Combined Intravascular Ultrasound and Photoacoustic Imaging of Atherosclerosis

描述(申请人提供)：仅在美国，就有大约500,000例死亡病例是由于血管造影评估认为“微不足道”的斑块破裂造成的。现有的筛查和诊断方法不足以在事件发生前确定可能的受害者。因此，临床上迫切需要一种能够在冠状动脉介入治疗中识别和表征动脉粥样硬化斑块易损性的成像技术。我们研究计划的总体目标是开发一种体内成像技术-结合血管内超声和光声成像-能够可视化动脉粥样硬化斑块的结构和功能属性。该项目的基本假设是，血管内光声(IVPA)成像与血管内超声(IVUS)成像相结合是可能的，并可用于区分易损斑块，从而辅助介入前计划、介入本身，并改善介入后的结果。最重要的是，拟议的光声成像不会显著改变目前的冠状动脉介入治疗方案。必须解决广泛的科学和工程、生物医学和临床问题，以充分探索血管内光声成像在介入心脏病学中的能力。当前项目的中心主题是在广泛的临床研究之前开发和测试IVUS/IVPA联合体内成像系统的原型。因此，我们多学科应用的主要目标是开发一种体内、微创、功能甚至分子特异性的成像技术--结合IVUS/IVPA成像--能够在关键阶段立即和准确地评估动脉粥样硬化斑块的存在和易损性。为了实现我们的目标，首先，我们将基于现有的IVUS成像系统和与可调谐激光光源接口的导管，设计和建造IVUS/IVPA成像系统的原型。此外，我们还将开发信号/图像处理算法，并对系统性能进行优化。其次，我们将开发一种适用于IVUS/IVPA成像系统的新型分子敏感造影剂。第三，我们将测试开发的IVPA/IVUS成像技术在组织模拟模型、3D细胞组织结构、动脉粥样硬化的小动物模型中的应用，最后是人体组织的切除。最后，基于项目期间收集到的见解，我们将设计密集的动物和临床研究，以证明IVUS/IVPA成像系统可能成为介入心脏病学所需的一种优越的临床成像工具。公共卫生相关性：动脉粥样硬化性心血管疾病每年导致1900多万人死亡，而冠心病占死亡人数的大部分。尽管在治疗冠心病患者方面取得了重大进展，但大量表面上健康的患者突然死亡，没有先前的症状。现有的筛查和诊断方法不足以在事件发生前识别可能的受害者--仅在美国，每年就有大约50万人死于血管造影评估认为“微不足道”的斑块破裂。临床上迫切需要一种技术，能够a)识别动脉粥样硬化斑块的存在和位置，b)表征预测斑块破裂的病理特征，包括斑块内大量脂质聚集、纤维帽变薄和纤维帽肩部的巨噬细胞浸润，以及c)指导冠状动脉介入治疗，包括经皮球囊血管成形术、血管内支架置入术、消融/汽化和近距离放射治疗。为了满足这一临床需求，我们建议开发一种先进的、基于导管的超声和光声成像技术，能够可视化动脉粥样硬化斑块的功能特性。因此，我们研究计划的总体目标是开发一种体内、微创、功能甚至分子特异性的成像技术--结合IVUS/IVPA成像--能够在关键阶段立即准确地评估动脉粥样硬化斑块的存在和易损性。为了全面测试IVUS/IVPA成像，必须解决广泛的科学和工程、生物医学和临床问题。目前应用的中心主题有三个：设计和构建IVUS/IVPA成像系统的原型，开发适用于IVUS/IVPA成像系统的新型分子敏感造影剂，以及初步测试开发的IVPA/IVUS成像技术在组织模拟模型、三维细胞组织结构、小动物动脉粥样硬化模型中的应用，最后是切除人体组织。目前的研究旨在证明体内IVUS/IVPA成像是实用和可行的。在这项研究结束后，并与业界合作伙伴合作，我们将准备建立临床IVUS/IVPA成像系统，展示开发的技术在介入心脏病学中的应用。

DESCRIPTION (provided by applicant): In the United States alone, approximately 500,000 deaths will result from rupture of plaques considered "insignificant" on an angiographic evaluation. Available screening and diagnostic methods are insufficient to identify possible victims before the event occurs. Therefore, there is a definite and urgent clinical need for an imaging technique that can identify and characterize the vulnerability of atherosclerotic plaques during coronary artery interventions. The overall goal of our research program is to develop an in-vivo imaging technology - combined intravascular ultrasound and photoacoustic imaging - capable of visualizing both structural and functional properties of atherosclerotic plaques. The underlying hypothesis of this project is that intravascular photoacoustic (IVPA) imaging combined with intravascular ultrasound (IVUS) imaging is possible and can be used to distinguish vulnerable plaques, thus assisting pre-intervention planning, the intervention itself, and improving the post-intervention outcome. Most importantly, the proposed photoacoustic imaging will not significantly change the current protocol of coronary artery intervention. A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully explore the capabilities of intravascular photoacoustic imaging in interventional cardiology. The central theme of the current project is to develop and test the prototype of the combined IVUS/IVPA in- vivo imaging system prior to extensive clinical studies. Therefore, the main objective of our multi- disciplinary application is to develop an in-vivo, minimally invasive, functional and even molecular specific imaging technology - combined IVUS/IVPA imaging - capable of immediate and accurate assessment of the presence and vulnerability of atherosclerotic plaques at critical stages. To achieve our objective, first we will design and build a prototype of the IVUS/IVPA imaging system based on an available IVUS imaging systems and catheters interfaced with a tunable laser source. Furthermore, we will develop the signal/image processing algorithms and optimize the performance of the system. Second, we will develop a novel molecularly sensitive contrast agent appropriate for the IVUS/IVPA imaging system. Third, we will test the developed IVPA/IVUS imaging technology in tissue-mimicking phantoms, 3-D cell tissue constructs, small animal model of atherosclerosis, and, lastly, excised human tissue. Finally, based on the insights gathered during the project, we will design the intensive animal and clinical studies to demonstrate that the IVUS/IVPA imaging system may become a superior clinical imaging tool needed in interventional cardiology. PUBLIC HEALTH RELEVANCE: Atherosclerotic cardiovascular disease results in more than 19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify possible victims before the event occurs - in the United States alone, approximately 500,000 deaths per year will result from rupture of plaques considered "insignificant" on an angiographic evaluation. There is a definite and urgent clinical need for a technique that can a) identify the presence and location of atherosclerotic plaques, b) characterize pathologic features that predict plaque rupture including large lipid collection within the plaque, thinning of the fibrous cap, and infiltration of macrophages at the shoulders of the fibrous cap, and c) guide coronary artery interventions including percutaneous balloon angioplasty, endovascular stenting, ablation/vaporization and brachytherapy. To address this clinical need, we propose to develop an advanced, catheter-based combined ultrasound and photoacoustic imaging technique capable of visualizing functional properties of atherosclerotic plaques. Therefore, the overall goal of our research program is to develop an in-vivo, minimally invasive, functional and even molecular specific imaging technology - combined IVUS/IVPA imaging - capable of immediate and accurate assessment of presence and vulnerability of atherosclerotic plaques at critical stages. A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully test IVUS/IVPA imaging. The central theme of the current application is threefold: to design and build a prototype of the IVUS/IVPA imaging system, to develop novel molecularly sensitive contrast agent appropriate for IVUS/IVPA imaging system, and to initially test the developed IVPA/IVUS imaging technology in tissue-mimicking phantoms, 3-D cell tissue constructs, small animal model of atherosclerosis, and, finally, excised human tissue. The current study is designed to demonstrate that in-vivo IVUS/IVPA imaging is practical and feasible. At the conclusion of this study and in cooperation with industrial partners, we will be ready to build the clinical IVUS/IVPA imaging system demonstrating the application of developed technology in interventional cardiology.