EVOLVING MECHANICS OF INTRALUMINAL THROMBUS: FROM FORMATION TO ORGANIZATION

描述（由申请人提供）：凝血过程是止血的基础，但也可能导致血管疾病进展、介入手术受损和植入心血管器械失效等毁灭性并发症。腔内血栓的破坏性并发症中最值得注意的可能是易损斑块破裂后冠状动脉的急性闭塞，这可能导致猝死。然而，此外，约75%的腹主动脉瘤涉及管腔内血栓，这被认为会对动脉瘤壁的生物力学以及与慢性炎症和向中膜输送氧气相关的生化过程产生不利影响;约21%的颅内囊状动脉瘤介入弹簧圈治疗失败，显然是由于诱导的管腔内凝块缺乏“成熟”;脑血管痉挛是颅内动脉瘤破裂后患者发病率和死亡率的主要原因，其严重程度与凝块负荷和凝块清除率密切相关。管腔内血栓也仍然是许多植入式心血管器械（包括支架、心脏瓣膜和在线血管辅助器械）设计和使用中的限制性问题之一。考虑到管腔内血栓的结构完整性或缺乏结构完整性是其在这些和许多其他心血管疾病和治疗实例中的作用的基础，迫切需要更好地理解潜在的生物力学。所有过去对血凝块机械性质的研究都集中在新形成的主要基于纤维蛋白的凝块或从患者获得的具有未知自然史的成熟凝块上。因此，我们将首先在一个新的、控制良好的体内模型中量化、建模和关联管腔内凝块的演变组成、结构和性质。为此，我们将是第一个使用结构激励约束混合物理论，自然占材料不均匀的组织，包括可能的机械刺激压实的新合成的胶原蛋白的机械性能的演变。我们认为，数据和模型将填补我们理解中的重要空白，从而为我们和其他人在各种心血管问题上的后续工作提供重要基础，从理解疾病进展到设计改进的干预措施和设备。 公共卫生相关性：心血管疾病仍然是美国人死亡和残疾的主要原因。血管疾病进展（包括动脉粥样硬化和动脉瘤）、介入手术（包括治疗动脉粥样硬化的支架和治疗动脉瘤的弹簧圈）受损以及植入的心血管器械（包括心脏瓣膜和心室辅助器械）失效的许多破坏性并发症直接由腔内血凝块引起。由于凝块的结构完整性是其在大多数并发症中的作用的基础，因此需要更好地了解潜在的生物力学。我们将开发一种新的体内凝块模型，并成为第一个量化凝块组成，结构和机械性能作为其开发时间的函数。我们认为，这种量化将是许多基础科学和工业研究，寻求改善血管健康的基础。

DESCRIPTION (provided by applicant): The clotting process is fundamental to hemostasis, yet it can also lead to devastating complications in vascular disease progression, compromised interventional procedures, and failure of implanted cardiovascular devices. Perhaps most notable of the devastating complications of intraluminal thrombus is the acute occlusion of a coronary artery following rupture of a vulnerable plaque, which can cause sudden death. In addition, however, ~75% of abdominal aortic aneurysms involve an intraluminal thrombus, which is thought to adversely affect the biomechanics of the aneurysmal wall as well as biochemical processes related to chronic inflammation and oxygen transport to the media; ~21% of interventional coil treatments of intracranial saccular aneurysms fail, apparently due to the lack of "maturation" of the induced intraluminal clot; and severity of cerebral vasospasm, the leading cause of morbidity and mortality in patients surviving the rupture of an intracranial aneurysm, correlates strongly with clot burden and clot clearance rates. Intraluminal thrombus also continues to be one of the limiting concerns in the design and use of many implanted cardiovascular devices, including stents, heart valves, and in-line vascular assist devices. Given that the structural integrity, or lack thereof, of the intraluminal thrombus is fundamental to its role in these and many other examples of cardiovascular disease and treatment, there is a pressing need to understand better the underlying biomechanics. All past studies of the mechanical properties of blood clots have focused on either newly formed, primarily fibrin-based, clots or mature clots having an unknown natural history that were obtained from patients. We will be first, therefore, to quantify, model, and correlate the evolving composition, structure, and properties of intraluminal clots in a novel, well controlled in vivo model. Toward this end, we will be the first to use a structurally-motivated constrained mixture theory that accounts naturally for the evolution of mechanical properties of materially nonuniform tissues, including possible mechano-stimulated compaction of the newly synthesized collagen. We submit that both data and model will fill important gaps in our understanding and thereby provide an important foundation for subsequent work by us and others on diverse cardiovascular problems ranging from understanding disease progression to designing improved interventions and devices. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the leading cause of death and disability among Americans. Many devastating complications of vascular disease progression (including atherosclerosis and aneurysms), compromised interventional procedures (including stents for treating atherosclerosis and coils for treating aneurysms), and failures of implanted cardiovascular devices (including heart valves and ventricular assist devices) result directly from intraluminal blood clots. Because the structural integrity of the clot is fundamental to its role in most of these complications, there is a need to understand better the underlying biomechanics. We will develop a novel in vivo clot model and be the first to quantify clot composition, structure, and mechanical properties as a function of its time of development. We submit that such quantification will be fundamental to many basic science and industrial studies seeking to improve vascular health.