Multiscale Model of Thrombosis in Artificial Circulation

人工循环血栓形成的多尺度模型

• 批准号: 9925233
• 负责人: JAMES F. ANTAKI
• 金额: $ 59.13万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925233
• 关键词: Adhesions; Adverse event; Agonist; Agreement; Animals; Anticoagulants; Anticoagulation; Antithrombin III; Aspirin; Basic Science; Biochemical; Biological Phenomena; Blood; Blood Cells; Blood Circulation; Blood Platelets; Blood coagulation; Calcium; Cardiovascular system; Chemicals; Chemistry; Clinical; Clinical Trials; Computer Models; Computer Simulation; Computers; Convection; Deposition; Development; Devices; Diffusion; Elements; Erythrocytes; Event; Feedback; Forensic Medicine; Growth; Heart-Lung Transplantation; Hematocrit procedure; Hematology; Hemorrhage; Incidence; Infection; Injury; International; Liquid substance; Maps; Mathematics; Mediating; Membrane Oxygenators; Methods; Microfluidics; Modeling; Numeric Rating Scale; Pathway interactions; Patients; Pattern; Performance; Phase; Platelet Count measurement; Process; Property; Reaction; Reporting; Risk; Risk Management; Saint Jude Children' s Research Hospital; Side; Societies; Stents; Stroke; Surface; Thrombin; Thrombosis; Thrombus; Translations; Transplantation; Triad Acrylic Resin; blood oxygenator; blood pump; clinically relevant; clopidogrel; cost; design; dosage; experience; hemodynamics; implantable device; improved; meetings; multi-scale modeling; neglect; patient population; predictive modeling; pressure; programs; simulation; success; synergism; thrombolysis; tool; trafficking; ventricular assist device; virtual

ALL blood-wetted devices, without exaggeration, are susceptible to unintended thrombosis and bleeding – with dire consequences. In spite of decades of clinical experience, basic research, and computational fluid dynamics modeling, it is still virtually impossible to avoid deleterious hematological effects without experimental trail-and-error. In fact, in recent years, the incidence of thromboembolic and hemorrhagic adverse events in ventricular assist devices (VADs) has increased, not decreased. The unfortunate consequence is an unacceptable rate of debilitating adverse events such as stroke and hemorrhage. This has motivated the PI and colleagues over the past two decades to develop an accurate, computational model to simulate the process of thrombus deposition on artificial surfaces. The computer simulation is unique in its ability to account for physical and biological phenomena on multiple-scales, including the trafficking of red blood cells and platelets in small spaces, synthesis and transport of chemical agonists, and several pathways for positive- and negative feedback of platelet adhesion to artificial surfaces. The current model has demonstrated excellent agreement with experimental observations in microfluidic channels and the HeartMate-2 blood pump. The objective of this competitive renewal is to continue improvement of the versatility of this model, and to demonstrate its translation to full-scale blood-wetted devices. The two Specific Aims of this study are: SA1, to improve the fidelity of the model by adding important mechanisms of platelet disaggregation, thrombolysis, and von Willebrand mediated platelet adhesion; and SA2, to demonstrate and further validate the performance of the model with contemporary blood pumps and oxygenators in clinical use. Successful completion of these aims will yield a comprehensive computational model for thrombosis in blood-wetted devices, which we believe will contribute to the inevitable paradigm shift in developing these devices: replacing trial-and-error with prescriptive quantitative methods. Combined with computer optimization, the use of this model will greatly accelerate development of safe and effective new devices, and will reduce the occurrence of adverse complications. We also envision that the models will also be used forensically to analyze thrombosis-related adverse events, and help guide management of anticoagulation therapy.

毫不夸张地说，所有沾有血液的装置都容易发生意外血栓形成和 流血——带来可怕的后果。尽管有数十年的临床经验、基础研究， 和计算流体动力学建模，实际上仍然不可能避免有害的 无需实验反复试验即可获得血液学效应。事实上，近年来， 心室辅助装置 (VAD) 中血栓栓塞和出血不良事件的发生率 增加，而不是减少。不幸的后果是令人无法接受的衰弱率 中风和出血等不良事件。这激励了 PI 和同事 在过去的二十年里开发了一个精确的计算模型来模拟这个过程 人造表面上的血栓沉积。计算机模拟的独特之处在于它能够 解释多尺度的物理和生物现象，包括贩运 小空间内的红细胞和血小板、化学激动剂的合成和运输，以及 血小板粘附到人造表面的正反馈和负反馈的几种途径。 当前模型与实验观察结果非常吻合 微流体通道和 HeartMate-2 血泵。 此次竞争性更新的目的是继续提高该产品的多功能性 模型，并展示其转化为全尺寸的血液润湿设备。两个具体 本研究的目的是：SA1，通过添加重要的参数来提高模型的保真度 血小板解聚、溶栓和冯·维勒布兰德介导的血小板机制 附着力；和 SA2，以证明并进一步验证模型的性能 现代临床使用的血泵和氧合器。 成功完成这些目标将产生一个全面的计算模型 血液湿润装置中的血栓形成，我们相信这将导致不可避免的范例 开发这些设备的转变：用规定性定量取代试错法 方法。结合计算机优化，使用该模型将大大加速 开发安全有效的新设备，将减少不良事件的发生 并发症。我们还设想这些模型也将用于法医分析 血栓形成相关的不良事件，并有助于指导抗凝治疗的管理。