Terahertz biological sensing detection device and biological detection method

Abstract

The invention relates to the technical field of terahertz biosensing, in particular to a terahertz biosensing detection device and a biological detection method. The system is used for detecting a biological sample and comprises a transmission-type terahertz time-domain spectroscopy system for providing a transmission-type terahertz light path; the metasurface sensor is located on a transmission-type terahertz light path, the metasurface sensor comprises a plurality of first gold films and second gold films of asymmetric structures in a periodic array, and under normal incidence of terahertz waves in the polarization direction, a transmission spectrum harmonic peak is excited to characterize a biological sample; the captured DNA is modified on the surface of the super-surface sensor and is used for capturing a biological sample; the gold nanoprobe is used for being specifically combined with a biological sample after capturing the biological sample so as to enhance the sensing sensitivity to the biological sample. According to the invention, the metasurface sensor and the gold nanoprobe are combined for detection, so that high-sensitivity detection of trace micromolecular biological samples can be realized.

Description

Technical Field

[0001] The present invention relates to the technical field of terahertz biosensing, and more particularly to a terahertz biosensing detection device and a biological detection method. Background Art

[0002] Let-7a is a typical miRNA that can inhibit the growth and spread of tumors and is promising for cancer diagnosis and treatment. Its content is significantly correlated with the postoperative survival period of cancer patients. Let-7a has only 20 - 24 nucleotides, and the molecular weight of this miRNA is relatively low, and it is detected in trace amounts in living organisms. Therefore, the development of a non-destructive and accurate Let-7 detection technology is of great significance for cancer detection, prevention, and treatment.

[0003] Terahertz waves, due to their non-ionizing characteristics and small damage to biological tissues, are considered powerful tools in biosensing research. Their frequencies match the skeletal vibrations and rotational modes of many biomolecules and have currently been used in the analysis of numerous biochemical substances including proteins, viruses, antibiotics, cells, and nucleic acids (DNA / RNA). However, terahertz biosensing faces severe challenges in trace substance detection. The mismatch between the terahertz wavelength and the size of biomolecules makes it very difficult to achieve high-sensitivity sensing, especially in the trace detection of clinical samples. On the one hand, biosensing based on metasurfaces essentially utilizes the response of sensor devices to changes in the dielectric environment of the surrounding space and can only macroscopically reflect the refractive index changes caused by the analyte. The sensor itself cannot specifically recognize target biomolecules. On the other hand, there are multiple different components in clinical samples, which are likely to interfere with the detection results of metasurface sensors and reduce their sensitivity to trace targets.

[0004] Traditional Let-7a recognition methods such as fluorescence detection are complex, costly, and time-consuming. At the same time, fluorescence staining is prone to generating additional influencing factors. In addition, it is currently difficult for the metasurfaces of terahertz biosensors to achieve specific sensing of trace small biomolecule Let-7a, especially to achieve stable and specific detection in serum samples that are closer to the actual detection requirements. At the same time, the existing designs of terahertz biosensors are generally complex, and their detection functions are generally relatively single, making it difficult to simultaneously achieve multiplexing of multifunctional detection. Summary of the Invention

[0005] The present invention aims to at least improve one of the technical problems existing in the prior art. For this purpose, the present invention proposes a terahertz biosensing detection device and a biological detection method.

[0006] The technical solution of the present invention is as follows: A terahertz biosensing detection device for detecting biological samples, comprising: A transmission terahertz time-domain spectroscopy system for providing a transmission terahertz optical path; A sample holder disposed on the transmission terahertz optical path of the transmission terahertz time-domain spectroscopy system; A metasurface sensor disposed on the sample holder, the metasurface sensor including a first gold film and a second gold film with a plurality of asymmetric structures in a periodic array, and under the normal incidence of terahertz waves in the polarization direction, exciting a transmission spectrum resonance peak to characterize a biological sample; Captured DNA, modified on the surface of the metasurface sensor for capturing a biological sample; A gold nanoprobe for specifically binding to a biological sample after capturing the biological sample to enhance the sensing sensitivity to the biological sample.

[0007] In a possible technical solution, further, the transmission terahertz time-domain spectroscopy system includes a terahertz lens emission end, a first terahertz lens, a second terahertz lens, a third terahertz lens, a fourth terahertz lens, and a terahertz detector sequentially arranged along the optical path, and the sample holder is disposed between the second terahertz lens and the third terahertz lens.

[0008] In a possible technical solution, further, the lengths of the first gold film and the second gold film in the Y direction on the surface of the metasurface sensor are equal; the lengths of the adjacent first gold film and the second gold film in the X direction on the surface of the metasurface sensor are not equal to form an asymmetric structure for breaking the symmetry in the X direction. When the polarization direction of the incident terahertz wave is X, a Q-BIC resonance mode can be excited, and a Q-BIC resonance peak (transmission spectrum resonance peak) can be observed near 0.7 terahertz. The concentration of the biological sample can be characterized by using the frequency shift of the resonance peak.

[0009] It should be noted that the metasurface sensor has a glass substrate with a refractive index of 2 and a thickness of 300 μm to ensure that the transmittance of terahertz waves is greater than 90%.

[0010] In a possible technical solution, further, the first gold film and the second gold film have the same thickness, both being 200 nm, which can enhance the optical performance while ensuring the structural stability and biochemical compatibility. The optical performance is mainly reflected in enhancing the plasmonic effect and suppressing background noise.

[0011] In a possible technical solution, further, the particle diameter of the gold nanoprobe is 60 nm to 90 nm, enabling it to have a stronger optical response, a higher molecular loading capacity, and excellent field enhancement ability.

[0012] In a possible technical solution, further, the length and width dimensions of the first gold film are the same, both being 62 μm to 66 μm; The length dimension of the second gold film is 70 μm to 110 μm, and the width dimension is 62 μm to 66 μm.

[0013] It should be noted that the gold nanoprobe is modified with phenylboronic acid to enhance the electromagnetic response between the metasurface sensor and Let-7a The terahertz biosensing detection device of the present invention adopts the combined detection of a metasurface sensor and a gold nanoprobe, and can realize the high-sensitivity detection of trace small-molecule biological samples (especially Let-7a), and the sensing sensitivity can reach 7.4 GHz / nM.

[0014] A biological detection method, wherein the above-mentioned terahertz biosensing detection device is used for biological detection, and it includes the following steps: Configure biological sample solutions, solutions containing gold nanoprobes, and modification solutions containing thiolated single-stranded DNA (HS-ssDNA) and 6-mercapto-1-hexanol (MCH) with different concentration gradients; Clean the metasurface sensor, and immerse the cleaned metasurface sensor in the modification solution for modification to obtain captured DNA; Place the metasurface sensor containing the captured DNA in the biological sample solution, soak it sufficiently and then take it out, and immerse it in the solution containing the gold nanoprobe for reaction to obtain a processed biological sample; Take out the metasurface sensor and let it dry, and place it on the sample holder; Turn on the transmission terahertz time-domain spectroscopy system. After the incident terahertz wave is collimated and focused, it passes through the processed biological sample and the metasurface sensor, and is collimated and focused again, and the transmitted terahertz wave is detected by the terahertz detector to obtain the terahertz transmission spectrum of the processed biological sample, so as to obtain the transmission spectrum resonance peaks of each biological sample with different concentrations; Characterize the concentration of the biological sample according to the frequency shift of the transmission spectrum resonance peaks of the biological samples with different concentrations.

[0015] In a possible technical solution, further, the modification solution is a KH2PO4 solution of thiolated single-stranded DNA (HS-ssDNA) and 6-mercapto-1-hexanol (MCH) in a 1:1 ratio, ensuring sufficient spacing between HS-ssDNA molecules to promote the hybridization reaction.

[0016] According to the biological detection method of the present invention, a method combining different biological modifications is adopted, which can achieve multifunctional multiplex biological molecule detection. It can not only specifically detect Let-7a, but also support the discrimination of RNA and DNA with the same sequence. The detection limit for complementary sequences is one order of magnitude higher than that for non-complementary sequences, and the response to RNA is more than three times that of DNA.

[0017] According to the terahertz biosensing detection device and biological detection method of the present invention, it is relatively simple compared with the prior art, the device is easy to process and can be reused, and the manufacturing cost is low.

[0018] An electronic device includes 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 terahertz biosensing detection device.

[0019] A computer storage medium, wherein instructions are stored in the computer storage medium, and when the instructions are executed on a computer, the computer is caused to execute the above-mentioned biological detection method based on the terahertz biosensing detection device.

[0020] Additional aspects and advantages of the present invention will be given in part in the following description, will become apparent in part from the following description, or will be learned through the practice of the present invention. Description of the Drawings

[0021] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required to be used in the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0022] Figure 1 It is a schematic diagram of a transmission terahertz time-domain spectroscopy system of a terahertz biosensing detection device according to an embodiment of the present invention; Figure 2 It is a schematic diagram of a metasurface sensor of a terahertz biosensing detection device according to an embodiment of the present invention; Figure 3 It is a schematic diagram of the working principle of a terahertz biosensing detection device according to an embodiment of the present invention; Figure 4 It is a schematic diagram of the working principle of a terahertz biosensing detection device according to an embodiment of the present invention; Figure 5 It is a transmission spectrum diagram of a terahertz biosensing detection device according to an embodiment of the present invention for different concentrations of Let-7a; Figure 6It is a detection result diagram of Let-7a, DNA with the same sequence as Let-7a, and three random sequence DNAs by the terahertz biosensing detection device according to an embodiment of the present invention.

[0023] Reference numerals: Transmission terahertz time-domain spectroscopy system 1, terahertz lens emission end 100, first terahertz lens 110, second terahertz lens 120, third terahertz lens 130, fourth terahertz lens 140, terahertz detector 150; Sample holder 2; Metasurface sensor 3, first gold film 31, second gold film 32; Capture DNA 4; Gold nanoprobe 5. Detailed implementation manners

[0024] The embodiments of the present invention will be described in detail below. The embodiments described with reference to the accompanying drawings are exemplary. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0025] It should be noted that when an element is referred to as "fixed to" another element, it can be directly on the other element or there may also be a middle element. When an element is considered to be "connected" to another element, it can be directly connected to the other element or there may be a middle element at the same time.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention herein are only for the purpose of describing specific implementation manners and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0027] The terms "first", "second", "third", etc. in the description and claims of the present application and the accompanying drawings are used to distinguish different objects and are not used to describe a specific order. In addition, the terms "comprising" and "having" and any variations thereof are intended to cover non-exclusive inclusion. For example, a series of steps or units are included, or optionally, steps or units not listed are also included, or optionally, other steps or units inherent in these processes, methods, products or devices are also included.

[0028] Only the parts relevant to the present application are shown in the accompanying drawings, rather than all the content. Before discussing the exemplary embodiments in more detail, it should be mentioned that some exemplary embodiments are described as processes or methods depicted as flowcharts. Although the flowcharts describe the operations (or steps) as sequential processes, many of the operations can be performed in parallel, concurrently, or simultaneously. In addition, the order of the operations can be rearranged. The process can be terminated when its operations are completed, but it can also have additional steps not included in the drawings. The process can correspond to a method, function, procedure, subroutine, subprogram, and so on.

[0029] The terms "component", "module", "system", "unit", etc. used in this specification are used to represent computer-related entities, hardware, firmware, combinations of hardware and software, software, or software in execution. For example, a unit can be, but is not limited to, a process running on a processor, a processor, an object, an executable file, an execution thread, a program, and / or distributed between two or more computers. In addition, these units can be executed from various computer-readable media storing various data structures. A unit can communicate, for example, through signals with other systems through local and / or remote processes according to signals having one or more data packets (such as data from a second unit interacting with a local system, a distributed system, and / or a network. For example, the Internet interacting with other systems through signals).

[0030] Embodiment 1 This embodiment provides a terahertz biosensing detection device for detecting biological samples, which includes: A transmissive terahertz time-domain spectroscopy system 1 for providing a transmissive terahertz optical path. The transmissive terahertz time-domain spectroscopy system 1 includes a terahertz lens emission end 100, a first terahertz lens 110, a second terahertz lens 120, a third terahertz lens 130, a fourth terahertz lens 140, and a terahertz detector 150 arranged in sequence along the optical path. The sample holder 2 is arranged between the second terahertz lens 120 and the third terahertz lens 130; A sample holder 2 arranged on the transmissive terahertz optical path of the transmissive terahertz time-domain spectroscopy system 1; A metasurface sensor 3 arranged on the sample holder 2. The metasurface sensor 3 includes a plurality of first gold films 31 and second gold films 32 with asymmetric structures in a periodic array. Under the normal incidence of terahertz waves in the polarization direction, a transmissive spectrum resonance peak is excited to characterize biological samples; Captured DNA 4 modified on the surface of the metasurface sensor 3 for capturing biological samples; Gold nanoprobes 5 for specifically binding to biological samples after capturing biological samples to enhance the sensing sensitivity to biological samples.

[0031] It should be noted that the lengths of the first gold film and the second gold film located in the Y direction on the surface of the metasurface sensor are equal; the lengths of the adjacent first gold film and the second gold film in the X direction on the surface of the metasurface sensor are not equal to form an asymmetric structure, which is used to break the symmetry in the X direction. When the polarization direction of the incident terahertz wave is X, a Q-BIC resonance mode can be excited, and a Q-BIC resonance peak can be observed near 0.7 terahertz. The concentration of the biological sample can be characterized by using the frequency shift of the resonance peak.

[0032] It should be noted that the metasurface sensor 3 has a glass substrate with a refractive index of 2 and a thickness of 300 μm to 500 μm. In this embodiment, the thickness of the glass substrate is preferably 300 μm to ensure that the transmittance of terahertz waves is greater than 90%.

[0033] It should be noted that the thicknesses of the first gold film 31 and the second gold film 32 are equal, both being 200 nm, which can enhance the optical performance while ensuring the structural stability and biochemical compatibility. The optical performance is mainly reflected in enhancing the plasmonic effect and suppressing background noise.

[0034] It should be noted that the particle diameter range of the gold nanosensor 5 is 60 nm to 90 nm. In this embodiment, the particle diameter of the gold nanosensor 5 is preferably 90 nm, making it have a stronger optical response, a higher molecular loading capacity, and excellent field enhancement ability.

[0035] It should be noted that the length and width dimensions of the first gold film 31 are the same, both being 62 μm to 66 μm; the length dimension of the second gold film 32 is 70 μm to 110 μm, the width dimension is 62 μm to 66 μm, the period along the X axis is 256 μm to 260 μm, and the period along the Y axis direction is 256 μm to 300 μm. In this embodiment, the length and width dimensions of the first gold film 31 are the same, both being 64 μm; the length dimension of the second gold film 32 is 110 μm, the width dimension is 64 μm, the period along the X axis is 256 μm, and the period along the Y axis direction is 256 μm.

[0036] It should be noted that the gold nanosensor 5 is modified with phenylboronic acid to enhance the electromagnetic response between the metasurface sensor and Let-7a.

[0037] It should be noted that in this embodiment, the devices in the transmission terahertz time-domain spectroscopy system have no special requirements for the environmental temperature and can work at room temperature. The working frequency range of the devices is 0.1 THz to 3 THz.

[0038] The working principle of this embodiment is as follows: The transmission terahertz time-domain spectroscopy system can detect the transmission spectrum of the metasurface sensor, and use the transmission spectrum resonance peak generated by the Q-BIC metasurface structure of the metasurface sensor to characterize the biological sample to be measured. Specifically, as Figure 1 shown, in the transmission terahertz time-domain spectroscopy system, the terahertz wave is emitted from the emission end 100 of the terahertz lens. After the incident linearly polarized wave is collimated by the first terahertz lens 110 and focused by the second terahertz lens 120, it is normally incident on the sample holder 2. The transmitted wave is collimated by the third terahertz lens 130 and focused by the fourth terahertz lens 140, and converges to the terahertz detector 150, so that the outgoing terahertz wave can be detected, and then the complete terahertz transmission spectrum can be restored through theoretical calculation. In addition, the sensing sensitivity and sensing accuracy of the device are respectively defined as: where represents the frequency shift of resonance, represents the concentration change of the sample, = 1 GHz, which refers to the frequency resolution of the terahertz time-domain spectroscopy system. The designed metasurface sensor is composed of an asymmetric metal wire array. The lengths of all metal wires are the same in the Y direction, while the lengths of adjacent metal wires are inconsistent in the X direction. Therefore, it can be considered that the metasurface sensor breaks the symmetry in the X direction. When the terahertz wave with a polarization direction of x is normally incident, the metasurface sensor structure itself can excite the Q-BIC resonance mode, generating an extremely strong local electric field enhancement. When using it to detect RNA / DNA molecules, the interaction between the terahertz wave and the biological sample molecules to be measured will be significantly enhanced, so as to achieve the purpose of trace sensing of RNA / DNA. In the present invention, a Q-BIC resonance peak can be observed near 0.7 terahertz, and the concentration of the biological sample can be characterized by using the frequency shift of the resonance peak. And as Figure 3As shown, the present invention utilizes capture DNA to modify the metasurface sensor. The capture DNA can perform nucleic acid complementary pairing with the sequence of the biological sample to be detected (taking Let-7a as an example in this embodiment). It can capture Let-7a through base complementary pairing and will not pair with non-complementary sequences, enabling the metasurface to specifically sense Let-7a. In addition, the present invention also utilizes gold nanoprobes modified with phenylboronic acid to achieve the discrimination of RNA / DNA and selectively amplify the detection signal of Let-7a. When the metasurface sensor captures Let-7a and DNA with the same sequence, the gold nanoprobe solution can be allowed to flow through the metasurface. Phenylboronic acid molecules can specifically bind to vicinal diols. The structural unit of RNA is ribonucleotide, and its pentose part contains two adjacent hydroxyl groups, which can interact with phenylboronic acid molecules. In contrast, the structural unit of DNA is deoxyribonucleotide, and its pentose contains only one hydroxyl group, so it cannot be specifically recognized by phenylboronic acid molecules. Since the gold nanoprobes modified with phenylboronic acid can only bind to Let-7a and not to DNA with the same sequence, the electromagnetic response between the metasurface and Let-7a will be further enhanced, and the sensing sensitivity and detection accuracy will be greatly improved, thereby achieving the discrimination of RNA / DNA. In addition, the gold nanoprobes have a surface ionization enhancement effect in the terahertz band, which can significantly improve the sensing sensitivity and accuracy of the sensor to Let-7a. In the embodiment of the present invention, through the frequency shift of the Q-BIC resonance peak, the concentration sensing of the sample and nucleic acid discrimination can be achieved.

[0039] According to the terahertz biosensing detection device of the present invention, the combined detection of a metasurface sensor and gold nanoprobes is adopted, which can achieve high-sensitivity detection of trace small-molecule biological samples (Let-7a), and the sensing sensitivity can reach 7.4 GHz / nM.

[0040] Example 2 On the basis of the above embodiment, this embodiment provides a biological detection method. Among them, the terahertz biosensing detection device as described above is used for biological detection, including the following steps: Prepare biological sample solutions, solutions containing gold nanoprobes, and modification solutions containing thiolated single-stranded DNA (HS-ssDNA) and 6-mercapto-1-hexanol (MCH) with different concentration gradients. The modification solution is specifically a KH2PO4 solution containing 1 pM HS-ssDNA and 1 pM MCH. The super surface sensor is cleaned, and the cleaned super surface sensor is immersed in the modification solution for modification to obtain captured DNA. In this embodiment, the super surface sensor is immersed in the modification solution for 2 hours. During this process, HS-ssDNA is used as captured DNA and can be complementary to the target Let-7a. Both HS-ssDNA and MCH can be chemically bonded to the gold film surface through S-Au bonds. By using a 1:1 ratio of HS-ssDNA and MCH, it is ensured that there is sufficient spacing between HS-ssDNA molecules to promote hybridization reactions; The super-surface sensor containing the captured DNA is placed in a prepared biological sample solution and fully immersed therein, then taken out and immersed in a solution containing a gold nanoprobe for reaction to obtain a processed biological sample; Take out the metasurface sensor, dry it, and place it on a sample holder; Turn on the transmission terahertz time-domain spectroscopy system, collimate and focus the incident terahertz wave, collimate and focus again through the processed biological sample and metasurface sensor, and detect the outgoing terahertz wave through the terahertz detector to obtain the terahertz transmission spectrum of the processed biological sample, thereby obtaining the transmission spectrum resonance peak of each biological sample with different concentrations; The concentration of the biological sample is characterized according to the frequency shift of the resonance peak of the transmission spectrum of the biological sample with different concentrations.

[0041] It should be noted that in the control experiment and serum sample detection, the metasurface sensor was immersed in a DNA solution with the same concentration as the Let-7a sequence and a human serum sample containing Let-7a, respectively. After a sufficient period of immersion, the metasurface was taken out and immersed in a solution containing gold nanoprobes. After a sufficient period of time, the metasurface sensor was taken out and dried, and also placed in Figure 1 The samples were characterized on the shown holder.

[0042] Experiments were conducted based on the above detection device and detection method, and the results are as follows: like Figure 4 As shown, it is the transmission spectrum of Let-7a with concentration of 0.01nM to 10nM, where Figure 4 (a) is the experimental result without adding gold nanoprobes. When the concentration of Let-7a increases from 0.01 nM to 10 nM, the corresponding Q-BIC resonance peak also moves significantly. When the sample concentration is 10 nM, the Q-BIC resonance peak position is red-shifted by about 24 GHz compared with the initial value. At the same time, it can be seen that when the concentration of Let-7a is very low, it can still cause a slight change in the refractive index, but the displacement of the Q-BIC metasurface resonance peak is very small (about 3 GHz). At this time, it is necessary to use gold nanoprobes 11 to amplify the response. Figure 4As shown in (b), by using gold nanoprobes, the frequency shift response of the Q-BIC resonance peak was significantly improved. In the same sample concentration range, the maximum frequency shift increased to 74 GHz. Notably, at this time, the metasurface sensor showed a more obvious frequency shift response to low-concentration samples, which means that the gold nanoprobes improved the sensitivity of the metasurface sensor. According to the calculation results, the gold nanoprobes increased the sensitivity of the metasurface sensor from 2.4 GHz / nM to 7.4 GHz / nM, and the biosensing performance was improved by more than 3 times. Therefore, by utilizing the high sensitivity of the metasurface sensor to refractive index changes and the signal amplification from the gold nanoprobes, the sensing of Let-7a at the nM level was achieved.

[0043] As Figure 5 shown, the detection results of Let-7a, DNA with the same sequence as Let-7a (CP DNA), and three random sequence DNAs are presented. As can be seen from Figure 5 (a), compared with non-complementary random DNA, the metasurface sensor showed a significantly larger frequency shift response to Let7a and CP DNA (both having complementary base sequences). Notably, for non-complementary sequence random DNA with a concentration as low as 0.01 nM, only a nearly negligible frequency shift could be observed. Even as the concentration increased, a smaller frequency shift response could be gradually observed, but it was always lower than the frequency shift response of Let-7a and CP DNA at the same concentration. This indicates that the detection limit of the sensor for complementary sequences is one order of magnitude higher than that for non-complementary sequences, demonstrating the specific recognition ability of the sensor for specific sequences. In addition, as Figure 5 shown in (b), when the concentration of all samples was 10 nM, the frequency shift of the resonance peak caused by CP DNA (complementary sequence) was approximately 22 GHz, which was much lower than the 74 GHz caused by Let-7a. This is due to the high binding constant between the gold nanoprobes and RNA (containing cis-diol groups) compared to its weak interaction with DNA (lacking adjacent diol moieties).

[0044] As Figure 6 shown, the detection results of human serum samples doped with different concentrations (0.01 nM to 10 nM) of Let-7a are presented. As can be observed from Figure 6 (a), the sensor could still accurately detect Let-7a at four concentrations, and a distinguishable frequency shift response was maintained even for a Let-7a concentration as low as 0.01 nM, which demonstrates the potential application of the present invention in clinical sample analysis. Then, the frequency shift amplitudes between purified samples and serum samples with different Let-7a concentrations were compared, and linear regression analysis was performed on these concentration-dependent reactions, as Figure 6 shown in (b). Visual quantitative proof (R 2=0.970) The signal attenuation induced by the matrix in the serum environment results in a 39.2% reduction in detection sensitivity compared to the pure sample control. Importantly, the linear correlation maintained between the logarithmic concentration of Let-7a and the frequency shift in the serum matrix verifies the clinical applicability of the present invention.

[0045] According to the biological detection method of the present invention, a method combining different biological modifications is adopted, which can achieve multi-functional multiplexed biomolecule detection. It can not only specifically detect Let-7a, but also support the discrimination of RNA and DNA with the same sequence. The detection limit for complementary sequences is one order of magnitude higher than that for non-complementary sequences, and the response to RNA is more than three times that of DNA.

[0046] According to the terahertz biosensing detection device and the biological detection method of the present invention, it is relatively simple compared with the prior art. The device is easy to process and can be reused, and the manufacturing cost is low.

[0047] Example 3 This embodiment provides an electronic device, which can be a mobile electronic device or a non-mobile electronic device. Exemplarily, the mobile electronic device can be a mobile phone, a tablet computer, a notebook computer, a handheld computer, an ultra-mobile personal computer (UMPC), a netbook, or a personal digital assistant (PDA), etc. The non-mobile electronic device can be a server, a Network Attached Storage (NAS), a personal computer (PC), etc. The embodiments of the present application do not make specific limitations. The electronic device includes 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 terahertz biosensing detection device. When the program or instruction is executed by the processor, it realizes each process of the above-mentioned embodiment of a biological detection method and can achieve the same technical effect. To avoid repetition, it will not be elaborated here.

[0048] The embodiment of the present application also provides a computer storage medium, wherein instructions are stored in the computer storage medium. When the instructions are executed on the computer, the computer is made to execute each process of the above-mentioned embodiment of the biological detection method based on the terahertz biosensing detection device and can achieve the same technical effect. To avoid repetition, it will not be elaborated here.

[0049] Among them, the processor is the processor in the electronic device in the above-mentioned embodiment. The readable storage medium includes computer-readable storage media, such as computer read-only memory (ROM), random access memory (RAM), magnetic disks, or optical discs, etc.

[0050] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "schematic embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example.

[0051] Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all embodiments. The mention of "embodiment" in this article means that the specific features, structures, or characteristics described in connection with the embodiment can be included in at least one embodiment of the present application. The appearance of this phrase in various positions in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment mutually exclusive with other embodiments. Those skilled in the art can explicitly and implicitly understand that the embodiments described herein can be combined with other embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present application.

[0052] Although the embodiments of the present invention have been shown and described, those of ordinary skill in the art can understand that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and purposes of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A terahertz biosensing detection device, characterized in that, For detecting biological samples, including: A transmission terahertz time-domain spectroscopy system (1) for providing a transmission terahertz optical path; A sample holder (2) disposed on the transmission terahertz optical path of the transmission terahertz time-domain spectroscopy system (1); A metasurface sensor (3) disposed on the sample holder (2), the metasurface sensor (3) including a plurality of first gold films (31) and second gold films (32) with asymmetric structures in a periodic array, and under the normal incidence of terahertz waves in the polarization direction, exciting a transmission spectrum resonance peak to characterize biological samples; Capturing DNA (4) modified on the surface of the metasurface sensor (3) for capturing biological samples; A gold nanoprobe (5) for specifically binding to a biological sample after capturing the biological sample to enhance the sensing sensitivity to the biological sample.

2. The terahertz biosensing detection device according to claim 1, wherein The transmission terahertz time-domain spectroscopy system (1) includes a terahertz lens emission end (100), a first terahertz lens (110), a second terahertz lens (120), a third terahertz lens (130), a fourth terahertz lens (140), and a terahertz detector (150) sequentially arranged along the optical path, and the sample holder (2) is disposed between the second terahertz lens (120) and the third terahertz lens (130).

3. The terahertz biosensing detection device according to claim 1, wherein The lengths of the first gold film (31) and the second gold film (32) in the Y direction on the surface of the metasurface sensor (3) are equal; the lengths of the adjacent first gold film (31) and second gold film (32) in the X direction on the surface of the metasurface sensor (3) are not equal to form an asymmetric structure.

4. The terahertz biosensing detection device according to claim 3, wherein, The first gold film (31) and the second gold film (32) have the same thickness, both being 200 nm.

5. The terahertz biosensing detection device according to claim 4, wherein The length and width dimensions of the first gold film (31) are the same, both being 62 μm to 66 μm; The length dimension of the second gold film (32) is 70 μm to 110 μm, and the width dimension is 62 μm to 66 μm.

6. The terahertz biosensing detection device according to claim 1, wherein The particle diameter of the gold nanoprobe (5) is 60 nm to 90 nm.

7. A biological detection method, characterized in that, Using the terahertz biosensing detection device according to any one of claims 1 to 6 for biological detection, including the following steps: Preparing biological sample solutions, solutions containing gold nanoprobes, and modification solutions containing thiolated single-stranded DNA and 6-mercapto-1-hexanol with different concentration gradients; Cleaning the metasurface sensor and immersing the cleaned metasurface sensor in the modification solution for modification to obtain capturing DNA; Placing the metasurface sensor with the capturing DNA in the biological sample solution for sufficient soaking and then taking it out, and immersing it in the solution containing gold nanoprobes for reaction to obtain a processed biological sample; Taking out the metasurface sensor, drying it, and placing it on the sample holder; Turning on the transmission terahertz time-domain spectroscopy system, after the incident terahertz waves are collimated and focused, passing through the processed biological sample and the metasurface sensor, being collimated and focused again, and detecting the outgoing terahertz waves by the terahertz detector to obtain the terahertz transmission spectrum of the processed biological sample, thereby obtaining the transmission spectrum resonance peak of each biological sample with different concentrations; Characterize the concentration of a biological sample based on the frequency shift of the resonance peak in the transmission spectrum of biological samples at different concentrations.

8. The biological detection method according to claim 7, characterized in that, The modification solution is a KH2PO4 solution of thiolated single-stranded DNA and 6-mercapto-1-hexanol in a 1:1 ratio.

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 described in claim 7.

10. A computer storage medium, characterized in that, Instructions are stored in the computer storage medium, and when the instructions are executed on a computer, the computer is caused to execute the biological detection method described in claim 7.

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