An ultrafast high-resolution spatially independent gating raman spectral imaging tumor diagnosis system

Abstract

The application discloses a kind of ultrafast high-resolution spatial independent gating Raman spectrum imaging tumor diagnosis system, including illumination and laser excitation module, Raman signal collection module and signal receiving processing module;The application combines Raman spectrum imaging with optical fiber bundle independent resolution imaging technology, uses optical fiber bundle to realize single-cell level ultrafast time-space resolution independent gating Raman spectrum imaging detection and identification, reaches high-resolution, fast Raman imaging, realizes large-area imaging and Raman spectrum detection in short time, and realizes single-cell level spatial resolution Raman imaging of tumor tissue, finds abnormal cells and pathological tissue by detecting tiny tissue composition changes, identifies precancerous lesions, benign lesions and normal tissue, accurately defines tumor edge, and then realizes the accurate diagnosis of early cancer, provides key information for taking treatment as soon as possible.

Description

Technical Field

[0001] This invention belongs to the field of optical imaging technology, and relates to tumor Raman spectroscopy detection and imaging technology, specifically to an ultrafast high-resolution spatially independent gated Raman spectroscopy imaging tumor diagnostic system. Background Technology

[0002] Cancer is the leading cause of death from disease, posing a tremendous threat to human life. China has the highest number of new cancer cases and cancer deaths globally. The key to cancer treatment is early detection, early diagnosis, and early treatment. Studies have confirmed a close correlation between tumor diameter and postoperative annual survival rate; tumors <2cm in diameter have a 100% 5-year survival rate, while for every 1cm increase in tumor diameter, the 5-year survival rate decreases by 20%. Therefore, early detection of tumors can significantly increase a patient's chances of survival, and early diagnosis of tumors has always been a top priority for the scientific community.

[0003] In tumor identification and diagnosis, accurate detection of early-stage micro-tumors and early identification of pathological tissues and abnormal cells are key factors in improving cancer treatment and cure rates. In tumor detection, high-resolution imaging (single-cell level at the micrometer scale), high recognition accuracy, speed, and real-time performance are crucial for tumor detection and imaging diagnostic technologies. Raman spectroscopy imaging, as a highly accurate tumor identification and detection method, has attracted increasing attention from researchers and clinicians. Currently, Raman spectroscopy imaging primarily employs a point-by-point scanning imaging mode. For tumor tissue within the millimeter range, imaging time often requires tens of minutes or even longer. Furthermore, its imaging resolution varies from tens to hundreds of micrometers; higher resolution results in longer imaging times. This significantly limits the application requirements for rapid and accurate early tumor identification and diagnosis. In addition, fluorescence noise interferes with the Raman signal in tumor tissue detection, further reducing the recognition rate and accuracy of tumor Raman signals. Currently, Raman detection instruments cannot simultaneously meet the requirements of rapid imaging, high resolution, and convenient compactness for clinical diagnosis. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, the present invention aims to provide an ultrafast, high-resolution, spatially independent gated Raman spectroscopy imaging tumor diagnostic system, suitable for rapid, high-resolution Raman imaging and single-cell level detection of early-stage cancer.

[0005] To achieve the above objectives, this application adopts the following technical solution:

[0006] An ultrafast, high-resolution, spatially independent gated Raman spectroscopy imaging tumor diagnostic system includes an illumination and laser excitation module, a Raman signal collection module, and a signal receiving and processing module.

[0007] The illumination and laser excitation module includes a cold light source and a laser; the Raman signal collection module includes an imaging adjustment device coaxially assembled via an optical system and an optical fiber bundle disposed in the endoscope. The imaging adjustment device, composed of a lens assembly, is installed at the front end of the optical fiber bundle, and the rear end of the optical fiber bundle is connected to the signal receiving and processing module; the signal receiving and processing module includes a spectrometer, a CCD camera, and imaging and signal processing software. The end of the optical fiber bundle connected to the imaging adjustment device is arranged in a circular pattern, and the end of the optical fiber bundle connected to the signal receiving and processing module is arranged in a linear pattern, corresponding one-to-one with the arrangement of the circular end.

[0008] The white light emitted by the cold light source and the laser emitted by the laser are transmitted to the endoscope through the light guide system. The fiber bundle transmits the white light and laser light through the single fiber of the fiber bundle and illuminates the object under test. The cold light source provides illumination for the endoscope of the diagnostic system for preliminary imaging and positioning. After positioning and imaging, laser excitation and Raman spectroscopy testing are performed. The front end of the fiber bundle receives the light signal from the imaging adjustment device. After the light signal is processed by the spectrometer, it enters the CCD camera to collect and image the single signal of the fiber bundle, realizing rapid tumor identification and detection with single-cell resolution.

[0009] Furthermore, the signal receiving and processing module realizes an automatic integrated data acquisition and processing process through imaging and signal processing software, directly obtaining Raman imaging information of the tumor site and identifying and sampling the site of hazardous substances.

[0010] Furthermore, the imaging adjustment device consists of a lens assembly with focal lengths of 75mm and 50mm.

[0011] Furthermore, the fiber bundle is composed of optical fibers with a core diameter of 10 to 100 μm and a number of 50 to 5000 fibers.

[0012] Furthermore, the light guiding system includes a dichroic mirror and a lens.

[0013] Furthermore, the total diameter of the fiber bundle is approximately 1 mm, and the diameter for collecting Raman spectral information is 1 mm to 1 cm.

[0014] Compared with the prior art, the advantages of the present invention are as follows:

[0015] 1) This invention combines rapid, high-resolution tumor detection and identification with fiber bundle imaging and spatially resolved independent spectral acquisition technology. It utilizes fiber bundles for tumor detection imaging and single-fiber spectral acquisition. Since the imaging resolution of the fiber bundle is determined by the distance between the fiber cores, and the minimum spectral acquisition range is the size range of a single fiber, spatial imaging resolution as low as a few micrometers can be achieved. Utilizing the independent spatial resolution imaging capability of a single fiber bundle, spatially resolved independent gated remote Raman spectroscopy detection is achieved. By detecting and identifying biological tissues at the single-cell level, accurate identification and detection of tumor regions and adjacent non-tumor tissues are achieved, enabling rapid, high-resolution Raman imaging and early cancer diagnosis.

[0016] 2) Rapid imaging is achieved by using a bundle of 50 to 5000 optical fibers in conjunction with an endoscopic optical imaging system. The total diameter of the fiber bundle is about 1 mm. Combined with the imaging system, Raman spectral information within a diameter range of 1 mm to 1 cm can be collected in one go without point-by-point scanning, which greatly reduces the imaging time. All Raman spectral information within the fiber bundle can be obtained within 0-180 seconds.

[0017] 3) A single micrometer-sized fiber bundle is used as the Raman signal receiver, and spectral acquisition is performed on each fiber. The imaging resolution of the fiber bundle is determined by the distance between the fiber cores. By using a fiber bundle composed of single fibers with a core diameter of 20 μm, combined with an imaging adjustment device, single-cell-level imaging resolution can be achieved. One end of the fiber bundle is rounded to facilitate receiving the Raman signal transmitted by the lens. The other end is linear, used to connect the spectrometer and CCD camera, facilitating independent reception, acquisition, and data analysis of the Raman signal from each fiber in the bundle. Computer software performs one-to-one correspondence and image reconstruction of the signal from each fiber in the bundle, and combines this with sample imaging of the fiber bundle to achieve spatially resolved, independently gated Raman spectroscopy detection.

[0018] 4) By designing an imaging adjustment device, the range of the laser-irradiated detection area can be magnified or reduced. First, a large area can be detected and imaged, achieving a spatial resolution of several hundred micrometers for the sample. Then, a small, suspicious area can be precisely imaged, achieving a horizontal resolution of several micrometers. This allows for flexible selection of the detection area and further shortens the imaging and detection time. Attached Figure Description

[0019] Figure 1 Schematic diagram of a single-cell resolution rapid tumor identification and detection system using spatial resolution independent gating technology;

[0020] Figure 2 Schematic diagram of the principle of using fiber optic bundles for Raman spectroscopy detection and imaging;

[0021] Figure 3 Arrangement of the two ends of the fiber bundle;

[0022] Figure 4 Relationship between different image magnifications and fiber bundle Raman imaging;

[0023] Figure 5 A diagram illustrating the differences between laser spectral acquisition and fiber optic bundle spectral acquisition in tumor and normal tissues;

[0024] Figure 6 This invention applies to imaging images of different tissues using fiber optic bundles. Detailed Implementation

[0025] The technical solutions in the embodiments of the present invention will be clearly and completely described below.

[0026] like Figure 1 As shown, this invention combines fiber optic bundle imaging technology with an imaging adjustment device to achieve rapid single-cell tumor identification and detection based on spatially resolved independent gating technology. The ultrafast, high-resolution spatially independent gating Raman spectroscopy imaging tumor diagnostic system of this invention includes an illumination and laser excitation module, a Raman signal collection module, and a signal receiving and processing module.

[0027] In the illumination and laser excitation module, the illumination system uses a cold light source to illuminate the endoscope. Light emitted from an external laser source is transmitted via a light guide system to the optical fiber in the center of the fiber bundle inside the endoscope, and then through this fiber to illuminate the sample. The laser can be either continuous or pulsed, depending on the imaging requirements. White light illumination and laser light are transmitted through a single optical fiber in the center of the fiber bundle, and the size of the white light and laser spot illuminating the sample is adjusted by an imaging adjustment device; the illumination system is used for initial imaging and positioning. The laser excitation and illumination systems use the same optical path. After positioning and imaging, laser excitation and Raman spectroscopy testing are performed.

[0028] The Raman signal collection module mainly consists of an imaging adjustment device combined with an optical fiber bundle, and is assembled using coaxial optical system technology. The imaging adjustment device, installed at the front end of the optical fiber bundle, is composed of a lens assembly. Lenses with focal lengths of 75mm and 50mm are used in conjunction to adjust the image. The parameters of this convex lens can be further adjusted according to imaging requirements. The end of the optical fiber bundle connected to the imaging adjustment device is arranged in a circular pattern, while the end connected to the spectrometer and CCD camera is arranged in a linear pattern, corresponding one-to-one with the circular end. The front end of the optical fiber bundle receives the optical signal from the imaging adjustment device, and the rear end connects to the signal receiving and processing module for imaging and receiving Raman signals, and for independent spatial signal transmission.

[0029] The Raman signal is coupled into the fiber bundle after passing through a lens assembly for further signal acquisition and imaging. One end of the fiber bundle is linear, and the other is circular. Each fiber in the linear and circular bundle corresponds one-to-one for easy imaging analysis. The circular end connects to the lens assembly to receive the Raman signal, while the linear end connects to the spectrometer and CCD camera for single-fiber signal acquisition. Each fiber in the bundle is the smallest pixel unit for spatially resolved imaging, and different fiber parameters can be selected according to the required resolution. The fiber bundle uses fibers with core diameters of 10–100 μm and a number of fibers of 50–5000 for spatially resolved independently gated Raman spectroscopy detection. The core diameter and number of fibers can also be adjusted according to actual needs.

[0030] The signal receiving and processing module includes a spectrometer, a CCD camera, and imaging and signal processing software. The fiber bundle's rear end is connected to the spectrometer and CCD camera. After signal processing by the spectrometer, the signal enters the CCD camera for single-strand signal acquisition and imaging. The imaging and signal processing software enables automated, integrated data acquisition and processing, directly obtaining Raman imaging information of the tumor site and accurately identifying hazardous material locations. Through the cooperation of the laser excitation module, Raman signal collection module, and signal receiving and processing module, rapid single-cell resolution tumor identification and detection is achieved. This technology can be applied to various Raman spectroscopy detection devices for spatially resolved, independently gated Raman spectroscopy detection and identification, and can be used for clear identification of cancer tissue boundaries and detection of small tumor tissues.

[0031] In this invention, to achieve adjustable detection area and facilitate connection of fiber optic bundles, a lens assembly is used as an imaging adjustment device to realize this function. Under the condition of determining the lens assembly's operating parameters (focal length, field of view, relative aperture, operating wavelength, and root mean square value of the dot plot), and in conjunction with imaging parameters such as the fiber optic bundle's size and numerical aperture, ZEMAX simulation is used to further achieve magnification and reduction of the fiber optic bundle imaging and detection area.

[0032] After the Raman signal passes through the imaging adjustment device, it is coupled into the fiber bundle for further signal acquisition and imaging. One end of the fiber bundle, connected to the imaging lens group, is arranged in a circular pattern, ensuring that all imaging and optical signals received by the imaging system are received through this circular end and enter the fiber. The other end of the fiber bundle is arranged linearly, matching the arrangement of the circular end, and connected to the spectrometer's CCD camera, facilitating the CCD camera's acquisition and imaging of individual signals from each fiber bundle.

[0033] The signal receiving and processing module achieves automated operation and real-time imaging algorithm processing through software. Through an automated and integrated data acquisition and processing process, it directly obtains Raman imaging information of the tumor site and accurately identifies the tumor location and contour.

[0034] like Figure 2 As shown, in a further preferred embodiment, the optical signal enters from one end of the hexagonal fiber bundle and exits from the other linearly arranged end of the fiber bundle. The linear arrangement of the optical fibers facilitates spectrometer spectral processing. After processing by the spectrometer, the optical signal enters the CCD camera for reception. Because the optical fibers are linearly arranged, the different pixel positions of the optical signal received by the CCD camera can correspond one-to-one with the position of the signal transmitted by each fiber. By extracting the spectral information of each fiber on the spectrometer and performing imaging analysis and comparison, the accurate spatial position of the analyte can be obtained. If the detection area contains tumor and normal cell tissue, this fiber bundle array can effectively identify the characteristics of different analyte molecules. For example, red, blue, and green represent different parts of biological tissue (tumor cells and normal cells) and their corresponding spectral information, respectively. After using the fiber bundle for optical signal transmission and spectral analysis, the spectral signal in a small area can be accurately read and analyzed, and the accurate spectral information of different parts and cell tissues can be identified. At the same time, the Raman spectra of each fiber are compared and processed by algorithms for resolution.

[0035] like Figure 3 As shown, in a further preferred embodiment, the end of the fiber bundle connected to the imaging adjustment device is arranged in a circular pattern, while the end connected to the spectrometer and CCD camera is arranged in a linear pattern, corresponding one-to-one with the circular end. The fiber bundle at the very center of the circular end serves as the transmission fiber for illumination and laser. The laser can use different wavelengths of continuous or pulsed laser light according to imaging requirements, while the other fibers receive Raman signals. Simultaneously, to achieve Raman spectroscopy detection and imaging at single-cell resolution, a fiber bundle composed of fibers with a core diameter of 20 μm is selected for independent acquisition and analysis of Raman spectra. Due to the large range of biological tissue detection and imaging, a fiber bundle consisting of 817 fibers is selected to receive Raman signals, enabling large-area and wide-range detection.

[0036] like Figure 4 As shown, in a further preferred embodiment, to achieve flexible adjustment of the detection area, an optical imaging lens group is designed in front of the circular end of the fiber bundle, enabling simultaneous controllable adjustment of the laser excitation area and the fiber bundle imaging area. First, the incident laser spot and imaging range are enlarged to obtain a larger area of ​​Raman imaging information. Then, suspicious areas within the large Raman imaging information (centimeter-level area) are precisely located. Next, the incident laser spot and imaging range are reduced by adjusting the lens group to perform fine Raman imaging detection within a small area (millimeter-level area), further improving the overall Raman imaging detection speed. For example, when the laser spot area is increased by 4 times, the detection range is simultaneously increased by 4 times. When the laser spot area is reduced by 4 times, the detection range is simultaneously reduced by 4 times.

[0037] like Figure 5 As shown, the spatially resolved independent gating technique of this invention enables direct Raman spectroscopy detection of tumor tissue and adjacent normal tissue based on fiber bundles. Through spatially resolved independent gating Raman spectroscopy using fiber bundles, high-quality and accurate differentiation between tumor tissue and normal tissue is achieved. In contrast, conventional Raman detection yields the total spectrum of the detection area, which cannot effectively distinguish between tumor tissue and adjacent normal tissue.

[0038] Example 1: Pure Raman peaks for each tissue were tested beforehand, and machine learning classification was performed to train the model and establish a database. Based on a convolutional neural network-based image reconstruction algorithm, the collected Raman data was automatically classified into two types of substances using the convolutional neural network, and the peaks at 1450 cm⁻¹ were calculated. -1 The peak intensity of Raman characteristic peaks, classification results, and Raman peak intensity serve as the basis for spectral reconstruction. During image reconstruction, Raman spectral data of the same type are marked with pixels of similar colors. In this invention, cancerous tissue is marked with warm colors, and normal tissue with cool colors, thus obtaining pixel information from different locations. Finally, the pixel information is recombine and filled into the corresponding positions, ensuring a one-to-one correspondence between Raman data, classification results, and fiber optic pixels, thereby generating a Raman image. Figure 6 (a) Because the data acquired by the fiber optic bundle is very limited, the resulting Raman image contains a finite number of pixels, resulting in low imaging resolution. To meet human visual requirements, image resolution enhancement is generally performed, specifically through image segmentation and image interpolation. This paper segments the Raman image into 255 pixels. Figure 6 (b) After multiple interpolations Figure 6 (c) This yields high-resolution Raman imaging. The results of data reconstruction and interpolation are as follows: Figure 6 As shown in (d), the warm-colored area represents the distribution of cancerous tissue, while the cool-colored area represents the distribution of normal tissue. It can be seen that there is a clear boundary between the two, and the classification and reconstruction effect is good.

Claims

1. An ultrafast, high-resolution, spatially independent gated Raman spectroscopy imaging tumor diagnostic system, characterized in that: It includes an illumination and laser excitation module, a Raman signal collection module, and a signal receiving and processing module; The illumination and laser excitation module includes a cold light source and a laser; the Raman signal collection module includes an imaging adjustment device coaxially assembled via an optical system and an optical fiber bundle disposed in the endoscope. The imaging adjustment device, composed of a lens assembly, is installed at the front end of the optical fiber bundle, and the rear end of the optical fiber bundle is connected to the signal receiving and processing module; the signal receiving and processing module includes a spectrometer, a CCD camera, and imaging and signal processing software. The end of the optical fiber bundle connected to the imaging adjustment device is arranged in a circular pattern, and the end of the optical fiber bundle connected to the signal receiving and processing module is arranged in a linear pattern, corresponding one-to-one with the arrangement of the circular end. The white light emitted by the cold light source and the laser emitted by the laser are transmitted to the endoscope through the light guide system. The fiber bundle transmits the white light and laser light through the single fiber of the fiber bundle and illuminates the object under test. The cold light source provides illumination for the endoscope of the diagnostic system for preliminary imaging and positioning. After positioning and imaging, laser excitation and Raman spectroscopy testing are performed. The front end of the fiber bundle receives the light signal from the imaging adjustment device. After the light signal is processed by the spectrometer, it enters the CCD camera to collect and image the single fiber bundle signal. By utilizing the independent spatial resolution imaging capability of the single fiber bundle, spatial resolution independent gated remote Raman spectroscopy detection is realized, enabling rapid tumor identification and detection with single-cell resolution.

2. The ultrafast high-resolution spatially independent gated Raman spectroscopy imaging tumor diagnostic system as described in claim 1, characterized in that: The signal receiving and processing module realizes an automatic integrated data acquisition and processing process through imaging and signal processing software, directly obtaining Raman imaging information of the tumor site and identifying and sampling the site of hazardous substances.

3. The ultrafast high-resolution spatially independent gated Raman spectroscopy imaging tumor diagnostic system as described in claim 1, characterized in that: The imaging adjustment device consists of two convex lenses.

4. The ultrafast high-resolution spatially independent gated Raman spectroscopy imaging tumor diagnostic system as described in claim 1, characterized in that: The fiber bundle is composed of optical fibers with a core diameter of 10~100 μm and a number of 50~5000 fibers.

5. The ultrafast high-resolution spatially independent gated Raman spectroscopy imaging tumor diagnostic system as described in any one of claims 1-4, characterized in that: The light guiding system includes a dichroic mirror and a lens.

6. The ultrafast high-resolution spatially independent gated Raman spectroscopy imaging tumor diagnostic system as described in any one of claims 1-4, characterized in that: The total diameter of the fiber bundle is about 1 mm, and the diameter for collecting Raman spectral information is 1 mm to 1 cm.

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