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Tissue Engineering Approaches to the Treatment of Bisphosphonate-Related Osteonecrosis of the Jaw George Bullock

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Tissue Engineering Approaches to the Treatment of Bisphosphonate-Related Osteonecrosis of the Jaw George Bullock Tissue engineering approaches to the treatment of bisphosphonate-related osteonecrosis of the jaw George Bullock A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Sheffield Faculty of Engineering Department of Materials Science and Engineering March 2019 Abstract Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a disease defined by necrotic jaw bone that has become exposed through the surrounding soft tissue, which affects patients with osteoporosis and bone metastases taking the anti-resorptive bisphosphonate (BP) drugs. Currently this disease is without a specific treatment, in part due to its complex, and not fully understood, pathophysiology. This research used tissue engineering principles to further investigate the effects of BPs on the soft tissue, both in two and three dimensions, and investigated a potential preventative treatment for the disease in vitro. The BPs investigated were pamidronic acid (PA) and zoledronic acid (ZA), two BPs most commonly associated with BRONJ. We explored the effects of PA and ZA on human oral fibroblasts and keratinocytes at clinically relevant concentrations in 2D. Both PA and ZA caused significant reductions to metabolic activity, and further study indicated an increase in apoptosis in fibroblasts, and apoptosis and necrosis in keratinocytes. PA and ZA led to a significant reduction in proliferation, and ZA reduced the adhesion of keratinocytes. However, BPs did not affect cellular migration. A 3D oral mucosa model was used to investigate PA and ZA. PA prevented the stratification of newly formed epithelia and reduced the thickness of healthy epithelia. ZA showed the same effects, but at higher concentrations was also toxic. We began the development of a 3D wound healing assay which could be used as an in vitro model of BRONJ, and indicated that BPs also inhibit oral mucosa wound healing. Finally, we examined the ability of hydroxyapatite (HA) to bind BPs. The abilities of a variety of spectroscopic methods to detect BP binding were tested. Biological assays were also performed to examine the ability of HA to prevent BP toxicity. We have successfully demonstrated that HA could be used to reduce PA and ZA toxicity in vitro. This indicates a potential mechanism by which BRONJ development could be prevented. i Acknowledgements I would like to begin this thesis by extending my gratitude and appreciation to my supervisors. Their patience, guidance, support and belief have allowed for me to become the scientist I am today, and I feel privileged to have worked with them. Firstly, thank you to Dr. Vanessa Hearnden, who was always there with ideas, encouragement and understanding. Thanks also go to Dr. Cheryl Miller, who instilled in me the high standards which I now pride myself on. I would also like to thank Mr. Alasdair McKechnie, whose clinical insight was invaluable for this project. And finally, to Dr. Robert Moorehead, for ably stepping up during Cheryl’s maternity leave and for his assistance in the DTU and with the FormLabs printer. This project would not have been possible without funding, and therefore thanks go to the EPSRC for allowing me the opportunity to complete this research. Thanks also go to the Armourers and Brasiers’ Company and the University of Sheffield Learned Society for funding me to attend conferences, share my research and gain new ideas. I would also like to thank Ceramisys Limited for the generous gift of hydroxyapatite granules. I could not have completed this work alone, and I would therefore like to thank those that assisted me throughout this project. Thanks go to Vanessa Singleton, who was always there to take requests and listen to me moan about lab matters, and to Robert Dickinson, whose help made working at Kroto easy. Special thanks go to Sue and Kay from the Flow Cytometry facility for training me, Dr. Toby Holmes for help with the cauteriser, Dr. Joss Atkinson for XRD assistance, Dr. Chris Holland and Dr. Pete Laity for UV-vis and FTIR use and expertise, Dr. Marcela Garcia-Martinez for Raman help, and finally to Dr. Sam Pashneh-Tala and Jonathan Field for assistance in the designing and printing of the cell culture ring. I would like to acknowledge all the other colleagues I had in both Materials Science and the Dental School for their knowledge and camaraderie, especially on the days where nothing seemed to be going right. In particular, thanks go to Hossein Bahmaee, Mehri Behbehani, Alex Bolger, Liam Boyle, Sarina Chand, Kat Murray, and Rob Owen. And to my friends away from work who helped keep me sane throughout this work, particularly Ed, Ethan, Joey, Lizzie and Matt. And, finally, I would like to thank my family for all their support. Thank you to my father, Jason, to Mathew and Deryn, to Louis and Georgia, and to Amelia and Oscar, who were always there to brighten my mood when I needed it most. I would especially like to thank my mother, Lisa, and dedicate this work to her, as without her constant support, pride and encouragement, I would not be where I am today. iii Outputs Publications in preparation “Hydroxyapatite inhibits bisphosphonate toxicity to the oral mucosa in vitro” G Bullock, CA Miller, A McKechnie, V Hearnden Oral presentations “Hydroxyapatite granules prevent bisphosphonate toxicity to oral fibroblasts and keratinocytes in 2D and 3D in vitro” G Bullock, CA Miller, A McKechnie, V Hearnden. BiTEG 2018. Sheffield, UK. “Bisphosphonates prevent the formation and re-epithelialisation of the oral mucosa in vitro in 3D” G Bullock, CA Miller, A McKechnie, V Hearnden. TCES 2018. Keele, UK. “The development of a 3D in vitro model of bisphosphonate-related osteonecrosis of the jaw” G Bullock, CA Miller, A McKechnie, V Hearnden. BiTEG 2017. Leeds, UK. (Flash presentation and poster) Poster presentations “Tissue engineering a model of bisphosphonate-related osteonecrosis of the jaw” G Bullock, CA Miller, A McKechnie, V Hearnden. ESB 2018. Maastricht, Netherlands. “The development of a 3D in vitro model of bisphosphonate-related osteonecrosis of the jaw” G Bullock, CA Miller, A McKechnie, V Hearnden. BiTEG 2017. Leeds, UK. “The effect of bisphosphonates on the viability and migration of oral keratinocytes and fibroblasts” G Bullock, CA Miller, RD Moorehead, A McKechnie, V Hearnden. TCES 2017. Manchester, UK. v Table of contents Abstract ............................................................................................................................ i Acknowledgements ......................................................................................................... iii Outputs ........................................................................................................................... v List of abbreviations ....................................................................................................... xii List of figures .................................................................................................................. xv List of tables ................................................................................................................. xxii List of equations ........................................................................................................... xxii 1. Introduction .............................................................................................................. 1 2. Literature review ...................................................................................................... 3 2.1 Bone .............................................................................................................. 3 2.2 Diseases associated with high bone resorption ............................................. 4 2.2.1 Osteoporosis .............................................................................................. 4 2.2.2 Osteogenesis imperfecta............................................................................ 4 2.2.3 Paget’s disease of bone ............................................................................. 5 2.2.4 Bone metastases ....................................................................................... 5 2.3 Bisphosphonates ........................................................................................... 7 2.3.1 Chemical structure and mechanism of action ............................................. 9 2.3.2 Effects of treatment .................................................................................. 12 2.4 Oral mucosa ................................................................................................ 15 2.4.1 Oral wound healing .................................................................................. 17 2.5 Bisphosphonate-related osteonecrosis of the jaw (BRONJ) ......................... 20 2.6 Pathophysiology of BRONJ ......................................................................... 23 2.7 BRONJ treatment ........................................................................................ 25 2.8 Current position of BRONJ research ............................................................ 26 2.8.1 2D effects of BPs ..................................................................................... 26 2.8.2 3D effects of BPs ..................................................................................... 36 2.8.3 Models of BRONJ .................................................................................... 41 2.8.4 Novel BRONJ treatments ........................................................................
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