Alfio Quarteroni is Director of the Chair of Modelling and Scientific Computing at the EPFL (Swiss Federal Institute of Technology), Lausanne (Switzerland) since 1998 and Professor of Numerical Analysis at the Politecnico di Milano (Italy) since 1989. He is the founder (and first director) of MOX at Politecnico of Milan (2002) and MATHICSE at EPFL, Lausanne (2010). He is author of 22 books, editor of 5 books, author of more than 300 papers published in international Scientific Journals and Conference Proceedings, member of the editorial board of 25 International Journals and Editor in Chief of two book series published by Springer. Among his awards and honors are: the NASA Group Achievement Award for the pioneering work in Computational Fluid Dynamics in 1992, the Fanfullino della Riconoscenza 2006, Città di Lodi, the Premio Capo D'Orlando 2006, the Ghislieri prize, 2013 and the Galileo Galilei prize for Sciences 2015. He is the Recipient of the ERC advanced grant “MATHCARD”, 2008, Recipient of the Galileian Chair from the Scuola Normale Superiore, Pisa, Italy ,2001, doctor Honoris Causa in Naval Engineering from University of Trieste, Italy, 2003, SIAM Fellow (first row) since 2009, IACM (International Association of Computational Mechanics) Fellow since 2004. He is member of the Italian Academy of Science, the European Academy of Science, the Academia Europaea. His research interest concern Mathematical Modelling, Numerical Analysis, Scientific Computing and Application to : fluid mechanics, geophysics, medicine and the improvement of sports performance.
Numerical Models for Heart Function
In this presentation I will introduce a coupled mathematical model for heart function, present numerical approximation methods, address data and parameter variability by Reduced Basis methods, and illustrate numerical simulations on some cases of clinical relevance.
George Karniadakis received his S.M. (1984) and Ph.D. (1987) from Massachusetts Institute of Technology. He was appointed Lecturer in the Department of Mechanical Engineering at MIT in 1987 and subsequently he joined the Center for Turbulence Research at Stanford / Nasa Ames. He joined Princeton University as Assistant Professor in the Department of Mechanical and Aerospace Engineering and as Associate Faculty in the Program of Applied and Computational Mathematics. He was a Visiting Professor at Caltech (1993) in the Aeronautics Department. He joined Brown University as Associate Professor of Applied Mathematics in the Center for Fluid Mechanics on January 1, 1994. He became a full professor on July 1, 1996. He has been a Visiting Professor and Senior Lecturer of Ocean/Mechanical Engineering at MIT since September 1, 2000. He was Visiting Professor at Peking University (Fall 2007 & 2013). He is a Fellow of the Society for Industrial and Applied Mathematics (SIAM, 2010-), Fellow of the American Physical Society (APS, 2004-), Fellow of the American Society of Mechanical Engineers (ASME, 2003-) and Associate Fellow of the American Institute of Aeronautics and Astronautics (AIAA, 2006-). He received the Ralf E Kleinman award from SIAM (2015), the (inaugural) J. Tinsley Oden Medal (2013), and the CFD award (2007) by the US Association in Computational Mechanics. His research interests focus on stochastic multiscale mathematics and modeling of physical and biological systems. Current thrusts include machine learning and scientific computing, stochastic simulation, fractional PDEs, and multiscale modeling of complex systems.
Multiscale Modeling of Blood Clotting
We develop a new multiscale framework that seamlessly integrates four key components of blood clotting namely, blood rheology, cell mechanics, coagulation kinetics and transport of species and platelet adhesive dynamics.We use transport dissipative particle dynamics (tDPD), which is the extended form of original DPD, as the base solver, while a coarsegrained representation of blood cell’s membrane accounts for its mechanics. Our results show the dominant effect of blood flow and high Peclet numbers on the reactive transport of the chemical species signifying the importance of membrane bound reactions on the surface of adhered platelets. This new multiscale particle-based methodology helps us probe synergistic mechanisms of thrombus formation, and can open new directions in addressing other biological processes from sub-cellular to macroscopic scales.
Eleuterio Toro is currently Professor and Chair of Numerical Analysis at the Laboratory of Applied Mathematics, DICAM, University of Trento, Italy. He holds a PhD in computational mathematics from Teesside University (UK 1982). Professor Toro has received several honours and distinctions, which include the honorary title OBE from Queen Elizabeth II (UK, 2000); Distinguished Citizen of the City of Carahue (Chile, 2001); Life Fellow, Claire Hall, University of Cambridge (UK, 2003); Fellow of the Indian Society for Shock Wave Research (Bangalore, 2005); Doctor Honoris Causa (Universidad de Santiago de Chile, 2008); William Penney Fellow, University of Cambridge (UK, 2010); Doctor Honoris Causa (Universidad de la Frontera, Chile, 2012) and Honorary Professor, Moscow Institute of Physics and Technology, Russia. Professor Toro’s research has for many years focused on the construction of computational methods for solving partial differential equations, with particular emphasis on hyperbolic balance laws. Contribution highlights include: WAF (1989), HLLC (1992), FORCE (1996), ADER (2001), MUSTA (2004), TV flux splitting (2012). Professor Toro’s research is currently focused on the study of the biophysics of neurodegenerative diseases and their association to the disturbed dynamical interaction of fluid compartments in the central nervous system (arterial blood, venous blood, interstitial fluid, cerebrospinal fluid, the brain parenchyma and the newly discovered brain lymphatic system). Ofparticular interest is the theoretical elucidation of the hypothesized link between extra-‐cranial venous anomalies and neuropathologies, such as Multiple Sclerosis, Meniere’s disease and Parkinson’s disease. In the last ten years he has been an invited and a keynote speaker in more than 100 international scientific events. Professor Toro has held many visiting appointments round the world, which include several European countries, Japan, China and USA. He is author of more than 300 research works. (eleuteriotoro.com)
Neurological Diseases and Interacting Fluid Compartments of the Central Nervous System: A Holistic Modeling Approach
Fluid compartments that are relevant to the understanding of the physiology of the central nervous system (CNS) are first reviewed, emphasising some very recent findings that include the discovery of a meningeal lymphatic system. There follows a brief review of some neurodegenerative diseases thought to be associated to malfunctions of CNS fluid compartments, such as multiple sclerosis, Meniere’s Disease, Idiopathic Parkinson’s Disease, Alzheimer’s Disease and Idiopathic Intracranial Hypertension. I then describe a global, closed loop mathematical model for the entire human circulation coupled to the dynamics of cerebrospinal fluid (CSF) and brain dynamics. Sample computations on the effect of extracranial venous strictures on CNS haemodynamics and CSF dynamics are presented. Intracranial venous hypertension and disturbed CSF dynamics are predicted. These computational results support recent medical hypotheses and may help to unravel some of the underlying mechanisms of some of these diseases. To conclude I point out some of the limitations of our present mathematical model and describe current work aimed at enhancing it, to include the peripheral as well as the newly discovered brain lymphatic system.
Elisa Budyn is Professor of Mechanical Engineering at Ecole Normale Superieure de Cachan in France. She is also Adjunct Associate Professor to the Departments of Mechanical Engineering and Oral Medicine and Diagnostic Sciences at the University of Illinois at Chicago. She graduated her Ph.D. from Northwestern University in 2004, earned a one year CNRS post-doctoral fellowship to study at CNRS LMSSMat Laboratory at Ecole Centrale Paris, after which she joined UIC Mechanical Engineering Department in 2005 as Assistant Professor and ENS Cachan in 2013 as Professor. Her research focus on the design, implementation, testing and 3D morphological modelling of biological systems such as organ-on-chip and cellularized implants, in particular bone, heart or liver. She investigates human cell mechano-transduction in in vitro recellularized native tissue functions in conditions close to in vivo to further create allogenic implants. Her research has been funded by NSF, AFOSR, CNRS, ANR-RHU and the Farman Institute.
Bone-on-Chip to Study Osteocyte Mechano-Transduction and ECM Formation
With increasing life expectancy, pathologies related to massive bone loss carry $10 billion financial burden on the U.S. healthcare system. Successful techniques to repair massive tissue regeneration can be however difficult and require the addition of functional materials. We propose to build in vitro systems where human osteocyte progenitors are seeded in a previously decellularized human bone tissue for more than fifteen months. The systems are compared to in vitro systems seeded with mature osteocytes. To design successful cellularized implants it is essential to quantify the relationship between in situ mechanical stimulation and the cell biological response at different stages of their differentiation and to characterize the ECM formed by the seeded cells. The bone-on-chip produced after 109 days an ECM of which the strength was nearly a quarter of native bone, contained type I collagen at 256 days and was mineralized at 39 days. The cytoplasmic calcium concentrations were higher in mature osteocytes than in progenitor cells and were maintained constant under mechanical loading. The cytoplasmic calcium concentration variations seemed to adapt to the expected in vivo mechanical load at the successive stages of cell differentiation.
Alison Marsden is an associate professor and Wall Center scholar in the departments of Pediatrics, Bioengineering, and, by courtesy, Mechanical Engineering at Stanford University. From 2007-2015 she was a faculty member in the Mechanical and Aerospace Engineering Department at the University of California San Diego. She graduated with a bachelor's degree in Mechanical Engineering from Princeton University in 1998, and a PhD in Mechanical Engineering from Stanford in 2005 working with Prof. Parviz Moin. She was a postdoctoral fellow at Stanford University in Bioengineering and Pediatric Cardiology from 2005-07 working with Charles Taylor and Jeffrey Feinstein. She was the recipient of a Burroughs Wellcome Fund Career Award at the Scientific Interface in 2007, an NSF CAREER award in 2011, and is a member of an international Leducq Foundation Network of Excellence. She received the UCSD graduate student association faculty mentor award in 2014 and MAE department teaching award at UCSD in 2015. She has published over 80 peer reviewed journal papers and has received extramural funding from multiple governmental agencies and private sources. She serves on the editorial boards of the Journal of Biomechanical Engineering and PLOS Computational Biology. Her work focuses on the development of numerical methods for cardiovascular blood flow simulation, medical device design, optimization in fluid mechanics, and application of engineering to impact patient care in cardiovascular and congenital heart disease.
Computational Investigations of the Biomechanical Underpinnings of Vein Graft Failure
Coronary bypass graft surgery (CABG) is performed on approximately 500,000 patients every year in the United States. Because most patients require multi-vessel revascularization, roughly 70% of CABG surgeries employ saphenous vein grafts, despite the superior performance of arterial grafts. Vein graft failure continues to be a major clinical problem, with as many as 50% of grafts failing within 5 years of surgery. When a vein graft is implanted in the arterial system it adapts to the high flow and pressure of the arterial environment by changing composition and geometry. Though hemodynamics is known to play an active role in growth and remodeling of blood vessels, the underlying mechanisms of vein graft failure remain poorly understood. We will describe our two-pronged approach to investigating the biomechanical underpinnings of vein graft failure. First, we perform patient-specific simulations of coronary and bypass graft hemodynamics to compare the biomechanical forces acting on venous and arterial grafts. Second, we adapt a constrained mixture theory of growth and remodeling for use in vein grafts, and explore potential causes and amelioration of vein graft failure. Throughout, we will discuss recent advances in computational methodology allowing for accurate simulation of coronary flow and physiology, including multi-domain modeling, fluid structure interaction, and uncertainty quantification. role in their format
James Moore received his Bachelor of Mechanical Engineering in 1987, his Master of Science in Mechanical Engineering in 1988 and his Ph.D. in 1991, all from the Georgia Institute of Technology. He was the first PhD student of Dr. David N. Ku, MD PhD, and his thesis work was a collaborative project with vascular surgeon Dr. Christopher Zarins and vascular pathologist Dr. Seymour Glagov. He had postdoctoral training at the Swiss Institute of Technology at Lausanne, 1991 - 1994, where he also helped set up a new biomedical engineering lab. From 1994 - 2003 Dr. Moore served as a professor of Mechanical and Biomedical Engineering, Florida International University. He moved to Texas A&M University in 2003, where he served as the Carolyn S. and Tommie E. Lohman 59 Professor of Biomedical Engineering and Director of Graduate Studies. In Jaunary 2013, he joined Imperial College as the Bagrit and Royal Academy of Engineering Chair in Medical Device Design, and Director of Research for the Department of Bioengineering. Dr. Moore’s research interests include Cardiovascular Biomechanics, Stents, Implantable Devices, Atherosclerosis, and the Lymphatic System. His cardiovascular biomechanics research includes the first finite element models of artery walls to include residual stress, the first studies of the effects of combined flow and stretch on vascular endothelium, early work on the effects of myocardial contraction on coronary artery flow patterns, and the first studies of the effects of stents on both blood flow patterns and artery wall stress. This work resulted in the development of two novel stent designs aimed at optimizing post-implant biomechanics for the prevention of restenosis. His research on lymphatic system biomechanics, initiated in 2004 with Dr. David Zawieja, has provided unprecedented insight into the pumping characteristics of the system and the transport of nitric oxide, antigens, and chemokines in lymphatic tissues.
Modeling Mass Transport in the Lymphatic System
All of the deadliest forms of cancer are transported through the lymphatic system. The metastatic cells that travel through lymphatics eventually set up secondary tumors that are responsible for over 90% of cancer deaths. Despite its importance in cancer spread, little is actually known about transport mechanisms in the lymphatic system. We have quantified various aspects of lymphatic system pumping based on a multiscale modelling approach combined with a unique experimental skill set. In addition to the general insight on lymphatic pumping, we have elucidated the phenomena by which the lymphatic system is able to generate subatmospheric interstitial tissue pressures while still generating positive fluid flow out of those tissues. These findings, in which computational modeling suggested a targeted set of experiments, resolve a decades-old mystery of basic physiology.
Along the pathway back to the blood vessels, all lymph must pass through at least one lymph node. These are highly compartmentalized structures in which leukocytes process antigens and tumor cells. There are also specialized direct communication ports with the blood circulation in which fluid and cells can traverse in either direction. Our studies of flow patterns and mass transport in lymph nodes reveal that under basal conditions only about 10% of the incoming flow passes through the cortex, or the innermost part of the node where the T and B cells reside. Upon antigen recognition, nodes quickly adapt their flow resistance to send more of the flow through the cortex. These flow patterns are also important for shaping chemokine concentration gradients. The long term goals of this research include developing medical devices for treating fluid balance disorders such as lymphedema (a common side effect of breast cancer surgery). More broadly, we aim to contribute to the knowledge base of lymphatic function and dysfunction with the insight provided by computational analysis and carefully coordinated experiments.
Ralph Müller is currently a Professor of Biomechanics at ETH Zurich. His research employs state-of-the-art biomechanical testing and simulation techniques as well as novel bioimaging and visualization strategies for musculoskeletal tissues. His approaches are now often used for precise phenotypic characterization of tissue response in mammalian genetics, mechanobiology as well as tissue engineering and regenerative medicine. A prolific and highly cited author, Dr. Müller has received numerous awards and in 2015 was elected to the Swiss Academy of Engineering Sciences (SATW) and as a Fellow of the European Alliance for Medical and Biological Engineering and Science (EAMBES).
Systems Mechanobiology of Bone Remodeling and Adaptation
Cyclic mechanical loading is perhaps the most important physiological factor regulating bone mass and shape in a way which balances optimal strength with minimal weight. This skeletal adaptation process spans multiple length and time scales. Vibrational forces resulting from physiological exercise at the organ scale are sensed at the cellular scale by osteocytes, which reside inside the bone matrix. Via biochemical pathways, osteocytes orchestrate the local remodeling action of osteoblasts (bone formation) and osteoclasts (bone resorption). Together, these local adaptive remodeling activities sum up to strengthen the skeleton globally at the organ scale. To resolve the underlying mechanisms, it is required to identify and quantify both cause and effect across the different scales. A systems mechanobiology approach to understanding mechanical regulation in biological systems demands the development of high-throughput experimental methods, which are capable of yielding spatiotemporal information at single cell resolution. Given the diverse micro-mechanical environments, which exist in bone, the availability of such data for individual osteocytes would undoubtedly enhance our understanding of their role in bone remodelling and adaptation. As part of this lecture, emerging as well as state-of-the-art experimental and computational techniques will be presented and how these techniques are used in a systems mechanobiology approach to further our understanding of the mechanisms governing load induced bone remodeling and adaptation, i.e. ways will be outlined in which experimental and computational approaches could be coupled, in a quantitative manner to create more reliable multiscale models of the skeleton. Systems mechanobiology will allow coupling of the biochemical information with the mechanical microenvironment of osteocytes.
Yoed Rabin is a Professor of Mechanical Engineering at Carnegie Mellon University. He received his DSc from the Technion – Israel Institute of Technology (1994). Previously, Dr. Rabin held primary academic affiliations with the Division of Surgical Oncology (1994-1996) and the Department of Human Oncology (1996-1998) at the Allegheny University of the Health Sciences—affiliated with Hahnemann University Hospital, and with the Department of Mechanical Engineering at the Technion – Israel Institute of Technology (1997-2000). Dr. Rabin has a broad range of research interests in area of energy modalities in biology and medicine, including cryopreservation, cryosurgery, thermal ablation, photodynamic therapy, and thermal regulation in biological systems.
Computation Tools and Mathematical Modeling in the Service of Cryosurgery
Cryosurgery is the controlled destruction of cancerous tissues by freezing. Cryosurgery of internal organs is most frequently practiced as an image-guided minimally invasive procedure, using an array of cooling probes in the shape of long hypodermic needles. Critical to cryosurgery success is maximizing freezing damage within a confined target region, while minimizing cooling injury to its surrounding tissues. To a large extent, planning of an effective cryosurgical procedure is associated with geometrical matching of a planning isotherm to the shape of the target region. This matching could benefit from a computer-assisted optimization process for the best cryoprobe layout, where the planning isotherm shape is the outcome of a bioheat transfer simulation. Cryosurgery is an art held by the cryosurgeon, which predominantly relies on experience and accepted practices. Unfortunately, it makes little to no use of computation tools and information technology. Suboptimal cryoprobe layout and thermal history may incompletely treat the cancerous tumor, cause collateral damage, elongate the operation time, and lead to post-operation complications, all of which affect the cost and quality of the medical treatment. This presentation reviews orchestrated efforts to provide the cryosurgeon with an array of computation tools for planning, monitoring, and training. These tools include a real-time bioheat transfer simulator, an automated cryosurgery planner, and an ultrasound simulator which integrates freezing artifacts. These tools have been integrated to create the first prototype of a cryosurgery training software package, which has been evaluated by medical residents and by engineering students having no formal education in medicine. Preliminary training results by medical residents display improvement in cryoprobe layout planning from 4.4% in a pretest to 44.4% in a posttest over a course of only 50 minutes. Comparing those results with the performance of engineering students display similar results, supporting the notion that planning of an optimal cryoprobe layout essentially revolves around geometric considerations. While this presentation focuses on cryotherapy, many of the presented computation tools and mathematical models are translational to other multifocal therapies, such as brachytherapy, high frequency ultrasound (HIFU), interstitial photodynamic therapy (I-PDT), radio frequency (RF) ablation, irreversible electroporation (IRE), and thermal ablation using nanoparticles.
Natalia Trayanova is a Professor of Biomedical Engineering at Johns Hopkins University. She is the inaugural Murray B. Sachs Endowed Chair. She directs the Computational Cardiology Laboratory at the Institute for Computational Medicine. In 2013, she received the very prestigious NIH Director’s Pioneer Award for innovative science. Dr. Trayanova was also the inaugural William R. Brody Faculty Scholar at Johns Hopkins University. Dr. Trayanova is a Fellow of Heart Rhythm Society, American Heart Association, Biomedical Engineering Society, and American Institute for Medical and Biological Engineering. The translational research in Dr. Trayanova’s Computational Cardiology Laboratory centers around improvement of the clinical therapies of atrial and ventricular ablation, and the risk stratification for arrhythmias using a personalized approach. The basic science research in Dr. Trayanova lab focuses on understanding the pathological electrophysiological and electromechanical behavior of the heart, with emphasis on the mechanisms for cardiac arrhythmogenesis and pump dysfunction. Dr. Trayanova is the author of over 250 peer-reviewed publications in prestigious journals, among which Science Translational Medicine, Nature Communications, and Journal of Clinical Investigations. She and her lab members are the recipients of numerous research awards. Dr. Trayanova serves as Associate Editor and is on the Editorial Board of several journals.
Sudden cardiac death (SCD) from arrhythmias is a leading cause of mortality. For patients at high SCD risk, prophylactic insertion of implantable cardioverter-defibrillators (ICDs) reduces mortality. Current approaches to identify patients at risk for arrhythmia are, however, of low sensitivity and specificity, which results in a low rate of appropriate ICD therapy. There is a critical clinical need to develop risk metrics that directly assess the interplay between abnormal myocardial structure and electrical instability in the heart, that together predispose to SCD. Here we present a novel non-invasive personalized approach to assess SCD risk in post-infarction patients based on cardiac imaging and computational modeling. We construct personalized 3D computer models of post-infarction hearts from patients’ clinical magnetic resonance imaging data. Each heart model incorporates not only myocardial structure, but electrophysiological functions from the sub-cellular to the organ, allowing for representation of electrical instability. Thus the interplay between abnormal myocardial structure and electrical instability in the heart that predisposes to SCD can be directly assessed. In each heart model, we conduct a virtual multi-site delivery of electrical stimuli from ventricular locations at different distances to remodeled tissue so that the patient’s heart propensity to develop infarct-related ventricular arrhythmias can be comprehensively evaluated. Simulations are conducted for each virtual heart, probing its propensity to develop infarct-related ventricular arrhythmia. We term this non-invasive SCD risk assessment approach VARP, a virtual-heart arrhythmia risk predictor. In a proof-of-concept retrospective study, we assessed the predictive capability of the VARP approach as compared to that of other clinical metrics in a cohort of 41 patients. Statistical analysis demonstrated that a positive VARP test was significantly associated with the primary endpoint, with a four-fold higher arrhythmia risk than patients with negative VARP test. Our results also demonstrate that VARP significantly outperformed clinical metrics in predicting future arrhythmic events.
Yuri Vassilevski is the deputy director of the Institute of Numerical Mathematics, Russian Academy of Science, professor at Moscow State University and Moscow Institute of Physics and Technology, managing editor of Russian Journal of Numerical Analysis and Mathematical Modelling. He is the PI of the Russian Science Foundation Project "Multiscale modeling of blood flow system in personalized medical technologies of cardiology, vascular neurology, oncology'" 2014-2016 (25 researchers). Author and co-author of 70+ journal papers. Research interests: Theory of quasi-optimal meshes, mesh generation and adaptation, iterative methods for PDEs, discretization methods for PDEs, Reservoir Simulation, Computational Fluid Dynamics, Computational Hemodynamics. (dodo.inm.ras.ru/vassilevski/)
Personalized Computation of Fractional Flow Reserve
Atherosclerosis of coronary arteries is the most general disease. Its main medical treatment is the invasive endovascular intervention (stenting or shunting). The contemporary gold standard of indication for the intervention at a particular location of the coronary vasculature is the fractional flow reserve (FFR). FFR is defined as the ratio of the mean pressure distal to a stenosis and the mean pressure in the aorta measured under vasodilating administration. The present methods of FFR measurement are invasive (a non-reusable pressure gauge is delivered to coronary arteries) and expensive. We have developed a non-invasive method of personalized evaluation of the FFR on the basis of a computationally efficient numerical model of blood flow in the network of coronary arteries. The network is reconstructed from CT and angiographic data.