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; 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）：主动脉解剖是一个威胁生命的事件；它负责从儿童到年轻人和老年人的年龄范围内的个体发病率和死亡率。当解剖与真实的管腔通信并在主动脉壁内形成所谓的假管腔时，该假管腔可能会保留专利或部分或完全溶栓。越来越多的临床证据表明，完全血栓的假管腔会导致预后的改善，而部分血栓的假管腔可能使墙壁更容易进一步解剖或破裂。然而，迫切需要更好地理解错误的管腔的机制和条件，这些机制期望有一个错误的管腔发展部分或完整的血栓，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虚假管腔内的血流动力学，并且部分血栓解剖是危险的，因为与流动血液接触的壁内血栓持续释放质蛋白可以激活组成型产生的潜在的基质金属蛋白酶在Remnant的壁中，以使其在弱弱的情况下降低。我们将开发第一个数据驱动的，多尺度的，多物理模型的主动脉夹层中壁内血栓总线的生物力学模型。具体而言，我们将扩展并将血液流动，血小板动力学，纤维蛋白组织和纤溶酶传输（Karniadakis组）的多尺度模型与主动脉/纤维蛋白/纤维蛋白/胶原蛋白重塑（Humphrey组）的多尺度模型（HUMPHREY组）进行，这些模型将被告知并验证广泛的新成像和免疫数据的模型动脉瘤（即，在载脂蛋白null小鼠中对血管紧张素II的28天输注）。此外，我们的模型将旨在模拟两种抗凝剂的潜在益处，从而在交付的时间上。实现我们的三个特定目标将大大提高我们对血栓在主动脉夹层中的作用的理解，并有望最终导致预后能力和介入计划的提高。此外，本研究获得的洞察力将具有重要的含义 对于其他许多血管疾病，包括其他动脉的解剖，导管插入后用血栓蛋白治疗伪动脉瘤，以及腹部主动脉瘤内腔内血栓的不同作用和颅内动脉瘤。因此，我们认为该项目具有重要的希望，可以提高我们对血管生物学关键问题的基本理解，并为更好地治疗广泛的临床问题做出贡献。 1