Multi-Scale Integration of Extracellular Matrix Mechanics in Vascular Remodeling

项目总结 主动脉夹层(AD)是一种毁灭性的心血管疾病，以其快速传播和高发病率而闻名 和死亡率。诊断AD的最初表现是一项挑战，因为其症状类似于 还有许多其他的健康问题。在没有干预的情况下，AD的死亡率高达90%， 这些死亡大多发生在AD发病后48小时内。AD是排名前20位的死因之一 在美国，20%-40%的患者甚至在到达医院之前就死亡了。我们的能力有一个明显的问题 在AD患者发展的关键初始阶段进行管理，并制定及时治疗的策略。 AD通常在一个焦点区域启动，该区域显示被破坏的微体系结构和受损的机械 属性。一旦解剖，分离的主动脉壁组织的力学行为会受到很大影响， 提示分层不连续可能在AD的触发中起作用。考虑到这些不同的机械 过程中，我们希望了解焦点和分层异常的演变可能会提供 对早期诊断和干预发展的有益见解。这项拟议研究的目标是 为了加深我们对局部组织力学性能和微观结构的重要作用的理解 动脉壁在AD的发生发展中起重要作用。 大的弹性动脉由不均匀分布的同心层弹性板组成 弹性和胶原细胞外基质(ECM)纤维。我们最近的研究揭示了之前的几个 未被认可的发现，这些发现提供了强有力的证据，表明ECM的不均一性在生理上是重要的。这个 这项研究的总体假设是局部力学中非均质性的演化 沿动脉壁和跨动脉壁的性质和ECM微观结构都是AD的触发因素。我们会 使用最先进的定量ECM成像、非侵入性局部机械特性来验证这一假设 有三个目标的测绘、离散-有限元建模以及组织测试和验证：具体目标1： 人胸主动脉局部ECM结构与力学性能的亚毫米映射 决议。具体目的2：研究主动脉层分层的深度和区域相关性。特定的 目标3：创建一个包含ECM结构不均质性和局部墙的计算模型 力学性能来预测AD的倾向。 我们从这项研究中获得的知识有望为生物力学标记提供有用的见解 用于AD的诊断和治疗。考虑局部结构和结构的新型生物力学标记物 机械不均匀将确定AD的起源和倾向，并直接影响临床 新的早期诊断和干预措施的发展。

PROJECT SUMMARY Aortic dissection (AD) is a devastating cardiovascular disease known for its rapid propagation and high morbidity and mortality. Diagnosis of the initial presentation of AD is a challenge because the symptoms are similar to those of many other health problems. In the absence of intervention, AD results in a mortality rate of up to 90%, with most of these deaths occurring within 48 hours of the onset of AD. AD is among the top 20 causes of death in the US, with 20-40% of patients die even before reaching hospital. There is a clear problem in our ability to manage AD patients in their crucial initial stage of development and to develop strategies for a timely treatment. AD usually initiates at a focal region that shows disrupted microarchitecture and compromised mechanical properties. Once dissected, the mechanical behavior of the separated aortic wall tissues become greatly affected, suggesting that layering discontinuity may play a role in triggering AD. Considering these distinct mechanical processes, we expect that understanding the evolvement of the focal and layering abnormalities may provide useful insights into the development of early diagnostic and intervention. The goal of this proposed research is to advance our understanding of the important role of local tissue mechanical properties and microstructures of the arterial wall in in the initiation and progression of AD. Large elastic arteries consist of concentric layers of elastic lamellae with inhomogeneously distributed elastic and collagen extracellular matrix (ECM) fibers. Our recent studies revealed several previously unrecognized findings, which provide strong evidence that ECM inhomogeneity is physiologically important. The overarching hypothesis of this proposed research is that the evolvement of inhomogeneity in local mechanical properties and ECM microstructure, both along and across the arterial wall, are triggering factors of AD. We will test this hypothesis using state-of-the-art quantitative ECM imaging, noninvasive local mechanical property mapping, discrete-finite element modelling, and tissue testing and validation with three aims: Specific Aim 1: To establish mappings of local ECM structure and mechanical properties of human thoracic aorta with sub-millimeter resolution. Specific Aim 2: To investigate the depth- and region-dependence of aortic layer delamination. Specific Aim 3: To create a computational model that incorporates ECM structural inhomogeneity and local wall mechanical properties to predict the propensity of AD. The knowledge we gain from this research is expected to provide insights into biomechanical markers useful for the diagnosis and treatment of AD. The new biomechanical markers considering local structural and mechanical inhomogeneities will identify the origin and propensity of AD with direct clinical impact on the developments of new early diagnostics and interventions.