本研究為利用紫外光起始自由基聚合法合成具溫度敏感性的抗菌水凝膠，以氮-異丙基丙烯醯胺 (N-isopropylacrylamide，NIPAAm，NP)為主體，添加親水性良好的2-丙烯醯胺-2-甲基丙磺酸 (2-acrylamido-2-methylpropane sulfonic acid，AMPS)、2-丙烯酸羥乙酯 (2-Hydroxyethyl acrylate，HEA)以及幾丁聚醣 (Chitosan，CS)，並加入N,N'-亞甲基雙丙烯醯胺 (N,N'-methylenebisacrylamide，MBA)和2,2-二乙氧基苯乙酮 (2,2-diethoxyacetophenone，DEAP)做為交聯劑與光起始劑，形成半互穿型的網狀水凝膠，利用FTIR對其化學結構進行分析，確定水凝膠有成功合成，並用SEM觀察水凝膠之表面型態，接著進行拉伸機械性質、熱性質、膨潤測試、藥物包覆/釋放、生物相容性、抗菌等一系列測試，對水凝膠進行評估，根據拉伸測試結果可以知道交聯劑及NP含量的提升都可以增加抗張強度及破壞伸長率，膨潤的情況下，抗張強度與拉伸率最高可以達到67.5 kPa和55.6%；熱性質方面，隨著NP相對含量的提升，玻璃轉移溫度可以從N9A1-1.0的116 oC提升至N99A1-1.0的125 oC，有助於增強水凝膠的熱穩定性；膨潤率的結果顯示出水凝膠的平衡膨潤率隨著交聯劑和NP的相對含量提升而下降；水凝膠對於鹽酸四環素 (Tetracycline hydrochloride，TC)的包覆與釋放結果可以發現，其鹽酸四環素的包覆率會隨著NP的含量提高而下降，藥物釋放行為不會受到pH值所影響且經由動力學的描述皆屬於異常擴散 (Anomalous transport，n介於0.5到1.0之間)；透過人類表皮纖維母細胞HS 68所進行的生物相容性結果可以知道水凝膠對於細胞是沒有毒性的；大腸桿菌的抗菌實驗顯示出水凝膠具有抗菌性。

In this study, N-isopropylacrylamide, 2-acrylamido-2-methylpropane sulfonic acid and 2-Hydroxyethyl acrylate were polymerized by UV-initiated free radical polymerization in the presence of chitosan to prepare the semi-interpenetrating hydrogels with thermo-responsive and antibacterial properties. N,N'-methylenebisacrylamide and 2,2-diethoxyacetophenone were applied as crosslinker and photo-initator, respectively. Chemical structure and surface morphology of hydrogels were characterized by respective FTIR and SEM. Furthermore, a series of tests iucluding tensile mechanical properties, thermal properties, swelling, drug loading/release, biocompatibility, antibacterial properties were carried out to evaluate the prepared hydrogels. The results showed that increasing the contents of NP and crosslinking agent would enhance the tensile mechanical properties in which the tensile strength and enlongation at break could reach 67.5 kPa and 55.6%, respectively, under swelling state. Moreover, glass transition temperature (Tg) increased from 116 oC for the N9A1-1.0 to 125 oC at the NP content was increased. The results also showed that the increases of crosslinker and NP content would reduce the equilibrium swelling ratio. The loading amount of tetracycline hydrochloride in the hydrogels decreased with the increasing NP content and the drug-release behavior would not be influenced by pH value. The drug-release behavior could be described by an empirical equation of non-fickian diffusion. In vitro studies showed that hydrogels were non-toxic and they could promote cell growth of human foreskin fibroblast (HS-68). The antibacterial test against E. coli showed that these hydrogels had antibacterial properties.

目錄
目錄	V
圖目錄	VIII
表目錄	XIII
第一章	緒論	1
1.1前言	1
1.2研究動機	2
第二章	文獻回顧	3
2.1傷口護理&傷口敷料	3
2.1.1人體皮膚構造	3
2.1.2傷口形成&癒合機制	4
2.1.3傷口敷料之發展	8
2.1.4傷口敷料之種類與選擇	9
2.2水凝膠	12
2.2.1水凝膠簡介	12
2.2.2水凝膠作為傷口敷料之介紹	14
2.3幾丁聚醣	15
2.3.1幾丁質與幾丁聚醣簡介	15
2.3.2幾丁聚醣作為傷口敷料之潛力	17
2.4環境敏感型高分子	20
2.4.1環境敏感型高分子簡介	20
2.4.2聚(N-異丙基丙烯醯胺)與其共聚合體	25
2.5光起始聚合反應	27
第三章	實驗	29
3.1實驗藥品	29
3.2實驗儀器	32
3.3實驗步驟	36
3.3.1幾丁聚醣純化	36
3.3.2 NIPAAm單體純化	36
3.3.3水凝膠製備	36
3.4結構分析	39
3.4.1幾丁聚醣去乙醯度測量 (H-NMR、UV-VIS、電位滴定)	39
3.4.2幾丁聚醣黏度平均分子量測定 (毛細管黏度計)	40
3.4.3官能基分析 (FTIR)	42
3.4.4水凝膠型態分析 (SEM)	42
3.5性質測試	43
3.5.1拉伸機械性質測試	43
3.5.2熱性質分析	43
3.5.3膨潤率 & 膨潤動力學	44
3.5.4膨潤/去膨潤響應	44
3.5.5藥物包覆&釋放	45
3.5.6生物相容性測試	46
3.5.7抗菌測試	48
第四章	結果與討論	49
4.1幾丁聚醣結構分析	49
4.1.1去乙醯度 (Degree of deacetylation，DDA%)	49
4.1.2黏度平均分子量	54
4.1.3幾丁聚醣結構鑑定 (FTIR)	56
4.2水凝膠結構分析	57
4.2.1結構鑑定 (FTIR)	57
4.2.2水凝膠型態分析 (SEM)	59
4.3水凝膠性質分析	62
4.3.1拉伸機械性質	62
4.3.2熱重損失分析 (TGA)	63
4.3.3玻璃轉移溫度 (DSC)	67
4.3.4膨潤特性	69
4.3.5膨潤動力	74
4.3.6膨潤/去膨潤響應	79
4.3.7藥物包覆&釋放	80
4.3.8釋放動力學	84
4.3.9生物相容性測試	90
4.3.10抗菌測試	91
第五章	結論	93
5.1 幾丁聚醣性質測試	93
5.2水凝膠結構分析	93
5.3水凝膠性質測試	93
第六章	建議事項	95
第七章	文獻回顧	96
第八章	附錄	105
8.1膨潤動力學 (Zero order & Higuchi equation)	105
8.2藥物包覆後之表面形態	118
8.3背景吸光值對於生物相容性結果的影響	119

 
圖目錄
圖2-1皮膚構造圖	3
圖2-2正常傷口和慢性傷口的癒合過程	4
圖2-3傷口修復各階段	6
圖2-4傷口癒合各階段細胞作用示意圖	7
圖2-5傷口敷料之簡易分類	8
圖2-6合成敷料的種類	11
圖2-7理想創傷敷材的標準	11
圖2-8物理交聯葡萄糖響應水凝膠示意圖	13
圖2-9化學交聯水凝膠示意圖	13
圖2-10幾丁質結構	16
圖2-11纖維素結構	16
圖2-12不同排列方式的幾丁質	16
圖2-13幾丁聚醣結構	17
圖2-14幾丁聚醣之生物應用	19
圖2-15幾丁聚醣之加工型態	19
圖2-16溫度敏感型高分子之溶解度相變化圖	20
圖2-17 PNIPAAm & PDEAAm結構圖	21
圖2-18 PNIPAAm溫感性細胞吸脫附作用示意圖	22
圖2-19 (a)PAA、(b)PMAA、(c)PDMAEMA、(d)PDEAEMA結構式	23
圖2-20紫外光誘導濕潤性變化	24
圖2-21新型二硒化物交聯水凝膠之藥物釋放示意圖	26
圖2-22電磁波譜	28
圖3-1經紫外光硬化之水凝膠	37
圖4-1幾丁聚醣H-NMR光譜圖	49
圖4-2不同濃度之N-乙醯基-D-葡萄糖胺一次微分吸光圖	50
圖4-3 N-乙醯基-D-葡萄糖胺一次微分吸光值對濃度之檢量線	51
圖4-4幾丁聚醣溶液之導電度與pH值隨加入的NaOH體積變化曲線	52
圖4-5幾丁聚醣溶液之pH值變化曲線一次微分	53
圖4-6幾丁聚醣溶液在不同濃度下之還原黏度 (ηred)與固定黏度 (ηinh)	55
圖4-7幾丁聚醣紅外線吸收光譜圖	56
圖4-8(a)NIPAAm、(b)AMPS、(c)2-HEA、(d)N9A1-1.0、(d)N29A1-1.0	58
圖4-9 N9A1-0.5水凝膠之掃描式電子顯微鏡圖	60
圖4-10 N9A1-1.0水凝膠之掃描式電子顯微鏡圖	60
圖4-11 N29A1-1.0水凝膠之掃描式電子顯微鏡圖	61
圖4-12不同組成水凝膠在完全膨潤的情況下之抗張強度(kPa)與伸長率(%)	62
圖4-13不同交聯劑比例之水凝膠的熱重損失圖	65
圖4-14不同交聯劑比例之水凝膠的熱重損失微分圖	65
圖4-15不同NP/AMPS比例之水凝膠的熱重損失圖	66
圖4-16不同NP/AMPS比例之水凝膠的熱重損失微分圖	66
圖4-17不同交聯劑含量之水凝膠的DSC一次升溫曲線圖	68
圖4-18不同NP/AMPS比例之水凝膠的DSC一次升溫曲線圖	68
圖4-19不同組成的水凝膠在25 oC、pH 5.5緩衝溶液中膨潤率隨時間之變化	70
圖4-20不同組成的水凝膠在25 oC、pH 7.4緩衝溶液中膨潤率隨時間之變化	71
圖4-21不同組成的水凝膠在37 oC、pH 5.5緩衝溶液中膨潤率隨時間之變化	71
圖4-22不同組成的水凝膠在37 oC、pH 7.4緩衝溶液中膨潤率隨時間之變化	72
圖4-23不同組成的水凝膠在不同溫度及不同pH值緩衝液中的平衡膨潤率	73
圖4-24水凝膠在pH 5.5、25 oC緩衝溶液下膨潤率ln(SRt/SReq)對lnt作圖	75
圖4-25水凝膠在pH 7.4、25 oC緩衝溶液下膨潤率ln(SRt/SReq)對lnt作圖	76
圖4-26水凝膠在pH 5.5、37 oC緩衝溶液下膨潤率ln(SRt/SReq)對lnt作圖	77
圖4-27水凝膠在pH 7.4、37 oC緩衝溶液下膨潤率ln(SRt/SReq)對lnt作圖	78
圖4-28不同組成水凝膠於25 oC及37 oC水溶液下交替膨潤/去膨潤響應行為	79
圖4-29鹽酸四環素檢量線 (D.I.W，274 nm)	80
圖4-30鹽酸四環素檢量線 (PBS，274 nm)	82
圖4-31不同組成的水凝膠在37 oC、pH 5.5緩衝溶液中藥物累積釋放率隨時間之變化	83
圖4-32不同組成的水凝膠在37 oC、pH 7.4緩衝溶液中藥物累積釋放率隨時間之變化	83
圖4-33水凝膠在pH 5.5、37 oC緩衝溶液下藥物累積釋放率Mt/M0對t作圖	85
圖4-34水凝膠在pH 7.4、37 oC緩衝溶液下藥物累積釋放率Mt/M0對t作圖	85
圖4-35水凝膠在pH 5.5、37 oC緩衝溶液下藥物累積釋放率Mt/M0對t1/2作圖 	86
圖4-36水凝膠在pH 7.4、37 oC緩衝溶液下藥物累積釋放率Mt/M0對t1/2作圖 	87
圖4-37水凝膠在pH 5.5、37 oC緩衝溶液下藥物累積釋放率ln(Mt/Mmax)對lnt作圖	88
圖4-38水凝膠在pH 7.4、37 oC緩衝溶液下藥物累積釋放率ln(Mt/Mmax)對lnt作圖	89
圖4-39不同組成水凝膠對HS68細胞存活率之影響	90
圖4-40不同比例水凝膠對於大腸桿菌之抗菌活性百分比	92
圖8-1水凝膠在pH 5.5、25 oC緩衝溶液下膨潤率SRt對t作圖 (前60 min) 	106
圖8-2水凝膠在pH 7.4、25 oC緩衝溶液下膨潤率SRt對t作圖 (前60 min)	106
圖8-3水凝膠在pH 5.5、37 oC緩衝溶液下膨潤率SRt對t作圖 (前60 min)	107
圖8-4水凝膠在pH 7.4、37 oC緩衝溶液下膨潤率SRt對t作圖 (前60 min)	108
圖8-5水凝膠在pH 5.5、25 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前60 min) 	109
圖8-6水凝膠在pH 7.4、25 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前60 min)    	 109
圖8-7水凝膠在pH 5.5、37 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前60 min)    	    110
圖8-8水凝膠在pH 7.4、37 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前60 min)   	111
圖8-9水凝膠在pH 5.5、25 oC緩衝溶液下膨潤率SRt對t作圖 (前120 min)    	112
圖8-10水凝膠在pH 7.4、25 oC緩衝溶液下膨潤率SRt對t作圖 (前120 min) 	112
圖8-11水凝膠在pH 5.5、37 oC緩衝溶液下膨潤率SRt對t作圖 (前120 min) 	113
圖8-12水凝膠在pH 7.4、37 oC緩衝溶液下膨潤率SRt對t作圖 (前120 min)   	 114
圖8-13水凝膠在pH 5.5、25 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前120 min)	115
圖8-14水凝膠在pH 7.4、25 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前120 min)	115
圖8-15水凝膠在pH 5.5、37 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前120 min)	116
圖8-16水凝膠在pH 7.4、37 oC緩衝溶液下膨潤率SRt對t1/2作圖 (前120 min)	117
圖8-17鹽酸四環素水凝膠之掃描式電子顯微鏡表面圖 (a) N9A1-0.5、	118
圖8-18 CCK-8測試中背景組在400~600 nm之光譜吸收圖 (背景組含CCK-8試劑與培養基)	120
圖8-19不同組成水凝膠對HS68細胞存活率之影響 (不扣除背景值之結果) 	120

 
 
表目錄
表2-1市面上常見敷料之原料與優缺點	9
表2-2不同類型的傷口適合之傷口敷料	10
表2-3 UVA、UVB、UVC紫外光波長與強度統整	28
表3-1水凝膠各添加物之比例與重量	38
表3-2幾丁聚醣的黏度常數a和K與溶劑、溫度、去乙醯度之關係	41
表4-1不同方法所測定之幾丁聚醣去乙醯度統整表	53
表4-2不同濃度的幾丁聚醣樣品所測得之滯留時間與其黏度參數	54
表4-3各單體之官能基紅外線吸收峰位置整理	58
表4-4不同組成水凝膠在完全膨潤的情況下之抗張強度(kPa)與破壞伸長率(%)	63
表4-5不同組成水凝膠之起始重量損失溫度 (Td, 5%)、最大速率裂解溫度 (Tmax)以及炭焦殘餘量 (C.Y.)	64
表4-6不同比例水凝膠之一次升溫玻璃轉移溫度 (Tg)	67
表4-7不同組成的水凝膠在不同溫度及pH值緩衝液中的平衡膨潤率 (ESR, %)	72
表4-8不同組成的水凝膠在不同溫度下 (25與37oC)之平衡膨潤率差異百分比 (SRD，%)	73
表4-9不同水凝膠之膨潤動力學參數n、k、R2值 (pH 5.5、25 oC)	75
表4-10不同水凝膠之膨潤動力學參數n、k、R2值 (pH 7.4、25 oC)	76
表4-11不同水凝膠之膨潤動力學參數n、k、R2值 (pH 5.5、37 oC)	77
表4-12不同水凝膠之膨潤動力學參數n、k、R2值 (pH 7.4、37 oC)	78
表4-13不同組成之水凝膠於鹽酸四環素水溶液之包覆結果 (藥物濃度: 1 mg/ml，25 oC)	81
表4-14 不同水凝膠之Zero order equation釋放動力學參數kz、R2值 (37 oC)	86
表4-15不同水凝膠之Higuchi equation釋放動力學參數kH、R2值 (37 oC)	87
表4-16不同水凝膠之經驗方程式釋放動力學參數n、k、R2值 (pH 5.5、37 oC)	88
表4-17不同水凝膠之經驗方程式釋放動力學參數n、k、R2值 (pH 7.4、37 oC)	89
表4-18不同比例水凝膠對於大腸桿菌之抗菌活性與落菌形成單位	91
表8-1不同水凝膠之Zero order equation膨潤動力學參數kz、R2值 (25 oC，前60 min)	107
表8-2不同水凝膠之Zero order equation膨潤動力學參數kz、R2值 (37 oC，前60 min)	108
表8-3不同水凝膠之Higuchi equation膨潤動力學參數kH、R2值 (25 oC，前60 min)	110
表8-4不同水凝膠之Higuchi equation膨潤動力學參數kH、R2值 (37 oC，前60 min)	111
表8-5不同水凝膠之Zero order equation膨潤動力學參數kz、R2值 (25 oC，前120 min)	113
表8-6不同水凝膠之Zero order equation膨潤動力學參數kz、R2值 (37 oC，前120 min)	114
表8-7不同水凝膠之Higuchi equation膨潤動力學參數kH、R2值 (25 oC，前120 min)	116
表8-8不同水凝膠之Higuchi equation膨潤動力學參數kH、R2值 (37 oC，前120 min)	117

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