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。在这项研究中，我们将开发一种新型的基于离子电流的离子电池设备 安全地施加高强度电流以将治疗有效的抗生素浓度输送到生物膜中 在短时间内实现慢性伤口生物膜感染的有效根除。慢性的 目前，在美国，伤口正在影响超过600万人。超过78％的慢性伤口具有 生物膜在长时间的炎症阶段阻止伤口并防止伤口愈合。生物膜是 很难治疗，因为生物膜细菌对抗生素具有更耐药性和细胞外保护基质 聚合物物质降低了抗生素对生物膜的扩散速率。结果，当前的抗生素递送 技术无法提供足够的抗生素浓度来有效消除慢性 伤口生物膜感染。 离子噬菌体是一种非侵入性的，基于电流的药物输送技术。常规的离子电池 由于其使用的电流强度低，设备的抗生素递送效率低。虽然电流较高 强度提高了抗生素递送效率，由于温度，它们可能导致大量组织燃烧 在设备/组织界面上增加和pH变化。在此提案中，基于离子电流导导 我们实验室中发明的水凝胶离子电路（HIC），我们旨在开发一种可以安全的离子电池设备 应用明显高于当前离子电池设备使用的电流强度。较高的电流 强度将使我们能够提供更高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。在特定目标1中，我们将首先设计并优化 通过计算机辅助元件，基于HIC的，以HIC为基础的皮肤植入式抗生素输送装置 模拟。然后，我们将确定设备的抗生素递送效率和生物膜消除功效 使用切除的人皮肤伤口感染模型。高强度离子电流应用的安全性 还将使用体外细胞培养物和健康大鼠评估。在特定目标2中，我们将确定体内 生物膜根除疗效和伤口愈合的增强功效，使用大鼠双皮皮肤 基于皮瓣的缺血性伤口感染模型。我们的结果将建立最佳设备设计和关键 体内安全性，生物膜消除功效和慢性伤口愈合的概念证明 我们的高强度离子遗传抗生素输送装置的功效。慢性伤口的愈合增强 由我们的设备启用将大大改善患者的生活质量，并降低整体医疗保健成本。