Cerenkov excited luminescence sheet imaging (CELSI)

切伦科夫激发发光片成像 (CELSI)

• 批准号: 9536812
• 负责人: Brian W. Pogue
• 金额: $ 57.86万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9536812
• 关键词: Algorithms; Animals; Aphorisms; Basic Science; Biological; Cancer Model; Clinical; Clinical Oncology; Collaborations; Collimator; Coupled; Custom; Detection; Development; Diffuse; Diffusion; Disease; Dose; Fluorescence; Functional disorder; Gamma Rays; Glioma; Growth; Hospitals; Human; Hybrids; Image; Imaging Device; Immune; Immunologics; Knowledge; Light; Lighting; Linear Accelerator Radiotherapy Systems; Location; Low Dose Radiation; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Metabolism; Methods; Microscopy; Modality; Molecular; Molecular Probes; Monte Carlo Method; Mus; Nature; Noise; Optics; Organ; Pancreas; Performance; Physiologic pulse; Production; Radiation; Radiation Oncology; Rattus; Recovery; Reporter; Research; Resolution; Rodent; Roentgen Rays; Sampling; Scanning; Signal Transduction; Skin; Source; Specificity; System; Testing; Therapeutic; Thinness; Time; Tissue imaging; Tissues; Tracer; Work; absorption; attenuation; base; cancer imaging; cancer therapy; clinical imaging; cost; design; detector; high resolution imaging; human disease; imaging approach; imaging system; in vivo; invention; luminescence; lymph nodes; microscopic imaging; molecular imaging; nanomolar; novel strategies; operation; optical imaging; phosphorescence; pre-clinical; prototype; reconstruction; research and development; response; standard measure; subcutaneous; tomography; tumor; tumor immunology; tumor metabolism; uptake; whole body imaging

ABSTRACT Pre-clinical imaging provides wonderful structural features, but is lacking in the spatial resolution for molecular features which are deep into the animal body. This is due to fundamental physical limits on optical scattering & absorption, and is especially problematic for orthotopic tumors, such as pancreas or glioma, which are grown in the middle of the body. The most relevant molecular tracers of tumor metabolism and immunology are often imaged well through the skin in subcutaneous tumors, but these images are highly superficial or achieved with microscopic imaging. There is no method to image 1-3 cm into tissue with molecular sensitivity in the microMolar to nanoMolar range. A new high-resolution, deep-tissue, imaging approach has been invented, and in this application will be further developed for whole body scanning of concentrations in the sub-microMolar range. The new approach uses thin sheets of MegaVolt (MV) x-ray from a linear accelerator (LINAC) shaped by a multileaf collimator, to induce Cherenkov excitation of luminescence for scanned imaging (CELSI). These sheets are swept over the animal to localize the excitation via Cherenkov within the animal, allowing precise knowledge of where the detected light came from. The emission is captured with time-gated low-light detector array, using an approach similar to sheet illumination microscopy. The key benefit is that the spatial resolution is determined by the LINAC beam size and location in an otherwise optically turbid sample. The design implicitly allows high precision spatial localization, and we hypothesize and test the functionality of linear correction algorithms such as spatial deconvolution and depth-dependent attenuation correction, as compared to non-linear diffusion based reconstruction. The proposed project develops the basic science of a working prototype system, as well as a collaboration to develop a commercial prototype system. The Cerenkov emission excites either phosphorescent or fluorescence molecules, which are used to directly measure metabolism or to tag molecular reporters. Initial animal studies showed CELSI could be achieved either i) at therapeutic doses at a very low molecular probe concentration (2Gy with nanoMolar probe) or ii) low radiation doses for moderately higher probe doses (0.1 Gy with microMolar probe). Recovery of images with spatial resolution less than 300 microns is readily achieved, throughout the entire body of an animal. Three parameters directly influence image quality, including 1) sheet depth, 2) delivered dose, and 3) probe concentration, and the reciprocity between these will be quantitatively examined to define acceptable and biologically relevant modes of operation. In this work, the system to image multiple rodents is developed with detection sensitivity being optimized for luminescence in a clinical LINAC. A commercial partner will provide a custom short pulsed LINAC for superior signal-to-noise and production of a prototype commercial system. Metabolic and immune sensing probes will be optimized for orthotopic pancreas cancer imaging, which is critical to understand responses of tumors that effectively recapitulate the growth and pathophysiology of human disease within the pancreas. This full-body high-resolution molecular optical imaging has particular relevance to advancing research into orthotopic cancer models and internal organ diseases, which are not resolved well with any current molecular imaging tools.

抽象的 临床前成像提供了出色的结构特征，但缺乏分子的空间分辨率 深入到动物体内的特征。这是由于光学散射的基本物理限制和 吸收，对于原位肿瘤（例如胰腺或神经胶质瘤）来说尤其成问题，这些肿瘤生长在 身体的中间。肿瘤代谢和免疫学最相关的分子示踪剂通常是 在皮下肿瘤中可以通过皮肤很好地成像，但这些图像非常肤浅或通过 显微成像。没有方法可以在微摩尔中以分子灵敏度对 1-3 cm 的组织进行成像 至纳摩尔范围。发明了一种新的高分辨率深层组织成像方法 应用程序将进一步开发用于亚微摩尔范围浓度的全身扫描。 新方法使用来自线性加速器 (LINAC) 的兆伏 (MV) X 射线薄片，该加速器由 多叶准直器，诱导切伦科夫激发扫描成像 (CELSI) 发光。这些床单 扫过动物，通过切伦科夫在动物体内定位激发，从而获得精确的知识 检测到的光来自哪里。使用时间选通微光探测器阵列捕获发射 类似于片状照明显微镜的方法。主要好处是空间分辨率是确定的 通过 LINAC 光束尺寸和在其他光学混浊样品中的位置来确定。该设计隐含地允许高 精确空间定位，我们假设并测试线性校正算法的功能，例如 与基于非线性扩散的空间反卷积和深度相关的衰减校正相比 重建。拟议的项目开发了工作原型系​​统的基础科学，以及 合作开发商业原型系统。切伦科夫发射激发磷光 或荧光分子，用于直接测量新陈代谢或标记分子记者。最初的 动物研究表明 CELSI 可以通过以下任一方式实现：i) 在极低分子探针的治疗剂量下 浓度（2Gy，使用纳摩尔探针）或 ii) 低辐射剂量，用于较高的探针剂量（0.1 Gy） 与微摩尔探针）。空间分辨率小于 300 微米的图像的恢复很容易实现， 遍及动物的整个身体。三个参数直接影响图像质量，包括1）片材 深度、2) 输送剂量和 3) 探针浓度，并且这些之间的倒数将被定量 检查以确定可接受的和生物学相关的操作模式。在这项工作中，系统将图像 开发了多种啮齿动物，其检测灵敏度针对临床直线加速器中的发光进行了优化。一个 商业合作伙伴将提供定制的短脉冲直线加速器，以实现卓越的信噪比并生产 原型商业系统。代谢和免疫传感探针将针对原位胰腺进行优化 癌症成像，这对于了解肿瘤的反应至关重要，有效地再现生长和 人类胰腺疾病的病理生理学。这种全身高分辨率分子光学成像 与推进原位癌症模型和内脏器官疾病的研究特别相关， 目前的任何分子成像工具都不能很好地解决这一问题。