Advances in Heart Valve Biomechanics

Michael S. Sacks • Jun LiaoEditors

Advances in Heart ValveBiomechanicsValvular Physiology, Mechanobiology,and Bioengineering

EditorsMichael S. SacksThe Oden Institute and theDepartment of Biomedical EngineeringThe University of Texas at AustinAustin, TX, USA

Jun LiaoThe Department of BioengineeringThe University of Texas at ArlingtonArlington, TX, USA

ISBN 978-3-030-01991-4 ISBN 978-3-030-01993-8 (eBook)https://doi.org/10.1007/978-3-030-01993-8

© Springer Nature Switzerland AG 2018This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or partof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformation storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in thispublication does not imply, even in the absence of a specific statement, that such names are exemptfrom the relevant protective laws and regulations and therefore free for general use.The publisher, the authors, and the editors are safe to assume that the advice and information in this bookare believed to be true and accurate at the date of publication. Neither the publisher nor the authors or theeditors give a warranty, express or implied, with respect to the material contained herein or for any errorsor omissions that may have been made. The publisher remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.

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Preface

Heart valves (HVs) are cardiac structures that ensure unidirectional blood flowduring the cardiac cycle. However, this description does not adequately describetheir biomechanical function, which is multimodal, and their loading cycle isrepeated every second. While they are primarily passive structures driven by forcesexerted by the surrounding blood and heart, this description also does not adequatelydescribe their elegant and complex biomechanical performance. The semilunarvalves (pulmonary (PV) and aortic (AV)) prevent retrograde flow back into theventricles during diastole, while the atrioventricular valves (tricuspid (TV) andmitral (MV)) prohibit reverse flow from the ventricle to the atrium during systole.They must replicate this feat with each heartbeat; over a single lifetime, HVs willopen and close at least 3 � 109 times.

As in many physiological systems, one can approach heart valve biomechanicsfrom a multi-length scale approach, since mechanical stimuli occur and have bio-logical impact at the organ, tissue, and cellular scales. For example, valve interstitialcells (VICs) are known to respond to local tissue stress by altering cellular stiffnessthrough valvular remodeling and valvular pathologies. On the other hand, the factthat AV diseases preferentially occur in the aortic side (fibrosa) of the valvularleaflets, where they are exposed to unstable flow conditions, highlights the impor-tance of shear in AV biology and pathobiology. Another important point is thatvalvular extracellular matrix (ECM) is composed of dense network of collagen,elastin, and GAGs and is thus functionally and mechanically very different fromother cardiovascular structures (e.g., blood vessels, myocardium). In fact, valvularECM is structurally and behaves mechanically much more like the dense planarconnective tissues of the musculoskeletal system. They are unique, however, in thatthey must function within a blood-contacting environment and are thus coated withendothelial cell monolayer. Moreover, there is evidence that endothelium/interstitialcell communication may play an important role in valvular ECM homeostasis. Yet,despite its clinical importance, the unique and demanding valvular biological/bio-mechanical environment is relatively unexplored, with most research focusing onvalvular prosthetic design and development. In addition to deepening our

v

understanding of physiological and biological function, simulation and imagingtechnologies have reached a level of sophistication that major contributions tomedicine and pathophysiology are now possible. Heart valves represent one of themost demanding areas in cardiovascular simulation due to issues such as complex3D surface geometry, rapid motion, hemodynamic force levels, complex tissuemechanical behavior, and strong mechanical interactions with the surroundingcardiac and vascular structures. This book focuses on heart valve functional biome-chanics. Specifically, we refer to the unique aspects of valvular function, valvularmechanobiology, mechanical behavior at various hierarchical levels, tissueremodeling in repair/regeneration, hemodynamics, assessment technologies, andsimulation technologies that achieve this remarkable feat.

The editors would like to thank all the chapter contributors, whose hard work,invaluable support, and patience made this book possible.

Austin, TX, USA Michael S. SacksArlington, TX, USA Jun Liao

vi Preface

Abbreviations

5-HT/5-HTR Serotonin/serotonin receptor SALSAC Against curvatureAFM Atomic force microscopyALP Alkaline phosphataseAPC Adenomatous polyposis coliAV Aortic valveAV AtrioventricularAVC Atrioventricular canalaVIC Activated valve interstitial cellAVIC Aortic valve interstitial cellBAV Bicuspid aortic valveBMP Bone morphogenic proteinBMP/BMPR Bone morphogenic protein/bone morphogenic protein receptorCAVD Calcific aortic valve diseaseCFA Collagen fiber architectureCHD Congenital heart diseaseCRGDS Adhesive peptide sequence (Cys-Arg-Gly-asp-Ser)dpc Days post conceptionE Embryonic dayECM Extracellular matrixEeff Effective stiffnessEGF Epidermal growth factorEMT Endothelial-to-mesenchymal transformationEndoMT Endothelial-mesenchymal transformationERK Extracellular signal-regulated kinaseET-1 Endothelin 1FBN1 Fibrillin-1FE Finite elementFGF Fibroblast growth factorFIB-SEM Focused ion beam—scanning electron microscope

vii

HSP47 Heat shock protein 47IP3 Inositol triphosphateLPS LipopolysaccharideLRP Low-density lipoprotein receptor-related proteinMA Micropipette aspirationMEK Mitogen-activated protein kinaseMMP Matrix metalloproteinaseMV Mitral valveMVAL Mitral valve anterior leafletMVIC Mitral valve interstitial cellMVP Mitral valve prolapseNAR Nuclear Apsect ratioNFAT Nuclear factor of activated T-cellsNFATc1 Nuclear factor of activated T-cellsNF-κB Nuclear factor kappa-light-chain-enhancer of activated B cellsNICD Notch intracellular domainNO Nitric oxideNOI Normalized orientation indexNOS3 Nitric oxide synthase 3OFT Outflow tractpAVIC Porcine aortic valve interstitial cellPDGFR Platelet derived growth factor receptorPECAM Platelet/endothelial cell adhesion moleculePEG Poly (ethylene glycol)PKC Protein kinase CPLC Phospholipase CPV Pulmonary valvePVIC Pulmonary valve interstitial cellqVIC Quiescent valve interstitial cellRNA Ribonucleic acidRVE Representative volume elementSALS Small angle light scatteringSAXS Small angle X-ray scatteringShp2 Src homology phosphatase 2SL SemilunarSMA Smooth muscle actinSVK Saint-Venant KirchhoffTEHV Tissue engineered heart valveTEM Transmission Electron microscopyTGF-β Transforming growth factor-βTGF-β1 Transforming growth factor beta 1TIMPs Tissue inhibitor of metalloproteinasesTLR4 Toll-like receptor 4TV Tricuspid valve

viii Abbreviations

TVIC Tricuspid valve interstitial cellTVP Transvalvular pressureUS United StatesVEC Valve endothelial cellVEC Valve interstitial cellVE-cadherin Vascular endothelial-cadherinVEGF Vascular endothelial growth factorVEGF/VEGFR Vascular endothelial growth factor/vascular endothelial growth

factor receptorVIC Valve endothelial cellVIC Valve interstitial cellWC With curvatureWnt Wingless-related integration siteα-SMA α-Smooth muscle actin

Abbreviations ix

Contents

Part I Native Heart Valve Function

Biological Mechanics of the Heart Valve Interstitial Cell . . . . . . . . . . . . 3Alex Khang, Rachel M. Buchanan, Salma Ayoub, Bruno V. Rego,Chung-Hao Lee, and Michael S. Sacks1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Major Questions and Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Advances in Investigating VIC Mechanobiology . . . . . . . . . . . . . . . . . 6

3.1 Isolated Cell Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.2 In Situ Tissue-Level Evaluation of VIC Contraction

Behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143.3 Interlayer Micromechanics of the AV Leaflet . . . . . . . . . . . . . . 163.4 Down-Scale Model of the VIC Within ECM . . . . . . . . . . . . . . . 183.5 Use of 3D Hydrogel for Mechanobiological Studies . . . . . . . . . 213.6 Uniaxial Planar Stretch Bioreactors . . . . . . . . . . . . . . . . . . . . . 233.7 Model-Driven Experimental Design . . . . . . . . . . . . . . . . . . . . . 28

4 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Endothelial Mechanotransduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37James N. Warnock1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

1.1 Mechanical Environment of the Aortic Valve Endothelium . . . . 381.2 Mechanisms of Mechanosensation . . . . . . . . . . . . . . . . . . . . . . 391.3 Pathological Implications of Mechanotransduction . . . . . . . . . . 401.4 In Vitro and Ex Vivo Methods for Mechanotransduction

Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Shear Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

2.1 Aortic Valve Endothelial Cells Under PhysiologicFlow Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

2.2 Role of Shear Stress in Aortic Valve Pathology . . . . . . . . . . . . . 44

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3 Cyclic Strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463.1 Endothelial Layer Integrity Under Elevated Cyclic Strain . . . . . . 473.2 Pro-inflammatory Response of Endothelial Cells

to Cyclic Strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

The Role of Proteoglycans and Glycosaminoglycansin Heart Valve Biomechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Varun K. Krishnamurthy and K. Jane Grande-Allen1 Introduction and Chapter Overview . . . . . . . . . . . . . . . . . . . . . . . . . . 592 Proteoglycans and Glycosaminoglycans in Valves: Composition,

Distribution, and Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 Glycosaminoglycan Stability Affects Tissue Biomechanics in

Bioprostheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624 Theoretical and Experimental Determination of Glycosaminoglycan

Biomechanics in Native Valve Tissue . . . . . . . . . . . . . . . . . . . . . . . . . 645 Bioreactor Studies to Evaluate Valve Tissue Biomechanics and ECM

Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666 Correlating Glycosaminoglycan Levels with Tissue Biomechanics

(Normal vs. Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697 Effect of Cell Stimulation on Proteoglycan and Glycosaminoglycan

Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

On the Unique Functional Elasticity and Collagen FiberKinematics of Heart Valve Leaflets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Jun Liao and Michael S. Sacks1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

1.1 Function of Heart Valve Leaflets . . . . . . . . . . . . . . . . . . . . . . . 821.2 Composition and Ultrastructure and Heart Valve Leaflets . . . . . . 821.3 Valvular Diseases and Viscoelastic Properties

of Leaflet Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842 Conventional Concepts on Viscoelasticity of Soft Tissues . . . . . . . . . . 853 The Unique Viscoelastic Properties of Heart Valve Tissues:

Normal Stress Relaxation but Negligible Creep . . . . . . . . . . . . . . . . . . 874 Collagen Fibril Kinematics in Valve Leaflet Stretch,

Stress Relaxation, and Creep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894.1 Hierarchical Structure of Collagen in Heart Valve Leaflets . . . . . 894.2 SAXS, Biaxial Device for SAXS Beamline,

and Experimental Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . 924.3 Collagen Fibril Kinematics in MV Leaflets . . . . . . . . . . . . . . . . 96

5 Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

xii Contents

Tricuspid Valve Biomechanics: A Brief Review . . . . . . . . . . . . . . . . . . . 105William D. Meador, Mrudang Mathur, and Manuel K. Rausch1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1052 Tricuspid Leaflets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

2.1 Morphology and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . 1062.2 In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062.3 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072.4 In Silico Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

3 Tricuspid Annulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083.1 Morphology and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . 1083.2 In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093.3 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093.4 In Silico Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

4 Tricuspid Chordae Tendineae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104.1 Morphology and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . 1104.2 In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114.3 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114.4 In Silico Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

5 Most Recent Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1126 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

Measurement Technologies for Heart Valve Function . . . . . . . . . . . . . . 115Morten O. Jensen, Andrew W. Siefert, Ikechukwu Okafor,and Ajit P. Yoganathan1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1162 Experimental Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

2.1 Aortic and Pulmonary Pulse Duplicators . . . . . . . . . . . . . . . . . . 1162.2 Right and Left Heart Bench Models . . . . . . . . . . . . . . . . . . . . . 1162.3 Steady Backpressure Model . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192.4 Restored Contractility Model . . . . . . . . . . . . . . . . . . . . . . . . . . 1192.5 Large Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1192.6 Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

3 Assessing Valve Geometry, Dynamics, and Tissue Deformation . . . . . . 1203.1 Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203.2 Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 1213.3 Cardiac Computed Tomography and Micro Computed

Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233.4 Sonomicrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1233.5 Biplane Videofluoroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243.6 Stereophotogrammetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243.7 High-Speed Photography and Videography . . . . . . . . . . . . . . . . 1253.8 Trigonometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Contents xiii

4 Assessing Flow Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264.1 Bulk Flow Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1264.2 Doppler Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . 1284.3 Detailed Flow Field Characterization . . . . . . . . . . . . . . . . . . . . 130

5 Technologies for Quantifying Atrioventricular Valveand Repair Device Mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1345.1 Assessing Subvalvular Mechanics of the Atrioventricular

Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1355.2 Assessing Annular-Based Mechanics . . . . . . . . . . . . . . . . . . . . 1375.3 Heart Valve Force Transducers with External Anchoring . . . . . . 140

6 Additional Modalities for Assessing Prosthetic Heart Valves . . . . . . . . 1417 General Discussion and Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . 141References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Part II Heart Valve Disease and Treatment

Calcific Aortic Valve Disease: Pathobiology, Basic Mechanisms,and Clinical Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Payal Vyas, Joshua D. Hutcheson, and Elena Aikawa1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1532 Normal Aortic Valve Physiology and Function . . . . . . . . . . . . . . . . . . 155

2.1 Anatomy of Normal Aortic Valve . . . . . . . . . . . . . . . . . . . . . . 1552.2 Function of Normal Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . 1572.3 Aortic Valve Microstructure . . . . . . . . . . . . . . . . . . . . . . . . . . 1572.4 Aortic Valve Cell Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

3 Calcific Aortic Valve Disease Pathobiology . . . . . . . . . . . . . . . . . . . . 1614 Mechanisms of Calcific Aortic Valve Disease . . . . . . . . . . . . . . . . . . . 163

4.1 Cellular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1634.2 Molecular Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

5 Diagnostic and Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . . . . 1695.1 Aortic Valve Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1695.2 Potential Drug Targets and Clinical Trials . . . . . . . . . . . . . . . . . 1705.3 Clinical Imaging and Identification . . . . . . . . . . . . . . . . . . . . . . 171

6 Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Remodelling Potential of the Mitral Heart Valve Leaflet . . . . . . . . . . . . 181Bruno V. Rego, Sarah M. Wells, Chung-Hao Lee,and Michael S. Sacks1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

2.1 Mechanical Database and Processing . . . . . . . . . . . . . . . . . . . . 1842.2 Accounting for Changes in Leaflet Dimensions . . . . . . . . . . . . . 1852.3 Constitutive Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

xiv Contents

2.4 Parameter Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1892.5 Interpretation of Parameter Values . . . . . . . . . . . . . . . . . . . . . . 1912.6 MVIC Geometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1933.1 Leaflet Dimensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1933.2 Collagen and Elastin Fractions . . . . . . . . . . . . . . . . . . . . . . . . . 1943.3 Elastin Moduli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1953.4 Collagen Fibre Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . 1953.5 Structural Effects of Growth and Remodelling . . . . . . . . . . . . . 1963.6 Quantitative MVIC Geometry . . . . . . . . . . . . . . . . . . . . . . . . . 197

4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1994.1 General Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1994.2 Delayed Restoration of Homeostasis . . . . . . . . . . . . . . . . . . . . . 2014.3 Generalization and Special Considerations . . . . . . . . . . . . . . . . 2024.4 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2034.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

Molecular and Cellular Developments in Heart ValveDevelopment and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207Lindsey J. Anstine, Anthony S. Baker, and Joy Lincoln1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2082 Structure-Function Relationships of Mature Heart Valves . . . . . . . . . . 208

2.1 Extracellular Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2092.2 Valve Cell Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

3 Heart Valve Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2113.1 Embryonic Precursor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 2113.2 Molecular Regulators of Endocardial Cushion Formation . . . . . . 2113.3 The Contribution of Non-endothelial Cell Lineages to the

Developing Heart Valve Structures . . . . . . . . . . . . . . . . . . . . . . 2173.4 Molecular Regulation of Embryonic Heart

Valve Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2184 Heart Valve Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

4.1 Bicuspid Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2204.2 Mitral Valve Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2224.3 Pathobiology of Valve Interstitial Cells . . . . . . . . . . . . . . . . . . . 2254.4 Pathobiology of Valve Endothelial Cells . . . . . . . . . . . . . . . . . . 226

5 Current Treatments and Clinical Perspectives . . . . . . . . . . . . . . . . . . . 229References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

Mechanical Mediation of Signaling Pathways in Heart ValveDevelopment and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Ishita Tandon, Ngoc Thien Lam, and Kartik Balachandran1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2412 The Mechanical Environment of the Developing and Adult

Heart Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

Contents xv

2.1 The Developing Heart Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . 2432.2 The Mature Heart Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2442.3 Signaling Pathways Involved During Valve

Morphogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2462.4 Signaling Pathways During Valve Disease . . . . . . . . . . . . . . . . . 251

3 Mechanobiology of Valvulogenesis and Disease . . . . . . . . . . . . . . . . . 2544 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Tissue Engineered Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263Jay M. Reimer and Robert T. Tranquillo1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

1.1 Existing Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2652 Tissue Engineered Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

2.1 Cell Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2672.2 Scaffold Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2692.3 Stimulation Paradigms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

3 Valve Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2734 In Vitro Functional Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2755 In Vivo Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

5.1 Animal Models for TEHVs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2765.2 Preclinical Testing Results with TEHVs . . . . . . . . . . . . . . . . . . . 277

6 Remaining Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2807 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Decellularization in Heart Valve Tissue Engineering . . . . . . . . . . . . . . . 289Katherine M. Copeland, Bo Wang, Xiaodan Shi, Dan T. Simionescu,Yi Hong, Pietro Bajona, Michael S. Sacks, and Jun Liao1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2902 Fundamentals of Tissue-Engineered Heart Valves . . . . . . . . . . . . . . . . . 2923 Components and Ultrastructure of Aortic Valves . . . . . . . . . . . . . . . . . . 293

3.1 Structure of Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2933.2 Cellular Components of Aortic Valve . . . . . . . . . . . . . . . . . . . . . . 293

4 Decellularization and Applications in TEHV . . . . . . . . . . . . . . . . . . . . . 2944.1 Concept of Decellularization and Acellular HV Scaffolds . . . . . . . 2944.2 Decellularization Techniques Available for HV

Decellularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2955 Effects of Decellularization Protocols on Leaflet Biomechanics

and a Study on Fatigue Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . 2966 Cell Sources for TEHV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3027 Bioreactors for TEHV Development . . . . . . . . . . . . . . . . . . . . . . . . . . . 3048 TEHV via Decellularization Approach: Large Animal Studies

and Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

xvi Contents

9 Current Challenges in TEHV via Decellularization . . . . . . . . . . . . . . . 30710 Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

Novel Bioreactors for Mechanistic Studies of EngineeredHeart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319Kristin Comella and Sharan Ramaswamy1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3202 Bioreactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

2.1 Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3202.2 Mechanical Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

3 Scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3253.1 Synthetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3263.2 Natural . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

4 Cell Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3274.1 Mesenchymal Stem Cells (MSCs) . . . . . . . . . . . . . . . . . . . . . . . 3274.2 Fibroblasts/Smooth Muscle Cells/Valvular Interstitial Cells . . . . . 3284.3 Endothelial Progenitor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 3284.4 Embryonic/IPS/Amniotic/Cord . . . . . . . . . . . . . . . . . . . . . . . . . 328

5 Preclinical/Clinic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3306 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

Bioprosthetic Heart Valves: From a Biomaterials Perspective . . . . . . . . 337Naren Vyavahare and Hobey Tam1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3382 Growing the Heart Valve Market Space . . . . . . . . . . . . . . . . . . . . . . . 3383 Current Indications for Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3394 Current Treatments for Valvular Disease . . . . . . . . . . . . . . . . . . . . . . 3415 Current Gold Standards in Heart Valve Replacements . . . . . . . . . . . . . 3446 Mechanical Heart Valves (MHVs) . . . . . . . . . . . . . . . . . . . . . . . . . . . 3447 Bioprosthetic Heart Valves Overview (BHVs) . . . . . . . . . . . . . . . . . . . 3468 BHV Base Materials: Bovine Pericardium (BP) and Porcine

Aortic Heart Valve Leaflets (PAVs) . . . . . . . . . . . . . . . . . . . . . . . . . . 3479 BHV Drawbacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35210 Industry Practice of BHV Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . 35611 Underlying Factors in Failure Modes of BHVs . . . . . . . . . . . . . . . . . . 35812 Mechanisms of Calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35813 Mechanisms of Structural Degradation . . . . . . . . . . . . . . . . . . . . . . . . 36014 Barriers to Innovation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36515 Add on Methods to Curb Shortcomings of Glutaraldehyde

Crosslinking in BHVs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36616 Alternative Crosslinking Chemistries to Innovate a Novel

Biomaterial for BHV Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Contents xvii

17 Combined Approaches to Curb Structural Degradationand Calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

18 Serving a New Demographic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37219 Contrasting Patient Demographics; Contrasting Design

Requirements for Heart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37320 Designing for Emerging Markets and Developed Markets . . . . . . . . . . 37421 Summary and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

Part III Computational Approaches for Heart Valve Function

Computational Modeling of Heart Valves: Understandingand Predicting Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385Ahmed A. Bakhaty, Ali Madani, and Mohammad R. K. Mofrad1 Introduction to Computational Modeling of Heart Valves . . . . . . . . . . 386

1.1 Computational Mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3871.2 Tissue Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3891.3 Computational Fluid Dynamics (CFD) and Fluid Structure

Interaction (FSI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3901.4 Molecular Dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3921.5 Multiscale Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

2 Aortic Valve Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3942.1 Aortic Valve Computational Models . . . . . . . . . . . . . . . . . . . . . 3942.2 Modeling of Calcific Aortic Stenosis . . . . . . . . . . . . . . . . . . . . . 3962.3 Bicuspid Aortic Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3962.4 Aortic Valve Surgical Modeling . . . . . . . . . . . . . . . . . . . . . . . . . 397

3 Mitral Valve Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3983.1 Mitral Valve Computational Models . . . . . . . . . . . . . . . . . . . . . . 3983.2 Mitral Valve Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

4 Pulmonary and Tricuspid Valve Models . . . . . . . . . . . . . . . . . . . . . . . 3994.1 Pulmonary Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3994.2 Tricuspid Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

5 Artificial Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4015.1 Artificial Valve Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4015.2 Mechanical Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4035.3 Bioprosthetic Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4045.4 Tissue-Engineered Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

6 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4056.1 Summary: A Discussion on the Validity of Models . . . . . . . . . . . 4056.2 Heart Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4056.3 Multiscale Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4066.4 Patient-Specific Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4066.5 Intraoperative Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4066.6 Non-Physics-Based Computation . . . . . . . . . . . . . . . . . . . . . . . . 406

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

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Biomechanics and Modeling of Tissue-Engineered Heart Valves . . . . . . 413T. Ristori, A. J. van Kelle, F. P. T. Baaijens, and S. Loerakker1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414

1.1 In Vitro Heart Valve Tissue Engineering . . . . . . . . . . . . . . . . . . 4141.2 In Situ Heart Valve Tissue Engineering . . . . . . . . . . . . . . . . . . . 4151.3 Limitations and Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4151.4 Outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416

2 Biomechanical Properties of Native and Tissue-EngineeredHeart Valves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4162.1 Heart Valve Structure, Function, and Biomechanics . . . . . . . . . . 4162.2 TEHV Biomechanical Properties . . . . . . . . . . . . . . . . . . . . . . . . 4182.3 Computational Simulations of TEHVs . . . . . . . . . . . . . . . . . . . . 418

3 Mathematical Models of Collagen Remodeling . . . . . . . . . . . . . . . . . . 4193.1 Collagen Architecture in Native Aortic Heart Valves . . . . . . . . . . 4193.2 Collagen Remodeling in Response to Mechanical Stimuli . . . . . . 4203.3 Early Computational Models . . . . . . . . . . . . . . . . . . . . . . . . . . . 4203.4 Realignment with Principal Loading Directions . . . . . . . . . . . . . . 4213.5 Realignment in Between Principal Loading Directions . . . . . . . . 4223.6 Inclusion of Fiber Dispersity . . . . . . . . . . . . . . . . . . . . . . . . . . . 4223.7 Main Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423

4 Modeling Stress Fiber Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . 4244.1 Actin Stress Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4244.2 SF Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4244.3 Computational Models for SF Remodeling . . . . . . . . . . . . . . . . . 4254.4 Stress Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4254.5 Stress and Strain Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . 4274.6 SF Assembly Dependent on Strain and Strain Rate . . . . . . . . . . . 4284.7 Model Based on Thermodynamics . . . . . . . . . . . . . . . . . . . . . . . 4294.8 Main Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429

5 Prestress and Cell-Mediated Collagen Remodeling . . . . . . . . . . . . . . . 4305.1 Cell-Mediated Collagen Turnover . . . . . . . . . . . . . . . . . . . . . . . 4305.2 Cell-Mediated Prestress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4315.3 Phenomenological Models of Cell-Mediated

Collagen Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4315.4 Biologically Motivated Models for Cell-Mediated Collagen

Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4325.5 Inclusion of SF Remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . 4335.6 Remodeling of TEHVs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4345.7 Future Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

6 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4346.1 Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4356.2 Agent-Based Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4366.3 How Far Should We Go? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4366.4 Implications for TEHVs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437

Contents xix

Fluid–Structure Interaction Analysis of Bioprosthetic Heart Valves:the Application of a Computationally-Efficient TissueConstitutive Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447Rana Zakerzadeh, Michael C. H. Wu, Will Zhang, Ming-Chen Hsu,and Michael S. Sacks1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4482 Modeling Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

2.1 Thin Shell Formulations for the BHV Leaflets . . . . . . . . . . . . . . 4502.2 Leaflet Tissue Material Model . . . . . . . . . . . . . . . . . . . . . . . . . . 4522.3 Implementation Verification of the Material Model . . . . . . . . . . . 457

3 Numerical Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4583.1 Setup of the Immersogeometric FSI Simulation . . . . . . . . . . . . . . 4593.2 Different Levels and Directions of Anisotropy Using Effective

Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4603.3 A Qualitative Study of the Crosslinking Effects on FSI

Simulation of BHV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4624 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4655 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467

Towards Patient-Specific Mitral Valve Surgical Simulations . . . . . . . . . 471Amir H. Khalighi, Bruno V. Rego, Andrew Drach, Robert C. Gorman,Joseph H. Gorman, and Michael S. Sacks1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4722 Image-Guided 3D MV Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4733 A Comprehensive Pipeline for Multi-Resolution Modeling

of the Mitral Valve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4744 Exploitation of Image-Based Biomechanical Modeling . . . . . . . . . . . . 477

4.1 rt-3DE In Vivo Data Acquisition and Segmentation . . . . . . . . . . 4784.2 In Vivo Leaflet Geometric Model Development Pipeline . . . . . . . 4784.3 Development of the MV FE Model . . . . . . . . . . . . . . . . . . . . . . 4794.4 Development of a Functionally Equivalent

Subvalvular Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4805 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

xx Contents

Contributors

Elena Aikawa Department of Cardiovascular Medicine, Brigham and Women’sHospital, Harvard Medical School, Boston, MA, USA

Lindsey J. Anstine Center for Cardiovascular Research and The Heart Center atNationwide Children’s Hospital Research Institute, Columbus, OH, USA

Salma Ayoub James T. Willerson Center for Cardiovascular Modeling and Simu-lation, The Oden Institute and the Department of Biomedical Engineering, TheUniversity of Texas at Austin, Austin, TX, USA

F. P. T. Baaijens Department of Biomedical Engineering, Eindhoven University ofTechnology, Eindhoven, The Netherlands

Institute for Complex Molecular Systems, Eindhoven University of Technology,Eindhoven, The Netherlands

Pietro Bajona Department of Cardiovascular and Thoracic Surgery, University ofTexas Southwestern Medical Center, Dallas, TX, USA

Anthony S. Baker Health Sciences Library Medical Visuals, The Ohio StateUniversity, Columbus, OH, USA

Ahmed A. Bakhaty Department of Civil and Environmental Engineering, Univer-sity of California, Berkeley, CA, USA

Department of Electrical Engineering and Computer Science, University of Califor-nia, Berkeley, CA, USA

Department of Mathematics, University of California, Berkeley, CA, USA

Kartik Balachandran Department of Biomedical Engineering, University ofArkansas, Fayetteville, AR, USA

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Rachel M. Buchanan James T. Willerson Center for Cardiovascular Modeling andSimulation, The Oden Institute and the Department of Biomedical Engineering, TheUniversity of Texas at Austin, Austin, TX, USA

Kristin Comella Tissue Engineered Mechanics, Imaging and Materials Laboratory(TEMIM Lab), Department of Biomedical Engineering, College of Engineering andComputing, Florida International University, Miami, FL, USA

Katherine M. Copeland Department of Bioengineering, University of Texas atArlington, Arlington, TX, USA

Andrew Drach James T. Willerson Center for Cardiovascular Modeling and Sim-ulation, Institute for Computational Engineering and Sciences, Department of Bio-medical Engineering, The University of Texas at Austin, Austin, TX, USA

Joseph H. Gorman Gorman Cardiovascular Research Group, Smilow Center forTranslational Research, Perelman School of Medicine, University of Pennsylvania,Philadelphia, PA, USA

Robert C. Gorman Gorman Cardiovascular Research Group, Smilow Center forTranslational Research, Perelman School of Medicine, University of Pennsylvania,Philadelphia, PA, USA

K. Jane Grande-Allen Department of Bioengineering, Rice University, Houston,TX, USA

Yi Hong Department of Bioengineering, University of Texas at Arlington, Arling-ton, TX, USA

Ming-Chen Hsu Department of Mechanical Engineering, Iowa State University,Ames, IA, USA

Joshua D. Hutcheson Department of Cardiovascular Medicine, Brigham andWomen’s Hospital, Harvard Medical School, Boston, MA, USA

Morten O. Jensen Department of Biomedical Engineering, University of Arkan-sas, Fayetteville, AR, USA

Amir H. Khalighi James T. Willerson Center for Cardiovascular Modeling andSimulation, Institute for Computational Engineering and Sciences, Department ofBiomedical Engineering, The University of Texas at Austin, Austin, TX, USA

Alex Khang James T. Willerson Center for Cardiovascular Modeling and Simula-tion, The Oden Institute and the Department of Biomedical Engineering, TheUniversity of Texas at Austin, Austin, TX, USA

Varun K. Krishnamurthy Department of Bioengineering, Rice University, Hous-ton, TX, USA

Ngoc Thien Lam Department of Biomedical Engineering, University of Arkansas,Fayetteville, AR, USA

xxii Contributors

Chung-Hao Lee School of Aerospace and Mechanical Engineering, The Univer-sity of Oklahoma, Norman, OK, USA

James T. Willerson Center for Cardiovascular Modeling and Simulation, Institute forComputational Engineering and Sciences, Department of Biomedical Engineering,The University of Texas at Austin, Austin, TX, USA

Jun Liao Tissue Biomechanics and Bioengineering Laboratory, The Department ofBioengineering, The University of Texas at Arlington, Arlington, TX, USA

Joy Lincoln Center for Cardiovascular Research and The Heart Center at Nation-wide Children’s Hospital Research Institute, Columbus, OH, USA

Department of Pediatrics, The Ohio State University, Columbus, OH, USA

S. Loerakker Department of Biomedical Engineering, Eindhoven University ofTechnology, Eindhoven, The Netherlands

Institute for Complex Molecular Systems, Eindhoven University of Technology,Eindhoven, The Netherlands

Ali Madani Department of Applied Science and Technology and MechanicalEngineering, University of California, Berkeley, CA, USA

Mrudang Mathur Department of Mechanical Engineering, University of Texas atAustin, Austin, TX, USA

William D. Meador Department of Biomedical Engineering, University of Texasat Austin, Austin, TX, USA

Mohammad R. K. Mofrad Department of Mechanical and Bioengineering, Uni-versity of California, Berkeley, CA, USA

Ikechukwu Okafor School of Chemical and Biomolecular Engineering, GeorgiaInstitute of Technology, Atlanta, GA, USA

Sharan Ramaswamy Tissue Engineered Mechanics, Imaging and Materials Lab-oratory (TEMIM Lab), Department of Biomedical Engineering, College of Engi-neering and Computing, Florida International University, Miami, FL, USA

Manuel K. Rausch Department of Aerospace Engineering and EngineeringMechanics, University of Texas at Austin, Austin, TX, USA

Bruno V. Rego James T. Willerson Center for Cardiovascular Modeling andSimulation, Institute for Computational Engineering and Sciences, Department ofBiomedical Engineering, The University of Texas at Austin, Austin, TX, USA

Jay M. Reimer Department of Biomedical Engineering, University of Minnesota,Minneapolis, MN, USA

Contributors xxiii

T. Ristori Department of Biomedical Engineering, Eindhoven University of Tech-nology, Eindhoven, The Netherlands

Institute for Complex Molecular Systems, Eindhoven University of Technology,Eindhoven, The Netherlands

Michael S. Sacks The Oden Institute and the Department of Biomedical Engineer-ing, The University of Texas at Austin, Austin, TX, USA

Xiaodan Shi Department of Bioengineering, University of Texas at Arlington,Arlington, TX, USA

Andrew W. Siefert Cardiac Implants LLC, Tarrytown, NY, USA

Dan T. Simionescu Department of Bioengineering, Clemson University, Clemson,SC, USA

Hobey Tam Clemson University, Clemson, SC, USA

Ishita Tandon Department of Biomedical Engineering, University of Arkansas,Fayetteville, AR, USA

Robert T. Tranquillo Department of Biomedical Engineering, University of Min-nesota, Minneapolis, MN, USA

A. J. van Kelle Department of Biomedical Engineering, Eindhoven University ofTechnology, Eindhoven, The Netherlands

Institute for Complex Molecular Systems, Eindhoven University of Technology,Eindhoven, The Netherlands

Payal Vyas Department of Cardiovascular Medicine, Brigham and Women’s Hos-pital, Harvard Medical School, Boston, MA, USA

Naren Vyavahare Clemson University, Clemson, SC, USA

Bo Wang College of Science, Mathematics and Technology, Alabama State Uni-versity, Montgomery, AL, USA

James N. Warnock School of Chemical, Materials and Biomedical Engineering,University of Georgia, Athens, GA, USA

SarahM.Wells School of Biomedical Engineering, Dalhousie University, Halifax,NS, Canada

Michael C. H. Wu Department of Mechanical Engineering, Iowa State University,Ames, IA, USA

Ajit P. Yoganathan School of Chemical and Biomolecular Engineering, GeorgiaInstitute of Technology, Atlanta, GA, USA

Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute ofTechnology, Atlanta, GA, USA

xxiv Contributors

Rana Zakerzadeh James T. Willerson Center for Cardiovascular Modeling andSimulation, The Oden Institute and the Department of Biomedical Engineering, TheUniversity of Texas at Austin, Austin, TX, USA

Will Zhang James T. Willerson Center for Cardiovascular Modeling and Simula-tion, The Oden Institute and the Department of Biomedical Engineering, TheUniversity of Texas at Austin, Austin, TX, USA

Contributors xxv