时域非接触型空间光扫描近红外光学层析成像系统研究
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摘要
相对于目前临床应用的乳腺影像方法,漫射光层析成像(Diffuse Optical Tomography, DOT)因其良好的特异性以及实时、安全性而成为有潜力的乳腺影像新技术。在此基础上发展起来的荧光层析成像(Fluorescence Diffuse Optical Tomography,FDOT)采用吲哚菁绿(Indocyanine green, ICG)作为荧光增强剂,可使图像对比度比DOT高2-4倍。FDOT不仅可采用产率作为重建参数,也可通过同时重建荧光寿命为癌症的早期诊断提供组织体功能信息,从而提高乳腺癌早期诊断的准确率。
光学成像中的传统探测模式采用光纤与成像仓直接接触进行测量。这种接触测量方式限制了数据规模和空间分辨率的提高,调节过程繁琐、耗时,并且在光纤匹配以及调整中易出现误差。为解决以上问题,本组以现有的单通道基于时间相关单光子计数(Time-Correlated Single Photon Counting Techniques, TCSPC)的时间分辨测量系统为基础,搭建了适于在体乳房成像的时域非接触式空间光扫描系统,相对于传统测量方法本方案可增大空间采样量、减小测量误差,提高空间分辨率。为实现系统的连续扫描及集成控制,利用集成了Qt插件的Visual Studio 2008平台进行了集成控制软件开发,实现了连续测量扫描以及测量曲线的实时显示等功能。
利用仿体实验对所搭建系统进行了验证。在DOT实验中,利用该系统对目标仿体中异质体的吸收与约化散射系数进行了成像。在FDOT实验中,分别对单目标体和双目标体进行成像。基于本组已发展的DOT和FDOT图像重建算法进行了图像重建,结果表明: DOT实验中光学参数重建值与实际值基本相符,重建目标与真实目标位置大小相符;FDOT单目标体实验中对荧光目标的产率与寿命进行重建;通过荧光产率的重建可有效对中心距为20mm、边距为15mm的目标体进行分辨进行分辨且能够实现不同浓度的双目标体相对定量重建。实验结果证明了该系统重建组织体光学参数以及进行荧光层析成像的可行性,进一步发展可推动应用于乳腺癌检测的光学层析技术发展。
Compared with the current breast imaging methods such as mammography, ultrasonic imaging and nuclear magnetic resonance, diffuse optical tomography (DOT) becomes one of the most promising breast imaging technique due to its advantages of good specialty, sensitivity and safety. Based on the technology of DOT, fluorescence diffuse optical tomography (FDOT) introduces Indocyanine Green (ICG) as fluorescence enhancement agent, which can greatly improve the image contrast. Tumor-to-normal tissue contrast based on FDOT with the fluorophore Indocyanine Green is two-to-four-fold higher than contrast obtained with traditional diffuse optical tomography. FDOT can not only reconstruct the yield but also the lifetime, which improves the accuracy of early cancer diagnosis and provides functional information for the early cancer diagnosis.
Conventionally, tomography imaging systems require the use of a number of detector fibers put in contact with the object of investigation, which limits the data scale and the improvement of spatial resolution. In order to solve above problems, a time domain noncontact fluorescence tomography system towards the early diagnosis of breast cancer is developed. The time domain system based on the time-correlated single photon counting technique (TCSPC) is adopted to provide both the high sensitivity in detection and good capability in multi-parameter reconstruction. Compared with the conventional contact measurement mode, the noncontact system with light scanning can provide more measurement data for improving the spatial resolution of the images. The controlling software is developed on the platform of Visual Studio 2008 integrated with Qt and the functions of continuous measurement and real-time display of the measurement curves are realized.
The performance of the system is evaluated with measurements on solid phantoms. In the DOT experiment, both the absorption coefficient and the scattering coefficient can be well constructed. The reconstructed value is corresponded to the real value and the reconstructed position and size of the target can well reflect the real position and size; In the FDOT experiments, for the phantom with single fluorescent target, the fluorescence yield and lifetime were simultaneously reconstructed with good quality. For the phantom with two fluorescent targets, the targets with the center-to-center separation of 20mm and the edge separation of 15mm can be distinguished. Measurements also show that the reconstructed yields are linear to the concentration of the fluorescence dye. The results demonstrated the potential of the system in the in vivo diagnosis of the early breast cancer.
光学成像中的传统探测模式采用光纤与成像仓直接接触进行测量。这种接触测量方式限制了数据规模和空间分辨率的提高,调节过程繁琐、耗时,并且在光纤匹配以及调整中易出现误差。为解决以上问题,本组以现有的单通道基于时间相关单光子计数(Time-Correlated Single Photon Counting Techniques, TCSPC)的时间分辨测量系统为基础,搭建了适于在体乳房成像的时域非接触式空间光扫描系统,相对于传统测量方法本方案可增大空间采样量、减小测量误差,提高空间分辨率。为实现系统的连续扫描及集成控制,利用集成了Qt插件的Visual Studio 2008平台进行了集成控制软件开发,实现了连续测量扫描以及测量曲线的实时显示等功能。
利用仿体实验对所搭建系统进行了验证。在DOT实验中,利用该系统对目标仿体中异质体的吸收与约化散射系数进行了成像。在FDOT实验中,分别对单目标体和双目标体进行成像。基于本组已发展的DOT和FDOT图像重建算法进行了图像重建,结果表明: DOT实验中光学参数重建值与实际值基本相符,重建目标与真实目标位置大小相符;FDOT单目标体实验中对荧光目标的产率与寿命进行重建;通过荧光产率的重建可有效对中心距为20mm、边距为15mm的目标体进行分辨进行分辨且能够实现不同浓度的双目标体相对定量重建。实验结果证明了该系统重建组织体光学参数以及进行荧光层析成像的可行性,进一步发展可推动应用于乳腺癌检测的光学层析技术发展。
Compared with the current breast imaging methods such as mammography, ultrasonic imaging and nuclear magnetic resonance, diffuse optical tomography (DOT) becomes one of the most promising breast imaging technique due to its advantages of good specialty, sensitivity and safety. Based on the technology of DOT, fluorescence diffuse optical tomography (FDOT) introduces Indocyanine Green (ICG) as fluorescence enhancement agent, which can greatly improve the image contrast. Tumor-to-normal tissue contrast based on FDOT with the fluorophore Indocyanine Green is two-to-four-fold higher than contrast obtained with traditional diffuse optical tomography. FDOT can not only reconstruct the yield but also the lifetime, which improves the accuracy of early cancer diagnosis and provides functional information for the early cancer diagnosis.
Conventionally, tomography imaging systems require the use of a number of detector fibers put in contact with the object of investigation, which limits the data scale and the improvement of spatial resolution. In order to solve above problems, a time domain noncontact fluorescence tomography system towards the early diagnosis of breast cancer is developed. The time domain system based on the time-correlated single photon counting technique (TCSPC) is adopted to provide both the high sensitivity in detection and good capability in multi-parameter reconstruction. Compared with the conventional contact measurement mode, the noncontact system with light scanning can provide more measurement data for improving the spatial resolution of the images. The controlling software is developed on the platform of Visual Studio 2008 integrated with Qt and the functions of continuous measurement and real-time display of the measurement curves are realized.
The performance of the system is evaluated with measurements on solid phantoms. In the DOT experiment, both the absorption coefficient and the scattering coefficient can be well constructed. The reconstructed value is corresponded to the real value and the reconstructed position and size of the target can well reflect the real position and size; In the FDOT experiments, for the phantom with single fluorescent target, the fluorescence yield and lifetime were simultaneously reconstructed with good quality. For the phantom with two fluorescent targets, the targets with the center-to-center separation of 20mm and the edge separation of 15mm can be distinguished. Measurements also show that the reconstructed yields are linear to the concentration of the fluorescence dye. The results demonstrated the potential of the system in the in vivo diagnosis of the early breast cancer.
引文
[1] Desantis, Siegel, R,Bandi, P, Jemal, et al, Cancer Statistics 2011, Cancer J.Clin., 2011, 49(3):8-31
[2] A.P. Gibson, J.C. Hebden, S.R. Arridge, Recent advances in diffuse optical imaging, Phys. Med. Biol., 2005,50(5): 1-43
[3] V. Noziachristos, R. Weissider, Experimental three-dimensional fluorescence reconstruction of diffuse media by use of a normalized Born approximation, Opt. Lett., 2001,26(8):893-895
[4]王瑜,乳腺癌的早期诊断方法,中国临床医生,2011,39(7):14-15
[5] J.Keyrilinen, A. Bravin, M.Fernndez, et al, Phase-contrast x-ray imaging of breast, Acta radiologica, 2010, 51(8):866-884
[6] Van Beek M, De Vries U, Wasser M, et al, Automated 3d whole-breast ultrasound imaging: Results of a clinical pilot study, Medical Imaging, 2010, 76(29): 2-10
[7] D. B. Kopans, Breast Imaging, Lippincott-Raven Publishers, Philadelphia, NY, 1998.56-58
[8] Rosario Esposito, Sergio De Nicola, Marco Brambilla, et al, Depth dependence of estimated optical properties of a scattering inclusion by time-resolved contrast functions, Optics Express, 2008, 16(22):17667-17680
[9] H. Rinneberg, D. Grosenick, K. Moesta, et al, Scanning time-domain optical mammography: detection and characterization of breast tumors in vivo, Techno Cancer Res Treat, 2005,4(23): 483-496
[10] Q. Zhu, E.B. Cronin, A.A. Currieer, et al, Beingn versus malignant breast masses, optical differentiation with US guided optical imaing reconstruction, Radiology, 2005, 237(3):57-66
[11] Anuradha Godavarty, M. Sevick-Muraca, J. Eppstein, Three-dimensional ?uorescence lifetime tomography, Med. Phys. , 2005,32 (4):992-998
[12] A.T.N. Kumar, J. Skoch, B.J. Bacskai, D.A. Boas, et al ,Fluorescence lifetime based tomography for turbid media, Opt. Lett., 2005,24(4): 3347-3349
[13] Costas Balas, Review of biomedical optical imaging-a powerful, non-invasive,non-ionizing technology for improving in vivo diagnosis, Measurement Science and Technology, 2009,20(5):725-731
[14] Keren, S, Gheysens, O, Levin, C.S, et al, A Comparison Between a Time Domain and Continuous Wave Small Animal Optical Imaging System, Medical Imaging, 2008, 27(9):58-63
[15] D.A. Boas, A. M. Dale, M.A. Franceschini, Diffuse optical imaging of brain activation: approaches to optimizing image sensitivity, resolution, and accuracy, NeuroImage, 2004,23(8):275-288
[16] B. Yuan, Q. Zhu, Separately reconstructing the structural and functional parameters of a fluorescent inclusion embedded in a turbid medium, Opt. Exp. 2006,14(71): 72-87
[17] Roy R,Godavarty A, Fluorescence-enhanced optical tomography of a large tissue phantom using point illumination geometry, J.Biomed.Opt., 2006, 11(44): 7-20
[18] Ralf B.Schulz, Jorg Peter, Wolfhard Semmler, Comparison of noncontact and fiber-based fluorescence-mediated tomography, Optics Letters, 2006, 31(5):6-7
[19] Ignacio Iglesias, Jorge Ripoll, Scanning illumination-acquisition system for noncontact optical tomography, Journal of Biomedical Optics, 2009,24(3): 1-7
[20]姚俊杰,胡刚,白净,非接触式近红外荧光断层成像中光在自由空间中的传播模型及验证,红外与毫米波学报,2008,27(5):330-333
[21]马艺闻,面向早期乳腺癌检测的时域光学方法研究:[博士学位论文],天津;天津大学,2009
[22] F.Leblond, S. Davis, P. Valders, et al, Pre-clinical whole body fluorescence imaging:Review of instruments, methods and applications, J.Photochem., 2010,98(6):77-94
[23]徐可欣,高峰,赵会娟,生物医学光子学,北京:科学出版社,2007,41-58
[24]张修石,近红外线光学成像诊断微小肝癌的初步研究,中国医学影像技术,2007,23(7):25-30
[25] R. Choe, T. Durduran, J. P. Culver, et al, Bulk optical properties of normal breast with endogeneous and exogeneous contrast, Optical Tomography and Spectroscopy of Tissue, 2001, 4250(46):462-464
[26] Dirk Grosenick, K. Thomas, Heidrun Wabnitz, Time-domain optical mammography: initial clinical results on detection and characterization of breast tumors, Applied Optics, 2003, 42(16):3170-3186
[27]沈世杰,刘炳玉,李清,人体乳腺组织的特征红外光谱研究,光谱学与光谱分析,2000,12(1):28-30
[28]刘立新,荧光寿命成像及其在生物医学中的应用,深圳大学学报,2005,22(2):133-141
[29]高峰,李娇,张丽敏等,基于透射解析模型的时域扩散荧光层析原理与实验,天津大学学报,2010,43(6):557-561
[30]杨芳,基于平板检测模式的时域乳腺扩散光学层析先进方法研究:[博士学位论文],天津;天津大学,2010
[31]范晓飞,张永红,白净,单光源、单探测器的近红外光学乳腺成像系统,红外与毫米波学报,2006,25(1):10-16
[32] L. lglesias, J. Ripoll, Scanning illumination-acquisition system for noncontact optical tomography, Journal of Biomedical Optics, 2009, 14(2):3-6
[33] Becker W, Advanced time-correlated single photon counting techniques. Berlin: Springer, 2005,256-280
[34] M. Brambilla, L.Spinelli, A.Piffer, Time-revolved scanning system for double reflectance and transmittance fluorescence imaging of diffusive media, Review of scientific instruments, 2008, 79(103):34-41
[35]顾而立,基于Linux和ARM的嵌入式智能控制系统软件编程的设计与实现,微型电脑应用,2008,34(8):8-10
[36]王敏,嵌入式数据管理系统的研究与设计:[硕士学位论文],武汉;华中科技大学,2009
[37]唐洁,VC++多线程开发技术,电脑编程技巧与维护,2007,7(3):21-32
[38]王静怡,多通道时间相关单光子计数DOT/FMT系统集成和操作平台开发:[硕士学位论文],天津;天津大学,2009
[39] W.Becker,屈军乐,高级时间相关单光子计数技术,北京:科学出版社,2009,315-316
[40]张丽敏,时域荧光扩散光层析的基本理论与实验研究:[博士学位论文],天津;天津大学,2009
[41] R. Philip, A. Penzkofer, W. Baumler, et al, Absorption and fluorescence spectroscopic investigation of indocyanine green, J. Photochem. Photobiol. A Chenm. ,1996,96(3):137-148
[42] Qixiao Chen, Shuo Mao, Jing Bai, In-vivo Measurement of Indocyanine Green Biodistribution in Mammalian Organs using Fiber Based System, OSA/ACP, 2009,23(5):45-47
[43] V. Ntziachristos, C.Tung, C. Bremer, et al, Fluorescence molecular tomography resolves protease activity in vivo, Nature Med., 2002, 8(12):757-760
[44] Frederic Leblond, M. Tichauer, Robert W. Holt, et al., Toward whole-body optical imaging of rats using single-photon counting fluorescence tomography, Optics Letters, 2011,36(19):3723-3725
[2] A.P. Gibson, J.C. Hebden, S.R. Arridge, Recent advances in diffuse optical imaging, Phys. Med. Biol., 2005,50(5): 1-43
[3] V. Noziachristos, R. Weissider, Experimental three-dimensional fluorescence reconstruction of diffuse media by use of a normalized Born approximation, Opt. Lett., 2001,26(8):893-895
[4]王瑜,乳腺癌的早期诊断方法,中国临床医生,2011,39(7):14-15
[5] J.Keyrilinen, A. Bravin, M.Fernndez, et al, Phase-contrast x-ray imaging of breast, Acta radiologica, 2010, 51(8):866-884
[6] Van Beek M, De Vries U, Wasser M, et al, Automated 3d whole-breast ultrasound imaging: Results of a clinical pilot study, Medical Imaging, 2010, 76(29): 2-10
[7] D. B. Kopans, Breast Imaging, Lippincott-Raven Publishers, Philadelphia, NY, 1998.56-58
[8] Rosario Esposito, Sergio De Nicola, Marco Brambilla, et al, Depth dependence of estimated optical properties of a scattering inclusion by time-resolved contrast functions, Optics Express, 2008, 16(22):17667-17680
[9] H. Rinneberg, D. Grosenick, K. Moesta, et al, Scanning time-domain optical mammography: detection and characterization of breast tumors in vivo, Techno Cancer Res Treat, 2005,4(23): 483-496
[10] Q. Zhu, E.B. Cronin, A.A. Currieer, et al, Beingn versus malignant breast masses, optical differentiation with US guided optical imaing reconstruction, Radiology, 2005, 237(3):57-66
[11] Anuradha Godavarty, M. Sevick-Muraca, J. Eppstein, Three-dimensional ?uorescence lifetime tomography, Med. Phys. , 2005,32 (4):992-998
[12] A.T.N. Kumar, J. Skoch, B.J. Bacskai, D.A. Boas, et al ,Fluorescence lifetime based tomography for turbid media, Opt. Lett., 2005,24(4): 3347-3349
[13] Costas Balas, Review of biomedical optical imaging-a powerful, non-invasive,non-ionizing technology for improving in vivo diagnosis, Measurement Science and Technology, 2009,20(5):725-731
[14] Keren, S, Gheysens, O, Levin, C.S, et al, A Comparison Between a Time Domain and Continuous Wave Small Animal Optical Imaging System, Medical Imaging, 2008, 27(9):58-63
[15] D.A. Boas, A. M. Dale, M.A. Franceschini, Diffuse optical imaging of brain activation: approaches to optimizing image sensitivity, resolution, and accuracy, NeuroImage, 2004,23(8):275-288
[16] B. Yuan, Q. Zhu, Separately reconstructing the structural and functional parameters of a fluorescent inclusion embedded in a turbid medium, Opt. Exp. 2006,14(71): 72-87
[17] Roy R,Godavarty A, Fluorescence-enhanced optical tomography of a large tissue phantom using point illumination geometry, J.Biomed.Opt., 2006, 11(44): 7-20
[18] Ralf B.Schulz, Jorg Peter, Wolfhard Semmler, Comparison of noncontact and fiber-based fluorescence-mediated tomography, Optics Letters, 2006, 31(5):6-7
[19] Ignacio Iglesias, Jorge Ripoll, Scanning illumination-acquisition system for noncontact optical tomography, Journal of Biomedical Optics, 2009,24(3): 1-7
[20]姚俊杰,胡刚,白净,非接触式近红外荧光断层成像中光在自由空间中的传播模型及验证,红外与毫米波学报,2008,27(5):330-333
[21]马艺闻,面向早期乳腺癌检测的时域光学方法研究:[博士学位论文],天津;天津大学,2009
[22] F.Leblond, S. Davis, P. Valders, et al, Pre-clinical whole body fluorescence imaging:Review of instruments, methods and applications, J.Photochem., 2010,98(6):77-94
[23]徐可欣,高峰,赵会娟,生物医学光子学,北京:科学出版社,2007,41-58
[24]张修石,近红外线光学成像诊断微小肝癌的初步研究,中国医学影像技术,2007,23(7):25-30
[25] R. Choe, T. Durduran, J. P. Culver, et al, Bulk optical properties of normal breast with endogeneous and exogeneous contrast, Optical Tomography and Spectroscopy of Tissue, 2001, 4250(46):462-464
[26] Dirk Grosenick, K. Thomas, Heidrun Wabnitz, Time-domain optical mammography: initial clinical results on detection and characterization of breast tumors, Applied Optics, 2003, 42(16):3170-3186
[27]沈世杰,刘炳玉,李清,人体乳腺组织的特征红外光谱研究,光谱学与光谱分析,2000,12(1):28-30
[28]刘立新,荧光寿命成像及其在生物医学中的应用,深圳大学学报,2005,22(2):133-141
[29]高峰,李娇,张丽敏等,基于透射解析模型的时域扩散荧光层析原理与实验,天津大学学报,2010,43(6):557-561
[30]杨芳,基于平板检测模式的时域乳腺扩散光学层析先进方法研究:[博士学位论文],天津;天津大学,2010
[31]范晓飞,张永红,白净,单光源、单探测器的近红外光学乳腺成像系统,红外与毫米波学报,2006,25(1):10-16
[32] L. lglesias, J. Ripoll, Scanning illumination-acquisition system for noncontact optical tomography, Journal of Biomedical Optics, 2009, 14(2):3-6
[33] Becker W, Advanced time-correlated single photon counting techniques. Berlin: Springer, 2005,256-280
[34] M. Brambilla, L.Spinelli, A.Piffer, Time-revolved scanning system for double reflectance and transmittance fluorescence imaging of diffusive media, Review of scientific instruments, 2008, 79(103):34-41
[35]顾而立,基于Linux和ARM的嵌入式智能控制系统软件编程的设计与实现,微型电脑应用,2008,34(8):8-10
[36]王敏,嵌入式数据管理系统的研究与设计:[硕士学位论文],武汉;华中科技大学,2009
[37]唐洁,VC++多线程开发技术,电脑编程技巧与维护,2007,7(3):21-32
[38]王静怡,多通道时间相关单光子计数DOT/FMT系统集成和操作平台开发:[硕士学位论文],天津;天津大学,2009
[39] W.Becker,屈军乐,高级时间相关单光子计数技术,北京:科学出版社,2009,315-316
[40]张丽敏,时域荧光扩散光层析的基本理论与实验研究:[博士学位论文],天津;天津大学,2009
[41] R. Philip, A. Penzkofer, W. Baumler, et al, Absorption and fluorescence spectroscopic investigation of indocyanine green, J. Photochem. Photobiol. A Chenm. ,1996,96(3):137-148
[42] Qixiao Chen, Shuo Mao, Jing Bai, In-vivo Measurement of Indocyanine Green Biodistribution in Mammalian Organs using Fiber Based System, OSA/ACP, 2009,23(5):45-47
[43] V. Ntziachristos, C.Tung, C. Bremer, et al, Fluorescence molecular tomography resolves protease activity in vivo, Nature Med., 2002, 8(12):757-760
[44] Frederic Leblond, M. Tichauer, Robert W. Holt, et al., Toward whole-body optical imaging of rats using single-photon counting fluorescence tomography, Optics Letters, 2011,36(19):3723-3725