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Functional Co-Substituted Poly[(Amino Acid Ester)Phosphazene] Biomaterials

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Functional Co-Substituted Poly[(Amino Acid Ester)Phosphazene] Biomaterials Western University Scholarship@Western Electronic Thesis and Dissertation Repository 7-7-2014 12:00 AM Functional Co-substituted Poly[(amino acid ester)phosphazene] Biomaterials Amanda L. Baillargeon The University of Western Ontario Supervisor Dr. Kibret Mequanint The University of Western Ontario Graduate Program in Biomedical Engineering A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Engineering Science © Amanda L. Baillargeon 2014 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biomaterials Commons Recommended Citation Baillargeon, Amanda L., "Functional Co-substituted Poly[(amino acid ester)phosphazene] Biomaterials" (2014). Electronic Thesis and Dissertation Repository. 2249. https://ir.lib.uwo.ca/etd/2249 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. FUNCTIONAL CO-SUBSTITUTED POLY[(AMINO ACID ESTER)PHOSPHAZENE] BIOMATERIALS (Thesis format: Monograph) by Amanda Lee Baillargeon Graduate Program in Biomedical Engineering A thesis submitted in partial fulfillment of the requirements for the degree of Master of Engineering Science The School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario, Canada © Amanda Lee Baillargeon 2014 Abstract The development of new and improved biomaterials is essential for tissue engineering and regenerative medicine applications. Amino acid-based polyphosphazenes are being explored as scaffold materials for tissue engineering applications due to their non-toxic degradation products and tunable material properties. This work focuses on the synthesis of non- functional and novel functional poly[(amino acid ester)phosphazene]s using a facile method of thermal ring opening polymerization followed by one-pot room temperature substitution. The family of polyphosphazenes developed in this work is based on L-alanine (PP-A’s), L- phenylalanine (PP-F’s), and L-methionine (PP-M’s) with L-glutamic acid imparting the functionality. Characterization of these materials demonstrated that the one-pot substitution was successful in developing mono- and co-substituted poly[(amino acid ester)phosphazene]s. Cytotoxicity studies on two-dimensional films showed these materials to be compatible with NIH-3T3 fibroblasts over the five-day study. The PP-F’s also showed significantly enhanced cell viability over tissue culture polystyrene at day 1 (p<0.001) and day 3 (p<0.01). As a proof of concept, electrospinning of PP-A100 blended with poly(caprolactone) (PCL) (50% PP-A100/50% PCL) was conducted to fabricate three- dimensional scaffolds. Overall, this study has shown that poly[(amino acid ester)phosphazene]s can be synthesized with good yields and better reaction conditions, leading to materials with promising cytocompatibility for use in biomedical applications. Keywords Polyphosphazenes, poly[(amino acid ester)phosphazene]s, biomaterials, biodegradable polymers, tissue engineering, scaffolds, electrospinning ii Acknowledgments I would like to acknowledge my supervisor, Dr. Kibret Mequanint, for his continued support and guidance throughout my Master’s degree. I really appreciated the amount of time he designated weekly to meet with his students and ensure that they were progressing well with their research; it definitely pushed me to always have new findings to share with him. I would also like to thank the Natural Sciences and Engineering Research Council (NSERC) of Canada and the Strategic Training Program in Vascular Research supported by the Canadian Institutes for Health Research (CIHR) for the financial aid and skills training. I would like to thank Dr. Darryl Knight and Dr. Kalin Panev for their help in synthetic chemistry problems, experimental setup, and elucidation of NMR spectra. I also would like to acknowledge Dr. Shigang Lin for his help with the design and implementation of the cell culture experiments. I would like to thank Ryan Guterman of the Ragogna research group for his help in running TGA, DSC, and FTIR analyses. Lastly, I would like to thank Somiraa Said for her guidance with the electrospinning and planning of cell culture studies. All of the helpful feedback and discussions from other lab members (especially Tierney Deluzio) were greatly appreciated. Finally, I would like to thank my mother and grandparents for their continued love and support throughout my study. I would not have been able to push through these stressful two years without you by my side. Table of Contents Abstract ............................................................................................................................... ii Acknowledgments.............................................................................................................. iii Table of Contents ............................................................................................................... iv List of Tables ................................................................................................................... viii List of Figures ..................................................................................................................... x List of Appendices ........................................................................................................... xvi List of Abbreviations ...................................................................................................... xvii Chapter 1 ............................................................................................................................. 1 1 Scope and Thesis Outline ............................................................................................... 1 1.1 Scope ....................................................................................................................... 1 1.2 Thesis Outline ......................................................................................................... 2 Chapter 2 ............................................................................................................................. 3 2 Literature Review, Objectives, and Rationale ................................................................ 3 2.1 Tissue Engineering Methodology ........................................................................... 3 2.2 Requirements of Tissue Engineering Scaffolds ...................................................... 5 2.2.1 Natural Polymers ........................................................................................ 7 2.2.2 Biodegradable Synthetic Polymers ............................................................. 8 2.2.3 Biomimetic Materials .................................................................................. 9 2.2.4 Scaffold Fabrication .................................................................................. 10 2.3 Synthesis of Polyphosphazenes ............................................................................ 11 2.3.1 Polymerization to Poly[(dichloro)phosphazene] ...................................... 13 2.3.2 Macromolecular Substitution of Poly[(dichloro)phosphazene] with Organic Nucleophiles................................................................................ 18 2.4 Suitability of Polyphosphazene Biomaterials ....................................................... 20 iv 2.4.1 In Vitro and In Vivo Biocompatibility ...................................................... 21 2.4.2 Biodegradability ........................................................................................ 23 2.4.3 Mechanical Properties ............................................................................... 28 2.5 Objectives and Rationale ...................................................................................... 29 Chapter 3 ........................................................................................................................... 32 3 Materials and Methods ................................................................................................. 32 3.1 Thermal Ring Opening Polymerization (TROP) .................................................. 32 3.1.1 Materials ................................................................................................... 32 3.1.2 Equipment ................................................................................................. 32 3.1.3 Method ...................................................................................................... 33 3.2 Macromolecular Substitution of Non-Functional Amino Acid Esters ................. 35 3.2.1 Materials ................................................................................................... 35 3.2.2 Sample Nomenclature ............................................................................... 35 3.2.3 Methods..................................................................................................... 35 3.3 Preparation of Glutamic Acid Ethyl Ester (E*) ..................................................... 40 3.3.1 Materials ................................................................................................... 40 3.3.2 Methods..................................................................................................... 41 3.4 Macromolecular Co-substitution of Non-Functional Amino
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