Selenium Coated Dialysis Catheters for Reduced Biofilm Formation

描述(申请人提供)：感染是影响透析管功能和寿命的主要问题。导管相关性败血症的发生率高得惊人，通常需要介入治疗或拔除导管。这笔赠款正在评估这样一个假设，即共价结合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。选定的硒化合物是催化的，通过与硫醇反应产生超氧阴离子自由基(O2-)。这些超氧化物的高局部浓度会导致细菌细胞的裂解，并可能在防止生物膜形成方面特别有效，因为超氧化物的作用机制不需要细胞在代谢上保持活跃。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。由于它是催化的，共价结合的Se化合物将保留在表面并永久具有活性，不像传统的洗脱涂层通常在30天内消失，可能会引起有害的全身影响。此外，由于超氧自由基只有很短的扩散寿命，因此硒涂层将只在局部活跃，不会对设备与邻近人体细胞的生物兼容性产生不利影响。第一阶段成功地显示，在涂有硒的聚氨酯导管材料上，革兰氏阳性菌(金黄色葡萄球菌)和革兰氏阴性菌(铜绿假单胞菌)的生物被膜形成显著减少(&gt；90%)。利用独特的等离子体前处理、表面活化处理和化学沉积步骤相结合的方法，在表面附着了一层硒涂层。对涂层密度的研究表明，该工艺可以控制表面的Se浓度。继第一阶段项目成功后，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的优化，目标是确定最佳的硒涂层浓度水平，同时考虑到工艺的抗菌效果、生物兼容性和稳健性。使用微量平板分析和多细胞流动连续培养系统，该计划将检查涂层对单物种和双物种生物膜形成的有效性。涂层的稳定性将被长期监测，以证明该技术在慢性应用中防止感染的能力。最后，一个动物模型(小鼠)将被用来展示体内的效果。这项研究将利用细菌的生物发光菌株来动态评估生物膜的形成，时间长达25天。相关性：拟议的研究正在开发硒涂层，以减少透析导管上生物膜的形成和设备中心的感染。这种涂层可以通过保留通路和减少因导管感染而导致的继发并发症，为透析患者提供显著的好处。由于透析导管感染的流行，有效的治疗可以显著影响使用导管作为主要途径的患者的医疗保健提供成本。公共卫生相关性：血液透析是一种过滤肾功能衰竭或严重受损患者血液中杂质的方法。血液透析过程使用体外系统来清除患者血液中的毒素。导管是为这些患者提供血管通路的方法之一。尽管美国肾脏疾病结果质量倡议(K/DOQI)指南不鼓励使用袖带、隧道的中心静脉导管作为永久通道，但由于防止形成和维持房室瘘或其他通道方法的合并症的发生率较高，以及血管通道转诊延迟等因素，此类导管的使用率正在增加。事实上，在2004年底，超过23%的血液透析患者正在使用导尿管进行透析。目前每年销售约30万根慢性透析导管，构成美国8000万至1亿美元的市场。尽管导尿管具有一定的优势，例如能够立即使用，易于插入和更换，而且几乎普遍适用于透析患者，但在主要的透析方法中，导尿管的感染率最高。已经研究了许多解决导管感染的技术，但没有一种技术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路和减少感染导管引起的继发性并发症而为透析患者提供显著的好处。由于透析导管中感染问题的普遍存在，有效的涂层可以显著影响使用导管作为主要途径的透析患者的医疗保健服务成本。这项技术将立即应用于Spire现有的慢性血液透析导管生产线。

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.