面向肿瘤恶性生物学研究的小动物全身XCT/DOT/FMT多模态成像先进方法

Optical molecular imaging provides an effective means of exploring the pathogenesis and malignent biological characteristics of tumors in vivo. The modality possesses a combined advantage of high-sensitivity, excellent specificity, tagging multiformity and non-ionizing radiation, rendering it a powerful complement to the established imaging modalities. As one of the advanced forms of optical imaging, Fluorescence Molecular Tomography (FMT) combines diffuse optical tomography (DOT) theory and specific fluorescence-tagging technique to accoplish further quantitative potential. The performances of FMT strongly rely on the three fundamental factors: accuracy of the photon migration modeling, condition of the inverse issue for image reconstruction and completeness of the measured information. For in vivo monitoring of tumor cells and/or their relavant bio-marks in small animal whole-bady as required in research of tumor malignent biology, it is requisite that the limitations of the current FMT methods on the aforementioned aspects should be overcome effectively. This proposal offers to develop advanced theory and technology of multi-modality time-domain (TD) FMT of small animal whole body for in vivo tracing of tumor cells. The project aims at appropreciately advancing the three primary components that are essential to the quantitative performance,sensitivity and specificity of the FMT implementations: 1) To develop an accurate model of the photon migration in highly heterogeneous tissue based on the x-ray computed tomography (XCT) mouse atlas and the region-based DOT methodology; 2) To build a quantitative and robust inversion framework for TD-FMT image reconstruction with the support of XCT structural a-priori；3) To implement a highly synergistic multi-modality scheme of XCT/DOT/FMT and the prototype system with high-sensitivity, high temporally- and spatially-resolutions. The ultimate goal of the research is to transcend the limitations on the state-of-the-art FMT methodologies, and to work out not only an innovative three-dimensional in vivo visualization and quantitation tool for disclosure of the pathological and physiological mechanisms of tumor, but also a beneficial guide to developing in vivo optical imaging techniques for small-animal based tumor malignant biology aplications.

在体光学分子影像提供了探索肿瘤发病机理和恶性生物学行为的有效手段，具有高特异性、高灵敏度和无创性等综合优势，荧光分子层析 (FMT)则是结合扩散光学层析（DOT）理论和特异性荧光标记技术的定量化高级模态，其性能取决于光子输运模型的精确性、图像重建逆问题的适定性和测量信息的完备性等三个基本要素。而在肿瘤恶性生物学研究中肿瘤细胞及标志物在体观测涉及之小动物全身成像应用中，必须有效克服现有FMT方法在上述三个关键因素上的局限性。 本课题以实现小动物模型肿瘤细胞的在体示踪和定量监测为目标，深入探讨基于XCT数字鼠模型和形状DOT理论的组织光子输运精确建模方法、XCT先验信息支持的时域FMT先进反演理论和高灵敏、高时空分辨XCT/DOT/FMT协同测量技术等三个关键科学问题，力争突破现有FMT方法学局限性，建立面向肿瘤恶性生物学研究的小动物全身XCT/DOT/FMT多模态成像先进理论和技术。

在体光学分子影像提供了探索肿瘤发病机理和恶性生物学行为的有效手段，具有高特异性、高灵敏度和无创性等综合优势，荧光分子层析 (FMT)则是结合扩散光学层析（DOT）理论和特异性荧光标记技术的定量化高级模态，其性能取决于光子输运模型的精确性、图像重建逆问题的适定性和测量信息的完备性等三个基本要素。而在肿瘤恶性生物学研究中肿瘤细胞及标志物在体观测涉及之小动物全身成像应用中，必须有效克服现有FMT方法在上述三个关键因素上的局限性。. 本课题以实现小动物肿瘤模型的在体定量化多模态光学成像为目标，围绕上述要素涉及的科学问题展开研究：(1) 建立了基于数字鼠技术和结构/形状DOT重建技术的目标体光学结构的在体获取理论与方法, 为组织体内光子输运过程的精确建模提供必要器官区域及光学参数先验知识；(2)发展了基于辐射传输方程和蒙特卡洛模拟的精确建模方法及高效数值求解和并行计算技术，为图像重建算法研究提供先进光子输运模型和客观的模拟验证工具；(3) 建立基于所发展的先进光子输运精确模型的时域FMT图像反演方法，包括高效全时间分辨DFT图像重建技术和基于早期到达光的高空间分辨率FMT图像重建技术；(4) 建立了一套仿CT扫描式5通道TCSPC-DOT/FMT双模态测量系统和小动物Micro-XCT系统，实现了异机联合测量; (5) 采用数值模拟、仿体实验和在体实验对所发展理论、算法及系统的综合特性和实用能力进行评估。本课题研究在传统FMT局限性上实现突破性创新，为肿瘤恶性生物学研究方向成功提供了一种多模态光学成像方法。研究工作将会继续针对不同细胞来源的肿瘤小动物模型进行展开，实现对肿瘤发生、增殖、转移、调亡、耐药等恶性生物学行为的时空规律在体观测和定量测量。

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