Novel Janus-type Antimicrobial Dressings for the Treatment of Biofilms in Chronic Wounds

用于治疗慢性伤口生物膜的新型 Janus 型抗菌敷料

基本信息

批准号：
10030925
负责人：
GUANGSHUN WANG
金额：
$ 48.8万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10030925
关键词：
3-Dimensional Affect Aftercare Alanine Amputation Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteria Biopolymers Cells Cellular Infiltration Cessation of life Communities Custom Databases Debridement Diabetes Mellitus Diabetic Foot Ulcer Diabetic mouse Diffusion Disease ESKAPE pathogens Electrospinning Engineering Expenditure Failure Foot Ulcer Gelatin Genes Geometry Health Health Care Costs High Pressure Liquid Chromatography Human Immobilization Immune response In Vitro Individual Infection Inflammation Leg Ulcer Legal patent Liquid substance Membrane Methods Microbial Biofilms Microscopic Molds Molecular Monitor Morphology Operative Surgical Procedures Patients Peptide Hydrolases Peptides Performance Porosity Process Protocols documentation Pseudomonas aeruginosa Quality of life Refractory Resistance Scanning Electron Microscopy Sepsis Spectrum Analysis Staphylococcus aureus Sterile coverings Streptococcus Structure Surface Testing Tissues Treatment outcome Type 2 diabetic Ulcer United States Venous Wound Infection antimicrobial antimicrobial dressing antimicrobial peptide base biomaterial compatibility chronic infection chronic wound cost cytokine decubitus ulcer density design diabetic patient diabetic wound healing effective intervention effective therapy efficacy testing immunoregulation improved in vivo invention mortality nanofiber novel novel therapeutics pathogen pathogenic bacteria peptide analog prevent screening skin wound standard care ultraviolet wound wound care wound healing wound treatment

项目摘要

Infections of chronic wounds, including diabetic foot ulcers, pressure ulcers, and venous leg ulcers, pose a major challenge to wound management. Biofilms are microscopically identifiable in up to 90% of chronic wounds. For example, diabetes mellitus affects 23.6 million people in the United States and approximately 20-25% of diabetic patients will develop foot ulceration during the course of the disease. Among them, 63.4% of diabetic patients develop infections. The direct annual expenditure toward managing these ulcers is $9 billion to $13 billion in the United Sates alone. Bacteria in biofilms are more likely to cooperate and exchange their genes resulting in much higher antibiotic resistance than planktonic bacteria. The composition and organization of biofilms limits diffusion of molecules, including antibiotics, through the structure and into the biofilm or out to the bulk fluid. Consequently, bacteria in a biofilm are refractory to host response and antibiotic treatment. The poor treatment outcomes result in high healthcare cost, amputations, a decreased quality of life, and an increased mortality. There is an urgent need to develop novel therapies for effective treatment of biofilms in chronic wounds. The primary objective of this proposal is to develop a Janus-type antimicrobial dressing by immobilizing dissolvable microneedle arrays to the surface of three-dimensional (3D) nanofiber foams to effectively treat biofilms and promote diabetic wound healing. This proposed study is framed on important inventions made by both PIs, allowing us to generate a unique platform to treat biofilm in chronic wounds. To prove the concept, we have recently demonstrated that Janus-type antimicrobial dressings are indeed effective against the biofilms of resistant pathogens ex vivo and in vivo. Based on the findings, we hypothesize that the Janus-type dressings, consisting of microneedle arrays and 3D nanofiber foams with incorporation of molecularly engineered peptides, can physically penetrate biofilms and release peptides both inside and outside biofilms to effectively eradicate biofilms in chronic wounds and promote cellular infiltration and wound healing. To test the hypothesis and accomplish the objective, we propose the following specific aims: 1) Establish methods for fabrication and characterization of novel Janus-type dressings; 2) Assess the antibacterial efficacy, biocompatibility and antibiofilm mechanism of engineered peptides and their Janus-type dressings in vitro; and 3) Test the efficacy and immune regulation of optimized Janus-type dressings against biofilms in type 2 diabetic mice wounds and ex vivo human skin wounds. We expect completion of these aims to generate an effective intervention with great commercial potential that could effectively treat biofilms, improve quality of wound care, decrease costs, avoid amputations, and most importantly save lives of patients.

慢性伤口感染，包括糖尿病足溃疡、压力性溃疡和腿部静脉性溃疡，是导致糖尿病足溃疡的主要原因。对伤口处理的挑战。高达 90% 的慢性伤口中都可以通过显微镜识别生物膜。为了例如，美国有 2360 万人患有糖尿病，其中大约 20-25% 的糖尿病患者患者在病程中会出现足部溃疡。其中，63.4%的糖尿病患者发生感染。每年用于治疗这些溃疡的直接支出为 90 亿至 130 亿美元唯有美国。生物膜中的细菌更有可能合作并交换基因，从而产生更多的结果。比浮游细菌具有更高的抗生素耐药性。生物膜的组成和组织限制扩散包括抗生素在内的分子通过结构进入生物膜或流出到大量液体中。最后，生物膜中的细菌难以抵抗宿主反应和抗生素治疗。导致治疗效果不佳医疗费用高昂、截肢、生活质量下降和死亡率增加。有紧急情况需要开发有效治疗慢性伤口生物膜的新疗法。主要目标该提案是通过固定可溶解微针阵列来开发Janus型抗菌敷料三维（3D）纳米纤维泡沫表面，有效处理生物膜并促进糖尿病伤口康复。这项拟议的研究以两位 PI 的重要发明为框架，使我们能够生成治疗慢性伤口生物膜的独特平台。为了证明这个概念，我们最近证明了 Janus型抗菌敷料确实能有效对抗离体耐药病原体的生物膜，并且体内。根据这些发现，我们假设由微针阵列组成的 Janus 型敷料和 3D 纳米纤维泡沫结合了分子工程肽，可以物理穿透生物膜并在生物膜内外释放肽，有效消除慢性伤口和伤口中的生物膜促进细胞浸润和伤口愈合。为了检验假设并实现目标，我们建议具体目标如下： 1）建立新型Janus型的制造和表征方法敷料； 2) 评估工程化材料的抗菌功效、生物相容性和抗生物膜机制肽及其Janus型体外敷料； 3）测试优化后的功效和免疫调节针对 2 型糖尿病小鼠伤口和离体人体皮肤伤口生物膜的 Janus 型敷料。我们预计这些目标的完成将产生具有巨大商业潜力的有效干预措施有效治疗生物膜，提高伤口护理质量，降低成本，避免截肢，最重要的是挽救患者的生命。