Cerenkov excited luminescence sheet imaging (CELSI)

切伦科夫激发发光片成像 (CELSI)

• 批准号: 9923639
• 负责人: Brian W. Pogue
• 金额: $ 43.7万
• 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/9923639
• 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 Dose Unit; Radiation Oncology; Rattus; Recovery; Reporter; Research; Resolution; Rodent; Roentgen Rays; Sampling; Scanning; Signal Transduction; Skin; Source; Specificity; Structure; System; Testing; Therapeutic; Thinness; Time; Tissue imaging; Tissues; Tracer; Work; absorption; attenuation; base; cancer imaging; cancer therapy; 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; preclinical imaging; prototype; reconstruction; research and development; response; standard measure; subcutaneous; tomography; tumor; tumor immunology; tumor metabolism; uptake; whole body imaging; 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 Dose Unit; Radiation Oncology; Rattus; Recovery; Reporter; Research; Resolution; Rodent; Roentgen Rays; Sampling; Scanning; Signal Transduction; Skin; Source; Specificity; Structure; System; Testing; Therapeutic; Thinness; Time; Tissue imaging; Tissues; Tracer; Work; absorption; attenuation; base; cancer imaging; cancer therapy; 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; preclinical imaging; 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 深入动物身体的特征。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）尤其有问题，这些肿瘤生长在 身体中间。肿瘤代谢和免疫学最相关的分子示踪剂通常是 在皮下肿瘤的皮肤中成像很好，但是这些图像是高表面的或可以实现的 微观成像。没有方法可以将1-3 cm成像在微摩尔中具有分子灵敏度的组织中 到纳摩尔范围。已经发明了一种新的高分辨率，深层组织，成像方法，在此中 将进一步开发用于在亚微摩尔范围内浓度的全身扫描。 这种新方法使用由线性加速器（Linac）形成的薄薄的Megavolt（MV）X射线 多动物准直仪，以诱导扫描成像（CELSI）的发光的Cherenkov激发。这些床单 被扫除动物以在动物中通过Cherenkov定位激发，允许精确的知识 检测到的光来自哪里。使用时间门控的低光检测器阵列捕获发射 一种类似于板照明显微镜的方法。关键好处是确定空间分辨率 通过Linac梁的尺寸和位置，在原本光学的浑浊样品中。该设计隐含地允许高 精确的空间定位，我们假设并测试线性校正算法的功能 与非线性扩散基于非线性扩散相比 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。 Cerenkov发射会激发任何一种磷光 或荧光分子，用于直接测量新陈代谢或标记分子报告基因。最初的 动物研究表明，可以在非常低的分子探针下以i）治疗剂量实现摄氏 浓度（2GY用纳摩尔探针）或II）适度较高探针剂量的低辐射剂量（0.1 Gy 使用微摩尔探针）。恢复空间分辨率小于300微米的图像很容易实现， 在整个动物的整个身体中。三个参数直接影响图像质量，包括1） 深度，2）递送剂量和3）探针浓度，这些探针浓度将是定量的 检查以定义可接受和生物学相关的操作模式。在这项工作中，图像的系统 开发了多种啮齿动物，检测灵敏度可针对临床Linac中的发光进行优化。一个 商业合作伙伴将提供自定义的简短脉冲线，用于卓越的信号到噪声和生产 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，这对于了解有效概括生长和的肿瘤反应至关重要 胰腺内人类疾病的病理生理学。这种全身高分辨率分子光学成像 与推进对原始癌症模型和内部器官疾病的研究特别相关，这 使用当前的任何分子成像工具都无法很好地解决。