MULTI-SCALE MODEL OF THORMBOSIS IN ARTIFICIAL CIRCULATION

描述（由申请人提供）：控制血液流动的物理和生物学过程对所有血液润湿医疗器械的安全性和有效性有密切关系。然而，由于目前对血液创伤和血栓形成的理解不足，设计改进的心血管装置的探索受到抑制。尽管在器械设计、血液创伤研究和计算流体动力学建模方面有数十年的经验，但在没有实验性试错的情况下，几乎不可能避免有害的血液学效应。当代设计依赖于古老的血液数学公式，它更多的是描述性的而不是预测性的。此外，我们现在了解到，这三种现象比以前认识到的更密切地联系在一起。事实上，以前的模型几乎忽略了这三个过程之间的任何耦合的存在。拟议项目的目的是提高血液润湿心血管器械中血栓形成预测模型的准确性和实用性。该研究建立在PI及其同事开发的剪切介导血栓形成先前模型和细胞尺度血流动力学建模最新进展的组合基础上。进一步纳入血小板激动剂协同作用模型旨在产生一种全面的设计工具，可用于心血管器械的设计优化。计算机模拟将预测血液流动中红细胞（RBC）与血小板（Plts）的动态相互作用，并将依赖于一个复杂的相互作用连续体理论，该理论可以预测细胞在任意流动路径中的分布。该模型将通过微尺度计算机模拟和微通道中血细胞的显微可视化来验证和校准。模型的预测能力将在儿童心血管器械开发的三个基准应用中得到证明：（1）包含各种微观台阶和裂缝的平行板研究，（2）旋转血泵叶片尖端内的流动，以及（3）儿科旋转血泵的流体动力轴承。这些目标的成功完成将为心血管设备中的血液创伤产生一个全面的计算模型，我们相信这将有助于这些设备开发方式的范式转变：用规定的生物工程方法取代试错法。结合计算机优化，该模型的使用将大大加快创新新器械的开发，并将减少不良并发症的发生。我们还设想，这些模型也将为诊断各种临床事件提供信息，并帮助指导抗凝治疗的管理。公共卫生相关性：目前植入的心血管器械存在意外凝血的风险，可能导致严重损伤，包括中风。该项目的目的是创建一个计算机模拟程序，预测何时可能发生这种情况，从而指导这些设备的开发人员生产更安全有效的设备。

DESCRIPTION (provided by applicant): The physical and biological processes governing the flow of blood are intimately responsible for safety and efficacy of all blood-wetted medical devices. The quest to design improved cardiovascular devices is however stifled by the inadequacies of current understanding of blood trauma and thrombosis. In spite of decades of experience with device design, hemotrauma research, and computational fluid dynamics modeling, it is virtually impossible to avoid deleterious hematological effects without experimental trail-and-error. Contemporary design relies upon venerable mathematical formula for blood that is more descriptive than predictive. Furthermore, we now understand that that these three phenomena are more closely coupled that previously appreciated. Indeed, previous models virtually neglected the existence of any coupling between these three processes. The objective of proposed project is to advance the accuracy and utility of a predictive model for thrombosis in blood-wetted cardiovascular devices. The research is built upon a combination of a previous model developed by the PI and colleagues for shear- mediated thrombosis and recent progress in modeling cellular-scale hemodynamics. Further incorporation of a model for synergy of platelet agonists is intended to yield a comprehensive design tool that is practical for design optimization of cardiovascular devices. Computer simulations will predict the dynamic interaction of red blood cells (RBCs) with platelets (Plts) in blood flow, and will rely upon a sophisticated theory of interacting continua that can predict the distribution of cells in any arbitrary flow path. The model will be validated and calibrated by both micro-scale computer simulations and microscopic visualization of blood cells in micro-channels. The predictive capacity of model will be demonstrated in three benchmark applications motivated by the development of cardiovascular devices for children: (1) parallel plate study incorporating various microscopic steps and crevices, (2) flow within blade tip of rotary blood pump, and (3) hydrodynamic bearing for pediatric rotary blood pump. Successful completion of these aims will produce a comprehensive computational model for blood trauma in cardiovascular devices, which we believe will contribute to the paradigm shift in the way these devices are developed: replacing trial-and-error with prescriptive bioengineering methods. Combined with computer optimization, the use of this model will greatly accelerate development of innovative new devices, and will reduce the occurrence of adverse complications. We also envision that the models will also be informative for diagnosing various clinical events, and help guide management of anticoagulation therapy. PUBLIC HEALTH RELEVANCE: Cardiovascular devices that are implanted today carry a risk of un-intended blood clotting, which may cause serious injury including stroke. The purpose of this project is to create a computer simulation program that will predict when this might occur, and thereby guide developers of these devices to produce more safe and effective devices.