Chemically modified co substituted hydroxyapatite nanomaterial for biomedical applications

CHEMICALLY-MODIFIED CO-SUBSTITUTED HYDROXYAPATITE NANOMATERIAL FOR BIOMEDICAL APPLICATIONS LIM POON NIAN NATIONAL UNIVERSITY OF SINGAPORE 2013 CHEMICALLY-MODIFIED CO-SUBSTITUTED HYDROXYAPATITE NANOMATERIAL FOR BIOMEDICAL APPLICATIONS LIM POON NIAN B.Eng.(Hons), Nanyang Technological University A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF MECHANICAL ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2013 Declaration I hereby declare that this thesis is my original work and it has been written by me in its entirety. I have duly acknowledged all the sources of information, which have been used in the thesis. This thesis has also not been submitted for any degree in any university previously. LIM POON NIAN 18 December 2013 i Abstract Bioactivity of a biomaterial plays an integral role for bone regeneration. During this process, optimal healing of the defect region is heavily reliant upon the prevention of bacterial infection after implant placement. Hydroxyapatite (HA) is commonly used as a bone replacement material, but has slow osseointegration rate and tends to represent a site of weakness for the host defence, making it susceptible to implant-related infections. The rate of osseointegration in HA can be enhanced by the substitution of silicon whilst antibacterial property can be created by the substitution of silver. Given the beneficial properties of both elements, it is thus desirable to incorporate both silver and silicon ions into HA to achieve antibacterial and enhanced osseointegration properties, respectively. Current literature reported on the use of silver-substituted HA and silicon-substituted HA. However, the cosubstitution of these two elements into HA has not been explored yet. Therefore, this motivates the development of silver, silicon co-substituted hydroxyapatite (Ag,Si-HA). In this study, Ag,Si-HA is a novel bi-functional bone graft material that possesses antibacterial and enhanced biological properties, to facilitate bone healing. A phase-pure Ag,Si-HA with a bonemimicking morphology (60 nm x 10 nm) was successfully synthesised using an aqueous precipitation technique. Phosphate, hydroxyl and silicate functional groups were observed in the FTIR spectra. Silver and silicon ions were structurally incorporated in the HA structure as reflected by the increment of the lattice parameters and unit cell volume. A silver content of 0.5 wt.% was demonstrated to produce the optimum antibacterial effect with a ii 7-log reduction in the growth of adherent Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) over a period of days. Subsequently, the antibacterial action and biological properties of Ag,Si-HA containing optimised content of 0.5 wt.% of silver and 0.7 wt.% silicon were investigated. Silver ions of Ag,Si-HA was first reported to diffuse towards the crystal surface, damaging the cell wall and thereby inducing potassium ions leakage from the adherent S. aureus. Furthermore, the substitution of silicon promoted the proliferation of human adipose-derived mesenchymal stem cells on Ag,SiHA, which in turn, permitted greater bone differentiation (alkaline phosphatase, type I collagen and osteocalcin) as compared to HA and AgHA. On the whole, this study shows that Ag,Si-HA functions by firstly allowing the incorporated silver in Ag,Si-HA to exert its antibacterial action against adherent bacteria and subsequently, the incorporated silicon promotes the bone differentiation process. All these results demonstrated that the approach of cosubstituting silver and silicon could complement their functions in the apatite by facilitating bone regeneration, to perform as an ideal bone graft material. iii Acknowledgements The following are my heartfelt appreciations to those people who gave me the support, knowledge and insight to begin, conduct and complete this thesis. First and foremost, I would like to thank my supervisors Dr. Thian Eng San and Dr. Tay Bee Yen, both of whom provided excellent support in terms of their guidance, scientific input, encouragement and opportunities. I would like to thank Prof. Ho Bow for his expert advice and help in the antibacterial work, and also to Mr. Ng Han Chong and the members of Prof Ho Bow's lab for their assistance and help when conducting the antibacterial experiments. Special thanks also go to Dr. Shi Zhilong and Dr. Teo Yiling, Erin. It is my great pleasure to work with all of them. I am grateful for their help of Dr. Li Tao, Dr. Florencia Wira, Ms. Ma Cho Cho and Ms. Xie Hong from SIMTech. Thanks to Mr. Lucas Lu for his assistance in the TEM preparation work. On a personal level, I would like to thank Dr. Thian Eng San and Dr. Tay Bee Yen for their help and time in reading the first drafts of this thesis and making valuables suggestions for its improvement. My greatest appreciations would also go to Jing Wen for reading parts of this thesis, checking and giving improvement for the grammatical errors. I would also like to say a big thank you to the members of BIOMAT lab. In particular, Ruey Na, Yi Min, Chang Lei, Zu Yong, Qinyuan, Jason, Jin Lan, iv Wu Yang and Yiling, without them the past years wouldn't have been half as much fun. I would also like to thank Mr. Thomas Tan, Mr. Khalim and Mr. Ng Hong Wei of Materials lab for their constant kind assistance. I would like to acknowledge the National University of Singapore for the financial support. Finally, I would like thank my family and friends especially Jianyi, Abriena, Jiahui, Jialing, Xiu Ning, Chew Yen, Beverly and Fan Yan for their constant friendship, patience, encouragement and support during good and bad times. v Publications, Conferences and Awards Journals: 1) Lim PN, Shi ZL, Neoh KG, Ho B, Tay BY, Thian ES. The Effects of Silver and Silicon in Co-Substituted Apatite Towards Bacteria and Cell Responses, Biomedical Materials, 2014, 9: 015010. 2) Lim PN, Teo YL E, Ho B, Tay BY, Thian ES. Effect of Silver Content on the Antibacterial and Bioactive Properties of Silver-Substituted Hydroxyapatite. Journal of Biomedical Materials Research: Part A, 2013, 101A: 2456-2464. 3) Thian ES, Chang L, Lim PN, Gurucharan B, Sun J, Fuh JYH, Ho B, Tay BY, Teo EY, Wang W. Chemically-Modified Calcium Phosphate Coatings via Drop-On-Demand Micro-Dispensing Technique. Surface & Coatings Technology, 2013, 231: 29-33. 4) Thian ES, Konishi T, Kawanobe Y, Lim PN, Choong C, Ho B, Aizawa M. Zinc-Substituted Hydroxyapatite: A Biomaterial with Enhanced Bioactivity and Antibacterial Property. Journal of Materials Science: Materials in Medicine, 2013, 24:437-445. 5) Lim PN, Tay BY, Chan ML C, Thian ES. Synthesis and Characterisation of Silver/Silicon Co-Substituted Nanohydroxyapatite Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012, 100B: 285–291. Conferences (Oral): 1) Lim PN, Chang L, Ho B, Tay BY, Choong C, Thian ES. Development of New Generation Bone Graft Material: Silicon and Silver Co-substituted Apatite with Bi-Functional Properties. Material Research Society Fall Meeting and Exhibit (MRS), Boston, Massachusetts, 1st-6th December 2013. 2) Lim PN, Teo YL E, Ho B, Tay BY, Thian ES. Silver-Substituted Hydroxyapatite: A Potential Bone Substitute Material for Postoperative Infection Treatment. International Conference of Young Researchers on Advanced Materials (ICYRAM), Singapore, 1st July- 6th July 2012. 3) Lim PN, Shi ZL, Tay BY, Neoh KG, Thian E. Silver/Silicon CoSubstituted Hydroxyapatite: A Potential Biomaterial with Antibacterial and Bioactive Properties. 9th World Biomaterials Congress (WBC), Chengdu, China, 1st June – 5th June 2012. 4) Thian ES, Lim PN, Shi Z, Tay BY, Neoh KG. Silver-Doped Apatite as a Bioactive and an Antimicrobial Bone Material. 23rd International Symposium on Ceramics in Medicine (ISCM), Istanbul, Turkey, 6th November – 9th November 2011. 5) Lim PN; Yu ET J; Thian ES, Tay BY; Chan ML C. Physiochemical Stability of Chemically-Modified Nanoapatites Sintered at Different Temperatures. Defence Science Research Conference and Expo (DSR) Singapore, 3rd August-5th August 2011. vi 6) Lim PN, Tay BY, Chan ML C, Thian ES. Silver/Silicon Co-Substituted Nanohydroxyapatite: A Novel Bone Material for Biomedical Applications. International Conference on Materials for Advanced Technologies, Singapore (ICMAT), 26th June – 1st July 2011. Conferences (Poster): 1) Lim PN, Ho B, Tay BY, Choong C, Thian ES. Development of Next Generation Bone Substitute Material: Silicon and Silver Co-Substituted Apatite with Bi-Functional Properties, SIMTech Post-Graduate Research Posters Exhibition, 16th August 2013. 2) Thian ES, Lim PN, Ho B, Teo EY, Tay BY. The Effect of Silver Concentration on Antimicrobial Property of Silver-Substituted Apatite. 9th World Biomaterials Congress, Chengdu, China, 1st June – 5th June 2012. 3) Lim PN, Ho B, Tay BY, Thian ES. Evaluation on the Antibacterial Capability of Silver-Substituted Hydroxyapatite for Implant-Associated Infection, SIMTech Post-Graduate Research Poster Exhibition, 7th September 2012. 4) Lim PN, Ho B, Chan ML C, Tay BY, Thian ES. Silver/Silicon CoSubstituted Hydroxyapatite: A New Generation of Functional Biomaterial, SIMTech Post-Graduate Research Posters Exhibition, 23 September 2011. 5) Thian ES , Lim PN, Lee LY, Zhang ZY, Tay BY, Chan J, Teoh SH Nanostructured Substituted Apatites for Bone Tissue Engineering. MRS-S Trilateral Conference, Singapore 11th August- 13 August 2010. Conference Proceedings: 1) Lim PN, Chang L, Ho B, Tay BY, Choong C, Thian ES. Development of New Generation Bone Graft Material: Silicon and Silver Co-Substituted Apatite with Bi-Functional Properties. MRS Online Proceedings Library, 2013, accepted. 2) Thian ES, Lim PN, Shi Z, Tay BY, Neoh KG. Silver-Doped Apatite as a Bioactive and an Antimicrobial Bone Material. Key Engineering Materials, 2012 (493-494), 27-30. 3) Lim PN; Yu ET J; Thian ES, Tay BY; Chan ML C. Physiochemical Stability of Chemically-Modified Nanoapatites Sintered at Different Temperatures. Defense Science Research Conference and Expo (DSR), 3rd-5th August. 2011, pp.1-4, doi: 10.1109/DSR.2011.6026836. Awards 1) SIMTech Best Ph.D Student of the Year, 15 March 2013 2) Best Poster Presenter Award (First Runner-Up) at the SIMTech PostGraduate Research Posters Exhibition, 23 September 2011 vii Table of Contents Declaration . i Abstract . ii Acknowledgements iv Publications, Conferences and Awards vi Table of Contents . viii Lists of Figures . xii Lists of Tables . xvii Lists of Symbols xviii CHAPTER INTRODUCTION 1.1 Background . 1.2 Objectives 1.3 Scope . CHAPTER LITERATURE REVIEW 2.1 Bone Physiology . 2.1.1 Structure of Bone . 2.1.2 Bone Cells 12 2.1.3 Bone Matrix . 13 2.2 Bone Repair . 17 2.2.1 Bone Graft . 18 2.2.2 Synthetic Bone Graft . 21 2.2.3 Factors Affecting Bone Healing and Implant-Related Infections . 26 2.3 Calcium Phosphate: Hydroxyapatite (HA) . 31 2.3.1 Synthesis of HA . 34 2.3.2 Crystal Structure of HA . 37 2.3.3 Substituted Apatite 39 2.3.4 Biological Properties of HA 43 2.4 Silver-Substituted Hydroxyapatite (AgHA) 48 2.4.1 Silver as an Antibacterial Agent 49 2.4.2 Synthesis of AgHA 51 2.4.3 Chemical and Physical Characterisation of AgHA . 53 2.4.4 Antibacterial Properties of AgHA . 56 viii References 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. Vaughan, J.M., The physiology of bone 1975: Clarendon Pres. Kielty, C.M., Hopkinson, I., Grant, M. E. , Connective Tissue and Its Heritable Disorders. 1993: Willey-Liss, Inc. Ascenzi, A. and Bonucci, E., The Osteon Calcification As Revealed by the Elctron Microscope 1966: Springer Berlin Heidelberg. Boskey, W. and Behiri, J.C., Structure and Formation of Bone Mineral. 1984: CRC Press Legeros, R.Z. and Legeros, J.P., Dense Hydroxyapatite. 1993: World Scientific Publishing Co. Pte.Ltd. Wolpers, G., Elektronrn-Mikroskopic Der Plasmaderivate. Grenzg Med, 1949. 2: p. 527-530. Fernandez-Moran, J. and Engstrom, A., Electron Microscopy and Xray Diffraction of Bone Biochimica et Biophysica Acta, 1957. 23: p. 260-264. Menczel, J., Posner, A. S., and Harper, R. A., Age Changes in the Crystallinity of Rat Bone Apatite Israel Journal of Medical Sciences 1965. 1: p. 251-252. Posner, A.S., Crystal Chemistry of Bone Mineral Physilogical Reviews, 1969. 49: p. 706-792. Harper, R.A. and Posner, A.S., Measurement of Non-Crystalline Calcium Phosphate in Bone Mineral Proceedings of the Society for Experimental Biology and Medicine, 1966. 122: p. 136-142. Robinson, R.A. and Watson, M.L., Crystal-Collagen Relationships in Bone as Observed in the Electron Microscope. III. Crystal and Collagen Morphology as a Function of Age Annals of the New York Academy of Sciences, 1955. 60(5): p. 596-630. Glimcher, M.J., Bonar, L.C., Grynpas, M.D., Landis, W.J., and Roufosse, A.H., Recent Studies of Bone Mineral: Is the Amorphous Calcium Phosphate Theory Valid? Journal of Crystal Growth, 1981. 53(1): p. 100-119. Legeros, R.Z. and Lazzarai, E.P., Handbook of Experimental Aspects of Oral Biochemistry 1983: CRC Press. Posner, A.S., The Chemistry of Bone Mineral Bulletin of the Hospital for Joint Diseases, 1978. 39: p. 126-144. Eanes, E.D. and Posner, A.S., The Formation and Structure of Bone Mineral 1969: Appleton-Croft. Driessens, F.C.M., Verbeeck, R.M.H., and Kiekens, P., Mechanism of Substitution in Carbonated Apatites. Zeitschrift für anorganische und allgemeine Chemie, 1983. 504(9): p. 195-200. Wang, L. and Nancollas, G.H., Calcium Orthophosphates: Crystallization and Dissolution. Chemical Reviews, 2008. 108(11): p. 4628-4669. Schwartz, R., Magnesium Metabolism 1990: Oxford University Press. Sobel, A.E., Rockenmacher, M., and Kramer, B., Composition of Bone in Relation to Blood and Diet. Journal of Biological Chemistry, 1945. 159(1): p. 159-171. Revell, P.A., Pathology of Bone. 1986: Springer-Verlag. 196 References 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. CORNELL, C.N. and LANE, J.M., Newest Factors in Fracture Healing. Clinical Orthopaedics and Related Research, 1992. 277: p. 297-311. Keating, J.F. and McQueen, M.M., Substitutes for Autologous Bone Graft in Orthopaedic Trauma Journal of Bone & Joint Surgery, British Volume, 2001. 83B(1): p. 3-8. Arrington, E.D., Smith, W.J., Chambers, H.G., Bucknell, A.L., and Davino, N.A., Complications of Iliac Crest Bone Graft Harvesting. Clinical Orthopaedics and Related Research, 1996. 329: p. 300-309. Ehrler, D.M. and Vaccaro, A.R., The Use of Allograft Bone in Lumbar Spine Surgery. Clinical Orthopaedics 2000. 371: p. 38. Enneking, W.F., Burchardt, H., and Puhl, J.J., Observations on Massive Retrieved Human Allografts. Journal of Bone & Joint Surgery, 1991. 73A: p. 1123. Muscolo, D.L., Petracchi, L.J., and Ayerza, M.A., Massive Fermoral Allografts Followed for 22 to 36 Years. Journal of Bone & Joint Surgery, 1992. 74B: p. 887. Henman, P. and Finlayson, D., Ordering Allograft by Weight: Suggestions for the Efficient Use of Frozen Bone-Graft for Impaction Grafting. The Journal of Arthroplasty, 2000. 15(3): p. 368-371. Black, J., Biological Performance of Materials. 1981: Marcel Dekker. Daniels, A.U., Chang, M.K.O., and Andriano, K.P., Mechanical Properties of Biodegradable Polymers and Composites Proposed for Internal Fixation of Bone. Journal of Applied Biomaterials, 1990. 1: p. 57-78. Jarcho, M., Bolen, C.H., Thomas, M.B., Bobick, J., Kay, J.F., and Doremus, R.H., Hydroxylapatite Synthesis and Characterization in Dense Polycrystalline Form. Journal of Materials Science, 1976. 11(11): p. 2027-2035. Hench, L.L., Bioceramics: From Concept to Clinic. Journal of the American Ceramic Society, 1991. 74(7): p. 1487-1510. Kokubo, T., Ito, S., Huang, Z.T., Hayashi, T., Sakka, S., Kitsugi, T., and Yamamuro, T., Ca,P-Rich Layer Formed on High-Strength Bioactive Glass-Ceramic A-W. Journal of Biomedical Materials Research, 1990. 24(3): p. 331-343. Bonfield, W., Grynpas, M.D., Tully, A.E., Bowman, J., and Abram, J., Hydroxyapatite Reinforced Polyethylene -- A Mechanically Compatible Implant Material for Bone Replacement. Biomaterials, 1981. 2(3): p. 185-186. Hench, L.L. and Wilson, J., An Introduction to Bioceramics. 1993: World Scientific Publishing Co. Pte. Ltd. Heimke, G., Osseo-Intergrated Implants. 1990: CRC Press. Niki, M., Ito, G., Matsuda, T., and Ogino, M., Comparative Push-Out Data of Bioactive and Non-Bioactive Materials of Similar Rugosity 1991: University of Toronto Press. Hing, K.A., Gibson, I.R., Revell, P.A., Best, S.M., and Bonfield, W. Influence of Phase Purity on the In Vivo Response to Hydroxyapatite 2001. Bioceramic 13. 13: p. 373-376. 197 References 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. Van der Stok, J., Van Lieshout, E.M.M., El-Massoudi, Y., Van Kralingen, G.H., and Patka, P., Bone Substitutes in the Netherlands - A Systematic Literature Review. Acta Biomaterialia, 2011. 7(2): p. 739750. Porter, J.R., Ruckh, T.T., and Popat, K.C., Bone Tissue Engineering: A Review in Bone Biomimetics and Drug Delivery Strategies. Biotechnology Progress, 2009. 25(6): p. 1539-1560. Mastrogiacomo, M., Muraglia, A., Komlev, V., Peyrin, F., Rustichelli, F., Crovace, A., and Cancedda, R., Tissue Engineering of Bone: Search for a Better Scaffold. Orthodontics & Craniofacial Research, 2005. 8(4): p. 277-284. Vallet-Regí, M. and González-Calbet, J.M., Calcium Phosphates as Substitution of Bone Tissues. Progress in Solid State Chemistry, 2004. 32(1-2): p. 1-31. Penttinen, R., Biochemical Studies on Fracture Healing in the Rat. Acta Chirurgica Scandinavica. Supplementum, 1972. 432. Darouiche, R.O., Anti-Infective Efficacy of Silver-Coated Medical Prostheses. Clinical Infectious Diseases, 1999. 29(6): p. 1371-1377. Jarvis, W.R., Selected Aspects of the Socioeconomic Impact of Nosocomial Infections: Morbidity, Mortality, Cost, and Prevention. Infection Control and Hospital Epidemiology, 1996. 17: p. 552-557. Stamm, W.E., Infections Related to Medical Devices. Annals of Internal Medicine, 1978. 89(5 Part 2): p. 764-769. Capanna, R., Morris, H., Campanacci, D., Del Ben, M., and Campanacci, M., Modular Uncemented Prosthetic Reconstruction After Resection of Tumours of the Distal Femur. Journal of Bone & Joint Surgery, 1994. 76-B(2): p. 178-186. Segreti, J., Prothesric Joint Infections. Current Treatment Options in Infectious Diseases, 2000. 2: p. 200-207. Virk, A. and Osman, D., Prosthetic Joint Infections. Current Treatment Options in Infectious Diseases, 2001. 3: p. 287-300. Gristina, A., Biomaterial-Centered Infection: Microbial Adhesion Versus Tissue Integration. Science, 1987. 237(4822): p. 1588-1595. Mack, D., Becker, P., Chatterjee, I., Dobinsky, S., Knobloch, J.K.M., Peters, G., Rohde, H., and Herrmann, M., Mechanisms of Biofilm Formation in Staphylococcus Epidermidis and Staphylococcus Aureus: Functional Molecules, Regulatory Circuits, and Adaptive Responses. International Journal of Medical Microbiology, 2004. 294(2–3): p. 203-212. Zimmerli, W., Lew, P.D., and Waldvogel, F.A., Pathogenesis of Foreign Body Infection. Evidence for a Local Granulocyte Defect. The Journal of Clinical Investigation, 1984. 73(4): p. 1191-1200. Campoccia, D., Montanaro, L., and Arciola, C.R., The Significance of Infection Related to Orthopedic Devices and Issues of Antibiotic Resistance. Biomaterials, 2006. 27(11): p. 2331-2339. Zilberman, M. and Elsner, J.J., Antibiotic-Eluting Medical Devices for Various Applications. Journal of Controlled Release, 2008. 130(3): p. 202-215. 198 References 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. Schnieders, J., Gbureck, U., Thull, R., and Kissel, T., Controlled Release of Gentamicin from Calcium Phosphate--Poly(lactic acid-coglycolic acid) Composite Bone Cement. Biomaterials, 2006. 27(23): p. 4239-4249. Takechi, M., Miyamoto, Y., Ishikawa, K., Nagayama, M., Kon, M., Asaoka, K., and Suzuki, K., Effects of Added Antibiotics on the Basic Properties of Anti-Washout-Type Fast-Setting Calcium Phosphate Cement. Journal of Biomedical Materials Research, 1998. 39(2): p. 308-316. Van de Belt, H., Neut, D., Schenk, W., van Horn, J.R., van der Mei, H.C., and Busscher, H.J., Infection of Orthopedic Implants and the Use of Antibiotic-Loaded Bone Cements - A Review. Acta Orthopaedica Scandinavica, 2001. 72(6): p. 557-571. Ip, M., Lui, S.L., Poon, V.K.M., Lung, I., and Burd, A., Antimicrobial Activities of Silver Dressings: An In Vitro Comparison. Journal of Medical Microbiology, 2006. 55(1): p. 59-63. Taylor, P.L., Ussher, A.L., and Burrell, R.E., Impact of Heat on Nanocrystalline Silver Dressings: Part I: Chemical and Biological Properties. Biomaterials, 2005. 26(35): p. 7221-7229. Rupp, M.E., Fitzgerald, T., Marion, N., Helget, V., Puumala, S., Anderson, J.R., and Fey, P.D., Effect of Silver-Coated Urinary Catheters: Efficacy, Cost-Effectiveness, and Antimicrobial Resistance. American Journal of Infection Control, 2004. 32(8): p. 445-450. Bohner, M., Calcium Orthophosphates in Medicine: from Ceramics to Calcium Phosphate Cements. Injury, 2000. 31(Supplement 4): p. D37D47. Ravagliolo, A.a.K., A., Bioceramic: Material Properties Applications. 1992: Chapman and Hall. Osborn, J.F. and Newesely, H., The Material Science of Calcium Phosphate Ceramics. Biomaterials, 1980. 1(2): p. 108-111. Gauthier, O., Goyenvalle, E., Bouler, J.M., Guicheux, J., Pilet, P., Weiss, P., and Daculsi, G., Macroporous Biphasic Calcium Phosphate Ceramics versus Injectable Bone Substitute: A Comparative Study and Weeks after Implantation in Rabbit Bone. Journal of Materials Science: Materials in Medicine, 2001. 12(5): p. 385-390. De Jong, W.F., Le Substance Minerale Dans Le Os. Recueil des Travaux Chimiques des Pays-Bas, 1926. 45: p. 445. Denissen, H.W., Van Dijk, H.J.A., De Groot, K., Klopper, P.J., Vermeiden, J.P.W., and Gehring, A.P., Biological and Mechanical Evaluation of Dense Calcium Hydroxyapatite made by Continuous Hot Pressing. 1980: John Willey and Sons. Oosterbos, C., Rahmy, A., Tonino, A., and Witpeerd, W., High Survival Rate of Hydroxyapatite-Coated Hip Prostheses: 100 Consecutive Hips followed for 10 Years. Acta Orthopaedica Scandinavica, 2004. 75: p. 127-33. Capello, W., Antonio, J.D., Manley, M., and Feinberg, J., Hydroxyapatite in Total Hip Arthroplasty-Clinical Results and Critical 199 References 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. Issues Clinical Orthopaedics and Related Research, 1998. 355: p. 20011. Costantino, P.D., Chaplin, J.M., Wolpoe, M.E., Catalano, P.J., Sen, C., Bederson, J.B., and Govindaraj, S., Applications of Fast-Setting Hydroxyapatite Cement: Cranioplasty. Otolaryngology -- Head and Neck Surgery, 2000. 123(4): p. 409-412. Burstein, F.D., Cohen, S.R., Hudgins, R., Boydston, W., and Simms, C., The Use of Hydroxyapatite Cement in Secondary Craniofacial Reconstruction. Plastic and Reconstructive Surgery, 1999. 104(5): p. 1270-1275. Ueda, M., Yamada, Y., and Ozawa, R., Clincal Case Reports of Injectable Tissue-Engineered Bone for Alveolar Augmentation with Simultaneous Implant Placement International Journal of Periodontics and Restorative Dentistry, 2005. 25: p. 129-37. Knowles, J.C., Hastings, G.W., Ohta, H., Niwa, S., and Boeree, N., Development of a Degradable Composite for Orthopaedic Use: In Vivo Biomechanical and Histological Evaluation of Two Bioactive Degradable Composites Based on the Polyhydroxybutyrate Polymer. Biomaterials, 1992. 13(8): p. 491-496. Doyle, C., Tanner, E.T., and Bonfield, W., In Vitro and In Vivo Evaluation of Polyhydroxybutyrate and of Polyhydroxybutyrate Reinforced with Hydroxyapatite. Biomaterials, 1991. 12(9): p. 841-847. Bonfield, W., Doyle, C., and Tanner, K.E., Biological and Biomedical Perfomance of Biomaterials. 1986: Christel, P., Meunier, A. and Lee, A.J.C.(eds), Elsevier. Rathje, W., Zur Kentnis De Phosphate I. Uber hydroxyapatite. Bodenk Pflernah, 1939. 12: p. 121-128. Hayek, E., Newesely, H., and Rumpel, M.L., Inorganic Syntheses. 1963: John Wiley & Sons Inc. Royer, A., Viguie, J.C., Heughebaert, M., and Heughebaert, J.C., Stoichiometry of Hydroxyapatite: Influence on the Flexural Strength. Journal of Materials Science: Materials in Medicine, 1993. 4(1): p. 7682. Akao, M., Aoki, H., and Kato, K., Mechanical Properties of Sintered Hydroxyapatite for Prosthetic Applications. Journal of Materials Science, 1981. 16(3): p. 809-812. Giannoudis, P.V., Dinopoulos, H., and Tsiridis, E., Bone Substitutes: An Update. Injury, 2005. 36(3, Supplement 1): p. S20-S27. Gibson, I.R., Best, S.M., and Bonfield, W., Effect of Silicon Substitution on the Sintering and Microstructure of Hydroxyapatite. Journal of the American Ceramic Society, 2002. 85(11): p. 2771-2777. Fang, Y., Agrawal, D.K., Roy, D.M., and Roy, R., Fabrication of Porous Hydroxyapatite Ceramics by Microwave Processing. Journal of Materials Research, 1992. 7(02): p. 490-494. Monma, H., Ueno, S., and Kanazawa, T., Properties of Hydroxyapatite Prepared by the Hydrolysis of Tricalcium Phosphate. Journal of Chemical Technology and Biotechnology, 1981. 31(1): p. 15-24. 200 References 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. Rootare, H.M. and Craig, R.G., Charecterization of Hydroxyapatite Powders and Compacts at Room Temperature and After Sintering at 1200°C. Journal of Oral Rehabilitation, 1978. 5(3): p. 293-307. Legeros, R.Z., Calcium Phosphates in Oral Biology and Medicine Chemical Reviews, 2008. 108(11): p. 4742-4753. Perloff, A. and Posner, A.S., Preparation of Pure Hydroxyapatite Crystals. Science, 1956. 124(3222): p. 583-584. Narasaraju, T.S.B., Rao, V.L.N., and Rai, U.S., Preparation and Some Physicochemical Aspects of Hydroxypatite and Fluorapatite Indian Journal of Chemistry, 1975. 13: p. 369-375. Naray-Szabo, S., The Structure of Apatite (CaF) Ca4(PO4)3. Zeits Krist, 1930. 75(387-398). Mehmel, M., Über die Strucktur des Apatits I. Zeits Krist, 1930. 75: p. 323-331. Posner, A.S., Perloff, A., and Dionio, A.F., Refinement of the Hydroxyapatite Structure Acta Crystallographica, 1958. 11: p. 308309. M.I., K., Young, R.A., and Posner, A.S., Crystal Structure of Hydroxyapatite. Nature, 1964. 204(4963): p. 1050-1052. Mori.K., Oshiba, M., Hara, T., Mizugaki, T., Ebitani, K., and Kaneda, K., Creation of Monomeric La Complexes on Apatite Surfaces and Their Application as Hetergeneous Catalysts for Michael Reactions. . New Journal of Chemistry, 2006. 30: p. 44. Terra, J., Dourado, E.R., Eon, J.-G., Ellis, D.E., Gonzalez, G., and Rossi, A.M., The Structure of Strontium-Doped Hydroxyapatite: An Experimental and Theoretical Study. Physical Chemistry Chemical Physics, 2009. 11(3): p. 568-577. Park, J.B. and Brozino, J.D., Biomaterials: Prinicples and Applications. 2003: CRC Press. Boanini, E., Gazzano, M., and Bigi, A., Ionic Substitutions in Calcium Phosphates Synthesized at Low Temperature. Acta Biomaterialia, 2010. 6(6): p. 1882-1894. LeGeros, R.Z., LeGeros, J.P., Trautz, O.R., and Klein, E., Spectral Properties of Carbonate in Carbonate-Containing Apatites Developments in Applied Spectroscopy 1970. 7B: p. 3-12. Zipkin, Biological Minerlization. 1973: Wiley-interscience. Legeros, R.Z., Apatites in Biological Systems. Progress in Crystal Growth and Characterization of Materials, 1981. 4: p. 1-45. Yasukawa, A., Ouchi, S., Kandori, K., and Ishikawa, T., Preparation and Characterization of Magnesium-Calcium Hydroxyapatites. Journal of Materials Chemistry, 1996. 6: p. 1401. Matsunaga, K., Murata, H., and Shitara, K., Theoretical Calculations of the Thermodynamic Stability of Ionic Substitutions in Hydroxyapatite Under an Aqueous Solution Environment. Journal of Physics: Condensed Matter, 2010. 22(38): p. 384210. De Maeyer, E.A.P., Verbeeck, Ronald M. H., Possible Substitution Mechanisms for Sodium and Carbonate in Calciumhydroxyapatite. Bulletin des Sociétés Chimiques Belges, 1993. 102(9): p. 601-609. 201 References 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. 171. LeGeros, R.Z., Trautz, D.R., Klein, E., and LeGeros, J.P., Two Types of Carbonate Substitution in the Apatite Structure Experimentia, 1969. 25: p. 5-7. Legero, R.Z., Effect of Carbonate on the Lattice Parameters of Apatite. Nature 1965. 205: p. 403-404. Hayakawa, S., Kanaya, T., Tsuru, K., Shirosaki, Y., Osaka, A., Fujii, E., Kawabata, K., Gasqueres, G., Bonhomme, C., Babonneau, F., Jäger, C., and Kleebe, H.-J., Heterogeneous Structure and In Vitro Degradation Behavior of Wet-Chemically Derived Nanocrystalline Silicon-Containing Hydroxyapatite Particles. Acta Biomaterialia, 2013. 9(1): p. 4856-4867. Gomes, S., Nedelec, J.M., Jallot, E., Sheptyakov, D., and Renaudin, G., Silicon Location in Silicate-Substituted Calcium Phosphate Ceramics Determined by Neutron Diffraction. Crystal Growth & Design, 2011. 11(9): p. 4017-4026. Arcos, D., Rodríguez-Carvajal, J., and Vallet-Regí, M., The Effect of the Silicon Incorporation on the Hydroxylapatite Structure. A Neutron Diffraction Study. Solid State Sciences, 2004. 6(9): p. 987-994. LeGeros, R.Z., Properties of Osteoconductive Biomaterials: Calcium Phosphates. Clinical Orthopaedics and Related Research, 2002. 395: p. 81-98. Dorozhkin, S.V. and Epple, M., Biological and Medical Significance of Calcium Phosphates. Angewandte Chemie International Edition, 2002. 41(17): p. 3130-3146. Hing, K.A., Bioceramic Bone Graft Substitutes: Influence of Porosity and Chemistry. International Journal of Applied Ceramic Technology, 2005. 2(3): p. 184-199. Eniwumide, J.O., Yuan, H., Cartmell, S.H., Meijer, G.J., and De Brujin, J.D., Ectopic Bone Formation in Bone Marrow Stem Cell Seeded Calcium Phosphate Scaffolds as Compared to Autograft and (Cell Seeded) Allograft. European Cells and Materials 2007. 14. Tay, B.K., Patel, V.V., and Bradford, D.S., Calcium Sulfate- and Calcium Phosphate-Based Bone Substitutes. Mimicry of the Mineral Phase of Bone. Orthopedic Clinics of North America 1999. 30: p. 61523. Schepers, E., Clercq, M.D., Ducheyne, P., and Kempeneers, R., Bioactive Glass Particulate Material as a Filler for Bone Lesions. Journal of Oral Rehabilitation, 1991. 18(5): p. 439-452. Daculsi, G., Legeros, R.Z., Nery, E., Lynch, K., and Kerebel, B., Transformation of Biphasic Calcium Phosphate Ceramics In Vivo: Ultrastructural and Physicochemical Characterization. Journal of Biomedical Materials Research, 1989. 23(8): p. 883-894. Anselme, K., Noël, B., Flautre, B., Blary, M.C., Delecourt, C., Descamps, M., and Hardouin, P., Association of Porous Hydroxyapatite and bone Marrow Cells for Bone Regeneration. Bone, 1999. 25(2): p. 51S-54S. Yazdi, M., Bernick, S., Paule, W.J., and Nimni, M.E., Postmortem Degradation of Demineralized Bone Matrix Osteoinductive Potential: 202 References 172. 173. 174. 175. 176. 177. 178. 179. 180. 181. 182. 183. 184. 185. Effect of Time and Storage Temperature. Clinical Orthopaedics and Related Research, 1991. 262: p. 281-285. Aspenberg, P., Johnsson, E., and Thorngren, K., Dose-Dependent Reduction of Bone inductive Properties by Ethylene Oxide. Journal of Bone & Joint Surgery, 1990. 72-B(6): p. 1036-1037. Ando, Y., Miyamoto, H., Noda, I., Sakurai, N., Akiyama, T., Yonekura, Y., Shimazaki, T., Miyazaki, M., Mawatari, M., and Hotokebuchi, T., Calcium Phosphate Coating Containing Silver shows High Antibacterial Activity and Low Cytotoxicity and Inhibits Bacterial Adhesion. Materials Science and Engineering: C, 2010. 30(1): p. 175180. Campbell, A.A., Song, L., Li, X.S., Nelson, B.J., Bottoni, C., Brooks, D.E., and DeJong, E.S., Development, Characterization, and AntiMicrobial Efficacy of Hydroxyapatite-Chlorhexidine Coatings Produced by Surface-Induced Mineralization. Journal of Biomedical Materials Research, 2000. 53(4): p. 400-407. Melville, A., Rodríguez-Lorenzo, L., and Forsythe, J., Effects of Calcination Temperature on the Drug Delivery Behaviour of Ibuprofen from Hydroxyapatite Powders. Journal of Materials Science: Materials in Medicine, 2008. 19(3): p. 1187-1195. Gosheger, G., Hardes, J., Ahrens, H., Streitburger, A., Buerger, H., Erren, M., Gunsel, A., Kemper, F.H., Winkelmann, W., and von Eiff, C., Silver-Coated Megaendoprostheses in a Rabbit Model--An Analysis of the Infection Rate and Toxicological Side Effects. Biomaterials, 2004. 25(24): p. 5547-5556. Klasen, H.J., Historical Review of the Use of Silver in the Treatment of Burns. I. Early Uses. Burns, 2000. 26(2): p. 117-130. Lansdown, A., Silver. II. Toxicity in Mammals and How Its Products Aid Wound Repair. Journal of Wound Care, 2002. 11(5): p. 173-177. Lansdown, A.B., Silver. I. Its Antibacterial Properties and Mechanism of Action. Journal of Wound Care, 2002. 11(4): p. 125-130. Oh, K.S., Park, S.H., and Jeong, Y.K. Cytotoxicity and Antimicrobial Effect of Ag Doped Hydroxyapatite. 2004. Key Engineering Materials. 264-268: p. 2107-2110. Bellantone, M., Williams, H.D., and Hench, L.L., Broad-Spectrum Bactericidal Activity of Ag2O-Doped Bioactive Glass. Antimicrobial Agents and Chemotherapy, 2002. 46(6): p. 1940-1945. Kawashita, M., Tsuneyama, S., Miyaji, F., Kokubo, T., Kozuka, H., and Yamamoto, K., Antibacterial Silver-Containing Silica Glass Prepared by Sol-Gel Method. Biomaterials, 2000. 21(4): p. 393-398. Schreurs W, R.H., Effect of silver ions on transport and retention of phosphate by Escherichia coli. J Bacteriol, 1982. 152: p. 7-13. Chen, W., Liu, Y., Courtney, H.S., Bettenga, M., Agrawal, C.M., Bumgardner, J.D., and Ong, J.L., In Vitro Anti-Bacterial and Biological Properties of Magnetron Co-Sputtered Silver-Containing Hydroxyapatite Coating. Biomaterials, 2006. 27(32): p. 5512-5517. Holt, K.B. and Bard, A.J., Interaction of Silver(I) Ions with the Respiratory Chain of Escherichia coli:  An Electrochemical and 203 References 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. Scanning Electrochemical Microscopy Study of the Antimicrobial Mechanism of Micromolar Ag+. Biochemistry, 2005. 44(39): p. 1321413223. Liau, S.Y., Read, D.C., Pugh, W.J., Furr, J.R., and Russell, A.D., Interaction of Silver Nitrate with Readily Identifiable Groups: Relationship to the Antibacterial Action of Silver Ions. Letters in Applied Microbiology, 1997. 25(4): p. 279-283. Petering, H.G., Pharmacology and Toxicology of Heavy Metals: Silver. Pharmacology & Therapeutics. Part A: Chemotherapy, Toxicology and Metabolic Inhibitors, 1976. 1(2): p. 127-130. Russell, A.D. and Hugo, W.B., Antimicrobial Activity and Action of Silver. Progress in Medicinal Chemistry, 1994. 31: p. 351-370. Feng, Q.L., Wu, J., Chen, G.Q., Cui, F.Z., Kim, T.N., and Kim, J.O., A Mechanistic Study of the Antibacterial Effect of Silver Ions on Escherichia Coli and Staphylococcus Aureus. Journal of Biomedical Materials Research, 2000. 52(4): p. 662-668. Yamanaka, M., Hara, K., and Kudo, J., Bactericidal Actions of a Silver Ion Solution on Escherichia coli, Studied by Energy-Filtering Transmission Electron Microscopy and Proteomic Analysis. Applied and Environmental Microbiology, 2005. 71(11): p. 7589-7593. Yang, W., Shen, C., Ji, Q., An, H., Wang, J., Liu, Q., and Zhang, Z., Food Storage Material Silver Nanoparticles Interfere with DNA Replication Fidelity and Bind with DNA. Nanotechnology, 2009. 20(8): p. 085102. Hwang, E., Lee, J., Chae, Y., Kim, Y., Kim, B., Sang, B., and Gu, M., Analysis of the Toxic Mode of Action of Silver Nanoparticles Using Stress-Specific Bioluminescent Bacteria. Small, 2008. 4: p. 746-750. Kim, J., Kuk, E., Yu, K., Kim, J., Park, S., Lee, H., Kim, S., Park, Y., Park, Y., Hwang, C., Kim, Y., Lee, Y., Jeong, D., and Cho, M., Antimicrobial Effects of Silver Nanoparticles. Nanomedicine: Nanotechnology, 2007. 3: p. 95-101. Choi O, H.Z., Size dependent and reactive oxygen species related nanosilver toxicity to nitrifying bacteria. Environ Sci Technol, 2008. 42: p. 4583-4588. Raffi, M., Hussain, Bhatti, T., Akhter, J., Hameed, A., and Hasan, M., Antibacterial Characterization of Silver Nanoparticles Against E. Coli ATCC-15224. Journal of Materials Science and Technology, 2008. 24: p. 192-196. Jung, W.K., Koo, H.C., Kim, K.W., Shin, S., Kim, S.H., and Park, Y.H., Antibacterial Activity and Mechanism of Action of the Silver Ion in Staphylococcus aureus and Escherichia coli. Applied and Environmental Microbiology, 2008. 74(7): p. 2171-2178. Jelínek, M., Weiserová, M., Kocourek, T., Zezulová, M., and Strnad, J., Biomedical Properties of Laser Prepared Silver-Doped Hydroxyapatite. Laser Physics, 2011. 21(7): p. 1265-1269. Noda, I., Miyaji, F., Ando, Y., Miyamoto, H., Shimazaki, T., Yonekura, Y., Miyazaki, M., Mawatari, M., and Hotokebuchi, T., Development of Novel Thermal Sprayed Antibacterial Coating and Evaluation of 204 References 199. 200. 201. 202. 203. 204. 205. 206. 207. 208. 209. Release Properties of Silver Ions. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2009. 89B(2): p. 456-465. Chen, Y., Zheng, X., Xie, Y., Ding, C., Ruan, H., and Fan, C., AntiBacterial and Cytotoxic Properties of Plasma Sprayed SilverContaining HA Coatings. Journal of Materials Science: Materials in Medicine, 2008. 19(12): p. 3603-3609. Sygnatowicz, M., Keyshar, K., and Tiwari, A., Antimicrobial Properties of Silver-Doped hydroxyapatite Nano-Powders and Thin Films. Journal of the Minerals, Metals and Materials Society, 2010. 62(7): p. 65-70. Chen, W., Oh, S., Ong, A.P., Oh, N., Liu, Y., Courtney, H.S., Appleford, M., and Ong, J.L., Antibacterial and osteogenic properties of silver-containing hydroxyapatite coatings produced using a sol gel process. Journal of Biomedical Materials Research Part A, 2007. 82A(4): p. 899-906. Zyman, Z., Rokhmistrov, D., Ivanov, I., and Epple, M., The Influence of Foreign Ions on the Crystal Lattice of Hydroxyapatite upon Heating. Materialwissenschaft und Werkstofftechnik, 2006. 37(6): p. 530-532. Chung, R.J., Hsieh, M.F., Huang, C.W., Perng, L.H., Wen, H.W., and Chin, T.S., Antimicrobial Effect and Human Gingival Biocompatibility of Hydroxyapatite Sol-Gel Coatings. Journal of Biomedical Materials Research Part B, 2006. 76B: p. 169-178. Chung, R.J., Hsieh, M.F., Huang, K.C., Perng, L.H., Chou, F.I., and Chin, T.S., Anti-Microbial Hydroxyapatite Particles Synthesized by a Sol–Gel Route. Journal of Sol-Gel Science and Technology, 2005. 33(2): p. 229-239. Singh, B., Dubey, A.K., Kumar, S., Saha, N., Basu, B., and Gupta, R., In Vitro Biocompatibility and Antimicrobial Activity of Wet Chemically Prepared Ca10−xAgx(PO4)6(OH)2 (0.0 £ x £ 0.5) Hydroxyapatites. Materials Science and Engineering: C, 2011. 31(7): p. 1320-1329. Bai, X., More, K., Rouleau, C.M., and Rabiei, A., Functionally Graded Hydroxyapatite Coatings Doped with Antibacterial Components. Acta Biomaterialia, 2010. 6(6): p. 2264-2273. Yang, L., Ning, X., Xiao, Q., Chen, K., and Zhou, H., Development and Characterization of Porous Silver-Incorporated Hydroxyapatite Ceramic for Separation and Elimination of Microorganisms. Journal of Biomedical Materials Research Part B, 2007. 81B(1): p. 50-56. Badrour, L., Sadel, A., Zahir, M., Kimakh, L., and El Hajbi, A., Synthesis and Physical and Chemical Characterization of Ca10xAgx(PO4)6(OH)2-xx apatites. Annales de Chimie Science des Matériaux, 1998. 23(1-2): p. 61-64. ukomanovi , M., ko, I., Pol an ek, I., skokovi , D., kapin, S.o.D., and Suvorov, D., The Growth of Silver Nanoparticles and Their Combination with Hydroxyapatite To Form Composites via a Sonochemical Approach. Crystal Growth & Design, 2011. 11(9): p. 3802-3812. 205 References 210. 211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. Wu, X., Li, J., Wang, L., Huang, D., Zuo, Y., and Li, Y., The Release Properties of Silver Ions from Ag-nHA/TiO /PA66 Antimicrobial Composite Scaffolds. Biomedical Materials, 2010. 5(4): p. 044105. Benger, J.R., Kelly, A.J., and Winson, I., G., Does Early Wound Infection after Elective Orthopaedic Surgery lead on to Chronic Sepsis? Journal of the Royal College of Surgeons of Edinburgh, 1998. 43(1): p. 43-44. Hu, C., Guo, J., Qu, J., and Hu, X., Efficient Destruction of Bacteria with Ti(IV) and Antibacterial Ions in Co-Substituted Hydroxyapatite Films. Applied Catalysis B: Environmental, 2007. 73(3-4): p. 345-353. Chen, Y., Zheng, X., Xie, Y., Ji, H., and Ding, C., Antibacterial Properties of Vacuum Plasma Sprayed Titanium Coatings after Chemical Treatment. Surface and Coatings Technology, 2009. 204(5): p. 685-690. Choi, J.W., Cho, H.M., Kwak, E.K., Kwon, T.G., Ryoo, H.M., Jeong, Y.K., Oh, K.S., and Shin, H.I. Effect of Ag-Doped Hydroxyapatite as a Bone Filler for Inflamed Bone Defects 2004. Key Engineering Materials. 254-256: p. 47-50. Vik, H., Andersen, K.J., Julshamn, K., and Todnem, K., Neuropathy caused by Silver Absorption from Arthroplasty Cement. Lancet, 1985. 325: p. 872. Hidalgo, E. and Domínguez, C., Study of Cytotoxicity Mechanisms of Silver Nitrate in Human Dermal Fibroblasts. Toxicology Letters, 1998. 98(3): p. 169-179. Leaper, D.L., Silver Dressings: Their Role in Wound Management International Wound Journal, 2006. 3(4): p. 282-294. Marchat, D., Zymelka, M., Coelho, C., Gremillard, L., Joly-Pottuz, L., Babonneau, F., Esnouf, C., Chevalier, J., and Bernache-Assollant, D., Acurate Characterisation of Pure Silicon-Substituted Hydroxyapatite Powders Synthesized by a New Precipitation Route. Acta Biomaterialia, 2013. 9: p. 6992-7004. Pietak, A.M., Reid, J.W., Stott, M.J., and Sayer, M., Silicon Substitution in the Calcium Phosphate Bioceramics. Biomaterials, 2007. 28(28): p. 4023-4032. Vallet-Regi, M. and Arcos, D., Silicon substituted hydroxyapatites. A method to upgrade calcium phosphate based implants. Journal of Materials Chemistry, 2005. 15(15): p. 1509-1516. Porter, A.E., Patel, N., Skepper, J.N., Best, S.M., and Bonfield, W., Effect of Sintered Silicate-Substituted Hydroxyapatite on Remodelling Processes at the Bone-Implant Interface. Biomaterials, 2004. 25(16): p. 3303-3314. Porter, A.E., Botelho, C.M., Lopes, M.A., Santos, J.D., Best, S.M., and Bonfield, W., Ultrastructural Comparison of Dissolution and Apatite Precipitation on Hydroxyapatite and Silicon-Substituted Hydroxyapatite In Vitro and In Vivo. Journal of Biomedical Materials Research Part A, 2004. 69A(4): p. 670-679. Patel, N., Follon, E.L., Gibson, I.R., Best, S.M., and Bonfield, W. Comparision of Sintering and Mechanical Properties of 206 References 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. Hydroxyapatite and Silicon-Substituted Hydroxyapatite. 2002. Key Engineering Materials. 240-242: p. 919-922. Reffitt, D.M., Ogston, N., Jugdaohsingh, R., Cheung, H.F.J., Evans, B.A.J., Thompson, R.P.H., Powell, J.J., and Hampson, G.N., Orthosilicic Acid Stimulates Collagen Type Synthesis and Osteoblastic Differentiation in Human Osteoblast-Like Cells In Vitro. Bone, 2003. 32(2): p. 127-135. Schwarz, K. and Milne, D.B., Growth Promoting Effects of Silicon in Rats. Nature, 1972. 239: p. 465-482. Carlisle, E.M., The Nutritional Essentiality of Silicon. Nutrition Reviews, 1982. 40(7): p. 193-198. Jugdaohsingh, R., Calomme, M.R., ., Robinson, K., Nielsen, F., Anderson, S.H., D'Haese, P., Geusens, P., Loveridge, N., Thompson, R.P., and Powell, J.J., Increased Longitudinal Growth in Rats on a Silicon-Depleted Diet. Bone, 2008. 43: p. 596-606. Arumugam, M.Q., Ireland, D.C., Brooks, R.A., Rushton, N., and Bonfield, W. Orthosilicic Acid Increases Collagen Type I mRNA Expression in Human Bone-Derived Osteoblasts In Vitro. 2003. Key Engineering Materials. 254-256: p. 869-873. Hench, L.L., Life and Death: The Ultimate Phase Transformation. Thermochim Acta, 1996. 280/281: p. 1-13. Hidebrand, M., Higgins, D.R., Busser, K., and Volcani, B.E., Silicon Responsive c-DNA Clone Isolated from the Marine Diatom Cylindrotheca Fusiformis. Gene, 1993. 132: p. 213-218. Hench, L.L. and Andersson, O., Bioactive Glasses. 1993: World Scientific Publishing Co. Pte. Ltd. . Kokubo, T., Ito, S., Huang, Z.T., Hayashi, T., Sakka, S., Kitsugi, T., and Yamamuro, T., CA. P-Rich Layer Formed on High-Strength Bioactive Glass-Ceramic A-W. Journal of Biomedical Materials Research, 1990. 24: p. 331-343. Kokubo, T., Ito, S., Shigematsu, M., Sakka, S., and Yamamuro, T., Mechnical Properties of a New Type of Apatite-Containing GlassCeramic for Prosthetic Application Journal of Materials Science, 1985. 20: p. 2001-2004. Kokubo, T., Kim, H.M., Kawashita, M., and Nakamura, T., What Kinds of Materials Exhibit Bone-Bonding? 2000: Em Squared Wilson, J., Yli-Urpo, A., and Risto-Rekka, H., Bioactive Glasses: Clincal Applications. 1993: World Scientific Publishing Co. Pte. ltd. Hench, L.L., Glass Surfaces. Journals of Physics, 1982. 43: p. 625-636. Tanizawa, Y. and Suzuki, T., X-Ray Photoelectron Spectroscopy Study of Silicate-Containing Apatite. Phosphorus Research Bulletin, 1994. 4: p. 83-88. Sugiyama, K., Suzuki, T., and Satoh, T., Bactericidal Activity of Silicate-Containing Hydroxyapatite Journal of Antibacterial and Antifungal Agents, 1995. 23: p. 67-71. Boyer, L., Carpena, J., and Lacout, J.L., Synthesis of PhosphateSilicate Apatites at Atmospheric Pressure. Solid State Ionics, 1997. 95(1-2): p. 121-129. 207 References 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. Gibson, I.R., JHA, L.J., Santo, J.D., Best, S.M., and Bonfield, W., Effect of Silicon Content on the Chemical and Phase Composition of Novel Silicon-Substituted Hydroxyapatites 1998: World Scientific Publishing Co. Pte. Ltd. Arcos, D., Rodríguez-Carvajal, J., and Vallet-Regí, M., Silicon Incorporation in Hydroxylapatite Obtained by Controlled Crystallization. Chemistry of Materials, 2004. 16(11): p. 2300-2308. Elliot, J.C., Structure and Chemistry of the Apatites and Other Calcium Orthophosphates. 1994: Elsevier. Okada, K., Kameshima, Y., and Yasumori, A., Chemical Shifts of Silicon X-ray Photoelectron Spectra by Polymerization Structures of Silicates. Journal of the American Ceramic Society, 1998. 81(7): p. 1970-1972. Hartmann, P., Barth, S., Vogel, J., and Meyer, K., Solid State NMR, Xray Diffraction, and Infrared Characterization of Local Structure in Heat-Treated Oxyhydroxyapatite Microcrystals: An Analog of the Thermal Decomposition of Hydroxyapatite during Plasma-Spray Procedure. Journal of Solid State Chemistry, 2001. 160: p. 460-468. Gasquères, G., Bonhomme, C., Maquet, J., Babonneau, F., Hayakawa, S., Kanaya, T., and Osaka, A., Revisiting Silicate Substituted Hydroxyapatite by Solid-State NMR Magnetic Resonance in Chemistry, 2008. 46: p. 42-46. Vandiver, J., Dean, D., Patel, N., Botelho, C., Best, S.M., Santos, J.D., Lopes, M.A., Bonfield, W., and Ortiz, C., Silicon Addition to Hydroxyapatite Increases Nanoscale Electrostatic, Wan Der Waals, and Adhesive Interactions. Journal of Biomedical Materials Research Part A, 2006. 78A(2): p. 352-363. Raemdonck, W.V., Ducheyne, P., and De Messster, P., Metal and Ceramic Biomaterials. 1984: CRC Press Weiner, S. and Price, P., Disaggregation of Bone into Crystals. Calcified Tissue International, 1986. 39(6): p. 365-375. Thian, E.S., Huang, J., Best, S.M., Barber, Z.H., and Bonfield, W., Novel Silicon-Doped Hydroxyapatite (Si-HA) for Biomedical Coatings: An In Vitro Study using Acellular Simulated Body Fluid. Journal of Biomedical Materials Research Part B, 2006. 76B(2): p. 326-333. Thian, E.S., Ahmad, Z., Huang, J., Edirisinghe, M.J., Jayasinghe, S.N., Ireland, D.C., Brooks, R.A., Rushton, N., Bonfield, W., and Best, S.M., The Role of Electrosprayed Apatite Nanocrystals in Guiding Osteoblast Behaviour. Biomaterials, 2008. 29(12): p. 1833-1843. Lai, W., Garino, J., and Ducheyne, P., Silicon Excretion from Bioactive Glass Implanted in Rabbit Bone. Biomaterials, 2002. 23(1): p. 213-217. Apatech., L. 2007: 370 Centennial Avenue, Centennial park, Elstree, Hertfordshire, WD63TJ, UK. Vignoles, M., Bonel, G., Holcomb, D., and Young, R., Influence of Preparation Conditions on the Composition of Type B Carbonated Hydroxyapatite and on the Localization of the Carbonate Ions. Calcified Tissue International, 1988. 43(1): p. 33-40. 208 References 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267. Vignoles, M., Bonel, G., and Young, R., Occurrence of Nitrogenous Species in Precipitated B-Type Carbonated Hydroxyapatites. Calcified Tissue International, 1987. 40(2): p. 64-70. Featherstone, J., Mayer, I., Driessens, F., Verbeeck, R., and Heijligers, H., Synthetic Apatites Containing Na, Mg, and CO3 and Their Comparison with Tooth Enamel Mineral. Calcified Tissue International, 1983. 35(1): p. 169-171. Stephen, J.A., Skakle, J.M.S., and Gibson, I.R. Synthesis of Novel High Silicate-Substituted Hydroxyapatite by Co-Substitution Mechanisms. 2007. Key Engineering Materials. 330-332. Aina, V., Lusvardi, G., Annaz, B., Gibson, I.R., Imrie, F.E., Malavasi, G., Menabue, L., Cerrato, G., and Martra, G., Magnesium- and Strontium-Co-Substituted Hydroxyapatite: the Effects of Doped-Ions on the Structure and Chemico-Physical Properties. Journal of Materials Science: Materials in Medicine, 2012. 23: p. 2867-2879. El Feki, H., Savariault, J.M., Ben Salah, A., and Jemal, M., Sodium and Carbonate Distribution in Substituted Calcium Hydroxyapatite. Solid State Sciences 2000. 2: p. 577-586. Ahn, E.S., Gleason, N.J., Nakahira, A., and Ying, J.Y., Nanostructure Processing of Hydroxyapatite-Based Bioceramics. Nano Letters, 2001. 1(3): p. 149-153. Webster, T.J., Ergun, C., Doremus, R.H., Siegel, R.W., and Bizios, R., Specific Proteins Mediate Enhanced Osteoblast Adhesion on Nanophase Ceramics. Journal of Biomedical Materials Research, 2000. 51(3): p. 475-483. Xin, R., Leng, Y., and Wang, N., HRTEM Study of the Mineral Phases in Human Cortical Bone. Advanced Engineering Materials, 2010. 12(9): p. B552-B557. Boyan, B.D., Lohmann, C.H., Dean, D.D., Sylvia, V.L., Cochran, D.L., and Schwartz, Z., Mechanisms Involved in Osteoblast Response to Implant Surface Morphology. Annual Review of Materials Research, 2001. 31(1): p. 357-371. Zandi, M., Mirzadeh, H., Mayer, C., Urch, H., Eslaminejad, M.B., Bagheri, F., and Mivehchi, H., Biocompatibility Evaluation of NanoRod Hydroxyapatite/Gelatin Coated with Nano-HAp as a Novel Scaffold using Mesenchymal Stem Cells. Journal of Biomedical Materials Research Part A, 2010. 92A(4): p. 1244-1255. Hwang, K.S., Hwangbo, S., and Kim, J.T., Silver-Doped Calcium Phosphate Nanopowders Prepared by Electrostatic Spraying. Journal of Nanoparticle Research, 2008. 10(8): p. 1337-1341. Square, N., in PDF Card no: 9-432. ICDD: Pennsylvania. Rehman, I. and Bonfield, W., Characterization of Hydroxyapatite and Carbonated Apatite by Photo Acoustic FTIR Spectroscopy. Journal of Materials Science: Materials in Medicine, 1997. 8(1): p. 1-4. Tang, X.L., Xiao, X.F., and Liu, R.F., Structural Characterization of Silicon-Substituted Hydroxyapatite Synthesized by a Hydrothermal Method. Materials Letters, 2005. 59(29-30): p. 3841-3846. 209 References 268. 269. 270. 271. 272. 273. 274. 275. 276. 277. 278. 279. 280. 281. 282. Material Safety Data Sheet Silver Nitrate MSDS. 2005, Sciencelab.com, Inc. Yao, C., Perla, V., McKenzie, J.L., Slamovich, E.B., and Webster, T.J., Anodized Ti and Ti6Al4V Possessing Nanometer Surface Features Enhances Osteoblast Adhesion. Journal of Biomedical Nanotechnology, 2005. 1(1): p. 68-73. Webster, T.J., Schadler, L.S., Siegel, R.W., and Bizios, R., Mechanisms of Enhanced Osteoblast Adhesion on Nanophase Alumina Involve Vitronectin. Tissue Engineering, 2001. 7(3): p. 291-301. Dorozhkin, S.V., Nanosized and nanocrystalline calcium orthophoshates. Acta Biomaterialia, 2010. 6: p. 715-734. Landau, U., Bactericidal and Oligodynamic Action of Silver and Copper in Hygiene, Medicine and Water Treatment. 2007: Royal Society of Chemistry. Shrestha, R., Gopali, J. and Piya, S., Oligodynamic Action of Silver, Copper and Brass on Enteric Bacteria Isolated from Water of Kathmandu Valley. Nepal Journal of Science and Technology, 2009. 10: p. 189-. Poelstra, K.A., Barekzi, N.A., Rediske, A.M., Felts, A.G., Slunt, J.B., and Grainger, D.W., Prophylactic treatment of gram-positive and gram-negative abdominal implant infections using locally delivered polyclonal antibodies. Journal of Biomedical Materials Research, 2002. 60(1): p. 206-215. Li, K., Xie, Y., Huang, L., Ji, H., and Zheng, X., Antibacterial Mechanism of Plasma Sprayed Ca2ZnSi2O7 Coating against Escherichia Coli. Journal of Materials Science: Materials in Medicine, 2013. 24(1): p. 171-178. Bergey, D.H., Holt, J.G., Krieg, N.R., and P.H.A., S., Bergey's Manual of Determinative Bacteriology 1994: Lippincott Williams & Wilkins. Saito, T., Iwase, T., Horie, J., and Morioka, T., Mode of Photocatalytic Bactericidal Action of Powdered Semiconductor TiO2 on Mutans Streptococci. Journal of Photochemistry and Photobiology B, 1992. 14(4): p. 369-379. Lambert, P.A. and Hammond, S.M., Potassium Fluxes, First Indications of Membrane Damage in Micro-Organisms. Biochemical and Biophysical Research Communications, 1973. 54(2): p. 796-799. Nester, E., Anderson, D., and Roberts, C.E.J., Microbiology: A Human Perspective. 2004: McGraw-Hill. Aparicio, C., Gil, F.J., Planell, J.A., and Engel, E., Human-Osteoblast Proliferation and Differentiation on Grit-Blasted and Bioactive Titanium for Dental Applications. Journal of Materials Science: Materials in Medicine, 2002. 13(12): p. 1105-1111. Donahue, H.J., Li, Z., Zhou, Z.i., and Yellowley, C.E., Differentiation of Human Fetal Osteoblastic Cells and Gap Junctional Intercellular Communication. American Journal of Physiology - Cell Physiology, 2000. 278(2): p. C315-C322. Setzer, B., Bächle, M., Metzger, M.C., and Kohal, R.J., The GeneExpression and Phenotypic Response of hFOB 1.19 Osteoblasts to 210 References 283. 284. 285. Surface-Modified Titanium and Zirconia. Biomaterials, 2009. 30(6): p. 979-990. Sun, Z.L., Wataha, J.C., and Hanks, C.T., Effects of Metal Ions on Osteoblast-Like Cell Metabolism and Differentiation. Journal of Biomedical Materials Research, 1997. 34(1): p. 29-37. Ducheyne, P. and Qiu, Q., Bioactive Ceramics: The Effect of Surface Reactivity on Bone Formation and Bone Cell Function. Biomaterials, 1999. 20(23–24): p. 2287-2303. Neo, M., Nakamura, T., Ohtsuki, C., Kokubo, T., and Yamamuro, T., Apatite Formation on Three Kinds of Bioactive Material at an Early Stage In Vivo: A Comparative Study by Transmission Electron Microscopy. Journal of Biomedical Materials Research, 1993. 27(8): p. 999-1006. 211 [...]... Although studies concerning substituted apatites are conventionally performed by the addition of single cation or anion, co- substitution has been considered in recent years [43-48], and is certainly becoming a considerable field of research for apatites Co- substitution combines the functions of various ions into a single apatite compound, which can eliminate problems encountered in the composite system... AgHA Silver -Substituted Hydroxyapatite Ag,Si-HA Silver, Silicon Co- substituted Hydroxyapatite ALP Alkaline Phosphatase ANOVA Analysis of Variance ATP Adenosine-5'-Triphosphate BEs Binding Energies C albicans Candida albicans Ca Calcium COL I Type I Collagen ECM Extracellular Matrix E coli Escherichia coli FESEM Field Emission Scanning Electron Microscope FTIR Fourier Transform Infrared HA Hydroxyapatite. .. 60 2.5 Silicon -Substituted Hydroxyapatite (SiHA) 62 2.5.1 Silicon as Bone Promoter 63 2.5.2 Synthesis of SiHA 65 2.5.3 Chemical and Physical Characterisation of SiHA 66 2.5.4 Biological Characterisation of SiHA 74 2.6 Co- Substituted Hydroxyapatite 80 2.6.1 Various Types of Co- Substituted Hydroxyapatite 81 2.6.2 Synthesis of Co- Substituted Hydroxyapatite ... Hydroxyapatite 81 2.6.2 Synthesis of Co- Substituted Hydroxyapatite 81 2.6.3 Chemical Characterisation of Co- Substituted Hydroxyapatite 82 2.6.4 Biological Characterisation of Co- Substituted Hydroxyapatite 85 2.7 Summary 86 CHAPTER 3 SILVER, SILICON CO- SUBSTITUTED HYDROXYAPATITE: SYNTHESIS AND CHARACTERISATION 3.1 Introduction 88 3.2 Materials and Methods ... Procollagen molecules consist of 3 pro-α chains, which undergo processing to α-chains, and subsequently assemble to form collagen fibrils (tropocollagen), which are coiled to form a helical structure Each tropocollagen molecule is longitudinally displaced by approximately one quarter of its length relative to its nearest neighbour when they are aggregated together This staggering effect of tropocollagen... tissue metabolism, particularly for bone and cartilage To mimic the mineral component of bone better, silicon -substituted HA (SiHA) has been extensively investigated by many researchers [13-26] The incorporation of silicon into HA has been shown to have the potential to increase the rate of bone apposition on HA implants significantly [19, 21, 27, 28] Therefore, SiHA is considered as state-of-the-art... Properties of Ag,Si-HA 136 5.3.2 Silver Composition on the Surface of Ag,Si-HA 141 5.3.3 Antibacterial Assessment of Ag,Si-HA 142 5.3.4 Surface Silver Ions of Ag,Si-HA for Antibacterial Action 147 5.3.5 Effect on S aureus treated by Ag,Si-HA 149 5.4 Conclusions 158 x CHAPTER 6 IN-VITRO BIOCOMPATIBILITY OF SILVER, SILICON CO- SUBSTITUTED HYDROXYAPATITE 6.1 Introduction ... The specific objectives of this research project are as follows:  To determine the feasibility of co- substituting silver and silicon into hydroxyapatite to form Ag,Si-HA via a wet precipitation method, and characterise its physicochemical properties,  To optimise the silver content in hydroxyapatite for effective antibacterial properties,  To determine the mechanism of the antibacterial action in... effects of silver and silicon on the biological properties of Ag,Si-HA 1.3 Scope Chapter 1 established the background, illustrating the need for synthetic bone substitute materials Particularly, HA and improvements to its property were discussed The co- substitution of silver and silicon was also proposed to incorporate antibacterial property in conjunction with enhanced bone formation in HA Subsequently,... matrix is composed of two major phases namely the organic phase (~ 30-40 wt.% protein) and the inorganic phase (~ 50-60 wt.% minerals), with the remaining making up of biological compounds [58] Collagen is the most abundant protein found in the human body, which comprises approximately 95 % of the non-mineralised component of bone matrix Osteoblasts synthesise collagen in the form of long procollagen . CHEMICALLY- MODIFIED CO- SUBSTITUTED HYDROXYAPATITE NANOMATERIAL FOR BIOMEDICAL APPLICATIONS LIM POON NIAN NATIONAL UNIVERSITY OF SINGAPORE 2013 CHEMICALLY- MODIFIED CO- SUBSTITUTED. 2.6 Co- Substituted Hydroxyapatite 80 2.6.1 Various Types of Co- Substituted Hydroxyapatite 81 2.6.2 Synthesis of Co- Substituted Hydroxyapatite 81 2.6.3 Chemical Characterisation of Co- Substituted. ML C, Thian ES. Silver/Silicon Co- Substituted Nanohydroxyapatite: A Novel Bone Material for Biomedical Applications. International Conference on Materials for Advanced Technologies, Singapore