The link between hemodynamics and wall structure in cerebral aneurysms

脑动脉瘤血流动力学与壁结构之间的联系

• 批准号: 8512060
• 负责人: Juan R Cebral
• 金额: $ 20.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512060
• 关键词: Adult; Aneurysm; Animal Model; Animals; Architecture; Area; Automobile Driving; Berry Aneurysm; Biological; Biomechanics; Blood flow; Brain hemorrhage; Cells; Cellular Structures; Cerebral Aneurysm; Clinical; Collagen; Collagen Fiber; Custom; Data; Development; Device Designs; Device or Instrument Development; Devices; Disease; Disease Progression; Elastases; Endothelium; Environment; Evaluation; Extracellular Matrix; Failure; Fiber; Functional disorder; Future; Goals; Growth; Health; Heterogeneity; Human; Impairment; Intervention; Intracranial Aneurysm; Knowledge; Lead; Link; Liquid substance; Maintenance; Mechanics; Methods; Microscopy; Mission; Modality; Modeling; Morbidity - disease rate; Nature; Oryctolagus cuniculus; Outcome; Pathology; Pathway interactions; Patients; Pharmacological Treatment; Play; Population; Population Heterogeneity; Process; Property; Research; Resected; Resolution; Risk Assessment; Role; Rupture; Ruptured Aneurysm; Science; Specimen; Spontaneous Rupture; Staging; Structure; Surgical Clips; Testing; Tissues; Validation; Work; animal model development; base; burden of illness; cell type; cerebral artery; common treatment; disability; experience; hemodynamics; improved; in vivo; innovation; mortality; multi-photon; public health relevance; repaired; scaffold; shear stress; sobriety

DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of the mechanism by which blood flow within saccular aneurysms influences the structural integrity of the wall. Prior studies did not directly evaluate the influence of hemodynamics on wall structure, but rather looked for a correlation with rupture. However, a large percentage of aneurysms are hypocellular and therefore have limited ability to sense flow or renew the collagen architecture. Clearly, the influence of hemodynamics must be different in these cases. This gap in knowledge is an important problem because until we understand the connection between hemodynamics and wall integrity, we cannot resolve recent failures of flow altering devices nor validate animal models. The long-term objectives of our research team are to establish new biologically based treatment methods for cerebral aneurysms. This will include the development of animal models appropriate for evaluating the impact of endovascular and pharmacological treatments on wall integrity. The objective here, which is our next step in pursuit of these goals, is to determine how i) hemodynamics ii) wall structure (cellular and extra-cellular) and iii) wall strength are interrelated in human cerebral aneurysms. Our central hypothesis is the magnitude of the wall shear stress influences the quality of the endothelium and that once the endothelium is compromised, the capacity for wall maintenance and remodeling are reduced, causing impairment of the extracellular matrix, resulting in diminished structural integrity of the aneurysm wall. Our hypothesis is supported by the large body of work demonstrating the sensitivity of the endothelium structure and function to hemodynamic conditions, as well as our preliminary results on cellular content and collagen architecture in aneurysms. We plan to test this hypothesis, and thereby achieve these objectives, through the following three specific aims: 1) Identify the hemodynamic conditions under which the endothelium is lost; 2) Determine how collagen architecture depends on cellular content; 3) Determine how mechanical properties of the aneurysm depend on collagen architecture. Under the first aim, the association of endothelium status to wall shear stress will be evaluated in tissue resected from 20-25 human aneurysms after surgical clipping. Patient-specific computational fluid dynamics modeling will be used to assess the in vivo hemodynamic environment. Under Aims 2 & 3, non-destructive multi-photon microscopy will be used with biaxial testing for simultaneous non-destructive evaluation of cellular content, collagen architecture, and mechanical properties in human aneurysm tissue. The proposed work is innovative, in our opinion, because it seeks to shift the way aneurysm disease is currently studied by using an integrated, multi-scale approach to connect hemodynamic conditions to wall structure (cellular and extra- cellular) and strength. The proposed research is significant because it will create a paradigm shift in how the biomechanics of cerebral aneurysms are studied. Rather than considering the role of hemodynamics as similar for all aneurysms, distinct stages will be considered depending on cell content. Further it will provide knowledge that can be used to improve biomechanical modeling of aneurysm progression and identify the appropriate use of animal models for device development.

描述（由申请人提供）：我们对囊状动脉瘤内血流影响壁结构完整性的机制的理解存在根本性差距。以前的研究没有直接评价血液动力学对壁结构的影响，而是寻找与破裂的相关性。然而，很大比例的动脉瘤是细胞过少的，因此感知血流或更新胶原结构的能力有限。显然，在这些情况下，血液动力学的影响一定是不同的。这种知识上的差距是一个重要的问题，因为直到我们了解血液动力学和壁完整性之间的联系，我们不能解决最近的失败的流量改变设备，也验证动物模型。我们研究团队的长期目标是建立新的基于生物学的脑动脉瘤治疗方法。这将包括开发适用于评价血管内和药物治疗对血管壁完整性影响的动物模型。这里的目标，这是我们追求这些目标的下一步，是确定i）血液动力学ii）壁结构（细胞和细胞外）和iii）壁强度在人类脑动脉瘤中如何相互关联。我们的中心假设是壁切应力的大小影响内皮的质量，并且一旦内皮受损，壁维持和重塑的能力降低，导致细胞外基质受损，导致动脉瘤壁的结构完整性降低。我们的假设得到了大量工作的支持，这些工作证明了内皮结构和功能对血流动力学条件的敏感性，以及我们对动脉瘤中细胞含量和胶原结构的初步结果。我们计划通过以下三个具体目标来检验这一假设，从而实现这些目标：1）确定内皮丢失的血流动力学条件; 2）确定胶原结构如何取决于细胞含量; 3）确定动脉瘤的机械性能如何取决于胶原结构。在第一个目标下，将在手术夹闭后从20-25例人类动脉瘤切除的组织中评价内皮状态与壁剪切应力的相关性。患者特定计算流体动力学建模将用于评估体内血液动力学环境。根据目标2和3，将使用非破坏性多光子显微镜和双轴测试，同时对人体动脉瘤组织中的细胞含量、胶原蛋白结构和机械性能进行非破坏性评价。在我们看来，拟议的工作是创新的，因为它试图通过使用综合的多尺度方法将血流动力学条件与壁结构（细胞和细胞外）和强度联系起来，改变目前研究动脉瘤疾病的方式。这项研究意义重大，因为它将在如何研究脑动脉瘤的生物力学方面创造一个范式转变。不是认为所有动脉瘤的血流动力学作用相似，而是根据细胞含量考虑不同的阶段。此外，它将提供可用于改善动脉瘤进展的生物力学建模并确定器械开发中动物模型的适当使用的知识。