Cold triggered Local Anesthesia for Pain Management

冷触发局部麻醉用于疼痛管理

• 批准号: 10688175
• 负责人: Chao Zhao
• 金额: $ 30.86万
• 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/10688175
• 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; Postoperative Period; 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; drug action; 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; self assembly; 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 临床和科学上对开发按需局部麻醉有兴趣，其中局部麻醉剂可以 仅在首次给药后需要时和需要时通过外部触发器释放。过去几 多年来，已经开发了可注射的局部麻醉制剂，其可以产生按需局部麻醉。 光和超声波引发的麻醉。然而，它们的临床应用受到缺点的阻碍， 例如当未应用触发时的基础药物释放、对于一个或多个事件的少量重复触发事件 注射（通常4至6次），触发事件仅发生在注射后几小时内，潜在的局部 由外部触发引起的组织毒性和昂贵的制备程序。在这项研究中，为了 为了克服这些缺点，我们的目标是探索冷触发局部麻醉。配方设计 由三种成分组成：河豚毒素（TTX）、冷疗法和热响应聚合物囊泡。我们 假设TTX是一种非常有效局部麻醉剂，少量TTX可以成功地产生局部麻醉剂， 麻醉，从而提高每个触发的功效并增加触发事件的数量;冷 亚低温治疗是医学治疗中常用的一种方法，具有成本低、操作简便、 操作，和非侵入性;温度响应聚合物囊泡可以有效地封装TTX在体内 在低温下，由于聚合物囊泡的解构，释放TTX。此外，本发明还提供了一种方法， 微米大小的聚合物囊泡可以长时间停留在注射部位，作为药物储存器， 长期影响。具体地，具有各种结构（尺寸和孔隙率）和 性能（结构稳定性和壳体刚度）将被制造。这样的图书馆将是一个收藏 候选人将进行迭代筛选以鉴定具有所需体外冷的聚合物囊泡。 可降解的TTX释放，增强的组织局部保留，以及优异的生物相容性（细胞毒性， 炎症、肌肉毒性、器官毒性）。然后，建立大鼠足垫麻醉模型和大鼠足爪切口创面 渗透模型将用于评估所选聚合物囊泡在冷环境中的体内功效和安全性 引发了局部麻醉该项目的预期成果是一个方便和适用的按需本地 麻醉制剂这样的系统将使患者能够根据以下条件来调整局部镇痛的程度： 他们不断变化的需求和条件，并将尽量减少全身止痛药物的管理 例如阿片类药物。