Cold triggered Local Anesthesia for Pain Management

冷触发局部麻醉用于疼痛管理

• 批准号: 10521600
• 负责人: Chao Zhao
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521600
• 关键词: Absence of pain sensation; Analgesics; Anatomy; Anesthesia procedures; Body Temperature; Bupivacaine; Cell Survival; Characteristics; Clinical; Cold Therapy; Collection; Dose; Drug Carriers; Drug Kinetics; Emulsions; Encapsulated; Event; Extravasation; Feasibility Studies; Formulation; Frostbite; Goals; Hour; In Vitro; Infiltration; Inflammation; Injectable; Injections; Injury; Libraries; Light; Liposomes; Local Anesthetics; Local anesthesia; Long-Term Effects; Medical; Methods; Microscopic; Microspheres; Modeling; Molecular Weight; Morphology; Opioid; Organ; Outcome; Pain management; Patients; Pharmaceutical Preparations; Plasma; Polymers; Porosity; Postoperative Pain; Preparation; Procedures; Property; Propylene Glycols; Rattus; Reaction; Research; Rupture; Safety; Sedimentation process; Site; Sodium Fluorescein; Stimulus; Structure; Surgical incisions; System; Temperature; Tetrodotoxin; Time; Tissues; Toxic effect; Water; aqueous; biomaterial compatibility; capsule; chronic pain; clinical application; cost; cytotoxicity; design; efficacy evaluation; ethylene glycol; improved; in vivo; in vivo evaluation; in vivo imaging system; interest; natural hypothermia; operation; pain relief; perineural; poly(lactide); polyglycerol; prevent; response; sciatic nerve; screening; ultrasound; wound

PROJECT SUMMARY There is clinical and scientific interest in developing on-demand local anesthesia, in which local anesthetics can only be released by an external trigger when and where needed after the first administration. In the past few years, injectable local anesthetic formulations have been developed that can generate on-demand local anesthesia triggered by light and ultrasound. However, their clinical application is hindered by shortcomings, such as basal drug release when the trigger is not applied, a small number of repetitive trigger events for one injection (usually 4 to 6 times), the trigger event only occurs within a few hours after the injection, potential local tissue toxicity caused by the external triggers, and expensive preparation procedures. In this research, in order to overcome these shortcomings, we aim to explore cold triggered local anesthesia. The formulation design consists of three components: tetrodotoxin (TTX), cold therapy, and thermo-responsive polymersomes. We hypothesize that TTX is an extremely potent local anesthetic, a small amount can successfully produce local anesthesia, thereby improving the efficacy of each trigger and increasing the number of trigger events; cold treatment is a common use of hypothermia in medical therapy, which has the characteristics of low cost, easy operation, and non-invasiveness; thermo-responsive polymersomes can efficiently encapsulate TTX at body temperature, but release TTX due to the deconstruction of the polymersomes under cold treatment. In addition, the micron-sized polymersomes can stay at the injection site for a long time, acting as a drug reservoir to achieve long-term effects. Specifically, a large library of polymersomes with various structures (size and porosity) and properties (structurally stability and shell stiffness) will be fabricated. Such a library will be a collection of candidates. Iterative screening will be conducted to identify the polymersomes with the desired in vitro cold triggerable TTX release, enhanced local retention in tissues, and excellent biocompatibility (cytotoxicity, inflammation, myotoxicity, organ toxicity). Then, the rat footpad anesthesia model and rat paw incision wound infiltration model will be used to evaluate the in vivo efficacy and safety of the selected polymersomes in cold triggered local anesthesia. The expected outcome of this project is a convenient and applicable on-demand local anesthetic formulation. Such a system will enable patients to adjust the degree of local analgesia according to their changing needs and conditions, and will minimize the administration of systemic analgesic medications such as opioids.

项目摘要 在开发按需局部麻醉方面存在临床和科学兴趣，局部麻醉可以在其中 仅在第一个管理后需要的何时及时才能通过外部触发器释放。在过去的几个 几年，已经开发了可注射的局部麻醉配方，可以产生按需局部 麻醉是由光线和超声引发的。但是，他们的临床应用受到缺点的阻碍 例如，当不应用触发器时，基础药物释放，一个重复的触发事件是一个 注射（通常为4到6次），触发事件仅发生在注射后的几个小时内，潜在的局部 由外部触发因素引起的组织毒性和昂贵的准备程序。在这项研究中 为了克服这些缺点，我们旨在探索触发的局部麻醉。配方设计 由三个成分组成：四毒素（TTX），冷疗法和热反应性聚合物体。我们 假设TTX是一种极有效的局部麻醉，少量可以成功产生本地 麻醉，从而提高每个触发因素的功效并增加触发事件的数量；寒冷的 治疗是在药物疗法中的低温使用，其特征低成本，容易 操作和非侵入性；热响应性聚合物体可以有效地将TTX封装在人体 温度，但由于冷处理下的聚合物体的解构而释放TTX。此外， 微米大小的聚合物体可以长期保留在注射部位，充当药物储存库 长期影响。具体而言，具有各种结构（尺寸和孔隙率）的大型聚合物组和 将制造特性（结构稳定性和壳刚度）。这样的库将是 候选人。将进行迭代筛查以鉴定所需的体外冷的聚合物体 可触发的TTX释放，增强组织中的局部保留率以及出色的生物相容性（细胞毒性， 炎症，肌毒性，器官毒性）。然后，大鼠脚踩麻醉模型和大鼠爪切口伤口 渗透模型将用于评估所选聚合物体在冷的体内功效和安全性 触发了局部麻醉。该项目的预期结果是一个方便且适用的按需本地 麻醉配方。这样的系统将使患者根据 它们不断变化的需求和条件，将最大程度地减少全身性镇痛药的管理 例如阿片类药物。