Novel Anti-infective and Anti-thrombotic Micro-patterned Central Venous Catheter

描述(由申请人提供)：医疗保健获得性感染的发生率和严重性正在增加；作为美国十大主要死亡原因，它们对医学界构成了重大挑战。这些感染中近一半与医疗器械的使用有关。中心静脉导管(CVC)约占所有导管相关性血流感染(CRBSI)的90%。由此导致的30万例感染每年仅在美国就导致多达2.8万人死亡。CRBSI延长住院时间，引发人类痛苦，并放大医疗成本(高达26.8亿美元)。感染发生在导管相关血栓形成(CRT)的患者中的可能性是普通患者的四倍，而CVC患者中高达67%的患者发生CRT。CRT除了增加感染风险外，还与血栓栓塞症有关，血栓栓塞症是美国住院死亡的主要原因。目前预防CRBSI和CRT的方法是引入抗菌或抗血栓药物，以减少导管表面的细菌或血小板浓度。抗菌导管的活性可能会被高浓度的细菌所淹没，其效力主要限于最初几天的药物洗脱高峰。涂有抗凝剂的导管可能会受到污染问题的困扰，而且还没有显示出能降低与血栓事件相关的死亡率。Sharklet Technologies Inc.(STI)的目标是证明将我们的专利Sharklet微图案(Sharklet MP)集成到导管表面以最终减少CVC相关感染的可行性，并验证Sharklet表面防止血小板黏附导致血栓形成的能力。STI的初步数据表明，Sharklet MP抑制细菌定植以及血小板黏附和激活-从而提供预防CRBSI和CRT的双重能力。这个多阶段SBIR项目的总体目标是开发、验证Sharklet MP表面，并将其商业化应用于下一代抗感染、抗血栓的CVC。第一阶段的具体目标是通过追求以下目标来展示Sharklet MP的有效性：1)证明我们可以在血管环境中延缓致病葡萄球菌在Sharklet表面的定植；2)证明我们可以减少Sharklet表面的血小板黏附和随后的凝血酶形成，而不是没有图案的对照表面。然后，第二阶段的工作将集中在体内动物模型的验证、其他病原体的体外测试、对有害药物化合物的耐久性测试，以及Sharklet CVC的制造方法。第一阶段和第二阶段的结果对于第三阶段与私营部门伙伴/投资者的合作至关重要，我们已经在与这些伙伴/投资者讨论这一申请。成功的多阶段SBIR的潜在影响将是生产一种新的Sharklet CVC，它将使临床医生/医院能够改善患者护理，并通过大幅减少因血栓形成而造成的医院感染和住院死亡率的主要负担而大幅节省成本。 公共卫生相关性：中心静脉导管(CVC)最严重和最常见的并发症是导管相关血流感染(CRBSI)，它占医院感染所致死亡的30%以上，仅在美国每年造成的医疗费用就高达20亿美元，以及导管相关血栓形成(CRT)，它可能导致血栓栓塞，这是导致住院死亡的主要因素。与在导管表面浸渍抗菌剂或涂层抗凝剂在解决CRBSI和CRT方面具有严重限制的情况不同，下一代解决方案在导管表面结合了非杀伤性Sharklet微观图案，可以抑制导致CRBSI的细菌定植和导致CRT的血小板黏附，从而改善患者护理。这一多阶段的研究工作将有助于开发抗感染、抗血栓的CVC，并将其商业化，其导管表面集成了Sharklet微图案，目的是通过减少医院感染、发病率、死亡率和成本来提高患者的安全性。

DESCRIPTION (provided by applicant): Healthcare-acquired infections are increasing in rate and severity; they present a significant challenge to the medical community as a top-ten leading cause of death in the U.S. Nearly half of these infections are associated with the use of a medical device. Central venous catheters (CVCs) are responsible for approximately 90% of all catheter-related bloodstream infections (CRBSIs). The resulting 300,000 infections are associated with as many as 28,000 deaths per year in America alone. CRBSIs prolong hospital stays, induce human suffering, and magnify healthcare costs (up to $2.68 billion). Infection is four times more likely to occur in patients with catheter-related thrombosis (CRT), and up to 67% of patients with CVC develop CRT. In addition to increasing the risk of infection, CRT is associated with thromboembolic conditions that are the leading cause of in-hospital mortality in the U.S. The current paradigm for preventing CRBSI and CRT has been to introduce antimicrobial or antithrombotic agents to reduce the concentrations of bacteria or platelets on the catheter surface. The activity of antimicrobial catheters can be overwhelmed by high concentrations of bacteria, and their efficacy is primarily limited to the initial elution spike of agents in the first few days. Anticoagulant-coated catheters can suffer from contamination issues and have not been shown to reduce mortality rates associated with thrombotic events. Sharklet Technologies Inc. (STI) aims to demonstrate the feasibility of integrating our proprietary Sharklet micro-pattern (Sharklet MP) into catheter surfaces to ultimately reduce CVC-related infection and to validate the ability of the Sharklet surface to prevent platelet adhesion leading to thrombosis. STI's preliminary data demonstrates that the Sharklet MP inhibits bacterial colonization as well as platelet adhesion and activation-thereby offering a dual capacity to prevent CRBSI and CRT. The overall goal of this multi-phase SBIR project is to develop, validate, and commercialize the application of the Sharklet MP surface on a nextgeneration anti-infective, anti-thrombotic CVC. The specific Phase I goal is to show the efficacy of the Sharklet MP by pursuing the following Aims: 1) prove that we can retard pathogenic Staphylococci colonization on Sharklet surfaces in a vascular environment, and 2) prove that we can decrease platelet adhesion and subsequent thrombin formation on Sharklet surfaces compared to un-patterned control surfaces. Phase II work will then focus on validation with an in vivo animal model, in vitro testing with other pathogens, durability testing against deleterious drug compounds, and manufacturing methods for the Sharklet CVC. Phase I & II results are essential for Phase III collaboration with private-sector partners/investors with whom we are already discussing this application. The potential impact of a successful multi-phase SBIR will be the production of a new Sharklet CVC that will allow clinicians/hospitals to improve patient care and reap significant cost savings by substantially reducing the major burden of nosocomial infections and in-hospital mortality due to thrombosis. PUBLIC HEALTH RELEVANCE: The most serious and common complications of central venous catheters (CVC) are catheter-related bloodstream infection (CRBSI), which accounts for more than 30% of the deaths that result from hospital-acquired infections and incurs medical costs as high as $2 billion annually in the U.S. alone, and catheter-related thrombosis (CRT), which can lead to thromboembolism, a major contributor to in-hospital mortality. Unlike impregnation of the CVC surface with antimicrobial agents or coating with anticoagulants that have severe limitations in addressing CRBSI and CRT, a next-generation solution that incorporates the non-kill Sharklet" microscopic pattern onto the catheter surface can inhibit both bacterial colonization that leads to CRBSI and platelet adhesion that leads to CRT, thereby improving patient care. This multi-phase research effort will help develop and commercialize an anti-infective, anti-thrombotic CVC that has the Sharklet micro- pattern integrated on the catheter surface with the objective of improving patient safety by reducing in-hospital infection, morbidity, mortality, and costs.