Multiscale modeling of blood flow and clotting in cardiovascular devices

描述（申请人提供）：植入式血液循环装置的出现为严重心血管疾病患者提供了挽救生命的解决方案。心室辅助装置（VAD）、血泵和人工心脏瓣膜（PHV）为这类患者提供了短期到长期的解决方案。然而，血栓的形成和随之而来的中风风险仍然是这些设备的障碍。他们需要复杂的终身抗凝药物治疗方案，这导致出血的易感性，对一些患者来说不是一种可行的治疗方法，并不能消除这种风险。与异物表面的接触和非生理性流动模式通过慢性激活血小板而增强止血反应，从而增强凝块的形成。它现在被认为是器械血液创伤的突出方面。我们提供开发最先进的多尺度数值模拟方法，能够预测和描述设备中血流诱导的血栓形成性。血小板血流引起的应力可以用<m级的连续介质力学模型来表示。然而，黏附-聚集键的分子效应是在纳米量级的，这种不同时空尺度的耦合是一个主要的计算挑战。我们的方法结合了一个宏观模型，该模型提供了可能激活凝血的流动诱导应力的信息，并传输到基于离散粒子动力学（DPD）方法的微纳米尺度模型。这种多尺度模型通过允许血小板在机械刺激下不断改变其形状，弥合了宏观流动和细胞尺度之间的差距。该项目有以下具体目标：(1)开发血流诱导血栓形成的DPD模型；结合生物化学和细胞反应动力学导致血小板聚集，凝块形成和栓塞。(2)通过将该模型纳入血流诱导血栓形成的多尺度模型，弥合宏观和分子尺度之间的差距，将应激动力学转化为血小板相关的生化和细胞事件。(3)通过将DPD预测与计算流体动力学（CFD）进行比较，并将其血小板活化和聚集预测与血液再循环回路的测量结果相关联，从而验证DPD的有效性。(4)进行误差估计和参数敏感性分析，优化多集群超级计算机跨尺度的计算效率。随着预期寿命的延长，越来越多的患者将需要CVS设备。器械致血栓性的棘手问题需要创新的方法，将跨越空间和时间尺度的生物物理和生化运输结合起来。在拟议的研究中开发的工具对于优化下一代设备至关重要，以降低死亡率和随之而来的医疗保健成本，并改善患者的生活质量。计算方法和高性能计算的最新进展使这些重大挑战触手可及。提出的方法可能会刺激新兴的多尺度模拟领域，并将其应用于解决工程和生物学界面的复杂临床问题。它代表了这种模拟的范式转变，将我们对生物运输过程的理解提升到一个新的水平，可能对生物学和医学的重要问题产生重大影响。小灵通398/2590 （Rev. 06/09）页1延续格式页

DESCRIPTION (provided by applicant): The advent of implantable blood recirculating devices has provided life saving solutions to patients with severe cardiovascular diseases. Ventricular assist devices (VAD), blood pumps, and prosthetic heart valves (PHV) provide short to long term solutions for such patients. However, blood clots formation and the attendant risk for stroke remains an impediment to these devices. The complex life-long anticoagulant drug regimen they require, which induces vulnerability to hemorrhage and is not a viable therapy for some patients, does not eliminate this risk. Clot formation is potentiated by contact with foreign surfaces and the non-physiologic flow patterns that enhance the hemostatic response by chronically activating platelets. It is now recognized as the salient aspect of blood trauma in devices. We offer to develop state of the art multiscale numerical simulation methodology that will be able to predict and depict flow induced thrombogenicity in devices. Stresses induced by blood flow on platelets can be represented by a continuum mechanics models down to the order of the <m level. However, molecular effects of adhesion- aggregation bonds are on the order of nm. The coupling of such disparate spatiotemporal scales represents a major computational challenge. Our approach couples a macroscopic model that provides information about the flow induced stresses that may activate clotting, transmitted to a micro-to-nanoscale model based on Discrete Particle Dynamics (DPD) approach. This multi-scale model bridges the gap between macroscopic flow and the cellular scales by allowing the platelets to change their shape continuously in response to the mechanical stimuli. The project follows specific aims (1) develop a DPD model of flow induced thrombogenicity; incorporating biochemical and cellular reaction kinetics leading to platelet aggregation, clot formation and embolization. (2)Bridge the gap between macroscopic and molecular scales by incorporating this model into a multiscale model of flow-induced thrombogenicity, translating the stress dynamics to platelet associated biochemical and cellular events. (3) Validate DPD by comparing its predictions to computational fluid dynamics (CFD), and correlating its platelets activation and aggregation predictions to measurements in a blood recirculation loop. (4) Conduct error estimation and parameter sensitivity analysis, and optimize the computational efficiency across the scales in multi-cluster supercomputers. With extended life expectancy, increasing numbers of patients will require CVS devices. The vexing problem of device thrombogenicity calls for innovative approaches that couple biophysical and biochemical transport spanning the spatial and temporal scales. The tools developed in the proposed research are essential for optimizing the next generation of devices in order to reduce mortality rates and the ensuing healthcare costs, and improve patients' quality of life. Recent progress in computational methods and HPC has put such major challenges within our reach. The proposed methodology may stimulate the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. It represents a paradigm shift in such simulations, advancing our understanding of biotransport processes to a new level that may have a major impact on important problems in biology and medicine. PHS 398/2590 (Rev. 06/09) Page 1 Continuation Format Page PUBLIC HEALTH RELEVANCE: Better understanding of the complex interactions between living tissues and mechanical stimuli, as represented by the vexing problem of flow-induced cardiovascular devices thrombogenicity, calls for innovative multidisciplinary approaches that couple biophysical and biochemical transport phenomena spanning the spatial and temporal scales. In this proposal a multi-scale modeling approach will be developed that will efficiently utilize high performance computing (HPC) resources. The knowledge that will be gained by the proposed research is essential for developing the next generation of devices that will reduce mortality rates, improve patients' quality of life, and reduce the ensuing healthcare costs. The innovative methodology that will be developed may stimulate the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. It has the potential to advance our understanding of biotransport processes to a new level that will have a major impact on important problems in biology and medicine.