Biomechanics of Blast Injury

描述（由申请人提供）：爆炸引起的创伤性脑损伤（bTBI）是由爆炸事件引起的，被称为现代战争的“标志性损伤”。许多报告显示令人信服的证据表明，即使没有明显的症状，bTBI也会导致长期的脑损伤，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，因为它排除了早期治疗，错过了理想的治疗窗口，以防止损伤进展和由此产生的病理后遗症。提出了一种多模态分析，以确定将bTBI诱导的机械损伤与可能导致bTBI后病理发展的干预生物学机制联系起来的机制。通过结合计算建模和尖端的基于纳米颗粒的传感器技术的力量，我们的目标是更深入地了解bTBI的生物力学，大脑结构损伤和持续bTBI后损伤的后续生物介质之间的联系。我们的假设是，快速的动态颅内压变化在脑中产生对神经元和脑微血管有害的变形梯度，启动导致bTBI后神经元变性和功能障碍的病理机制。我们提出了一种新的传感器的能力，第一次确定脑变形在真实的时间在体内爆炸伤的初步证据。这些测量结果将指导生成校准的、经验证的全脑计算应力/应变模型，从而增加对bTBI期间大脑所经历的力的理解。此外，我们证明了bTBI诱导的血脑屏障损害的证据，表明微血管损伤以及丙烯醛，一种有效的神经毒素，神经元损伤的标志物和促炎剂的上调。脑组织和尿液中的丙烯醛在bTBI后至少5天升高，这表明它可能是由于爆炸暴露期间神经元和微血管结构损伤导致的初始损伤后很长时间内介导持续脑损伤的原因。它的持续升高和无创测量能力将其确定为亚临床bTBI的潜在可行的筛选生物标志物和治疗靶点。通过探索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，通过一个独特的，多模式的方法，我们的目标是揭示新的机制，bTBI机械损伤的持续性损伤的二级生物介质。最终，这项研究旨在加深对bTBI和新的诊断和治疗靶点的理解，希望改善bTBI患者，亲人和护理提供者的生活质量并减轻医疗负担。

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.