臺灣博碩士論文加值系統

植牙手術在口腔外科領域中，成功率高達90-95％。細菌感染、廣泛的發炎反應、骨整合能力差，是植牙早期失敗的主要原因。有文獻指出使用藥物載體，將藥物直接送達目標處(手術植入處)，且逐漸並持續釋放藥物，使得植入後癒合處不但有最直接的藥物治療，且還可降低人體對於藥物所需的含量，減輕身體代謝負擔。
在本篇研究中，我們欲發展一種能穩定控制藥物釋放的藥物載體系統。本研究係利用微弧氧化(micro-arc oxidation, MAO)處理，將鈦基材上披覆上一層氧化鈦鍍層與鈣磷鍍層，在表面上形成微米級多孔結構，並且添加含有鈣、磷的成分，增加泰基材的生物親和性。之後使用壓力噴塗法，將含有藥物之溶液均勻噴塗於孔洞內以及表面，以利藥物攜帶。完成後藉由全天然生物且可分解的聚麩胺酸(gamma polyglutamic acid, γ-PGA)可水降解性的鈉離子型，以及不可水降解的氫離子型，使用不同比例混合後，作為表面塗層，同時利用旋轉塗佈法(spin coating)使其均勻披覆於材料表面，期望植入後藉由人體週期代謝來控制藥物的釋放速率。將製備好的試片浸泡於有機溶劑中，於不同時間點收取其溶液並且使用紫外光/可見分光光度法(Ultraviolet‒visible spectroscopy，UV-Vis)進行吸光值測定。利用藥物不同吸光值波長之特性，來判別不同時間點的藥物釋放濃度。期望藉由藥物噴塗搭配高分子鍍膜披覆的控制，以達到藥物穩定釋放之曲線。
在抗菌測試方面，使用大腸桿菌(ATCC® PTA-10989TM)，結果由紫外光/可見光光度法分析證實藥物不僅成功的攜帶並隨時間連續且穩定的釋放，與抗菌實驗中抗生素對大腸桿菌的高殺菌作用結果上是一致的。這些結果證明，使用含有聚麩胺酸的多孔結構植體是可成為具有成本效益的藥物釋放製劑，可提供局部且持續的藥物釋放功能。並且於抗菌活性試驗中證實，抗生素對抑制大腸桿菌生長的抗菌活性不會因為藥物被裝載到多孔結構後受到損害而降低。該多孔結構為基礎的藥物釋放系統不僅可以保留藥物的活性，並且可廣泛應用在組織工程及藥物學等的各種應用上。

Titanium and titanium alloys are frequently used in orthopaedic implants because of their good biocompatibility and reliable mechanical properties. After implantation the formation of a bacterial surface biofilm and compromised immunity at the implant/tissue interface may lead to persistent infections on and around titanium implants. Bacterial infection, extensive inflammation and poor osseointegration have been identified as the major reasons for early orthopaedic implant failures based on titanium (Ti).
In this study, we focuses 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 spray coating method, aqueous drug was loaded into the porous surface. Finally, gamma polyglutamic acid (r-PGA), a well-known natural hydrophilic biodegradable polymer, dependent on two types of r-PGA mixing ratio, water soluble Na+ type and water insoluble H+ type, was coated layer-by-layer through spin coating as a barrier to control drug release. The bactericidal effect of antibiotic on the porous surface was evaluated by using Escherichia coli (E. coli) bacteria (ATCC® PTA-10989TM). Additionally, the results obtained from UV-Vis analysis suggested that the drug was successfully filled into coatings and released over time with antibiotic/r-PGA solution could provide a high bactericidal effect against E.coli by the bactericidal effect of antibiotic.
These findings demonstrate that using porous structure with -PGA is promising as cost-effective drug delivery formulation for delivering drugs locally and continuously. Further antimicrobial activity demonstrate that the antimicrobial activity of antibiotic toward the growth inhibition of a model bacterium of E-coli is not compromised after being loaded into the porous structure. With the reserved drug activity, the porous structure based drug delivery system may find various applications in tissue engineering and pharmaceutical science.

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 Dental titanium 5
1-3 Surface modification of dental implant 6
1-4 Implant failure 10
1-5 Local drug delivery 11
1-6 Controlling drug release 12
1-7 Poly gamma glutamic acid 14
1-8 Motivation and objective 15
Chapter 2 Material and Method 17
2-1 Experimental procedure 17
2-2 Materials 17
2-3 Experimental instruments 18
2-4 Preparation of specimens 19
2-4-1 Titanium substrates 19
2-4-2 Polish 19
2-4-3 Micro-arc oxidized 20
2-4-4 Drug loading 20
2-4-5 Polymer coating of drug-loaded MAO 21
2-5 Specimens surface characteristic analysis 22
2-5-1 Surface morphology (SEM/EDS) 22
2-5-2 Surface wettability 22
2-5-3 Electron spectroscopy for chemical analysis 22
2-5-4 Thermogravic analysis 23
2-6 In vitro test 23
2-6-1 Cell culture 23
2-6-2 Bacterial culture 24
2-6-3 Bacterial growth curve 24
2-6-4 Samples sterilization 25
2-6-5 Bacterial adhesion and proliferation 25
2-6-6 Bacterial immobilization 25
2-7 Cells photodynamic therapy (MTT assay) 26
2-8 Statistical analysis 28
Chapter 3 Result 29
3-1 Specimens surface characteristic analysis 29
3-1-1 Surface morphology 29
3-1-2 Surface chemical composition analysis 30
3-1-3 Surface wettability 30
3-1-4 Thermogravimetry Analysis 31
3-2 Drug release test 31
3-3 In vitro test 34
3-3-1 Bacterial growth curve 34
3-3-2 Zone of inhibition 34
3-3-3 Bacterial adhesion 34
3-3-4 Bacterial proliferation 35
3-3-5 Cell growth curve 36
3-3-6 Cell attachment 37
3-3-7 Cell proliferation 37
Chapter 4 Discussion 39
Chapter 5 Conclusion 44
References 46
Table 51
Figure 78

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