CN111351765A - High-resolution detection method for biological tissue based on near-field terahertz lesion - Google Patents
High-resolution detection method for biological tissue based on near-field terahertz lesion Download PDFInfo
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Abstract
The invention discloses a near-field terahertz lesion biological tissue high-resolution detection method, which comprises the following steps of: (1) selecting a near field detector: selecting a terahertz detector capable of realizing space resolution detection superior to half-wavelength detection; (2) selecting a near field mode; (3) processing a sample, namely flatly placing a cell slice of a biological tissue on a glass slide with a micro-nano structure, vacuumizing, and attaching the cell slice of the tissue to the glass slide; (4) and (3) placing the attached glass slide on an object stage of a near-field terahertz spectrometer, moving the object stage to the lower part of the needle point, adjusting the Z-axis displacement, keeping the distance between the cell slice of the biological tissue and the needle point at a micron level, and detecting according to a near-field terahertz spectrum imaging detection method to obtain the terahertz spectrum of the cell of the biological tissue and the spectrum image of the characteristic substance. The method can obtain high-resolution biological tissue imaging and characteristic spectrum, and provides a high-resolution detection technology for pathological changes of biological tissues and mechanism research thereof.
Description
Technical Field
The invention relates to the field of biological tissue spectral imaging detection, in particular to a high-resolution detection method for biological tissue based on near-field terahertz lesion.
Background
Terahertz waves (Teraherz, THz) are sensitive to moisture content, biomolecule category and structural change and are not easy to generate ionization hazard to organisms, so that the terahertz waves are very beneficial to the diagnosis and research of biomedicine, especially the detection and research of biological tissues.
Compared with the traditional technology based on chemical staining detection, such as histopathological section, immunohistochemistry and the like, the tissue lesion detection based on the terahertz spectral imaging technology does not need to carry out any staining treatment on a sample, can disclose abundant physical and chemical information about the sample from a biomolecule level, and provides an objective and accurate detection result. At present, the traditional terahertz spectral imaging technology is beginning to be applied to the detection research of biological tissues, especially pathological tissues. However, due to the limitation of the optical diffraction limit of the rayleigh criterion, the spatial resolution of the conventional terahertz imaging cannot break through the limitation of half wavelength, the imaging spatial resolution is usually in the millimeter or sub-millimeter level, and the accurate detection of a tissue sample cannot be realized, so that the application of the terahertz technology in the detection of biological tissues, particularly pathological biological tissues, is greatly limited.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide a high-resolution detection method for pathological change biological tissues based on near-field terahertz, so that the defects of low imaging resolution and low detection accuracy of pathological change biological tissues are overcome.
In order to achieve the aim, the invention provides a method for high-resolution detection of biological tissues based on near-field terahertz lesion, which comprises the following steps:
(1) selecting a near field detector: selecting a terahertz detector capable of realizing space resolution detection superior to half-wavelength detection;
(2) selecting a near field mode;
(3) processing a sample, namely flatly placing a cell slice of a biological tissue on a glass slide with a micro-nano structure, then placing the glass slide on a vacuumized negative pressure laminating device, vacuumizing for a period of time, and laminating the tissue cell slice and the glass slide;
(4) and (3) placing the attached glass slide on an object stage of a near-field terahertz spectrometer, moving the object stage to the lower part of the needle point, adjusting Z-axis displacement, ensuring that the distance between a cell slice of the biological tissue and the needle point keeps in a micron order, and then detecting according to a near-field terahertz spectrum imaging detection method to obtain the terahertz spectrum of the biological tissue cell and the spectral image of the characteristic substance.
Preferably, in the above technical solution, the terahertz detector in step (1) includes a photoconductive micro-antenna probe.
Preferably, in the above technical solution, the selecting of the near field mode in step (2) includes: the system comprises a far field terahertz source irradiation-near field probe detection transmission mode, a near field terahertz source irradiation-near field probe detection transmission mode, a far field terahertz source detection-near field probe detection reflection mode and a near field terahertz source irradiation-near field probe detection reflection mode.
Preferably, in the above technical solution, a resonance ring is arranged on the glass slide in the step (3), and the resonance ring can resonate with a probe of the terahertz detector.
Preferably, in the above technical solution, the resonance ring is made of metal, the line width of the split ring of the resonance ring is 150-.
Preferably, among the above-mentioned technical scheme, negative pressure laminating device includes the seal box body, seal box body one end is equipped with the interface of breathing in, and the other end is equipped with sealed lid, be equipped with the objective table in the seal box body for put the slide glass.
Preferably, in the above technical solution, the biological tissue in step (3) is a diseased tissue of a human or an animal.
Preferably, in the above technical solution, the diseased tissue includes lung cancer tissue, brain tumor tissue, skin cancer tissue, gastric cancer tissue, and melanoma tissue.
Preferably, in the above technical scheme, the cell section in step (3) includes an embedded section, a frozen section and a direct section.
Preferably, in the above technical solution, the preparation method of the embedded slice includes: fixing the inherent form of the histiocyte, then washing the fixed histiocyte block with water for 10-20min, then embedding the histiocyte with an embedding agent, taking out after embedding for 5-8h, placing in a slicer with the temperature of-30 to-20 ℃, placing for 30-60min, and then slicing to obtain slices with the size below hundred microns;
preferably, in the above technical solution, the method for preparing the frozen section includes: taking out the biological tissue at-90- -70 deg.C for 20-60min, placing in a slicing machine, and slicing to obtain slices with size below hundred micrometers.
Preferably, in the above technical solution, the distance between the cell section of the biological tissue and the tip of the needle in step (4) is maintained at 10 μm or less.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention is based on the near field terahertz pathological change biological tissue high-resolution detection method, selects the near field detection method, then determines the detection mode under the method, processes the biological tissue according to different modes, finally carries out the near field terahertz spectrum detection, and can obtain the point spectrum, the two-dimensional scanning imaging spectrum and the three-dimensional scanning imaging spectrum through different scanning modes. The method can obtain high-resolution biological tissue imaging and characteristic spectrum, and provides a high-resolution brand-new detection technology for pathological changes of biological tissues and mechanism research thereof.
(2) The method of the invention can break through the optical diffraction limit, enables the spatial resolution to be better than half wavelength and reach several micrometers, and provides a new detection means for pathological change detection, boundary division and mechanism research of biological tissues.
Drawings
FIGS. 1- (a) to 1- (b) are schematic diagrams of ordinary and near-field terahertz microscope resolutions;
fig. 1- (a) is a schematic diagram of the principle that the conventional terahertz imaging technology has different spatial resolution capabilities in lesion tissue detection;
FIG. 1- (b) is a schematic diagram illustrating the principle of different spatial resolution capability of the near-field terahertz imaging technology in lesion tissue detection according to the present invention;
FIGS. 2- (a) to 2- (d) are schematic structural diagrams of a near-field terahertz biological detection mode according to the invention;
FIG. 2- (a) is a perspective view showing a structure of radiation from a far-field terahertz source and detection by a near-field probe;
FIG. 2- (b) is a perspective view showing the structure of the radiation of the near-field terahertz source and the detection of the near-field probe;
FIG. 2- (c) is a schematic diagram of a structure of a reflection type far-field terahertz source radiation and a near-field probe detection;
FIG. 2- (d) is a schematic structural diagram of a reflection type, near-field terahertz source radiation and near-field probe detection;
FIG. 3 is a schematic structural diagram of a slide with micro-nano structure according to the invention;
FIG. 4 is a schematic structural view of a negative pressure applying apparatus according to the present invention;
fig. 5 is a front view of a negative pressure applying apparatus according to the present invention.
Detailed Description
The following detailed description of the present invention is provided in conjunction with the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
As shown in fig. 1- (a) to 5, a method for high-resolution detection of biological tissue based on near-field terahertz lesion according to an embodiment of the present invention includes the following steps:
(1) selecting a near field detector: selecting a terahertz detector which can realize space resolution detection better than half wavelength, such as a photoconductive micro-antenna probe;
(2) selecting a near field mode; the near field mode selection includes: the system comprises a far field terahertz source irradiation-near field probe detection transmission mode, a near field terahertz source irradiation-near field probe detection transmission mode, a far field terahertz source detection-near field probe detection reflection mode and a near field terahertz source irradiation-near field probe detection reflection mode.
The terahertz source comprises any radiation source capable of emitting terahertz waves, such as a photoconductive antenna, a quantum cascade laser, a solid-state source and the like.
As shown in fig. 2- (a), far-field terahertz source irradiation-near-field probe detects the transmission mode: a terahertz wave is radiated by a far-field terahertz source 1 to transmit a sample 2, the sample 2 is placed on a glass slide 3, and a near-field probe 4 is used for detecting signals.
As shown in fig. 2- (b), the near-field terahertz source irradiation-near-field probe detects the transmission mode: a terahertz wave is radiated by a near-field terahertz source to transmit a sample 2, the sample 2 is placed on a glass slide 3, and a signal is detected by a near-field probe 4.
Far field terahertz source detection-near field probe detection reflection (scattering) mode: a far-field terahertz source radiates terahertz waves to irradiate a sample 2 from the side, the sample 2 is placed on a glass slide 3, and then a near-field probe 4 detects signals. Fig. 2- (c) is only for illustrative purposes, and the incident terahertz wave and the probe angle are not limited to those shown in the figures, and the terahertz wave and the probe can be coupled by the position angle relationship.
Irradiation of a near-field terahertz source-detection of a reflection mode by a near-field probe: a terahertz wave is radiated by a near-field terahertz source to irradiate a sample 2 from the side, the sample 2 is placed on a glass slide 3, and a signal is detected by a near-field probe 4. Fig. 4- (d) is only for illustrative purposes, and the incident terahertz wave and the probe angle are not limited to those shown in the figures, and the terahertz wave and the probe can be coupled by the position angle relationship.
(3) Sample treatment: the selected sample is a biological tissue, and the biological tissue is a tissue which is diseased in a human or an animal. The pathological tissue includes lung cancer tissue, brain tumor tissue, skin cancer tissue, gastric cancer tissue, melanoma tissue, etc. Flatly placing the cell section of the biological tissue on a glass slide with a micro-nano structure, then placing the glass slide in a vacuumized negative pressure laminating device, vacuumizing to 30KPa, keeping for 10 minutes, and tightly laminating the tissue cell section and the glass slide. The slice is closely attached to a glass slide (which can be provided with a micro-nano structure to enhance terahertz signals), plasma resonance is better realized, and terahertz characteristic signals of biological tissues are enhanced to provide support for final near-field terahertz spectral imaging detection.
(4) Near field detection: and (3) placing the attached glass slide on an object stage of the near-field terahertz spectrometer, moving the object stage to the lower part of the needle tip, setting a X, Y plane scanning step, automatically and dynamically adjusting the distance between the needle tip and the sample, namely adjusting the Z-axis displacement of the needle tip, and keeping the distance between the cell section of the biological tissue and the needle tip below 10 mu m. Under the condition of ensuring the safety of the probe, the probe is as close to a sample to be detected as possible, and terahertz spectrum scanning is carried out. After scanning, imaging is carried out according to the characteristic spectrum of the biological tissue, the image not only has terahertz spectrum information of the biological tissue substance structure, but also can carry out high-precision distinguishing and boundary identification on different substances.
When the near field detection is carried out, the scanning step pitch of the plane of the terahertz spectrograph X, Y is set, and terahertz scanning spectral imaging is carried out. Further, X, Y plane scanning step distance and a Z axis are set simultaneously to carry out scanning imaging up and down, and terahertz three-dimensional scanning imaging can be obtained.
As shown in fig. 1, a resolution diagram of a common and near-field terahertz microscope is shown. In the diagram of FIG. 1- (a) the box 5 represents the biological tissue, the oval portion 6 represents the tissue that has been diseased and the circle 7 portion represents the resolution of the different microscopes. The left side shows that the ordinary terahertz microscope can not break through diffraction limit, the resolution ratio is low, the light spot is large, the boundary of the pathological change tissue is difficult to accurately find out due to the fact that the pathological change tissue and the normal tissue cannot be well distinguished, the resolution ratio of the near-field terahertz microscope on the right side is high, the resolution ratio of the near-field terahertz microscope on the right side can reach several micrometers, the light spot is small, the pathological change tissue and the normal tissue can be well distinguished when scanning imaging is carried out, and the boundary of the pathological change tissue is accurately found out.
Preferably, as shown in fig. 3, the micro-nano structure on the glass slide 3 is a resonance ring 31, and the resonance ring 31 can resonate with the probe 4 of the terahertz detector, so that the terahertz characteristic signal of the biological tissue is enhanced, and the signal-to-noise ratio is increased.
Preferably, the resonant ring 31 is manufactured by micro-nano processing means such as etching, sputtering and the like. Preferably, the resonant ring is made of metal materials such as gold and silver, the line width of the split ring of the resonant ring 31 is 150-. The structure of the resonance ring 31 in this embodiment, such as a square or a circle, may also be any geometric structure that can cause terahertz resonance.
Preferably, as shown in fig. 4 and 5, the negative pressure attaching device 8 includes a sealed box 81, one end of the sealed box 81 is provided with an air suction port 82, the air suction port 82 is externally connected with an air compressor, the sealed box is vacuumized by the air compressor, and the vacuum pressure is-30 KPa. The other end of the sealing box body is provided with a sealing cover 83, and a sealing rubber ring 84 is arranged in the sealing cover 83, so that the sealing performance of the sealing box body 81 is improved. The sealed box 81 has a stage 85 disposed therein for holding a slide glass house on the stage 85. Inside the sealed box 81, there are provided a plurality of stages 85, in this embodiment 3 stages.
Preferably, the cell section in step (3) includes an embedded section, a frozen section and a direct section.
The preparation method of the embedded section comprises the following steps: the diluted paraformaldehyde solution is used for fixation, and other methods can be used for fixation, so that the inherent shape of tissue cells is maintained, and the tissue autolysis, decay and the like are avoided. Washing with deionized water, and washing the fixed tissue cell blocks with deionized water for 10-20 min. Embedding, wherein tissue cells are embedded by OCT embedding medium, or embedding by substances including paraffin and the like, taking out after embedding for 5-8h, and cutting off redundant embedding medium around the tissue by a blade. And (3) slicing, namely fixing the embedded body in a slicer, setting the temperature of the slicer to be-30-20 ℃, standing for 30-60min, and then slicing to obtain slices with the size of hundreds of microns and below.
The preparation method of the frozen section comprises the following steps: taking out the biological tissue at-90- -70 deg.C for 20-60min, placing in a slicing machine, and slicing to obtain slices with size below hundred micrometers. (follow-up was completed within 5 minutes after slicing).
The preparation method of the direct slice comprises the following steps: the biological tissue is directly sliced without any treatment. The slicing ensures that the slices have even thickness and smooth surface as much as possible.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (10)
1. A method for high-resolution detection of biological tissues based on near-field terahertz lesion is characterized by comprising the following steps:
(1) selecting a near field detector: selecting a terahertz detector capable of realizing space resolution detection superior to half-wavelength detection;
(2) selecting a near field mode;
(3) processing a sample, namely flatly placing a cell slice of a biological tissue on a glass slide with a micro-nano structure, then placing the glass slide on a vacuumized negative pressure laminating device, vacuumizing for a period of time, and laminating the tissue cell slice and the glass slide;
(4) and (3) placing the attached glass slide on an object stage of a near-field terahertz spectrometer, moving the object stage to the lower part of the needle point, adjusting the Z-axis displacement, keeping the distance between the cell slice of the biological tissue and the needle point at a micron level, and detecting according to a near-field terahertz spectrum imaging detection method to obtain the terahertz spectrum of the cell of the biological tissue and the spectrum image of the characteristic substance.
2. The method for high-resolution detection of biological tissues based on near-field terahertz lesion in claim 1, wherein the terahertz detector in step (1) comprises a photoconductive micro-antenna probe.
3. The method for high-resolution detection of biological tissue based on near-field terahertz lesion in claim 1, wherein the near-field mode selection in the step (2) comprises: the system comprises a far field terahertz source irradiation-near field probe detection transmission mode, a near field terahertz source irradiation-near field probe detection transmission mode, a far field terahertz source detection-near field probe detection reflection mode and a near field terahertz source irradiation-near field probe detection reflection mode.
4. The method for high-resolution detection of biological tissues based on near-field terahertz pathological changes according to claim 1, wherein a resonance ring is arranged on the glass slide in the step (3), and the resonance ring can resonate with a probe of the terahertz detector.
5. The method as claimed in claim 4, wherein the resonance ring is made of metal, the width of the open ring line of the resonance ring is 150-250 μm, the height is 120-170nm, and the opening gap is 4-8 μm.
6. The method for high-resolution detection of biological tissues based on near-field terahertz lesion according to claim 1, wherein the negative pressure attaching device comprises a sealed box body, one end of the sealed box body is provided with a suction port, the other end of the sealed box body is provided with a sealing cover, and a stage for placing a glass slide is arranged in the sealed box body.
7. The method for high-resolution detection of biological tissue based on near-field terahertz lesion in claim 1, wherein the biological tissue in step (3) is a tissue diseased in a human or an animal.
8. The method for high-resolution detection of biological tissues based on the near-field terahertz lesion in accordance with claim 7, wherein the lesion tissues comprise lung cancer tissues, brain tumor tissues, skin cancer tissues, stomach cancer tissues and melanoma tissues.
9. The method for high-resolution detection of biological tissues based on near-field terahertz lesion in claim 1, wherein the cell section in the step (3) comprises an embedded section, a frozen section and a direct section;
the preparation method of the embedded section comprises the following steps: fixing the inherent form of the histiocyte, then washing the fixed histiocyte block with water for 10-20min, then embedding the histiocyte with an embedding agent, taking out after embedding for 5-8h, placing in a slicer with the temperature of-30 to-20 ℃, placing for 30-60min, and then slicing to obtain slices with the size below hundred microns;
the preparation method of the frozen section comprises the following steps: taking out the biological tissue at-90- -70 deg.C for 20-60min, placing in a slicing machine, and slicing to obtain slices with size below hundred micrometers.
10. The method for high-resolution detection of biological tissues based on near-field terahertz lesion in claim 1, wherein in the step (4), the distance between the cell section of the biological tissues and the needle tip is kept at 10 μm or less.
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