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)是糖尿病患者住院治疗的最常见原因之一， 它经常会导致截肢。在接受非创伤性腿部手术的100万人中 全世界每年有75%的截肢手术发生在患有2型糖尿病(T2 DM)的患者身上。存在以下风险 有DFU的糖尿病患者10年后死亡的风险是没有DFU的患者的两倍。这一速度 DFU截肢率为38.4%。感染是DFU常见的(50%)并发症。在那些有 闭合后1年内复发率40%，3年内复发率60%，5年内复发率65%。因此， DFU的最强预测因素是既往足部溃疡。拟议的工作建立在一系列临床前和 临床发现为DFU生物膜感染损害屏障的假说奠定了基础 闭合的DFU的功能。这种有缺陷的闭合为DFU的复发铺平了道路。据估计，生物膜 占慢性伤口感染的60%。在生物膜形式中，细菌处于休眠代谢状态。这个 像菌落形成单位(CFU)检测感染这样的标准临床技术可能无法检测到生物被膜 感染。因此，生物被膜感染可以被视为伤口护理中的一种无声的恶意威胁。拟议中的工作 是一项由两个中心组成的研究--印第安纳大学和斯坦福大学--这两所大学都是由一名飞行员竞争资助的 由NIDDK-DIACOMP机制授予，以生成关于DFU关闭和复发的初步数据。这个 拟议的工作解决了DFU护理中的一种新范式，这种范式从未在全功率患者身上进行过测试- 以研究为基础。拟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最重要的主要终点--伤口闭合本身。 首次在以DFU患者为基础的研究中，生物被膜感染诱导分子 损害再上皮化DFU功能完整性的机制将被阐明。在DFU的护理中， 拟议的工作可以确定伤口闭合的当前终点(这不能解释任何 功能参数)可能不是停止照顾DFU的合适时间。这种提前终止的行为 目前报道的DFU的高复发率可能是由护理引起的。延续下来的观念 护理，直到达到功能性伤口关闭，是必要的，以减少复发和截肢将是 在提供DFU护理方面具有变革性的价值。这项建议完全基于对DFU患者的研究 寻求进行一项双中心的强有力的临床研究，测试有生物被膜感染史的伤口 因障碍功能不足而关闭(目标2)。目标3测试这种缺陷的伤口闭合是否 表现为高TEWL与更大的伤口复发有关。AIM 1利用这项以患者为基础的研究 阐述生物膜导致皮肤上皮屏障完整性丧失的分子机制。