Surface Engineering in Contact Activation of Coagulation

接触激活凝结的表面工程

• 批准号: 8316160
• 负责人: CHRISTOPHER A SIEDLECKI
• 金额: $ 37.69万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316160
• 关键词: Accounting; Adsorption; Area; Atomic Force Microscopy; Biochemical; Biocompatible Materials; Blood; Blood Clot; Blood Proteins; Blood coagulation; Bolus Infusion; Buffers; Chemistry; Chromatography; Coagulation Process; Communities; Complex; Development; Diagnosis; Disease; Dose; Electrophoresis; Engineering; Enzyme Precursors; Enzymes; Event; Exhibits; Frequencies; Generations; In Vitro; Informal Social Control; Kinetics; Link; Measures; Medical Device; Membrane Proteins; Methods; Modeling; Molecular; Pathway interactions; Plasma; Play; Production; Property; Proteins; Reaction; Relative (related person); Research; Resolution; Role; Scheme; Science; Series; Spectrum Analysis; Structure; Sum; Surface; Surface Properties; Suspension substance; Suspensions; Testing; Thrombin; Thrombosis; Time; Ventricular; Work; activation product; blood pump; design; improved; nanoscale; parent grant; prospective; submicron; synthetic construct; synthetic protein

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.

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要障碍。血浆凝血的接触激活是通过材料表面与接触激活复合物的蛋白质之间的相互作用发生的。最近的结果表明，主要的接触激活机械模型与测量的血液蛋白的吸附性能不一致，并且无法说明激活剂表面特性之间的关系，酶中间体的产生以及体外血浆凝血的时间。这项工作已经确定了要解决的关键问题，以提出一种修订后的血浆凝结表面激活方案，并在此中心假设的指导下提出了工作。 血浆凝血通过与材料表面的接触通过复杂的表面催化活化反应开始，该反应迅速将酶原FXII转化为表现出proco凝剂和/或普通酰化活性的活化片段的分布。片段的分布取决于激活剂表面化学和该化学的纳米镜分布。 proc仪片段刺激了内在途径的后续步骤的比例激活，最终导致凝血级联倒数第二步中凝血酶的比例产生。该假设与材料诱导的血液凝结的常规范式不同，因为它设想接触激活是一种非特异性的，表面诱导的事件，产生了各种FXII激活产物，其中一些能够诱导凝结。此外，假设指出，级联反应的传播是通过一系列的自限反应发生的。该假设将通过使用生化和表面分析方法来量化血表面接触形成的FXII片段的数量和活性来检验。结果将用于开发具有亚微米的新材料，与在宏观尺度上分布的化学材料相比，有证据表明血液相容性的证据提高了。前瞻性设计的生物材料一直是生物材料社区的长期目标，它代表了医疗设备的合成，血液相容的材料的新代。