Cardiovascular diseases remain the leading cause of death in the developed world, accounting for near 30% of all deaths globally and 35% in the US annually. Coronary artery disease (CAD) with its associated thrombotic risk is responsible for 1 of 6 deaths in the US. Coincidentally, implantable blood recirculating devices, which have provided lifesaving solutions to patients with severe cardiovascular diseases, are burdened with thrombosis and thromboembolic complications, mandating complex life-long anticoagulation. The mechanisms underlying vascular disease processes and device-related thrombotic complications are intertwined. Thrombosis in vascular disease is potentiated by the interaction of blood constituents with an injured vascular wall and the non-physiologic flow patterns generated in cardiovascular pathologies initiate and enhance the hemostatic response by chronically activating the platelets. Similarly, device thrombogenicity is induced by pathological flow fields and contact with foreign surfaces. Upon activation platelets undergo complex biochemical and morphological changes. The coupling of the disparate spatio-temporal scales between molecular level events and the macroscopic transport represents a major modeling and computational challenge, which requires a multidisciplinary integrated multiscale numerical approach. Continuum approaches are limited in their ability to cover the smaller molecular mechanisms such as filopodia formation during platelet activation. Utilizing molecular dynamics (MD) to cover the multiscales involved is computationally prohibitive. In this application we offer to develop a comprehensive state-of-the-art multiscale numerical methodology that will be able to bridge the gap between the macroscopic transport and the ensuing molecular events. We will use an integrated Dissipative Particle Dynamics (DPD) and Coarse Grained Molecular Dynamics (CGMD) approach that allows platelets to continuously change their shape and synergistically activate by a biomechanical transductive linkage chain, interact with other blood constituents and clotting factors, aggregate, and interact and adhere to the blood vessels and devices. In this multiscale model, a mechanotransduction CGMD bottom platelet activation model is embedded into a DPD blood flow top model. The dynamic stresses of the macroscale model will be interactively translated to the micro to nanoscale model of the intra-platelet associated intracellular events. The model predictions will be validated in vitro in a carefully designed set of experiments. This will be achieved according to the following specific aims: We will develop a mechanotransduction model of platelet mediated thrombosis where a top/macro-scale model of flow-induced thrombogenicity using DPD at the m-length and ms-time scales, in which multiple flowing platelets interact with each other and blood vessel walls or devices, will be fully coupled with a bottom/micro-scale model using CGMD at the nm-length and ps-time scales, in which platelets with multiple intracellular constituents evolve during activation as platelet lose their quiescent discoid shape and filopodia grow. The top and bottom models will be interfaced such that the hemodynamics will interactively respond to platelet shape change upon activation and platelet aggregation and thrombus is formed. The effect of modulating platelet mechanical properties via antiplatelet agents will be modeled as well. All model aspects will be validated in vitro in a series of carefully designed experiments characterizing the mechanical properties of platelets and using blood flow experiments where conditions leading to flow induced platelet activation will be replicated, as well as experiments where platelet-wall and platelet device interactions will be measured and where platelets will be pretreated with modulating agents. These data will be used to fine tune the large number of model parameters involved in this multiscale simulation and for validating the model predictions. An independent 3rd party evaluation of the model credibility is also included as an integral part of the project. e will also concentrate on the development of efficient algorithms adapted for ultra-scalable large HPC clusters to reduce prohibitive computation costs, so as to bring such ambitious large multiscale simulations within the reach of the multiscale modeling community at large and enable to adopt it to other relevant modeling needs and interests. To further enable these technologies, large sharable data base will be created where software tools, numerical codes, model and experimental data and protocols will be deposited and guidance will be provided for using them. The leaders of the project will be active in various MSM consortium working groups to further disseminate the project outcomes and share them with the modeling community. The methodology proposed represents a paradigm shift in the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. Predicting the progression of arterial thrombosis under circulation conditions, providing tools for improved pharmacological management as compared to existing empirics-based treatments, and providing a modeling tool for developing the next generation of devices with reduced thrombogenicity may lead to reduced mortality rates, improved patients' quality of life, and an overall reduction of the financial burden of the ensuing healthcare costs.

Public Health Relevance

Cardiovascular diseases remain the leading cause of death in the developed world. Blood flow and platelet mediated thrombosis are a major culprit in this devastating process. Numerical simulations help us understand the processes that are involved in such phenomena as to offer better therapeutic solutions. However, it covers a vast range of scales- from molecular micro to nanoscales to the macroscales of blood flow in big arteries and cardiovascular devices. To address this challenge, this project aims to develop a computationally efficient multiscale model of blood flow and platelet mediated thrombosis using cutting edge molecular dynamics and dissipative particle dynamics numerical approaches. The methodology proposed represents a paradigm shift in the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. Predicting the progression of arterial thrombosis under circulation conditions, providing tools for improved pharmacological management as compared to existing empirics-based treatments, and providing a modeling tool for developing the next generation of devices with reduced thrombogenicity may lead to reduced mortality rates, improved patients' quality of life, and an overall reduction of the financial burden of the ensuing healthcare costs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL131052-03
Application #
9418110
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Qasba, Pankaj
Project Start
2016-05-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Chiu, Wei-Che; Alemu, Yared; McLarty, Allison J et al. (2017) Ventricular Assist Device Implantation Configurations Impact Overall Mechanical Circulatory Support System Thrombogenic Potential. ASAIO J 63:285-292
Dimasi, Annalisa; Rasponi, Marco; Consolo, Filippo et al. (2017) Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices. Med Eng Phys 48:31-38
Slepian, Marvin J; Sheriff, Jawaad; Hutchinson, Marcus et al. (2017) Shear-mediated platelet activation in the free flow: Perspectives on the emerging spectrum of cell mechanobiological mechanisms mediating cardiovascular implant thrombosis. J Biomech 50:20-25
Consolo, Filippo; Sheriff, Jawaad; Gorla, Silvia et al. (2017) High Frequency Components of Hemodynamic Shear Stress Profiles are a Major Determinant of Shear-Mediated Platelet Activation in Therapeutic Blood Recirculating Devices. Sci Rep 7:4994
Bluestein, Danny (2017) Utilizing Computational Fluid Dynamics in Cardiovascular Engineering and Medicine-What You Need to Know. Its Translation to the Clinic/Bedside. Artif Organs 41:117-121
Zhang, Peng; Zhang, Na; Gao, Chao et al. (2016) Scalability Test of Multiscale Fluid-Platelet Model for Three Top Supercomputers. Comput Phys Commun 204:132-140
Marom, Gil; Bluestein, Danny (2016) Lagrangian methods for blood damage estimation in cardiovascular devices--How numerical implementation affects the results. Expert Rev Med Devices 13:113-22
Leung, Siu Ling; Lu, Yi; Bluestein, Danny et al. (2016) Dielectrophoresis-Mediated Electrodeformation as a Means of Determining Individual Platelet Stiffness. Ann Biomed Eng 44:903-13
Tran, Phat L; Pietropaolo, Maria-Grazia; Valerio, Lorenzo et al. (2016) Hemolysate-mediated platelet aggregation: an additional risk mechanism contributing to thrombosis of continuous flow ventricular assist devices. Perfusion 31:401-8

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