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

慢性伤口的感染，包括糖尿病足溃疡、压疮和静脉性腿部溃疡，是主要的 对伤口管理的挑战。生物膜在显微镜下可在高达90%的慢性伤口中识别。为 例如，在美国，糖尿病影响2360万人，大约20%-25%的糖尿病患者 在疾病过程中，患者会发展成足部溃疡。其中，63.4%的糖尿病患者 发展成感染。每年用于管理这些溃疡的直接开支为90亿至130亿美元。 美国孤军奋战。生物膜中的细菌更有可能合作和交换它们的基因，从而导致 比浮游细菌具有更高的抗药性。生物膜的组成和组织限制了扩散 包括抗生素在内的分子，通过结构进入生物膜或进入体液。因此， 生物膜中的细菌对宿主的反应和抗生素治疗都是难耐的。治疗结果不佳 高额的医疗费用，截肢，生活质量下降，死亡率上升。有一件急事 需要开发新的疗法来有效治疗慢性伤口的生物膜。的主要目标是 这项提议是通过固定可溶解的微针阵列来开发Janus类型的抗菌敷料 在三维(3D)纳米纤维泡沫表面有效地治疗生物膜和促进糖尿病伤口 治愈。这项拟议的研究是基于两个PI所做的重要发明，使我们能够生成 治疗慢性伤口生物膜的独特平台。为了证明这一概念，我们最近展示了 Janus型抗菌敷料对体外和体外耐药病原体的生物被膜确实有效 在活体内。根据这些发现，我们假设由微针阵列组成的Janus型敷料 加入分子工程多肽的3D纳米纤维泡沫可以物理地穿透生物膜 并在生物膜内外释放多肽，有效地清除慢性创面和 促进细胞渗透和伤口愈合。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型化合物的制备和表征方法 2)评价工程材料的抗菌效果、生物相容性和抗菌机理。 多肽及其Janus型敷料的体外实验；3)优化后的多肽及其免疫调节作用的检测 Janus型敷料对2型糖尿病小鼠伤口和体外人类皮肤伤口生物膜的保护作用。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， 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 救死扶伤。

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.