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

非技术总结血液凝固是一个自然过程，可以防止血液从受损血管中流失，并恢复体内正常的血液循环。在损伤时，一系列事件最终形成细胞栓和附着于伤口边缘的聚合物生物材料。血小板是循环中的小圆盘形细胞，被激活并施加收缩力以缩小凝块的整体尺寸，并机械稳定修复，使其能够承受流动血液和身体运动施加的力。凝血过程的不健康变化是全球死亡和残疾的主要原因，并与一系列严重的医疗条件，如血友病，中风和心脏病发作有关。该项目旨在利用最先进的实验和计算方法研究血凝块中血小板的复杂动力学行为。由于血小板的生物物理特性，如大小，力量和活动可以在物种之间有很大的差异，来自人类，小鼠，狗，牛和鸡的血小板的特性将进行比较，以确定其对血液凝固的影响。该项目的结果将促进新的治疗方法和医学诊断的发展，以减轻不健康凝血的不良影响。此外，该项目将培训研究生和本科生解决跨学科工程和生物医学问题。该项目将推进HealthReach，这是一项教育计划，旨在让患有慢性疾病的K-12学生参与STEM学习，这些学生由于频繁的治疗，缺课和其他与医疗有关的问题而经常处于教育劣势。技术概述本项目旨在研究基本的生物物理行为和血小板在血凝块中的相互作用，血凝块是一种积极收缩的材料。在血凝块形成期间，收缩的血小板拉动新生的聚合纤维蛋白网，然而尽管与出血和凝血障碍有关，但对这种活跃过程的力学和动力学仍然知之甚少。这部分是由于我们对血小板性质和功能的了解有限，特别是当它们共同向凝块纤维蛋白网络施加力时，它们的协同作用。这个跨学科的项目将整合实验和计算建模，以研究不同物种的凝块收缩，包括人类，小鼠，狗，牛和鸡血小板，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。该信息将用于开发凝块收缩的中尺度模型，该模型将考虑血小板的微观力学和动力学，并将提供对由于血小板活性和收缩引起的凝块结构变化的洞察。该项目将重点了解血小板异质性、合作、激活模式和血栓收缩机制的作用，以揭示单个血小板行为、集体血小板行为和大块血栓性质之间的联系。通过提供血小板异质性对凝块动力学影响的基本见解，该项目将开发设计新型生物活性材料的新策略。此外，该项目将为出血和凝血研究所用的动物模型提供重要的见解。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知识价值和更广泛的影响审查标准进行评估来支持。

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.