Vascular endoluminal cellular paving using acoustic radiation force

利用声辐射力进行血管腔内细胞铺路

• 批准号: 8240691
• 负责人: Catalin Toma
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240691
• 关键词: Acoustics; Acute; Address; Allogenic; Angioplasty; Anticoagulants; Aorta; Area; Arterial Fatty Streak; Arterial Injury; Arteries; Autologous; Automobile Driving; Blood Vessels; Cardiovascular system; Catheters; Cell Communication; Cell Survival; Cells; Chronic; Clinical; Coagulation Process; Collaborations; Complex; Contrast Media; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Drug Delivery Systems; Effectiveness; Electrostatics; Endothelium; Energy-Generating Resources; Event; FDA approved; Frequencies; Gases; Glycocalyx; Goals; Grant; Healed; Hyperplasia; In Vitro; Injury; Intervention; Lead; Link; Lipids; Mediating; Medicine; Mesenchymal Stem Cells; Methods; Microbubbles; Microbubbles Ultrasound Contrast Medium; Modeling; Morbidity - disease rate; Motion; Natural regeneration; Oryctolagus cuniculus; Outcome; Particle Size; Patients; Pharmaceutical Preparations; Physics; Physiological; Play; Procedures; Radiation; Research; Role; Safety; Stem cells; Stents; Surface; System; Technology; Testing; Therapeutic; Thrombosis; Time; Tissues; Translating; Treatment Efficacy; Ultrasonography; Universities; absorption; base; clinical application; clinically relevant; design; efficacy testing; falls; healing; improved; in vivo; injured; interest; molecular imaging; mortality; multidisciplinary; novel; particle; percutaneous coronary intervention; prevent; radiation effect; repaired; research study; restenosis; restoration; scaffold; sound; tool

DESCRIPTION (provided by applicant): Coronary stents represent an important tool in the armamentarium available to treat symptomatic atherosclerotic plaques, with over 1 million procedures performed annually in the US alone. The delayed endothelialization of the artery following percutaneous interventions can predispose to acute thrombosis, while the associated injury leads to neo-intimal hyperplasia, both linked to significant clinical events. We are proposing a novel way of addressing this problem by employing endoluminal cellular paving of the stented surface with cells capable of regenerating functional endothelium. To achieve this we are harnessing on the physics of acoustic radiation force, which essentially states that compressible objects in an ultrasound field are displaced away from the energy source due to absorption of the sound wave momentum. This effect is particularly strong with gas-filled lipid microbubbles used as ultrasound contrast agents. By coating the progenitor cells with microbubbles, which can act as the driving engine, the cells can be forced to marginalize and interact with the injured arterial surface when passing by a centrally placed intravascular US catheter. We have a substantial in vitro and in vivo body of data demonstrating the feasibility of the concept for vascular endoluminal cell painting. The current methods for vascular cell seeding require prolonged period of flow cessation, a problem that our current approach minimizes. In collaboration with a multidisciplinary team at the Center for Ultrasound Molecular Imaging and Therapeutics at University of Pittsburgh we will test the therapeutic efficacy of this idea in a step wise fashion testing both autologous endothelial progenitor cells (EPC) and allogeneic mesenchymal stem cells (MSCs), and using electrostatic interaction for cell:bubble association. Under Specific Aim 1, we will define the optimal conditions for delivery of cells to the wall of a vascular phantom in terms of flow conditions, optimal microbubble coating and ultrasound parameters. Potential detrimental effects of the microbubbles and/or ultrasound on cell viability will be tested as well. Using an existing FDA approved ultrasound catheter, we will then translate this approach under Specific Aim 2 to a rabbit model of arterial injury, and test the efficacy of each cell in promoting re-endothelialization and using the 2 different types. Again, the safety of the ultrasound delivery in vivo will be specifically addressed. If successful, these translational experiments could represent the basis developing clinically relevant strategies for accelerated re-endothelialization of coronary stents. PUBLIC HEALTH RELEVANCE: Percutaneous intervention with stents has made a major impact in the treatment of symptomatic atherosclerotic blockages in the coronary arteries. One of the current issues with these vascular scaffolds is the slow healing and tissue integration, in particular with drug coated stents, requiring prolonged treatment with blood thinners. The current application explore a novel way of paving the inside of the stent-treated arteries with progenitor cells, using acoustic energy generated by a catheter inside the vessel, harnessed to selectively push the cells to their target. The progenitor cells will then have the potential to regenerate the normal endothelial lining of healthy arteries, thus preventing clot formation inside the stent, and at the same time inhibit the tissue ingrowth associated with restenosis. This is an entirely new concept, and we will develop the cellular paving method from the bench top to a translational model emulating the proposed clinical application.

描述（由申请人提供）：冠状动脉支架是可用于治疗有症状的动脉粥样硬化斑块的重要工具，仅在美国每年就进行超过 100 万例手术。经皮介入治疗后动脉内皮化延迟可能导致急性血栓形成，而相关损伤会导致新内膜增生，两者都与重大临床事件有关。我们提出了一种解决这个问题的新方法，即使用能够再生功能性内皮的细胞对支架表面进行腔内细胞铺砌。为了实现这一目标，我们正在利用声辐射力的物理学，它本质上表明超声波场中的可压缩物体由于吸收声波动量而远离能量源。对于用作超声造影剂的充气脂质微泡，这种效果尤其强烈。通过在祖细胞上涂上微泡（可以充当驱动引擎），当细胞通过位于中央的血管内超声导管时，可以被迫边缘化并与受损的动脉表面相互作用。我们拥有大量的体外和体内数据，证明了血管腔内细胞涂色概念的可行性。目前的血管细胞接种方法需要长时间的停止流动，我们目前的方法最大限度地减少了这个问题。与匹兹堡大学超声分子成像和治疗中心的多学科团队合作，我们将通过测试自体内皮祖细胞 (EPC) 和同种异体间充质干细胞 (MSC) 逐步测试这一想法的治疗效果。 ，并使用静电相互作用进行细胞：气泡缔合。在具体目标 1 下，我们将根据流动条件、最佳微泡涂层和超声参数定义将细胞输送到血管模型壁的最佳条件。还将测试微泡和/或超声波对细胞活力的潜在有害影响。使用 FDA 批准的现有超声导管，我们将在特定目标 2 下将此方法转化为兔动脉损伤模型，并测试每种细胞在促进再内皮化和使用 2 种不同类型方面的功效。再次，将具体讨论体内超声传递的安全性。如果成功，这些转化实验可以为开发加速冠状动脉支架再内皮化的临床相关策略奠定基础。 公共卫生相关性：经皮支架介入治疗对冠状动脉症状性动脉粥样硬化阻塞的治疗产生了重大影响。这些血管支架目前的问题之一是愈合和组织整合缓慢，特别是药物涂层支架，需要用血液稀释剂进行长期治疗。目前的应用探索了一种用祖细胞铺平支架处理的动脉内部的新方法，利用血管内导管产生的声能，选择性地将细胞推向目标。然后，祖细胞将有可能再生健康动脉的正常内皮衬里，从而防止支架内形成凝块，同时抑制与再狭窄相关的组织向内生长。这是一个全新的概念，我们将开发蜂窝铺路方法，从实验室到模拟所提出的临床应用的转化模型。