Dentala implantat är en väletablerad behandling för att ersätta för- lorade tänder med långsiktigt goda resultat. Det finns en uppsjö av implantat med olika ytor på marknaden och bakom dessa ligger stora forskningssatsningar. Aktuell forskning syftar till att leda fram till nya ytor med fördelaktiga egenskaper jämfört med dagens ytor avse- ende inläkningen i benet och kontakten med den orala slemhinnan, för att även kunna behandla patienter med sämre läkförmåga samt för att förkorta behandlingstiden för samtliga patienter. Forskning syftar dessutom till att kartlägga mekanismerna för osseointegration och till att förstå inläkningen av implantat på en molekylär och cel- lulär nivå. En moderat rå yta är vanligen förekommande på kom- mersiella implantat då djurstudier har visat att en råare yta stimulerar benceller i större utsträckning, har mer ben i kontakt samt retineras hårdare av benet vid urvridningsförsök i större utsträckning än en slät yta. Ytorna är även i flertalet fall kemiskt modifierade och fram- förallt en modifierad kemi har föreslagits ge en yta egenskaper av en bioaktiv natur. Bioaktivitet är ett frekvent använt uttryck vilket kan spegla en kemisk bindning mellan exempelvis en implantatyta och omgivande vävnader (vilket idag ej har kunnat påvisas) eller en effekt på omgivande vävnader (exempelvis attraktion av specifika proteiner eller benceller). Ytegenskaperna syftar, sammanfattningsvis, till att påskynda läkningsprocessen och eventuellt förbättra inläkningen av implantaten. Något att alltid ha i åtanke vid patientrelaterad forsk- ning eller behandling är eventuella konsekvenser med en negativ influens på patienten. I fallet med dentala implantat är en konsekvens bennedbrytning kring implantaten och därmed en större blottlagd
implantatyta exponerad för munhålans bakterierika miljö. Biofilmer etableras i stort sett direkt på ytor om möjligt, då det finns flera för- delar för majoriteten av bakterier att leva i en biofilm. Friska tillstånd är starkt kopplade till en mikrobiologisk balans, det vill säga att det inte är en dominans av bakterier med sjukdomsorsakande egenska- per. Då balansen av någon anledning rubbas, förslagsvis på grund av en okontrollerbart stor mängd bakterier, stimulering av bakterier att utveckla sjukdomsframkallande egenskaper eller ett nedsatt försvar hos värden, kan biofilmer orsaka sjukdomstillstånd. Att en implan- tatyta inte ökar risken för att biofilmer med sjukdomsframkallande karaktär etableras på ytan är viktigt och bör utredas. Det är idag inte säkerställt vilka eller överhuvudtaget om det finns ytegenskaper med positiva eller negativa effekter på biofilmsetableringen. Ökad ytenergi och framförallt ökad ytråhet har dock kopplats till en ökad bakterie- vidhäftning.
Den aktuella avhandlingen har syftat till att utreda hur kalciumjo- ner i ett förtjockat titanoxidlager påverkar inläkningen i ben genom att installera implantat i kaninben och sedan utvärdera dessa genom histologiska snitt samt genom biomekanisk urvridning. Resultaten blev att kalciummodifieringar ledde till mer benkontakt med ytan samt en starkare retention vid urvridning. Det var heller ingen skillnad i retention mellan släta kalciummodifierade implantat och moderat råa implantat. Inom avhandlingen har även effekten av nanoporosi- tet för inläkning i munslemhinna studerats genom en experimentell studie i människa. En klinisk uppskattning framhöll fördelar för den nanoporösa ytan jämfört med den ickemodifierade kontrollytan och histologiskt hade den nanoporösa ytan mer vävnad i kontakt. För att utvärdera olika ytor avseende bakterievidhäftning och biofilmbild- ning sattes bakterielösningar till ytorna och sedan fick dessa fästa till ytan under två eller 14 timmar. Även filtersteriliserad saliv och hel- saliv från en frisk individ användes i studierna. Resultatet blev att en ökad ytråhet tenderade till att öka bakterievidhäftningen och biofilm- bildningen på ytan samt att en större mängd bakterier fanns kvar på moderat råa ytor jämför med släta efter rengöring.
Sammanfattningsvis kan möjligen en specifik ytkemi kompensera för en minimal ytråhet, vilket eventuellt minskar risken för etablering av sjukdomsframkallande biofilmer på ytorna om dessa exponeras i munhålan. Nanoporösa ytor har möjligen en positiv influens på anslutningen av mjukvävnad mot implantatytan, vilket är av bety-
Acknowledgements
Many persons have contributed and inspired along the way of this work. I feel lucky to be in all of yours presence. I would especially like to thank:
My superb supervisor, Professor Ann Wennerberg. You are an inspiration and role model, both as a researcher and as a person. I am more than happy to have had your supervision and I am extremely thankful for you tutoring me. Thank you for caring and supporting, at the same time as encouraging and urging for progression.
My co-supervisor professor Gunnel Svensäter, a great and inspiring researcher and person, who has taken her time to discuss biofilms along with other matters. You have clearly influenced my way of thinking.
My co-supervisor, Victoria Franke-Stenport, for being really helpful, to the point, and skilful, in addition to fun and caring. I have learnt a lot from you in various ways.
Luiz Chávez de Paz, whom I really enjoy working with. I very much appreciate your intelligence, kindness, and great sense of humour. Professor Tomas Albrektsson for always being helpful and for sharing his great knowledge, furthermore, for creating a very pleasant atmosphere at the department.
The Professors Peter Thomsen, Carina Johansson, Lars Sennerby, Ulf Nannmark, and Young-Taeg Sul, for sharing their knowledge and freely discussing various matters during lab hours as well as coffee breaks.
My greatest thanks to everyone at the departments of Prosthodontics and Oral Biology in Malmö, and the department of Biomaterials in Gothenburg who have made these years really enjoyable. A special thanks to: Petra, Maria, and Ann, for contributing to this work, for teaching me the techniques in the lab, and for just being great, Ulf for handling the administration, Julia for improving the work, interesting discussions, and English expertise, Luiz: for from the start being helpful, Lena: for great support, Anna W: for being such a lovely, inspiring, and helpful person, Felicia and Carina: for being inspirations, Bertil: for being The Mac-expert, Kostas and Ryo: for brightening up both Malmö and Gothenburg, Sara and Anders: for being good friends, for making it fun, and for many interesting discussions. Dear Marjan, so happy to have gained your friendship, you are just fabulous.
Great thanks to Professor Lars Rasmusson for direct response to my interest in research and for helping along the way.
Thanks to Lennart Carlsson for all help, as well as fun and interesting discussions.
Oscar, your complete understanding and pure encouragements were great inspiration to progression and future challenges.
Thanks to all mentioned above for adding that little something extra to the fantastic world of research.
Thanks to Jan Wennström, Sanjiv Kanagaraja, Patrick Palacci, Iain Hutchison, and Bertil Friberg, for letting me experience their brilliance in the clinic. It has been significant and great fun to get a clinical insight.
Thanks to all my great colleagues at the clinic in Frölunda, my friends at the Swedish Dental Society, and, not the least, my personal friends who make my life really joyful. Of special importance during these years have been: Malin – always there and just extraordinary brilliant, smart, and wise. Marta and Malin - you are the best of friends. Sandra – you are so important to me. Ami - my stunning friend, always making me burst into laughter. Elisabeth – I admire your controlled manners and professionalism, at the same time as you are full of life and warm at heart. Erika – you are just amazingly supporting and inspiring. Carl-Martin - I really appreciate your
wisdom since it so often is striking to me. Sofia – bright, enterprising, fun, and great inspiration in many ways. Camilla – so easy-going and relaxing. Per - I am inspired by your way of making the most out of your life. Emma – you are just a lovely person. Tania and Lisa - great to have shared some South American adventures with you. Dear Erik, David, Brandon, Emil, and Hanna - thank you for the security you have provided in addition to all hilarious memories. Margaretha, I have really treasured our regular lunches and all discussions during the time I have known you, as well as your support.
Thanks to my dear uncles and their loved ones, Håkan, Bosse, Tobbe, Sune, Margaretha, Marcella, and Inga-Lill, and my cousins Cecilia, Kjell, Henke, Eva, Johan, Åsa, John, Carl-Johan, Erik, and Johan with their families for always being joy-bringing when I see you. Johann – I have always had the greatest respect for you and you have influenced me greatly. Camilla, you have inspired me incredibly much regarding school and research, at the same time as you have always provided guidance - you are truly amazing.
My grandmother, Ulla, whom I love and appreciate. Your advice, support, and exhortations, have been significant.
My dear mother Carina - thank you for giving me the inborn feeling that anything is possible. I have always admired your strength and capacity, as well as appreciated your love.
My always supporting beloved father Pelle, who I really enjoy sharing thoughts with. Thank you for making me secure enough to never doubt go testing my wings.
My brilliant brother Dan, whom I adore and admire. You simplify things for me and I really enjoy discussing various matters with you.
Grants from the Swedish Research Council, the Hjalmar Svensson Research Foundation, the Wilhelm and Martina Lundgren Research Foundation, Biomaterials Research Center, and the Swedish Dental Society allowed this work and are gratefully acknowledged.
REFERENCES
1. Brunette DM, Tengvall P, Textor M, Thomsen P. Titanium in medicine:
material science, surface science, engineering, biological responses and medical applications. Berlin, Heidelberg: Springer-Verlag; 2001.
2. Davies JE. Understanding peri-implant endosseous healing. J Dent Educ.
2003 Aug;67(8):932-49.
3. Futami T, Fujii N, Ohnishi H, Taguchi N, Kusakari H, Ohshima H, et al.
Tissue response to titanium implants in the rat maxilla: ultrastructural and histochemical observations of the bone-titanium interface. J Periodontol. 2000 Feb;71(2):287-98.
4. Shirakura M, Fujii N, Ohnishi H, Taguchi Y, Ohshima H, Nomura S,
et al. Tissue response to titanium implantation in the rat maxilla, with special reference to the effects of surface conditions on bone formation. Clin Oral Implants Res. 2003 Dec;14(6):687-96.
5. Larsson C, Thomsen P, Aronsson BO, Rodahl M, Lausmaa J, Kasemo
B, et al. Bone response to surface-modified titanium implants: studies on the early tissue response to machined and electropolished implants with different oxide thicknesses. Biomaterials. 1996 Mar;17(6):605-16.
6. Roberts WE, Smith RK, Zilberman Y, Mozsary PG, Smith RS. Osseous
adaptation to continuous loading of rigid endosseous implants. Am J Orthod. 1984 Aug;86(2):95-111.
7. Sennerby L, Thomsen P, L. E. E. Early tissue response to titanium
implants inserted in rabbit cortical bone. Journal of Materials Science: Materials in Medicine. 1993;4(3):240-50.
8. Zhou Y, Jiang T, Qian M, Zhang X, Wang J, Shi B, et al. Roles of
bone scintigraphy and resonance frequency analysis in evaluating osseointegration of endosseous implant. Biomaterials. 2008 Feb;29(4):461-74.
9. Berglundh T, Abrahamsson I, Lang NP, Lindhe J. De novo alveolar bone formation adjacent to endosseous implants. Clin Oral Implants Res. 2003 Jun;14(3):251-62.
10. Degidi M, Piattelli A, Shibli JA, Perrotti V, Iezzi G. Bone formation
around immediately loaded and submerged dental implants with a modified sandblasted and acid-etched surface after 4 and 8 weeks: a human histologic and histomorphometric analysis. Int J Oral Maxillofac Implants. 2009 Sep-Oct;24(5):896-901.
11. Strassburger C, Kerschbaum T, Heydecke G. Influence of implant and
conventional prostheses on satisfaction and quality of life: A literature review. Part 2: Qualitative analysis and evaluation of the studies. The International journal of prosthodontics. 2006 Jul-Aug;19(4):339-48.
12. Lekholm U, Grondahl K, Jemt T. Outcome of oral implant treatment in
partially edentulous jaws followed 20 years in clinical function. Clinical implant dentistry and related research. 2006;8(4):178-86.
13. Ekelund JA, Lindquist LW, Carlsson GE, Jemt T. Implant treatment in the
edentulous mandible: a prospective study on Branemark system implants over more than 20 years. Int J Prosthodont. 2003 Nov-Dec;16(6):602-8.
14. Suska F. On the initial inflammatory response to variations in biomaterial
surface chemsitry. Gothenburg: University of Gothenburg; 2004.
15. Suska F, Gretzer C, Esposito M, Emanuelsson L, Wennerberg A, Tengvall
P, et al. In vivo cytokine secretion and NF-kappaB activation around titanium and copper implants. Biomaterials. 2005 Feb;26(5):519-27.
16. Suska F, Esposito M, Gretzer C, Kalltorp M, Tengvall P, Thomsen P.
IL-1alpha, IL-1beta and TNF-alpha secretion during in vivo/ex vivo cellular interactions with titanium and copper. Biomaterials. 2003 Feb;24(3):461-8.
17. Perala D, Chapman R, Gelfand J. Complement activation by dental
implants. Int J Oral Maxillofac Implants. 1991 Summer;6(2):136-41.
18. Kanagaraja S, Lundstrom I, Nygren H, Tengvall P. Platelet binding
and protein adsorption to titanium and gold after short time exposure to heparinized plasma and whole blood. Biomaterials. 1996 Dec;17(23):2225-32.
19. Hulander M, Hong J, Andersson M, Gerven F, Ohrlander M, Tengvall
P, et al. Blood interactions with noble metals: coagulation and immune complement activation. ACS Appl Mater Interfaces. 2009 May;1(5):1053-62.
20. Linderback P, Harmankaya N, Askendal A, Areva S, Lausmaa J, Tengvall
P. The effect of heat- or ultra violet ozone-treatment of titanium on complement deposition from human blood plasma. Biomaterials. 2010
Jun;31(18):4795-801.
21. Branemark PI, Hansson BO, Adell R, Breine U, Lindstrom J, Hallen O,
et al. Osseointegrated implants in the treatment of the edentulous jaw. Experience from a 10-year period. Scand J Plast Reconstr Surg Suppl. 1977;16:1-132.
22. Sennerby L, Ericson LE, Thomsen P, Lekholm U, Astrand P. Structure of
the bone-titanium interface in retrieved clinical oral implants. Clin Oral Implants Res. 1991 Jul-Sep;2(3):103-11.
23. Hansson HA, Albrektsson T, Branemark PI. Structural aspects of the
interface between tissue and titanium implants. The Journal of prosthetic dentistry. 1983 Jul;50(1):108-13.
24. Steinberg D, Sela MN, Klinger A, Kohavi D. Adhesion of periodontal
bacteria to titanium, and titanium alloy powders. Clinical oral implants research. 1998 Apr;9(2):67-72.
25. Palmquist A, Lindberg F, Emanuelsson L, Branemark R, Engqvist H,
Thomsen P. Biomechanical, histological, and ultrastructural analyses of laser micro- and nano-structured titanium alloy implants: a study in rabbit. J Biomed Mater Res A. 2010 Mar 15;92(4):1476-86.
26. Linder L, Albrektsson T, Branemark PI, Hansson HA, Ivarsson B,
Jonsson U, et al. Electron microscopic analysis of the bone-titanium interface. Acta Orthop Scand. 1983 Feb;54(1):45-52.
27. Osborn J, Newesely H. Dynamic aspects of the implant-bone-interface.
München: Hanser; 1980.
28. Pilliar RM. Overview of surface variability of metallic endosseous dental
implants: textured and porous surface-structured designs. Implant Dent. 1998;7(4):305-14.
29. Cooper LF, Zhou Y, Takebe J, Guo J, Abron A, Holmen A, et al. Fluoride
modification effects on osteoblast behavior and bone formation at TiO2 grit-blasted c.p. titanium endosseous implants. Biomaterials. 2006 Feb;27(6):926-36.
30. Dinarello CA. Role of pro- and anti-inflammatory cytokines during
inflammation: experimental and clinical findings. J Biol Regul Homeost Agents. 1997 Jul-Sep;11(3):91-103.
31. Athanasou NA. Cellular biology of bone-resorbing cells. J Bone Joint
Surg Am. 1996 Jul;78(7):1096-112.
32. Tengvall P. Proteins at Titanium Interfaces. In: Brunette DM, Tengvall
P, Textor M, Thomsen P, editors. Titanium in medicine: material science, surface science, engineering, biological responses and medical applications. Berlin, Heidelberg: Springer-Verlag; 2001.
33. Weiner S, Traub W. Bone structure: from angstroms to microns. Faseb J. 1992 Feb 1;6(3):879-85.
34. Lindhe J, Berglundh T. The interface between the mucosa and the
implant. Periodontol 2000. 1998 Jun;17:47-54.
35. Gould TR, Brunette DM, Westbury L. The attachment mechanism
of epithelial cells to titanium in vitro. J Periodontal Res. 1981 Nov;16(6):611-6.
36. Abrahamsson I, Berglundh T, Lindhe J. The mucosal barrier following
abutment dis/reconnection. An experimental study in dogs. J Clin Periodontol. 1997 Aug;24(8):568-72.
37. Etter TH, Hakanson I, Lang NP, Trejo PM, Caffesse RG. Healing
after standardized clinical probing of the perlimplant soft tissue seal: a histomorphometric study in dogs. Clin Oral Implants Res. 2002 Dec;13(6):571-80.
38. Chavrier C, Couble ML, Hartmann DJ. Qualitative study of collagenous
and noncollagenous glycoproteins of the human healthy keratinized mucosa surrounding implants. Clin Oral Implants Res. 1994 Sep;5(3):117-24.
39. Glauser R, Schupbach P, Gottlow J, Hammerle CH. Periimplant soft
tissue barrier at experimental one-piece mini-implants with different surface topography in humans: A light-microscopic overview and histometric analysis. Clin Implant Dent Relat Res. 2005;7 Suppl 1:S44- 51.
40. Buser D, Weber HP, Donath K, Fiorellini JP, Paquette DW, Williams RC.
Soft tissue reactions to non-submerged unloaded titanium implants in beagle dogs. J Periodontol. 1992 Mar;63(3):225-35.
41. Wennerberg A, Sennerby L, Kultje C, Lekholm U. Some soft tissue
characteristics at implant abutments with different surface topography. A study in humans. J Clin Periodontol. 2003 Jan;30(1):88-94.
42. Schupbach P, Glauser R. The defense architecture of the human
periimplant mucosa: a histological study. J Prosthet Dent. 2007 Jun;97(6 Suppl):S15-25.
43. Kurashina K, de Lange GL, de Putter C, de Groot K. Reaction of
surrounding gingiva to permucosal implants of dense hydroxyapatite in dogs. Biomaterials. 1984 Jul;5(4):215-20.
44. Rutar A, Lang NP, Buser D, Burgin W, Mombelli A. Retrospective
assessment of clinical and microbiological factors affecting periimplant tissue conditions. Clin Oral Implants Res. 2001 Jun;12(3):189-95.
45. Berglundh T, Lindhe J, Ericsson I, Marinello CP, Liljenberg B, Thomsen P. The soft tissue barrier at implants and teeth. Clin Oral Implants Res. 1991 Apr-Jun;2(2):81-90.
46. Oates TW, Maller SC, West J, Steffensen B. Human gingival fibroblast
integrin subunit expression on titanium implant surfaces. J Periodontol. 2005 Oct;76(10):1743-50.
47. Klinge B, Meyle J. Soft-tissue integration of implants. Consensus report
of Working Group 2. Clin Oral Implants Res. 2006 Oct;17 Suppl 2:93-6.
48. Lausmaa J. Surface oxides on titanium: Preparation, characterization
and biomaterial applications. Gothenburg: Chalmers University of Technology; 1991.
49. Freese H, Volas M, Wood R. Metallurgy and Technological Properties
of Titanium and Titanium Alloys. In: Brunette DM, Tengvall P, Textor M, Thomsen P, editors. Titanium in medicine: material science, surface science, engineering, biological responses and medical applications. Berlin, Heidelberg: Springer-Verlag; 2001. p. p. 25-51.
50. Palmquist A, Lindberg F, Emanuelsson L, Branemark R, Engqvist
H, Thomsen P. Morphological studies on machined implants of commercially pure titanium and titanium alloy (Ti6Al4V) in the rabbit. J Biomed Mater Res B Appl Biomater. 2009 Oct;91(1):309-19.
51. Johansson CB. On tissue reactions to metal implants. Göteborg,; 1991.
52. Hanawa T, Ota M. Calcium phosphate naturally formed on titanium in
electrolyte solution. Biomaterials. 1991 Oct;12(8):767-74.
53. Ellingsen JE. A study on the mechanism of protein adsorption to TiO2.
Biomaterials. 1991 Aug;12(6):593-6.
54. Collis JJ, Embery G. Adsorption of glycosaminoglycans to commercially
pure titanium. Biomaterials. 1992;13(8):548-52.
55. Sela MN, Badihi L, Rosen G, Steinberg D, Kohavi D. Adsorption of
human plasma proteins to modified titanium surfaces. Clinical oral implants research. 2007 Oct;18(5):630-8.
56. Steinberg D, Klinger A, Kohavi D, Sela MN. Adsorption of human
salivary proteins to titanium powder. I. Adsorption of human salivary albumin. Biomaterials. 1995 Nov;16(17):1339-43.
57. MacDonald DE, Deo N, Markovic B, Stranick M, Somasundaran
P. Adsorption and dissolution behavior of human plasma fibronectin on thermally and chemically modified titanium dioxide particles. Biomaterials. 2002 Feb;23(4):1269-79.
58. MacDonald DE, Rapuano BE, Deo N, Stranick M, Somasundaran P, Boskey AL. Thermal and chemical modification of titanium- aluminum-vanadium implant materials: effects on surface properties, glycoprotein adsorption, and MG63 cell attachment. Biomaterials. 2004 Jul;25(16):3135-46.
59. Hench L. Bioactive glasses and glass ceramics: A perspective. In:
Yamamuro T, Hench L, Wilson J, editors. Handbook of bioactive ceramics. Boca Raton, FL: CRC; 1990. p. 7-23.
60. Williams DF. The Williams Dictionary of Biomaterials. Liverpool:
Liverpool University Press; 1999.
61. Göransson A. On possibly bioactive CP titanium implant surfaces.
Göteborg: Dept. of Biomaterials, Institute for Clinical Sciences, Dept. of Prosthetic Dentistry / Dental Material Sciences, Dept. of Orthodontics, Sahlgrenska Academy at Göteborg University; 2006.
62. Sawase T, Wennerberg A, Hallgren C, Albrektsson T, Baba K. Chemical
and topographical surface analysis of five different implant abutments. Clin Oral Implants Res. 2000 Feb;11(1):44-50.
63. Wang R, Hashimoto K, Fujishima A, Chikuni M, Kojima E, Kitamura
A, et al. Light-induced amphiphilic surfaces. Nature 1997;388:431–43.
64. Guillemot F, Porte MC, Labrugere C, Baquey C. Ti4+ to Ti3+ conversion
of TiO2 uppermost layer by low-temperature vacuum annealing: interest for titanium biomedical applications. J Colloid Interface Sci. 2002 Nov 1;255(1):75-8.
65. Jimbo R, Sawase T, Baba K, Kurogi T, Shibata Y, Atsuta M. Enhanced
initial cell responses to chemically modified anodized titanium. Clin Implant Dent Relat Res. 2008 Mar;10(1):55-61.
66. Sawase T, Jimbo R, Baba K, Shibata Y, Ikeda T, Atsuta M. Photo-induced
hydrophilicity enhances initial cell behavior and early bone apposition. Clin Oral Implants Res. 2008 May;19(5):491-6.
67. Sawase T, Jimbo R, Wennerberg A, Suketa N, Tanaka Y, Atsuta M.
A novel characteristic of porous titanium oxide implants. Clin Oral Implants Res. 2007 Dec;18(6):680-5.
68. Sul YT, Johansson CB, Jeong Y, Albrektsson T. The electrochemical
oxide growth behaviour on titanium in acid and alkaline electrolytes. Medical engineering & physics. 2001 Jun;23(5):329-46.
69. Kang BS, Sul YT, Oh SJ, Lee HJ, Albrektsson T. XPS, AES and SEM
analysis of recent dental implants. Acta Biomater. 2009 Jul;5(6):2222-9.
70. Palmquist A, Omar OM, Esposito M, Lausmaa J, Thomsen P. Titanium
oral implants: surface characteristics, interface biology and clinical outcome. J R Soc Interface. 2010 Jun 30.
71. Jarmar T, Palmquist A, Branemark R, Hermansson L, Engqvist H, Thomsen P. Characterization of the surface properties of commercially available dental implants using scanning electron microscopy, focused