A novel nonthrombogenic vascular circuit

我们正在开发一种新型的主动非血栓形成表面，用于预防心肺转流手术引起的术后血小板功能障碍和消耗。该专利材料将作为由聚乙烯亚胺（PEI）纳米纤维组成的微米厚网应用于旁路电路的管腔表面。该材料的药理活性是由PEI与释放一氧化氮（NO）的二醇二氮烯鎓（PEI-NO）的共价键合产生的。PEI-NO释放的NO可能通过激活鸟苷酸环化酶抑制血小板通过旁路的功能。这将导致在血液-移植物界面的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降低体内血小板活化。具体目标1：构建PEI-NO缓释合成血管回路，并表征NO的比活性和释放曲线。我们将首先制备足够量的PEI-NO纳米纤维，用于聚氨酯管材的微米厚度应用。利用荧光分析，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涂覆电路对血小板活化的抑制。具体目标#2：证明PEI-NO表面可降低体外静脉-静脉回路中的血小板粘附和活化。为了确定PEI-NO NO释放纳米纤维对体内血小板功能的影响，将对照和PEI-NO涂覆的回路在良好建立的兔模型中暴露于体外循环。这些动物未使用肝素抗凝或给予其他已知影响血小板功能的药物。通过铟-111标记的血小板的闪烁计数来定量血小板的积聚。在移植物移除和固定后，还通过电子显微镜分析测量血小板沉积。将通过聚集测定法评估血小板功能。我们期望上述工作范围能够验证PEI-NO作为新型非血栓形成表面材料的体内功效。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释放曲线适用于心肺转流手术的临床测试。拟议的商业应用：考虑到每年500，000例手术发生率，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为每年5000万美元。全球市场估计为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.