Nano-Pulsed Optoacoustic Neuromodulation for Reducing Traumatic Brain Injury-Driven Neuropathology and Improving Cognitive Outcome

摘要 目前，数以百万计的创伤性脑损伤尚无有效的治疗方法。 每年在美国诊所就诊的患者；因此，识别和开发有效的 在公共卫生领域，治疗仍然是一个迫切的、尚未得到满足的需求。我们的多学科团队已经 开发了一种使用纳米脉冲的非侵入性、经颅神经调节技术 光声激光疗法(NPLT)我们的专有系统在光能水平上运行 对眼睛和皮肤安全，易于传递，对受试者没有压力。这项技术 结合近红外激光，减少脑部炎症，刺激神经元 电路--但不能深入脑组织--和光声波，这也 减少炎症并刺激神经回路--但它们会深入脑组织， 允许治疗人脑的关键区域(如海马体) 记忆和认知能力会受到损伤，这是脑外伤的结果。我们之前已经 研究表明，在两种脑外伤大鼠模型中，NPLT改善神经认知结果，减少 神经炎症和神经退行性变，并使神经发生正常化。在这份提案中， 利用生物工程师、医生和医生组成的多学科团队的综合专业知识 神经学家集体研究了30多年的脑损伤，我们将系统地 开发这种有希望的神经调节疗法，通过评估发病和进展 液压冲击大鼠的神经病理及相关认知功能障碍 颅脑损伤急性期或慢性期给予NPLT治疗。此外，我们还将 对频率(每周1次或5次)将如何影响NPLT进行系统评估 减轻脑损伤转归的有效性。在完成建议的研究后，我们的 期望我们将帮助开发一种非侵入性治疗，通过 减少脑外伤引起的神经病理和认知损害的发病，具有潜在的 以减轻全球TBI的医疗负担。用于NPLT的激光器已收到非 UTMB机构审查委员会对无关临床的重大风险状态 因此支持将NPLT用于人类患者的可行性的应用 一旦本申请书中提出的工作完成后，将不再提交申请。

ABSTRACT Currently there are no effective treatments for the millions of traumatic brain injury (TBI) patients that are seen each year in US clinics; therefore, identifying and developing effective treatments remains an urgent, unmet need in public health. Our multidisciplinary team has developed a non-invasive, transcranial neuromodulation technique using nano-pulsed optoacoustic laser therapy (NPLT). Our proprietary system operates at levels of optical energy that are eye-safe and skin-safe, easy to deliver, and stress-free for the subject. This technology combines near-infrared laser light, which reduces brain inflammation and stimulates neuronal circuitry - but does not penetrate deeply into brain tissue - and optoacoustic waves, that also reduce inflammation and stimulate neural circuitry - yet they penetrate deeper into brain tissue, allowing treating areas of the human brain (such as the hippocampus) that are critical for memory and cognition and are known to be damaged as a result of TBI. We have previously shown that, in two rat models of TBI, NPLT improves neurocognitive outcomes, reduces neuroinflammation and neurodegeneration and normalizes neurogenesis. In this proposal, leveraging the combined expertise of a multidisciplinary team of bioengineers, physicians and neuroscientists who have collectively studied TBI for over 30 years, we will systematically develop this promising neuromodulation therapy by evaluating the onset and progression of neuropathology and associated cognitive dysfunctions in rats subjected to fluid percussion injury (FPI) and treated with NPLT in the acute or chronic phase of TBI. Moreover, we will conduct a systematic evaluation of how frequency (1 or 5 weekly applications) will affect NPLT efficacy to mitigate TBI outcomes. At the completion of the proposed studies, it is our expectation that we will have aided the development of a non-invasive treatment that, by reducing the onset of TBI-driven neuropathology and cognitive impairments, has the potential to reduce the global healthcare burden of TBI. The laser used for NPLT has received non- significant risk status by institutional review boards at UTMB for unrelated clinical applications thus supporting the feasibility of translating the use of NPLT to human patients once the work proposed in the present application will be completed.