Surface Engineering in Contact Activation of Coagulation

描述(由申请人提供)：血栓形成仍然是使用与血液接触的医疗设备治疗疾病的一个重要障碍。血浆凝固的接触激活是通过材料表面和接触激活复合体的蛋白质之间的相互作用而发生的。最近的研究结果表明，目前流行的接触活化机理模型与血液蛋白的吸附性质测量结果不一致，并且未能解释激活剂表面性质、酶中间体的产生和体外血浆凝固时间之间的关系。这项工作确定了需要解决的关键问题，以便提出一种修正的等离子体凝固表面激活方案，所提出的工作以这一中心假设为指导。血浆凝固是通过与材料表面接触而启动的，通过复杂的表面催化的活化反应，将酶原FXII迅速转化为分布的具有促凝剂和/或普通酰胺分解活性的活性片段。碎片的分布取决于活化剂的表面化学和该化学的纳米分布。促凝血剂片段刺激内部通路后续步骤的比例激活，最终导致凝血级联倒数第二步凝血酶的比例产生。这一假说不同于传统的材料诱导的血液凝固模式，因为它设想接触激活是一种非特异性的、表面诱导的事件，产生各种FXII激活产物，其中一些能够诱导凝血。此外，该假设指出，级联的传播是通过一系列自限反应进行的。这一假设将通过四个具体目标进行验证，这些目标利用生化和表面分析方法来量化血液与表面接触形成的FXII片段的数量和活性。结果将被用来开发具有亚微米空间分布的化学成分的新材料，并且与化学成分分布在宏观尺度上的材料相比，这些材料的血液相容性有明显改善。前瞻性设计的生物材料一直是生物材料界长期追求的目标，代表着用于医疗器械的新一代合成的、血液兼容的材料。

DESCRIPTION (provided by applicant): Thrombosis remains a significant barrier to the use of blood contacting medical devices for treatment of disease. Contact activation of blood plasma coagulation occurs via interactions between material surfaces and proteins of the contact activation complex. Recent results show that the prevailing mechanistic model of contact activation is inconsistent with measured adsorption properties of blood proteins and fails to account for relationships among activator surface properties, production of enzyme intermediates, and time to plasma coagulation in vitro. This work has identified key problems to be solved in order to propose a revised scheme for surface activation of plasma coagulation, with work proposed guided by this central hypothesis. Blood plasma coagulation is initiated by contact with material surfaces through a complex surface-catalyzed activation reaction that rapidly converts the zymogen FXII into a distribution of activated fragments exhibiting procoagulant and/or ordinary amidolytic activity. The distribution of fragments depends on activator surface chemistry and nanoscopic distribution of that chemistry. Procoagulant fragments stimulate proportional activation of subsequent steps of the intrinsic pathway, ultimately leading to proportional production of thrombin in the penultimate step of the coagulation cascade. This hypothesis differs from the conventional paradigm of material-induced blood coagulation in that it envisions contact activation as a non-specific, surface-induced event producing a variety of FXII activation products, some of which are capable of inducing coagulation. Furthermore, the hypothesis states that propagation of the cascade occurs through a series of self-limiting reactions. The hypothesis will be tested through four specific aims that utilize biochemical and surface analysis methods to quantify the amount and activity of FXII fragments formed by blood-surface contact. Results will be used to develop new materials with sub-micron spatially distributed chemistries and for which there is evidence improved hemocompatibility compared to materials having chemistries distributed at the macro scale. Prospectively designed biomaterials have been a long-sought objective of the biomaterials community and represent a new-generation of synthetic, hemocompatible materials for medical devices.