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

项目总结 导管相关血流感染(CRBSI)是医疗保健获得性感染(HAIs)和 与高死亡率(12%-25%)和成本(在美国为90亿美元)有关。导管相关血栓(CRT)是 中心静脉导管(CVCs)的另一个常见并发症是41%的早产装置 在治疗结束前取出。尽管各种涂层，包括那些具有抗血栓形成或 抗菌药物的应用，这些涂层的安全性和临床疗效，以降低发病率 CRBSI和/或CRT仍然不能令人满意，特别是对于扩大种植。LiquiGlide正在调查一起 新的涂层解决方案，克服了这些限制。液体浸渍表面(LIS)提供了一种非粘附性， 自愈性和可补充性，是其他涂层无法达到的。用来配制LIS涂料 已获FDA批准静脉给药的肠外营养成分，确认其 安全，我们已经开发了一种涂层表面，显著减少血栓形成和细菌 殖民主义。当涂层涂在血管导管上时，肠外营养可以得到补充 通过导管管腔来增加疗效的持续时间，这是特别有益的作为闭塞和 长期CRBSI主要通过腔内途径发生。在初步研究中，我们 在猪模型上展示了涂层导管的安全性和通畅性 补给。该方案的目的是在外周插入的中央上开发LIS涂层 PICC导管在长期并排植入术中消除堵塞和减少感染的作用 在同一只动物身上进行比较。为了达到这一目的，我们将首先在PICC上涂抹涂层，满足 作为血管植入物的安全性和耐用性要求。然后，将对LIS包被的PICC进行体外评估 评估其防止血栓形成(减少95%)并实现100%消除闭塞的能力 (目标1)在模拟外流和输液注射下。我们将进一步证明涂覆的装置 具有广谱的抗微生物耐药性(目标2)，目标是减少细菌定植和生物被膜 与通常引起CRBSI的三种典型微生物形成的&gt；99%减少。要评估 安全性和体内抗闭塞/抗感染效果，我们将用猪模型进行七种动物研究， 植入术中监测导管通畅度和导管上微生物定植及评估 血栓形成和微生物培养/鉴定的外植体(目标3)。拟议的第一阶段研究将 解决与可补充LIS涂层的PICC相关的挑战，实现完全消除闭塞和 显著降低了CRBSI。一旦达到第一阶段的里程碑，涂有涂层的中国人民保险公司将为 下一阶段的产品开发。下一阶段的目标是扩大LiquiGlide的涂层工艺 内部cGMP设施，为监管提交进行验证性临床前研究，并 准备好推出产品了。

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.