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PVA-Based Scaffolds for Controlled Release of Neuroprotective Compounds

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PVA-Based Scaffolds for Controlled Release of Neuroprotective Compounds PVA-Based Scaffolds for Controlled Release of Neuroprotective Compounds by Zachary Blaine Visser Submitted in partial fulfilment of the requirements for the degree of Master of Applied Science at Dalhousie University Halifax, Nova Scotia July 2021 Dalhousie University is located in Mi’kma’ki, the ancestral and unceded territory of the Mi’kmaq. We are all Treaty people. © Copyright by Zachary Blaine Visser 2021 TABLE OF CONTENTS List of Tables .................................................................................................................... vi List of Figures .................................................................................................................. vii Abstract ............................................................................................................................. ix List of Abbreviations Used ............................................................................................... x 1. Introduction .................................................................................................... 1 1.1 Significance and Prevalence of Nerve Injuries .......................................................... 1 1.2 Understanding Neurobiology of Nerve Injuries ........................................................ 2 1.3 Classification Systems of Nerve Injuries ................................................................... 3 1.4 Wallerian Degeneration in the PNS and CNS ........................................................... 5 1.5 Overview of Approaches to Nerve Regeneration and Repair ................................... 7 1.6 Biomaterial Approaches to Nerve Regeneration and Repair ..................................... 9 1.6.3 Optimizing Material Characteristics of Biomaterial Fibers .............................. 13 1.7 Contact Drawing of Viscous Polymer Solutions ..................................................... 15 1.7.1 Contact Drawing versus Other Fiber Fabrication Methods ............................... 15 1.7.2 Contact Drawing is Driven by Polymer Entanglement ..................................... 17 1.8 Research Questions, Aims, and Objectives ............................................................. 20 1.8.1 Polymer Selection ............................................................................................. 20 1.8.2 Quercetin as a Model Drug for Controlled Release .......................................... 23 2. Materials and Methods ................................................................................ 28 2.1 Polymer Selection – Preliminary Screening ............................................................ 28 2.1.1 Contact Drawing of Viscous Polymer Solutions............................................... 28 2.2 Glyoxal Cross-linking – Secondary Screening ........................................................ 29 ii 2.2.1 Reaction Scheme ............................................................................................... 29 2.2.2 Cross-linking Contact Drawn Fibers and Rehydration Experiments ................ 30 2.2.3 Optimization of Cross-linking Protocol for Contact Drawn Fibers .................. 31 2.3 Small Molecule Loading ......................................................................................... 32 2.3.1 Analysis of Quercetin Loading via Fluorescence Microscopy ......................... 33 2.4 Characterization of Quercetin Loading and Glyoxal Cross-linking on PVA .......... 35 2.4.1 IR Spectroscopy for Quantification of Glyoxal Cross-linking.......................... 35 2.4.2 IR Spectroscopy for Analysis of Quercetin Loading ........................................ 36 2.5 Quercetin Release Studies ....................................................................................... 36 2.5.1 Ultraviolet-Visible Spectroscopy for Quantification of Quercetin Release ...... 38 2.5.2 Scanning Electron Microscopy for Morphological Analysis ............................ 41 2.6 Characterization of Quercetin Loaded, Glyoxal Cross-Linked PVA Fibers ........... 41 2.6.1 Overview of Apparatus for Observing Single Fiber Formation ........................ 41 2.6.2 Failure Rate Analysis of Fiber Formation ......................................................... 42 2.6.3 Scanning Electron Microscopy Fiber Diameter Analysis ................................. 44 2.6.4 Fiber Swelling ................................................................................................... 45 2.7 Cell-based experiments............................................................................................ 45 2.7.1 PC12Adh Cell Culture ...................................................................................... 46 2.7.2 Initial Cytotoxicity Screening for PVA Fiber Formulations ............................. 47 3. Results .......................................................................................................................... 48 3.1 Polymer Selection – Preliminary Screening for Stability Following Rehydration . 48 3.2 Optimization of Cross-linking Protocol .................................................................. 49 3.3 Quercetin Loading – Dose Response....................................................................... 51 iii 3.4 Characterization ....................................................................................................... 54 3.4.1 IR Spectroscopy for Quantification of Glyoxal Cross-Linking ........................ 55 3.4.2 IR Spectroscopy for Analysis of Quercetin Loading ........................................ 56 3.5 Quercetin Release .................................................................................................... 57 3.5.1 Degradation and Cumulative Drug Release Profiles ......................................... 57 3.5.2 Morphological Analysis of Scaffolds via SEM................................................. 58 3.6 Fiber Formation Behaviour ..................................................................................... 60 3.6.1 PVA Concentration Effects ............................................................................... 60 3.6.2 Glyoxal Concentration Effects .......................................................................... 61 3.6.3 Time Following Glyoxal Addition Effects........................................................ 63 3.7 Fiber Diameter Analysis .......................................................................................... 65 3.7.1 Pull Speed Effects ............................................................................................. 65 3.7.2 Glyoxal Cross-linking and Quercetin Loading Effects ..................................... 67 3.8 Fiber Swelling Experiments .................................................................................... 68 3.9 Cell Viability Evaluation ......................................................................................... 69 3.9.1 Cell Viability – Screening Potential Cytotoxic Fiber Formulations ................. 70 4. Discussion..................................................................................................................... 73 4.1 Material Fabrication and Characterization .............................................................. 73 4.1.1 Hybrid cross-linking protocol and quantification ............................................. 74 4.1.2 Quercetin loading .............................................................................................. 75 4.1.3 Experimental factors affecting PVA fiber formation and diameters................. 77 4.2 Material Response ................................................................................................... 80 4.2.1 Degradation of fibrous scaffolds ....................................................................... 80 iv 4.2.2 Quercetin release ............................................................................................... 82 4.2.3 Swelling ............................................................................................................. 85 4.3 Material Application ................................................................................................ 86 4.3.1 Efficacy in vitro as neuroprotective biomaterial ............................................... 86 4.3.2 Translation to use in NGC for in vivo explorations .......................................... 87 5. Conclusions .................................................................................................................. 90 5.1 Significance and Future Directions ......................................................................... 90 5.2 Future Perspectives in Nerve Tissue Engineering ................................................... 91 Works Cited ..................................................................................................................... 94 Appendix A – Developing Vapour Chamber Protocol ................................................ 106 Appendix B – IR Spectrum for Quercetin ................................................................... 109 v List of Tables Table 1 User needs and corresponding design inputs for fiber development. ............ 14 Table 2 Potential polymers for biomaterial based-nerve guide. ................................. 21 vi List of Figures Figure 1 Seddon’s classification of peripheral nerve injuries (14)................................. 4 Figure 2 Ongoing cellular actions during Wallerian degeneration. ............................... 6 Figure 3 Schematic
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