Characterization of the Properties and Mechanisms of Photobiomodulation-Induced Axonal Block and Evaluation as a Treatment for Neuropathic Pain

项目摘要/摘要 最近的研究表明，当~808到830 nm的光被立即并列到靶神经元上时 或轴突(毫米内)通过侵入性技术，传递疼痛相关信息的C和Aδ纤维可以 暂时和可逆地“关闭”，而不影响较大的A纤维的功能。如果进一步 发展起来，这种光生物调节(PBM)效应作为一种植入性设备具有令人兴奋的可能性 治疗各种慢性疼痛综合征，包括神经性疼痛。该项目采取了重要步骤来 建立基础性和机械性的理解，并为翻译提供基础。 从基本和机理上理解--第一，PBM剂量和波长对 轴突阻滞(在体外周围神经制剂中)和伤害性反应(在体内啮齿动物疼痛中) 模型)将被严格描述。这些数据将提供重要的机械性洞察和翻译 价值。第二，观察到的微管失稳和由此引起的轴突静脉曲张的作用将是 被认为是独立观察到的动作电位阻断机制的贡献者。我们会 确定效应大小(功能数据)与微管程度之间是否存在相关性 不稳定性(共聚焦显微镜和电子显微镜数据)。将使用计算模型来评估 轴索静脉曲张对动作电位传播的影响。最后，药理微管的作用 (去)对PAB剂量的稳定剂进行评估。 在翻译活动方面-该项目包括开发临床前级别的系统，使 将长期应用于神经的PBM，最终目标是证明慢性PBM可以提供 在大型动物疼痛模型(猪)中的持久和深刻的止痛效果。一个完全可植入的系统 基于现有的商业神经刺激器，将使PBM能够在更长的时间内提供。 经皮系统将需要随着时间的推移进行重复干预(例如，每周干预大约 分钟)，但将能够使用完全可植入系统无法实现的更高峰值功率。这个 系统将用于猪的疼痛模型(外周神经炎)，以更好地模拟人类对 药物干预比啮齿动物模型已经能够做到。临床前研究将包括 30天的先导性研究，然后是为期6个月的小型猪研究。 综上所述，该项目将扩大对PBM诱导的轴突阻滞的基本了解 转向适合于治疗慢性疼痛的平移设备。

Project Summary / Abstract Recent research indicates that when ~808 to 830 nm light is applied in immediate juxtaposition to target neurons or axons (within mm) through invasive techniques, C and Aδ fibers that convey pain-related information can temporarily and reversibly be “turned off” without affecting the functionality of the larger A fibers. If further developed, this photobiomodulation (PBM) effect has exciting possibilities as an implantable device-based treatment for various chronic pain syndromes, including neuropathic pains. This project takes important steps to develop fundamental and mechanistic understanding, and to provide a foundation for translation. In terms of fundamental and mechanistic understanding – first, the effect of PBM dose and wavelength on axonal block (in an ex vivo peripheral nerve preparation) and nociceptive response (in an in vivo rodent pain model) will be rigorously characterized. These data will provide important mechanistic insight and translational value. Second, the role of observed microtubule destabilization and the resulting axonal varicosities will be explored as contributors to the mechanism of the independently-observed action potential block. We will determine whether or not there is a correlation between effect size (functional data) and degree of microtubule instability (confocal microscopy and electron microscopy data). Computational models will be used to evaluate the effect of axonal varicosities on action potential propagation. Finally, the effect of pharmacological microtubule (de)stabilizers on PAB dose will be assessed. In terms of translational activities – the project includes development of pre-clinical-grade systems that allow PBM at the nerve to be applied chronically with the ultimate goal of demonstrating that chronic PBM can provide a persistent and profound analgesic effect in a large animal pain model (porcine). A fully implantable system based on an existing commercial neurostimulator will enable PBM to be delivered over extended periods of time. A percutaneous system will require repeated interventions over time (e.g., weekly interventions on the order of minutes), but will enable use of higher peak powers not achievable with the fully implantable system. The systems will be used in a porcine pain model (peripheral neuritis) that better mimicked the human response to pharmacological interventions than rodent models have been able to do. The pre-clinical studies will include a 30-day pilot study followed by a 6-month study in minipigs. In summary, this project will expand fundamental understanding of PBM-induced axonal block with an eye toward translational devices suitable for the treatment of chronic pain.