On enhancement of bone formation using local drug delivery systems

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(1)DOCTOR AL DISSERTATION IN ODONTOLOGY. ALI ALENEZI ON ENHANCEMENT OF BONE FORMATION USING LOCAL DRUG DELIVERY SYSTEMS.

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(3) ON ENHANCEMENT OF BONE FORMATION USING LOCAL DRUG DELIVERY SYSTEMS.

(4) Malmö University Faculty of Odontology Doctoral Dissertation 2018. © Ali Alenezi 2018 ISBN 978-91-7104-910-0 (print) ISBN 978-91-7104-911-7 (pdf) Holmbergs, Malmö 2018.

(5) ALI ALENEZI ON ENHANCEMENT OF BONE FORMATION USING LOCAL DRUG DELIVERY SYSTEMS. Malmö University, 2018 Faculty of Odontology Department of Prosthodontics Malmö, Sweden.

(6) This publication is also available at: www.mah.se/muep.

(7) To my beloved wife Dalal, my precious kids Johanna and Basil, and my father and mother..

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(9) This thesis is number 52 in a series of investigations on implants, hard tissues and the loco-motor apparatus originating from the Department of Biomaterials, University of Gothenburg and the Department of Prosthodontics/Material Sciences, Malmö University, Sweden. 1. Anders R Eriksson DDS, 1984. Heat-induced Bone Tissue Injury. An in vivo investigation of heat tolerance of bone tissue and temperature rise in the drilling of cortical bone. Thesis defended 21.2.1984. External examiner: Docent KG. Thorngren. 2. Magnus Jacobsson MD, 1985. On Bone Behaviour after Irradiation. Thesis defended 29.4.1985. External examiner: Docent A. Nathanson. 3. Fredric Buch MD, 1985. On Electrical Stimulation of Bone Tissue. Thesis defended 28.5.1985. External examiner: Docent T. Ejsing- Jörgensen. 4. Peter Kälebo MD, 1987. On Experimental Bone Regeneration in Titanium Implants. A quantitative microradiographic and histologic investigation using the Bone Harvest Chamber. Thesis defended 1.10.1987. External examiner: Docent N. Egund. 5. Lars Carlsson MD, 1989. On the Development of a new Concept for Orthopaedic Implant Fixation. Thesis defended 2.12.1989. External examiner: Docent L-Å Broström. 6. Tord Röstlund MD, 1990. On the Development of a New Arthroplasty. Thesis defended 19.1.1990. External examiner: Docent Å. Carlsson. 7. Carina Johansson Res Tech, 1991. On Tissue Reaction to Metal Implants. Thesis defended 12.4.1991. External examiner: Professor K. Nilner. 8. Lars Sennerby DDS, 1991. On the Bone Tissue Response to Titanium Implants. Thesis defended 24.9.1991. External examiner: Dr J.E. Davies. 9. Per Morberg MD, 1991. On Bone Tissue Reactions to Acrylic Cement. Thesis defended 19.12.1991. External examiner: Docent K. Obrant. 7.

(10) 10. Ulla Myhr PT, 1994. On factors of Importance for Sitting in Children with Cerebral Palsy. Thesis defended 15.4.1994. External examiner: Docent K. HarmsRingdahl. 11. Magnus Gottlander MD, 1994. On Hard Tissue Reactions to Hydroxyapatite-Coated Titanium Implants. Thesis defended 25.11.1994. External examiner: Docent P. Aspenberg. 12. Edward Ebramzadeh MScEng, 1995. On Factors Affecting Long-Term Outcome of Total Hip Replacements. Thesis defended 6.2.1995. External examiner: Docent L. Linder. 13. Patricia Campbell BA, 1995. On Aseptic Loosening in Total Hip Replacement: the Role of UHMWPE Wear Particles. Thesis defended 7.2.1995. External examiner: Professor D. Howie. 14. Ann Wennerberg, DDS, 1996. On Surface Roughness and Implant Incorporation. Thesis defended 19.4.1996. External examiner: Professor P-O. Glantz. 15. Neil Meredith BDS MSc FDS RCSm, 1997. On the Clinical Measurement of Implant Stability Osseointegration. Thesis defended 3.6.1997. External examiner: Professor J. Brunski. 16. Lars Rasmusson DDS, 1998. On Implant Integration in Membrane-Induced and Grafter Bone. Thesis defended 4.12.1998. External examiner: Professor R. Haanaes. 17. Thay Q Lee MSc, 1999. On the Biomechanics of the Patellfemoral Joint and Patellar Resurfacing in Total Knee Arthroplasty. Thesis defended 19.4.1999. External examiner: Docent G. Nemeth. 18. Anna Karin Lundgren DDS, 1999. On Factors Influencing Guided Regeneration and Augmen-tation of Intramembraneous Bone. Thesis defended 7.5.1999. External examiner: Professor B. Klinge. 19. Carl-Johan Ivanoff DDS, 1999. On Surgical and Implant Related Factors Influencing Integration and Function of Titanium Implants. Experimental and Clinical Aspects. Thesis defended 12.5.1999. External examiner: Professor B. Rosenquist. 8.

(11) 20. Bertil Friberg DDS MDS, 1999. On Bone Quality and Implant Stability Measurements. Thesis defended 12.11.1999. External examiner: Docent P. Åstrand. 21. Åse Allansdotter Johansson MD, 1999. On Implant Integration in Irradiated Bone. An Experimental Study of the Effects of Hyperbaric Oxygeneration and Delayed Implant Placement. Thesis defended 8.12.1999. External examiner: Docent K. Arvidsson- Fyrberg. 22. Börje Svensson FFS, 2000. On Costochondral Grafts Replacing Mandibular Condyles in Juvenile Chronic Arthritis. A Clinical, Histologic and Experimental Study. Thesis defended 22.5.2000. External examiner: Professor Ch. Lindqvist. 23. Warren Macdonald BEng, MPhil, 2000. On Component Integration on Total Hip Arthroplasties: Pre-Clinical Evaluations. Thesis defended 1.9.2000. External examiner: Dr A.J.C. Lee. 24. Magne Røkkum MD, 2001. On Late Complications with HA Coated Hip Arthroplasties. Thesis defended 12.10.2001. External examiner: Professor P. Benum. 25. Carin Hallgren Höstner DDS, 2001. On the Bone Response to Different Implant Textures. A 3D analysis of roughness, wavelength and surface pattern of experimental implants. Thesis defended 19.11.2001. External examiner: Professor S. Lundgren. 26. Young-Taeg Sul DDS, 2002. On the Bone Response to Oxidised Titanium Implants: The role of microporous structure and chemical composition of the surface oxide in enhanced osseointegration. Thesis defended 7.6.2002. External examiner: Professor J.E. Ellingsen. 27. Victoria Franke Stenport DDS, 2002. On Growth Factors and Titanium Implant Integration in Bone. Thesis defended 11.6.2002. External examiner: Associate Professor E. Solheim. 28. Mikael Sundfeldt MD, 2002. On the Aetiology of Aseptic Loosening in Joint Arthroplasties and Routes to Improved cemented Fixation. Thesis defended 14.6.2002. External examiner: Professor N. Dahlén. 9.

(12) 29. Christer Slotte CCS, 2003. On Surgical Techniques to Increase Bone Density and Volume. Studies in Rat and Rabbit. Thesis defended 13.6.2003. External examiner: Professor C.H.F. Hämmerle. 30. Anna Arvidsson MSc, 2003. On Surface Mediated Interactions Related to Chemomechanical Caries Removal. Effects on surrounding tissues and materials. Thesis defended 28.11.2003. External examiner: Professor P. Tengvall. 31. Pia Bolind DDS, 2004. On 606 retrieved oral and craniofacial implants. An analysis of consequently received human specimens. Thesis defended 17.12.2004. External examiner: Professor A. Piattelli. 32. Patricia Miranda Burgos DDS, 2006. On the influence of micro- and macroscopic surface modifications on bone integration of titanium implants. Thesis defended 1.9.2006. External examiner: Professor A. Piattelli. 33. Jonas P. Becktor DDS, 2006. On factors influencing the outcome of various techniques using endosseous implants for reconstruction of the atrophic edentulous and partially dentate maxilla. Thesis defended 17.11.2006. External examiner: Professor K.F. Moos. 34. Anna Göransson DDS, 2006. On Possibly Bioactive CP Titanium Surfaces. Thesis defended 8.12.2006. External examiner: Professor B. Melsen. 35. Andreas Thor DDS, 2006. On platelet-rich plasma in reconstructive dental implant surgery. Thesis defended 8.12.2006. External examiner: Professor E.M. Pinholt. 36. Luiz Meirelles DDS MSc, 2007. On Nano Size Structures for Enhanced Early Bone Formation. Thesis defended 13.6.2007. External examiner: Professor Lyndon F. Cooper. 37. Pär-Olov Östman DDS, 2007. On various protocols for direct loading of implant-supported fixed prostheses. Thesis defended 21.12.2007. External examiner: Professor B. Klinge.. 10.

(13) 38. Kerstin Fischer DDS, 2008. On immediate/early loading of implant supported prostheses in the maxilla. Thesis defended 8.2.2008. External examiner: Professor K. Arvidsson Fyrberg. 39. Alf Eliasson 2008. On the role of number of fixtures, surgical technique and timing of loading. Thesis defended 23.5.2008. External examiner: Professor K. Arvidsson Fyrberg. 40. Victoria Fröjd DDS, 2010. On Ca2+ incorporation and nanoporosity of titanium surfaces and the effect on implant performance. Thesis defended 26.11.2010. External examiner: Professor J.E. Ellingsen. 41. Lory Melin Svanborg DDS, 2011. On the importance of nanometer structures for implant incorporation in bone tissue. Thesis defended 01.06.2011. External examiner: Associate professor C. Dahlin. 42. Byung-Soo Kang MSc, 2011. On the bone tissue response to surface chemistry modifications of titanium implants. Thesis defended 30.09.2011. External examiner: Professor J. Pan. 43. Kostas Bougas DDS, 2012. On the influence of biochemical coating on implant bone incorporation. Thesis defended 12.12.2012. External examiner: Professor T. Berglundh. 44. Arne Mordenfeld DDS, 2013. On tissue reaction to and adsorption of bone substitutes. Thesis defended 29.5.2013. External examiner: Professor C. Dahlin. 45. Ramesh Chowdhary DDS, 2014. On efficacy of implant thread design for bone stimulation. Thesis defended 21.05.2014. External examiner: Professor Flemming Isidor. 46. Anders Halldin MSc, 2015. On a biomechanical approach to analysis of stability and load bearing capacity of oral implants. Thesis defended 28.05.2015. External examiner: Professor J. Brunski.. 11.

(14) 47. Francesca Cecchinato MSc, 2015. On magnesium-modified titanium coatings and magnesium alloys for oral and orthopaedic applications: in vitro investigation. Thesis defended 20.11.2015. External examiner: Professor C. Stanford. 48. Jonas Anderud DDS, 2016. On guided bone regeneration using ceramic membranes. Thesis defended 27.05.2016. External examiner: Professor S. Lundgren 49. Silvia Galli DDS, 2016. On magnesium-containing implants for bone applications. Thesis defended 08.12.2016. External examiner: Professor J.E. Ellingsen. 50. Bruno Chrcanovic DDS MSc, 2017. On Failure of Oral Implants. Thesis defended 08.06.2017. External examiner: Associate Professor B. Friberg. 51. Pär Johansson DDS, 2017. On hydroxyapatite modified peek implants for bone applications. Thesis defended 15.12.2017. External examiner: L. Rasmusson. 52. Ali Alenezi DDS MSc, 2018. On enhancement of bone formation using local drug delivery systems. Thesis to be defended 05.06.2018. External examiner: Professor J.E. Ellingsen. See www.mah.se/muep. 12.

(15) TABLE OF CONTENTS. THESIS AT A GLANCE ................................................. 17 ABSTRACT ................................................................ 18 LIST OF PAPERS ......................................................... 22 Contribution by the respondent ............................................ 23 ABBREVIATIONS AND ACRONYMS ............................... 24 INTRODUCTION ........................................................ Background ....................................................................... Titanium as a biomaterial .................................................... Bone tissue ........................................................................ Osseointegration ................................................................ Healing process ................................................................. Why the need for improvement ............................................ Strategies to enhance bone response .................................... Local drug release around implants ....................................... Polymers for local drug release ........................................ Assessment of drug release ............................................. Some techniques used for in vitro release tests .................... 27 27 30 31 31 33 36 37 40 42 49 50. AIMS ....................................................................... 53 MATERIALS AND METHODS ......................................... Data collection (Systematic review) ....................................... Principles of the new developed drug delivery system ............. Materials preparations ........................................................ PNIPAAm Polymers synthesis ........................................... PLGA microspheres loaded with Clarithromycin ................. Gold nanorods (GNRs) .................................................... 54 54 55 56 56 57 58.

(16) Characterization of materials ............................................... Differential scanning calorimetry (DSC) ............................. Scanning electron microscopy (SEM) ................................ UV/VIS spectroscopy ..................................................... Quartz crystal microbalance with dissipation monitoring (QCM-D) ....................................................... Bacterial test ...................................................................... In vivo methods .................................................................. Surgical procedures ....................................................... Micro- computed tomography (μCT) ................................. Preparation of histological sections .................................. Histomorphometry .......................................................... Statistics ............................................................................ RESULTS .................................................................... Systematic review ............................................................... Main methods for local drug delivery ............................... Type of Drugs/Chemical Compounds ............................... Characterization of materials ............................................... Differential scanning calorimetry (DSC) ............................. Scanning electron microscopy (SEM) ................................ Quartz crystal microbalance with dissipation monitoring (QCM-D) ....................................................... Strontium ranelate absorption and release rate .................. UV/VIS spectroscopy .......................................................... Phenol release behavior .................................................. Release proﬁle of Clarithromycin .......................................... Bacterial test ...................................................................... In vivo results ..................................................................... Micro-computed tomography ........................................... Histomorphometry ............................................................... 59 59 59 60 61 62 64 64 66 66 67 67 69 69 69 70 71 71 72 78 79 80 81 82 83 87 87 89. DISCUSSION ............................................................. 98 Systematic review .......................................................... 98 In vitro study ................................................................ 101 In vivo study (Clarithromycin & PLGA) ............................. 105 In vivo study (Sr- ranelate) ............................................. 107.

(17) CONCLUSIONS ........................................................ 111 FUTURE PERSPECTIVES ............................................... 113 POPULÄRTVETENSKAPLIG SAMMANFATTNING .............. 115 ACKNOWLEDGEMENTS ............................................ 116 REFERENCES ............................................................ 121 PAPERS I- IV .............................................................. 165.

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(32) 'd$'*+1L5&'!&51 -32e2'+#1+-0#2&,2&#- 1#04#"+-3,2 -,2&#h,+'d$'*+1Xcdbb,%U!+dYO &#&'12-+-0.&-+#20'!,*71#10#4#*#"&'%&#0.#0!#,2%#1-$ -,#'+.*,2!-,2!2X Y," -,#0#XY$-0'+.*,215'2&0P 0,#*2# !-+.0#" 2- '+.*,21 ', 2&# !-,20-* %0-3. $2#0 d ," h 5##)1 -$ &#*',%O -5#4#0L 2&#1# "'$$#0#,!#1 5#0# $-3," ,-2 2- # 1'%,'$'!,2X 5'2&*P4*3#-$bOfe$2#0d5##)1,"bOcid$2#0 h5##)1YLX5'2&*P4*3#-$bOgbe$2#0d5##)1L,"bObjj$2#0 h 5##)1YO &# +#, ," 4*3#1 5'2&', 2&# 1+# %0-3. 1&-5#"1'%,'$'!,2',!0#1#+-,%**%0-3.1$2#0!-+.0',%d," h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dc . 21.

(33) . LIST OF PAPERS. &'1 "'11#022'-, '1 1#" -, 2&# $-**-5',% $-30 ..#01L 5&'!& 5'** #0#$#00#"2-',2&#+',2#62 72&#'0-+,,3+#0*1O&#..#01 0#..#,"#"22&##,"-$2&#2&#1'1O . O $$#!21 -$ *-!* "03% ," !&#+'!* !-+.-3," "#*'4#07 -, -,# 0#%#,#02'-, 0-3," "#,2* '+.*,21 ', ,'+* +-"#*1N 1712#+2'!0#4'#5,"+#2P,*71'1O *#,#8'L&0!,-4'!L#,,#0 #0%O " (.,(.#)(& )/,(&) ,&62#&&) #& '*&(.-Odbcj ,U# MeeXcYN#cP#cjO . O #4#*-.+#,2 -$ &-2-, ,"3!#" 03%P#*'4#07 +.*,2 -2',%O *#,#8'L 3*,"#0L2#$7#)2L,"#011-,O X3 +'22#"YO . O -,20-**#" 0#*#1# -$ !*0'2&0-+7!', $0-+ +'!0-1.&#0#1 #,&,!#1 -,#0#%#,#02'-,',0 '2!*40'"#$#!21O *#,#8' L '2- L #03)', L 0,,',%03+ L ',,- L %+'L8#)'L**'L '+ -O )/,(& ) #)'#& .,#&- -,": ,. 8 **&# #)'.,#&-LdbcjOcbhXcYN.OdbcPdbjO . 22.

(34) . O. 11#-',2#%02'-, #$$#!21 -$ *-!* 0#*#1# -$ 120-,2'3+ 0,#*2# $0-+'+.*,2130$!#1',021O *#,#8'L**'L2#$7#)2L,"#011-,L#,,#0 #0%O X3 +'22#"YO. ** .3 *'1&#" ..#01 5#0# 0#.0',2#" 5'2& .#0+'11'-, $0-+ 2&# !-.70'%&2&-*"#01O . Contribution by the respondent &# 0#1.-,"#,2 .#0$-0+#" +-12 -$ 2&# 5-0) $0-+ .*,,',%L #6.#0'+#,2*5-0)X5'2&#6!#.2'-,-$2&#130%'!*.0-!#"30#15'2& ,'+*1L !*0'2&0-+7!', 0#*#1# 2#12L ," 2&# s ,*71#1Y ," &# .#0$-0+#" 2&# ,*71'1 -$ 2&# "2O &# 0#1.-,"#,2 51 *1- 2&# +',!-,20' 32-02-50'2',%2&#+,31!0'.21O . de . 23.

(35) . ABBREVIATIONS AND ACRONYMS. .$. & &

(36) "'0 05

(37) =! ! ! !0!

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