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: 10634602
• 负责人: Jingwei Xie
• 金额: $ 20.26万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634602
• 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; Histocompatibility; Hour; Human; Hydrogels; In Vitro; Infection; Inflammatory; Inflammatory Response; Ions; Iontophoresis; Ischemia; Microbial Biofilms; Mission; Modeling; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Needles; Outcome; Patients; Persons; Phase; Polymers; Process; Public Health; Quality of life; Rattus; Research; Safety; Skin; Skin Tissue; Technology; Temperature; Time; Tissues; Topical application; Treatment Efficacy; Vancomycin; Vancomycin Resistance; Wound Infection; antibiotic design; chronic wound; combat; design; extracellular; healing; improved; in vivo; invention; 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.

项目总结。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导入装置，它可以 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创面生物被膜感染。慢性 目前，美国有600多万人受到创伤的影响。超过78%的慢性伤口有 生物膜，它将伤口阻止在长期的炎症阶段，并防止伤口愈合。生物膜是 很难治疗，因为生物被膜细菌对抗生素和细胞外基质的保护性更强 聚合物降低了抗生素向生物膜中的扩散速度。因此，目前的抗生素投放 技术不能提供足够的抗生素浓度来有效地根除慢性 伤口生物被膜感染。 离子导入是一种基于电流的非侵入性药物传递技术。常规离子导入 由于使用的电流强度较低，设备的抗生素输送效率较低。虽然电流较大 强度会增加抗生素的输送效率，因为温度会导致严重的组织灼伤。 增加，并且装置/组织界面处的pH改变。在这项提议中，基于离子电流传导 水凝胶离子回路(HIC)是我们实验室发明的，我们的目标是开发一种新型的离子导入装置，可以安全地 施加的电流强度明显高于当前离子导入设备使用的电流强度。大电流 强度将使我们能够提供更多的抗生素来有效地消除生物被膜 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一个 基于HIC的计算机辅助有限元可贴装离子导入抗生素给药装置 模拟。然后，我们将测定我们设备的抗生素输送效率和生物被膜清除效率 使用切除的人类皮肤为基础的伤口感染模型。高强度离子流应用的安全性 也将使用体外细胞培养和健康大鼠进行评估。在具体目标2中，我们将确定体内的 我们的装置在大鼠双蒂皮肤上的生物被膜清除效果和伤口愈合促进效果 以皮瓣为基础的创面缺血性感染模型。我们的结果将建立一个最优的设备设计和一个关键的 体内安全性、生物膜清除效率和促进慢性创面愈合的概念验证 我们的高强度离子导入抗生素输送装置的功效。促进慢性创面的愈合 通过我们的设备实现，将极大地提高患者的生活质量，并降低整体医疗成本。

项目成果

Biofilms: Formation, Research Models, Potential Targets, and Methods for Prevention and Treatment.

• DOI: 10.1002/advs.202203291
• 发表时间: 2022-10
• 期刊: ADVANCED SCIENCE
• 影响因子: 15.1
• 作者: Su, Yajuan;Yrastorza, Jaime T.;Matis, Mitchell;Cusick, Jenna;Zhao, Siwei;Wang, Guangshun;Xie, Jingwei
• 通讯作者: Xie, Jingwei