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

描述（由申请人提供）：这一竞争性更新申请将促进血管内双模技术的发展，用于诊断动脉壁病变，包括易破裂（易损）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，该系统结合了快速、时间分辨荧光光谱（TRFS）来动态评估后拉运动下动脉粥样硬化斑块的组成，以及血管内超声（IVUS），允许斑块显微解剖的视觉重建和TRFS测量的指导。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）。在本次更新申请中，我们建议通过以下具体目标推进该双模技术的整合和体内验证，并为临床血管内评估做准备：设计、构建和优化原型双模态（TRFS-IVUS）血管内导管，以证明(1)TRFS与单元件换能器IVUS导管集成的技术可行性；(2)双模态系统提供动脉壁组成和结构实时诊断反馈信息的能力。为了实现这一目标，我们将建立两个导管系统并验证其体外技术性能（组织幻影，动脉段）。目标2。验证在回拉运动和IVUS引导下连续/径向TRFS数据采集的体内有效性。为了实现这一目标，我们将在使用导管组件i的动脉粥样硬化猪模型中进行腔内手术。我们将确定脉动血流条件下动态TRFS采集的最佳实验参数，评估双峰导管的限制设计因素，并确定设计和实验参数以优化TRFS和IVUS数据的共同注册。目标3。确定优化后的导管组件II在包括冠状动脉在内的各种动脉床的血管内操作能力，并确定其诊断能力。这将通过在动脉粥样硬化猪模型（体内）和人类冠状动脉段（离体）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运行，收集共同注册的TRFS/IVUS，并生成诊断信息的可行性。目标4。建立TRFS-IVUS在动态和近实时（几秒钟）表征、区分和可视化相关血管内病变的可行性。为了实现这一目标，我们将开发计算/分类模型，利用trfs数据、IVUS rf数据（“虚拟组织学”）和IVUS灰度（“回声性”）图像的特征；将这些模型应用于来自双峰测量的数据（目标2和3），以确定所提出方法的敏感性、特异性和总体预测值；用组织病理学来验证这个数据。目标5。准备并提交FDA申办者-研究者研究器械豁免（IDE）申请，用于双模式系统的未来临床评估。这将利用在Aim 3和Aim 4中获得的实验数据和结果，以及FDA要求的安全性、有效性和诊断能力评估的额外测试。

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.