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

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装置， 安全地施加高强度电流以将治疗有效浓度的抗生素递送到生物膜中 以实现慢性伤口生物膜感染的有效根除。慢性 目前，美国有超过600万人受到创伤的影响。超过78%的慢性伤口 生物膜，其在延长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和细胞外基质的保护性基质更具抗性。 聚合物物质降低抗生素向生物膜中的扩散速率。因此，目前的抗生素输送 技术不能提供足够的抗生素浓度来有效地根除慢性 伤口生物膜感染。 离子电渗疗法是一种非侵入性的、基于电流的药物递送技术。常规离子导入 装置由于其使用的电流强度低而具有低的抗生素输送效率。虽然目前 强度增加抗生素递送效率，它们可由于温度而引起显著的组织烧伤 增加，器械/组织界面的pH值发生变化。在该提议中，基于离子电流传导 本实验室开发的水凝胶离子电路（HIC），旨在开发一种新型的离子电渗装置， 施加明显高于当前离子电渗疗法装置使用的电流强度。较高电流 强度将允许我们递送显著更高量的抗生素以有效地消除生物膜 细菌和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 通过计算机辅助有限元的基于皮肤的可安装在皮肤上的离子电渗抗生素递送装置 仿真然后，我们将确定我们的装置的抗生素递送效率和生物膜根除功效 使用基于离体人类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价。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 皮瓣缺血性伤口感染模型。我们的结果将建立最佳的设备设计和关键的 体内安全性、生物膜根除有效性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。促进慢性伤口愈合 我们的设备所实现的功能将大大提高患者的生活质量，并降低整体医疗成本。

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.