A novel nonthrombogenic vascular circuit

我们正在开发一种新的、积极的非血栓形成表面，用于预防手术后血小板功能障碍和体外循环手术引起的消耗。这种专利材料将作为由聚乙烯亚胺(PEI)纳米纤维组成的微米厚的网状物应用于旁路电路的管腔表面。该材料的药理活性源于PEI与释放一氧化氮(NO)的重氮二酸酯(PEI-NO)的共价键。PEI-NO释放的NO可能通过激活鸟苷酸环化酶而抑制通过旁路的血小板的功能。这应该会在血液移植界面产生局部和不稳定的抗血小板作用。为了证实这一假设，我们建议证明PEI-NO在体内减少了血小板的激活。具体目标#1：构建PEI-NO缓释合成血管环路，并表征其比活性和释放谱。我们将首先制备足够数量的PEI-NO纳米纤维，用于微米厚的聚氨酯管材。利用化学发光分析，我们将计算在各种化学和物理条件下NO释放的产率和体外半衰期。然后，我们将比较PEI和PEI-NO涂层电路对血小板激活的抑制作用。具体目标#2：证明PEI-NO表面可减少体外静脉循环中的血小板黏附和激活。为了确定PEI-NO释放纳米纤维对体内血小板功能的影响，对照和PEI-NO涂层电路将在一个成熟的Lapine模型中暴露于体外循环中。这些动物不会被肝素抗凝，也不会被给予其他已知会影响血小板功能的药物。通过用铟-111标记的血小板的闪烁计数来定量血小板数。在移植物移除和固定后，还通过电子显微镜分析来测量血小板沉积。血小板功能将通过聚集计量法进行评估。我们期望上述工作范围能够验证PEI-NO作为一种新型的非血栓形成表面材料的体内疗效。在此基础上，我们计划在第二阶段优化化学和材料工艺，以确保稳定的NO释放谱适合于体外循环手术的临床测试。拟议的商业应用：考虑到每年50万的手术发病率，用于心脏搭桥手术的新型、有效的非血栓形成血管导管的国内市场估计每年为5000万美元。据估计，全球市场规模为2亿美元。SBIR第一和第二阶段的资金将允许在3.5年内进入市场。

We are developing a novel, actively non-thrombogenic surface for the prevention of post-operative platelet dysfunction and consumption induced by cardiopulmonary bypass surgery. This proprietary material will be applied to the luminal surface of bypass circuitry as a micron- thick web composed of polyethyleneimine (PEI) nanofibers. The pharmacologic activity of the material results from the covalent linkage of PEI to a nitric oxide (NO) releasing diazeniumdiolate (PEI-NO). NO released from PEI-NO may depress the function of platelets transiting the bypass circuit via its activation of guanylyl cyclase. This should result in a localized and labile anti-platelet effect at the blood-graft interface. To confirm this hypothesis, we propose to demonstrate that PEI-NO reduces platelet activation in vivo. Specific Aim #1: Construct a PEI-NO sustained-release synthetic vascular circuit and characterize the specific activity and release profile of NO. We will first prepare sufficient quantities of PEI-NO nanofibers for micron-thick application to polyurethane tubing. Utilizing chemiluminescent analysis, we will calculate the yield and in vitro half-life of NO release under a variety of chemical and physical conditions. We will then compare the inhibition of platelet activation by PEI and PEI-NO coated circuits. Specific Aim #2: Demonstrate that PEI-NO surfaces reduce platelet adhesion and activation in an extracorporeal venovenous circuit. To determine the effect of PEI-NO NO-releasing nanofibers on platelet function in vivo, control and PEI-NO coated circuits will be exposed to extracorporeal circulation in a well-established lapine model. These animals are not anti-coagulated with heparin or given other agents known to affect platelet function. The accumulation of blood platelets is quantified by scintillation counting of platelets labeled with indium-111. Platelet deposition is also measured by electron microscopic analysis after removal and fixation of the graft. Platelet function will be assessed by aggregometry. We expect the above scope of work to validate the in vivo efficacy of PEI-NO as a novel non-thrombogenic surface material. On this basis, we plan in Phase II to optimize the chemistry and material processes to ensure a stable NO release profile suitable for clinical testing in cardiopulmonary bypass surgery. PROPOSED COMMERCIAL APPLICATIONS: The domestic market for a novel, effective non-thrombogenic vascular catheter for use in cardiac bypass surgery is estimated at $50 million per annum, given an annual operative incidence of 500,000. Global markets are estimated $200 million. Funding of SBIR Phases I and II will allow for market entry in 3.5 years.