Selenium Coated Dialysis Catheters for Reduced Biofilm Formation

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。导管相关性脓毒症的发生率高得惊人，通常需要干预或拔除导管。这项资助正在评估一种假设，即共价附着的硒涂层可以减少透析导管表面的细菌定植和生物膜的形成，从而降低器械中心感染的发生率。硒是人类必需的食物。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-）。这些局部高浓度的超氧化物会引起细菌细胞的裂解，并可能特别有效地阻止生物膜的形成，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，硒化合物被证明对90%的临床分离的MRSA菌株有效。由于它具有催化作用，因此共价附着的Se化合物将留在表面并永久保持活性，而传统的洗脱涂层通常在30天内就会消失，并且会引起有害的全身影响。此外，由于超氧化物自由基只有很短的扩散寿命，硒涂层将只在局部具有活性，不会对装置与邻近人体细胞的生物相容性产生不利影响。第一阶段成功地证明了革兰氏阳性（金黄色葡萄球菌）和革兰氏阴性（铜绿假单胞菌）细菌在硒涂层聚氨酯导管材料上的生物膜形成显著减少（>90%）。利用等离子体预处理表面活化过程和化学沉积步骤的独特组合，将硒涂层附着在表面上。对涂层密度的研究表明，该工艺可以控制表面的硒浓度。在第一阶段项目成功之后，第二阶段将扩展成果，以生产一种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，其目标是确定最佳水平的硒涂层浓度，考虑抗菌功效、生物相容性和工艺的稳健性。使用微滴板测定和多细胞连续培养系统，该计划将检查涂层对单一和双物种生物膜形成的有效性。涂层稳定性将在很长一段时间内进行监测，以证明该技术在长期应用中防止感染的能力。最后，将采用动物模型（小鼠）来验证体内功效。这项研究将利用生物发光菌株来动态评估长达25天的生物膜形成。相关性：建议的研究是开发硒涂层，以减少透析导管上的生物膜形成和设备中心感染。涂层可以通过保留通道和减少感染导管引起的继发性并发症，为透析患者提供显着的益处。由于透析导管感染的普遍存在，有效的治疗可能会显著影响使用导管作为主要途径的患者的医疗保健服务成本。公共卫生相关性：血液透析是一种过滤血液杂质的方法，用于肾功能衰竭或肾功能严重下降的患者。血液透析过程使用体外系统来清除患者血液中的毒素。导管是为这些病人提供血管通道的方法之一。尽管美国肾脏疾病结局质量倡议（K/DOQI）指南不鼓励将套管式、隧道式中心静脉导管用于永久通路，但由于合并症发生率较高，防止形成和维持房室瘘或其他通路方法，以及晚期转诊血管通路等因素，此类导管的使用率正在增加。事实上，在2004年底，超过23%的血液透析患者使用导管进行透析。目前，美国每年售出约30万根慢性透析导管，市场规模达8000万至1亿美元。尽管导管具有一定的优势，例如能够立即使用，易于插入和更换，并且几乎普遍适用于透析患者，但导管在主要透析途径中感染率最高。已经研究了许多解决导管感染的技术，但没有一个成功地缓解了这个问题。如果成功，硒涂层导管将通过保留通道和减少感染导管引起的继发性并发症，为透析患者提供显著的益处。由于透析导管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主要途径的透析患者的医疗保健交付成本。这项技术将立即应用于Spire现有的慢性血液透析导管。

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.