Photonic Analgesia: Controlled Inhibition of Peripheral Nerve with Infrared Light

描述(由申请人提供)：急性和慢性疼痛的有效治疗仍然是医学上未得到满足的需求。疼痛影响了很大一部分人，特别是老年人。疼痛除了对生活质量有重大影响外，还在直接医疗成本和经济生产力损失方面产生了巨大的经济影响。缓解疼痛的策略应该理想地针对传递伤害性信号的局部疼痛产生器或疼痛通路。最常见的疼痛控制方案(药理学)是全身性的，而不是针对所涉及的特定疼痛途径，具有显著的中枢神经系统副作用，和/或具有很高的成瘾潜力(阿片类)。区域麻醉和周围神经阻滞可以避免许多副作用，但仍然需要药物来阻断所应用区域的所有神经活动。作为药物的替代方法，可以进行神经横断术，或者可以使用基于植入的中央或外周电极的疼痛调节剂，尽管这两种方法都与许多不良副作用有关。基于电极的技术通过在组织中注入电流来过度刺激或抑制伤害性神经通路。虽然可能有效，但植入的电极是相对非选择性的(清华大学通常会刺激不受影响的神经通路)，可能会迁移或断裂，导致失去止痛效果，需要手术矫正，伴随着风险。我们建议开发一种新的非药理学方法来管理急性和慢性神经病理性疼痛，而没有全身副作用或成瘾风险。提出的方法是基于我们对红外神经刺激(INS)的工作。我们先前已经证明，脉冲红外激光具有在可兴奋组织中诱发动作电位的能力。INS具有比电刺激更强的空间特异性，而且已经证明，这项技术在急性和慢性环境中都可以安全使用，而不会造成热损伤(组织学)或功能缺陷。使用与惯导系统不同的参数，红外光也可以防止动作电位的启动，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手段，以精确(即仅阻断神经的必要部分)和非药理学神经抑制来调节神经活动，从而抑制急性和慢性疼痛。我们为这项新技术创造了名字Pain(通过抑制神经的光子止痛)。这项拟议工作的目标是(1)优化空间和时间激光参数，从而有效、可靠和安全地阻断神经传导传播；以及2)展示光子疼痛调制设备的有效性和安全性。为了实现这些目标，我们将追求以下具体目标：1)确定有效、可靠和安全的光学抑制神经活动的全部光学参数空间(波长、辐射暴露、脉冲持续时间、脉冲频率)，并将其与用于神经活动的参数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，我们将确定疼痛的空间特异性、其打开或关闭元素的能力，并开发多个单元这样做的技术；2)基于生理测试、广泛的多物理数值建模以及目前针对其他应用而创建的基于激光的植入物的研究工作，我们将开发一个4通道红外照明装置原型，用于在急性疼痛准备中对周围神经和脊髓进行可行性测试；3)我们将在急性疼痛动物(大鼠)模型中进行疼痛的安全性和有效性的初步测试。以目标1中的优化参数为起点，我们将验证并进一步提炼这种有髓神经元模型中疼痛的有效性和安全性，以此作为迈向人类可行性的垫脚石；最后，我们在一项小规模的人类研究中展示了在顽固性慢性疼痛患者中的可行性(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.