High resolution 3D functional imaging of cerebrovascular perfusion in mice

小鼠脑血管灌注的高分辨率 3D 功能成像

• 批准号: 7841429
• 负责人: Ruikang Wang
• 金额: $ 15.37万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841429
• 关键词: Acute; Affect; Aftercare; Algorithms; Alteplase; Angiography; Animals; Architecture; Beds; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular Occlusions; Cerebrum; Clinical; Complement; Confocal Microscopy; Contrast Media; Craniotomy; Data; Diagnosis; Dimensions; Disease; Dyes; Environment; Enzymes; Etiology; Experimental Models; Functional Imaging; Functional disorder; Future; Histopathology; Human; Image; Imagery; Imaging Device; Imaging Techniques; Individual; Infarction; Injection of therapeutic agent; Injury; Intervention; Ischemic Brain Injury; Ischemic Stroke; Laboratory Research; Lasers; Life; Light; Microcirculation; Microcirculatory Bed; Modeling; Monitor; Mus; Neurologic; Noise; Operative Surgical Procedures; Optics; Organ; Outcome; Outcomes Research; Performance; Perfusion; Property; Reperfusion Therapy; Research; Research Personnel; Resolution; Rheology; Sampling; Scanning; Signal Transduction; Speed; Stroke; Surface; System; Techniques; Therapeutic Intervention; Thrombosis; Time; Tissue Sample; Tissues; Trees; Vascular Diseases; Vascular blood supply; blood perfusion; capillary; cerebrovascular; cerebrovascular imaging; cranium; design; disease diagnosis; imaging modality; improved; microangiography; mouse model; novel; novel therapeutics; optical imaging; prevent; prototype; research study; tool

DESCRIPTION (provided by applicant): Non-invasive techniques for imaging blood flow - down to capillary-level resolution - are of paramount importance in order to research and diagnose diseases that have vascular etiology or involvement. Current optical imaging techniques are able to achieve this resolution, but most are typically confined to two dimensions, such as laser-speckle and optical intrinsic-signal imaging techniques, while other techniques, like confocal microscopy, has limited imaging depth (<300¿m). However, a three-dimensional (3D) visualization of vascular blood perfusion deep within microcirculatory beds at capillary-level resolution is often required to reveal the detailed architecture of the perfused microvascular network so that the volumetric rheology and perfusion status of the tissue can be quantified. We propose to develop, optimize, and characterize 3D optical micro-angiography (OMAG), a novel, non-invasive optical imaging method that can be used to assess vascular perfusion at capillary-level resolution, deep within microcirculation beds. OMAG involves shining a near infrared light onto a living sample and then analyzing the backscattered light using novel algorithms to obtain, in parallel, volumetric microstructural architecture and blood perfusion images. We will develop rigorous mathematical and experimental models of the backscattering signals originating from a tissue sample in order to better understand how OMAG senses blood flow. We will develop OMAG algorithms to quantitatively assess dynamic blood perfusion in tissue. We will utilize a mouse model (under either normal or pathophysiologic conditions) to assist in developing OMAG. We will obtain transcranial images of cerebral blood flow in the mice and will use the data to improve and validate the OMAG system. This mouse model was chosen because it has been found to be a useful tool in quantifying cerebral blood flow in individual vessels and tissues, in order to better understand mechanisms of human cerebrovascular disease and therapeutic interventions. We will manipulate cortical blood flow by inducing acute thrombotic ischemic stroke (ATIS) in the mice. We will correlate the blood flow images obtained by OMAG with the expected outcomes (experimental end points) of the models. We will also verify the usefulness of OMAG for studying experimental stroke and the effects of pharmacological interventions by confirming that thrombolytic enzyme, tissue plasminogen activator accelerates reperfusion and/or prevents thrombosis progression during ATIS in mice. An exciting aspect of this project is that in the preliminary studies, we have consistently achieved high-quality OMAG images of blood perfusion through the cerebrovascular tree down to the capillary level in mice. These images were obtained through the intact skull of the mouse without the need for dye injections, contrast agents, or surgical craniotomy. Using our preliminary OMAG system, we have been able to capture focal cerebral perfusion cessation during experimental ischemic stroke, with subsequent visualization of the spatial progression of cerebrovascular occlusions over time. The immediate outcomes of this research are twofold: a) a new imaging tool that will allow researchers and clinicians to better understand the pathophysiology of tissue perfusion and ischemic tissue injury, and b) specifically, with respect to cortical brain injury and ischemic tissue perfusion important new information will be obtained in a well-established mouse model. Once validated in this way, we anticipate that the OMAG system will be used to considerable advantage in future studies of stroke and other disorders as new questions arise and as new therapeutic strategies are developed. The OMAG system that we intend to develop in the proposed research will be compact, fast, optically stable, and easily implemented and adaptable in both research laboratories and clinical environments.

描述（由申请人提供）：血流成像的非侵入性技术-低至毛细血管水平分辨率-对于研究和诊断具有血管病因或累及的疾病至关重要。目前的光学成像技术能够实现这种分辨率，但大多数通常局限于二维，如激光散斑和光学固有信号成像技术，而其他技术，如共焦显微镜，具有有限的成像深度（<300 μ m）。然而，通常需要以毛细血管水平分辨率对微循环床深处的血管血液灌注进行三维（3D）可视化，以揭示灌注的微血管网络的详细结构，从而可以量化组织的体积流变学和灌注状态。我们建议开发，优化和表征3D光学微血管造影术（OMAG），一种新型的，非侵入性的光学成像方法，可用于评估血管灌注毛细血管水平的分辨率，深微循环床内。OMAG涉及将近红外光照射到活体样本上，然后使用新算法分析反向散射光，以并行获得体积显微结构结构和血液灌注图像。我们将开发严格的数学和实验模型的后向散射信号源于组织样本，以更好地了解如何OMAG的感觉血流。我们将开发OMAG算法来定量评估组织中的动态血液灌注。我们将利用小鼠模型（在正常或病理生理条件下）来帮助开发OMAG。我们将获得小鼠脑血流的经颅图像，并将使用这些数据来改进和验证OMAG系统。之所以选择这种小鼠模型，是因为它被发现是量化单个血管和组织中脑血流量的有用工具，以便更好地了解人类脑血管疾病和治疗干预的机制。我们将通过诱导小鼠急性血栓性缺血性中风（ATIS）来操纵皮质血流。我们将OMAG获得的血流图像与模型的预期结果（实验终点）相关联。我们还将通过确认溶血栓酶、组织型纤溶酶原激活剂在小鼠ATIS期间加速再灌注和/或防止血栓形成进展来验证OMAG在研究实验性卒中和药理学干预作用中的有用性。该项目的一个令人兴奋的方面是，在初步研究中，我们始终获得了小鼠脑血管树至毛细血管水平的高质量血液灌注OMAG图像。这些图像是通过小鼠的完整颅骨获得的，而不需要染料注射、造影剂或外科开颅术。使用我们初步的OMAG系统，我们已经能够捕获局灶性脑灌注停止在实验性缺血性中风，随后可视化的空间进展的脑血管闭塞随着时间的推移。这项研究的直接结果是双重的：a）一种新的成像工具，将使研究人员和临床医生更好地了解组织灌注和缺血性组织损伤的病理生理学，和B）具体而言，关于皮质脑损伤和缺血性组织灌注的重要新信息将在一个完善的小鼠模型中获得。一旦以这种方式得到验证，我们预计OMAG系统将在未来的中风和其他疾病的研究中发挥相当大的优势，因为新的问题出现了，新的治疗策略正在开发中。我们打算在拟议的研究中开发的OMAG系统将是紧凑，快速，光学稳定，易于实施和适应研究实验室和临床环境。