Understanding Mechano-Fibrinolysis: Fiber-Scale Multiphysics Experiments and Models

非技术总结：了解自然发生的生物材料是设计新的、更好的材料的关键一步，这些材料可以克服当今许多科学和健康挑战。一种这样的生物材料是纤维蛋白，其是血凝块的重要成分。为了成功且安全地密封伤口，纤维蛋白已经进化为高度可拉伸和弹性的材料。同时，随着伤口的逐渐愈合，纤维蛋白很容易被去除。纤维蛋白的结构与其化学性质之间的复杂的、机械介导的相互作用使得这些径向功能成为可能。在这个项目中，不同的显微镜技术将与计算模型结合使用，以更好地理解这种相互作用。该项目的知识也将直接适用于其他突出的纤维生物材料-如胶原蛋白和弹性蛋白-及其机械介导的结构-功能关系。除了其科学范围，该项目的影响将扩大，因为它有助于培养未来的科学家，为本科生和研究生创造研究机会。通过与非营利性科学工厂的合作，它还将把关于纤维蛋白和其他纤维生物材料在人类健康和疾病中的作用的课程整合到非营利性夏令营的课程中。这项工作的结果是，从幼儿园到九年级的各行各业的学生，包括少数民族背景的学生，将为健康，科学，技术，工程和数学的职业生涯做好更好的准备。技术概述：Fiorium是一种具有显着性能的半柔性生物聚合物。例如，纤维蛋白可以经历百分之几百应变的变形而不失效。它的可变形性和许多其他物理壮举源于它跨越许多数量级的层次结构。因此，它是一种典型的生物聚合物，其研究将使人们能够对其他天然来源的以及合成的生物材料有基本的了解，这些材料可以解决许多社会上最紧迫的问题。然而，关于纤维蛋白仍有许多未知之处。在关于纤维蛋白的那些未回答的问题中-因此关于其他生物材料-是纤维蛋白的机械变形状态如何影响其酶消化的速率，即，其机械裂解。这个问题是一个关键的问题，因为酶消化在许多重要的组织功能如组织生长和重塑以及组织功能障碍如癌症的调节中是重要的。在这项研究中，这个问题将在光纤尺度上得到回答，也就是说，在单个光纤跨越的100纳米尺度上。为此，设计了一组基于原子力显微镜的实验，其中单个纤维蛋白纤维将变形，而它们在酶负载下的消化将在显微镜下定量。这些实验将结合一个详细的建模方法，集成到实验设计。通过这种协同方法，可以描述机械变形对多种物理现象（例如酶转运、结合和酶活性）的影响，这些物理现象决定了纤维蛋白对酶消化的反应。为了确保这项研究揭示了机械的洞察力，而不仅仅是拟合观察，计算模型和机械的理解，纤维蛋白溶解将在纤维网络规模上进行验证，其中将预测负载纤维组件的降解并与实验进行比较。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的评估来支持。影响审查标准。

Non-Technical Summary: Understanding naturally occurring, biological materials is a critical step toward designing new, better materials that can overcome many of today’s scientific and health challenges. One such biomaterial is fibrin, which is an important constituent of blood clot. To successfully and securely seal wounds, fibrin has evolved to be a highly stretchable and resilient material. At the same time, fibrin is easily removable as the wound is progressively healing. These diametrical functions are made possible by an intricate, mechanically-mediated interplay between fibrin’s structure and its chemistry. In this project, different microscopy techniques will be used in combination with computational models to better understand this interplay. The knowledge from this project will also have direct applicability to other prominent, fibrous biomaterials – such as collagen and elastin - and their mechanically-mediated structure-function relationships. Beyond its scientific scope, this project’s impact will be broadened as it contributes to the training of future scientists by creating research opportunities for undergraduate and graduate students. Through a collaboration with the non-profit Science Mill it will also integrate lessons about the role of fibrin - and other fibrous biomaterials - in human health and disease into the curriculum of the non-profit’s summer camps. As a result of this work, Kindergarten through grade 9 students from all walks of life including students with minoritized backgrounds will be better prepared for careers in health, science, technology, engineering, and mathematics.Technical Summary: Fibrin is a semi-flexible biopolymer with remarkable properties. For example, fibrin can undergo deformations of several hundred percent strain without failure. Its deformability and many other physical feats originate from its hierarchical architecture that spans many orders of magnitude. As such, it is a prototypical biopolymer whose study will enable fundamental understanding of other, nature-derived as well as synthetic biomaterials that can solve many of society’s most pressing problems. However, much remains unknown about fibrin. Among those unanswered questions about fibrin - and therefore about other biomaterials - is how fibrin’s state of mechanical deformation affects its rate of enzymatic digestion, i.e., its mechano-lysis. This question is a critical one to answer as enzymatic digestion is important in the regulation of many vital tissue functions such as tissue growth and remodeling as well as in tissue dysfunction such as in cancer. In this study, this question will be answered on the fiber scale, that is, on the 100s-of-nanometer-scale that a single fiber spans. To this end, a regiment of atomic force microscopy-based experiments was designed in which single fibrin fibers will be deformed, while their digestion under enzymatic loading will be microscopically quantified. These experiments will be combined with a detailed modeling approach that is integrated into the experimental design. Through this synergistic approach, it will be possible to delineate the effect of mechanical deformation on the multiple physical phenomena – such as enzyme transport, binding, and enzymatic activity – that determine fibrin’s response to enzymatic digestion. To ensure that this study reveals mechanistic insight rather than merely fitting observations, the computational model and understanding of mechano-fibrinolysis will be validated on the fiber network scale in which the degradation of an assembly of loaded fibers will be predicted and compared to experiments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.