Cooling-Triggered Release Of Anesthetics From Thermoresponsive Gels For On Demand Pain Relief

摘要 全美阿片成瘾和滥用的日益严重导致 对更有针对性和更有控制的疼痛管理方法感兴趣。特别是，延长了 持续时间局部麻醉有可能治疗慢性和急性疼痛，而不需要太多的 系统性治疗的缺点和风险。如果病人自己能有一个 可控和非侵入性地触发麻醉剂的释放来控制自己的疼痛。要启用 这种能力，已经开发了几种方法；然而，在这些系统中使用的刺激， 必须由复杂的设备提供，这些设备可以在光热、超声波、 或电磁形式来触发释放。作为一种更简单的选择，我们将开发一个平台，使 冷却触发麻醉剂从植入的热响应聚合物凝胶中释放，使得 将冰块或冷敷敷在皮肤上可以延长疼痛缓解时间。这种方法利用了 刺激，患者已经将其与暂时的疼痛缓解联系在一起，即降温，并避免了需要 复杂的设备，以适当的形式提供能量以供触发。 而可注射热凝胶配方的降解已经被用来可控制地释放 治疗分子，到目前为止还没有对利用冷却的概念进行探索- 注射这些制剂时形成的物理交联凝胶的诱导解体(应 从室温升温到生理温度)。我们将利用由冷却引起的 物理交联凝胶的液化以触发隔离在凝胶内的有效载荷的释放。 释放速率将由围绕储液器的速率控制膜来调节。我们将首先 开发适当的配方来表征这一概念如何实现冷却触发的释放 一个模型药物在体外，然后转移到体内研究，将证明该平台的稳定性 在生理温度和模型有效载荷尼罗河红的释放下，将冰应用于 皮肤。此外，我们还将表征模拟止痛肽的有效载荷的释放行为。 最后，我们将演示温度响应性聚合物稳定装载典型麻醉剂的能力， 布比卡因，当在生理温度下物理交联时，在冷却时缓慢释放 这种治疗性的局部麻醉持续时间较长。这项研究工作的最终结果将是 一种可提供持久疼痛的植入性热敏治疗配方的开发 降温后通过局部麻醉缓解，使降温成为治疗的新刺激 释放策略。

SUMMARY The growing severity of opioid addiction and abuse throughout the United States has led to increased interest in more targeted and controlled approaches to pain management. In particular, prolonged duration local anesthesia has the potential to treat both chronic and acute pain without the many disadvantages and risks of systemic therapies. It would be highly desirable for patients themselves to controllably and non-invasively trigger the release of an anesthetic to manage their own pain. To enable such capability, several approaches have been developed; the stimuli used in these systems, however, must be provided by complex apparatus that can send the necessary energy in photothermal, ultrasound, or electromagnetic form to trigger release. As a simpler alternative, we will develop a platform enabling cooling-triggered release of anesthetics from an implanted thermoresponsive polymer gel, such that application of ice or a cold pack to the skin triggers prolonged pain relief. This approach leverages a stimulus that patients already associate with temporary pain relief, i.e. cooling, and avoids the need for complex apparatus to deliver energy in the appropriate form for triggering. While degradation of injectable thermogelling formulations has been used to controllably release therapeutic molecules, to date there has been no exploration into the concept of utilizing the cooling- induced disassembly of the physically crosslinked gel that forms upon injection of these formulations (due to warming from room temperature to physiological temperature). We will exploit cooling-induced liquification of a physically crosslinked gel to trigger release of a payload sequestered within the gel. Release rate will be modulated by a rate-controlling membrane surrounding the reservoir. We will first develop appropriate formulations to characterize how this concept enables cooling-triggered release of a model drug in vitro, and then move to in vivo studies that will demonstrate the stability of this platform at physiological temperature and the release of a model payload, Nile Red, upon application of ice to the skin. Additionally, we will characterize the release behavior of payloads modeling analgesic peptides. Finally, we will demonstrate the ability of a thermoresponsive polymer to stably load a typical anesthetic, bupivacaine, when physically crosslinked at physiological temperature, and, upon cooling, slowly release this therapeutic for prolonged duration local anesthesia. The end result of this research effort will be the development of an implantable thermoresponsive therapeutic formulation that provides prolonged pain relief via local anesthetic delivery upon cooling, establishing cooling as a new stimulus for therapeutic release strategies.