Mechanisms of mechano-chemical rupture of blood clots and thrombi

血凝块和血栓的机械化学破裂机制

• 批准号: 10411976
• 负责人: Prashant Kishore Purohit
• 金额: $ 57.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411976
• 关键词: Address; Affect; Biocompatible Materials; Biological; Biomedical Engineering; Biopolymers; Blood; Blood Cells; Blood Platelets; Blood coagulation; Blood flow; Cardiovascular Diseases; Cause of Death; Chemicals; Clinical; Clinical Medicine; Coagulation Process; Complex; Computer Simulation; Confocal Microscopy; Cytolysis; Dependence; Diagnosis; Disease; Electron Microscopy; Elements; Enzymes; Erythrocytes; Evolution; Fiber; Fibrin; Fibrinogen; Fibrinolysis; Fracture; Frustration; Gel; Glean; Goals; Growth; Hydrogels; Knowledge; Laws; Length; Life; Link; Liquid substance; Machine Learning; Maps; Measurement; Measures; Mechanical Stress; Mechanics; Methodology; Modeling; Molecular; Molecular Structure; Output; Patients; Physicians; Physiological; Plasma; Predisposition; Prevention; Process; Property; Prophylactic treatment; Proteins; Research; Research Proposals; Resistance; Resources; Rupture; Specimen; Spectrum Analysis; Stress; Structural Models; Structural defect; Structure; Testing; Theoretical Studies; Theoretical model; Therapeutic Embolization; Thermodynamics; Thick; Thrombin; Thromboembolism; Thrombosis; Thrombus; Traction; Work; base; crosslink; density; design; disability; experimental study; fiber cell; fluid flow; in silico; in vivo; insight; instrumentation; interdisciplinary approach; materials science; mechanical properties; models and simulation; molecular dynamics; molecular scale; multi-scale modeling; nanoscale; neutrophil; novel strategies; predictive modeling; prevent; response; simulation; synergism; theories; thrombotic; tool; venous thromboembolism; viscoelasticity

Mechanisms of mechano-chemical rupture of blood clots and thrombi Prashant K. Purohit, John L. Bassani, Valeri Barsegov and John W. Weisel The goal of this proposal is to explore and understand the fracture toughness of blood clots and thrombi, thus providing a mechanistic basis for life-threatening thrombotic embolization. A combination of experiments, theoretical modeling and computer simulations will reveal how mechanical stresses (due to blood flow) in synergy with enzymatic lysis induce structural damage from the molecular to continuum scales and affect the propensity of a clot to embolize. The specific aims of this proposal are: (1) Measure and model fracture toughness of fibrin gels in quasi-static conditions, (2) Investigate rate dependent dissipative effects on toughness of fibrin gels, and (3) Study the effects of blood cells, prothrombotic blood composition, and fibrinolysis on rupture of blood clots. In Specific Aim (SA) 1, we will measure toughness of fibrin clots and provide a structural basis for rupture at the micron and nanometer scales. In SA2, we will delve into the thermodynamics and rate-dependence of the fracture of fibrin gels, including fluid flow through pores and fluid drag on fibrin fibers to capture how energy dissipation increases toughness. In the translational SA3, we will investigate toughness of physiologically relevant clots with effects of platelets, red blood cells, and neutrophils in the absence and presence of the physiological fibrinolytic activator (tPA). We will also study the rupture of clots made from the blood of venous thromboembolism patients to explore the effects of (pro)thrombotic alterations of blood composition on clot mechanical stability. Our preliminary studies show that i) the toughness of cross-linked fibrin gels is in the range of those for synthetic hydrogels, ii) the addition of tPA to a crack tip reduces the loads for crack growth, iii) fibers are aligned and broken along the tensile direction at the crack tip, and iv) crack propagation results from the rupture of covalent and non-covalent bonds. We also developed v) dynamic force spectroscopy in silico to mechanically test fibrin fibers and fibrin networks using pulling simulations and vi) atomic stress approach to map the stress-strain fields using the output from simulations. We will use continuum and finite element models of swellable biopolymer hydrogels, and statistical mechanical models for the forced unfolding of fibrin molecules. We will employ multiscale computational modeling based on Molecular Dynamics simulations of atomic structures of fibrin fibers, and Langevin simulations of fibrin networks accelerated on Graphics Processing Units. The proposed experiments cover the whole gamut of macroscopic tensile tests, shear rheometry, electron microscopy and confocal microscopy to visualize and quantitate the structural alterations of ruptured blood clots. Our experiments and modeling will help us to understand the mechanisms of thrombotic embolization and will address the clinically important question: why is there a strong association between clot structure/mechanical properties and cardiovascular diseases? The new knowledge will also help to design new hydrogel-based biomaterials that are currently at the forefront of research in mechanics, materials science and bioengineering.

血凝块和血栓的机械化学破裂机制 Prashant K. Purohit、John L. Bassani、Valeri Barsegov 和 John W. Weisel 该提案的目标是探索和了解血凝块和血栓的断裂韧性，从而 为危及生命的血栓栓塞提供机制基础。结合实验， 理论模型和计算机模拟将揭示机械应力（由于血流）如何 与酶裂解的协同作用会引起从分子到连续尺度的结构损伤，并影响 凝块栓塞的倾向。该提案的具体目标是： (1) 测量和模拟断裂 纤维蛋白凝胶在准静态条件下的韧性，(2) 研究速率依赖性耗散效应 纤维蛋白凝胶的韧性，以及 (3) 研究血细胞、血栓前血液成分的影响， 和血凝块破裂时的纤维蛋白溶解。在特定目标 (SA) 1 中，我们将测量纤维蛋白凝块的韧性 并为微米和纳米尺度的破裂提供结构基础。在 SA2 中，我们将深入研究 纤维蛋白凝胶断裂的热力学和速率依赖性，包括通过孔隙的流体流动和流体 拖动纤维蛋白纤维以捕捉能量耗散如何增加韧性。在翻译 SA3 中，我们将 研究生理相关凝块的韧性以及血小板、红细胞和中性粒细胞的影响 在生理纤溶激活剂 (tPA) 存在和不存在的情况下。我们还将研究破裂 由静脉血栓栓塞患者的血液制成的凝块，以探索（促）血栓形成的影响 血液成分的改变对凝块机械稳定性的影响。我们的初步研究表明 i) 韧性 交联纤维蛋白凝胶的含量在合成水凝胶的范围内，ii) 在裂纹尖端添加 tPA 减少裂纹扩展的载荷，iii) 纤维在裂纹尖端沿拉伸方向排列和断裂， iv) 裂纹扩展是由共价键和非共价键断裂引起的。我们还开发了v) 计算机动态力谱通过拉力机械测试纤维蛋白纤维和纤维蛋白网络 模拟和 vi) 原子应力方法，使用模拟的输出来绘制应力-应变场。 我们将使用可膨胀生物聚合物水凝胶的连续体和有限元模型以及统计力学 纤维蛋白分子强制展开的模型。我们将采用基于多尺度计算模型 纤维蛋白纤维原子结构的分子动力学模拟和纤维蛋白的朗之万模拟 网络在图形处理单元上加速。所提出的实验涵盖了整个领域 宏观拉伸测试、剪切流变测定、电子显微镜和共焦显微镜，以可视化和 定量破裂血凝块的结构变化。我们的实验和建模将帮助我们 了解血栓栓塞的机制并解决临床上重要的问题：为什么 血块结构/机械特性与心血管疾病之间是否存在密切关联？这 新知识还将有助于设计目前处于前沿的新型水凝胶生物材料 研究领域为力学、材料科学和生物工程。