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: 10165811
• 负责人: Prashant Kishore Purohit
• 金额: $ 63.96万
• 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/10165811
• 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 Models; 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 该提议的目的是探索和了解血块和血栓的骨折韧性，从而 为威胁生命的血栓栓塞提供了机械基础。实验的组合， 理论建模和计算机模拟将揭示机械应力（由于血流引起的） 与酶促裂解的协同作用会引起分子至连续体尺度的结构损害，并影响 凝块栓塞的倾向。该提案的具体目的是：（1）测量和模型断裂 纤维蛋白凝胶在准静态条件下的韧性，（2）研究对速率依赖性耗散作用对 纤维蛋白凝胶的韧性，（3）研究血细胞的作用，血栓性血液组成， 和纤维蛋白溶解对血凝块破裂。在特定的目标（SA）1中，我们将测量纤维蛋白血块的韧性 并为微米和纳米尺度上的破裂提供结构性基础。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，包括流体流动和流体 拖动纤维蛋白纤维，以捕获能量耗散如何增加韧性。在翻译SA3中，我们将 研究生理上相关的凝块的韧性，血小板，红细胞和中性粒细胞的影响 在不存在和存在生理纤维蛋白水解活化剂（TPA）的情况下。我们还将研究 由静脉血栓栓塞患者的血液制成的血块，以探索（Pro）血栓形成的影响 血液组成对凝块机械稳定性的改变。我们的初步研究表明，我）韧性 交联的纤维蛋白凝胶的范围为合成水凝胶的范围，ii）将TPA添加到裂纹尖端 减少裂纹生长的载荷，iii）纤维在裂纹尖端处的拉伸方向对齐并破裂， iv）裂纹繁殖是由于共价和非共价键破裂而产生的。我们还开发了v） 硅中的动态力光谱法，使用拉力进行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。 我们将使用膨胀生物聚合物水凝胶的连续性和有限元模型以及统计机械 纤维蛋白分子强迫展开的模型。我们将采用基于多尺度计算建模的 关于纤维蛋白纤维原子结构的分子动力学模拟，以及纤维蛋白的Langevin模拟 网络在图形处理单元上加速。提出的实验涵盖了整个范围 宏观拉伸测试，剪切流变计，电子显微镜和共聚焦显微镜可视化和 定量破裂的血凝块的结构改变。我们的实验和建模将帮助我们 了解血栓栓塞的机制，并将解决临床上重要的问题：为什么 凝块结构/机械性能与心血管疾病之间有很强的关联吗？这 新知识还将有助于设计新的基于水凝胶的生物材料，这些生物材料目前处于 力学，材料科学和生物工程研究。