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.

血栓和血栓的机械力化学破裂机制 普拉尚特·K·普罗希特，约翰·L·巴萨尼，瓦莱里·巴塞戈夫和约翰·W·韦塞尔 这项建议的目的是探索和了解血栓和血栓的断裂韧性，从而 为危及生命的血栓栓塞术提供了力学基础。一系列实验的结合， 理论建模和计算机模拟将揭示机械应力(由于血液流动)是如何 与酶裂解的协同作用会导致从分子到连续层级的结构破坏，并影响 血栓形成血栓的倾向。这一建议的具体目的是：(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)研究纤维蛋白凝胶的速率依赖耗散效应 纤维蛋白凝胶的韧性，以及(3)研究血细胞、血栓前血液成分、 血栓破裂时的纤溶作用。在特定目标(SA)1中，我们将测量纤维蛋白凝块的韧性 并为微米级和纳米级的断裂提供了结构基础。在SA2中，我们将深入研究 纤维蛋白凝胶破裂的热力学和速率依赖性，包括流体流过孔隙和流体 拖动纤维蛋白纤维，捕捉能量耗散如何增强韧性。在翻译版SA3中，我们将 研究血小板、红细胞和中性粒细胞对生理性血栓韧性的影响 在没有和存在生理性纤溶激活剂(TPA)的情况下。我们还将研究断裂的原因 血栓形成对静脉血栓栓塞症患者(PRO)的影响 血液成分的变化对凝块机械稳定性的影响。我们的初步研究表明，i)韧性 交联性纤维蛋白凝胶的含量处于合成水凝胶的含量范围内，ii)在裂纹尖端添加tPA 减少了裂纹扩展的载荷，iii)纤维在裂纹尖端沿拉伸方向排列和断裂， 裂纹扩展是共价键和非共价键断裂的结果。我们还开发了v) 硅胶中用拉力机械测试纤维和纤维网络的动态力光谱 模拟和vi)使用模拟的输出来映射应力-应变场的原子应力方法。 我们将使用可溶胀生物聚合物水凝胶的连续介质和有限元模型，以及统计力学 纤维蛋白分子被迫展开的模型。我们将采用基于多尺度计算建模 纤维蛋白原子结构的分子动力学模拟和纤维蛋白的朗之万法模拟 图形处理器上的网络加速。拟议的实验涵盖了以下所有方面 宏观拉伸测试，剪切流变仪，电子显微镜和共聚焦显微镜，以可视化和 量化破裂血栓的结构变化。我们的实验和建模将帮助我们 了解血栓栓塞术的机制，并将解决临床上重要的问题：为什么 血栓结构/机械性能与心血管疾病之间是否有很强的关联性？这个 新的知识还将有助于设计新的基于水凝胶的生物材料，这些材料目前处于 从事力学、材料科学和生物工程方面的研究。