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血液接触医疗设备的重大障碍。接触激活的血浆凝血级联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。发现亲水材料是非常有效的等离子体凝血活化剂，而疏水材料是相对低效的。经典生物化学将这一现象归因于激活剂复合物蛋白直接在亲水性表面上的优先吸附/组装。然而，这种解释与实验发现蛋白质不吸附在亲水表面而吸附在疏水表面是不一致的。本提案的目的是通过测试“疏水促凝剂表面抑制血浆凝血级联内在途径的激活”这一假设来纠正这种明显的不一致。亲水性促凝剂表面是最有效的活化剂，因为蛋白质在这些表面的吸附不会与AC蛋白的溶液相组装竞争，而相对疏水性促凝剂的接触活化会被AC蛋白直接吸附在这些表面上而减缓，从而导致活化降低。”这种提出的生物化学与传统的机制不同，因为它认为疏水表面是对血浆活化的抑制，而不是对亲水（阴离子）表面的特异性活化，因此解决了与观察到的蛋白质吸附行为明显不一致的问题。这一假设通过三个具体目标进行验证，这些目标利用表面科学技术和酶活化的实验/理论分析来了解蛋白质吸附、活化复合体蛋白的活化和随后FXIa的产生之间的关系。这一信息对于改善各种心血管装置血液相容性的材料的生物工程前景至关重要。

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.