Surface Engineering in Contact Activation of Coagulation

描述（由申请人提供）：血栓形成仍然是使用血液接触医疗设备治疗疾病的重大障碍。血浆凝固的接触活化是通过材料表面与接触活化复合物蛋白之间的相互作用发生的。最近的研究结果表明，目前流行的接触活化机制模型与测定的血液蛋白吸附特性不一致，也无法解释活化剂表面特性、酶中间体的产生和体外血浆凝固时间之间的关系。这项工作已经确定了需要解决的关键问题，以便提出一种修订的血浆凝固表面活化方案，并在此中心假设的指导下提出了工作。血浆凝固是通过复杂的表面催化活化反应与物质表面接触而开始的，该反应迅速将酶原FXII转化为具有促凝剂和/或普通酶解活性的活化片段分布。碎片的分布取决于活化剂的表面化学性质和纳米化学性质的分布。促凝剂片段刺激内在途径后续步骤的比例激活，最终在凝血级联的倒数第二步导致凝血酶的比例产生。这一假说不同于传统的材料诱导凝血模式，因为它认为接触活化是一种非特异性的表面诱导事件，产生多种FXII激活产物，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我限制的反应发生的。该假设将通过四个具体目标进行检验，利用生化和表面分析方法来量化血液表面接触形成的FXII片段的数量和活性。研究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分布化学物质的材料相比，有证据表明其血液相容性得到改善。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，代表了新一代用于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.