臺灣博碩士論文加值系統

透明質酸 (hyaluronic acid，簡稱HA) 是由葡萄糖醛酸(D-glucuronic acid) 和 N-乙醯氨基葡萄糖 (N-acetyglucosamine) 雙糖單位重複建構而成的，因具有特殊生物相容性、保濕能力和獨特的流變學特性，目前已廣泛應用在生物醫學、化妝品工業等領域上。本研究係利用獸疫鏈球菌 (Streptococcus zooepidemicus) 菌株培養生成 HA，探討葡萄糖濃度、攪拌、曝氣和額外添加物對 HA 生產之影響；並探討轉速和曝氣速率對氧氣質傳係數 (kLa) 的影響。實驗結果顯示葡萄糖以 20 g/L 最高所得之 HA 產量最高，HA 產量為 0.61g/L，此時約有30 % 的葡萄糖被消耗並轉化成 HA 和菌量，此可知培養基中適當的葡萄糖濃度存在有助於 S. zoopidemicus 菌株生長，並且提升 HA 產量。在攪拌和間接曝氣實驗的探討中，則是以間接曝氣培養優於攪拌培養，且間接曝氣條件為不曝氣 (An)- 曝氣 (A) 為 24h-24h 時能獲得最高的 HA產量 (0.61 g/L)；結果亦顯示出的 kLa 變化確實會受到轉速和曝氣速率的影響，但不是主要影響 HA 生產的因素。但在添加物方面，實驗結果顯示皆對 HA 產量影響不大。而培養基之 pH 的調控上，則有助菌體生長和 HA 產量增加。另外，亦發現菌落型態亦會影響 HA 含量。最後，將純化之產物進行 FT-IR、NMR及 GPC 分析來確定產物之結構及分子量範圍，結果顯示此產物確實為 HA。
在固定化細胞方面，製備 alginate、PAA 和 PVA 菌體顆粒，進行重複批次試驗，結果發現以 PVA 顆粒最適合作為日後培養之固定化基材。

Hyaluronic acid composed of repeating disaccharide units of D-glucuronic acid and N-acetyglucosamine. Because of it’s special biocompatibility, moister-holding function and extraordinary rheological property, it has been used as biomedical, cosmetic industry and else relevance field.The effect of various cultures on glucose concentration, agitation speed, aeration rate and added various components of hyaluronic acid (HA) production by Streptococcal zooepidemicus was studies. And the effects of fermentation process variables on volumetric mass transfer coefficient (kLa) in agitation speed and aeration rate conditions were investigated. The result exhibited that glucose concentration of 20 g/L had the maximum yield of HA (0.61 g/L), and 30 % of the glucose was converted to HA and biomass. That known suitable glucose concentration in the medium can help Streptococcal zooepidemicus strain grown and improved the HA yield. Under agitation and intermittent aeration (IA) conditions, IA gave superior results compared to agitation. Anaeration - aeration = 24 h - 24 h of IA had the maximum yield of HA (0.61 g/L); Evalution of experimental datd also shows kLa value are in significant effected by process of agitation speed and aeration rate. The results are presented in added various components was clight affected the HA yield. The controlled of medium pH can also improve yield of HA and biomass. In addition, the physiogonomy of colonies also could effect the HA quantities. The purified samples were characterized by a fourier transform infrared (FTIR) spectroscopy, a nuclear magnetic resonance (NMR), gel permeation chromatography (GPC).The results show that the purifiedsample from the fermentation liquid was HA.
In this study, we investigate a bioprocess for the production of HA with high productivity by the immobilized-microorganism beads. The results show that PVA has the potential for cell-immobilizing materials.

封面內頁
簽名頁
授權書…… iii
中文摘要.. iv
英文摘要... vi
誌謝……… viii
目錄……… x
圖目錄…… xv
表目錄…… xix

第一章 前言 1
第二章 文獻回顧 5
2.1 黏多醣物質特性 5
2.1.1 黏多醣的化學組成 5
2.1.2 黏多醣的純化方法 9
2.2 HA 之簡介 10
2.2.1 HA 的來源 10
2.2.2 HA 的物理特性 11
2.2.3 HA 生化合成機制 13
2.3 可生產 HA 之微生物菌種-鏈球菌 17
2.4 影響微生物生產 HA 之因子 19
2.4.1氮源的影響 20
2.4.2 碳源的影響 21
2.4.3 溫度的影響 23
2.4.4 pH的影響 25
2.4.5 曝氣/攪拌速率的影響 26
2.4.6 額外添加物之影響 28
2.5 利用代謝工程方法生產高效能之 HA 29
2.6 HA 流變學 33
2.6.1 HA 分子量與黏度的相關性 34
2.6.2 HA分解後之黏度變化 35
2.6.3 HA 發酵系統中氧氣質傳係數的重要性 36
2.7 HA應用範疇 37
2.7.1 化妝品之應用 37
2.7.2 臨床醫學上之應用 38
2.7.3 藥物釋放之應用 41
2.7.4 其它方面應用 42
2.8 HA 市場 43
第三章 材料與方法 47
3.1實驗材料 47
3.1.1實驗藥品 47
3.1.2 儀器設備 49
3.2菌株培養 50
3.2.1 菌株來源 50
3.2.2菌株活化 51
3.2.3 HA生產培養 51
3.3 生產培養基的探討 52
3.3.1 環境因子之影響 52
3.3.2 添加物之影響 53
3.4 固定化微生物顆粒之製備及基本性質測定 54
3.4.1批次發酵大量培養 54
3.4.2 固定化微生物顆粒之製備 54
3.4.3 固定化顆粒基本性質 56
3.4.4 固定化菌體顆粒 SEM 觀察 57
3.4.5 吸附試驗 58
3.4.6 固定化菌體顆粒重複批次操作 58
3.5夾膜染色 58
3.6 分析方法 59
3.6.1 醣類分析 59
3.6.1.1 DNS法 59
3.6.1.2 酚-硫酸法 60
3.7 HA之濃度與分子量分析 61
3.7.1 醣醛酸分析 61
3.7.2 膠體滲透層析 62
3.7.3高效能液相層析儀 63
3.8 純化HA 之結構確定 66
3.8.1 HA 純化 66
3.8.2傅力葉轉換紅外線 67
3.8.3核磁共振 67
3.9 氧氣傳送係數測定 68
第四章 結果與討論 69
4.1 不同 HA 分析方法之比較 69
4.2環境因子之探討 72
4.2.1探討攪拌速率和曝氣量對懸浮 S. zoopidemicus 菌株生產HA 之影響 72
4.2.2 探討間接曝氣操作方式對懸浮 S. zoopidemicus 菌株生產HA 之影響 77
4.3 探討不同葡萄糖濃度對 S. zoopidemicus 生產 HA 之影響 82
4.4 額外添加物之培養基對懸浮 S. zoopidemicus 菌株 生產 HA之影響之探討 86
4.4.1 抗生素種類之影響 86
4.4.2 Losyzme、nisin、鹽類、界面活性劑和 黃豆萃取液之影響 89
4.4.3黃豆萃取液濃度之影響 93
4.5菌落與莢膜型態之觀察 95
4.5.1 菌落型態與溶血性之觀察 95
4.5.2 再次培養次數與莢膜形成之相關性 99
4.5.3 靜置、攪拌和曝氣培養之莢膜染色分析 101
4.6 固定化顆粒之基本性質探討 103
4.6.1 不同材料固定化顆粒之物性比較 103
4.6.2 顆粒之吸附試驗 108
4.6.3 顆粒之 SEM 觀察 110
4.7 固定化菌體顆粒之重複批次試驗 117
4.8 HA之黏度測量 119
4.9 純化HA 之結構分析與確定 126
4.9.1 純化 HA 之 FT-IR 分析 126
4.9.2純化 HA 之 NMR 分析 129
第五章 結論 133
參考文獻... 135
附錄……… 157

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