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，但它也可能导致血管疾病进展、介入程序受损和植入心血管装置失败等破坏性并发症。也许最显著的破坏性并发症的腔内血栓是急性冠状动脉闭塞易损斑块破裂后，可导致猝死。此外，75%的腹主动脉瘤涉及腔内血栓，这被认为会对动脉瘤壁的生物力学以及与慢性炎症和向介质输送氧气相关的生化过程产生不利影响；~21%的颅内囊状动脉瘤介入线圈治疗失败，显然是由于诱导的腔内血栓没有“成熟”；脑血管痉挛的严重程度，是颅内动脉瘤破裂存活患者发病率和死亡率的主要原因，与血块负荷和血块清除率密切相关。腔内血栓也一直是许多植入式心血管装置（包括支架、心脏瓣膜和血管辅助装置）设计和使用中的限制因素之一。鉴于腔内血栓的结构完整性或缺乏完整性是其在这些和许多其他心血管疾病和治疗中的作用的基础，因此迫切需要更好地了解其潜在的生物力学。过去对血凝块力学特性的所有研究都集中在从患者身上获得的新形成的、主要基于纤维蛋白的血凝块或具有未知自然史的成熟血凝块。因此，我们将首先在一种新的、控制良好的体内模型中量化、建模并关联腔内血块的组成、结构和特性的演变。为此，我们将是第一个使用结构驱动约束混合理论的人，该理论自然地解释了材料非均匀组织的机械特性的演变，包括新合成的胶原蛋白可能的机械刺激压实。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，从了解疾病进展到设计改进的干预措施和设备。

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.