Computational Modeling of Device-Induced Platelet Activation and Receptor Shedding Relevant to Thrombosis and Bleeding in Device-Assisted Circulation

虽然血液接触医疗器械（BCMD）已成为器官移植的救生替代品， 对于许多移植患者，血栓形成和出血事件仍然是术后最常见的 并发症往往是毁灭性的，往往危及生命。器械引起的止血功能障碍是 通常认为是这些并发症的罪魁祸首，并与血小板活化直接相关， 受体脱落相关的功能障碍所造成的非生理剪切应力（NPSS），在这些 装置.多年来，计算流体动力学（CFD）辅助的模拟和分析已经被广泛地应用。 用于实现对器械诱导的血小板功能障碍的重大研究工作。在芝加哥消防局的帮助下 技术，可以精确地识别血流路径中的异常NPSS和停滞流动的区域，以评估 进一步增加了装置中血栓形成和出血的潜在风险。然而，现有的CFD模型预测 剪切诱导的血小板活化和受体脱落以及相关的止血并发症（血栓形成和 出血），主要基于经验模型，从装置设计的角度来看，成功有限。 该提案旨在基于对血小板活化的最新解释， 血小板活化后的基本形态变化。它将被纳入CFD的发展 能够评估体外和体内器械诱导的血小板功能障碍和相关粘附的模型 能力到基板。数值算法和实施方案将发展到链接剪切- 诱导的血小板损伤模型与CFD变量相关联，以预测器械诱导的血小板功能障碍。定量 器械受损血小板对胶原蛋白、vWF和纤维蛋白原的粘附能力可用于代表 器械相关血栓形成和出血的可能性。然后将进行实验以验证 基于CFD的预测建模。最后，将进行绵羊研究，以测试体内CFD模型 预测建模CFD模型将纳入绵羊特定血液特性、器械几何形状、器械 预测体内器械诱导血小板的操作条件、血小板消耗和生成模型 绵羊在VAD和ECMO支持下的功能障碍和粘附能力改变。圆满完成 该项目的成果将产生基于CFD的预测工具。这些工具可用于提供定量评估 BCMD的性能和体内生物相容性，并帮助开发和优化新的 具有改进的功能特性和生物相容性的BCMD。

Although blood-contacting medical devices (BCMDs) have become lifesaving alternatives to organ transplantation for many patients, thrombotic and bleeding events remain the most common postoperative complications that tend to be devastating and often life-threatening. Device-induced hemostatic dysfunction is commonly believed to be the culprit of these complications and is directly related to platelet activation and receptor shedding associated dysfunction caused by the non-physiological shear stress (NPSS) in these devices. Over the years, computational fluid dynamics (CFD)-aided simulation and analysis have been widely adopted to achieve significant research efforts on device-induced platelet dysfunction. With the help of the CFD technique, regions of abnormal NPSS and stagnant flow in blood flow paths can be precisely identified to assess further the potential risk of thrombosis and bleeding in devices. However, the existing CFD models for predicting shear-induced platelet activation and receptor shedding and related hemostatic complications (thrombotic and bleeding), mainly based on the empirical models, have limited success from the device design perspective. This proposal aims to develop a novel platelet activation model based on the art-of-state interpretation of the platelet’s fundamental morphological change upon activation. It will be incorporated in the development of CFD models capable of assessing in-vitro and in-vivo device-induced platelet dysfunction and associated adhesion capacities to substrates. Numerical algorithms and implementation schemes will be developed to link shear- induced platelet damage models to CFD variables to predict device-induced platelet dysfunction. Quantitative adhesion capacities of device-damaged platelets to collagen, vWF, and fibrinogen could be used to represent device-associated potentials for thrombosis and bleeding. Experiments will then be performed to validate the CFD-based predictive modeling. Finally, a sheep study will be performed to test the CFD models for in-vivo predictive modeling. CFD models will incorporate sheep-specific blood properties, device geometry, device operating conditions, platelet consumption, and generation models to predict the in-vivo device-induced platelet dysfunction and altered adhesion capacities of sheep on VADs and ECMO support. The successful completion of this project will result in CFD-based predictive tools. These tools can be used to provide quantitative evaluation of the performance and in-vivo biocompatibilities of BCMDs and aid the development and optimization of new BCMDs with improved functional characteristics and biocompatibility.