Surface Engineering in Contact Activation of Coagulation

描述(由申请人提供)：血栓形成仍然是开发和实施接触血液的医疗设备的一个重要障碍。血浆凝固级联的接触激活已被证明是导致血栓形成的材料血液相容性差的重要因素。研究发现，亲水性材料是非常有效的等离子体凝聚激活剂，而疏水性材料是相对低效的激活剂。经典生物化学将这种现象归因于激活剂-复合体蛋白质直接在亲水表面的优先吸附/组装。然而，这一解释与蛋白质不吸附在亲水表面但确实吸附在疏水表面的实验发现是不一致的。这项建议的一个目的是通过检验这样的假设来纠正这种明显的不一致：“疏水促凝血剂表面对血浆凝固级联的内在途径的激活有抑制作用。亲水性促凝剂表面是最有效的激活剂，因为蛋白质吸附到这些表面并不与AC蛋白的溶液相组装竞争，而相对疏水的促凝剂的接触激活是通过AC蛋白直接吸附在这些表面上来调节的，从而导致活性降低。”这种生物化学与传统的机理不同，因为它认为疏水表面是对血浆激活的抑制，而不是对亲水(阴离子)表面的激活，从而解决了与观察到的蛋白质吸附行为明显不一致的问题。这一假说通过三个特定的目标得到验证，这三个目标利用表面科学技术和酶激活的实验/理论分析来了解蛋白质吸附、激活复合蛋白的激活以及随后产生FXIa之间的关系。这一信息对于为各种心血管设备改善血液相容性的材料的未来生物工程是至关重要的。 层面描述：在医疗器械中使用的材料上形成血栓是一个问题。血栓形成的原因尚不清楚，似乎与血液对材料的反应方式相矛盾。这项建议试图通过测量血液成分与材料的相互作用以及这些成分如何变化来了解材料上形成凝块的原因。

DESCRIPTION (provided by applicant): Thrombosis remains a significant barrier to the development and implementation of blood-contacting medical devices. Contact activation of the blood plasma coagulation cascade has been shown to be a significant contributor to poor hemocompatibility of materials that leads to thrombosis. It is found that that hydrophilic materials are very efficient activators of plasma coagulation whereas hydrophobic materials are relatively inefficient activators. Classical biochemistry attributes this observation to the preferential adsorption/ assembly of activator-complex proteins directly onto hydrophilic surfaces. However, this explantion is inconsistent with the experimental finding that proteins do not adsorb to hydrophilic surfaces but do adsorb to hydrophobic surfaces. An objective of this proposal is to remedy this apparent inconsistency by testing the hypothesis that "Hydrophobic procoagulant surfaces are inhibitory to activation of the intrinsic pathway of the plasma coagulation cascade. Hydrophilic procoagulant surfaces are the most efficient activators because protein adsorption to these surfaces does not compete with solution-phase assembly of AC proteins, whereas contact activation by relatively hydrophobic procoagulants is moderated by adsorption of AC proteins directly onto these surfaces, leading to decreased activation." This proposed biochemistry is different than the conventional mechanism because it views hydrophobic surfaces as inhibitory to plasma activation rather than activation being specific to hydrophilic (anionic) surfaces, and therefore resolves the apparent inconsistentencies with observed protein adsorption behavior. This hypothesis is tested through three specific aims that utilize surface-science techniques and experimental/theoretical analysis of enzyme activation to understand relationships among protein adsorption, activation of the activation complex proteins, and subsequent production of FXIa. This information is critical to the prospective bioengineering of materials with improved hemocompatibility for a wide variety of cardiovascular devices. Lay description: Formation of blood clots on materials used in medical devices is a problem. The reasons for clot formation are unclear, and seemingly contradict what is already known about how blood responds to materials. This proposal seeks to understand the reasons for clot formation on materials by measuring the interaction of blood components with materials and how those components change in response.