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: 7537914
• 负责人: ERIC J TOBIN
• 金额: $ 60.8万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537914
• 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; Compatible; Condition; 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; Physical Dialysis; Plasma; Polyurethanes; Prevalence; Process; Production; Property; Pseudomonas aeruginosa; Public Health; Rate; 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; day; density; design; dietary requirement; health care delivery; improved; in vivo; methicillin resistant Staphylococcus aureus; microbial; prevent; programs; prototype; 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。导管相关脓毒症的发生率高得惊人，并且通常需要干预或拔除导管。该拨款正在评估这样的假设：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，从而降低以设备为中心的感染的发生率。硒是人类必需的饮食需求。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会导致细菌细胞裂解，并且对于防止生物膜形成特别有效，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，一项研究表明，硒化合物对 90% 的临床分离 MRSA 菌株有效。由于具有催化作用，共价连接的 Se 化合物将保留在表面并永久保持活性，这与传统的洗脱涂层不同，传统的洗脱涂层通常在 30 天内消失，并可能引起有害的全身效应。此外，由于超氧自由基的扩散寿命非常短，因此硒涂层仅具有局部活性，不会对装置与邻近人体细胞的生物相容性产生不利影响。第一阶段成功证明，硒涂层聚氨酯导管材料上革兰氏阳性（金黄色葡萄球菌）和革兰氏阴性（铜绿假单胞菌）细菌的生物膜形成显着（>90%）减少。利用等离子体预处理表面活化工艺和化学沉积步骤的独特组合将硒涂层附着到表面。对涂层密度的研究表明，可以调整该工艺来控制表面的硒浓度。继一期项目成功之后，二期项目将扩展成果，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，其目标是考虑抗菌功效、生物相容性和工艺的稳健性，确定硒涂层浓度的最佳水平。该计划将使用微量滴定板测定和多细胞流通连续培养系统来检查涂层对单物种和双物种生物膜形成的有效性。将长期监测涂层稳定性，以证明该技术在长期应用中预防感染的能力。最后，将采用动物模型（小鼠）来证明体内功效。这项研究将利用细菌的生物发光菌株来动态评估长达 25 天的生物膜形成。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以设备为中心的感染。该涂层可以通过保留通路并减少导管感染引起的继发并发症，为透析患者带来显着的好处。由于透析导管感染的普遍存在，有效的治疗可能会显着影响使用导管作为主要途径的患者的医疗服务成本。公众健康相关性：血液透析是一种为肾功能衰竭或严重衰退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。尽管美国肾脏病结果质量倡议 (K/DOQI) 指南不鼓励使用带套囊的隧道式中心静脉导管进行永久通路，但由于并发疾病发生率较高等因素，此类导管的使用仍在增加，这些疾病阻止了形成和维持肾病的形成和维持。 AV 瘘或其他通路方法，以及后期转诊血管通路。事实上，到 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，美国每年销售约 300,000 根慢性透析导管，构成了价值 80 至 1 亿美元的市场。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。人们已经研究了许多技术来解决导管感染问题，但没有一个能够成功缓解这个问题。如果成功，硒涂层导管将通过保留通路并减少因受感染的导管引起的继发并发症，为透析患者带来显着的好处。由于透析导管中普遍存在感染问题，有效的涂层可能会显着影响使用导管作为主要通路的透析患者的医疗服务成本。该技术将立即应用于 Spire 现有的慢性血液透析导管系列。