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Development of Granulation Tissue Mimetic Scaffolds for Skin Healing

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Development of Granulation Tissue Mimetic Scaffolds for Skin Healing Western University Scholarship@Western Electronic Thesis and Dissertation Repository 10-4-2018 12:30 PM Development Of Granulation Tissue Mimetic Scaffolds For Skin Healing Adam Hopfgartner The University of Western Ontario Supervisor Hamilton, Douglas W. The University of Western Ontario Co-Supervisor Pickering, J. Geoffrey. 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 © Adam Hopfgartner 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biomaterials Commons, and the Molecular, Cellular, and Tissue Engineering Commons Recommended Citation Hopfgartner, Adam, "Development Of Granulation Tissue Mimetic Scaffolds For Skin Healing" (2018). Electronic Thesis and Dissertation Repository. 5767. https://ir.lib.uwo.ca/etd/5767 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]. Abstract Impaired skin healing is a significant and growing clinical concern, particularly in relation to diabetes, venous insufficiency and immobility. Previously, we developed electrospun scaffolds for the delivery of periostin (POSTN) and connective tissue growth factor 2 (CCN2), matricellular proteins involved in the proliferative phase of healing. This study aimed to design and validate a novel electrosprayed coaxial microsphere for the encapsulation of fibroblast growth factor 9 (FGF9), as a component of the POSTN/CCN2 scaffold, to promote angiogenic stability during wound healing. For the first time, we observed a pro-proliferative effect of FGF9 on human dermal fibroblasts (HDF) in vitro, indicating a potential cellular mechanism of action during wound healing. POSTN/CCN2 scaffolds containing encapsulated FGF9 decreased wound diameter, with no negative or adverse effects at day 7, in a porcine model of acute cutaneous wound healing. Future work is required to investigate the effect of the POSTN/CCN2/FGF9 scaffold during impaired healing. Keywords Skin Healing, Chronic Wound, Granulation Tissue Biomimetic Scaffold, Electrospinning, Electrospraying, Poly(Lactic-co-Glycolic Acid), Gelatin, Fibroblast Growth Factor 9, Periostin, Connective Tissue Growth Factor 2, Dermal Fibroblast. ii Co-Authorship Statement This thesis was written by A.J. Hopfgartner with input, suggestions, and revisions from Dr. D.W. Hamilton and Dr. J.G. Pickering. Experiments were designed by Dr. D.W. Hamilton and Dr. A. Rizkalla. All studies were conducted by A.J. Hopfgartner with the exception of UWO Animal Care and Veterinary Services performing all surgeries for both porcine studies. iii Acknowledgements Foremost, I would like to express my sincere gratitude to my supervisor Dr. Hamilton for the continuous support of my research, for his patience, motivation, enthusiasm, and immense knowledge. His guidance helped me in all the time of research and writing of this thesis. I would like to thank Dr. Rizkalla for his assistance during my many hours of electrospinning. I am also grateful to Dr. Pickering for providing valuable feedback during committee meetings, for focussing my project when I needed it, and for providing valuable input during the writing of this thesis. To my fellow lab members: Aref, Georgia, JT, Karrie, Madeleine, and Sarah, all of whom guided and supported me throughout my research, thank you for showing me the ropes and tolerating my inexperience during the first months of my project. Thank you to Hong, an unexpected friend, who showed me the value of persistence. I wish all of you the best in your future endeavors. Finally, thank you to my parents, sister, and to Jess for providing me with unfailing support and continuous encouragement throughout my years of study and through the process of researching and writing this thesis. This accomplishment would not have been possible without you. iv Table of Contents ABSTRACT ....................................................................................................................... II KEYWORDS ..................................................................................................................... II CO-AUTHORSHIP STATEMENT .............................................................................. III ACKNOWLEDGEMENTS ........................................................................................... IV TABLE OF CONTENTS ................................................................................................. V LIST OF TABLES .......................................................................................................... IX LIST OF FIGURES .......................................................................................................... X LIST OF APPENDICES ............................................................................................. XIII LIST OF ABBREVIATIONS ....................................................................................... XV CHAPTER 1 ....................................................................................................................... 1 GENERAL INTRODUCTION ......................................................................................... 1 1.1 – WOUND HEALING & CHRONIC WOUNDS – THE ROLE OF FIBROPLASIA AND ANGIOGENESIS .................................................................................................................. 1 1.1.1– The Skin – Anatomy & Physiology .................................................................... 1 1.1.2 – Cutaneous Wound Healing .............................................................................. 5 1.1.3 – Chronic Wounds – Pathophysiology ................................................................ 7 1.1.4 – Chronic Wounds – Classification & Prevalence ............................................. 9 1.2 – CHRONIC WOUND CARE & STRATEGIES CURRENTLY UNDER INVESTIGATION ...... 11 1.2.1 – Clinical Treatment of Chronic Wounds ......................................................... 11 1.2.2 – Strategies Currently Under Investigation ...................................................... 17 1.3 – ELECTROHYDRODYNAMIC ATOMIZATION AS A FABRICANT OF WOUND-HEALING THERAPIES ...................................................................................................................... 18 1.3.1 – Scaffold Design for Tissue Regeneration ....................................................... 18 1.3.2 – Methods of Scaffold Fabrication ................................................................... 18 1.3.3 – Electrospun Nanofibrous Scaffolds ................................................................ 21 1.3.4 – Coaxial Electrospraying ................................................................................ 26 v 1.3.5 – Scaffold Materials .......................................................................................... 28 1.4 – PERIOSTIN, CONNECTIVE TISSUE GROWTH FACTOR 2 & FIBROBLAST GROWTH FACTOR 9 AS THERAPEUTICS FOR CHRONIC WOUNDS .................................................... 31 1.4.1 – Periostin & Connective Tissue Growth Factor 2........................................... 31 1.4.2 – Fibroblast Growth Factor 9 ........................................................................... 35 1.5 – RATIONALE, HYPOTHESIS & OBJECTIVES ............................................................... 39 1.5.1 – Rationale ........................................................................................................ 39 1.5.2 – Hypothesis ...................................................................................................... 39 1.5.3 – Objectives ....................................................................................................... 40 1.6 – REFERENCES ........................................................................................................... 41 CHAPTER 2 ..................................................................................................................... 57 INFLUENCE OF NANOFIBROUS ELECTROSPUN PERIOSTIN AND CONNECTIVE TISSUE GROWTH FACTOR 2 SCAFFOLDS ON ANGIOGENESIS AND WOUND REPAIR IN A 28-DAY PORCINE MODEL ...... 57 2.1 – INTRODUCTION ....................................................................................................... 57 2.2 – MATERIALS AND METHODS .................................................................................... 59 2.2.1 – 28-Day Porcine Study .................................................................................... 59 2.2.2 – Scaffold Preparation ...................................................................................... 62 2.2.3 – Porcine Cutaneous Wound-Healing Outcomes ............................................. 65 2.3 – RESULTS ................................................................................................................. 67 2.3.1 – Wound Closure Kinetics ................................................................................ 67 2.3.2 – Angiogenesis .................................................................................................. 68 2.3.3 – Collagen Deposition ...................................................................................... 68 2.4 – DISCUSSION ...........................................................................................................
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