系統識別號 U0026-2408201621391701
論文名稱(中文) 利用高分子/抗生素薄膜與生物活性陶瓷調控多孔性鈦塗層植體表面之抗菌及骨生長
論文名稱(英文) The use of polymer/antibiotic film and bio-activated ceramic to regulate the antimicrobial and bone growth effects on porous titanium beads implant
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 104
學期 2
出版年 105
研究生(中文) 陳久芳
研究生(英文) Chiu-Fang Chen
學號 t46034094
學位類別 碩士
語文別 英文
論文頁數 125頁
口試委員 指導教授-李澤民
中文關鍵字 多功能  關節植入物  多孔塗層  生醫陶瓷  骨內生長 
英文關鍵字 Multifunction  joint implants  porous coating  bone ingrowth 
中文摘要 本研究目是開發設計一個能穩定控制藥物釋放的多功能性骨關節鈦植入物系統。對於人工關節,伴隨著植體之植入,通常會有導致發炎反應及細菌感染的發生,因此有文獻指出使用藥物載體,將藥物直接送達目標處,且持續釋放藥物,使得植體植入後有最直接的藥物治療,也可以降低人體對於藥物所需的含量,減輕身體負擔。
鈦和鈦合金經常使用於骨外科植入物,因為它們具有良好的生物相容性,無毒性和好的機械性能。以燒結方式將鈦珠粉末塗佈於鈦金屬人工關節上之技術已發展成熟,經燒結方式鍵結上多孔性鈦珠表面具有良好的粗糙度及孔隙率外,鈦珠表面亦具有良好之表面積。另外利用微弧氧化(micro-arc oxidation, MAO)一簡單且具成本效益的生物陶瓷技術,在表面形成多孔、耐磨耗及抗腐蝕陶瓷相硬化膜。由於多孔表面結構有相當重要的骨整合性,能有效使骨生長至其表面,以增加自然骨與植體間介面的機械咬合性,進一步提供骨內生長的特性,使增生的骨質能進入多孔鈦間隙,達到良好固定效果。而後使用drop-dry法將含有藥物之溶液滴在試片表面,使藥物於孔洞內及表面,以利藥物攜帶。完成後使用聚乳酸具甘醇酸(polylactic acid-polyglycolic acid, PLGA)一種長效型生物可降解高分子和聚麩胺酸(gamma polyglutamic acid, -PGA)為一親水性佳且可降解高分子,作為表面塗層,此高分子薄膜可以有效調控抗生素於身體內之釋放速率及藥量,進而達到長效型藥物釋放之效果。
英文摘要 Total hip arthroplasty (THA) is an established procedure to restore mobility and to improve quality of life in patients that suffer from severe osteoarthritis or femoral fractures in close proximity to the hip joint. The technology of sintering coated titanium (Ti) bead on titanium prosthesis has been developed for many years. The porous surface of the sintered titanium beads has good roughness and porosity to induce better bone ingrowth. After implantation the formation of a bacterial surface biofilm and compromised immunity at the implant/tissue interface may lead to persistent infections around titanium implants. So far, extensive inflammation and poor osseointegration have been identified as the major reasons for early orthopedic implant failures. In this study, we focus on the development of a polymer-coated ceramic composite for antimicrobial drug delivery. A micro-arc oxidation (MAO) was used to produce a porous structure comprising calcium acetate hydrate (Ca(CH3COO)2•H2O) and sodium phosphate monobasic monohydrate (NaH2PO4•H2O) for improving the biocompatibility of titanium. Using a drop-dry method aqueous drug was loaded into the porous surface. Finally, Polylactic acid-polyglycolic acid (PLGA), a biodegradable polymer and Poly gamma glutamic acid (-PGA) were coated through spin coating as a barrier to control drug release. The use of PLGA film can effectively regulate the release rate and amount of the antibiotic dose within the body. The phenomenon of inflammation or infection decreased for the effect of long-circulated drug release.
The bactericidal effect of antibiotic on the porous surface was evaluated by using MRSA bacteria (SA10780). Additionally, the results obtained from UV-Vis analysis suggested that the drug was successfully filled into coatings and released over time with antibiotic/Polymer solution, which could provide a high bactericidal effect against MRSA by the bactericidal effect of antibiotic. These findings demonstrate that using porous structure with PLGA and -PGA is promising as cost-effective drug delivery formulation for delivering drugs locally and continuously. Furthermore, antimicrobial study demonstrates that the antimicrobial activity of antibiotic toward the growth inhibition of a bacterium model of MRSA is not compromised after being loaded into the porous structure.
We demonstrate the preparation and characteristics of Ti implants with a layer of MAO porous coating that have extended drug release properties, biocompatibility for human osteoblasts and potentially improved antibacterial properties. With the reserved drug activity, the porous structure based drug delivery system may find various applications in tissue engineering and pharmaceutical science.
論文目次 Abstract I
摘要 III
誌謝 V
Contents VII
List of Tables X
List of Figures XII
Chapter 1 Introduction 1
1-1 Background 1
1-2 Titanium and titanium alloys 6
1-3 Porous coating 7
1-4 Biocompatibility implant surface modification 9
1-5 Primary total hip arthroplasty 13
1-6 Post-operative wound infection 14
1-7 Local drug delivery 15
1-8 Controlling drug release 16
1-9 Polylactic acid-polyglycolic acid 18
1-10 Poly gamma glutamic acid 18
1-11 Motivation and objective 19
Chapter 2 Material and Method 21
2-1 Experimental procedure 21
2-2 Materials 21
2-3 Experimental instruments 23
2-4 Preparation of specimens 23
2-4-1 Titanium beads onto the substrate of Ti-6Al-4V alloy 24
2-4-2 Micro-arc oxidized 24
2-4-4 Drug loading 24
2-4-5 Polymer coating of drug-loaded MAO 25
2-5 Specimens surface characteristic analysis 25
2-5-1 Surface morphology (SEM/EDS) 25
2-5-2 Surface wettability 26
2-5-3 Electron spectroscopy for chemical analysis 26
2-6 In vitro test 26
2-6-1 Cell culture 27
2-6-2 Bacterial culture 27
2-6-3 Bacterial growth curve 27
2-6-4 Samples sterilization 28
2-6-5 Bacterial adhesion and proliferation 28
2-6-6 Bacterial immobilization 29
2-6-7 Cells photodynamic therapy (MTT assay) 30
2-8 In vivo test 31
2-8-1 Animal Model 31
2-8-2 Surgical procedures 31
2-8-2 Organisms and Preparation of Inoculum 32
2-9 Statistical analysis 32
Chapter 3 Result 34
3-1 Specimens surface characteristic analysis 34
3-1-1 Surface morphology 34
3-1-2 Surface chemical composition analysis 34
3-1-3 Surface wettability 35
3-2 Drug release test 36
3-3 In vitro test 37
3-3-1 Bacterial growth curve 37
3-3-2 Zone of inhibition 37
3-3-3 Bacterial adhesion 37
3-3-4 Bacterial proliferation 38
3-3-5 Cell growth curve 40
3-3-6 Cell attachment 40
3-3-7 Cell proliferation 40
3-3-8 Determination of Toxicity to MG-63 41
3-4 In vivo test (Biological evaluation of medical devices) 41
Chapter 4 Discussion 43
Chapter 5 Conclusion 49
References 50
Table 55
Figure 84
參考文獻 Blom, A.W., et al., Infection after total hip arthroplasty. The Journal of Bone and Joint Surgery, 2003. 85(7): p. 956-959.
Shim, I.K., et al., Biofunctional porous anodized titanium implants for enhanced bone regeneration. J Biomed Mater Res A, 2014. 102(10): p. 3639-48.
Kasemo, B., Biocompatibility of titanium implants- Surface science aspects. The journal of prosthetic dentisrty, 1983. 49: p. 832-37.
Abbasi, S., et al., MAO-derivedhydroxyapatite–TiO2 nanostructured bio-ceramic films on titanium. Materials Research Bulletin, 2012.
Lu, P., et al., Corrosion and drug release properties of EN-plating/PLGA composite coating on MAO film. Materials Science and Engineering: C, 2011. 31(7): p. 1285-1289.
S.J.L. Billinge, M.G.K., Beyond crystallography: the study of disorder, nanocrystallinity and crystallographically challenged materials with pair distribution functions. Chem. Commun, 2004: p. 11.
Hermawan, H., Biodegradable metals: from concept to applications. 2012, Malaysia.
D. Campoccia, L.M., C.R. Arciola, The significance of infection related to orthopedic devices and issues of antibiotic resistance. Biomaterials, 2006. 27: p. 8.
Uçkay, P.H., D. Lew, D. Pittet, Prevention of surgical site infections in orthopedic surgery and bone trauma: state-of-the-art update. J. Hosp. Infect. , 2013. 84: p. 7.
Onche , O.A., Microbiology of post-operative wound infection in implant surgery. Nigerian Journal of Surgical Research, 2004. 6: p. 37-40.
Murthy, C.D., G. Sunkara, and D. Young, Pharmaceutical product development: in vitro-in vivo correlation. 2007: Taylor & Francis US.
Sebak, S., et al., Human serum albumin nanoparticles as an efficient noscapine drug delivery system for potential use in breast cancer: preparation and in vitro analysis. International Journal of Nanomedicine, 2010. 5: p. 525-532.
Wolinsky, J.B., Y.L. Colson, and M.W. Grinstaff, Local drug delivery strategies for cancer treatment: Gels, nanoparticles, polymeric films, rods, and wafers. Journal of Controlled Release, 2012. 159(1): p. 14-26.
Singh, R. and J.W. Lillard Jr, Nanoparticle-based targeted drug delivery. Experimental and Molecular Pathology, 2009. 86(3): p. 215-223.
Kazemzadeh-Narbat, M., et al., Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. Biomaterials, 2010. 31(36): p. 9519-9526.
Holzwarth, J.M. and P.X. Ma, Biomimetic nanofibrous scaffolds for bone tissue engineering. Biomaterials, 2011. 32(36): p. 9622-9629.
Daniel H Betz, R.T.E., Brian M Holt, Roy D Bloebaum, and Sujee Jeyapalina, A new trichrome technique for PMMA embedded percutaneous implants for the study and characterization of epithelial integration. . Journal of Histotechnology, 2012. 35(4): p. 6.
C.J. and J. Shi, Sterilization-free chitosan hydrogels for controlled drug release. Materials Letters, 2012.
Lyndon, J.A., B.J. Boyd, and N. Birbilis, Metallic implant drug/device combinations for controlled drug release in orthopaedic applications. J Control Release, 2014. 179: p. 63-75.
D.R. Holmes, M.B.L.J., J.W. Moses, F.J. Popma, D. Cutlip, P.J. Fitzgerald, C. Brown, and S.C.W. T. Fischell, M. Midei, D. Snead, R.E. Kuntz, Analysis of 1-year clinical outcomes
in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a
standard stent in patients at high risk for coronary restenosis. Circulation, 2004. 109: p. 6.
Roukoz, H., Comprehensive meta-analysis on drug-eluting stents versus bare-metal
stents during extended follow-up. Am. J. Med., 2009. 122 p. 581.e581-581.e510.
W.C. Carlyle, J.B.M., A.R. Tzafriri, L. Bailey, B.G. Zani, P.M. Markham, J.R.L. Stanley, E.R. Edelman, Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug. J. Control. Release 2012. 162: p. 7.
Ghicov, A., et al., TiO2–Nb2O5 Nanotubes with Electrochemically Tunable Morphologies. Angewandte Chemie International Edition, 2006. 45(42): p. 6993-6996.
Somayajula, D.A., Biocompatibility Of Osteoblast Cells On Titanium Implants, in Bachelor of Technology in Chemical Engineering. 2008, Cleveland State University. p. 1-3.
Gürsel, İ., et al., In vivo application of biodegradable controlled antibiotic release systems for the treatment of implant-related osteomyelitis. Biomaterials, 2000. 22(1): p. 73-80.
Lee, J.H., et al., Modification of TiO(2) nanotube surfaces by electro-spray deposition of amoxicillin combined with PLGA for bactericidal effects at surgical implantation sites. Acta Odontol Scand, 2013. 71(1): p. 168-74.
G.e., Biocompatibility of total joint replacements: a review. Journal of Biomedical Materials Research, 2008: p. 15.
Narayan, R., Porous Coatings on Metallic Implant Materials. Materials for Medical Devices, 2012. 23.
Nurul Husna Z., C.C.L., Processing and Characterization of Porous Mg Alloy for Biomedical Applications. Australian Journal of Basic and Applied Sciences, 2014. 8: p. 160-164.
YusufKhan, P., Michael J. Yaszemski, MD, PhD, Antonios G. Mikos, PhD, and Cato T. Laurencin, MD, PhD, Tissue Engineering of Bone: Material and Matrix Considerations. THE JOURNAL OF BONE AND JOINT SURGERY, 2008. 90: p. 36-42.
Fabrizio Matassi, M., Porous metal for orthopedics implants. Clinical Cases in Mineral and Bone Metabolism, 2013. 10: p. 111-115.
Berardi, D., New laser-treated implant surfaces. Clin Invest Med, 2011. 34: p. E202-212.
Jr., A.B.N., Influence of Implant Surfaces on Osseointegration. Braz Dent J, 2010. 21: p. 471-481.
Piattelli, A., Histologic and Histomorphometric Analysis of the Bone Response to Machined and Sandblasted Titanium Implants: An Experimental Study in Rabbits. The International Journal of Oral & Maxillofacial Implants, 1998. 13: p. 805-810.
Rd, S.P., Primary total hip arthroplasty. AORN JOURNAL, 2003. 78: p. 946-949.
Hans Zwipp, S.R., Sven Barthel, Calcaneal fractures—open reduction and internal fixation (ORIF). Injury, Int. J. Care Injured, 2004. 35: p. S-B46-54.
Young-Seok Park, J.-Y.C., Shin-Jae Lee, and Chee Il Hwang, Modified Titanium Implant as a Gateway to the Human Body : The Implant Mediated Drug Delivery System. BioMed Research International, 2014. 2014.
Mirza, R., Customized biomimetic coatings for hip and spinal implants to reduce implant-related infections and promote osseointegration, in Department of Biology. 2011, Case Western Reserve University. p. 91.
Makadia, H.K. and S.J. Siegel, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers (Basel), 2011. 3(3): p. 1377-1397.
Ivanovics, G., V. Bruckner, Chemische und immunologische Studien uber den Mechanimus der Milzbrandinfektion und Immunitat; die chemische Struktur der Kapdelsubstanz des Milzbrandbasillus und der serologisch identischen spezifischen Substanz des Bacillus mesentericus. Z. Immunitatsforsch, 1937. 90: p. 14.
Hsiang-Fa Liang, C.-T.C., Sung-Ching Chen, Paclitaxel-loaded poly(r-glutamic acid)-poly(lactide) nanoparticles as a targeted drug delivery system for the treatment of liver cancer. Biomaterials, 2006. 27: p. 2051–2059.
Gregory A. Birrer, A.-M.C.a.R.A.G., r-Poly(glutamic acid) formation by Bacillus licheniformis 9945a: physiological and biochemical studies. Int. J. Biol. Macromol, 1994. 16: p. 265-276.
Ming-Feng Chiang, T.-M.W., Intercalation ofγ-PGA in Mg/Al layered double hydroxides: An in situWAXD and FTIR investigation Applied Clay Science, 2011. 51: p.4
Ogawa Y, Y.F., Yuasa K, Tahara Y, Efficient production of gamma-polyglutamic acid by Bacillus subtilis (natto) in jar fementers. Biosci Biotechnol Biochem, 1997. 61: p. 4.
Guan-Huei Hoa, T.-I.H., Kuo-Huang Hsieh, Yuan-Chi Su, Pi-Yao Lin, Jeng Yang, Kun-Hsiang Yang and Shih-Ching Yang, γ-Polyglutamic Acid Produced by Bacillus subtilis (natto): Structural Characteristics, Chemical Properties and Biological Functionalities. Journal of the Chinese Chemical Society, 2006. 53: p. 21.
Xinhua Xu *, P.L., Meiqing Guo, Mingzhong Fang, Cross-linked gelatin/nanoparticles composite coating on micro-arc oxidation film for corrosion and drug release. Applied Surface Science, 2010. 256: p. 4.
Kazemzadeh-Narbat, M., et al., Multilayered coating on titanium for controlled release of antimicrobial peptides for the prevention of implant-associated infections. Biomaterials, 2013. 34(24): p. 5969-77.
A.D. Pye, D.E.A.L., M.P. Dawson, C.A. Murray, A.J. Smith, A review of dental implants and infection. Journal of Hospital Infection, 2009. 72: p. 6.
Huiying Jia, L.L.K., Kinetics of Drug Release from Drug Carrier of Polymer/TiO2 Nanotubes Composite—pH Dependent Study. Applied polymer science, 2015: p. 11.
Annunziata, M., Oliva, A., Basile, M.A., Giordano, M., Mazzola, N., Rizzo, A., Lanza, A., and Guida, L. , The effects of titanium nitride-coating on the topographic and biological features of TPS implant surfaces. Journal of Dentistry, 2011. 39(11): p. 9.
Stratford, A.F., D.E. Zoutman, and J.S. Davidson, Effect of lidocaine and epinephrine on Staphylococcus aureus in a guinea pig model of surgical wound infection. Plast Reconstr Surg, 2002. 110(5): p. 1275-9.
William Barker, M., George T. Rodeheaver, PhD, Damage to Tissue Defenses by a Topical Anesthetic Agent. Annals of Emergency Medicine, 1982. 11: p. 307-310.
Botchwey, E.A., Quantitative analysis of three-dimensional fluid flow inrotating bioreactors for tissue engineering. Journal of Biomedical Materials Research, 2004. 69: p. 205-15.
Edin, M.L., Eeffect of Cefazolin and Vancomycin on Osteoblasts In Vitro. 1996: p. 245-251.
Soriano, A., Pathogenic Significance of Methicillin Resistance for Patients. Clinical Infectious Diseases, 2000. 30: p. 368-73.
Cepeda, J.A., et al., Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study. J Antimicrob Chemother, 2004. 53(2): p. 345-55.
Howden, B.P., Treatment Outcomes for Serious Infections Caused. Clin Infect Dis, 2004. 38: p. 521-8
Epidemiological and Microbiological Characterization of Infections Caused
by Staphylococcus aureus with Reduced Susceptibility to Vancomycin, United States. Clinical Infectious Diseases, 2003. 36: p. 429-39.
K.H. Chen, G.A.L., S.D. Chen, J.e. Shiu, M.L. Yeh, Prolong Antibiotics Release by Encapsulating PLGA for Hip Prosthesis. 2009.
  • 同意授權校內瀏覽/列印電子全文服務,於2021-08-24起公開。

  • 如您有疑問,請聯絡圖書館