Photonic Analgesia: Controlled Inhibition of Peripheral Nerve with Infrared Light

描述（由申请人提供）：对急性和慢性疼痛的有效管理仍然是医学上未满足的需求。疼痛影响了很大一部分人，尤其是老年人。疼痛除了对生活质量产生重大影响外，还在直接保健费用和经济生产力损失方面产生巨大的经济影响。减轻疼痛的策略应该理想地针对局部疼痛产生器或疼痛通路，痛觉信号是沿着它传递的。最常见的疼痛管理选择（药理学）是全身性的，而不是针对特定的疼痛途径，有显著的中枢神经系统副作用，和/或有很高的成瘾潜力（阿片类药物）。区域麻醉和周围神经阻滞可以避免许多这些副作用，但仍然需要药物阻断所应用区域的所有神经活动。作为药物治疗的替代方法，可以进行神经横断，也可以使用基于植入中枢或外周电极的疼痛调节剂，尽管这两种方法都有许多不良副作用。基于电极的技术通过向组织内注射电流来过度刺激或抑制伤害性神经通路。虽然可能有效，但植入电极相对来说是非选择性的（因此通常会刺激未参与的神经通路），并且可能会迁移或断裂，导致镇痛效果的丧失，需要手术矫正，并伴有风险。我们建议开发一种新的，非药物的方法来管理急性和慢性神经性疼痛，没有全身副作用或成瘾的风险。提出的方法是基于我们的工作与红外神经刺激（INS）。我们以前已经证明，脉冲红外激光具有在可兴奋组织中诱导动作电位的能力。INS比电刺激具有更大的空间特异性，并且已经证明该技术可以安全地用于急性和慢性环境，而不会造成热损伤（组织学）或功能缺陷。使用不同于INS中使用的参数，红外光也能够阻止动作电位的启动，并可以以剂量依赖的方式阻止现有动作电位的传播。在这里，我们将发展视神经抑制作为一种精确（即仅阻断神经的必要部分）和非药物神经抑制调节神经活动的手段，从而抑制急性和慢性疼痛。我们将这项新技术命名为PAIN（光子抑制神经镇痛）。本研究的目标是：(1)优化激光的时空参数，实现高效、可靠、安全的神经传导阻滞；2)验证光子疼痛调制装置的有效性和安全性。为了实现这些目标，我们将追求以下具体目标：1)确定有效、可靠和安全的神经活动光学抑制的完整光学参数空间（波长、辐射暴露、脉冲持续时间、脉冲频率），并将其与用于INS或可能引起疼痛反应的参数区分开来。作为这些参数的函数，我们将确定PAIN的空间特异性，其开关元件的能力，并开发用于多个单元的技术；2)基于生理测试，广泛的多物理场数值模拟和目前为其他应用创建基于激光的植入物的工作，我们将开发一个原型4通道红外照明装置，用于周围神经和脊髓在急性准备中的可行性测试；3)我们将在急性疼痛动物（大鼠）模型上进行PAIN的安全性和有效性的初步试验。以aim 1的优化参数为出发点，我们将验证并进一步完善这种髓鞘神经元模型的有效性和安全性，作为人类可行性的踏脚石；最后，我们在一项针对难治性慢性疼痛患者的小规模人体研究中证明了可行性（有效性和安全性）。

DESCRIPTION (provided by applicant): Effective management of both acute and chronic pain continues to be an unmet need in medicine. Pain affects a large percentage of especially the older population. Besides having a significant impact on quality of life, pain has an enormous economic impact, both in terms of direct health care costs and in lost economic productivity. Strategies to alleviate pain should ideally target the localized pain generator or pain pathway along which the nociceptive signal is being transmitted. The most common pain management options (pharmacological) are systemic rather than addressing the specific pain pathway involved, have significant CNS side effects, and/or have high addiction potential (opiates). Regional anesthesia and peripheral nerve blocks avoid many of these side effects, but still require pharmaceutical agents that block all nerve activity in the region to which they ae applied. As alternatives to pharmaceutical approaches, nerve transections can be performed, or pain modulators based on implanted central or peripheral electrodes may be used, although both are associated with numerous undesirable side effects. Electrode-based techniques use overstimulation or inhibition of nociceptive neural pathways by injection of electrical currents ino the tissue. While potentially effective, implanted electrodes are relatively nonselective (and thu typically stimulate noninvolved neural pathways), and can migrate or break, resulting in loss of analgesic efficacy and requiring surgical correction with attendant risks. We propose to develop a novel, non-pharmacological approach to manage both acute and chronic neuropathic pain, without systemic side effects or risk of addiction. The proposed approach is based on our work with infrared nerve stimulation (INS). We have previously shown that pulsed infrared laser light has the ability to induce action potentials in excitable tissues. INS can have greater spatial specificity than electrical stimulation, and it has been shown that this technology can be used safely in both acute and chronic settings without causing thermal damage (histologically) or functional deficits. Using parameters different than those used in INS, infrared light is also abl to prevent the initiation of action potentials and can block the propagation of existing action potentials in a dose dependent fashion. Here we will develop optical nerve inhibition as a means of precise (i.e. blocking only the necessary portion of a nerve) and non-pharmacological nerve inhibition for modulating neural activity, thereby inhibiting both acute and chronic pain. We have coined the name PAIN (Photonic Analgesia by Inhibition of Nerves) for this novel technology. The goals of the proposed work are (1) to optimize the spatial and temporal laser parameters that will result in efficient, reliable and safe blocking of nerve conduction propagation; and 2) demonstrate the efficacy and safety of a photonic pain modulation device. To achieve these goals we will pursue the following specific aims: 1) determine the full optical parameter space (wavelength, radiant exposure, pulse duration, pulse frequency) for effective, reliable, and safe optical inhibition of nerve activity and distinguish this from parameters used fr INS or those that may elicit a pain response. As a function of these parameters we will determine the spatial specificity of PAIN, its ability to switch elements on or off, and develop technology to do so for multiple units; 2) based on physiological testing, extensive multi-physics numerical modeling and current work on creating laser-based implants for other applications, we will develop a prototype 4-channel IR illumination device for feasibility testing in peripheral nerves and the spinal cord in acute preparations; 3) we will perform initial test for safety and efficacy of PAIN in an acute-pain animal (rat) model. Using the optimized parameters from aim 1 as starting point, we will validate and further refine the efficacy and safety of PAIN in this myelinated neuron model as stepping stone towards human feasibility; finally, 4) we demonstrate feasibility (efficacy and safety) in a small scale human study in patients with intractable, chronic pain.