Multiscale, Multiphysics Model of Thrombus Biomechanics in Aortic Dissection

主动脉夹层血栓生物力学的多尺度、多物理模型

• 批准号: 9131777
• 负责人: Jay D. Humphrey
• 金额: $ 50.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131777
• 关键词: Abdominal Aortic Aneurysm; Accounting; Address; Age; Aneurysm; Angiotensin II; Animal Model; Aortic Rupture; Apolipoproteins; Arteries; Attention; Biological; Biology; Biomechanics; Biomedical Engineering; Blood; Blood Platelets; Blood Vessels; Blood flow; Blunt Trauma; Carotid Arteries; Catheterization; Cells; Cervical; Chest; Child; Clinical; Coagulants; Coagulation Process; Collagen; Collagen Fiber; Communities; Computer Simulation; Coupled; Data; Devices; Diagnosis; Dilatation - action; Disease; Dissecting aortic aneurysm; Dissection; Ehlers-Danlos Syndrome; Elderly; Event; Fibrin; Fibrinolysis; Genetic; Geometry; Growth and Development function; Healed; Health; Image; Individual; Infusion procedures; Intervention; Intracranial Aneurysm; Kinetics; Knockout Mice; Knowledge; Legal patent; Life; Liquid substance; Loeys-Dietz Syndrome; Marfan Syndrome; Matrix Metalloproteinases; Mechanics; Medical Imaging; Modeling; Morbidity - disease rate; Patients; Plasmin; Play; Pseudoaneurysms; Research; Role; Rupture; Stress; Testing; Thoracic Aortic Aneurysm; Thrombin; Thrombosis; Thrombus; Time; Vascular Diseases; biomechanical model; computer framework; design; healing; hemodynamics; improved; insight; model development; mortality; mouse model; multi-scale modeling; novel; outcome forecast; prognostic; subcutaneous; young adult

DESCRIPTION (provided by applicant): Aortic dissection is a life threatening event; it is responsible for significant morbidity and mortality in individuals ranging in age from children to young and older adults. When a dissection communicates with the true lumen and forms a so-called false lumen within the aortic wall, this false lumen may remain patent or become either partially or completely thrombosed. Increasing clinical evidence suggests that a completely thrombosed false lumen results in an improved prognosis whereas a partially thrombosed false lumen may render the wall more vulnerable to further dissection or rupture. Yet, there is a pressing need to understand better the mechanisms by which, and conditions under which, a false lumen is expected to develop either a partial or a full thrombus and why the latter is beneficial. We hypothesize that the extent of thrombus formation depends primarily on the hemodynamics within the false lumen and that partially thrombosed dissections are dangerous because the continued release of plasmin by an intramural thrombus in contact with flowing blood can activate constitutively produced, latent matrix metalloproteinases within the remnant aortic wall, which in turn weaken the wall. We will develop the first data-driven, multiscale, multiphysics model of the biomechanics of intramural throm- bus in aortic dissection. Specifically, we will extend and then couple a multiscale model of blood flow, platelet kinetics, fibrin organization, and plasmin transport (Karniadakis group) with a multiscale model of aortic wall mechanics and fibrin/collagen remodeling (Humphrey group) that will be informed and validated with extensive new imaging and immuno-histological data from the most widely accepted mouse model of dissecting aortic aneurysms (i.e., 28 day infusion of angiotensin II in the apolipoprotein null mouse). In addition, our model will be designed to simulate the potential benefits of two anti-coagulants in terms of the time(s) of delivery. Realization of our three Specific Aims will significantly increase our understanding of roles of thrombus in aortic dissection, with the promise of eventually leading to an improved prognostic capability and interventional planning. In addition, insight gained in this study will have important implications for a host of other vascular conditions, including dissections of other arteries, treatment of pseudo-aneurysms with thrombin following catheterization, and the different roles of intraluminal thrombus in abdominal aortic aneurysms and intracranial aneurysms. We submit, therefore, that this project has significant promise to increase our basic understanding of a key issue in vascular biology as well as to contribute to treating better a broad class of clinical problems. 1

描述（由申请人提供）： 主动脉夹层是一种危及生命的事件；它导致从儿童到年轻人和老年人的各个年龄段的个体的显着发病率和死亡率。当夹层与真腔连通并在主动脉壁内形成所谓的假腔时，该假腔可能保持开放或部分或完全血栓形成。越来越多的临床证据表明，完全血栓形成的假腔可改善预后，而部分血栓形成的假腔可能使假腔壁更容易进一步剥离或破裂。然而，迫切需要更好地了解假腔预计会形成部分或全部血栓的机制和条件，以及为什么后者是有益的。我们假设血栓形成的程度主要取决于假腔内的血流动力学，并且部分血栓形成的夹层是危险的，因为壁内血栓与流动的血液接触而持续释放纤溶酶，可以激活残余主动脉壁内组成性产生的潜在基质金属蛋白酶，从而削弱主动脉壁。我们将开发第一个数据驱动、多尺度、多物理场的主动脉夹层壁内血栓生物力学模型。具体来说，我们将扩展血流、血小板动力学、纤维蛋白组织和纤溶酶转运的多尺度模型（Karniadakis 组）与主动脉壁力学和纤维蛋白/胶原重塑的多尺度模型（Humphrey 组），并将其与来自最广泛接受的主动脉夹层小鼠模型的大量新成像和免疫组织学数据进行信息和验证。 动脉瘤（即在载脂蛋白缺失小鼠体内输注血管紧张素 II 28 天）。此外，我们的模型将旨在模拟两种抗凝血剂在给药时间方面的潜在益处。我们三个具体目标的实现将显着增加我们对血栓在主动脉夹层中的作用的理解，并有望最终提高预后能力和介入规划。此外，本研究中获得的见解将产生重要影响 用于许多其他血管疾病，包括其他动脉夹层、导管插入后用凝血酶治疗假性动脉瘤，以及腔内血栓在腹主动脉瘤和颅内动脉瘤中的不同作用。因此，我们认为该项目具有显着的前景，可以增加我们对血管生物学关键问题的基本理解，并有助于更好地治疗广泛的临床问题。 1