Controlling Catheter-Associated Urinary Tract Infections Using Smart Catheters with Rationally Designed Active Topographies

使用具有合理设计的主动拓扑的智能导管控制导管相关的尿路感染

基本信息

批准号：
10524038
负责人：
Dacheng Ren
金额：
$ 43.13万
依托单位：
SYRACUSE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524038
关键词：
Adhesions Affect Antibiotics Antimicrobial Resistance Bacteria Biomass Bladder Bladder Control Blinded Blood coagulation Catheterization Catheters Cells Cellular Structures Cessation of life Copper Development Dose Drainage procedure Electromagnetic Fields Engineering Environment Enzyme-Linked Immunosorbent Assay Excision Extracellular Matrix Failure Frequencies Gender Gene Expression Profiling Goals Growth High Prevalence Histologic Hour Immunity In Vitro Infection Infection Control Infection prevention Infective cystitis Inflammation Kidney Left Long-Term Care Magnetism Medical Methods Microbe Microbial Biofilms Modeling Molds Morbidity - disease rate Movement Mucous Membrane Mucous body substance Multiple Bacterial Drug Resistance Nosocomial Infections Operative Surgical Procedures Oryctolagus cuniculus Patient Care Patients Pattern Phagocytosis Physiology Play Polymers Predisposition Prevalence Prevention Production Proteus mirabilis Public Health Recovery Research Role Route Safety Side Surface Technology Testing United States Urease Urethra Urinary tract Urine Uropathogenic E. coli Virulence Factors active control antimicrobial antimicrobial drug aqueous catheter associated UTI cell motility cytokine design experimental study fabrication fluorescence imaging healthcare-associated infections in vivo in vivo evaluation lithography mechanical properties meter microbial mortality multidrug tolerance nanoparticle novel prevent prototype rational design simulation technology platform urinary

项目摘要

Catheter associated urinary tract infection (CAUTI) is one of the most common healthcare-associated infections (HAIs), with a prevalence of 13 – 15% in the United States. CAUTIs are also blamed for increased morbidity and mortality of affected patients with an estimated 13,000 deaths annually. It is well known that the abiotic catheter materials are prone to colonization of microbes, which then ascend the catheter via motility and biofilm formation, causing infections in the urinary tract. Due to the protection of the biofilm matrix and slow growth of attached cells, biofilm cells are up to 1,000 times more resistant to antimicrobials than the planktonic cells of the same species. Thus, CAUTIs are difficult to treat and blockage of the catheter lumen can occur especially during long-term use, leading to stone formation and infections of the bladder and even kidney. Treatment of CAUTIs with high doses of antimicrobial agents can also adversely promote the development of multidrug resistant bacteria. Despite extensive research to date, no current technology can provide long-term (>30 days) fouling control. This unmet challenge motivated us to engineer smart catheters to ultimately eradicate CAUTI. Recently, the PI’s lab developed a new antifouling strategy based on active topography that drives magnetically responsive micron-size pillars to beat with a tunable frequency and force level. This was achieved by loading Fe3O4 nanoparticles on the tip of each pillar and generating an electromagnetic field using an insulated copper coil embedded in the catheter wall (thus does not change the catheter profile). This novel design demonstrated unprecedented strong antifouling activities that can inhibit biofilm formation of multiple species by up to 3.6 logs (99.98%) for 48 hours and remove mature biofilms by up to 3.5 logs (99.97%) on demand with a stronger force, compared to the flat control. A prototype catheter with micron-size pillars on the inner wall was engineered and remained clean for more than 30 days under the flow of artificial urine and the challenge of uropathogenic Escherichia coli (UPEC), while both flat and static controls were completely blocked by UPEC biofilms within 5 days. These results motivated the team to further develop this technology to also control biofouling of the outer catheter wall, which is covered by urethral mucosa and involved in two thirds of CAUTIs. Integrated simulation and experimental studies will be conducted to understand the mechanism of biofouling control by active topography and the design principles for antifouling topographies on both sides of the catheter wall. The best design will be further tested in vivo using a rabbit model of CAUTI induced by UPEC. Both CAUTI prevention (up to 30 days) and removal of established biofilms will be evaluated.

导管相关性尿路感染 (CAUTI) 是最常见的医疗保健相关疾病之一 CAUTI 感染（HAI）在美国的患病率为 13-15%。受影响患者的发病率和死亡率增加，估计每年有 13,000 人死亡。众所周知，非生物导管材料容易滋生微生物，然后微生物会上升导管通过蠕动和生物膜形成，由于保护而引起尿路感染。生物膜基质和附着细胞生长缓慢，生物膜细胞的抵抗力高达 1,000 倍因此，CAUTI 很难治疗和治疗。特别是在长期使用期间，可能会发生导管管腔堵塞，导致结石形成使用高剂量抗菌药物治疗膀胱甚至肾脏感染。尽管广泛，药物也会不利地促进多重耐药细菌的发展。迄今为止的研究表明，目前还没有技术可以提供长期（>30 天）的污垢控制。这一挑战促使我们设计智能导管，以最终根除 CAUTI。最近，PI 的实验室开发了一种基于活性地形的新防污策略，可驱动磁响应微米尺寸的柱子以可调的频率和力水平进行敲击。通过在每个柱子的尖端加载 Fe3O4 纳米粒子并产生电磁来实现使用嵌入导管壁的绝缘铜线圈进行现场处理（因此不会改变导管这种新颖的设计表现出前所未有的强大防污活性，可以抑制 48 小时内多种物种的生物膜形成高达 3.6 个对数 (99.98%)，并去除成熟的生物膜与扁平控制 A 原型相比，可按需提高 3.5 个原木 (99.97%)，且力更强。设计了内壁带有微米尺寸柱子的导管，并在 30 多年内保持清洁在人工尿液流动和泌尿道致病性大肠杆菌 (UPEC) 的挑战下的天数，同时平坦和静态对照均在 5 天内被 UPEC 生物膜完全阻断。激励团队进一步开发这项技术，以控制外导管壁的生物污垢，它被尿道粘膜覆盖，参与三分之二的 CAUTI 综合模拟和治疗。将进行实验研究以了解活性物质控制生物污垢的机制导管壁两侧防污拓扑结构及设计原则。最佳设计将使用由 UPEC 诱导的 CAUTI 兔模型进行体内进一步测试。将评估预防（最多 30 天）和已形成生物膜的去除。