On Demand Dissoluble Supramolecular Hydrogels: Towards Pain Free Burn Dressings

摘要 本提案描述了第一个的合成、表征和彻底的评估 超分子杂化水凝胶烧伤敷料。我们的设计目标是a)按需溶解--为了简单 烧伤创面无创伤切除--b)综合抗菌活性--用于感染管理-- 以及c)自我修复--用于无问题的应用和使用。烧伤是最常见的伤害之一， 世界范围内毁灭性的、要求极高的危重护理问题。几乎每一分钟，都有人在美国 严重烧伤，每天有300多名儿童到急诊室就诊，其中2人死亡 因为烧伤的缘故。全球有数百万人患有烧伤相关的残疾，心理上有很重的负担， 对幸存者及其家人造成的情感和经济后果。去除烧伤敷料是 据报道，疼痛最严重的时候(烧伤后)，阿片类药物是治疗这种疼痛的主要方法 疼痛。重症监护病房一级护理的典型创伤的烧伤敷料更换至少为57.6 几分钟。随着麻醉的频繁应用，这一过程的时间和复杂性进一步增加。 重要的是，反复痛苦的敷料更换和伤口感染会导致更高的生命易感性- 有脓毒症和多器官衰竭的危险。目前可用的烧伤敷料-临床使用-粘附性 至伤口表面，并通过手术或机械方式从伤口上清创。这将导致 新上皮化组织创伤、愈合延迟和剧烈疼痛。因此，我们建议 创造一种结合了主-客体化学的超分子杂化水凝胶(南瓜[7]-托管 阳离子共聚物)和无机成分(即粘土)(Aim1)。这种水凝胶的独特之处在于 具有很高的生物相容性，能够通过金刚烷/金刚烷按需溶解 衍生品，轻松、快速地移除和消除清创。这将减少极端的疼痛和 痛苦(通过大幅减少痛苦的时间)。拟议中的水凝胶还将嵌入 减少细菌感染的抗生素。我们将在体外(小鼠和人)测试这种水凝胶 细胞，目标2)和体内(小鼠，目标3)和临床前(猪，目标3)实验。总体而言，我们的目标是 促进烧伤创面更好地愈合，阻止感染，并为患者提供无痛烧伤护理 肩负着NIAMS的使命。这个项目属于再生医学的范畴(伤口愈合， 组织修复、再生)和大面积急性皮肤创伤(烧伤和创伤)的治疗 在NIAMS 2020-2024财年战略计划中强调。该项目还侧重于a)改善 患者经验(减轻疼痛)，以及b)治疗烧伤伤口和感染并存的情况， NIAMS的两个重点领域。

Abstract This proposal describes the synthesis, characterization, and thorough evaluation of the first supramolecular hybrid hydrogel burn dressing. Our design goals are a) on-demand dissolubility -for easy trauma-free removal from burn wound-, b) integrated antimicrobial activity - for infection management-, and c) self-healing – for problem-free application and use. Burn injuries are one of the most prevalent, devastating, and demanding critical care problems, worldwide. Nearly every minute, someone in the US sustains a serious burn injury, and each day over 300 children visit emergency rooms and 2 of them die due to burn injuries. Millions, globally, suffer from burn-related disabilities with heavy psychological, emotional, and economic consequences on the survivors and their families. Burn dressing removal is reportedly the time of most pain (after the burn itself), and opioids are the primary treatment for such pain. The burn dressing change for a typical injury with intensive care unit level care is at least 57.6 minutes. The time and complexity of the process further grow with the frequently applied anesthesia. Importantly, repeated painful dressing changes and wound infection cause a higher predisposition to life- threatening sepsis and multi-organ failure. Currently available burn dressings – used clinically – adhere to the wound surface and are surgically or mechanically debrided from the wound. This results in the traumatization of newly epithelialized tissues, delayed healing and severe pain. We, thus, propose to create a supramolecular hybrid hydrogel combining the host-guest chemistry (cucurbituril [7]-hosted cationic copolymer) with inorganic components (i.e., clay) (Aim1). The unique feature of this hydrogel will be its high biocompatibility and ability to be dissolved on-demand via adamantane/diamantane derivatives, easily and quickly removed and eliminate debridement. This will reduce extreme pain and suffering (by drastically reducing time of pain). The proposed hydrogel will also be embedded with antibiotics to reduce bacterial infection. We will test this hydrogel through both in vitro (mouse and human cells, Aim 2) and in vivo (mouse, Aim 3) and preclinical (swine, Aim 3) experiments. Overall, our goal is to promote better burn wound healing, deter infection and provide pain-free burn care for patients, in line with the mission of NIAMS. This project falls under the umbrella of regenerative medicine (wound healing, tissue repair, regeneration) and treatment of large-area acute skin wounds (burns and trauma) highlighted in the NIAMS Strategic Plan for FY 2020-2024. The project also focuses on a) improving the patient experience (reducing pain), and b) treating co-occuring conditions of burn wounds and infections, two focus areas of NIAMS.