【作者】 张伟；

【导师】 高峰；

【作者基本信息】 天津大学 ， 生物医学工程， 2013， 博士

【摘要】 基于肿瘤与正常组织血红蛋白含氧量差异的扩散光学层析成像(diffuseoptical tomography, DOT)，被称为血氧─DOT (hemoglobin-DOT)，是新兴、具有研究前景的乳腺肿瘤检测方式，能够提供血红蛋白浓度、脂肪和水含量等功能图像，还能够提供细胞核尺寸、组织体积分数等形态学信息可以揭示肿瘤在病理和生理上的异常，有利于甄别良、恶性肿瘤，进行病情分期，但是图像分辨率低，量化精度差，妨碍了血氧─DOT在临床中的应用。采用荧光染料进行扩散光学层析荧光造影成像，称作荧光扩散层析成像(fluorescence diffuse optical tomography,FDOT)。FDOT继承了DOT在探测深度和三维成像上的优势，可以获得功能信息和反映微环境情况的pO2、pH等参数，成像灵敏度高，可以定位早期肿瘤。本文中将FDOT与血氧─DOT相结合，依靠FDOT对肿瘤的高灵敏度来可以提高早期乳腺肿瘤诊断的可靠性。本研究的目标是针对血氧─DOT和FDOT各自的特点，采用FDOT与血氧─DOT联合成像，利用FDOT提供的先验信息引导血氧─DOT重建，改善血氧─DOT的量化度，提高血氧─DOT早期肿瘤诊断的可靠性。与其他多模态成像方式相比，FDOT联合血氧─DOT的方案成本较低，对早期乳腺肿瘤的探测能力高。本研究涉及系统搭建和程序开发，提出了时域扩散荧光─光学混合层析成像的早期乳腺肿瘤诊断方法。完成的具体工作包括：(1)研制了一套基于时间相关单光子计数的32通道时间分辨系统，高重复频率皮秒脉冲半导体激光器输出780nm和830nm的激发光，采用基于时间相关单光子计数技术的方式并行测量获得时间分辨数据。(2)对多通道系统进行调试校正，消除通道光学性能差异和时间原点漂移对图像质量的影响。采用分层扫描/全三维重建的测量方法和阈值优化策略，提高了测量速度。(3)提出了基于广义脉冲谱技术的FDOT引导血氧─DOT的重建算法框架，对FDOT重建出的荧光产率图像进行分割，提取出“感兴趣区域”，引导血氧─DOT重建。(4)通过一系列二维仿体实验，测试了系统的线性响应和灵敏度；通过三维仿体实验，验证了FDOT和血氧─DOT的分层测量/全三维重建能力；通过FDOT引导的血氧─DOT实验，证明了混合层析成像方案能改善血氧─DOT量化精度。(5)进行了三维双波长DOT临床研究。对已诊断出肿瘤的患者进行三维双波长DOT测量，在获得了双波长光学参数的基础上，得到了血红蛋白浓度变化和氧饱和等功能信息，证明了光学层析成像这种无创的功能影像模式具有诊断早期乳腺肿瘤的能力。由于现有的多模态成像系统结构复杂，检测成本高，而且传统的解剖成像方式不适宜为DOT提供先验信息。针对此研发了基于时间相关单光子计数测量模式的时域扩散荧光―光学混合层析成像早期乳腺肿瘤诊断系统，涉及硬件系统的实现和软件系统的开发。包括光源模块，测量模块，数据采集处理模块和计算机控制模块，实现了多通道并行测量的自动化控制。由于已有的乳腺光学层析成像用于早期乳腺肿瘤诊断灵敏度低、量化精度差，提出了扩散荧光―光学联合层析成像早期乳腺肿瘤检测方法，将高对比度的FDOT与反映功能信息的内源性DOT相融合，提取出患病区域的目标，进而为下一步DOT重建提供精确的位置信息。将双波长DOT技术应用于人体三维乳腺成像，采用基于广义脉冲谱技术的特征数据算法重建，能够获得乳腺诊断的功能影像信息。证明时域血氧─DOT方法可用于早期乳腺肿瘤的诊断。更多还原

【Abstract】 The endogenouse-contrast-based diffuse optical tomography, referred ashemoglobin-DOT, is emerging as a potential imaging technique for breast cancerdetection. Hemoglobin-DOT provides not only the structural information, but also thefunctional images including oxy-hemoglobin, deoxy-hemoglobin, lipid and watercontent as well as the morphological images including nucleus size and volumefraction. It discloses the pathological and physiological abnormalities of in vivotissues by measuring its hemodynamic patterns is more preferred for differentiationbetween benign and malignant lesions as well as for tumor staging. However,hemoglobin-DOT suffers from low spatial resolution and quantitative reconstruction,that it is still clinically difficult to use hemoglobin-DOT. DOT with the use ofexogenous fluorescence dyes, referred to as fluorescence diffuse optical tomography(FDOT), not only inherits the advantages of DOT in detection depth andthree-dimension (3D) imaging, but also improves detection sensitivity as well as itspotential to simultaneously access tissue functionality and micro-environment indicessuch as pO2, pH etc. FDOT can markedly enhance detection sensitivity of breasttumor imaging and is reliable in tumor localization. Due to the high specificity ofFDOT, in the study, a combination of FDOT and hemoglobin-DOT is proposed forimproving the reliability of hemoglobin-DOT for early breast tumor diagnosis.The goal of this study is to make use of the advantages of FDOT andhemoglobin-DOT, a combination of both approaches is pursued, and that thequantitative accuracy of hemoglobin-DOT is improved and the capability of detectingearly lesions is enhanced. Compared with other multi-modality imaging systems, thishybrid scheme has the potential of cost-effectiveness of instrumentation and a highcapability of detection. This study involves imaging hardware implementation andsoftware development necessary for achieving the goal, and a combined time-domainfluorescence and hemoglobin-DOT image reconstruction scheme. The detail tasksinclude:(1) A time-domain32channels time resolved system based on thetime-correlated single photon counting technique (TCSPC) is developed. A highfrequence pico-second pulsed diode lasers at the wavelengths of780nm and830nm is employed as the source, a4-channel TCSPC module is applied to acquire the2-wavelength outward time-resolved flux.(2) Instrument calibration is used to eliminate the time-origins drifting anddifferences between system channels, which have a significant impact onreconstruction image quality. The3-D measurement is performed in a layered2-Dmeasuring way, and a counting threshold strategy is adopted to further optimize themeasurement performance and reduce the data-acquisition time.(3) A fluorescence-guided hemoglobin image reconstruction shceme within theframework of the generalized pulse spectrum technique (GPST) is proprosed. Thefluorescence yield image is segmented to extract the region of interest, which couldprovide a priori information to instruct hemoglobin-DOT reconstruction.(4) The linearity and sensitivity of the system responses to optical andfluorescence inclusions of various concentrations are assessed by using2-D scheme,respectively. The feasibility of3-D fluorescence-and hemoglobin-DOT is justifiedusing a realistic layered2D measuring and full3-D reconstructing strategy.Fluorescence-guided hemoglobin-DOT experiment is performed and demonstratedthat the reconstruction accuracy in hemoglobin-DOT could be significantly improvedby the regularization of a priori fluorescence location.(5) Clinicaly3-D hemoglobin-DOT has been studied.3-D2-wavelength DOTmeasurement is implemented to the MRI confirmed breast tumor, and reported thelesions could be identified by the hemoglobin concentration and oxygen saturationinformations, which prove that3-D hemoglobin-DOT is a useful technique for earlybreast tumor diagnosis.The existing multi-modality systems are usually structure complicated and veryexpensive in clinic usage. Moreover, traditional structure imaging modals are notsensitive to early tumor, that it is difficult to offer a priori information tohemoglobin-DOT. To cope with these limitations metioned above, a hybrid scheme oftime-domain fluorescence and hemoglobin tomographic imaging system based on thetime-correlated single photon counting technique is developed for early breast tumordiagnosis.A fluorescence-guided hemoglobin image reconstruction shceme is proposed, forthe reason that hemoglobin-DOT is low in sensitivity and reconstruction quanlity.Under this algorithm framework, fluorescence yield image is segmented to extract the region of interest, which could provide a priori information to instructhemoglobin-DOT reconstruction.In vivo3-D hemoglobin-DOT based on GPST could offer functional information,is tested an usful tool for early breast tumor diagnosis.更多还原