Biomechanics of Blast Injury

爆炸伤的生物力学

• 批准号: 8808857
• 负责人: RIYI SHI
• 金额: $ 19.38万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808857
• 关键词: Acrolein; Acute; Area; Awareness; Base of the Brain; Behavioral; Biochemical; Biological; Biological Markers; Biomechanics; Blast Cell; Blast Injuries; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Brain region; Caring; Chemicals; Collection; Computer Simulation; Conflict (Psychology); Data; Development; Diagnostic; Disputes; Dose; Early treatment; Elements; Ethics; Evaluation; Event; Explosion; Generations; Harvest; Head; Healthcare; Human; Impairment; Incidence; Industrial Accidents; Inflammation; Inflammatory; Injury; Intracranial Pressure; Label; Lead; Light; Link; Literature; Location; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Mental Health; Military Personnel; Modeling; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurotoxins; Pathologic; Pathology; Pathway interactions; Patients; Property; Provider; Quality of life; Rattus; Reporting; Research; Resources; Risk; Rodent; Rodent Model; Secondary to; Severities; Shock; Soldier; Stress; Structure; Symptoms; Targeted Research; Techniques; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Traumatic Brain Injury; Up-Regulation; Urine; Validation; Wireless Technology; base; brain tissue; cranium; experience; high risk; improved; in vivo; injured; insight; loved ones; migration; nanoparticle; neuropsychiatry; new therapeutic target; novel; novel diagnostics; pressure; prevent; prognostic; public health relevance; relating to nervous system; research study; screening; sensor; therapeutic development; therapeutic target; wasting

DESCRIPTION (provided by applicant): Blast-induced traumatic brain injuries (bTBIs) result from explosive events and have been labeled as the "signature injury" of modern warfare. Many reports show compelling evidence that, even in the absence of noticeable symptoms, bTBI can cause long-term brain damage leading to dire mental health and/or neurodegenerative consequences. The often subclinical nature of this "silent killer" is particularly alarming, as it precludes early treatment, missing the ideal therapeutic window to prevent damage progression and the resulting pathological sequelae. A multi-modal analysis is proposed to identify the mechanisms linking bTBI- induced mechanical damage to interceding biological mechanisms which may lead to development of post- bTBI pathologies. With a validated rodent model of bTBI combined with the power of computational modeling and cutting-edge, nanoparticle-based sensor technology, we aim to gain greater insight into the link between the biomechanics of bTBI, structural damage in the brain, and subsequent biological mediators of continued post-bTBI damage. Our hypothesis is that rapid, dynamic intracranial pressure changes produce deformation gradients in the brain that are injurious to neurons and brain microvasculature, initiating the pathologic mechanisms leading to post-bTBI neuronal degeneration and dysfunction. We present preliminary evidence of a novel sensor's capacity to for the first time determine brain deformation in real time during blast injury in vivo. These measurements will guide generation of calibrated, validated whole-brain computational stress/strain models leading to increased understanding of the forces experienced by the brain during bTBI. In addition, we demonstrate evidence of bTBI-induced blood-brain barrier compromise indicative of microvascular damage as well as upregulation of acrolein, a potent neurotoxin, marker of neuronal damage, and pro-inflammatory agent. Acrolein is elevated for at least five days post-bTBI in both brain tissue and urine, suggesting it may be responsible for mediating ongoing brain damage long after the initial injury as a result of structural damage to neurons and microvasculature during blast exposure. Its sustained elevation and capacity for noninvasive measurement identifying it as a potentially viable screening biomarker and treatment target for subclinical bTBI. By exploring the regional relationships between bTBI-induced neuronal and microvascular damage, acrolein elevation, and brain deformation through a unique, multi-modal approach, we aim to unveil new mechanisms linking bTBI mechanical damage to secondary biological mediators of sustained injury. Ultimately, this research seeks heightened understanding of bTBI and new diagnostic and therapeutic targets in hopes of improved quality of life and reduced healthcare burdens for bTBI patients, loved ones, and care providers.

描述（由申请人提供）：爆炸事件导致的爆炸性脑外伤（bTBI）被称为现代战争的“标志性损伤”。许多报告提供了令人信服的证据，表明即使没有明显的症状，bTBI 也会造成长期的脑损伤，从而导致可怕的心理健康和/或神经退行性后果。这种“沉默杀手”的亚临床性质尤其令人担忧，因为它阻碍了早期治疗，错过了防止损伤进展和由此产生的病理后遗症的理想治疗窗口。提出了多模态分析来确定 bTBI 引起的机械损伤与可能导致 bTBI 后病理发展的中介生物机制之间的联系机制。通过经过验证的 bTBI 啮齿动物模型，结合计算建模和基于纳米粒子的尖端传感器技术的力量，我们的目标是更深入地了解 bTBI 的生物力学、大脑结构损伤和随后的生物介质之间的联系bTBI 后持续的损伤。我们的假设是，快速、动态的颅内压变化会在大脑中产生变形梯度，从而损害神经元和脑微血管，启动导致 bTBI 后神经元变性和功能障碍的病理机制。我们提出了一种新型传感器首次能够实时确定体内爆炸损伤期间大脑变形的能力的初步证据。这些测量结果将指导生成经过校准、经过验证的全脑计算压力/应变模型，从而加深对 bTBI 期间大脑所经历的力的了解。此外，我们还证明了 bTBI 诱导的血脑屏障受损的证据，表明微血管损伤以及丙烯醛（一种强效神经毒素、神经元损伤标记物和促炎剂）的上调。 bTBI 后脑组织和尿液中的丙烯醛含量至少持续五天升高，这表明丙烯醛可能在初次损伤后很长一段时间内介导持续性脑损伤，这是由于爆炸暴露期间神经元和微血管的结构损伤造成的。其持续升高和无创测量能力使其成为亚临床 bTBI 潜在可行的筛查生物标志物和治疗目标。通过采用独特的多模式方法探索 bTBI 诱导的神经元和微血管损伤、丙烯醛升高和脑变形之间的区域关系，我们的目标是揭示将 bTBI 机械损伤与持续损伤的继发生物介质联系起来的新机制。最终，这项研究旨在加深对 bTBI 以及新的诊断和治疗目标的了解，希望提高 bTBI 患者、亲人和护理人员的生活质量并减轻医疗负担。