Roger D. Kamm
Depts. of Biological Engineering and Mechanical Engineering, MIT, USA
Modeling Single Cell and Endothelial Monolayer Mechanics during Metastatic Cancer
Despite the critical importance of metastasis in cancer, there is much we have to learn about the mechanisms by which a circulating tumor cell enters into the microcirculation, adheres to or becomes lodged in a small capillary, and transmigrates out of the circulation to enter the tissue and become a metastatic tumor. This presentation will address several of these processes through a combination of microfluidic and computational approaches. The computational models are multi-scale in that they involve the macroscopic (continuum) viscoelastic properties of the different cell types as well as cell-cell interactions of adhesion and monolayer junctional dynamics. We address the different cell receptors or internal structure using both discrete and continuum approaches to gain insight into the complex processes comprising the metastatic cascade. These are coupled with microfluidic studies that recreate the microvascular network in the metastatic organ and enable detailed characterization of adhesion and transmigration events. Together, they provide new understanding of these key phenomena.
Roger D. Kamm is currently the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering at MIT, where he has served on the faculty since 1978. Kamm has long been instrumental in growing research activities at the interface of biology and mechanics, in molecular mechanics, and now in engineered living systems. His research has included both computational and experimental aspects. In computation, he has used a variety of methods including traditional FEM approaches for arterial blood flow and airway wall buckling, molecular dynamics for protein conformational change and peptide self-assembly, agent-based models for angiogenesis, and Brownian dynamics simulations of cytoskeletal rheology. His experimental work now focuses on metastatic cancer, for which his lab has produced a variety of microphysiological models to simulate disease progression and for drug screening. Kamm has fostered biomechanics as Chair of the US National Committee on Biomechanics (2006-2009) and of the World Council on Biomechanics (2006-2010). In 2014, Kamm co- chaired the World Congress of Biomechanics. He is a recipient of the ASME Lissner Medal (2010), the the Huiskes Medal (2015), both for life-long achievements, and is the 2018 recipient of the Nerem Medal for education and mentorship. Kamm was elected to the National Academy of Medicine in 2015.
School of Medicine (Cardiology), Tokai University, Japan
Computer Simulation of Platelet Adhesion and Thrombus Formation
The biological function of platelet cell is relatively simple such as adhering to the site of endothelial damage, making aggregates to increase the size of platelet thrombi, providing procoagulant surface to induce activation of coagulation cascade locally, etc. Circulating platelet cell start to adhere immediately to thrombogenic molecules such as von Willebrand factor at site of endothelial injury. A micrometer scale biological phenomena of platelet adhesion could be constructed from nanometer scale of atomic movement with the use of high-performance computers. The growth of platelet thrombi could also be constructed at least partly as the physical events. Quantitative biological experiments provide necessary data to confirm the validity of computer calculation. Computational and mathematical engineering is now become strong tool to understand the mechanism of complex biological phenomena as the integration of simple physical and chemical events.
Shinya Goto, M.D., Ph.D. is currently a professor of medicine in the Department of Medicine (Cardiology) at the Tokai University School of Medicine, and a Director and Chairman, Research Center of Metabolic Disease, Tokai University Graduate School of Medicine in Japan. Professor Goto gained his qualification in medicine from the Keio University School of Medicine, Tokyo, Japan in 1986, trained as Clinical Cardiologist, then moved to the Department of Experimental Medicine, the Scripps Research Institute, La Jolla, CA, USA, where he completed a post-doctoral fellowship until 1996. Then, moved back to Japan as an instructor, for the Department of Cardiology Tokai University School of Medicine and become full title Professor at 2007. Professor Goto’s basic research achievements include dissecting the mechanism of platelet thrombus formation, especially under a high shear rate of flow condition, developing a method to separately evaluate the mechanism of platelet adhesion on the matrix surface and cohesion, and developing a method for measuring the number of ligand protein binding to platelet induced by shear stress. Professor Goto has published approximately 200 original peer-reviewed research papers, including highly respected journals such as New England Journal of Medicine, Journal of Clinical Investigation, Lancet, JAMA and Circulation. Prof. Goto is now associate Editor for Circulation and section Editor for Thrombosis and Haemostasis.
School of Mathematics and Statistics, University of St Andrews, UK
Mathematical Modelling of Tissue Invasion and Metastasis
Tissue invasion and metastasis (the spread of a primary tumour to secondary locations) have been identified as “hallmarks of cancer” [Hanahan, D., Wienberg, R.A. (2000) The Hallmarks of Cancer. Cell, 100, 57-70]. Indeed, the secondary tumours resulting from the metastatic spread– metastases – are the cause of over 90% of all deaths from cancer. Invasion of the surrounding tissue is a complex, multiscale phenomenon involving many inter-related genetic, intra-cellular, cellular and tissue processes at different spatial and temporal scales. Central to invasion is the ability of cancer cells to alter and degrade an extracellular matrix. Combined with abnormal excessive proliferation and migration which is enabled and enhanced by altered cell–cell and cell–matrix adhesion, the cancerous mass can invade the neighbouring tissue. Upon encountering any nearby blood (or lymph) vessels, the cancer cells then interact with endothelial cells and enter the local blood vessel network (intravasation), are carried throughout the blood system, at some later point in time adhere to a blood vessel and exit the network (extravasation) at a distant secondary location of the host body, thereby allowing for the growth of a secondary tumour, or metastasis. In this talk we first present a mathematical model of cancer invasion, where cell–cell and cell–matrix adhesion is accounted for through non-local interaction terms in a system of partial integro-differential equations. The change of adhesion properties during cancer growth and development is investigated here through time-dependent adhesion characteristics within the cell population as well as those between the cells and the components of the extracellular matrix. We then present a novel model of metastatic spread, using a hybrid (discrete-continuum) form of the invasion model, where, in addition to the growth and invasion of a primary tumour (e.g. breast tissue), we consider explicitly different spatial domains representing the secondary locations of metastatic spread (e.g. lung, bone, brain).
Professor Chaplain is the Gregory Chair of Applied Mathematics at the University of St Andrews, Scotland. He received a PhD in Mathematical Biology from the University of Dundee (Scotland, UK) in 1990 before taking up a lectureship in Bath University (UK). Returning to Dundee in 1996, he subsequently was Ivory Chair of Applied Mathematics there before moving to his current position in St Andrews in 2015. He was awarded a Whitehead Prize by The London Mathematical Society, July 2000 for his work in applied mathematics and mathematical biology and was elected a Fellow of The Royal Society of Edinburgh, March 2003. In 2008, he was awarded a prestigious European Research Council Advanced Investigator (ERC AdG) grant, “M5CGS: From Mutations to Metastases: Multiscale Mathematical Modelling of Cancer Growth and Spread”, which funded a 5 year programme of research, 2009-2014 on mathematical oncology. He was President of the Society of Mathematical Biology, 2005-2007, and was elected an inaugural Fellow of the Society for Mathematical Biology, July 2017. He is currently co-Chief Editor of the Journal of Theoretical Biology and Subject Editor, Mathematics, for the Royal Society Open Science (RSOS). Professor Chaplain’s main area of current research is “mathematical oncology”. Specifically, multiscale mathematical modelling of cancer growth and treatment where he has developed a variety of original mathematical models for all the main phases of solid tumour growth - avascular solid tumours (multicellular spheroids), the immune system response to cancer, tumour-induced angiogenesis, vascular tumour growth, invasion and metastasis. Recently he has developed novel multiscale models of chemotherapy and radiotherapy treatment of cancer and spatio-temporal models of intracellular signalling pathways (gene regulatory networks, transcription factors).
Department of Mechanical Engineering, John Hopkins University, USA
Coupled Multiphysics Models of Cardiac Hemodynamics: From Fundamental Insights to Clinical Translation
The mammalian heart has been sculpted by millions of years of evolution into a flow pump par excellence. During the typical lifetime of a human, the heart will beat over three billion times and pump enough blood to fill over 60 Olympic-sized swimming pools. Each of these billions of cardiac cycles is itself a manifestation of a complex and elegant interplay between several distinct physical domains including electrophysiology and mechanics of the cardiac muscles, hemodynamics, and flow-induced movement of the cardiac valves. Another multiphysics interaction that is key to hemostasis involves hemodynamics and blood biochemistry. The clotting cascade, which is a natural response to injury, is initiated by a sequence of biochemical and biomolecular reactions that are strongly modulated by local flow conditions. In this regard, how the chambers and valves of a healthy heart manage to avoid thrombosis, remains an open question. The presence of heart conditions such as myocadial infarction (MI), cardiomyopathies, valve anomalies and atrial fibrillations, disturb the hemostatic balance and can lead to thrombosis with devastating sequalae such as stroke and MI. Computational models for thrombogenesis in the cardiac system have the potential to provide useful insights into this important phenomenon. In the current talk, I will describe high-fidelity chemo-fluidic modeling of thrombogenesis in the left heart and demonstrate how fundamental insights from these studies have been translated into clinically relevant metrics. Application of these models to thrombogenesis in transcatheter aortic valves will also be described.
Rajat Mittal is Professor of Mechanical Engineering at the Johns Hopkins University (JHU) with a secondary appointment in the School of Medicine. He received the B. Tech. degree in Aeronautical Engineering from the Indian Institute of Technology at Kanpur in 1989, the M.S. degree in Aerospace Engineering from the University of Florida, Gainesville in 1991 and the Ph.D. degree in Applied Mechanics from The University of Illinois at Urbana-Champaign, in 1995. He joined the Center for Turbulence Research Stanford University, Stanford, CA, as a postdoctoral fellow in 1995, where he conducted research on large-eddy simulation and bluff-body wakes. Subsequently, he joined the Department of Mechanical Engineering, University of Florida where he taught from 1996 to 2001. Before coming to JHU he taught at George Washington University from 2001 to 2009 where he also founded the GW Center for Biomimetics and Bioinspired Engineering. His research interests include computational fluid dynamics, vortex-dominated flows, immersed boundary methods, bioinspired and biomedical engineering, and flow control. He is the recipient of the 1996 Francois Frenkiel Award from the Division of Fluid Dynamics of the American Physical Society, and the 2006 Lewis Moody Award from the American Society of Mechanical Engineers. He is a Fellow of American Society of Mechanical Engineers and the American Physical Society, and an Associate Fellow of the American Institute of Aeronautics and Astronautics. He is associate editor of the Journal of Computational Physics, Frontiers of Computational Physiology and Medicine and Journal of Experimental Biology.
Biomechanics Research Unit, GIGA In Silico Medicine, University of Liège, Belgium-Biomechanics Section, KU Leuven, Belgium
Computational Tissue Engineering: from living implants to virtual patients
The growing field of in silico medicine is focusing mostly on the two largest classes of medicinal products: medical devices and pharmaceuticals. However, also for advanced therapeutic medicinal products, which essentially combine medical devices with a viable cell or tissue part, the in silico approach has considerable benefits. In this talk an overview will be provided of the budding field of in silico regenerative medicine in general and computational bone tissue engineering (TE) in particular. As basic science advances, one of the major challenges in TE is the translation of the increasing biological knowledge on complex cell and tissue behavior into a predictive and robust engineering process. Mastering this complexity is an essential step towards clinical applications of TE. Computational modeling allows to study the biological complexity in a more integrative and quantitative way. Specifically, computational tools can help in quantifying and optimizing the TE product and process but also in assessing the influence of the in vivo environment on the behavior of the TE product after implantation. Examples will be shown to demonstrate how computational modeling can contribute in all aspects of the TE product development cycle: cells, carriers, culture conditions and clinics. Depending on the specific question that needs to be answered the optimal model systems can vary from single scale to multiscale. Furthermore, depending on the available information, model systems can be purely data-driven or more hypothesis-driven in nature. The talk aims to make the case for in silico models receiving proper recognition, besides the in vitro and in vivo work in the TE field.
Liesbet Geris is Collen-Francqui Research Professor in Biomechanics and Computational Tissue Engineering at the universities of Liège and Leuven in Belgium. Her research focusses on the multi-scale and multi-physics modeling of biological processes. Together with her team and their clinical and industrial collaborators, she uses these models to investigate the etiology of non-healing fractures, to design in silico potential cell-based treatment strategies and to optimize manufacturing processes of these tissue engineering constructs. Liesbet is scientific coordinator of the Prometheus platform for Skeletal Tissue Engineering (50+ researchers). She has edited several books on computational modeling and tissue engineering. She has received 2 prestigious ERC grants (starting in 2011 and consolidator in 2017) to finance her research and has received a number of young investigator and research awards. She is a former member and chair of the Young Academy of Belgium (Flanders) and member of the strategic alliance committee of the Tissue Engineering and Regenerative Medicine Society. She is the current executive director of the Virtual Physiological Human Institute and in that capacity she advocates the use of in silico modeling in healthcare through liaising with the clinical community, the European Commission and Parliament, regulatory agencies (EMA, FDA) and various other stakeholders. Besides her research work, she is often invited to give public lectures on the challenges of interdisciplinary in research, women in academia and digital healthcare.
Faculdade de Engenharia da Universidade do Porto, Portugal
Computational Image Analysis in Biomedicine: Methods and Applications
The computational analysis of images, which has become a paramount research topic, is very challenging as it usually comprises complex tasks like as of segmentation, i.e. the detection, of imaged structures, matching and registration, i.e. alignment, of structures, tracking of structures in images, deformation estimation between structures and 3D reconstruction from images. For example, to analyze the behavior of organs from medical image sequences, first the input images should be segmented, then suitable features of the organs under analysis should be extracted and tracked along the sequences and finally, the tracked behavior should be analyzed. Despite the inherent difficulties, computational methods of image analysis have been more and more used in a wide range of important applications of our society, exceptionally in Biomedicine. In this talk, computational methods of image analysis that we have developed in order to analyze structures in biomedical images will be introduced; particularly, those developed for image segmentation, matching, registration, tracking and 3D shape reconstruction. Furthermore, their use in several biomedical applications will be presented and discussed.
João Manuel R. S. Tavares graduated in Mechanical Engineering at the Universidade do Porto, Portugal in 1992. He also earned his M.Sc. degree and Ph.D. degree in Electrical and Computer Engineering from the Universidade do Porto in 1995 and 2001, and attained his Habilitation in Mechanical Engineering in 2015. He is a senior researcher at the Instituto de Ciência e Inovação em Engenharia Mecânica e Engenharia Industrial (INEGI) and Associate Professor at the Department of Mechanical Engineering (DEMec) of the Faculdade de Engenharia da Universidade do Porto (FEUP). João Tavares is co-editor of more than 40 books, co-author of more than 35 book chapters, 600 articles in international and national journals and conferences, and 3 international and 2 national patents. He has been a committee member of several international and national journals and conferences, is co-founder and co-editor of the book series “Lecture Notes in Computational Vision and Biomechanics” published by Springer, founder and Editor-in-Chief of the journal “Computer Methods in Biomechanics and Biomedical Engineering: Imaging & Visualization” published by Taylor & Francis, and co-founder and co-chair of the international conference series: CompIMAGE, ECCOMAS VipIMAGE, ICCEBS and BioDental. Additionally, he has been (co-)supervisor of several MSc and PhD thesis and supervisor of several post-doc projects, and has participated in many scientific projects both as researcher and as scientific coordinator. His main research areas include computational vision, medical imaging, computational mechanics, scientific visualization, human-computer interaction and new product development.
INRIA Centre de Paris, Paris, France
Computational investigations of liver multi-level hemodynamics and function: towards a better understanding of surgery outcomes and disease progression
Liver is a key organ of the body, which function might be severely impaired due to disease progression or partial resection (pHx). Both trigger hemodynamics changes, which causes and consequences are still matter of debate. The precise link between liver architecture, perfusion and function remains to be fully elucidated. First, computational simulations have qualitatively and quantitatively characterized the link between architecture and hemodynamics in the context of pHx, based on multi-level mathematical models of whole-body and hepatic hemodynamics. The hepatic model takes into account a lobe-specific perfusion, with both arterial and portal venous inflows. A dedicated numerical scheme of 1D hemodynamics equations was necessary to handle vessel collapse, which happens during surgery. Second, we characterize such link at different stages of cirrhosis development. For both different mechanisms impacting hemodynamics were studied (organ vascular dilation, liver micro-circulation changes, …) : systemic vascular responses seem particularly important to take into account to understand liver hemodynamics changes due to pHx, early days of regeneration and disease progression. The third piece of the puzzle is function. ICG is an injectable compound, which is a marker of liver function. Its fluorescence dynamics can be interpreted via a dedicated pharmacokinetics model to provide perfusion and function information. Such dynamic signal is a promising way to characterize the liver state.
Irene Vignon-Clementel, PhD is Directeur de recherche (Prof. equiv.) at Inria, Mathematics & Informatics. She holds a ‘habilitation’ degree in Applied Mathematics (UPMC), a PhD in mechanical engineering (Stanford University), an MS in Applied Mathematics (DAMTP, Cambridge U.) and a diplôme d’ingénieur from Ecole Centrale Paris (France). Her research focuses on modeling and numerical simulations of physiological flows to better understand certain pathophysiologies and their treatment (surgical planning, medical device design), especially around blood circulation and breathing. This requires developing models of different complexities, coupling them, that their numerical implementation is robust, and that their parameters are based on medical or experimental data specific to a subject. Applications include congenital cardiac diseases, liver (surgery, remodeling), emphysema and asthma, and more recently the interpretation of non-invasive dynamic imaging (MRI, fluorescence, etc.). She has written over 70 publications and several book chapters, is member of several conference committees and of the IJNMBE editorial board. She received the top recipient award of the western states American Heart Association fellowship (2004-2006), the student award at the World Congress of Computational Mechanics by the USACM and the USACM Executive Committee (2006), and Inria excellence award (2012 and 2016). Dr. Vignon-Clementel has been working with companies and clinicians as a PI in a number of national and international grants (such as a Leducq transatlantic network of excellence), and actively promoting the applied mathematics/bioengineering and medicine interface through co-supervision of MD-PhDs, joint research projects, conference organization and interface articles with clinicians.
Department of Mechanical Engineering and Materials Science, University of Pittsburgh, USA
Identifying physical causes of failure in brain aneurysms
Rupture of cerebral aneurysms is a central cause of subarachnoid hemorrhage, a devastating type of stroke with high mortality and disability rates. However, treatments for unruptured aneurysms have clinical risks that can exceed the risk of rupture. Hence there is a great need to develop reliable methods for assessing rupture risk. Presently, most efforts to improve risk assessment are directed at identifying correlations between outcome (rupture versus non rupture) and patient clinical characteristics, aneurysm geometry, and flow inside the aneurysm. Our group has identified a substantial vulnerable populationwithin the unruptured group with a large heterogeneity in collagen fiber architecture, cellular content and calcifications, These findings motivate our present studies to identify the actual physical causes for wall vulnerability. In this presentation, we discuss recent results in this area using data driven computational simulations to determine conditions that i) enable robust walls, ii) enable sufficient conditions for remodeling and stabilization following subfailure damage or iii) push subfailure damage to catastrophic failure. These studies are driven by data obtained from human aneurysm tissue, analyzed using new bioimaging methodologies that enable mechanical testing simultaneous with imaging of collagen fibers and calcification. New tools for mapping the heterogeneous experimental data for the wallto the 3D reconstructed vascular model make it possible to evaluate the associations between critical aspects of aneurysm wall structure and both hemodynamic and intramural stress.
Anne M. Robertson is a William Kepler Whiteford Endowed Professorship of Mechanical Engineering and Materials Science and Professor of Bioengineering at the University of Pittsburgh. A central theme in her research is the relationship between soft tissue structure and mechanical function in health and disease for soft tissues such as cerebral arteries, cerebral aneurysms, tissue engineered blood vessels and the bladder wall. Her group employs data driven theoretical and computational models of vascular tissue that leverage techniques they developed for simultaneous imaging and mechanical testing of intact tissue samples. Dr. Robertson earned her PhD in Mechanical Engineering from the University of California Berkeley where she was also a President’s Postdoctoral Fellow in the Department of Chemical Engineering. She joined the University of Pittsburgh in 1995, where she was the first tenure track female faculty member in Mechanical Engineering. Dr. Robertson’s research is heavily supported by the National Institutes of Health where she is a standing member of the Neuroscience and Ophthalmic Imaging Technologies (NOIT) Study Section.
System Physiology, Department of Biomedical Engineering, Graduate School of Medicine, The University of Tokyo, Japan
Endothelial cell mechanosensing and its role in vascular physiology
Vascular endothelial cells (ECs) play critical roles in regulating a variety of vascular functions, including maintenance of the vascular tone, blood coagulation and fibrinolysis, and provision of selective permeability to proteins. It has recently become apparent that ECs show alterations in their morphology, functions and gene expression profile in response to exposure to hemodynamic forces, namely, shear stress and stretch. These responses also play important roles in maintaining normal circulatory system functions and homeostasis, whereas their impairment leads to various vascular diseases, including hypertension, aneurysm and atherosclerosis. The mechanisms underlying the mechanotransduction, however, are not yet clearly understood. Plasma membranes of the ECs have recently been shown to respond differently to shear stress and stretch, by rapidly changing their lipid order, membrane fluidity, and cholesterol content. Artificial lipid-bilayer membranes also show similar changes of the lipid order in response to exposure to shear stress and stretch, indicating that these are physical phenomena rather than biological reactions. Such physical changes then activate the membrane receptors and cell responses specific to each type of force.These findings suggest that the plasma membranes of ECs act as mechanosensors, and in response to mechanical forces, they show alterations of their physical properties, with modification of the conformation and functions of the membrane proteins, which then trigger activation of the downstream signaling pathways.
Kimiko Yamamoto is an Associate Professor of the Graduate School of Medicine at the University of Tokyo. She received her BEng and MEng in Applied Chemistry from Waseda University (1987 and 1989), PhD in Polymer Chemistry from Yamagata University (1996), and MD from The University of Tokyo (2000). In 2000, she started her research career as an Assistant Professor of the Laboratory of System Physiology at the University of Tokyo, and from 2006 to 2010, she also held the additional post of researcher of Precursory Research for Embryonic Science and Technology in the Japan Science and Technology Agency. She has also been concurrently holding charge as the project leader of Advanced Research and Development Programs for Medical Innovation in the Japan Agency for Medical Research and Development (AMED-CREST) from 2015. Her area of expertise is vascular mechanobiology and mechanotransduction in vascular endothelial cells in response to blood flow.