A Novel High-Intensity Iontophoresis-Based Antibiotic Delivery Device for Efficacious Eradication of Chronic Wound Biofilms

一种新型高强度离子电渗疗法抗生素输送装置，可有效根除慢性伤口生物膜

• 批准号: 10433163
• 负责人: Jingwei Xie
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433163
• 关键词: Address; Affect; Amputation; Antibiotic Resistance; Antibiotics; Bacteria; Biological; Biological Models; Cell Culture Techniques; Cells; Characteristics; Chronic; Computer Assisted; Device Designs; Devices; Diffusion; Drug Delivery Systems; Drug resistance; Elements; Extracellular Matrix; Formulation; Goals; Growth; Health; Health Care Costs; Hour; Human; Hydrogels; In Vitro; Infection; Inflammatory; Inflammatory Response; Ions; Iontophoresis; Microbial Biofilms; Mission; Modeling; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Patients; Persons; Phase; Polymers; Process; Public Health; Quality of life; Rattus; Research; Safety; Skin; Skin Tissue; Surgical Flaps; Technology; Temperature; Time; Tissues; Topical application; Treatment Efficacy; Vancomycin; Vancomycin Resistance; Wound Infection; antibiotic design; base; chronic wound; combat; design; extracellular; healing; improved; in vivo; metabolic rate; methicillin resistant Staphylococcus aureus; mortality; nanoparticle; non-healing wounds; novel; prevent; resistance gene; simulation; skin regeneration; small molecule; therapeutically effective; wound; wound biofilm; wound healing

PROJECT SUMMARY. In this study, we will develop a novel ion current-based iontophoresis device that can safely apply high intensity currents to deliver a therapeutically effective concentration of antibiotics into biofilms within a short period of time to achieve efficacious eradication of chronic wound biofilm infections. Chronic wounds are currently affecting more than 6 million people in the US. More than 78% of chronic wounds have biofilms, which arrest the wounds in a prolonged inflammatory phase and prevent wound healing. Biofilms are difficult to treat, because biofilm bacteria are more resistant to antibiotics and a protective matrix of extracellular polymeric substances reduce the diffusion rate of antibiotics into biofilms. As a result, current antibiotic delivery technologies are not capable of delivering sufficient antibiotic concentrations to effectively eradicate chronic wound biofilm infections. Iontophoresis is a non-invasive, electrical current-based drug delivery technology. Conventional iontophoresis devices have low antibiotic delivery efficiency due to the low current intensities they use. Although higher current intensities increase antibiotic delivery efficiency, they can cause significant tissue burn due to the temperature increase and the pH changes at the device/tissue interface. In this proposal, based on an ion current-conducting hydrogel ionic circuit (HIC) invented in our lab, we aim to develop a novel iontophoresis device that can safely apply current intensities that are significantly higher than what current iontophoresis devices use. Higher current intensities will allow us to deliver significantly higher amount of antibiotics to efficaciously eliminate biofilm bacteria and restore the normal wound healing process. In Specific Aim 1, we will first design and optimize an HIC-based, skin-mountable iontophoretic antibiotic delivery device through computer-aided finite-element simulation. We will then determine the antibiotic delivery efficiency and biofilm eradication efficacy of our device using an excised human skin-based wound infection model. The safety of high-intensity ion current application will also be evaluated using in vitro cell cultures and healthy rats. In Specific Aim 2, we will determine the in vivo biofilm eradication efficacy and wound healing enhancement efficacy of our device using a rat bipedicled skin flap-based ischemic wound infection model. Our outcome will establish an optimal device design and a critical proof-of-concept for the in vivo safety, biofilm eradication efficacy, and chronic wound healing enhancement efficacy of our high-intensity iontophoretic antibiotic delivery device. The enhanced healing of chronic wounds enabled by our device will greatly improve the quality of life for patients and reduce the overall healthcare cost.

项目摘要。在本研究中，我们将开发一种新型的基于离子电流的离子电渗疗法装置，该装置可以 安全地施加高强度电流，将治疗有效浓度的抗生素输送到生物膜中 在短时间内实现有效根除慢性伤口生物膜感染。慢性的 目前美国有超过 600 万人受伤。超过 78% 的慢性伤口 生物膜，使伤口处于长期炎症阶段并阻止伤口愈合。生物膜是 难以治疗，因为生物膜细菌对抗生素和细胞外保护基质更具抵抗力 聚合物质降低了抗生素向生物膜的扩散速率。因此，目前的抗生素输送 技术无法提供足够的抗生素浓度来有效根除慢性病 伤口生物膜感染。 离子电渗疗法是一种非侵入性、基于电流的药物输送技术。传统离子电渗疗法 由于设备使用的电流强度较低，因此抗生素输送效率较低。虽然电流较高 强度会提高抗生素的输送效率，但可能会因温度而导致严重的组织烧伤 增加以及设备/组织界面处的 pH 值发生变化。在该提案中，基于离子电流传导 我们实验室发明了水凝胶离子电路（HIC），我们的目标是开发一种新型离子电渗疗法装置，可以安全地 应用明显高于当前离子电渗疗法设备使用的电流强度。更高电流 强度将使我们能够提供显着更高剂量的抗生素，以有效消除生物膜 细菌并恢复正常的伤口愈合过程。在具体目标1中，我们将首先设计和优化 基于 HIC、可安装在皮肤上的离子电渗抗生素输送装置，通过计算机辅助有限元技术 模拟。然后，我们将确定我们的设备的抗生素输送效率和生物膜根除功效 使用基于切除的人体皮肤的伤口感染模型。高强度离子流应用的安全性 还将使用体外细胞培养物和健康大鼠进行评估。在具体目标 2 中，我们将确定体内 我们的装置使用大鼠双蒂皮肤的生物膜根除功效和伤口愈合增强功效 基于皮瓣的缺血性伤口感染模型。我们的成果将建立最佳的设备设计和关键的 体内安全性、生物膜根除功效和慢性伤口愈合增强的概念验证 我们的高强度离子电渗抗生素输送装置的功效。促进慢性伤口的愈合 我们的设备所实现的功能将极大地提高患者的生活质量并降低总体医疗成本。