基于二次谐波和双光子激发荧光机制的胃癌诊断特征研究
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摘要
许多癌症发生于层状结构的生物组织,且大多数胃癌出现在胃粘膜。由于诊断效果欠佳,胃癌是第二大常见的致死性癌症。基于双光子激发荧光和二次谐波产生的多光子激发显微技术是一种新兴的非线性光谱成像技术,它结合了双光子激发显微术和光谱测量技术,因此它能同时获得生物组织不同深度的图像和光谱信息。在本论文中,首先,通过结合双光子激发荧光成像和二次谐波产生成像,我们观察了人体胃粘膜的固有层。研究表明,用多光子激发显微技术能够有效地描述人体正常的胃粘膜的固有层的微结构。接着,利用多光子激发显微技术,我们研究了人体正常的和癌变的胃组织的粘膜层和粘膜下层,并建立了区分这两层的诊断特征。研究结果显示,多光子激发显微技术不仅能表现正常的和癌变的胃组织的粘膜层和粘膜下层的微结构,还能测量这两层中异常细胞的分布和含量。更重要的是,这些结果为建立胃癌的临床诊断标准奠定了实验基础。总之,我们的研究表明,多光子激发显微技术极有可能为人体胃组织的生理分析和病理诊断提供更精确、更丰富的信息。随着临床用微型化的多光子激发显微术和多光子探针技术的发展,我们的实验研究结果将有助于利用多光子内窥镜技术实现胃癌的早期、活体和实时的诊断。
Many neoplasms occur in biological tissues with a fine stratified structure, and most of stomach cancers develop in the gastric mucosa. Due to poor diagnosis, the stomach cancer is the second most common cause of death. Multiphoton excitation microscopy (MPM) is an emerging nonlinear spectral imaging based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG). This microscopy combines two-photon excitation microscopy with spectral measurement technique, so it can be simultaneously used for obtaining tissue image and spectra at different depth. In this thesis, firstly, combining TPEF and SHG, the lamina propria of normal human gastric mucosa was observed. Our results demonstrated that MPM can be very effective to characterize the microstructure of lamina propria in normal human gastric mucosa. Then, by using MPM, the mucosa and submucosa of human normal and cancerous gastric tissues were investigated, and the diagnostic features for identifying the two layers were established. Our findings show that MPM can be capable of exhibiting the mucosal and submucosal microstructures of normal and cancerous gastric tissues, as well as the distribution and content of abnormal cells in the two layers. More importantly, the results can provide the groundwork for establishing clinical diagnostic criteria of gastric cancer. In a word, our findings suggested that MPM has great potential for providing more accurate and comprehensive information in physiological analysis and pathological diagnosis of human gastric tissue. With the development of clinically miniaturized MPM and multiphoton probe, our results can be helpful for applying multiphoton endoscopy to perform real-time in vivo early diagnosis of gastric cancer.
Many neoplasms occur in biological tissues with a fine stratified structure, and most of stomach cancers develop in the gastric mucosa. Due to poor diagnosis, the stomach cancer is the second most common cause of death. Multiphoton excitation microscopy (MPM) is an emerging nonlinear spectral imaging based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG). This microscopy combines two-photon excitation microscopy with spectral measurement technique, so it can be simultaneously used for obtaining tissue image and spectra at different depth. In this thesis, firstly, combining TPEF and SHG, the lamina propria of normal human gastric mucosa was observed. Our results demonstrated that MPM can be very effective to characterize the microstructure of lamina propria in normal human gastric mucosa. Then, by using MPM, the mucosa and submucosa of human normal and cancerous gastric tissues were investigated, and the diagnostic features for identifying the two layers were established. Our findings show that MPM can be capable of exhibiting the mucosal and submucosal microstructures of normal and cancerous gastric tissues, as well as the distribution and content of abnormal cells in the two layers. More importantly, the results can provide the groundwork for establishing clinical diagnostic criteria of gastric cancer. In a word, our findings suggested that MPM has great potential for providing more accurate and comprehensive information in physiological analysis and pathological diagnosis of human gastric tissue. With the development of clinically miniaturized MPM and multiphoton probe, our results can be helpful for applying multiphoton endoscopy to perform real-time in vivo early diagnosis of gastric cancer.
引文
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9. Tan YK, Fielding John WL. Early diagnosis of early gastric cancer. European Journal of Gastroenterology and Hepatology 2006; 18:821-9.
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14. Fu L, Jain A, Cranfield C, Xie H, Gu M. Three-dimensional nonlinear optical endoscopy. Journal of Biomedical Optics 2007; 12:040501.
15. Teh SK, Zheng W, Ho KY, Teh M, Yeoh KG, Huang Z. Diagnostic potential of near-infrared Raman spectroscopy in the stomach: differentiating dysplasia from normal tissue. British Journal of Cancer 2008; 98:457-65.
16. Gheorghe C, Iacob R, Becheanu G, Dumbrava M. Confocal endomicroscopy for in vivo microscopic analysis of upper gastrointestinal tract premalignant and malignant lesions. Journal of Gastrointestinal and Liver Diseases 2008; 17:95-100.
17. Hoffman A, Goetz M, Vieth M, Galle PR, Neurath MF, Kiesslich R. Confocal laser endomicroscopy: technical status and current indications. Endoscopy 2006; 38: 1275-83.
18. Wang BG, Konig K, Halbhuber KJ. Two-photon microscopy of deep intravital tissues and its merits in clinical research. Journal of Microscopy 2010; 238:1-20.
19. Provenzano PP, Eliceiri KW, Keely PJ. Multiphoton microscopy and fluorescence lifetime imaging microscopy (FLIM) to monitor metastasis and the tumor microenvironment. Clinical and Experimental Metastasis 2009; 26:357-70.
20. Rogart JN, Nagata J, Loeser CS, et al. Multiphoton imaging can be used for microscopic examination of intact human gastrointestinal mucosa ex vivo. Clinical Gastroenterology and Hepatology 2008; 6:95-101.
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24. Ling X, Xu Y, Weng S, et al. Investigation of normal and malignant tissue samples from the human stomach using Fourier Transform Raman spectroscopy. Applied Spectroscopy 2002; 56:570-573.
25. Li X, Lin J, Jia C, Wang R. Detection and characterization of stomach cancer and atrophic gastritis with fluorescence and Raman spectroscopy. Proceedings of the Biomolecular Photonics and Multidimensional Microscopy; 2003 June 8-11; Wuhan, China. WA:SPIE; 2003.
26. Liu L, Qu J, Lin Z, et al. Simultaneous time-and spectrum- resolved multifocal multiphoton microscopy. Journal of Applied Physics B:Laser and Optics 2006; 84: 379-83.
27. Chen J, Zhuo S, Chen R, Jiang X, Xie S, Zou Q. Depth-resolved spectral imaging of rabbit oesophageal tissue based on two-photon excited fluorescence and second-harmonic generation. New Journal of Physics 2007; 9:212.
28. Zhuo S, Chen J, Jiang X, et al. The layered-resolved microstructure and spectroscopy of mouse oral mucosa using multiphoton microscopy. Physics in Medicine and Biology 2007; 52:4967-80.
29.陈颖,吴云林,吴巍,蔚青,胡伟国,郭强苏.人胃癌与癌前病变组织的固有荧光特征.世界华人消化杂志2008；16：3055-9.
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