Optical Fluorescence and X-Ray Computed Tomography Scanner for Small Animal In-Vi

描述（由申请人提供）：本申请的总体目标是为荧光报告探针开发一种定量体内小动物成像系统，该系统将荧光发光计算机断层扫描（FLECT）与X射线计算机断层扫描（CT）融合在一起。提出的双模成像系统不仅将为更好地了解体内细胞或分子水平的生物功能和过程提供研究工具，而且还将有助于新药物治疗的开发并加速其转化为临床。传统的成像方法只能提供二维（2D）荧光表面图像，因此不能显示目标报告系统的实际空间位置和浓度。此外，目前的荧光层析成像（FT）系统仍处于发展阶段，存在一些局限性。首先，这些FT系统假设光学均匀的组织模型，因此，禁止报告探针的位置和浓度的准确定量。其次，平面荧光成像和傅里叶变换都不能提供任何解剖信息。因此，重建的报告探针的位置不能相对于动物的解剖定位。所提出的FLECT/CT系统将从两个方面克服这些限制。首先，我们将利用CT的高空间分辨率获得的解剖信息，并将光学性质分配给各种分节器官。这些不均匀的光学性质图将反过来改善定量荧光图像重建，从而获得准确的报告探针实际空间位置和浓度的图像。其次，来自CT的结构图像将提供解剖学信息，这是将荧光报告探针定位到动物解剖结构所必需的。在第一阶段，我们将进行数值模拟和组织模拟实验，为所提出的FLECT/CT系统提供原理证明。我们将证明(1)将非均匀光学性质图应用于反射反射法重建使得报告探针的定量层析成像成为可能；(2)可以从CT图像中分割出光学性质差异很大的器官的空间图。在第二阶段，将开发一个商业级的反射/CT系统，其中光学和x射线组件共享同一个旋转龙门。我们将开发全自动图像分割方法和为分割器官分配光学参数的不同技术。光学参数将通过(1)简化参数空间中的光学层析成像，(2)不同组织类型中已知的（氧-）血红蛋白浓度，或(3)先前实验的光学参数数据库来确定。最后，将在小动物成像实验中评估该系统的性能。一旦完成，我们的反射/CT系统将为癌症、神经病理学和心血管疾病的研究提供一个强大的工具。

DESCRIPTION (provided by applicant): The overall goal of this application is to develop a quantitative in-vivo small animal imaging system for fluorescent reporter probes that fuses fluorescence light emitting computed tomography (FLECT) with X- ray computed tomography (CT). The proposed dual-modality imaging system will not only provide a research tool for better understanding of biological function and processes on a cellular or molecular level in-vivo, but will also aid the development of new drug therapies and accelerate their translation into the clinic. Conventional imaging methods only provide two-dimensional (2D) fluorescence surface images and, hence, do not reveal the actual spatial location and concentration of the targeted reporter system. Furthermore, current fluorescence tomography (FT) systems are still in a developing stage and suffer from several limitations. First, these FT systems assume optically uniform tissue models that, consequently, prohibit the accurate quantification of the reporter probe's location and concentration. Second, neither planar fluorescence imaging nor FT provides any anatomical information. Hence, the reconstructed reporter probe location cannot be localized relative to the animal's anatomy. The proposed FLECT/CT system will overcome these limitations in two ways. First, we will leverage the anatomical information gained from CT with its high spatial resolution and assign optical properties to various segmented organs. These non-uniform optical property maps will in turn improve quantitative fluorescence image reconstruction leading to accurate images about the reporter probe's actual spatial location and concentration. Second, structural images from CT will provide the anatomical information that is necessary for co-locating the fluorescent reporter probe to the animal's anatomy. In Phase 1, we will perform numerical simulations and tissue phantom experiments that will provide a proof of principle for the proposed FLECT/CT system. We will demonstrate that (1) applying non-uniform optical property maps to FLECT reconstructions makes quantitative tomographic imaging of reporter probes feasible and (2) spatial maps of organs with largely varying optical properties can be segmented from CT images. In Phase 2, a commercial grade FLECT/CT system will be developed where the optical and X-ray components share the same rotating gantry. We will develop fully automated image segmentation methods and different techniques for assigning optical parameters to segmented organs. The optical parameters will be determined by (1) optical tomography in a reduced parameter space, (2) from known (oxy-)hemoglobin concentrations in different tissue types, or from (3) optical parameter databases of prior experiments. Last, the performance of the FLECT/CT system will be evaluated in small animal imaging experiments. Once completed, our FLECT/CT system will provide a powerful tool for research of cancer, neurological pathologies, and cardiovascular disease. PUBLIC HEALTH RELEVANCE: The proposed development of a combined fluorescence tomography and X-ray CT imaging system for small animals will reconstruct and display the three-dimensional in-vivo distribution of fluorescent reporter probes for studying molecular processes in a living biological system. The combination of fluorescence tomography with X-ray CT will significantly improve the image quality of fluorescence tomographic images and will co-register them to structural CT images showing the animal's anatomy. Therefore, the proposed imaging system would not only be of great significance for better understanding biological processes and pathological function in living small animals on a cellular and molecular level, but would also aid the development of new drug therapies and accelerate their translation into the clinic.