Rupture prone plaque diagnosis by IVUS-guided time-resolved spectroscopy

描述(由申请人提供)：这项竞争性续展申请将推动血管内双模式技术的发展，用于诊断动脉壁病理，包括容易破裂的(脆弱的)动脉粥样硬化斑块。我们建议优化、构建和测试一种独特的临床兼容系统，该系统将快速、时间分辨荧光光谱(TRFs)与血管内超声(IVUS)相结合，以在回拉运动下动态评估动脉粥样硬化斑块的组成，血管内超声(IVUS)允许可视化重建斑块微观解剖和指导TRFs测量。由此产生的系统将能够检测和监测具有临床相关性的动脉粥样硬化病变的生化、功能和结构特征(例如，预测斑块破裂)。在这一新的应用中，我们建议推进这种双模式技术的集成和体内验证，并通过以下具体目标为临床血管内评估做准备：目的1.设计、构建和优化原型双模式(TRFs-IVUS)血管内导管，以展示(1)将TRFs与单元件换能器IVUS导管集成的技术可行性；(2)双模式系统提供有关动脉壁成分和结构的实时诊断反馈信息的能力。为了实现这一点，我们将建立两个导管系统，并在体外验证它们的技术性能(组织模型、动脉节段)。目的2.在体上验证连续/径向TRFs数据采集在回拉运动和IVUS引导下的有效性。为了实现这一点，我们将使用导管组件I在动脉粥样硬化猪模型中进行腔内操作。我们将确定在脉动血流条件下动态TRFs采集的最佳实验参数，评估双模式导管的极限设计因素，并确定设计和实验参数以优化TRFs和IVUS数据的联合配准。目的3.确定优化的导管组件II在包括冠状动脉在内的各种动脉床上进行血管内操作的能力，并确定其诊断能力。这将通过在动脉粥样硬化猪模型(体内)和人类冠状动脉节段(体外)中测试双模式技术来实现。这将证明导管原型在血流和运动条件下有效地在血管内操作、收集共同登记的TRFs/IVUS和产生诊断信息的可行性。目的4.建立TRFS-IVUS动态、近实时(几秒)定性、鉴别和可视化相关血管内病变的可行性。为了实现这一点，我们将开发计算/分类模型，使用源自TRFs数据、IVUS RF数据(“虚拟组织学”)和IVUS灰度(“回声”)图像的特征；将这些模型应用于双模式测量(目标2和3)得出的数据，以确定建议方法的敏感性、特异性和总体预测价值；并对照组织病理学验证这些数据。目的5.准备并提交FDA赞助商-调查员研究设备豁免(IDE)的申请，用于未来对双模式系统的临床评估。这将利用在AIM 3和AIM 4中获得的实验数据和结果，以及FDA要求的用于评估安全性、有效性和诊断能力的附加测试。

DESCRIPTION (provided by applicant): This competitive renewal application will advance the development of an intravascular bi-modal technology for diagnosis of arterial wall pathologies including rupture-prone (vulnerable) atherosclerotic plaques. We propose to optimize, construct and test a unique clinically-compatible system that combines fast, time-resolved fluorescence spectroscopy (TRFS) to dynamically evaluate atherosclerotic plaque composition under pull-back motion, with intravascular ultrasound (IVUS) that allows for both visual reconstruction of plaque microanatomy and guidance of TRFS measurements. The resulting system will enable detection and monitoring of biochemical, functional and structural features of atherosclerotic lesions with clinical relevance (e.g. predictive of plaque rupture). In this renewal application, we propose to advance the integration and in-vivo validation of this bi-modal technology and prepare for clinical intravascular evaluation through the following specific aims: Aim 1. To design, construct and optimize prototype bi-modal (TRFS-IVUS) intravascular catheters to demonstrate (1) the technical feasibility of integrating the TRFS with single element transducer IVUS catheters and (2) the ability of the bi-modal system to provide real-time diagnostic feedback information concerning arterial wall composition and structure. To achieve this we will build two catheter systems and validate their technical performance in-vitro (tissue phantoms, arterial segments). Aim 2. To demonstrate in-vivo the validity of continuous/radial TRFS data acquisition under pull-back motion and under IVUS guidance. To achieve this we will conduct transluminal procedures in an atherosclerotic pig model using Catheter Assembly I. We will determine optimal experimental parameters for dynamic TRFS acquisition in pulsatile blood flow conditions, evaluate the limiting design factors for the bi-modal catheter, and determine design and experimental parameters to optimize co-registration of TRFS and IVUS data. Aim 3. To determine the ability of optimized Catheter Assembly II to operate intravascularly in various arterial beds, including coronary arteries, and to determine its diagnostic capability. This will be achieved by testing the bi-modal technique in an atherosclerotic pig model (in-vivo) and in human coronary segments (ex-vivo). This will demonstrate the feasibility of the catheter prototype to operate effectively intravascularly under conditions of blood flow and motion, to collect co-registered TRFS/IVUS, and to generate diagnostic information. Aim 4. Establish the feasibility of TRFS-IVUS to dynamically and in near-real time (few seconds) characterize, discriminate and visualize relevant intravascular pathologies. To achieve this we will develop computational/classification models employing features derived from TRFS-data, IVUS RF-data ("virtual histology") and IVUS greyscale ("echogenicity") images; apply these models to data derived from bi-modal measurements (Aims 2 & 3) to determine the sensitivity, specificity, and overall predictive value of the proposed method; and validate this data against tissue histopathology. Aim 5. Prepare and submit an application for an FDA Sponsor-Investigator Investigational Device Exemption (IDE) for future clinical evaluation of the bi-modal system. This will make use of experimental data and results obtained in Aim 3 and Aim 4 and additional tests for evaluation of safety, effectiveness, and diagnostic capabilities as required by the FDA.