Diabetic Foot Ulcer Biofilm Infection and Recurrence

糖尿病足溃疡生物膜感染和复发

• 批准号: 10376509
• 负责人: GEOFFREY C GURTNER
• 金额: $ 37.7万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376509
• 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

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.

摘要 糖尿病足溃疡（DFU）是糖尿病患者住院的最常见原因之一， 经常导致下肢截肢。在一百万接受非创伤性腿部手术的人中， 在全世界每年进行的截肢手术中，75%是在患有2型糖尿病（T2 DM）的人身上进行的。的风险 糖尿病合并糖尿病足溃疡患者10年死亡的风险是未合并糖尿病足溃疡患者的两倍。率 DFU患者截肢率为38.4%。感染是DFU的常见并发症（>50%）。在那些与 DFU，40%在伤口闭合后1年内复发; 60%在3年内复发，65%在5年内复发。因此 DFU的最强预测因子是既往足部溃疡。拟议的工作依赖于一系列临床前和 为DFU生物膜感染损害屏障的假设奠定基础的临床发现 关闭DFU的功能。这种闭合缺陷为DFU复发铺平了道路。生物膜估计 占慢性伤口感染的60%。在生物膜形式中，细菌处于休眠代谢状态。的 用于检测感染的标准临床技术如集落形成单位（CFU）测定可能检测不到生物膜 感染因此，生物膜感染可能被视为伤口护理中无声的恶意威胁。拟议工作 是一项两个中心的研究--印第安纳州大学和斯坦福大学--他们得到了一个试点项目的竞争性资助 由NIDDK-DIACOMP机制授予，以生成关于DFU关闭和复发的初步数据。的 拟议的工作解决了DFU护理中的一种新范式，这种范式从未在完全动力的患者中进行过测试- 基于研究。建议工作的成功执行可能会对现行标准产生直接影响 包括重新定义伤口护理的最重要的主要终点，伤口闭合本身。 在DFU基于患者的研究中，首次发现了生物膜感染诱导分子生物学改变的机制。 将阐明损害再上皮化DFU功能完整性的机制。在DFU护理中， 所提出的工作可以确定伤口闭合的当前终点（其不考虑任何 功能参数）可能不是停止照顾DFU的正确时机。这种过早的终止 护理可能是目前报道的DFU高复发率的原因。这个概念延续了 护理，直到功能性伤口闭合，是必要的，以尽量减少复发和截肢将是必要的。 在提供DFU护理方面具有变革性价值。该建议完全基于对DFU患者的研究 旨在进行一项双中心的稳健临床研究，测试具有生物膜感染史的伤口是否 关闭缺陷屏障功能（目标2）。目的3测试这种缺陷的伤口闭合， 表现为高TEWL与更大的伤口复发相关。目标1利用这项以患者为基础的研究， 解决生物膜诱导的皮肤上皮屏障完整性丧失中涉及的分子机制。