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Table of Contents

Acknowledgments ........................................................................................... i

Preface .......................................................................................................... iii

Abstract ....................................................................................................... vii

Table of Contents ..........................................................................................xi

List of Figures ............................................................................................ xiv

List of Tables .............................................................................................. xvi

1. NMR Theory ........................................................................................ 11.1. The Electromagnetic Field ...........................................................................11.2. Nuclear Spin .................................................................................................21.3. Rotating Frame of Reference and Radio-Frequency Pulses .........................81.4. The Free Induction Decay (FID) ................................................................111.5. Fourier Transform and the Frequency Domain ..........................................121.6. Relaxation Time Constants ........................................................................17

1.6.1. T1 Relaxation (Spin-Lattice or Longitudinal Relaxation) ..............171.6.2. T2 Relaxation (Spin-Spin Relaxation) ...........................................21

2. Spin Manipulation ............................................................................. 252.1. The Chemical Shift and Binomial Pulses ..................................................252.2. Spin Echoes (SE), Stimulated Echoes (STE) and Spurious Echoes ..........282.3. Magnetic Resonance Imaging ....................................................................31

2.3.1. Effect of Magnetic Field Gradients on Spins .................................312.3.1.1.Frequency Encoding ...........................................................32

2.3.1.2.Slice Selection ....................................................................33

2.3.1.3.Phase Encoding ..................................................................36

2.3.2. k-space and Imaging ......................................................................372.3.2.1.Two-Dimensional Fourier Imaging ....................................38

2.3.2.2.Saw-Tooth Echo-Planar Imaging .......................................40

2.4. Diffusion ....................................................................................................422.4.1. The Diffusion Process and Stochastic Modeling ...........................42

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2.4.2. Measuring Diffusion with Pulsed-Field Gradient NMR ................443. Murine Tumor 19F Experiments ...................................................... 50

3.1. Radiation Therapy ......................................................................................513.1.1. Abstract ..........................................................................................513.1.2. Introduction ....................................................................................52

3.1.2.1.Oxygen Sensitive 19F MRI and MRS .................................53

3.1.2.2.Hypoxia and Radioresistance .............................................54

3.1.3. Experimental Methods ...................................................................563.1.3.1.Hardware and Materials .....................................................56

3.1.3.2.Animal Preparation ............................................................56

3.1.3.3.Data Acquisition ................................................................57

3.1.3.4.Radiation Therapy ..............................................................58

3.1.3.5.Data Analysis .....................................................................593.1.4. Results ............................................................................................603.1.5. Discussion and Conclusion ............................................................653.1.6. Acknowledgements ........................................................................68

4. Murine Tumor Diffusion andpO2 Experiments ............................ 694.1. On the Correlation Between the Water Diffusion Coefficient and Oxygen

Tension in RIF-1 Tumors ...........................................................................70

4.1.1. Abstract ..........................................................................................714.1.2. Introduction ....................................................................................724.1.3. Background ....................................................................................754.1.4. Methods..........................................................................................764.1.5. Results ............................................................................................814.1.6. Discussion ......................................................................................884.1.7. Acknowledgements ........................................................................96

5. Yeast Experiments............................................................................. 985.1. Deconvolution of Restriction Effects on Compartmental Diffusion Using

Combined Relaxometric and Diffusimetric NMR .....................................98

5.1.1. Abstract ..........................................................................................985.1.2. Introduction ....................................................................................995.1.3.

Theory ..........................................................................................1025.1.4. Methods........................................................................................1085.1.4.1.Yeast Preparation .............................................................108

5.1.4.2.NMR Experiments ...........................................................109

5.1.4.3.Data Analysis ...................................................................111

5.1.5. Results ..........................................................................................1135.1.5.1.[Gd-DTPA] and Relaxographic Peak Separation ............113

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5.1.5.2.Inversion-Recovery Experiments with Varying Gradient

Strengths and Echo Times ...............................................114

5.1.5.3.Calculation of the Biexponential Diffusion Decay

Constants from the PFGSE Data ......................................117

5.1.5.4.Calculation of the ADCs Associated with the Fast and Slow

Relaxing Components of the Signal ................................117

5.1.6. Discussion ....................................................................................1216. Rabbit Achilles Tendon Experiments ........................................... 125

6.1. Characterization of Water ADC Behavior Under Tensile Loading andRecovery in Rabbit Achilles Tendon Using NMR ..................................126

6.1.1. Abstract ........................................................................................1276.1.2. Introduction ..................................................................................1286.1.3. Methods........................................................................................1296.1.3.1.Equipment and Apparatus ................................................129

6.1.3.2.Load Dependence of Tendon Water ADC .......................130

6.1.3.3.Diffusion-Time Dependence of the ADC ........................131

6.1.3.4.Fast Time Measurements of Water ADC in Response to

Uniaxial Tensile Loading .................................................132

6.1.3.5.Studies of Tendon Mechanical Behavior .........................134

6.1.4. Results ..........................................................................................1356.1.4.1.Load Dependence of Tendon Water ADC .......................135

6.1.4.2.Diffusion-Time Dependence of the ADC ........................136

6.1.4.3.Fast Time Measurements of Water ADC with Loading and

Unloading .........................................................................1396.1.4.4.Tendon Anisotropy and Effects of Storage Media ...........141

6.1.4.5.Mechanical Response of Tendon to Loading ...................142

6.1.5. Discussion ....................................................................................1437. Summary .......................................................................................... 1508. Bibliography .................................................................................... 1549. Appendix .......................................................................................... A.1