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

了解机械纤维蛋白溶解：纤维尺度多物理场实验和模型

• 批准号: 2105175
• 负责人: Manuel Rausch
• 金额: $ 56.3万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2105175&HistoricalAwards=false
• 关键词: Understanding; Mechano; Fibrinolysis; Fiber; Scale

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.

非技术摘要：了解天然存在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的许多科学和健康挑战，其中一种生物材料是纤维蛋白，它是血栓的重要组成部分。为了牢固地密封伤口，纤维蛋白已发展成为一种高度可拉伸和有弹性的材料，同时，随着伤口的逐渐愈合，纤维蛋白可以轻松去除，这些直接功能是通过复杂的机械介导实现的。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重要的纤维生物材料，例如胶原蛋白和纤维蛋白。除了其科学范围之外，该项目的影响还将扩大，因为它通过与本科生和研究生的合作，为未来的科学家提供了培训机会。非营利性科学工厂还将把有关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纳入该非营利性夏令营的课程中。这项工作的结果是，幼儿园到 9 年级的学生都可以参加。来自各行各业的学生，​​包括少数族裔背景的学生，将为健康、科学、技术、工程和数学领域的职业做好更好的准备。技术摘要：纤维蛋白是一种具有卓越性能的半柔性生物聚合物。纤维蛋白可以承受百分之几百的应变而不会失效，它的变形能力和许多其他物理特性源于其跨越多个数量级的层次结构，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自然现象有基本的了解。衍生和合成的生物材料可以解决社会上许多最紧迫的问题。然而，关于纤维蛋白以及其他生物材料的未解之谜还有很多。纤维蛋白的机械变形状态影响其酶促消化的速率，即其机械分解，这是一个需要回答的关键问题，因为酶促消化对于许多重要组织功能（例如生长组织和重塑）的调节非常重要。在这项研究中，这个问题将在纤维尺度上得到回答，即单根纤维跨越的数百纳米尺度。设计了基于原子力显微镜的实验，其中单个纤维蛋白纤维将变形，而它们在酶加载下的消化将通过这种协同作用与详细的建模方法相结合。通过这种方法，将有可能描述机械变形对多种物理现象的影响，例如酶转运、结合和酶活性，这些物理现象决定纤维蛋白对酶消化的反应。为了确保这项研究揭示机械洞察力而不仅仅是拟合观察结果，将在纤维网络规模上验证机械纤维蛋白溶解的计算模型和理解，其中将预测负载纤维组件的降解并与实验进行比较。授予 NSF 的法定使命，并通过评估反映使用基金会的智力优点和更广泛的影响审查标准，被认为值得支持。

项目成果

Cross-evaluation of stiffness measurement methods for hydrogels

• DOI: 10.1016/j.polymer.2022.125316
• 发表时间: 2022-09
• 期刊: Polymer
• 影响因子: 4.6
• 作者: N. Richbourg;M. Rausch;N. Peppas

Synthetic hydrogels as blood clot mimicking wound healing materials

• DOI: 10.1088/2516-1091/ac23a4
• 发表时间: 2021-09
• 期刊: Progress in Biomedical Engineering
• 作者: M. Rausch;S. Parekh;B. Dortdivanlioglu;A. Rosales

Teaching Material Testing and Characterization with an Open, Accessible, and Affordable Mechanical Test Device

使用开放、易于访问且经济实惠的机械测试设备进行教学材料测试和表征

• DOI: 10.1007/s43683-021-00056-x
• 发表时间: 2021
• 期刊: Biomedical Engineering Education
• 作者: Sugerman, Gabriella P.;Rausch, Manuel K.
• 通讯作者: Rausch, Manuel K.

An introduction to the Ogden model in biomechanics: benefits, implementation tools and limitations

• DOI: 10.1098/rsta.2021.0365
• 发表时间: 2022-10-17
• 期刊: PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES
• 影响因子: 5
• 作者: Lohr, Matthew J.;Sugerman, Gabriella P.;Rausch, Manuel K.
• 通讯作者: Rausch, Manuel K.

Nonlinear, dissipative phenomena in whole blood clot mechanics

• DOI: 10.1039/d0sm01317j
• 发表时间: 2020-11-21
• 期刊: SOFT MATTER
• 影响因子: 3.4
• 作者: Sugerman, Gabriella P.;Parekh, Sapun H.;Rausch, Manuel K.
• 通讯作者: Rausch, Manuel K.