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The Differential Modulation of Receptor Tyrosine Kinase Axl in Human Mesenchymal Stromal Cell Responses to Modified Titanium Surfaces

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The Differential Modulation of Receptor Tyrosine Kinase Axl in Human Mesenchymal Stromal Cell Responses to Modified Titanium Surfaces Title The differential modulation of receptor tyrosine kinase Axl in human mesenchymal stromal cell responses to modified titanium surfaces This thesis is submitted in part fulfillment of the requirements for the degree of PhD at UCL. By Mohammad Ramine Khan BSc, MSc August 2011 UCL Eastman Dental Institute Division of Biomaterials and Tissue Engineering i Declaration Declaration ‘I, Mohammad Ramine Khan confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' __________________________________________ Mohammad Ramine Khan Date ii Dedication Dedication I dedicate this thesis to my late father, Dr Habib Ullah Khan Afridi (29th December, 1951 to 14th December, 2011), who drew my path in science, and saw and encouraged me through to the point of completing this work. I am forever grateful to my supervisors and the examiners, Prof Timothy Arnett (UCL) and Dr Matt Dalby (Univ. of Glasgow), for letting me this honorable chance of making him a very proud man. iii Acknowledgements Acknowledgements I am grateful to the University College London and the UCL Eastman Dental Institute for allowing me the opportunity of scientific research in a first class academic institution. I thank Straumann AG (Walderberg) for providing the valuable titanium biomaterial substrates for this study. Further, I am grateful to the international Team for Implantology (ITI) for funding this project, as well as the University of London’s Central Research Fund for their generous award for the gene array analyses. More so, my whole hearted gratefulness extends to the following individuals whose contributions made this thesis a reality. My family- I am very blessed and lucky to have you. I feel especially for my late father who guided me through my career in science, and hopefully will so beyond. I am extremely grateful to my wife, mother, brothers and sister for bearing me through this tough period. My supervisors, Dr. Peter Mark Brett, Prof. Nikos Donos and Dr. Vehid Salih; forever in debt to them for the chance that they gave me at scientific research, their guidance and teaching, and their friendship. I would extend special thanks to Peter for accepting me into his research, at a time when most were closing their doors. A friend who gave me much needed motivation and technical help was Mohamad Hussein Parkar from biomaterials and tissue engineering. I extend a special thanks to Dr Nicola Mordan for her help in electron microscopy, Dr Hadwa Muawad for RNA isolation and PCR techniques; Mr. Paul Darkins and Dr Paul Buxton for their histological and technical advice, respectively. My friends who were there for me, thick or thin: Hsyun Shen, Dr Khalid Al-Qahtani, Dion Telesford, Bilal Hassan, Muhammad Bilal Nawazish, Atif Ahmad, Mohd Sardar Khan, Dr Harsh D Amin, Hy Jaynara, Dean, Robb, Lee, Kaha et al., and Krunal ‘Krondi’ Patel. Finally, I thank the many souls whose names I may have not mentioned here but was part of this journey. iv Abstract Abstract Osseointegration is the process of de novo bone regeneration on the surface of an endosseous titanium (Ti) implant in vivo. This neo formation of bone underlies the physical integration of a Ti implant in bone at a level sufficient to restore loss of function; for example, of mastication due to absent teeth. The outer atoms of a bulk of Ti metal form a stable and passive surface oxide layer that serves as a substrate for the amalgamation of tissue reparative components, which entail the formation of an osseous bond between tissue and fixture. This interaction was empirically demonstrated to be highly affected by the characteristics of the surface an implant in experimental studies querying the varied effects of additive or subtractive physical modifications, as well as altered chemical compositions, of Ti implant surfaces on osseointegration. Subsequent clinical and experimental practices have demonstrated that rough surfaced implants perform comparatively ‘better’ than their smooth surfaced counterparts by promoting bone growth on the fixture. Moreover, a particular surface modification that yields high surface energy combined with a widely tested micron scaled topographical roughness (modSLA) has been shown to further promote the timely enhancement of osseointegration compared to its hydrophobic rough counterpart (SLA). The biological mechanisms underlying this apparent enhancement of osseointegration by modified Ti implant surfaces are still subject to intense study due to the materials’ implications in bone related tissue engineering applications. Amongst the several views being opined is a proposition mainly arising from in vitro experimentation, which suggests modified Ti implant surfaces possess an ‘intrinsic’ osteoinductive potential that affects uncommitted reparative cells by inducing a temporal and magnitudinal enhancement in cellular differentiation and function; in turn, implying the early formation of functional osteoblasts and bone tissue matrix in an in vivo scenario. The observations of differential cellular behavior include the apparent modulation by the modified surfaces, of a cell surface receptor tyrosine kinase Axl in human osteoblasts. The proposed role of the receptor in negatively regulating osteogenic mineralisation in uncommitted pericytic cells suggests an association with the altered response of cells to these substrates. The aim of this project was to examine and test the hypothesised differential modulation of Axl in the responses of human marrow derived mesenchymal stromal cells to modified Ti implant substrates. v Table of contents Table of contents Title ....................................................................................................................................................i Declaration .......................................................................................................................................ii Dedication .......................................................................................................................................iii Acknowledgements....................................................................................................................... iv Abstract ............................................................................................................................................v Table of contents........................................................................................................................... vi List of figures................................................................................................................................ xv List of tables ................................................................................................................................ xix List of abbreviations .................................................................................................................... xx 1 Introduction ..............................................................................................................................1 1.1 Bone.......................................................................................................................................1 1.1.1 Bone tissue......................................................................................................................1 1.1.2 Ontogeny.........................................................................................................................5 1.1.2.1 Embryonic bone development .................................................................................6 1.1.2.2 Post natal bone development ..................................................................................7 1.1.3 Cells.................................................................................................................................8 1.2 Osseointegration ............................................................................................................... 10 1.2.1 Discovery...................................................................................................................... 10 1.2.2 Definition ...................................................................................................................... 12 vi Table of contents 1.2.2.1 Present working definitions ................................................................................... 12 1.2.2.2 Limitations of definitions........................................................................................ 12 1.2.2.3 Biological perspective ........................................................................................... 13 1.2.3 Biological paradigm of osseointegration ...................................................................... 14 1.2.4 Practicality of biological paradigm................................................................................ 14 1.3 Implant surface modifications ......................................................................................... 18 1.3.1 Titanium biocompatibility.............................................................................................. 18 1.3.2 Implant failure to surface modification.......................................................................... 19 1.3.3 Topographical modifications ........................................................................................ 21 1.3.4 In vivo effects of modified Ti surfaces.........................................................................
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