同步辐射X射线肿瘤新生血管成像及相衬成像理论研究
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摘要
肿瘤新生血管对于肿瘤的生长、转移具有重要作用,其直径约为几十微米甚至更小。但目前传统影像技术只能分辨直径大于200微米的血管。同步辐射相衬成像技术对生物软组织如血管、肿瘤等的成像具有巨大的优势,空间分辨率可达1微米。
本研究初步尝试了利用上海同步辐射光源观察正常小鼠和Lewis肺癌鼠的胸部结构和血管。利用同步辐射类同轴相衬成像技术,可以很好的区分Lewis肺癌鼠肺部的正常区域和肿瘤区域;同时,在使用硫酸钡造影剂的情况下,观察到了沿肿瘤边缘区域的肿瘤新生血管。此外,建立了小鼠4T1乳腺癌脊皮视窗模型,探索了在不使用造影剂的情况下对小鼠乳腺癌肿瘤新生血管的形态与结构进行观察。结果表明,利用同步辐射相衬成像能够在不使用造影剂的情况下观察到直径小于30微米的肿瘤新生血管。
此外,根据同步辐射类同轴相衬成像原理,利用计算机模拟研究能量,成像距离和样品厚度对成像质量的影响。结果表明,在医学影像成像的能量范围内,能量增高,会降低图像衬度;样品厚度对图像衬度的影响不明显;图像衬度随着成像距离的增加刚开始增强,距离进一步拉大,图像反而变模糊。模拟计算结果与实际实验结果能够较好的吻合,对下一步的实验具有一定的指导意义。
研究结果表明利用同步辐射光源观察肿瘤微血管的实验方法具有可行性。在今后的研究中,我们将通过建立肿瘤模型进一步研究它们的发病机理以及诊断治疗的方法。
Angiogenesis plays an important role in tumor growth and metastasis. However, only vessels lager than 200μm in diameter can be observed using conventional medical imaging system. Synchrotron radiation (SR) phase contrast imaging, whose spatial resolution can reach 1μm, as the highest, has great advantages in imaging soft tissue structure, such as blood vessels and tumors.
In this study, BALB/c nude mouse with Lewis lung cancer implanted was studied using Shanghai Synchrotron Radiation Facility. The images clearly showed the differences between the tumor tissue and the normal lung tissue. The effect of the object-detector distance and energy level on the phase contrast difference was investigated, in good agreement with the theory of in-line phase contrast imaging. Moreover, 3D tumor angiogenesis of lung cancer was obtained for the first time through reconstruction and using contrast agent, demonstrating the feasibility of micro-angiography with synchrotron radiation for imaging tumor angiogenesis deep inside the body. Meanwhile, angiogenesis in tumor chamber was imaged using SR in-line phase contrast imaging without contrast agent, showing that vessels less than 30μm in diameter can be observed.
On the other hand, computer simulation of in line phase contrast imaging was adopted to study the influences of energy level, imaging distance and thickness of sample on the image quality. The simulation results, in good accordance with the experiment results, showed that image contrast decreased when energy increased and the thickness of sample did not obviously affect the image quality and the image contrast first increased along with the distance then decreased in a longer distance.
The above results showed the feasibility of observation of micro-vessels in tumor using synchrotron radiation in line phase contrast imaging. Further study on the pathogenesis, diagnosis and treatment of tumor by establishing animal models will be investigated.
本研究初步尝试了利用上海同步辐射光源观察正常小鼠和Lewis肺癌鼠的胸部结构和血管。利用同步辐射类同轴相衬成像技术,可以很好的区分Lewis肺癌鼠肺部的正常区域和肿瘤区域;同时,在使用硫酸钡造影剂的情况下,观察到了沿肿瘤边缘区域的肿瘤新生血管。此外,建立了小鼠4T1乳腺癌脊皮视窗模型,探索了在不使用造影剂的情况下对小鼠乳腺癌肿瘤新生血管的形态与结构进行观察。结果表明,利用同步辐射相衬成像能够在不使用造影剂的情况下观察到直径小于30微米的肿瘤新生血管。
此外,根据同步辐射类同轴相衬成像原理,利用计算机模拟研究能量,成像距离和样品厚度对成像质量的影响。结果表明,在医学影像成像的能量范围内,能量增高,会降低图像衬度;样品厚度对图像衬度的影响不明显;图像衬度随着成像距离的增加刚开始增强,距离进一步拉大,图像反而变模糊。模拟计算结果与实际实验结果能够较好的吻合,对下一步的实验具有一定的指导意义。
研究结果表明利用同步辐射光源观察肿瘤微血管的实验方法具有可行性。在今后的研究中,我们将通过建立肿瘤模型进一步研究它们的发病机理以及诊断治疗的方法。
Angiogenesis plays an important role in tumor growth and metastasis. However, only vessels lager than 200μm in diameter can be observed using conventional medical imaging system. Synchrotron radiation (SR) phase contrast imaging, whose spatial resolution can reach 1μm, as the highest, has great advantages in imaging soft tissue structure, such as blood vessels and tumors.
In this study, BALB/c nude mouse with Lewis lung cancer implanted was studied using Shanghai Synchrotron Radiation Facility. The images clearly showed the differences between the tumor tissue and the normal lung tissue. The effect of the object-detector distance and energy level on the phase contrast difference was investigated, in good agreement with the theory of in-line phase contrast imaging. Moreover, 3D tumor angiogenesis of lung cancer was obtained for the first time through reconstruction and using contrast agent, demonstrating the feasibility of micro-angiography with synchrotron radiation for imaging tumor angiogenesis deep inside the body. Meanwhile, angiogenesis in tumor chamber was imaged using SR in-line phase contrast imaging without contrast agent, showing that vessels less than 30μm in diameter can be observed.
On the other hand, computer simulation of in line phase contrast imaging was adopted to study the influences of energy level, imaging distance and thickness of sample on the image quality. The simulation results, in good accordance with the experiment results, showed that image contrast decreased when energy increased and the thickness of sample did not obviously affect the image quality and the image contrast first increased along with the distance then decreased in a longer distance.
The above results showed the feasibility of observation of micro-vessels in tumor using synchrotron radiation in line phase contrast imaging. Further study on the pathogenesis, diagnosis and treatment of tumor by establishing animal models will be investigated.
引文
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[1]Lewis R A 2004 Medical phase contrast x-ray imaging: current status and future prospects Phys. Med. Biol. 49 3573-3583
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[13] McDonald D M, and Choyke P L 2003 Imaging of angiogenesis: from microscope to clinic Nat. Med. 9 713–725
[14] Fink C, Kiessling F, Bock M, Lichy M P, Misselwitz B, Peschke P, Fusenig N E, Grobholz R and Delorme Stefan 2003 High-resolution three-dimensional MR angiography of rodent tumors: morphologic characterization of intratumoral vasculature J. Magn. Reson. Imaging. 18 59–65
[15] Kobayashi S et al 2004 In vivo real-time microangiography of the liver in mice using synchrotron radiation Journal of Hepatology 40 405-408
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[1]Pogany A, Gao D, Wilkins SW. 1997 Contrast and resolution in imaging with a microfocus X-ray source, Rev.Sci.Instr. 68: 2774-2782
[2]Wu X Z, Liu H. 2003 A general theoretical formalism for X-ray phase contrast imaging. J. X-ray Sci. Technol. 11: 33-42
[3]Xiao T Q et al 2005 Effect of spatial coherence on application of in-line phase contrast imaging to synchrotron radiation mammography Nuclear Instruments and Methods in Physics Research A 548 155-162
[4] http://www.esrf.eu/computing/scientific/xop2.1/
[5]Peterzol A, Berthier J, Duvauchelle, et al 2007 X-ray phase contrast image simulation. Nuclear Instruments and Methods in Physics Research B 254 307-318
[2]Davis T J, Gao G, Gureyev T E, et al. Phase contrast imaging of weakly absorbing materials using hard X-rays [J]. Nature, 1995, 373:595-598.
[3]Wilkins S W, Gureyev T E, Gao D, et al. Phase-contrast imaging using polychromatic hard X-rays [J]. Nature, 1996, 384: 335-338.
[4]Fitzgerald R. Phase-sensitive X-ray imaging [J]. Physics Today, 2000, 53: 23.
[5]Arfelli et al. Mammography with synchrotron radiation: Phase-detection techniques. Radiology, 2000, 215(1): 285-293.
[6]Snigireva I, Snigirev A. X-Ray micro analytical techniques based on synchrotron radiation. J. Environ. Monit. 2006, 8: 33–42.
[7]Bonse U and Hart M. An X-ray interferometer with long Separated interfering beam path. Appl.Phys.Lett. 1965, 7: 99-103.
[8]Momose A. Demonstration of phase contrast X-ray computed tomography using a X-ray interferometer. Nucl.Instr and Meth. 1995, A352:622.
[9]Momose A, Takeda T, Itai Y, et al. Tomographic image reconstruction using X-ray phase information. SPIE Proc. 1996, 2708: 674.
[10] Momose A, Takeda T, Itai Y, et al. Phase-contrast X-ray computed tomograph for observing biological soft tissues. Nature Medicine. 1996, 2: 473.
[11]Chapman D, Thomlinson W, Johnston RE et al. Difffraction enhanced x-ray imaging. Phys.Med.Biol. 1997, 42: 2015-2025.
[12]Dilmanian F A, Zhong Z, Ren B, et al. Computed tomography of X-ray index of refraction using diffraction enhanced x-ray imaging. Phys.Med.Biol. 2000, 45: 933
[13]Menk R H, Rigon L, Arfelli F. Diffraction enhanced X-ray medical imaging at ELETTRA synchrotron light source. Nuclear Instruments and Methods in Physics Reasearch A. 2005, 548: 213-220.
[14]Crittell S, Cheung K C, Hall C, et al. Diffraction enhanced imaging of normal and arthritic mice feet. Nuclear Instruments and Methods in Physics Research A. 2007, 573: 126-128.
[15]Suortti P and Thomlinson W. Medical application of synchrotron radiation. Phys.Med.Biol. 2003, 48: R1-R35.
[16]Snigirev A, Snigireva I, Kohn V, et al. On the possibilities of X-ray phase contrastmicroimaging by coherent high energy synchrotron radiation. Rev.Sci.Instrum. 1995, 60: 2299.
[17]Wilkins S W, Gureyev T E, Gao D, et al. Phase contrast imaging using polychromatic hard X-ray. Nature. 1996, 384: 335-338.
[18]Gao D, Pogany A, Stevenson A W, Wilkins S W. Phase-contrast radiography. RadioGraphics. 1998, 18: 1257-1267.
[19]Ohtsuka S, Sugishita Y, Takeda T, et al. The British Journal of Radiology, 1999, 72.
[20] Yagi, N., Y. Suzuki, et al. (1999). "Refraction-enhanced x-ray imaging of mouse lung using synchrotron radiation source." Med Phys 26(10): 2190-3.
[21]Lewis, R. A., N. Yagi, et al. (2005). "Dynamic imaging of the lungs using x-ray phase contrast." Phys Med Biol 50(21): 5031-40.
[22]Hooper S B et al 2009 Imaging lung aeration and lung liquid clearance at birth using phase contrast x-ray imaging Clinical and Experimental Pharmacology and Physiology 36 117-125
[23]Hooper S B et al 2007 Imaging lung aeration and lung liquid clearance at birth The FASEB Journal 21 3329-3337
[24]Siew M L et al 2009 Positive end-expiratory pressure enhances development of a functional residual capacity in preterm rabbits ventilated from birth J Appl. Physiol. 106(5): 1487-93
[25]Siew M L et al 2009 Inspiration regulates the rate and temporal pattern of lung liquid clearance and lung aeration at birth J Appl. Physiol. 106(6): 1888-95.
[26]te Pas A B et al 2009 Effect of Sustained Inflation Length on Establishing Functional Residual Capacity at Birth in Ventilated Premature Rabbits Pediatric Research 66(3): 295-300.
[27]te Pas A B et al 2009 Establishing Functional Residual Capacity at Birth: The Effect of Sustained Inflation and Positive End-Expiratory Pressure in a Preterm Rabbit Model Pediatric Research 65(5): 537-541.
[28]Kitchen, M. J., R. A. Lewis, et al. (2005). "Phase contrast X-ray imaging of mice and rabbit lungs: a comparative study." Br J Radiol 78(935): 1018-27.
[29]Liu P, Sun J Q, Guan Y J et al 2006 Detection of lung cancer with phase contrastx-ray imaging using synchrotron radiation Conf. Proc. IEEE. Eng. Med. Biol. Soc. 1 2001-2004
[30]Liu P, Sun J Q, Guan Y J, Yue W, Xu L X, Li Y, Zhang G L, Hwu Y, Je J H, Margaritondo G 2008 Morphological study of early stage lung cancer using synchrotron radiation J.Synchrotron Rad. 15 36-42
[31]Sera T, Uesuki K, Yagi N, Umetani K, Kobatake M, Imai S 2008 High resolution visualization of tumors in rabbit lung using refraction contrast x-ray imaging Eur. J. Radiol 3898
[32]Rubenstein E, Giacomini J C, Gordon H J, et al. Xenon K-edge dichromographic bronchography SR-based medical imaging. Nucl Instr and Meth. 1995, A364:360
[33] Giacomini, J. C., H. Gordon, et al. (1998). "Bronchial imaging in humans using xenon K-edge dichromography." Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 406(3): 473-478.
[34]Bayat, S., G. Le Duc, et al. (2001). "Quantitative functional lung imaging with synchrotron radiation using inhaled xenon as contrast agent." Phys Med Biol 46(12): 3287-99.
[35]Chon, D., K. C. Beck, et al. (2007). "Effect of low-xenon and krypton supplementation on signal/noise of regional CT-based ventilation measurements." J Appl Physiol 102(4): 1535-44.
[36]Lam, W. W., D. W. Holdsworth, et al. (2007). "Micro-CT imaging of rat lung ventilation using continuous image acquisition during xenon gas contrast enhancement." J Appl Physiol 103(5): 1848-56.
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