Selenium Coated Dialysis Catheters for Reduced Biofilm Formation

用于减少生物膜形成的硒涂层透析导管

• 批准号: 7664457
• 负责人: ERIC J TOBIN
• 金额: $ 38.44万
• 依托单位: SPIRE CORPORATION
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664457
• 关键词: Address; Affect; Aging; Animal Model; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Binding; Biocompatible; Biological Assay; Blood; Blood Vessels; Catheters; Cells; Chemicals; Chronic; Cyclotrons; Cytolysis; Deposition; Devices; Dialysis patients; Dialysis procedure; Diffusion; Disease Outcome; Effectiveness; Electrons; Ethylene Oxide; Excision; Exhibits; Fistula; Gases; Goals; Grant; Growth; Guidelines; Hemodialysis; Human; Image; In Vitro; Incidence; Infection; Infection prevention; Intervention; Investigation; Kidney Diseases; Life; Longevity; Marketing; Mechanics; Methods; Microbial Biofilms; Modeling; Monitor; Mus; Organism; Patients; Phase; Plasma; Polyurethanes; Prevalence; Process; Production; Property; Pseudomonas aeruginosa; Reaction; Renal function; Research; Selenium; Selenium Compounds; Sepsis; Series; Staphylococcus aureus; Sterilization for infection control; Sulfhydryl Compounds; Superoxides; Surface; System; Technology; Tensile Strength; Testing; Time; Toxic effect; Toxin; Venous; antimicrobial; base; biomaterial compatibility; blood filter; clinically relevant; cost; density; design; dietary requirement; effective therapy; health care delivery; improved; in vivo; methicillin resistant Staphylococcus aureus; microbial; prevent; process optimization; programs; prototype; public health relevance; surface coating

DESCRIPTION (provided by applicant): Infection is a major problem affecting function and longevity of dialysis catheters. Catheter-related sepsis occurs at alarmingly high rates, and often necessitates intervention or catheter removal. This grant is evaluating the hypothesis that a covalently attached selenium coating can reduce bacterial colonization and biofilm formation on the surface of dialysis catheters, thereby lowering the incidence of device-centered infection. Selenium is an essential dietary requirement for humans. Selected selenium compounds are catalytic and produce superoxide radicals (O2-) by their reaction with thiols. High local concentrations of these superoxides cause lysis of bacterial cells, and could be particularly effective in preventing biofilm formation, since the mechanism of action for the superoxide does not require cells to be metabolically active. In fact, in one study, Se compounds were shown effective against 90% of clinically-isolated MRSA strains. Since it is catalytic, the covalently attached Se compound will remain on the surface and be active permanently, unlike conventional eluting coatings that are often gone within 30 days and that can elicit deleterious systemic effects. Additionally, since the superoxide radical has only a very short diffusion lifetime, the selenium coatings will be only locally active and will not adversely affect biocompatibility of the device with neighboring human cells. Phase I successfully demonstrated significant (>90%) reduction in biofilm formation for both gram positive (Staphylococcus aureus) and gram negative (Pseudomonas aeruginosa) bacteria on selenium coated polyurethane catheter material. Selenium coatings were attached to the surface utilizing a unique combination of plasma pre-treatment surface activation process followed by a chemical deposition step. Investigations of coating density revealed that the process can be tailored to control Se concentration on the surface. Following the successful Phase I project, Phase II will extend the results to produce a commercially viable anti-infective coating technology. A key objective in Phase II is coating processes optimization, where the goal is to determine optimal levels of selenium coating concentrations, considering antimicrobial efficacy, biocompatibility, and robustness of the process. Using both microtiter plate assays and a multi-cell flow-through continuous-culture system, the program will examine effectiveness of the coating against both single and dual-species biofilm formation. Coating stability will be monitored over long time periods to demonstrate ability of the technology to prevent infection in chronic applications. Finally, an animal model (murine) will be employed to demonstrate in vivo efficacy. This study will utilize bioluminescent strains of bacteria to permit dynamic assessment of biofilm formation for periods up to 25 days. Relevance: The proposed research is developing selenium coatings to reduce biofilm formation and device-centered infection on dialysis catheters. The coating could provide significant benefits to dialysis patients by preserving access and reducing secondary complications resulting from infected catheters. Due to the prevalence of dialysis catheter infection, an effective treatment could significantly impact cost of healthcare delivery for patients using catheters as their primary access. PUBLIC HEALTH RELEVANCE: Hemodialysis is a method of filtering blood of impurities in patients whose kidney function has either failed or has become severely diminished. The hemodialysis process uses an extracorporeal system to cleanse the patient's blood of toxins. Catheters are one of the methods used to provide the vascular access to these patients. Despite US Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines which discourage cuffed, tunneled central venous catheters for permanent access the utilization of such catheters is increasing due to factors such as a higher incidence of co-morbid conditions that prevent forming and sustaining an AV fistula or other access method, and late referrals for vascular access. In fact, over 23% of hemodialysis patients were being dialyzed with a catheter at the end of 2004. There are currently about 300,000 chronic dialysis catheters sold annually comprising a $80-$100 million US market. Although catheters offer certain advantages, such as the ability to use them immediately, ease of insertion and replacement, and their almost universal applicability for dialysis patients, catheters have the highest rates of infection among the primary dialysis access methods. Numerous technologies have been investigated for addressing catheter infection, but none have successfully mitigated the problem. If successful, selenium coated catheters would provide significant benefits to dialysis patients by preserving access and reducing secondary complications resulting from infected catheters. Due to the prevalence of the infection problem in dialysis catheters, an effective coating could significantly impact cost of healthcare delivery for dialysis patients using catheters as their primary access. The technology would have immediate application for Spire's existing chronic hemodialysis catheter line.

描述（由申请人提供）：感染是影响透析导管功能和寿命的主要问题。导管相关败血症的发生率高得惊人，通常需要干预或移除导管。该基金正在评估一种假设，即共价连接的硒涂层可以减少透析导管表面的细菌定植和生物膜形成，从而降低以器械为中心的感染的发生率。硒是人类必需的饮食。选定的硒化合物具有催化作用，通过与硫醇反应产生超氧自由基（O2-）。这些超氧化物的高局部浓度导致细菌细胞裂解，并且可以特别有效地防止生物膜形成，因为超氧化物的作用机制不需要细胞具有代谢活性。事实上，在一项研究中，硒化合物对90%的临床分离的MRSA菌株有效。由于它是催化性的，共价连接的Se化合物将保留在表面上并永久地具有活性，不像常规的洗脱涂层通常在30天内消失并且可能引起有害的全身效应。此外，由于超氧化物自由基仅具有非常短的扩散寿命，因此硒涂层将仅具有局部活性，并且不会不利地影响装置与邻近人类细胞的生物相容性。阶段I成功地证明了在硒涂覆的聚氨酯导管材料上的革兰氏阳性（金黄色葡萄球菌）和革兰氏阴性（铜绿假单胞菌）细菌的生物膜形成的显著（>90%）减少。利用等离子体预处理表面活化工艺的独特组合，然后进行化学沉积步骤，将硒涂层附着到表面。涂层密度的调查表明，该过程可以定制，以控制表面上的硒浓度。在第一阶段项目取得成功后，第二阶段将扩大成果，以生产商业上可行的抗感染涂层技术。第二阶段的一个关键目标是涂层工艺优化，目标是确定硒涂层浓度的最佳水平，同时考虑抗菌功效、生物相容性和工艺的稳健性。使用微量滴定板测定和多细胞流通连续培养系统，该计划将检查涂层对单种和双种生物膜形成的有效性。将长期监测涂层稳定性，以证明该技术在慢性应用中预防感染的能力。最后，将采用动物模型（鼠）证明体内疗效。本研究将利用细菌的生物发光菌株，以允许动态评估生物膜形成长达25天。相关性：拟议的研究正在开发硒涂层，以减少透析导管上的生物膜形成和器械中心感染。该涂层可通过保护通路和减少由感染的导管引起的继发性并发症为透析患者提供显著益处。由于透析导管感染的流行，有效的治疗可能会显著影响使用导管作为主要通路的患者的医疗保健提供成本。公共卫生关系：血液透析是一种为肾功能衰竭或严重下降的患者过滤血液中杂质的方法。血液透析过程使用体外系统来净化患者血液中的毒素。导管是为这些患者提供血管通路的方法之一。尽管美国肾脏疾病结局质量倡议（K/DOQI）指南不鼓励将套囊、隧道式中心静脉导管用于永久性入路，但由于以下因素，此类导管的使用正在增加，例如阻止形成和维持AV瘘或其他入路方法的合并症的发生率较高，以及血管入路的晚期转诊。事实上，在2004年底，超过23%的血液透析患者正在使用导管进行透析。目前，每年销售约300，000件慢性透析导管，构成8000万至1亿美元的美国市场。尽管导管具有某些优点，例如能够立即使用、易于插入和更换以及几乎普遍适用于透析患者，但导管在主要透析通路方法中的感染率最高。已经研究了许多技术来解决导管感染，但没有一种技术能够成功缓解该问题。如果成功，硒涂层导管将通过保留通路和减少感染导管导致的继发性并发症为透析患者提供显著益处。由于透析导管中感染问题的普遍存在，有效的涂层可能会显著影响使用导管作为其主要通路的透析患者的医疗保健提供成本。该技术将立即应用于Spire现有的慢性血液透析导管生产线。

项目成果

An organoselenium compound inhibits Staphylococcus aureus biofilms on hemodialysis catheters in vivo.

有机硒化合物可抑制体内血液透析导管上的金黄色葡萄球菌生物膜。

• DOI: 10.1128/aac.05680-11
• 发表时间: 2012
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Tran,PhatL;Lowry,Nathan;Campbell,Thomas;Reid,TedW;Webster,DanielR;Tobin,Eric;Aslani,Arash;Mosley,Thomas;Dertien,Janet;Colmer-Hamood,JaneA;Hamood,AbdulN
• 通讯作者: Hamood,AbdulN