A replenishable LIS coating that eliminates occlusion and reduces infection on vascular catheters

项目摘要 导管相关血流感染（CRBSI）是医疗保健获得性感染（HAI）的主要原因， 与高死亡率（12-25%）和成本（在美国为90亿美元）相关。导管相关血栓形成（CRT）是 中心静脉导管（CVC）的另一种常见并发症，导致41%的器械过早植入 在治疗结束之前，尽管各种涂层，包括具有抗血栓形成或 已经应用了抗菌剂，这些涂层的安全性和临床有效性，以减少率 CRBSI和/或CRT仍然不令人满意，特别是对于延长植入。LiquiGlide正在调查 新的涂层解决方案，以克服局限性。液体浸渍表面（LIS）提供非粘附性， 自修复和可分解的表面，这是其他涂层无法实现的。配制LIS涂层， 已被FDA批准用于静脉内给药的胃肠外营养成分，证实其 安全性，我们开发了一种涂层表面，可显著减少血栓形成和细菌感染。 殖民化当将该涂层施加在血管导管上时，可以补充肠胃外营养素 通过导管腔以增加功效的持续时间，这对于阻塞和 长期CRBSI主要通过腔内途径发生。在初步研究中，我们 证明了在猪模型中植入三种涂层导管的安全性和通畅性 我的职责。本提案的目的是在外周插入的中心静脉导管上开发LIS涂层。 导管（PICC），以消除阻塞，减少长期植入的感染， 在同一个动物中比较。为了达到这个目的，我们将首先将涂层涂在PICC上， 作为血管植入物的安全性和耐久性要求。然后，将对LIS涂层PICC进行体外评价， 评估其预防血栓形成（减少>95%）并实现100%消除阻塞的能力 (Aim 1）在模拟外部流和输注物注射下。我们将进一步证明， 具有广谱抗微生物耐药性（目标2），靶向减少细菌定植和生物膜 三种典型的微生物通常会导致CRBSI，其形成率降低>99%。评价 安全性和体内抗闭塞/抗感染功效，我们将用猪模型进行七动物研究， 在植入期间监测导管通畅性和器械上的微生物定植，并评估 用于血栓形成和微生物培养/鉴定的外植体（目标3）。第一阶段研究将 解决与易分解的LIS涂层PIC相关的挑战，实现完全闭塞消除， CRBSI显著降低。在实现第一阶段的里程碑后，涂层PICC将准备好用于 产品开发的下一个阶段。下一阶段的目标是扩大LiquiGlide涂层工艺 内部cGMP设施，为监管提交进行确证性临床前研究， 准备好产品发布。

PROJECT SUMMARY Catheter-related bloodstream infection (CRBSI) is a leading cause of healthcare-acquired infections (HAIs) and is associated with high mortality (12–25%) and cost ($9 billion in the US). Catheter-related thrombosis (CRT) is another common complication with central venous catheters (CVCs) that contributes to 41% of premature device removal before treatment is over. Although various coatings, including those with anti-thrombogenic or antimicrobial agents have been applied, the safety and clinical efficacy of these coatings to reduce the rates of CRBSI and/or CRT remains unsatisfactory, especially for extended implantation. LiquiGlide is investigating a new coating solution to overcome the limitations. Liquid-impregnated surface (LIS) provides a non-adherent, self-healing, and replenishable surface that other coatings cannot achieve. Formulating a LIS coating with parenteral nutrient ingredients that have been approved by FDA for intravenous administration, confirming their safety, we have developed a coated surface that significantly reduces thrombus formation and bacterial colonization. When the coating is applied on a vascular catheter, the parenteral nutrients can be replenished through the catheter lumen to increase the duration of efficacy, which is especially beneficial as occlusion and long-term CRBSI occur predominantly through the intralumenal pathway. In preliminary studies, we demonstrated the safety and patency of coated catheters in a swine model during an implantation with three replenishments. The objective of this proposal is to develop the LIS coating on a peripherally inserted central catheter (PICC) to eliminate occlusion and reduce infection in long-term implantation with a side-by-side comparison in a same animal. To achieve the objective, we will first apply the coating on a PICC, meeting the safety and durability requirements as a vascular implant. Then, the LIS-coated PICC will be evaluated in vitro to assess its ability to prevent thrombosis formation (>95% reduction) and achieve 100% elimination of occlusion (Aim 1) under simulated external flow and infusate injections. We will further demonstrate that the coated device has a broad spectrum anti-microbial resistance (Aim 2), targeting reducing both bacterial colonization and biofilm formation with >99% reduction with three typical microorganisms that commonly cause CRBSI. To evaluate the safety and anti-occlusion/anti-infection efficacy in vivo, we will perform a seven-animal study with a swine model, monitoring catheter patency and microorganism colonization on the devices during implantation and assessing explants for thrombus formation and microbial cultures/identification (Aim 3). The proposed phase I study will address challenges related to replenishable LIS-coated PICCs, achieving full occlusion elimination and significant CRBSI reduction. Upon achievement of the phase I milestones, the coated PICC will be ready for the next level of product development. The next phase will target at scaling-up the coating process with LiquiGlide in-house cGMP facility, preforming confirmatory preclinical investigation for regulatory submission, and being ready to product launch.