CAREER: Toward a Fundamental Understanding of Why Thrombus Dissolves, Persists, or Breaks Off

该学院早期职业发展（CAREER）奖将使用实验和计算策略来量化血凝块的基本生物物理特性。 这项研究工作将研究为什么血块有时会溶解，有时会持续存在，有时会栓塞（破裂）。为此，研究工作将使用高度可控且具有真实成分的凝块模拟系统。使用实验和计算策略，这项工作将使机械洞察到什么决定了血凝块的命运。 这项工作的未来扩展可能会改善患有血栓相关疾病（如心脏病发作，中风或深静脉血栓形成）的患者的诊断和治疗策略。 这种科学方法也适用于其他软材料和生物材料，因为血凝块与这些材料非常相似。因此，该研究项目将有助于许多科学领域的进步。最后，这项工作将其研究目标与教育目标和更广泛的影响目标相结合，这些目标将直接将我们在健康和科学方面的进步转化为公共价值。本研究的具体目标是使用深静脉血栓作为模型系统，从根本上理解和学习预测血栓微结构如何产生其生物物理特性，这些特性在血栓成熟和治疗过程中如何变化，以及成熟和治疗如何决定血栓的命运。为了实现这一目标，研究工作将首先使用经典的机械测试模式（如简单剪切测试、受限压缩测试和模式I断裂测试）量化成熟和溶解过程中血栓的微观和宏观生物物理特性。此外，它将利用策略进行共聚焦观察下的这些实验。其次，这项工作将校准和验证多尺度模型，以了解和预测血栓的命运。为此，将使用两种类型的模型：一个调查，微观结构模型和预测，连续模型。两种模型都将根据实验数据进行校准和验证，然后用于研究导致血栓溶解、持续和栓塞的机制。此外，这些模型将提供一个框架，在未来，将有助于优化深静脉血栓治疗和治疗技术。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

This Faculty Early Career Development (CAREER) award will use experimental and computational strategies to quantify fundamental biophysical properties of blood clot. The research work will study why blood clot sometimes dissolves, sometimes persists, and sometimes embolizes (breaks off.) To this end, the research work will use a clot mimic system that is highly controllable and of realistic composition. Using both experimental and computational strategies, the work will enable mechanistic insight into a what determines blood clot’s fate. Future extensions of this work may enable improved diagnostic and therapeutic strategies for patients that suffer from clot-related disease such as heart attacks, stroke, or deep vein thrombosis. This scientific approach may also be applicable to other soft and biological materials, as blood clot is very similar to these. Thus, this research project will contribute to the progress in many areas of science. Finally, the work integrates its research objectives with educational objectives and broader impact goals that will directly translate our advancements in health and science to public value. The specific goal of this research is to use deep vein thrombus as a model system to fundamentally understand and learn to predict how thrombus microstructure gives rise to its biophysical properties, how these properties change during thrombus maturation and with treatment, and how maturation and treatment determine thrombus fate. To accomplish this goal, the research work will first quantify thrombus’ micro- and macroscopic biophysical properties during maturation and lysis using classic mechanical testing modalities such as simple shear testing, confined compression testing, and mode I fracture tests. Additionally, it will make use of strategies to conduct these experiments under confocal observation. Second, this work will calibrate and validate multiscale models to understand and predict thrombus fate. To this end, two types of models will be used: an investigative, microstructural model and a predictive, continuum model. Both models will be calibrated and validated against the experimental data and then used to investigate the mechanisms that lead to thrombus dissolution, persistence, and embolization. Additionally, these models will provide a framework that, in the future, will aid in optimizing deep vein thrombus treatment and therapeutic technologies.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.