Extended short wave infrared three-dimensional fluorescence and X-ray CT molecular tomography (SWIR FMT)

近红外(NIR)荧光成像在过去的20年里被认为是用于生物和临床成像的。与可见光相比，近红外光可以穿透组织几厘米，因为光衰减减少。为了实现体内的定量和三维荧光成像，我们开发了荧光分子层析成像(FMT)，并使用不同类别的荧光剂演示了动物和人类的生物功能读数。我们进一步开发了混合FMT-XCT，通过将X射线计算机断层扫描(XCT)系统整合到与FMT系统相同的机架上实现。我们发现，混合系统不仅为荧光图像添加了解剖学参考，而且通过将XCT信息输入FMT反演码进行衰减校正和反问题的改进正则化，实现了比独立FMT更准确的FMT重建。近年来，FMT-XCT已被用于高分辨率三维成像，用于动物和人类的骨重建、肺癌、哮喘炎症的量化或类风湿性关节炎的表征。目前的应用提出了FMT技术发展的下一个宏伟步骤，通过使系统的操作适应所谓的短波红外窗口(SWIR，1000-1700 nm)，预计将带来所实现的分辨率的显著提高。与NIR-I相比，SWIR的优势在于显著减少了光子散射，这可以显著提高分辨率。目前为止，由于缺乏灵敏的相机和生物相容的荧光探针，SWIR区域的荧光成像一直受到阻碍，但最近有前景的造影剂和相机技术的发展使SWIR区域成为非常有前途的成像应用领域。因此，这项提议的目的是将我们现有的FMT-XCT系统转换为世界上第一个SWIR FMT系统。需要进行两个关键的调整。首先，我们必须使用砷化铟(InGaAs)相机，而不是目前使用的光谱响应有限的NIR-I FMT相机。其次，重要的是修改图像重建中使用的正向问题，以便它能够准确地模拟减少散射时的光子传播。然后，我们将通过评估新的SWIR FMT系统以高空间分辨率精确定位小肿瘤或在体内可视化少量荧光标记细胞的能力来验证该系统。我们预计，SWIR FMT将在荧光成像方面定义一个新的标准，实现前所未有的分辨率和准确性，用于组织的漫射、三维荧光图像。

Near-infrared (NIR) fluorescence imaging has been considered over the past 2 decades for biological and clinical imaging. In contrast to visible light, NIR light can penetrate tissues through several centimeters due to reduced light attenuation. To achieve quantification and three-dimensional fluorescence imaging in-vivo we have developed Fluorescence Molecular Tomography (FMT) and demonstrated readings of biological function in animals and humans using different classes of fluorescent agents. We have further developed hybrid FMT-XCT, achieved by incorporation of an X-ray Computed Tomography (XCT) system onto the same gantry as the FMT system. We showed that the hybrid system not only adds anatomical references to the fluorescence images but also achieves more accurate FMT reconstructions than stand-alone FMT, by feeding XCT information into the FMT inversion code for attenuation correction and improved regularization of the inverse problem. FMT-XCT has been employed in recent years for high resolution three-dimensional imaging of bone remodeling, lung cancer, quantification of asthmatic inflammation or characterization of rheumatoid arthritis in animals and humans. The current application proposes a next grand step into the development of the FMT technology, which is expected to bring a marked improvement in the resolution achieved, by adapting operation of the system to the so called short wave infrared window (SWIR, 1000-1700nm). The advantage of SWIR over NIR-I is that of significant reduced photon scattering, which can lead to significant improvements in the resolution achieved. While fluorescence imaging in the SWIR area has been impeded so far by the lack of sensitive cameras and biocompatible fluorescent probes suitable for this window, the recent development of promising contrast agents and camera technology has rendered SWIR region as very promising for imaging applications. Therefore, the aim of this proposal is to translate our existing FMT-XCT system into the world’s first SWIR FMT system. Two critical adaptations are required. First we must utilize Indium gallium arsenide (InGaAs) cameras, over the limited spectral response NIR-I FMT cameras used today. Second, it is important to modify the forward problem employed in image reconstruction, so that it accurately models photon propagation at reduced scatter. Then, we will validate the new SWIR FMT system by assessing its ability to pinpoint small tumors with high spatial resolution or to visualize small amounts of fluorescence-labelled cells in vivo. We expect that SWIR FMT will define a new standard in fluorescence imaging achieving resolution and accuracy that was never before available to diffuse, three-dimensional fluorescence images of tissues.