Multi-Scale Integration of Extracellular Matrix Mechanics in Vascular Remodeling

项目摘要 主动脉夹层（AD）是一种严重的心血管疾病，发病率高，传播快 and mortality. AD的初始表现的诊断是一个挑战，因为症状类似于 许多其他的健康问题。在没有干预的情况下，AD导致高达90%的死亡率， 其中大多数死亡发生在AD发作的48小时内。AD是导致死亡的20大原因之一 在美国，20-40%的患者甚至在到达医院之前死亡。很明显，我们的能力有问题， 管理处于发展关键初始阶段的AD患者，并制定及时治疗的策略。 AD通常起始于病灶区域，该区域显示出破坏的微结构和受损的机械结构。 特性.一旦被切开，分离的主动脉壁组织的机械性能受到很大影响， 提示分层不连续性可能在触发AD中起作用。考虑到这些不同的机械 过程中，我们希望了解的焦点和分层异常的演变可能会提供 对早期诊断和干预的发展提供了有益的见解。这项研究的目的是 促进我们对局部组织力学性能和微观结构重要作用的理解 动脉壁在AD的发生和发展中起重要作用。 大的弹性动脉由不均匀分布的同心弹性层组成， 弹性和胶原细胞外基质（ECM）纤维。我们最近的研究显示， 未识别的发现，这提供了ECM不均匀性在生理上重要的强有力证据。的 这项研究的首要假设是，局部力学不均匀性的演变 沿着和穿过动脉壁的ECM性质和微观结构是AD的触发因素。我们将 使用最先进定量ECM成像、非侵入性局部机械性能 标测、离散有限元建模、组织测试和确认，有三个目标：具体目标1： 人胸主动脉局部ECM结构与力学特性亚毫米映射建立 分辨率具体目标2：研究主动脉层分层的深度和区域依赖性。具体 目的3：创建一个计算模型，该模型包含ECM结构不均匀性和局部壁 机械性能来预测AD的倾向。 我们从这项研究中获得的知识有望为有用的生物力学标记提供见解 用于AD的诊断和治疗。新的生物力学指标考虑到局部结构和 机械不均匀性将确定AD的起源和倾向，对AD的临床影响直接 开发新的早期诊断和干预措施。

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.