本研究透過超音波輔助乳化揮發製程（Emulsification assisted with ultrasonic atomization, EUA）以低耗材且量產性之技術製備具粒徑均一性的生物降解性之聚己內酯（Polycaprolactone, PCL）微載體。藉由超音波霧化器的高頻(~43 kHz) 振動表面，打斷PCL油相溶液之薄液膜，指向柔性地噴灑出均勻油相高分子PCL微液滴(粒徑分佈〜20-55 μm)，其中並分析超聲音波霧化模組之參數對微液滴粒徑的影響，包括PCL油相溶液濃度、霧化器的振動幅度、PCL油相溶液的進料速率以及微液滴收集高度。接著利用攪拌設備使聚乙烯醇（Poly vinyl alcohol, PVA）水相溶產生垂直流場收集油相PCL微液滴，並將油/水相溶液之間表面張力優化至~12.51mN / m。其中約8至11 wt%的PVA溶液具有高穩定的分散性能，有效改善微載體的製造良率（PCL微載體產率提升至~89.8-98.2 wt%），並得到粒徑為~5-18μm的PCL微載體，顯示出從微液滴到固體微球的收縮率~60-75%。此外，EUA更應用於癌症用藥-艾梅素（Doxorubicin, Dox）之PCL載藥微載體的製備，在複乳化溶劑蒸發法(Double emulsion-solvent evaporation)中製程Dox的包覆率（Drug-loaded efficiency, DLE）可達~42.2%，粒徑為~5-20 μm的PCL載藥微載體（Dox-loaded PCL microspheres, DLPM）之載藥率（Encapsulation efficiency, EE）可達~3.21%，且DLPM在37 ℃下的磷酸鹽緩衝食鹽水（Phosphate buffered saline, PBS，pH = 7.4）與含有胎牛血清（Fetal bovine serum, FBS）的PBS中出現約兩周的藥物釋放效率，從掃描電子顯微鏡(Scanning electron microscope, SEM)觀察釋放前後的DLPM外貌並無太大改變，因此兩周內地釋放判斷為藥物從微球中持續擴散出來。而在含有假單胞菌脂肪酶（Pseudomonas lipase, PS）的PBS，釋放後DLPM的外貌疏鬆，其中PS具有效降解PCL材料的特性，使DLPM兩周內釋放~70%的藥物。

This study aims to develop biodegradable polycaprolactone (PCL) microspheres with uniform particle size by emulsification assisted with ultrasonic atomization (EUA) for mass production with low material loss. Through high frequency (~43 kHz) vibrating surface on an ultrasonic nozzle, a thin liquid film of PCL oil solution was broken and uinform PCL microdroplets (particle size ~ 20-55 μm) were sprayed out softly and directly. The influence on particle size of microdroplets by ultrasonic module parameters was analyzed, including concentration of PCL solution, vibrating amplitude of atomizer, feeding rate of PCL solution, and collection distance. A vertical circulation flow field of poly vinyl alcohol (PVA) solution was settled to collect the PCL microdroplets, and about 8~11 wt% of PVA solution with high stable dispersion property was used to effectively improve the yield rate of PCL microspheres (yield rate of PCL microspheres ~ 89.8-98.2 wt%). The final particle size of PCL microspheres was ~5-18 μm, which meant there were about 60-75% of particle size shrinkage from microdroplets to solid microspheres. Furthermore, EUA further demonstrated drug-loaded PCL microsphere fabrication with Doxorubicin (Dox). The drug-loaded efficiency (DLE) in EUA was ~ 42.2%, and encapsulation efficiency (EE) of Dox-loaded PCL microspheres (DLPM) was ~ 3.21% with particle size ~5-20 μm. The in vitro releasing indicated that DLPM had a well-sustained release efficacy for about two week at 37°C under phosphate buffer saline (PBS, pH=7.4) and PBS containing fetal bovine serum (FBS). The morphology of DLPM before and after releasing experiment wasn’t significantly changed, which was analyzed by scanning electron microscope (SEM). Therefore, the release within two weeks was judged as the continuous diffusion of the drug from the microspheres. In PBS containing Pseudomonas lipase (PS), the morphology of DLPM was loose after releasing experiment. Among these enzyme, PS has the property of degradation of PCL, making DLPM released ~70% of the drug in two weeks.

中文摘要 ii
Abstract iv
List of Figures viii
List of Tables xiii
Chapter 1 : Introduction 1
1.1 Foreword: Drug-loaded microsphere applications 1
1.1.1 Transcatheter arterial chemoembolization (TACE) for Hepatocellular carcinoma (HCC) treatment 1
1.1.2 Other microsphere applications 4
1.2 Polymer material - Polycaprolactone (PCL) 5
1.2.1 Biomaterial of PCL 5
1.2.2 Biodegradation and drug-releasing mechanisms of PCL 7
1.2.3 Factors affecting degradation of PCL 9
1.3 Polymer microsphere manufacture by emulsion-solvent evaporation (ESE) 11
1.3.1 Emulsion droplet formation 12
1.3.2 Solvent removal 13
1.3.3 Drug loading 14
1.4 UA system 17
1.5 Chapter overviews 19
Chapter 2 : Research methods 21
2.1 Materials 21
2.1.1 Oil phase (dispersion phase) 21
2.1.2 Aqueous phase (continuous phase) 22
2.2 EUA technology 23
2.2.1 ESE of O/W emulsion in EUA 23
2.2.2 Vertical circulation flow field 26
2.2.3 Fiber-like agglomeration phenomenon 27
2.2.4 UA system 28
2.3 Drug-loaded PCL microspheres fabrication with Dox in EUA 30
2.3.1 W/O/W emulsion 30
2.3.2 S/O/W emulsion 33
2.4 Property measurements of DLPM 35
2.4.1 Degradation of empty PCL microspheres 35
2.4.2 DLE and EE of DLPM 35
2.4.3 In vitro Releasing-rate profile of DLPM 38
Chapter 3 : Results and discussions 40
3.1 Characteristic of oil/aqueous solution 40
3.1.1 Density 40
3.1.2 Viscosity 41
3.1.3 Surface tension 41
3.2 Stability analysis of O/W emulsion process in EUA 42
3.3 PSD measurements 45
3.2.1 UA system 45
3.2.2 Shrinkage ratio of PCL microspheres 54
3.3 Drug-loaded microspheres 59
3.3.1 DLPM made by EUA 59
3.3.2 EE and DLE 63
3.3.3 Degradation rate of empty PCL microspheres 66
3.3.4 In vitro Releasing rate profile of DLPM 67
Chapter 4 : Conclusions 70
References 73

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