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

摘要 目前，对于数百万的创伤性脑损伤（TBI）没有有效的治疗方法。 每年在美国诊所看到的患者;因此，识别和开发有效的 治疗仍然是公共卫生领域一项紧迫而未得到满足的需求。我们的多学科团队 开发了一种非侵入性的经颅神经调节技术， 光声激光治疗（NPLT）。我们的专有系统在光能水平上运行 对眼睛和皮肤安全，易于输送，并且对受试者无压力。这项技术 结合近红外激光，减少大脑炎症，刺激神经元 电路-但不会深入脑组织-和光声波，也 减少炎症并刺激神经回路--但它们能更深入地渗透到脑组织中， 允许治疗人类大脑的区域（如海马体）， 记忆力和认知力，并且已知由于TBI而受损。我们先前已经 表明，在两种大鼠TBI模型中，NPLT改善神经认知结果，降低 神经炎症和神经变性并使神经发生正常化。在这一提议中， 利用生物工程师、医生和 神经科学家们共同研究了TBI超过30年，我们将系统地 通过评估这种有前途的神经调节疗法的发作和进展， 液压冲击大鼠的神经病理学和相关的认知功能障碍 在TBI的急性或慢性阶段，用NPLT治疗。而且还要 对频率（每周1次或5次应用）如何影响NPLT进行系统评估 有效缓解TBI结局。在建议的研究完成后， 期望我们将帮助开发一种非侵入性治疗方法， 减少TBI导致的神经病理学和认知障碍的发生， 减轻TBI的全球医疗负担。用于NPLT的激光器已收到非- UTMB机构审查委员会对无关临床 因此支持将NPLT的使用转化为人类患者的可行性 一旦完成本申请中提出的工作。

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.