Systematic multidisciplinary approach to study traumatic bleeding as a complex structural and biomechanical problem

纤维蛋白通过提供机械稳定性，在止血、血栓形成和伤口愈合中发挥关键作用。 由于(病理)生理条件而发生变形的血液凝块。纤维蛋白原迅速 创伤后从血液中耗尽，这可能导致凝血障碍的发展，或者 出血；这与死亡风险增加和适应不良的炎症有关。 回应。重要的是，创伤是年轻人死亡的主要原因。我们已经积累了 大量证据表明，纤维蛋白原、纤维蛋白和凝块结构是血栓性疾病的关键驱动因素。 然而，关于创伤过程中纤维蛋白原和纤维蛋白凝块形成的变化，我们知之甚少。 凝血障碍可能与创伤后的止血、炎症和免疫有关。在具体目标1中，我建议 采取多学科的方法，系统地研究血栓的形成，结构，力学， 以及创伤环境中的纤溶特性。在具体目标2中，我计划研究 纤维蛋白和炎症细胞，巨噬细胞，在凝血障碍中。尖端实验、成像和 机械测试技术将用于体外和体内重组和患者的测试 样本，以发展对这一复杂过程的整体理解。在具体目标3中，信息 在这项检查中获得的信息将被用于设计免疫调节性止血药物 创伤患者潜在使用的生物材料。掌握这里提出的基本知识将会 了解出血和止血，纤维蛋白和炎症细胞之间的相互作用， 以及在生物材料中使用纤维蛋白。

Fibrin plays a critical role in hemostasis, thrombosis and wound healing by providing mechanical stability to blood clots that undergo deformation due to (patho)-physiologic conditions. Fibrinogen is rapidly depleted from the blood following traumatic injury which can lead to the development of coagulopathy, or bleeding; this has been correlated with an increased risk of death and a maladaptive inflammatory response. Importantly, trauma is the leading cause of death among young people. We have amassed considerable evidence that fibrinogen, fibrin, and clot structure are key drivers of thrombotic disorders. However, little is known regarding how changes in fibrinogen and fibrin clot formation during trauma coagulopathy may link hemostasis, inflammation, and immunity after trauma. In Specific Aim 1 I propose to take a multidisciplinary approach to systematically examine blood clot formation, structure, mechanics, and fibrinolytic properties in the trauma setting. In Specific Aim 2 I plan to examine the interplay between fibrin and the inflammatory cells, macrophages, in coagulopathy. Cutting edge experimental, imaging, and mechanical testing techniques will be used in vitro and in vivo assays with both reconstituted and patient samples to develop a holistic understanding of this complex process. In Specific Aim 3, the information gained during this examination will be used to inform the design of immuno-modulatory hemostatic biomaterials for potential use in trauma patients. Gaining the fundamental knowledge proposed here will inform the understanding of bleeding and hemostasis, the interplay between fibrin and inflammatory cells, and the use of fibrin in biomaterials.