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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

基本信息

批准号：
10617840
负责人：
Prashant Kishore Purohit
金额：
$ 63.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617840
关键词：
Acceleration Affect Biocompatible Materials Biological Biomedical Engineering Biopolymers Blood Blood Cells Blood Platelets Blood coagulation Blood flow Cardiovascular Diseases Cause of Death 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 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 Statistical Mechanics Stress Structural Models Structural defect Structure Testing Theoretical Studies Theoretical model Therapeutic Embolization Thermodynamics Thick Thrombin Thromboembolism Thrombosis Thrombus Traction Visualization Work 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

项目摘要

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.

机械力-化学作用下血栓破裂的机制普拉尚特湾约翰·普罗希特放大图片作者：John W. Weisel 该提案的目的是探索和了解血液凝块和血栓的断裂韧性，从而为危及生命的血栓栓塞提供了机制基础。一系列实验，理论建模和计算机模拟将揭示机械应力（由于血液流动）在与酶裂解的协同作用诱导从分子到连续尺度的结构损伤，血栓栓塞的倾向。具体目标是：（1）测量和建模骨折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，和（3）研究血细胞，血栓前血液成分，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和纳米尺度断裂提供了结构基础。在SA 2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，包括流体流过孔隙和流体拖动纤维蛋白纤维，以捕捉能量耗散如何增加韧性。在平移SA 3中，我们将研究血小板、红细胞和中性粒细胞对生理相关凝块韧性的影响在不存在和存在生理纤维蛋白溶解激活剂（tPA）的情况下。我们还将研究静脉血栓栓塞症患者的血液制成的凝块，以探讨（促）血栓形成的作用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）韧性的交联纤维蛋白凝胶是在那些合成水凝胶的范围内，ii）tPA添加到裂纹尖端降低了裂纹生长的载荷，iii）纤维在裂纹尖端沿着拉伸方向排列和断裂，和iv）裂纹扩展由共价键和非共价键的断裂引起。我们还开发了V）动态力光谱学在计算机中使用拉伸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，以使用来自模拟的输出来映射应力-应变场。我们将使用可溶胀生物聚合物水凝胶的连续和有限元模型，纤维蛋白分子被迫展开的模型。我们将采用多尺度计算建模，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图形处理器上的网络加速。拟议的实验涵盖了所有的宏观拉伸试验、剪切流变仪、电子显微镜和共聚焦显微镜，定量分析破裂血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，并将解决临床上的重要问题：为什么血块结构/机械性能与心血管疾病之间是否存在强关联？的新的知识也将有助于设计新的水凝胶基生物材料，目前处于最前沿，机械、材料科学和生物工程的研究。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strength, deformability and toughness of uncrosslinked fibrin fibers from theoretical reconstruction of stress-strain curves.

DOI：
10.1016/j.actbio.2021.09.050
发表时间：
2021-12
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Maksudov F;Daraei A;Sesha A;Marx KA;Guthold M;Barsegov V
通讯作者：
Barsegov V

Effects of Hyperhomocysteinemia on the Platelet-Driven Contraction of Blood Clots.

DOI：
10.3390/metabo11060354
发表时间：
2021-06-01
期刊：
Metabolites
影响因子：
4.1
作者：
Litvinov RI;Peshkova AD;Le Minh G;Khaertdinov NN;Evtugina NG;Sitdikova GF;Weisel JW
通讯作者：
Weisel JW

Fluctuating nonlinear spring theory: Strength, deformability, and toughness of biological nanoparticles from theoretical reconstruction of force-deformation spectra.

DOI：
10.1016/j.actbio.2020.12.043
发表时间：
2021-03-01
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Maksudov F;Kononova O;Llauró A;Ortega-Esteban A;Douglas T;Condezo GN;Martín CS;Marx KA;Wuite GJL;Roos WH;de Pablo PJ;Barsegov V
通讯作者：
Barsegov V

Finite deformation near a crack tip terminated at an interface between two neo-Hookean sheets.

裂纹尖端附近的有限变形终止于两个新胡克板之间的界面。