Biomechanics of Blast Injury

描述(申请人提供)：爆炸导致的创伤性脑损伤(BTBI)是由爆炸事件引起的，已被贴上现代战争的“标志性损伤”的标签。许多报告显示，令人信服的证据表明，即使在没有明显症状的情况下，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的可能性，错过了防止损害进展和由此产生的病理后遗症的理想治疗窗口。我们建议用多模式分析来确定bTBI所致的机械损伤与可能导致bTBI后病理发展的生物学机制之间的联系。通过一个经过验证的bTBI啮齿动物模型，结合计算建模的力量和基于纳米颗粒的尖端传感器技术，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bTBI后持续损伤的后续生物介质之间的联系。我们的假设是，快速、动态的颅内压变化在大脑中产生变形梯度，对神经元和脑微血管造成损害，启动了导致bTBI后神经元退化和功能障碍的病理机制。我们提出的初步证据表明，一种新型传感器首次能够在体内爆炸伤期间实时确定脑变形。这些测量将指导产生校准的、经过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诱导的血脑屏障受损的证据表明微血管损伤以及丙烯醛的上调，丙烯醛是一种强有力的神经毒素，神经元损伤的标志，以及促炎剂。在bTBI后至少五天，脑组织和尿液中的丙烯醛都会升高，这表明它可能是在最初的损伤后很长一段时间内，由于冲击波暴露对神经元和微血管系统的结构性破坏而导致的持续脑损伤的原因。它的持续升高和非侵入性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靶点。通过一种独特的、多模式的方法探索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性关系，我们的目标是揭示bTBI机械损伤与持续损伤的二级生物介质之间的新机制。最终，这项研究寻求提高对bTBI和新的诊断和治疗目标的理解，希望改善bTBI患者、亲人和护理人员的生活质量，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.