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器械的重要障碍。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。发现亲水性材料是非常有效的血浆凝固活化剂，而疏水性材料是相对低效的活化剂。经典生物化学将这一观察结果归因于活化剂复合物蛋白直接吸附/组装到亲水表面上。然而，这一假设与蛋白质不吸附于亲水表面但吸附于疏水表面的实验发现不一致。本提案的目的是通过检验“疏水促凝血表面抑制血浆凝血级联的内在途径激活”的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，因为蛋白质吸附到这些表面不与AC蛋白质的溶液相组装竞争，而通过相对疏水性促凝剂的接触活化通过AC蛋白质直接吸附到这些表面上而缓和，导致活化降低。“这种提出的生物化学与传统机制不同，因为它将疏水表面视为对血浆活化的抑制，而不是对亲水（阴离子）表面特异性的活化，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。通过三个具体目标来验证这一假设，这些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和随后FXIa的产生之间的关系。该信息对于具有改善的血液相容性的材料用于各种心血管器械的前瞻性生物工程至关重要。 简单描述：在医疗器械所用材料上形成血凝块是一个问题。凝块形成的原因尚不清楚，似乎与已知的血液对材料的反应相矛盾。该提案旨在通过测量血液成分与材料的相互作用以及这些成分如何响应变化来了解材料上凝块形成的原因。

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.