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

系统性多学科方法将创伤性出血作为复杂的结构和生物力学问题进行研究

• 批准号: 10204239
• 负责人: Valerie Tutwiler
• 金额: $ 24.9万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204239
• 关键词: Acute; Affect; Biocompatible Materials; Biological Assay; Biomechanics; Blood; Blood Coagulation Disorders; Blood coagulation; Cause of Death; Cells; Cellular Immunity; Cessation of life; Coagulation Process; Coculture Techniques; Complex; Coupled; Development; Early-life trauma; Engineering; Environment; Failure; Fibrin; Fibrinogen; Finite Element Analysis; Hemorrhage; Hemostatic Agents; Hemostatic function; Humoral Immunities; Image; Immune; Immune response; Immunity; Immunoassay; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knowledge; Lead; Leukocytes; Link; Mechanics; Modeling; Optics; Patients; Phenotype; Physiological; Plasma; Plasma Proteins; Play; Polymers; Process; Property; Radiolabeled; Rattus; Rheology; Risk; Role; Sampling; Scanning Electron Microscopy; Structure; Techniques; Testing; Thrombosis; Trauma; Trauma patient; Traumatic injury; base; density; design; experimental study; healing; immunoregulation; improved outcome; in vivo; inflammatory marker; insight; interdisciplinary approach; macrophage; mathematical model; mortality; mortality risk; multi-scale modeling; novel; prevent; reconstitution; response; wound; wound healing

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.

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起关键作用 由于（病原） - 生理条件引起的变形群。纤维蛋白原迅速 创伤性损伤后的血液中枯竭，这可能导致凝血病的发展，或 流血；这与死亡风险增加和适应不良的炎症有关 回复。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。 但是，关于创伤期间纤维蛋白原和纤维蛋白血块形成的变化知之甚少 凝血病可能会将创伤后的止血，炎症和免疫力联系起来。在特定目标1中，我建议 采用多学科的方法来系统地检查血块形成，结构，力学， 和创伤设置中的纤维蛋白水解特性。在特定目标2中，我计划检查 纤维蛋白和炎性细胞，巨噬细胞，凝血病。尖端实验，成像和 机械测试技术将在体外和体内分析中使用，并在体内进行重组和患者 样本以对这一复杂过程有整体理解。在特定目标3中，信息 在此检查期间获得的将用于告知免疫调节止血的设计 用于创伤患者潜在用途的生物材料。获得这里提出的基本知识将 告知对出血和止血的理解，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。