Collaborative Research: Understanding emergent collective biophysical behavior of platelets in blood clotting

血液凝固是一种自然过程，可以防止受损血管的血液流失，恢复体内正常的血液循环。受伤后，一系列事件最终导致细胞和高分子生物材料的堵塞，附着在伤口边缘。血小板，循环中的小圆盘状细胞，被激活并施加收缩力来缩小血块的整体大小，并机械地稳定修复，使其能够承受血液流动和物理运动施加的力。血液凝固过程的不健康变化是世界范围内死亡和残疾的主要原因，并与血友病、中风和心脏病发作等一系列严重疾病有关。该项目旨在利用最先进的实验和计算方法来研究血小板在血凝块中的复杂动态行为。由于血小板的生物物理特性，如大小、力和活性在不同物种之间有很大差异，我们将比较人类、老鼠、狗、牛和鸡的血小板的特性，以确定它们对血液凝固的影响。该项目的成果将有助于开发新的治疗方法和医学诊断方法，以减轻不健康凝血的不利影响。此外，该项目将培养研究生和本科生解决跨学科工程和生物医学问题的能力。该项目将推进HealthReach，这是一个教育项目，旨在让患有慢性疾病的K-12学生参与STEM学习，这些学生往往因频繁治疗、缺课和其他医疗相关问题而处于教育劣势。技术总结：本项目旨在研究血小板在血栓中的基本生物物理行为和相互作用，血栓是一种主动收缩的物质。在血栓形成过程中，收缩的血小板拉住新生的聚合纤维蛋白网，尽管与出血和凝血障碍有关，但这一活跃过程的机制和动力学仍然知之甚少。这部分是由于我们对血小板特性和功能的理解有限，特别是当它们共同向凝块纤维蛋白网络施加力时，它们正在出现的协作性。这个跨学科的项目将结合实验和计算模型来研究不同物种的凝块收缩，包括人类、老鼠、狗、牛和鸡的血小板，它们表现出不同的生理特性。实验将表征血小板活性和纤维蛋白网络内的相互作用。这些信息将用于开发一个考虑血小板微观力学和动力学的凝块收缩的中尺度模型，并将深入了解由于血小板活性和收缩而引起的凝块结构变化。该项目将重点了解血小板异质性、合作、活化模式和凝块收缩机制的作用，以揭示单个血小板行为、集体血小板行为和大块凝块特性之间的联系。通过提供血小板异质性对凝块动力学影响的基本见解，该项目将为设计新型生物激发活性材料制定新的策略。此外，该项目将为用于出血和凝血研究的动物模型提供重要的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

NON-TECHNICAL SUMMARYBlood clotting is a natural process that prevents blood loss from damaged vessels and restores normal blood circulation in the body. Upon injury, a chain of events culminates in the formation of a plug of cells and polymeric biomaterial that attaches to the wound edges. Platelets, the small disk-shaped cells in circulation, become activated and apply contractile forces to shrink the overall size of the clot and mechanically stabilize the repair to allow it to withstand forces applied by flowing blood and physical movements. Unhealthy changes to the blood clotting process are a leading cause of death and disability worldwide and are associated with a range of severe medical conditions such as hemophilia, stroke, and heart attack. This project seeks to investigate the complex dynamic behavior of platelets within blood clots using state of the art experimental and computational methods. As platelet biophysical properties, such as size, force, and activity can vary widely among species, the properties of platelets from humans, mice, dogs, cows, and chickens will be compared to pinpoint their influence on blood clotting. The results of this project will facilitate the development of new treatments and medical diagnostics to mitigate adverse effects of unhealthy clotting. In addition, the project will train graduate and undergraduate students in solving cross-disciplinary engineering and biomedical problems. The project will advance HealthReach, an education program aiming to engage in STEM learning K-12 students with chronic illnesses, who are often educationally disadvantaged due to frequent treatments, school absences, and other medially related issues. TECHNICAL SUMMARYThis project seeks to investigate the fundamental biophysical behaviors and interactions of platelets within a blood clot that is an actively contracting material. During blood clot formation, contracting platelets pull on a nascent polymeric fibrin mesh, yet the mechanics and dynamics of this active process remain poorly understood, despite links to bleeding and clotting disorders. This is in part due to our limited understanding of platelet properties and function, especially their emerging cooperativity as they collectively apply forces to the clot fibrin network. This interdisciplinary project will integrate experiments and computational modeling to investigate clot contraction in different species including human, mouse, dog, cow, and chicken platelets that exhibit diverse physiological properties. The experiments will characterize platelet activity and interactions within the fibrin network. This information will be used to develop a mesoscale model of clot contraction that will take into account micromechanics and dynamics of platelets and will provide insight into the clot structural changes due to platelet activity and contraction. The project will focus on understanding the role of platelet heterogeneity, cooperation, activation patterns, and clot contraction mechanics to reveal the connection between the behavior of a single platelet, the collective platelet behavior, and the properties of bulk clots. By providing fundamental insights into the effects of platelet heterogeneity on the clot dynamics, the project will develop new strategies for designing novel bio-inspired active materials. Furthermore, the project will provide important insights into animal models used for bleeding and clotting researchThis 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.