Title Details

MRIGNAYANI KOTECHA is currently a research professor of bioengineering at University of Illinois at Chicago and directs the Biomolecular Magnetic Resonance Spectroscopy and Imaging Laboratory (BMRSI). In this position, she is developing proton and sodium magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) techniques for monitoring the growth of musculoskeletal engineered tissues. Her broad research interests include the application of MRI-based techniques to cell and tissue-based regenerative medicine.

RICHARD L. MAGIN is currently a professor of bioengineering at University of Illinois at Chicago and directs the Diagnostic NMR Systems Laboratory, USA. Professor Magin is a fellow of the IEEE and AIMBE and a former editor of Critical Reviews in Biomedical Engineering. In 2012 he was designated a "Distinguished" Professor of Bioengineering at UIC. His research interests focus on the applications of magnetic resonance imaging (MRI) in science and engineering.

JEREMY J. MAO is currently professor at Columbia University, USA, and also Edwin S. Robinson Endowed Chair. Dr. Mao's research team has been at Columbia for the past 7 years and made several important discoveries including a cover article in The Lancet. In addition, Dr. Mao's work has been published in Nature Medicine, The Lancet, Cell Stem Cell, JCI, and so on. Altogether Dr. Mao has published over 260 scientific papers and proceedings and written 2 books. Dr. Mao's research has led to over 70 patents and establishment of 2 biotechnology companies. Dr. Mao has received a number of prestigious awards including Yasuda Award and Spanadel Award.

List of Plates xiii

About the Editors xix

List of Contributors xxi

Foreword xxv

Preface xxvii

Book Summary xxxi

Part I Enabling Magnetic Resonance Techniques for Tissue Engineering Applications 1

1 Stem Cell Tissue Engineering and Regenerative Medicine: Role of Imaging 3
Bo Chen, Caleb Liebman, Parisa Rabbani, and Michael Cho

1.1 Introduction 3

1.2 3D Biomimetics 5

1.3 Assessment of Stem Cell Differentiation and Tissue Development 8

1.4 Description of Imaging Modalities for Tissue Engineering 8

1.4.1 Optical Microscopy 9

1.4.2 Fluorescence Microscopy 9

1.4.3 Multiphoton Microscopy 11

1.4.4 Magnetic Resonance Imaging 14

Acknowledgments 15

References 15

2 Principles and Applications of Quantitative Parametric MRI in Tissue Engineering 21
Mrignayani Kotecha

2.1 Introduction 21

2.2 Basics of MRI 25

2.2.1 Nuclear Spins 25

2.2.2 Radio Frequency Pulse Excitation and Relaxation 28

2.2.3 From MRS to MRI 31

2.3 MRI Contrasts for Tissue Engineering Applications 32

2.3.1 Chemical Shift 33

2.3.2 Relaxation Times—T1 and T2 33

2.3.3 Water Apparent Diffusion Coefficient 36

2.3.4 Fractional Anisotropy 37

2.4 X‐Nuclei MRI for Tissue Engineering Applications 38

2.5 Preparing Engineered Tissues for MRI Assessment 38

2.5.1 In Vitro Assessment 38

2.5.2 In Vivo Assessment 39

2.6 Limitations of MRI Assessment in Tissue Engineering 39

2.7 Future Directions 40

2.7.1 Biomolecular Nuclear Magnetic Resonance 40

2.7.2 Cell–ECM–Biomaterial Interaction 40

2.7.3 Quantitative MRI 40

2.7.4 Standardization of MRI Methods for In Vitro and In Vivo Assessment 40

2.7.5 Super‐Resolution MRI Techniques 41

2.7.6 Magnetic Resonance Elastography 41

2.7.7 Benchtop MRI 41

2.8 Conclusions 41

References 42

3 High Field Sodium MRS/MRI: Application to Cartilage Tissue Engineering 49
Mrignayani Kotecha

3.1 Introduction 49

3.2 Sodium as an MR Probe 50

3.3 Pulse Sequences 53

3.3.1 Pulse Sequences for Measuring TSC 53

3.3.2 TQC Pulse Sequences for Measuring ωQ and ω0τc 54

3.4 Assessment of Tissue‐Engineered Cartilage 55

3.4.1 Proteoglycan Assessment 57

3.4.2 Assessment of Tissue Anisotropy and Molecular Dynamics 60

3.4.3 Assessment of Osteochondral Tissue Engineering 61

3.5 Sodium Biomarkers for Engineered Tissue Assessment 63

3.5.1 Engineered Tissue Sodium Concentration (ETSC) 63

3.5.2 Average Quadrupolar Coupling (ωQ) 64

3.5.3 Motional Averaging Parameter (ω0τc) 64

3.6 Future Directions 64

3.7 Summary 64

References 65

4 SPIO‐Labeled Cellular MRI in Tissue Engineering: A Case Study in Growing Valvular Tissues 71
Elnaz Pour Issa and Sharan Ramaswamy

4.1 Setting the Stage: A Clinical Problem Requiring a Tissue Engineering Solution 71

4.2 SPIO Labeling of Cells 72

4.2.1 Ferumoxides 72

4.2.2 Transfection Agents 73

4.2.3 Labeling Protocols 75

4.3 Applications 76

4.3.1 Traditional Usage of SPIO‐Labeled Cellular MRI 76

4.3.2 SPIO‐Labeled Cellular MRI in Tissue Engineering 76

4.4 Case Study: SPIO‐Labeled Cellular MRI for Heart Valve Tissue Engineering 77

4.4.1 Experimental Design 77

4.4.2 Potential Approaches—In Vitro 78

4.4.3 Potential Approaches—In Vivo 81

4.5 Conclusions and Future Outlook 83

Acknowledgment 84

References 84

5 Magnetic Resonance Elastography Applications in Tissue Engineering 91
Shadi F. Othman and Richard L. Magin

5.1 Introduction 91

5.2 Introduction to MRE 93

5.2.1 Theoretical Basis of MRE 94

5.2.2 The Inverse Problem and Direct Algebraic Inversion 96

5.2.3 Direct Algebraic Inversion Algorithm 101

5.3 Current Applications of MRE in Tissue Engineering and Regenerative Medicine 108

5.3.1 In Vitro TE μMRE 108

5.3.2 In Vivo TE μMRE 110

5.4 Conclusion 114

References 114

6 Finite‐Element Method in MR Elastography: Application in Tissue Engineering 117
Yifei Liu and Thomas J. Royston

6.1 Introduction 117

6.2 FEA in MRE Inversion Algorithm Verification 118

6.3 FEM in Stiffness Estimation from MRE Data 120

6.4 FEA in Experimental Validation in Tissue Engineering Application 121

6.5 Conclusions and Discussion 124

Acknowledgment 125

References 125

7 In Vivo EPR Oxygen Imaging: A Case for Tissue Engineering 129
Boris Epel, Mrignayani Kotecha, and Howard J. Halpern

7.1 Introduction 129

7.2 History of EPROI 131

7.3 Principles of EPR Imaging 132

7.4 EPR Oxymetry 134

7.5 EPROI Instrumentation and Methodology 135

7.5.1 EPR Frequency 135

7.5.2 Resonators 135

7.5.3 Magnets 136

7.5.4 EPR Imagers 137

7.6 Spin Probes for Pulse EPR Oxymetry 138

7.7 Image Registration 139

7.8 Tissue Engineering Applications 140

7.8.1 EPROI in Scaffold Design 140

7.8.2 EPROI in Tissue Engineering 142

7.9 Summary and Future Outlook 142

Acknowledgment 142

References 143

Part II Tissue‐Specific Applications of Magnetic Resonance Imaging in Tissue Engineering 149

8 Tissue‐Engineered Grafts for Bone and Meniscus Regeneration and Their Assessment Using MRI 151
Hanying Bai, Mo Chen, Yongxing Liu, Qimei Gong, Ling He, Juan Zhong, Guodong Yang, Jinxuan Zheng, Xuguang Nie, Yixiong Zhang, and Jeremy J. Mao

8.1 Overview of Tissue Engineering with MRI 151

8.2 Assessment of Bone Regeneration by Tissue Engineering with MRI 152

8.3 MRI for 3D Modeling and 3D Print Manufacturing in Tissue Engineering 157

8.4 Assessment of Menisci Repair and Regeneration by Tissue Engineering with MRI 161

8.5 Conclusion 168

Acknowledgments 168

References 169

9 MRI Assessment of Engineered Cartilage Tissue Growth 179
Mrignayani Kotecha and Richard L. Magin

9.1 Introduction 179

9.2 Cartilage 181

9.3 Cartilage Tissue Engineering 182

9.3.1 Cells 183

9.3.1.1 Chondrocytes 183

9.3.1.2 Stem Cells 183

9.3.2 Biomaterials 183

9.3.3 Growth Factors 184

9.3.4 Growth Conditions 184

9.4 Animal Models in Cartilage Tissue Engineering 184

9.5 Tissue Growth Assessment 186

9.6 MRI in the Assessment of Tissue‐Engineered Cartilage 187

9.7 Periodic Assessment of Tissue‐Engineered Cartilage Using MRI 187

9.7.1 Assessment of Tissue Growth In Vitro 187

9.7.1.1 Accounting for Scaffold in Tissue Assessment 191

9.7.2 Assessment of Tissue Growth In Vivo 191

9.7.3 Assessment of Tissue Anisotropy and Dynamics 193

9.7.3.1 Assessment of Macromolecule Composition 194

9.7.3.2 Assessment of Tissue Anisotropy 198

9.8 Summary and Future Directions 199

References 200

10 Emerging Techniques for Tendon and Ligament MRI 209
Braden C. Fleming, Alison M. Biercevicz, Martha M. Murray, Weiguo Li, and Vincent M. Wang

10.1 Tendon and Ligament Structure, Function, Injury, and Healing 209

10.2 MRI Studies of Tendon and Ligament Healing 211

10.3 MRI and Contrast Mechanisms 219

10.3.1 Conventional MRI Techniques 219

10.3.2 Advanced MR Techniques 222

10.4 Significance and Conclusion 228

Acknowledgments 228

References 228

11 MRI of Engineered Dental and Craniofacial Tissues 237
Anne George and Sriram Ravindran

11.1 Introduction 237

11.2 Scaffolds 238

11.3 Extracellular Matrix 238

11.4 Tissue Regeneration of Dental–Craniofacial Complex 239

11.4.1 Advantages of Using ECM Scaffolds with Stem Cells 240

11.4.2 Stem Cells 242

11.5 MRI in Tissue Engineering and Regeneration 243

11.5.1 MRI of Human DPSCs 243

11.5.2 MRI of Tissue‐Engineered Osteogenic Scaffolds 244

11.5.3 MRI of Chondrogenic Scaffolds with Cells In Vitro 244

11.5.4 MRI of Chondrogenic Scaffolds with Cells In Vivo 245

11.5.5 MRI Can Differentiate Between Engineered Bone and Engineered Cartilage 246

11.5.6 MRI to Assess Angiogenesis 246

11.6 Challenges and Future Directions for MRI in Tissue Engineering 246

Acknowledgments 247

References 247

12 Osteochondral Tissue Engineering: Noninvasive Assessment of Tissue Regeneration 251
Tyler Stahl, Abeid Anslip, Ling Lei, Nilse Dos Santos, Emmanuel Nwachuku, Thomas DeBerardino, and Syam Nukavarapu

12.1 Introduction 251

12.2 Osteochondral Tissue Engineering 252

12.2.1 Osteochondral Tissue 252

12.2.2 Biomaterials/Scaffolds 252

12.2.3 Cells 255

12.2.4 Growth Factors 256

12.3 Clinical Methods for Osteochondral Defect Repair and Assessment 257

12.3.1 Diagnostic Modalities 257

12.3.2 Treatment Methods 260

12.3.2.1 Microfracture 260

12.3.2.2 Autografts and Allografts 260

12.3.2.3 Tissue Engineering Grafts 262

12.4 MRI Assessment of Tissue Engineered Osteochondral Grafts 262

12.4.1 In Vitro Assessment 263

12.4.2 In Vivo Assessment 264

12.5 MRI Assessment Correlation with Histology 264

12.6 Conclusions and Challenges 265

Acknowledgments 265

References 265

13 Advanced Liver Tissue Engineering Approaches and Their Measure of Success Using NMR/MRI 273
Haakil Lee, Rex M. Jeffries, Andrey P. Tikunov, and Jeffrey M. Macdonald

13.1 Introduction 273

13.2 MRS and MRI Compatibilization—Building Compact RF MR Probes for BALs 278

13.3 Multinuclear MRS of a Hybrid Hollow Fiber–Microcarrier BAL 280

13.3.1 Viability by 31P MRS 282

13.3.2 Quantifying Drug Metabolic Activity and Oxygen Distribution by 19F MRS 284

13.4 1H MRI of a Hollow Fiber Multicoaxial BAL 286

13.4.1 BAL Integrity and Quality Assurance 286

13.4.2 Inoculation Efficiency and Prototype Redesign Iteration 288

13.4.3 Flow Dynamics 289

13.4.4 Diffusion‐Weighted and Functional Annotation Screening Technology (FAST) Dynamic Contrast MRI 291

13.5 Magnetic Contrast Agents Used in MRI of Liver Stem Cell Therapy 293

13.6 31P and 13C MRS of a Fluidized‐Bed BAL Containing Encapsulated Hepatocytes 294

13.6.1 31P MRS Resolution, SNR, Viability, and pH 296

13.6.2 13C MRS to Monitor Real‐Time Metabolism 296

13.7 Future Studies 298

13.7.1 Dynamic Nuclear Polarization 298

13.7.2 Constructing Artificial Organs 300

13.8 Discussion 301

Acknowledgment 303

References 303

14 MRI of Vascularized Tissue‐Engineered Organs 311
Hai‐Ling Margaret Cheng

14.1 Introduction 311

14.2 Importance of Vascularization in Tissue Engineering 312

14.3 Vessel Formation and Maturation: Implications for Imaging 314

14.4 Imaging Approaches to Assess Vascularization 317

14.5 Dynamic Contrast‐Enhanced MRI for Imaging Vascular Physiology 318

14.6 Complementary MRI Techniques to Study Vascularization 321

14.7 Considerations for Preclinical Models and Translation to Clinical Implementation 325

14.8 Future Directions 326

14.9 Conclusions 327

References 327

15 MRI Tools for Assessment of Cardiovascular Tissue Engineering 333
Laurence H. Jackson, Mark F. Lythgoe, and Daniel J. Stuckey

15.1 The Heart and Heart Failure 333

15.2 Cardiac Engineering and Cell Therapy 334

15.3 Imaging Heart Failure 336

15.3.1 Cine MRI 336

15.3.2 Regional Heart Function 338

15.3.3 Viability Imaging 340

15.3.4 Relaxometry and Parametric Imaging 342

15.3.5 Myocardial Perfusion Imaging 344

15.4 Imaging Cardiac Regeneration 346

15.5 Monitoring Cardiac Regeneration 348

15.5.1 MRI to Track Stem Cells 348

15.5.2 MRI to Track Engineered Tissues 353

15.6 Translational Potential and Future Directions 355

References 357

16 Peripheral Nerve Tissue Engineering and Regeneration Observed Using MRI 367
Shan‐Ho Chan and Shan‐hui Hsu

16.1 Introduction 367

16.2 Receiver Coils Commonly Applied in Nerve Tissue Engineering 368

16.3 Various Tools for Real‐Time Monitoring of the Nerve Regeneration 368

16.4 Current Materials, Methods, and Concepts in Peripheral Nerve Repair 368

16.5 MRI Parameters in Peripheral Nerve Tissue Engineering 371

16.6 Advantages of Real‐Time Monitoring of Nerve Regeneration Using MRI 373

16.7 Choosing Animal Models for MRI Studies of Peripheral Nerve Tissue Engineering 374

16.8 Imaging Ability Through Nerve Conduits of Peripheral Nerve Tissue Engineering 375

16.9 Further Imaging Functions of MRI in Peripheral Nerve Tissue Engineering 376

16.10 Tractography in Peripheral Nerve Tissue Engineering 376

16.11 Novel Contrast Agents 378

16.12 Conclusions 378

References 379

Index 383