with the absorption cross section, demonstrating that the presence of GaP does not affect the photoacoustic signal response of the analyte itself.

[0035] exist Figure 5 (c) shows the photoacoustic signal enhancement factors at different wavelengths. GaP dimers significantly enhance the photoacoustic signal for different analytes, with the maximum enhancement at 650nm. Figure 5 Panel (d) shows the ratio of the C and Au signals before and after photoacoustic enhancement. Comparison reveals that the proportionality factors follow the same trend before and after photoacoustic signal enhancement. This demonstrates that the enhanced signal originates from the molecules themselves, and that the GaP dimer enhances the electric field, increasing the optical absorption capacity and boosting the photoacoustic signal intensity.

[0036] The above analysis demonstrates that GaP can effectively enhance molecular photoacoustic signals, with enhancement factors reaching up to 8.5 times for Au and 6 times for C. Since the photoacoustic signal varies based on the distribution of the analyte's light absorption, the distribution of the photoacoustic spectrum can be used to identify substances. Analysis has shown that the absorption cross section of the analyte and the photoacoustic spectrum before and after enhancement are consistent, demonstrating the validity of the results presented herein.

[0037] The theoretical feasibility provides a basis for subsequent experiments. Figure 6 System diagram.

[0038] A system based on enhancing molecular surface photoacoustic signals using a high-refractive-index dielectric includes a laser emitter 101, a trigger 102, a computer 103, a digitizer 104, a signal amplifier 105, a sensor 106, and a test container 107. The test container 107 is filled with water. An object to be tested 108 (i.e., an absorber) and the sensor 106 are placed in the water in the test container 107. The output end of the sensor 106 is connected to the signal amplifier 105, which is connected to the digitizer 104. Laser light from the laser emitter 101 is emitted into the object to be tested 108. The laser emitter 101 is connected to the trigger 102, which is connected to the digitizer 104, which is connected to the computer 103.

[0039] The key technical point of this invention lies in the fact that the introduced nanostructures themselves do not generate photoacoustic signals. Therefore, molecules located between the high-refractive-index dielectric nanoparticles effectively enhance imaging sensitivity while retaining the detection specificity of the molecular probe. This method of enhancing molecular photoacoustic signals is not only applicable to enhancing molecular photoacoustic signals but can also serve as a basis for distinguishing different molecules.

[0040] The present invention provides a method for enhancing molecular surface photoacoustic signals based on a high-refractive-index dielectric probe, which relates to photoacoustic signal enhancement technology. The method can be used as a contrast agent to improve the sensitivity of photoacoustic signals and is applied to imaging detection of tumors and pathologies.

[0041] The above is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention should not be considered to be limited to these descriptions. For those skilled in the art of the present invention, without departing from the concept of the present invention, several simple deductions or substitutions can be made, which should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for enhancing molecular surface photoacoustic signals based on a high refractive index dielectric, characterized by: The photoacoustic signal enhancement of molecular signals is achieved by using GaP dimers made of high-refractive-index dielectrics with ultra-low loss in the near-infrared region. Specifically, the GaP dimers made of high-refractive-index dielectrics have zero light absorption and do not generate photoacoustic signals themselves. The signals of molecular probes are enhanced by the GaP dimers, and the molecular probes are placed in the gaps between the GaP dimers, so that the molecular probes have greater light absorption capabilities.

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