RTE/FDPM for optical imaging of cancer in small animal models

描述（由申请人提供）：在拟定的II期研究中，将开发一种商业上可行的软件重建平台，采用辐射传输方程（RTE）的解，用于小动物体内荧光靶点的准确和稳健的体内成像。尽管最近已经引入了小动物光学断层扫描系统，但是当前的系统不采用荧光或生物发光，其已经被限制于平面投影。此外，当前的光学层析成像系统依赖于使用基于扩散近似的时间无关测量和重建算法。然而，众所周知，小鼠的小体积和异质性呈现扩散近似无效的情况。认识到这一点，基于传输的解决方案的RTE已被研究作为一个有前途的替代方案。然而，迄今为止的方法依赖于数值方法，其不具有商业部署所需的准确性或效率。在第一阶段的研究中，用于解决RTE的Transpire算法被成功地应用于概念验证过程，采用了TMF在频域光子迁移（FPDM）方面的专业知识，用于重建三维小鼠模型中的荧光团浓度。第二阶段的研究将扩展这项工作，开发一个基于RTE，断层重建软件平台的FDPM光子迁移。具体目标是：（1）开发优化的3-D RTE解算器，用于在前向和伴随模式中对激发和发射光传播进行建模，简化用于具有非接触、非匹配介质的小动物成像条件;（2）开发采用前向和伴随RTE解算器的自适应非线性算法，用于小动物体积中的荧光产率重建;（3）通过开发从microCT图像自动生成网格来实现混合microCT/光学成像;（4）将上述组件集成到用于FDPM断层摄影重建的自动软件系统中;和（5）通过肽靶向NIR和可见荧光造影剂在异种移植小鼠中的成像定量证明商业可行性。第二阶段的成功完成将产生一个自动化的软件产品，当与西门子在频域荧光小动物成像硬件技术方面的专业知识相结合时，可以产生一个商业上可行的小动物成像系统。拟议的第二阶段研究将大大推进光学小动物成像的最新技术，这可以促进药物发现，并为疾病过程的新认识做出重大贡献。通过临床前验证，拟议的研究最终可以迁移到临床成像领域，如淋巴结映射和黑色素瘤的肿瘤边缘定义。

DESCRIPTION (provided by applicant): In the proposed Phase II research, a commercially viable software reconstruction platform, employing the solution of the radiative transport equation (RTE), will be developed for accurate and robust in vivo imaging of fluorescent targets in small animals. Although small animal optical tomography systems have recently been introduced, current systems do not employ fluorescence or bioluminescence, which have been confined to planar projections. In addition, current optical tomography systems rely on the use of time independent measurements and reconstruction algorithms based on the diffusion approximation. However, it is well known that the small volumes and heterogeneities in mice present conditions where the diffusion approximation is not valid. Realizing this, transport based solutions of the RTE have been researched as a promising alternative. However, approaches to date have relied on numerical methods which do not have the accuracy or efficiency required for commercial deployment. In the Phase I research, Transpire's algorithms for solving the RTE were successfully applied towards a proof-of-concept process, employing BCM's expertise in frequency-domain photon migration (FPDM), for reconstruction of fluorophore concentrations in a 3-D mouse phantom. Phase II research will extend this work to develop an RTE based, tomographic reconstruction software platform for FDPM photon migration. The specific aims are: (1) to develop an optimized 3-D RTE solver for modeling excitation and emission light propagation in forward and adjoint modes, streamlined for small animal imaging conditions with non-contact, non-matching mediums; (2) to develop an adaptive non-linear algorithm employing forward and adjoint RTE solutions for fluorescence yield reconstructions in small animal volumes; (3) to enable hybrid microCT/optical imaging by developing automatic grid generation from microCT images; (4) to integrate the above components into an automated software system for FDPM tomographic reconstruction; and (5) to quantitative demonstrate commercial viability through imaging of a peptide targeted NIR and visible fluorescent contrast agent in xenograft mice. Successful completion of Phase II will result in an automated software product, when combined with BCM's expertise in hardware technologies for frequency-domain fluorescence small animal imaging, can result in a commercially viable small animal imaging system. The proposed Phase II research will substantially advance the state-of-the-art in optical small animal imaging, which could enhance drug discovery as well as contribute significantly to new understanding of disease processes. Through preclinical validation, the proposed research can ultimately be migrated towards clinical imaging in areas such as lymph node mapping and tumor margin definition in melanoma.