Experiment-based multi-scale modeling of the tensile and compressive deformations of fibrin

基于实验的纤维蛋白拉伸和压缩变形的多尺度建模

• 批准号: 9218422
• 负责人: Prashant Kishore Purohit
• 金额: $ 38.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9218422
• 关键词: Affect; Applications Grants; Atomic Force Microscopy; Behavior; Biocompatible Materials; Biological; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Caliber; Cardiovascular Diseases; Catheters; Clinical; Coagulation Process; Dependence; Devices; Electron Microscopy; Equilibrium; Fiber; Fibrin; Fibrinogen; Fluorescence Microscopy; Goals; Hemorrhage; Hemostatic function; Individual; Joints; Kinetics; Knowledge; Length; Link; Measurement; Measures; Mechanics; Modeling; Modulus; Molecular; Motion; Myocardial Infarction; Nature; Pathologic; Pennsylvania; Periodicity; Phase Transition; Philadelphia; Plasma; Play; Polymers; Property; Proteins; Research; Rheology; Statistical Mechanics; Stress; Stretching; Stroke; Structure; Testing; Theoretical model; Thrombin; Thrombosis; Thrombus; Time; Ultrasonography; Universities; Whole Blood; Work; base; clinically significant; crosslink; density; design; experience; experimental study; fibrinmonomer; fibrinopeptide; insight; mechanical behavior; mechanical properties; molecular mechanics; multi-scale modeling; nanoscale; predicting response; prevent; response; shear stress; theories; viscoelasticity

Experiment-based multi-scale modeling of the tensile and compressive deformations of fibrin Prashant K. Purohit and John W. Weisel University of Pennsylvania, Philadelphia, PA 19104. Abstract: The research objective of this proposal is to measure, model and predict the tensile and compressive response of fibrin clots at the molecular and continuum scales. This is important because there are no comprehensive models that link the molecular mechanics to the macroscopic deformation of clots and thrombi, even though they experience deformation/alteration at all scales during their normal function in hemostasis and in pathological situations of thrombosis. We have shown that macroscale fibrin clots can be stretched to three or four times their original length in uniaxial tension due to mechanical unfolding of fibrin monomers at the nanometer scale. In compression, we have shown that the deformation of a clot is analogous to that of a foam and proceeds by the motion of a compression front, behind which the network densifies due to buckling of fibers and creation of inter-fiber contacts. These features are captured in our models that can quantitatively describe and predict how molecular and fiber level mechanics has implications for the macroscopic response of clots. Our models allow us to tune the macroscale mechanical behavior of clots by altering the molecular building blocks and the structural parameters of the network. This idea will be put to the test when we (a) modulate the equilibrium tensile response of clots by altering the network structural parameters, and (b) investigate how cross-linking of oligomers affects the dependence of the tensile response on the strain rate. We can also alter the nanoscale structure of fibrin and use our model to predict the consequences for macroscopic clots. Our target is the  C region of fibrin, which is known to vary depending on the species and has been shown to play a part in controlling the tensile stiffness and extensibility of single fibrin fibers as well fibrin clots. For compression, we will show that the deformation of platelet-poor plasma clots, platelet-rich plasma clots, whole blood clots and thrombi is also foam-like, and then predict and measure their response to localized loads. Such localized loads could be encountered in clinical situations, such as the interaction of catheters or bubbles with thrombi. We will also investigate the effect of the  C region on the compression response of clots. Our models are based on continuum mechanical principles for the study of polymeric materials and foams, as well as statistical mechanics models describing forced unfolding of single protein molecules. The proposed experiments cover the whole gamut of macroscopic uniaxial tension tests, atomic force microscopy experiments including stretching of oligomers and indentation of clots, rheometry to measure the storage and loss moduli in compression, electron microscopy as well as fluorescence microscopy to visualize the structure of fibrin clots. Our models and experiments will help answer clinically important questions, such as why is there a strong correlation between clot structure/mechanical properties and cardiovascular disease, and also help design biomaterials with unique mechanical properties by altering the structure of fibrin at the nanoscale.

基于实验的纤维蛋白拉伸和压缩变形的多尺度建模 Prashant K. Purohit和John W. Weisel 宾夕法尼亚州宾夕法尼亚大学宾夕法尼亚大学，19104年。 摘要：该提案的研究目标是测量，建模和预测拉伸和 纤维蛋白布在分子和持续尺度上的压缩反应。这很重要，因为那里 没有将分子力学与凝块的宏观变形联系起来的综合模型 血栓，即使他们在正常功能中都经历了各个尺度的变形/变化 止血和血栓形成的病理状况。我们已经表明宏观纤维蛋白布可能是 由于纤维蛋白的机械展开，其原始长度延伸到其原始长度的三到四倍 纳米量表的单体。在压缩中，我们表明凝块的变形是类似的 到泡沫的泡沫，并通过压缩前线运动进行，在该趋势的后面，网络致密到期 要屈曲纤维并创建纤维间接触。这些功能在我们的模型中被捕获 定量描述并预测分子和纤维水平力学如何对 凝块的宏观反应。我们的模型使我们能够通过 改变网络的分子构建块和结构参数。这个想法将被提交给 当我们（a）通过更改网络结构来调节云的等效拉伸响应时测试 参数和（b）研究低聚物的交联如何影响拉伸反应的依赖性 关于应变率。我们还可以改变纤维蛋白的纳米级结构，并使用我们的模型预测 宏观凝块的后果。我们的目标是纤维蛋白的c区域，该区域已知会根据 在该物种上，已被证明可以控制单一的拉伸刚度和可扩展性 纤维蛋白纤维以及纤维蛋白布。对于压缩，我们将证明血小板贫血等离子体的变形 凝块，富含血小板的血浆CMLOT，全血CMLOTS和血栓也类似泡沫，然后预测和测量 他们对局部负载的反应。这种局部负载可能在临床情况下遇到 导管或气泡与血栓的相互作用。我们还将研究C区域对 凝块的压缩响应。我们的模型基于连续机械原理的研究 聚合物材料和泡沫，以及统计力学模型，描述了单一的强迫展开 蛋白质分子。提出的实验涵盖了宏观单轴张力测试的整个范围， 原子力显微镜实验，包括伸展寡聚物和凝块的凹痕，风化计算 测量压缩，电子显微镜以及荧光显微镜中的存储和损失模量 可视化纤维蛋白布的结构。我们的模型和实验将有助于回答临床上重要的 问题，例如为什么凝块结构/机械性能之间存在很强的相关性和 心血管疾病，还通过改变了具有独特机械性能的生物材料 纤维蛋白在纳米级的结构。