Diabetic Foot Ulcer Biofilm Infection and Recurrence

糖尿病足溃疡生物膜感染和复发

基本信息

批准号：
10256045
负责人：
GEOFFREY C GURTNER
金额：
$ 65.15万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2020-09-07 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10256045
关键词：
Address Amputation Animal Model Animals Area Award Bacteria Biological Caring Clinical Clinical Research Colony-Forming Units Assay Complication Complications of Diabetes Mellitus Data Data Collection Defect Diabetic Foot Ulcer Epithelial Epithelial Attachment Foot Ulcer Foundations Funding Gene Silencing Hospitalization Incidence Indiana Infection Infectious Skin Diseases Lead Leg Lower Extremity Measures Metabolic Methodology MicroRNAs Microbial Biofilms Molecular National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Patients Pilot Projects Recording of previous events Recurrence Reporting Research Research Design Rest Risk Series Site Skin Skin repair Techniques Testing Time Tissues Training Ulcer Universities Visit Water Work Wound Infection base chronic wound delta-catenin diabetic diabetic patient interest limb loss mortality risk novel pre-clinical premature primary endpoint recidivism recurrent infection repair function restoration skin barrier standard of care wound wound biofilm wound care wound closure wound healing

项目摘要

Abstract Diabetic foot ulcers (DFU) are one of the most common reason for hospitalization of diabetic patients and frequently it results in amputation of lower limbs. Of the one million people who undergo non-traumatic leg amputations annually worldwide, 75% are performed on people who have type 2 diabetes (T2DM). The risk of death at 10 years for a diabetic with DFU is twice as high as the risk for a patient without a DFU. The rate of amputation in patients with DFU is 38.4%. Infection is a common (>50%) complication of DFU. In those with DFU, 40% recur within one year after wound closure; 60% within 3 years, and 65% within 5 years. Thus, the strongest predictor of DFU is a previous foot ulcer. The proposed work rests on a series of pre-clinical and clinical findings laying the foundation to the hypothesis that biofilm infection of DFU compromises barrier function of the closed DFU. Such deficient closure paves the way to DFU recurrence. Biofilms are estimated to account for 60% of chronic wound infections. In the biofilm form, bacteria are in a dormant metabolic state. The standard clinical techniques like colony forming units (CFU) assay to detect infection may not detect biofilm infection. Thus, biofilm infection may be viewed as a silent maleficent threat in wound care. The proposed work is a two-center study – Indiana University and Stanford University – who were competitively funded with a pilot award by the NIDDK-DIACOMP mechanism to generate preliminary data on DFU closure and recurrence. The proposed work addresses a novel paradigm in DFU care that has never been tested in a fully powered patient- based study. Successful execution of the proposed work is likely to have direct impact on the current standards of wound care including re-defining the most important primary endpoint of wound care, wound closure itself. For the first time in a DFU patient-based study, mechanisms by which biofilm infection induces molecular mechanisms that compromise functional integrity of re-epithelialized DFU will be elucidated. In DFU care, the proposed work may identify that the current endpoint of wound closure (that does not account for any functional parameter) may be not the right time to stop caring for DFU. That such premature termination of care may be responsible for the high recurrence of DFU that is currently reported. The notion that continued care, until functional wound closure is achieved, is necessary to minimize recurrence and amputation would be of transformative value in the delivery of DFU care. This proposal, wholly based on the study of DFU patients seeks to conduct a two-centered robust clinical study testing whether wounds with a history of biofilm infection closes with deficient barrier function (Aim 2). Aim 3 tests whether such deficient wound closure which manifests as high TEWL is associated with greater wound recurrence. Aim 1 utilizes this patient-based study to address molecular mechanisms implicated in biofilm-induced loss of skin epithelial barrier integrity.

抽象的糖尿病足溃疡（DFU）是糖尿病患者住院和在一百万发生非创伤腿的人中每年在全球截肢，对患有2型糖尿病（T2DM）的患者进行75％。风险患有DFU的糖尿病的10年死亡是没有DFU的患者的风险的两倍。速率 DFU患者的截肢为38.4％。感染是DFU的常见并发症（> 50％）。在那些 DFU，在闭风后一年内复发40％； 3年内60％，5年内65％。那， DFU的最强预测因子是先前的脚溃疡。拟议的工作基于一系列临床前和临床发现为DFU的生物膜感染损害障碍的假设奠定了基础封闭DFU的功能。这种不足的闭合为DFU复发铺平了道路。估计生物膜占慢性伤口感染的60％。在生物膜形式中，细菌处于休眠的代谢状态。这标准临床技术（例如菌落成型单元（CFU）测定法检测感染可能无法检测到生物膜感染。这是生物膜感染在伤口护理中的沉默恶毒威胁。拟议的工作是一项两中心的研究 - 印第安纳大学和斯坦福大学 - 由飞行员竞争性资助 NIDDK-DIACOMP机制授予了有关DFU闭合和复发的初步数据。这拟议的工作解决了DFU护理中一种新型范式，该范式从未在完全动力的患者中进行过测试 - 基于研究。成功执行拟议的工作可能会对当前标准产生直接影响包括重新定义伤口护理的最重要的主要终点，伤口护理的伤口护理，伤口闭合本身。在基于DFU患者的研究中，生物膜感染诱导分子的机制首次将阐明重新上皮DFU的功能完整性的机制。在DFU护理中拟议的工作可能会确定当前伤口闭合的终点（这没有考虑到任何功能参数）可能不是停止关心DFU的合适时机。这样的过早终止护理可能导致目前报告的DFU的高复发。继续的观念护理，直到实现功能性伤口闭合，为了最大程度地减少复发性，截肢将是 DFU护理提供的变革价值。该提议完全基于对DFU患者的研究试图进行两中心的强大临床研究测试是否有生物膜感染史的伤口以不足的障碍功能关闭（AIM 2）。 AIM 3测试是否会闭合这种缺乏伤口表现为高TEWL与更大的伤口复发有关。 AIM 1利用此基于患者的研究解决生物膜诱导的皮肤上皮屏障完整性丧失的分子机制。