Surface Engineering in Contact Activation of Coagulation

描述（由申请方提供）：血栓形成仍然是使用血液接触医疗器械治疗疾病的一个重要障碍。血浆凝固的接触活化通过材料表面和接触活化复合物的蛋白质之间的相互作用发生。最近的研究结果表明，现行的机械模型的接触活化是不一致的测量吸附性能的血液蛋白质，并没有考虑到激活剂的表面性质，生产的酶中间体，和时间之间的关系，血浆凝固在体外。这项工作已经确定了要解决的关键问题，以提出一个修改后的计划，表面激活血浆凝固，工作提出了这个中心假设的指导下。 通过复杂的表面催化活化反应与材料表面接触来引发血浆凝固，所述表面催化活化反应将酶原FXII快速转化为表现出促凝血剂和/或普通酰胺分解活性的活化片段的分布。碎片的分布取决于活化剂表面化学和该化学的纳米级分布。促凝血片段刺激内源性途径后续步骤的成比例活化，最终导致凝血级联反应倒数第二步中凝血酶的成比例产生。该假设与材料诱导凝血的常规范例不同，因为它将接触活化设想为产生多种FXII活化产物的非特异性表面诱导事件，其中一些能够诱导凝血。此外，该假说指出，级联的传播是通过一系列自限反应发生的。该假设将通过四个具体目标进行测试，这些目标利用生物化学和表面分析方法来量化血液表面接触形成的FXII片段的量和活性。结果将用于开发具有亚微米空间分布化学物质的新材料，并且与具有宏观尺度化学物质分布的材料相比，有证据表明其血液相容性有所改善。专业设计的生物材料一直是生物材料界长期追求的目标，代表了新一代医疗器械的合成血液相容性材料。

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.