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研究生:黃琪雅
研究生(外文):Chi-Ya Huang
論文名稱:探討低彈性係數鈦合金表面利用天然交聯劑接枝攜帶VEGF、FGF-2及BMP-2之明膠奈米粒子之成骨反應
論文名稱(外文):Osteogenic response to low elastic modulus titanium alloy surface immobilized with gelatin nanoparticles containing VEGF, FGF-2 and BMP-2 through a natural cross-linker
指導教授:黃何雄
指導教授(外文):Her-Hsiung Huang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:口腔生物研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:104
中文關鍵詞:鈦鈮鋯錫合金明膠奈米顆粒京尼平血管內皮生長因子第二型成纖維細胞生長因子第二型骨形成蛋白成骨反應
外文關鍵詞:Ti-24 Nb-4 Zr-8 Sn alloyGelatin nanoparticlesGenipinVascular endothelial growth factorFibroblast growth -factor-2Bone morphogenetic protein-2Osteogenic response
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  鈦-24 wt%鈮-4 wt%鋯-8 wt%錫 (Ti-24 wt% Nb-4 wt% Zr-8 wt% Sn, Ti2448)合金之特性為具有良好的機械性質、耐蝕性質與生物相容性質,其與人體自然骨骼有相近的彈性係數 (Ti2448:≈ 42 GPa;骨骼:< 40 GPa),可降低手術後因應力遮蔽效應 (stress shielding effect)所引發之骨萎縮現象,進而提升手術成功率。近年來在臨床應用上被視為一種極具開發潛力之新型骨科植入材料。然而,Ti2448合金表面仍為生物惰性,與人體自然骨組織間不易產生連結,因此如何保留其低彈性係數之優點,並能同時提升其表面之生物活性與生物反應,以促進植入物與周圍骨組織之間的骨整合作用,為當前需要探討之議題。
  本研究利用噴砂、酸蝕及鹼洗處理使Ti2448合金表面材料表面具有微米、次微米及奈米混合尺寸大小之孔洞以促進細胞反應,並利用天然交聯劑京尼平 (genipin)接枝上生長因子以促進骨組織再生。本研究以明膠奈米粒子 (gelatin nanoparticles)作為載體分別攜帶多種生長因子,包括影響骨細胞分化前期之血管內皮生長因子 (vascular endothelial growth factor, VEGF)、第二型成纖維細胞生長因子 (fibroblast growth factor-2, FGF-2)以及影響骨細胞分化後期的第二型骨形成蛋白 (bone morphogenetic protein-2, BMP-2),形成外層具VEGF + FGF-2、內層具BMP-2生長因子之明膠奈米粒子複合層結構。接續再利用京尼平分別將攜帶BMP-2之明膠奈米粒子及攜帶VEGF + FGF-2之明膠奈米粒子接枝固定於經噴砂/酸蝕/鹼洗處理之粗糙Ti2448合金表面,期望可透過此內外層結構使生長因子依序釋放,以達到促骨組織再生之目的。利用分析材料表面各種特性 (包括表面形貌、化學組成及潤濕性)與材料表面人類骨髓間葉幹細胞 (human bone marrow mesenchymal stem cells, hMSCs)各種反應 (包括毒性、貼附、增生、胞外基質礦化及骨分化相關蛋白表現),以評估此複合層促進骨整合之能力。結果顯示,本研究利用天然交聯劑京尼平成功接枝攜帶有VEGF、FGF-2與BMP-2之明膠奈米粒子於粗糙Ti2448合金材料表面 (外層明膠奈米粒子:VEGF + FGF-2;內層明膠奈米粒子:BMP-2),且此外表接枝生長因子複合層結構之明膠奈米粒子不具潛在的細胞毒性。另一方面,表面僅接枝BMP-2之明膠奈米粒子組別有助於提升材料表面之細胞貼附及礦化表現;表面接枝BMP-2 (內層)及VEGF + FGF-2 (外層)複合層結構之明膠奈米粒子組別則可促進材料表面之礦化表現。本研究利用新穎且簡易之方法,成功將表面含有VEGF、FGF-2及BMP-2之明膠奈米粒子接枝於粗糙的Ti2448合金材料表面,期許此Ti2448合金表面改質技術具應用於骨科植入材料之潛力。
Titanium-24 wt% Niobium-4 wt% Zirconium-8 wt% Tin (Ti-24 wt% Nb-4 wt% Zr-8 wt% Sn, Ti2448) is a novel titanium alloy with high strength, high corrosion resistance, and good biocompatibility that makes it ideally suited for use as an implant material. Furthermore, its elastic modulus (42 GPa) is close to that of natural bone (< 40 GPa), which decreases the risk of stress shielding. Unfortunately, the bioinert nature of Ti2448 alloy means that surface modification is required to improve surface bioactivity and osteogenic response.
In this study, we employed sandblasting, acid etching and alkaline treatment to produce a roughened Ti2448 alloy surface with a submicron- and nano-scale porosity which was shown to promote the osteogenesis of bone cells. Non-cytotoxic gelatin nanoparticles containing vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and bone morphogenetic protein-2 (BMP-2) were then sequentially immobilized on the surface-modified Ti2448 alloy using the natural crosslinker genipin. These gelatin nanoparticles were used as carriers to enhance mesenchymal stem cell migration and regulate osteoblast differentiation and bone formation due to the presence of angiogenesis stimulators VEGF and FGF-2, and to play an important role in skeletal growth and bone formation due to the presence of osteogenesis stimulator BMP-2.
To summarize, in this study, we used genipin to immobilize gelatin nanoparticles that contained VEGF + FGF-2 (in the outer layer) and BMP-2 (in the inner layer) on roughened Ti2448 alloy in order to produce a non-toxic multilayered structure. The structure of Ti2448 alloy was designed with both inner and outer layers to ensure the sequential release of osteogenesis-inducing growth factors. As for cell responses, the BMP-2-only layer could enhance the cell adhesion and mineralization; the VEGF, FGF-2, and BMP-2 multilayer (outer: VEGF + FGF-2; inner: BMP-2) could enhance the cell adhesion of human bone marrow mesenchymal stem cells. This novel approach to the immobilization of VEGF, FGF-2, and BMP-2-containing gelatin nanoparticles on roughened Ti2448 alloy surface has potential utility in orthopedic implant applications.
致謝……………………………………………………………………i
中文摘要…………………………………………………………iii
Abstract ……………………………………………………v
目錄……………………………………………………………………vii
圖目錄………………………………………………………………xii
表目錄………………………………………………………………xvii
第一章 緒論……………………………………………………1
1.1 研究背景…………………………………………………1
1.2 文獻回顧…………………………………………………2
1.2.1 人體骨組織成分及性質………………………2
1.2.2 骨整合 (osseointegration)…………4
1.2.3 鈦及鈦合金植入物於骨科臨床應用之缺陷及隱憂…4
1.2.4 鈦鈮鋯錫 (Ti-24 wt% Nb-4 wt% Zr-8 wt% Sn, Ti2448) 合
金之特性…………………………………5
1.2.5 表面改質技術…………………………………………7
1.2.6 Gelatin nanoparticles接枝生長因子之研究…………10
1.2.7 Genipin之特性與應用……………………………11
1.2.8 Gelatin nanoparticles與genipin之鍵結………12
1.2.9 血管內皮生長因子 (VEGF)………………………13
1.2.10 第二型成纖維細胞生長因子 (FGF-2)………………13
1.2.11 第二型骨形成蛋白 (BMP-2)…………………………14
第二章 研究動機與假說………………………………………………16
第三章 實驗材料與方法……………………………………………18
3.1 .Ti2448合金試片……………………………18
3.2 Gelatin nanoparticles製備及接枝生長因子VEGF、FGF-2及
BMP-2…………………………………………………………18
3.3 材料表面孔洞化處理………………………………………19
3.3.1 噴砂處理 (sandblasting)……………………………19
3.3.2 酸蝕處理 (acid etching)……………………………19
3.3.3 鹼洗處理 (alkaline treatment)…………………………20
3.4 材料表面生長因子接枝處理………………………………20
3.4.1 材料表面genipin交聯處理…………………………20
3.4.2 材料表面BMP-2 gelatin nanoparticles接枝處理……20
3.4.3 Genipin交聯處理…………………21
3.4.4 材料表面VEGF + FGF-2 gelatin nanoparticles接枝處
理………………………………………………………21
3.5 材料表面特性分析………………………………22
3.5.1 材料表面之形貌觀察………………………22
3.5.2 材料表面之碳 (C1s)及氮 (N1s)元素分析……………22
3.5.3 材料表面之官能基 (functional base)種類分析………23
3.5.4 材料表面之潤濕性 (wettability)分析…………………24
3.5.5材料表面之粗糙度 (roughness)分析…………………24
3.5.6 材料表面之VEGF及FGF-2 gelatin nanoparticles觀察…25
3.6 材料表面之細胞反應分析……………………………26
3.6.1 細胞株……………………………………………26
3.6.2 保存細胞…………………………………28
3.6.3 解凍細胞…………………………………28
3.6.4 細胞繼代…………………………………29
3.6.5 材料表面之細胞毒性 (cytotoxicity)分析………29
3.6.6 材料表面與細胞間之貼附交互作用觀察………30
3.6.7 材料表面之細胞增生 (proliferation)分析………32
3.6.8材料表面之細胞礦化 (mineralization)及分化(differentiation)分析………………………………32
3.6.8.1 細胞外基質礦化分析……………………………33
3.6.8.2 骨分化標的蛋白分析……………………………33
3.6.9統計方法……………………………………………35
第四章 實驗結果……………………………………………………36
4.1 材料表面特性分析結果……………………………………36
4.1.1 材料表面之形貌觀察……………………………36
4.1.2 Gelatin nanoparticles之尺寸及形貌觀察……37
4.1.3 材料表面之元素鑑定……………………………37
4.1.4 材料表面之官能基種類分析………………………38
4.1.5 材料表面之潤濕性分析………………………………39
4.1.6 材料表面之粗糙度分析…………………………………39
4.1.7 材料表面之VEGF及FGF-2 gelatin nanoparticles觀察……40
4.2 材料表面之細胞反應分析…………………………………40
4.2.1 材料表面之細胞毒性分析………40
4.2.2 材料表面與細胞間之貼附交互作用觀察…………41
4.2.3 材料表面之細胞增生分析…………………………43
4.2.4 材料表面之細胞礦化及分化分析…………………43
4.2.4.1細胞外基質礦化分析………………………………43
4.2.4.2骨分化標的蛋白分析………………………………44
第五章 討論…………………………………………………………46
5.1 材料表面特性……………………………………………46
5.2 材料表面之細胞反應……………………………………53
第六章 結論……………………………………………………………59
參考文獻…………………………………………………………61
附圖…………………………………………………………72
附表…………………………………………………………103


圖目錄
圖一、應力遮蔽效應之機制〔Arifin et al., 2014〕。…………………72
圖二、(a) gelatin化學組成結構。(b) genipin化學組成結構。(c) gelatin與genipin交聯鍵結之化學反應式 〔Rose et al., 2014〕。(d) gelatin分子交聯形成gelatin nanoparticles之反應式及其他化學結構〔Sung et al., 2007〕。…………………………………73
圖三、(a) VEGF化學組成結構〔Muller et al., 1997〕。 (b) FGF-2化學組成結構〔Ago et al., 1991〕。 (c) BMP-2化學組成結構〔Scheufler et al., 1999〕。…………………………………74
圖四、材料製備流程示意圖。…………………………………………75
圖五、利用FE-SEM觀察TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片之表面形貌 (1,000倍)。……76
圖六、利用FE-SEM觀察TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片之表面形貌 (20,000倍)。…77
圖七、利用FE-SEM觀察不同濃度genipin製備gelatin nanoparticles之鍵結程度及形貌。 (a) 5% genipin;(b) 10% genipin;(c) 15% genipin。…………………………………………………………78
圖八、利用XPS分析TS、TSA、TSAA及TSAAG試片表面之C1s訊號強度。………………………………………………………79
圖九、利用XPS分析TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面之N1s訊號強度。……80
圖十、利用FTIR分析TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面之化學官能基。……………………81
圖十一、利用接觸角測量儀分析TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF材料表面之潤濕性。……………82
圖十二、利用表面輪廓儀分析TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF材料表面之粗糙度:(a) Ra (μm);(b) Rz (μm) (*p < 0.05)。………………………………83
圖十三、利用正立式螢光顯微鏡觀察TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面VEGF之分布情形。……………84
圖十四、 利用正立式螢光顯微鏡觀察TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面FGF-2之分布情形…………85
圖十五、根據ISO 10993-5規範分析TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面之細胞毒性。………86
圖十六、利用正立式螢光顯微鏡觀察hMSCs-GFP培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面2小時後之細胞數量及形貌。………………………87
圖十七、利用正立式螢光顯微鏡觀察hMSCs-GFP培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面24小時後之細胞數量及形貌。………………………88
圖十八、利用FE-SEM觀察hMSCs-GFP培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面2小時後之細胞貼附形貌 (1,000倍)。………………………89
圖十九、利用FE-SEM觀察hMSCs-GFP培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面2小時後之細胞貼附形貌 (5,000倍)。…………………………90
圖二十、利用FE-SEM觀察hMSCs-GFP培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面24小時後之細胞貼附形貌 (1,000倍)。……………………91
圖二十一、利用FE-SEM觀察hMSCs-GFP培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面24小時後之細胞貼附形貌 (5,000倍)。………………92
圖二十二、利用正立式螢光顯微鏡觀察hMSCs培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面6小時後,Actin表現之分布情形。………………93
圖二十三、利用正立式螢光顯微鏡觀察hMSCs培養於TS、TSA、TSAA、 TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面6小時後,Actin及Vinculin表現之分布情形。………………94
圖二十四、利用alamarBlue® assay分析hMSCs培養於TS、TSA、TSAA、00TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面經過1、3、5及7天後細胞增生情形 (*p < 0.05;**p < 0.01)。…………………95
圖二十五、利用Alizarin res S評估細胞培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面經過 (a) 7 天 (b) 10天 (c) 14天後細胞初期胞外基質礦化之定性情形。………96
圖二十六、利用Alizarin red S評估細胞培養於TS、TSA、TSAA、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面經過7、10及14天後細胞初期胞外基質礦化之定量情形。…………………………………………97
圖二十七、以Western blot分析細胞培養於TS、TSA、TSAA、TSAAG、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面經過 (a) 7天 (b) 14天後細胞分化相關蛋白 (BSP、OPN與OCN)之定性情形。…………………98
圖二十八、以Western blot分析細胞培養於TS、TSA、TSAA、TSAAG、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面經過 (c) 21天後細胞分化相關蛋白 (BSP、OPN與OCN)之定性情形。……………99
圖二十九、以Western blot分析細胞培養於TS、TSA、TSAA、TSAAG、TSAAG、TSAAGB、TSAAGBG及TSAAGBGF試片表面經過7天、14天及21天後細胞分化相關蛋白 (BSP、OPN與OCN)之定量情形 (*p < 0.05;**p < 0.01)。……………………………………100
圖三十、蛋白藥物由生物可降解性之載體複合物釋放之方法〔Tabata andand Ikada, 1998〕。……………………………101
圖三十一、Collagen經鹼及酸處理後水解產生gelatin之機制〔Tabata andand Ikada, 1998〕。……………………………102


表目錄
表一、骨科金屬植入材之彈性係數〔Yang et al., 2011〕。……103
表二、各組材料之組別代號。…………………………………104
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