Design and Manufacture of Functional Titanium- Palladium Devices for the Activation of Anti-cancer Prodrugs by Mohammad N. Alqahtani Wolfson School of Mechanical, Electrical and Manufacturing Engineering Loughborough University Supervised by: Dr. Carmen Torres-Sánchez Prof. Paul Conway A Doctoral thesis submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy March 2019 ©M.N.Alqahtani, 2019 Abstract National health organisations and authorities have reported an increment in death cases due to cancer. To overcome this issue and improve the survival rate, it is needed to find new clinical methods, early diagnoses techniques and treatments. Radiation and chemotherapy have been used for years to treat cancer. However, these types of treatments have serious side effects such as hair loosing, the mortality of healthy cells and other organs. A new treatment based on prodrugs therapy is in development with the intention to reduce these side effects or to replace the harmful treatments completely. Prodrug treatments need an activation agent, i.e. a catalyst, to convert the prodrug delivered to the cancerous cells to an active drug in-situ. Metals such as palladium can be used as a catalyst to activate the prodrug in targeted cancer cells. In this PhD study, the research was divided into two major aspects. The first aspect was to design and manufacture a catalyst carrier with specific properties and specifications such as biocompatibility of the materials used as the carrier, suitable mechanical properties to withstand physiological loads and conditions, and cost efficiency of the production. Two different manufacturing methods were used, Powder Metallurgy technique and Arc Melting technique, to achieve the optimal fabrication method. The carriers were characterised via XRD, SEM, EDS, DSC methods and mechanical tests to ensure the carrier meets the requirements. In the second stage, the carriers were coated with Palladium in its metallic state (i.e. Pd0). The coating was required to meet the requirements of being unalloyed, pure and free of any contamination, and its deposition cost and time effective. Four coating methods were employed. Powder Metallurgy technique and sintering (with and without space holder), Magnetron Sputtering, Pulsed Laser Deposition and Supersonic Beam Cluster Deposition methods were used to apply Palladium coating onto the carriers. The coating was characterised by XPS, XRD, FIB, XRF, SEM, EDS, biochemical and in-situ biological tests. The results obtained confirmed that the devices achieve high biocompatibility of the materials, and an excellent superelasticity can withstand the loads inside the human body. Also, the Magnetron sputtering methods as a coating method demonstrated it is the most effective for achieving a uniform and long-lasting deposited layer. The devices were able to activate a clinically approved prodrug. I Acknowledgement First, I thank Almighty Allah for being with me in this research and giving me all the power and ability to complete it. I would like to express my special thanks to my supervisors, Dr. Carmen Torres- Sánchez and Prof. Paul Conway, for the support and help during the research time. It was really a pleasure working with them on this research. I would like to thank them for the useful information related to this research and their patience to understand my needs. My special thanks to all my family members, especially my mother Mrs. Fatemah Alqasemi, who supported me during my studies and helped me a lot to complete this research successfully. Thank you for my kids Nasser and Jana for understanding the pressure and the hard work done in this research and try to help me to feel relieved. Thank you for my brothers and sisters for encouraging me to do my PhD degree and complete this research. In addition, I would like to thank Loughborough Material Characterization Centre (LMCC) for their continuous and unlimited support. Especially, Dr. Keith Yandall, Dr. David Grandy, Sam Davis and others for their help and advises. Finally, I would like to thank the Saudi Arabia government, represented by Royal Commission for Jubail and Yanbu, for the scholarship and the financial support for this research. In addition, thank you for the Saudi Cultural Bureau in London for their support and supervision during my studies in the UK. II List of Publications • Mohammad N. Alqahtani: “The Adhesion of Palladium Coating on Titanium Substrates used for Medical Applications’’, International Conference on Biomaterials 2018, 16th -18th August 2018, London, United Kingdom. • Carmen Torres-Sánchez, Ana M. Perez-Lopez, Mohammad N. Alqahtani, Asier Uncit-Broceta, Belen Rubio-Ruiz: “Design and manufacture of functional catalyst-carrier structures for the bioorthogonal activation of anticancer agents”, New J. Chem., 2019, 43,1449, accepted 10th December 2018. III Abbreviations and symbols 3DP Additive manufacturing GPa Gigapascal DED Directed energy deposition °C Celsius degree CAD Computer-aided drawing kN Kilonewton PBF Powder bed fusion mm millimetre MIM Metal injection moulding nm nanometre PM Powder metallurgy technique N Newton SP Magnetron sputtering Pd0 Palladium in its unalloyed state deposition PLD Pulsed laser deposition Ti Titanium SCBD Supersonic cluster beam Sn Tin deposition S Sintered wafers Nb Niobium Sx Sintered samples with space Ta Tantalum holder Sc Sintered samples with carrier NaCl Sodium chloride EDS Energy dispersive x-ray As Austenite start temperature spectrometry SEM Scanning electron microscope Af Austenite finish temperature XPS X-ray photoelectron Ms Martensitic start spectroscopy transformation temperature DSC Differential scanning Mf Martensitic finish temperature calorimetry XRD X-ray diffraction hcp Hexagonal closed pack PLD Pulsed laser deposition bcc Body centred cubic XRF X-ray fluorescence α Alpha phase FIB Focused ion beam β Beta phase θ Is the angle of both incidence CIP Cold isostatic pressing and reflection λ Wavelength of the illuminating %wt Percent in weight x-rays SD Standard deviation BH Before heat treatment π Pie = 3.14 AH After heat treatment ρ Density M Mass F Force A Area V Volume r Radius D Diameter h Height mbar Millibar pressure unit IV Contents Abstract........................................................................................................................................................... I Acknowledgement .................................................................................................................................... II List of Publications .................................................................................................................................. III Abbreviations and symbols ................................................................................................................. IV Contents ........................................................................................................................................................ V Table of figures ......................................................................................................................................... IX List of tables ............................................................................................................................................. XII 1 Introduction ....................................................................................................................................... 1 1.1 Background ....................................................................................................................... 1 1.2 Suitable Carrier ............................................................................................................... 3 1.2.1 Metallic Implants .................................................................................................... 4 1.2.2 Titanium and Titanium alloys ........................................................................... 4 1.3 Bioorthogonal Chemistry ............................................................................................ 5 1.4 Objectives .......................................................................................................................... 5 1.5 Contribution to Knowledge ........................................................................................ 6 1.6 Novelty Statement .......................................................................................................... 6 1.7 Research scope ................................................................................................................ 7 1.8 Summary ............................................................................................................................ 8 1.9 Thesis Outline .................................................................................................................. 9 2 Literature Review.......................................................................................................................... 11 2.1 Introduction .................................................................................................................... 11 2.2 Titanium ........................................................................................................................... 11 2.2.1 History of Titanium ............................................................................................. 11 2.2.2 Material structure of Titanium ......................................................................