Surface Engineering in Contact Activation of Coagulation

接触激活凝结的表面工程

基本信息

批准号：
7586732
负责人：
CHRISTOPHER A SIEDLECKI
金额：
$ 34.79万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-06 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586732
关键词：
Accounting Acute Adsorption Albumins Area Behavior Binding Biochemistry Biocompatible Materials Biomedical Engineering Blood Blood Clot Blood Proteins Blood coagulation Cardiovascular system Cells Coagulation Process Complex Development Devices Engineering Enzyme Activation Enzymes Equilibrium Exhibits FIIa Fibrinogen Hydrolysis Hydrophobic Surfaces Immunoglobulin G In Vitro Measurement Measures Medical Device Membrane Proteins Methods Modeling Partition Coefficient Pathway interactions Phase Plasma Plasma Proteins Production Property Proteins Route Science Solid Solutions Surface Surface Properties Techniques Testing Thermodynamics Thrombin Thrombosis Time Water Wettability blood pump hydrophilicity improved mathematical model member prospective protein activation protein complex protein distribution response ventricular assist device

项目摘要

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.

描述（由申请人提供）：血栓形成仍然是伴有血液接触医疗设备的开发和实施的重要障碍。血浆凝血级联反应的接触激活已被证明是导致血栓形成的材料的血液相容性不佳的重要原因。发现亲水材料是血浆凝血的非常有效的活化剂，而疏水材料是相对效率低下的活化剂。经典生物化学将这一观察结果归因于直接在亲水表面上的激活剂复合蛋白的优先吸附/组装。但是，这种膨胀与实验发现不一致，即蛋白质不吸附至亲水性表面，而是对疏水表面的吸附。该提议的一个目的是通过测试“疏水性突出表面表面”的假设来解决这种明显的不一致性，抑制了血浆凝结级联反应的固有途径的激活，而水亲水性表达是最有效的激活剂，因为这些激发剂与这些蛋白质的互动竞争，因为蛋白质的互联性激励症是竞争的，因为它是竞争的激活，因为它是竞争的，因为它是竞争的激活。通过相对疏水的凝血剂通过直接吸附AC蛋白在这些表面上的吸附，导致激活减少。”该提出的生物化学与常规机制不同，因为它认为疏水表面是血浆激活的抑制性，而不是针对亲水性（阴离子）表面的激活，因此可以解决与观察到的蛋白质吸附行为的明显不一致的不一致。通过三个特定目的检验了这一假设，这些特定目的利用了表面科学技术和酶激活的实验/理论分析，以了解蛋白质吸附之间的关系，激活复合蛋白的激活以及随后的FXIA产生。这些信息对于具有改善的各种心血管设备的血流相容性的材料的前瞻性生物工程至关重要。外行描述：在医疗设备中使用的材料上的血块形成是一个问题。凝块形成的原因尚不清楚，似乎与血液如何反应材料相矛盾。该提案试图通过测量血液成分与材料的相互作用以及这些组件的反应方式来理解材料形成凝块的原因。