Raman deep penetration imaging system based on safe laser irradiation dose

Abstract

The application discloses a Raman deep penetration imaging system based on a safe laser irradiation dose, which comprises a light source, a light spot amplifier, a sample table, a Raman optical fiber probe, a data processing module and a surface enhanced Raman spectrum probe contrast agent, the Raman optical fiber probe and the light spot amplifier are located on the two sides of the sample table, the Raman optical fiber probe is located on the side of the sample to be measured, the Raman optical fiber probe vertically faces the sample table, the Raman optical fiber probe is electrically connected with the data processing module, the outlet of the light source faces the light spot amplifier, the light spot amplifier is configured to expand the light spot emitted by the light source, the light spot output by the light spot amplifier vertically faces the sample table, and the surface enhanced Raman spectrum probe contrast agent comprises a surface enhanced Raman probe. Through the combination of the surface enhanced Raman spectrum probe contrast agent and the transmission type Raman detection device, accurate positioning and stable imaging of a tumor site are realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedical technology, and particularly relates to a Raman deep penetration imaging system based on a safe laser irradiation dose. BACKGROUND

[0002] Cancer seriously threatens the health and life safety of animals, and is one of the diseases with a higher mortality rate. At present, surgical resection is still one of the most effective methods for treating cancer. However, tumor tissues grow in an infiltrative manner, and have no obvious boundary with the surrounding normal tissues. If a doctor performs resection on the tumor tissues by relying on naked eyes, less resection may cause recurrence of cancer in the patient, and more resection may cause harm to the patient. Therefore, convenient and accurate positioning of tumors has always been the focus of clinical doctors and researchers, and is crucial for clinical cancer diagnosis and treatment. Optical detection methods have advantages such as real-time, high sensitivity, non-ionizing radiation, and convenient acquisition, and can further provide accurate information of biological structures, functions and molecules in combination with exogenous contrast agents, and are excellent tools for in vivo tumor diagnosis. In recent years, with the development of nanoscience and technology, nanomaterials for cancer imaging and treatment have also attracted widespread attention. Nanomaterials have small particle sizes, can easily pass through cell barriers, and due to the high permeability and retention effect caused by increased microvascular permeability of tumor tissues and an imperfect lymphatic drainage system, they can preferentially accumulate in tumor sites, thereby achieving accurate positioning of tumors.

[0003] Surface-enhanced Raman spectroscopy (SERS) refers to a great enhancement effect of Raman scattering of molecules adsorbed on the surface of metal nanostructures due to excitation of surface plasmons and surface chemical effects, and can realize single-molecule and single-particle detection, and has very high sensitivity. By adsorbing Raman molecules on the surface of rough noble metal particles, a surface-enhanced Raman spectroscopy probe with good specificity and high sensitivity can be prepared. Biological imaging based on the surface-enhanced Raman spectroscopy probe is not prone to photobleaching, is not disturbed by spontaneous fluorescence of biological tissues, and has simple sample preparation. In addition, its unique fingerprint spectrum has ultra-high specificity, the ultra-narrow half-peak width is conducive to multi-index detection of optical coding, and the optical stability is strong. Based on the above outstanding advantages, the surface-enhanced Raman probe has a very broad application prospect in the field of biomedicine.

[0004] However, the development of tumor Raman optical detection technology faces two important bottlenecks: laser safety and detection depth. First, due to the low sensitivity of existing Raman probe nanoparticles, a higher power laser is often used for excitation. In order to focus, the laser used at present is mainly Gaussian beam, which has a small spot, usually only microns, so that the power density far exceeds the clinical laser safety standard, that is, the maximum permissible exposure (MPE). The current standard is mainly implemented according to the laser product safety standards formulated by the American National Standards Institute (ANSI) and the People's Republic of China. Because the absorption capacity of biological tissues to light of different wavelengths is different, the MPE corresponding to different wavelengths is different, for example, the MPE threshold corresponding to 785nm wavelength is about 0.29W / cm 2 ; the threshold corresponding to 1064nm wavelength is about 1W / cm 2 . Generally, the way to solve laser safety is to reduce power, but this way makes the Raman signal intensity excited weak, which is not conducive to detection. Expanding the spot can reduce the power density, but for the backscattering Raman detection method widely used at present, the possible side effect is that the Raman signal intensity will be significantly reduced with the expansion of the spot, so it is difficult to apply to high-sensitivity detection applications.

[0005] Secondly, due to the strong scattering and absorption of photons by biological tissues, the tissue penetration depth of optical detection is low, for example, the backscattering Raman detection technology widely used at present can usually only detect Raman probe nanoparticles in tissues with a thickness of several millimeters, and cannot realize the detection of deep (such as 1cm deep in tissues) tumor lesions. In summary, the traditional backscattering Raman detection device is difficult to realize deep lesion imaging under the condition of safe laser irradiation dose standard, which seriously hinders the use of Raman optical detection technology in clinical practice.

[0006] Therefore, those skilled in the art are committed to providing a Raman imaging system that can perform deep detection under the condition of safe laser irradiation dose, providing more choices for clinical tumor detection and providing a new detection method for precision medicine. SUMMARY

[0007] In view of the defects in the prior art, the technical problem to be solved by the present application is how to provide an imaging system that can accurately position deep tumor sites under the condition of ensuring clinical laser safety.

[0008] In order to achieve the above-mentioned purpose, the application provides a Raman deep penetration imaging system based on safe laser irradiation dose, which comprises a light source, a light spot amplifier, a sample table, a Raman optical fiber probe, a data processing module and a surface enhanced Raman spectrum probe contrast agent, the sample table is used for placing a sample to be measured, the Raman optical fiber probe and the light spot amplifier are located on both sides of the sample table, the Raman optical fiber probe is located on the side of the sample to be measured, the Raman optical fiber probe is vertically oriented towards the sample table, the Raman optical fiber probe is electrically connected with the data processing module, the outlet of the light source is oriented towards the light spot amplifier, the light spot amplifier is configured to expand the light spot emitted by the light source, the light spot output by the light spot amplifier is vertically oriented towards the sample table, and the surface enhanced Raman spectrum probe contrast agent comprises a surface enhanced Raman probe and is configured to be injected into the sample to be measured.

[0009] Further, the light spot amplifier comprises an expander mirror, a collimator mirror and a reflecting mirror, and the light spot emitted by the light source sequentially passes through the expander mirror, the collimator mirror and the reflecting mirror and is transmitted to the sample table.

[0010] Further, the distance between the light source, the expander mirror and the collimator mirror is adjustable.

[0011] Preferably, the expander mirror comprises an input flat-concave lens, an output convex lens and a cage system connecting the two lenses, and the distance between the flat-concave lens and the convex lens is adjustable.

[0012] Further, the diameter of the light spot transmitted to the sample table is greater than 0.8 cm.

[0013] Preferably, the light source is one of a parallel light source, a Gauss light source and a point light source.

[0014] Further, the Raman optical fiber probe comprises an optical fiber bundle composed of a plurality of optical fibers, and the diameter of the Raman optical fiber probe is less than or equal to 3 mm.

[0015] Further, the surface enhanced Raman probe comprises a gold nanoparticle core, a Raman reporter molecule intermediate layer, a silver shell and a protective layer wrapped on the nanoparticle.

[0016] Further, the diameter of the surface enhanced Raman spectrum probe is 20-200 nm.

[0017] Preferably, the sample table adopts a light-transmitting material or a non-light-transmitting material with a hollow structure.

[0018] Further, the data processing module comprises a spectrometer, a charge-coupled device and a computer system.

[0019] The application has at least the following beneficial technical effects:

[0020] 1. The Raman deep penetration imaging system based on safe laser irradiation dose provided by the application reduces the power density of the laser through the light spot amplification device, and ultimately reaches the standard of clinical laser safety dose. Since the standard of clinical laser safety dose corresponding to different wavelengths is different, the application can adjust the power density by adjusting the distance between the beam expander, the collimator and the laser light source, or adjusting the distance between the plano-concave lens and the convex lens in the beam expander assembly, so as to adjust the light spot size irradiated onto the sample.

[0021] 2. The Raman deep penetration imaging system based on safe laser irradiation dose provided by the application collects deep layer Raman photons by adopting the transmission type Raman detection device technology, realizes the deep penetration detection mode, combines the high-sensitivity surface enhanced Raman spectrum probe contrast agent, realizes the Raman optical detection of deep layer tumors, and effectively avoids the problem of signal drop when the light spot is enlarged in the traditional backscattering detection technology. The application adopts an extremely thin Raman optical fiber probe to collect and scan the transmission Raman signal, so as to improve the resolution of imaging. The device of the application is simple, low in cost, strong in imaging signal, fast in speed, high in sensitivity, good in stability, not easy to cause light bleaching, and the like, and can realize accurate positioning and stable imaging of tumor parts.

[0022] The concept, specific structure and generated technical effects of the application will be further described below with reference to the drawings, so as to fully understand the purpose, features and effects of the application. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is a structural schematic diagram of the Raman deep penetration imaging system based on safe laser irradiation dose of the application;

[0024] Figure 2 is a structural schematic diagram of the core-shell structure surface enhanced Raman probe of the application;

[0025] Figure 3 is a transmission electron microscope characterization diagram of the core-shell structure surface enhanced Raman probe of the application;

[0026] Figure 4 is a Raman spectrum diagram of the core-shell structure surface enhanced Raman probe of the application;

[0027] Figure 5 is a result diagram of the imaging system of the application for imaging the surface enhanced Raman probe injected into a living mouse.

[0028] In the figure, 1 is a light source, 2 is a beam expander, 3 is a collimator, 4 is a reflector, 5 is a sample stage, 6 is a sample to be measured, 7 is a Raman probe nanoparticle, 8 is a Raman optical fiber probe, and 9 is a data processing module. DETAILED DESCRIPTION

[0029] The preferred embodiments of the present invention are described below to make the technical content clearer and easier to understand. The present invention can be embodied in many different forms, and the scope of protection of the present invention is not limited to the embodiments mentioned herein.

[0030] In the accompanying drawings, components with the same structure are indicated by the same numerical designation, and components with similar structures or functions are indicated by similar numerical designations. The dimensions and thicknesses of each component shown in the drawings are arbitrary, and the present invention does not limit the dimensions and thicknesses of each component. To make the illustrations clearer, the thickness of some components has been appropriately exaggerated in the drawings.

[0031] This invention provides a Raman deep-penetration imaging system based on a safe laser irradiation dose, such as... Figure 1 As shown, the imaging system of this embodiment includes a light source 1, a spot amplifier, a sample stage 5, a Raman fiber optic probe 8, a data processing module 9, and a Raman spectroscopy probe contrast agent. The sample stage 5 is used to place the sample 6 to be tested. Normally, the sample stage 5 is placed horizontally, with the sample 6 located on the upper side of the sample stage 5. The spot amplifier and the Raman fiber optic probe 8 are located on opposite sides of the sample stage 5. The Raman fiber optic probe 8 is located on the upper side of the sample stage 5 and faces it vertically; the spot amplifier is located on the lower side of the sample stage 5. The Raman fiber optic probe 8 is electrically connected to the data processing module 9, and the data collected by the Raman fiber optic probe 8 is input to the data processing module 9 for processing. The light spot output from the light source 1 is amplified by the spot amplifier and then transmitted to the lower surface of the sample stage 5. The surface-enhanced Raman spectroscopy probe contrast agent contains Raman probe nanoparticles 7. Before imaging, the contrast agent is injected into the sample 6 to ensure that the test area of ​​the sample 6 contains the Raman probe nanoparticles 7.

[0032] In the imaging system configured as described above, the light source 1 emits a laser, which is amplified by the spot amplifier and then vertically illuminates the sample 6 to be tested on the sample stage 5. The Raman photons of the Raman probe nanoparticles 7 are excited under the laser irradiation. The Raman fiber probe 8 collects the Raman signal passing through the sample 6 to be tested, and then transmits the signal to the data processing module 9 for processing.

[0033] The Raman fiber optic probe 8 includes a fiber bundle consisting of multiple collecting fibers, which is used to achieve electrical connection with the data processing module 9. In this embodiment, the Raman fiber optic probe 8 has a diameter of no more than 3 mm, making it an extremely fine Raman probe.

[0034] like Figure 2As shown, the surface-enhanced Raman probe of the embodiment includes a gold nanoparticle core, a Raman reporter molecule intermediate layer, a silver shell, and a protective layer wrapped around the nanoparticle. After the surface protective layer is coated, a targeting molecule antibody can be further coupled as an immunoreaction detection or imaging probe. When the core-shell surface-enhanced Raman probe is applied to biological imaging, it has the advantages of strong signal and good repeatability, and can realize high-sensitivity and quantifiable target detection.

[0035] The Raman reporter molecule is an organic fluorescent dye molecule with an absorption peak wavelength close to the laser wavelength, and the protective layer includes at least one of silicon dioxide, polyethylene glycol, and polylactic acid. The size of the core-shell surface-enhanced Raman spectrum probe formed in this way is 20-200 nm, and the transmission electron microscope characterization graph and Raman spectrum graph of the core-shell structure surface-enhanced Raman probe are as shown in Figure 3 and Figure 4

[0036] As shown in Figure 1 , the spot amplifier includes an expansion lens 2, a collimating lens 3, and a reflecting mirror 4 arranged in sequence. The light beam emitted by the light source 1 is enlarged after passing through the expansion lens 2, becomes parallel light after passing through the collimating lens 3, and then irradiates the surface of the reflecting mirror 4. After being reflected by the reflecting mirror 4, it is vertically irradiated to the lower surface of the sample stage 5. After being enlarged by the spot amplifier, the diameter of the laser spot irradiated to the lower surface of the sample stage 5 reaches 0.8 cm or more. Moreover, the diameter of the enlarged laser spot can be adjusted by adjusting the distance between the expansion lens 2, the collimating lens 3, and the light source 1, or adjusting the distance between the plano-concave lens and the convex lens in the expansion lens assembly, thereby realizing the amplification of the spot without changing the power of the light source 1.

[0037] The light source 1 is a laser light source, which can be one of a parallel light source, a Gaussian light source, or a point light source. According to the absorption characteristics of different wavelengths of light by biological tissues, the light spots emitted by the light source 1 of different wavelengths are amplified by the spot amplifier with a corresponding spacing, so as to adjust the power density, and obtain a spot that meets the clinical laser safety standard. For example, when excited at a wavelength of 785 nm, the power density can be adjusted to be lower than 0.29 W / cm 2 ; when excited by a 1064 nm wavelength laser, the power density can be adjusted to be lower than 1 W / cm 2 , so as to meet the laser safety dose standard under different wavelengths.

[0038] The sample stage 5 can be made of a light-transmitting material, and the light absorption rate of the light-transmitting material should be less than 0.01. The sample stage 5 can also be made of a non-light-transmitting material. When the sample stage 5 is made of a non-light-transmitting material, the sample stage 5 is a hollow table, and a square hole with a size of at least 1.5*1.5 cm is formed in the middle of the table, so that the light beam reflected by the reflecting mirror 4 can pass through the sample stage 5 and irradiate the sample to be measured 6. The sample stage 5 can be moved manually or electrically to facilitate operation. ​

[0039] The data processing module 9 comprises a spectrometer, a charge-coupled element and a computer system, the computer system comprising a software system and a hardware system, and the Raman signal collected by the Raman fiber probe 8 is transmitted to the spectrometer and the charge-coupled element through the optical fiber, and then transmitted to the software system of the computer system for data processing. The spectrometer, the charge-coupled element and the computer system used by the data processing module 9 are all conventional technologies, and will not be described in detail here.

[0040] The Raman deep penetration imaging system based on the safe laser irradiation dose of the application can be used for small animal imaging, and the steps are as follows: first, the surface-enhanced Raman probe is injected into the body of the sample 6 together with the contrast agent, and a period of time is waited for the enrichment of the surface-enhanced Raman probe to a specific area; then, the sample 6 is placed on the sample table 5; finally, the transmission detection device is used to detect and image the sample 6, specifically, the surface-enhanced Raman probe at the lesion is excited after the laser spot is enlarged, and the signal of the surface-enhanced Raman probe is collected by the fiber probe on the other side and scanned to form an image.

[0041] The imaging system of the application adopts the transmission Raman detection device technology to collect deep Raman photons, realizes the deep penetration detection mode, combines the high-sensitivity surface-enhanced Raman spectrum probe contrast agent, realizes the Raman optical detection of the deep tumor, and effectively avoids the problem of signal drop when the light spot is enlarged in the traditional backscattering detection technology. The extremely thin Raman fiber probe is used to collect and scan the transmission Raman signal, so as to improve the resolution of the image.

[0042] The application further discloses the following specific embodiments.

[0043] Embodiment 1

[0044] Step one: 5mL of the surface-enhanced Raman probe with a core-shell structure containing an IR-780 Raman signal molecule is prepared, centrifuged, and redispersed in 5mL of a 0.004mol / L cetyl ammonium chloride solution, 0.1mol / L NaOH solution is added to adjust the pH value of the solution to 10-11; the temperature of the solution is kept at 30℃, then 50μL of a 5% tetraethyl orthosilicate methanol solution is added three times, the time interval is 30 minutes each time, and the stirring reaction is continued for 15h to obtain nanoparticles coated with a 10nm mesoporous silica layer; the nanoparticles are centrifuged and washed, and then uniformly dispersed in a PBS (10mmol / L) buffer solution with a pH value of 7.4.

[0045] Step two: the surface-enhanced Raman probe nanoparticles obtained in the above step are uniformly dispersed in normal saline to prepare a 1nmol / L surface-enhanced Raman probe contrast agent; 200μL of the 1nmol / L surface-enhanced Raman probe contrast agent dispersed by ultrasonic dispersion is injected into the body of a normal mouse through the tail vein.

[0046] Step three: 24 hours after injection, the sample to be tested was placed on the stage of the imaging device described above, and the mouse abdomen was subjected to Raman detection. A parallel light beam with a wavelength of 785 nm was used, and the distance between the plano-concave lens and the convex lens in the beam expander assembly was adjusted to expand the light spot, obtaining a large light spot with a diameter of 1 cm and a power density of 0.2 W / cm 2 . The mouse was laid on the detection platform in an anesthetized state, and the expanded light spot was irradiated from bottom to top on the back. The Raman fiber probe was used to detect the characteristic Raman signal on the upper side of the abdomen, and the probe was moved step by step for scanning.

[0047] Step four: analysis of the detection and imaging results.

[0048] The experimental results are shown in Figure 5 . The intensity of the Raman characteristic peak (1203 cm -1 ) of the Raman signal molecule IR-780 in the surface-enhanced Raman probe was used to reconstruct a two-dimensional heat map, which can achieve non-invasive positioning of the distribution of the surface-enhanced Raman probe in the mouse body. The imaging is stable, not prone to photobleaching, and can be repeatedly imaged. The use of this surface-enhanced Raman probe for biomedical imaging improves the imaging depth and can achieve non-invasive detection and imaging.

[0049] Example 2

[0050] Step one: 5 mL of the surface-enhanced Raman probe with a core-shell structure containing a p-dimercapto benzene Raman signal molecule was obtained, centrifuged, and redispersed in 5 mL of a 0.004 mol / L cetyl ammonium chloride solution. A 0.1 mol / L NaOH solution was added to adjust the pH of the solution to 10-11. The solution temperature was maintained at 30°C, and then 60 μL of a 5% tetraethyl orthosilicate methanol solution was added three times at an interval of 30 minutes each time. The stirring reaction was continued for 15 h, 50 μL of aminopropyl triethoxysilane was added, and the reaction was continued for 12 h to obtain gold nanoparticles coated with a 12 nm mesoporous silica layer and having amino groups on the surface. The nanoparticles were centrifuged, washed, and dispersed in a MEST (10 mM, pH = 10) buffer solution. 10 mg of polylactic acid and 3 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) were added to modify the carboxyl groups on the particle surface, and the surface was further coupled with folic acid molecules in a similar EDC-NHS activation manner. Finally, the nanoparticles were uniformly dispersed in a PBS (10 mmol / L) buffer solution with a pH of 7.4.

[0051] Step two: Constructing the mouse orthotopic lung cancer model. The surface enhanced Raman probe obtained above is uniformly dispersed in normal saline to prepare a 100 pmol / L surface enhanced Raman probe contrast agent; 50 μL of the 100 pmol / L surface enhanced Raman probe contrast agent dispersed by ultrasound is injected into the tail vein of the mouse.

[0052] Step three: After 24 hours of injection, the mouse chest is subjected to Raman detection by using the imaging device described above. A 1064 nm wavelength Gaussian beam light source is used, and the light spot is expanded by adjusting the distance between the light source and the beam expander. After the laser light spot is expanded, a 0.8 cm diameter circular light spot is formed, and the power density is 1 W / cm 2 . The mouse is placed on the sample table in an anesthetized state, and the expanded light spot is irradiated on the back of the mouse from bottom to top. The Raman fiber probe is used to detect the characteristic Raman signal on the chest of the mouse, and the probe is moved step by step for scanning.

[0053] Step four: Analyzing the detection and imaging results. The intensity of the p-dimercaptobenzene signal molecule in the surface enhanced Raman probe is extracted according to the Raman characteristic peak (1560 cm -1 ), and an image is drawn to realize the non-invasive positioning of the distribution of the surface enhanced Raman probe in the mouse body.

[0054] Example 3

[0055] Step one: A surface enhanced Raman probe with a core-shell structure containing a p-nitrothiophenol Raman signal molecule is prepared, 5 mL of 0.6 nmol / L, centrifuged and redispersed in 5 mL of 0.004 mol / L cetyl ammonium chloride solution, 30 uL of 0.1 mol / L NaOH solution is added to adjust the pH value of the solution to 10-11; the temperature of the solution is kept at 30°C, then 50 μL of 5% tetraethyl orthosilicate methanol solution is added three times, each time with an interval of 30 minutes, and the stirring reaction is continued for 15 h, 50 μL of aminopropyltriethoxysilane is added, and the reaction is continued for 12 h to obtain gold nanoparticles coated with a 10 nm mesoporous silica layer and having amino groups on the surface; centrifugation and washing are performed, and the particles are dispersed in MEST (10 mM, pH = 10) buffer, 10 mg of polylactic acid and 3 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) are added to modify the carboxyl groups on the particle surface, and the surface is further coupled with folic acid molecules in a similar EDC-NHS activation manner. Finally, the nanoparticles are uniformly dispersed in a PBS (10 mmol / L) buffer with pH = 7.4.

[0056] Step two: Constructing the mouse orthotopic brain tumor model. The above obtained surface enhanced Raman probe is uniformly dispersed in physiological saline to prepare a 100 pmol / L surface enhanced Raman probe contrast agent; 50 μL of the ultrasonically dispersed 100 pmol / L surface enhanced Raman probe contrast agent is injected into the tail vein of the mouse.

[0057] Step three: After 24 hours of injection, the mouse brain is subjected to Raman detection using the above imaging device. A point light source laser with a wavelength of 830 nm is used, the distance between the light source and the beam expander is adjusted to expand the light spot, a circular light spot with a diameter of 1 cm is formed, and the power density is 0.30 W / cm 2 . The mouse is laid on the sample stage in an anesthetized state, and the expanded light spot is irradiated from bottom to top on the back. The Raman fiber probe is used to detect the characteristic Raman signal on the contralateral side of the mouse head, and the probe is moved step by step for scanning.

[0058] Step four: Analyzing the detection and imaging results. The intensity of the p-nitrothiophenol signal molecule in the surface enhanced Raman probe is extracted according to the Raman characteristic peak (1340 cm -1 ), and an image is drawn to realize the noninvasive positioning of the distribution of the surface enhanced Raman probe in the mouse body.

[0059] The above detailed the preferred embodiments of the present application. It should be understood that those of ordinary skill in the art can make many modifications and variations to the present application without creative labor based on the concept of the present application. Therefore, any modification and variation obtained by logical analysis, reasoning or limited experiment based on the concept of the present application and the prior art in the technical field can be obtained.

Claims

1. A Raman deep-penetrating imaging system based on a safe laser irradiation dose, characterized in that, The application relates to a surface-enhanced Raman spectroscopy probe contrast agent, which comprises a light source, a light spot amplifier, a sample table, a Raman fiber probe, a data processing module and the surface-enhanced Raman spectroscopy probe contrast agent, the sample table is used for placing a sample to be measured, the Raman fiber probe and the light spot amplifier are located on two sides of the sample table, the Raman fiber probe is located on the side of the sample to be measured, the Raman fiber probe vertically faces the sample table, the Raman fiber probe is electrically connected with the data processing module, the outlet of the light source faces the light spot amplifier, the light spot amplifier is configured to expand the light spot emitted by the light source, the light spot output by the light spot amplifier vertically faces the sample table, the diameter of the light spot transmitted to the sample table is greater than 0.8 cm, the light spot amplifier comprises a beam expander, a collimator and a reflector, the light spot emitted by the light source sequentially passes through the beam expander, the collimator and the reflector and is transmitted to the sample table, the surface-enhanced Raman spectroscopy probe contrast agent comprises a surface-enhanced Raman probe, the surface-enhanced Raman spectroscopy probe contrast agent is configured to be injected into the sample to be measured, the surface-enhanced Raman probe comprises a gold nanoparticle core, a Raman reporter molecule intermediate layer, a silver shell and a protective layer wrapped on the nanoparticle, the Raman fiber probe comprises a fiber bundle composed of a plurality of optical fibers, and the diameter of the Raman fiber probe is less than or equal to 3 mm.

2. The Raman deep-penetrating imaging system based on a safe laser exposure dose according to claim 1, wherein, The distance between the light source, the beam expander and the collimator is adjustable.

3. The Raman deep-penetrating imaging system based on a safe laser exposure dose according to claim 1, wherein, The light source is one of a parallel light source, a Gauss light source and a point light source.

4. The Raman deep-penetrating imaging system based on a safe laser exposure dose according to claim 1, wherein, The diameter of the surface-enhanced Raman spectroscopy probe is 20-200 nm.

5. The Raman deep-penetrating imaging system based on a safe laser exposure dose according to claim 1, wherein, The sample table adopts a light-transmitting material or a non-light-transmitting material with a hollow structure.

6. The Raman deep-penetrating imaging system based on a safe laser exposure dose according to claim 1, wherein, The data processing module comprises a spectrometer, a charge-coupled element and a computer system.

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