Diabetic Foot Ulcer Biofilm Infection and Recurrence

糖尿病足溃疡生物膜感染和复发

• 批准号: 10417228
• 负责人: GEOFFREY C GURTNER
• 金额: $ 64.22万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417228
• 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; Persons; 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.

抽象的 糖尿病足溃疡（DFU）是糖尿病患者住院的最常见原因之一 它常常导致下肢截肢。在接受非创伤性腿部手术的 100 万人中 全球每年都会进行截肢手术，其中 75% 是针对 2 型糖尿病 (T2DM) 患者进行的。的风险 患有 DFU 的糖尿病患者 10 岁时死亡的风险是未患有 DFU 的患者的两倍。的比率 DFU患者截肢率为38.4%。感染是 DFU 的常见（>50%）并发症。在那些有 DFU，40%在伤口闭合后一年内复发； 3年内达到60%，5年内达到65%。因此， DFU 的最强预测因素是既往足部溃疡。拟议的工作基于一系列临床前和 临床结果为 DFU 生物膜感染损害屏障的假设奠定了基础 关闭DFU的功能。这种封闭缺陷为 DFU 复发铺平了道路。生物膜估计 占慢性伤口感染的 60%。在生物膜形式下，细菌处于休眠代谢状态。这 用于检测感染的标准临床技术（如集落形成单位 (CFU) 测定）可能无法检测生物膜 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。拟议的工作 是一项两个中心的研究——印第安纳大学和斯坦福大学——他们获得了试点项目的竞争性资助 NIDDK-DIACOMP 机制授予的奖项，用于生成 DFU 闭合和复发的初步数据。这 拟议的工作提出了 DFU 护理的一种新颖范式，该范式从未在功能齐全的患者中进行过测试 - 基础研究。拟议工作的成功执行可能会对现行标准产生直接影响 伤口护理的最新进展，包括重新定义伤口护理最重要的主要终点——伤口闭合本身。 在基于 DFU 患者的研究中，首次发现生物膜感染诱导分子 损害再上皮化 DFU 功能完整性的机制将得到阐明。在 DFU 护理中， 拟议的工作可能会确定伤口闭合的当前终点（不考虑任何 功能参数）可能不是停止治疗 DFU 的合适时机。如此提前终止 护理可能是目前报道的 DFU 高复发率的原因。延续的观念 护理，直到实现功能性伤口闭合，对于尽量减少复发和截肢是必要的 在提供 DFU 护理方面具有变革价值。该建议完全基于对 DFU 患者的研究 寻求进行一项以两个中心为中心的稳健临床研究，测试伤口是否有生物膜感染史 屏障功能不足时关闭（目标 2）。目标 3 测试这种伤口闭合是否有缺陷 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 解决生物膜引起的皮肤上皮屏障完整性丧失所涉及的分子机制。