SYNTHESIS, CHARACTERIZATION, AND RISK ASSESSMENT PLANNING FOR NOVEL DEGRADABLE AND IMAGEABLE EMBOLIC AGENTS by Jensen S Doucet Submitted in partial fulfillment of the requirements for the degree of Master of Applied Science at Dalhousie University Halifax, Nova Scotia June 2018 © Copyright by Jensen Doucet, 2018 Table of Contents LIST OF TABLES .................................................................................................. vi LIST OF FIGURES ................................................................................................ vii ABSTRACT ............................................................................................................ ix LIST OF ABBREVIATIONS AND SYMBOLS USED ....................................... x ACKNOWLEDGEMENTS .................................................................................... xiii CHAPTER 1: INTRODUCTION .......................................................................... 1 1.1. Uterine Leiomyoma .......................................................................................... 1 1.1.1. Pathophysiology of Uterine Leiomyomas ................................................ 1 1.1.2. Current Treatments .................................................................................. 3 1.1.2.1. Surgical Options ............................................................................... 3 1.1.2.2. Commercially Available UAE Microspheres .................................. 6 1.2. Advances in Degradable Embolic Microspheres: A State of the Art Review ........................................................................................................ 8 1.2.1. Abstract .................................................................................................... 9 1.2.2. Introduction .............................................................................................. 9 1.2.3. Methodology ............................................................................................ 12 1.2.4. Current State of the Art ............................................................................ 14 1.2.4.1. PLGA ................................................................................................ 14 1.2.4.1.1. PLGA: Basic Chemistry and Mechanisms of Degradation .... 14 1.2.4.1.2. PLGA: Safety, Efficacy, and Performance ............................ 15 1.2.4.1.3. Key Advantages of PLGA Microspheres ............................... 19 1.2.4.1.4. Key Limitations of PLGA Microspheres ............................... 19 1.2.4.2. PLGA-PEG-PLGA ........................................................................... 20 1.2.4.2.1. PLGA-PEG-PLGA: Basic Chemistry and Mechanisms of Degradation ................................................... 20 1.2.4.2.2. PLGA-PEG-PLGA: Safety, Efficacy, and Performance ........ 20 ii 1.2.4.2.3. Key Advantages of PLGA-PEG-PLGA Microspheres .......... 24 1.2.4.2.4. Key Limitations of PLGA-PEG-PLGA Microspheres ........... 24 1.2.4.3. CMC-CNN ....................................................................................... 25 1.2.4.3.1. CMC-CNN: Basic Chemistry and Mechanisms of Degradation ............................................................................. 25 1.2.4.3.2. CMC-CNN: Safety, Efficacy, and Performance .................... 26 1.2.4.3.3. Key Advantages of CMC-CNN Microspheres ....................... 29 1.2.4.3.4. Key Limitations of CMC-CNN Microspheres ....................... 29 1.2.4.4. Chitosan ............................................................................................ 29 1.2.4.4.1. Chitosan: Basic Chemistry and Mechanisms of Degradation ............................................................................. 29 1.2.4.4.2. Chitosan: Safety, Efficacy, and Performance ......................... 30 1.2.4.4.3. Key Advantages of Chitosan Microspheres ........................... 34 1.2.4.4.4. Key Limitations of Chitosan Microspheres ........................... 34 1.2.4.5 HEA .................................................................................................. 34 1.2.4.5.1. HEA: Basic Chemistry and Mechanisms of Degradation ...... 34 1.2.4.5.2. HEA: Safety, Efficacy, and Performance ............................... 35 1.2.4.5.3. Key Advantages of HEA Microspheres ................................. 38 1.2.4.5.4. Key Limitations of HEA Microspheres ................................. 38 1.2.5. Preclinical Models .................................................................................... 38 1.2.6. Conclusion ............................................................................................... 40 1.3. Consolidated Design Inputs ............................................................................. 41 1.4. Glasses as Candidate Embolic Agents ............................................................ 42 1.4.1. Borate Glasses .......................................................................................... 43 1.4.2. Modifier Ions ............................................................................................ 45 1.4.2.1. Rubidium .......................................................................................... 46 1.4.2.2. Strontium .......................................................................................... 47 1.4.2.3. Gallium ............................................................................................. 48 1.5. The Problem Statement ................................................................................... 50 CHAPTER 2: OVERARCHING THESIS OBJECTIVES ................................. 51 iii CHAPTER 3: EXPERIMENT 1&2: MULTI-MODAL IMAGEABILITY & DEGRADATION CHARACTERISTICS OF BORATE NETWORKS ........... 53 3.1. Abstract ............................................................................................................. 56 3.2. Introduction ...................................................................................................... 56 3.3. Methods ............................................................................................................. 59 3.3.1. Glass Synthesis ........................................................................................ 59 3.3.2. X-Ray Diffraction Analysis ..................................................................... 60 3.3.3. Solid State NMR Spectroscopy ................................................................ 60 3.3.4. Glass Density ........................................................................................... 61 3.3.5. Thermal Analysis ..................................................................................... 61 3.3.6. Computed Tomography Imaging ............................................................. 61 3.3.7. Magnetic Resonance Imaging .................................................................. 62 3.3.8. Glass Cylinder Synthesis for Mass Loss Evaluation ............................... 62 3.3.9. Mass Loss Evaluation .............................................................................. 63 3.3.10. Statistical Analysis ................................................................................. 63 3.4. Results ............................................................................................................... 64 3.5. Discussion .......................................................................................................... 73 3.6. Limitations ........................................................................................................ 77 3.7. Conclusion ......................................................................................................... 78 CHAPTER 4: EXPERIMENT 3: PILOT BENCHTOP MIGRATION AND PRE-CLINCAL PREPARATION ............................................................... 80 4.1. Part 1: Benchtop Migration Method Development ....................................... 80 4.1.1. Objective .................................................................................................. 80 4.1.2. Rationale .................................................................................................. 80 4.1.3. Materials & Methods ............................................................................... 82 4.1.4.1. Model Set-Up ................................................................................... 82 4.1.4.2. Experimental Design ........................................................................ 82 4.1.4. Results and Discussion ............................................................................. 83 4.1.5. Limitations and Future Considerations .................................................... 86 4.2. Part 2: Microsphere Synthesis and Embolization Effectiveness................... 87 4.2.1. Objective .................................................................................................. 87 iv 4.2.2. Hypothesis ................................................................................................ 87 4.2.3. Rationale .................................................................................................. 87 4.2.4. Materials & Methods ............................................................................... 91 4.2.4.1. Glass Synthesis and Recharacterization ........................................... 91 4.2.4.2. Spherical Processing and Recharacterization ................................... 91 4.2.4.3. Packaging and Sterilization .............................................................