臺灣博碩士論文加值系統

在本論文研究中，開發與設計一套可用於微量、即時連續量測且適用於抗生
素奈米膠囊藥物釋放監測之奈米碳管電極式的電化學生醫感測平台。本研究首先
以微機電技術設計製作電化學感測電極與微流體晶片，並以檢測電路與虛擬控制
系統，進行感測訊號最佳化處理；最後以所研發之奈米碳管電極電化學生醫感測
平台應用於奈米抗生素膠囊藥物釋放臨床前評估探討。
電化學生醫感測平台中，電極的設計為影響感測訊號的關鍵元件之一，電極
材料與表面結構特性在生醫感測訊號上有重大影響。本研究結合奈米碳管於電化
學生醫感測器上，使用電泳或液滴塗佈方式將奈米碳管修飾在金電極表面，成功
提升電極強度及訊號放大能力，可承受最大電流從 0.0208 mA 提升至 0.6680
mA；訊號放大能力於 1/ml 抗生素濃度條件下，由 0.0222 mA 放大至 0.3051
mA，訊號放大 13.75 倍。抗生素純藥測試所建立的校正曲線線性回歸係數為
R2=0.9837，線性濃度範圍 1~ 10 g/ml，靈敏度為 0.023 mA‧ml/g。
傳統 HPLC 等大型儀器無法連續且即時量測奈米抗生素膠囊釋放狀況，本研
究所開發之結合奈米碳管電極的電化學生醫感測平台，在抗生素奈米膠囊的連
續釋放量測中，量得抗生素奈米膠囊於第 4 天開始啟動藥物釋放，釋放速率為
0.0258g/ml．hr，至第七天累積釋放濃度達 24.98 g/ml。以本論文所研究開發
之結合奈米碳管電極的電化學生醫感測平台可提供奈米藥物膠囊開發合成過程
的調整依據，同時也提供臨床前用藥資訊，提供在動物試驗上也無法獲得之局
部即時濃度值，增進奈米藥物膠囊開發速度，及降低未來臨床試驗風險。希望
藉由整合電化學奈米碳管電極設計與檢測平台，於臨床前針對奈米抗生素膠囊
藥物釋放特性作感測評估。未來可進一步整合被動式無線傳輸系統，植入在動
物體中，做長期藥物釋放監控。

ii
ABSTRACT
In this thesis, an electrochemical biosensing platform using carbon nanotubes
electrodes, which can be used to evaluate drug release profiles of antibiotic
nanocapsules in real time and continuous mode, has been successfully designed,
developed, and characterized. First, the electrochemical sensing electrode has been
fabricated by MEMS technologies. Then, the biosensing platform is connected to the
sensing circuit and LabVIEW program for signal acquire and processing. Finally,
the developed carbon nanotubes electrode and electrochemical biosensing platform
have been applied for pre-clinical evaluation of drug release profiles of antibiotic
nanocapsules.
The electrode is one of the key components for electrochemical sensing. The
materials and the surface characteristics of electrodes play an important role in
electrochemical sensing. Here, we successfully combined the carbon nanotubes
electrodes with electrochemical biosensor, using electrophoresis deposition or
drop-coating method to deposit carbon nanotubes on the surfaces of the gold
electrodes. The measurement results show that the maximum affordable current has
been improved 0.0208 mA to o.6680 mA. And, the sensing signals are amplified up to
13.75 times using carbon nanotube-modified electrodes. The linear range of the
developed electrochemical biosensing platform using carbon nanotubes electrodes is
from 1 g/ml to 10g/ml (R2=0.9837). The sensitivity of the developed system is
0.023 mA‧ml/g.
The HPLC and other traditional instrument could not detection the drug release
from nanocapsules in real time and continuous mode. According to the measurements
using our developed electrochemical biosensing platform, it shows that antibiotic nanocapsules start to increase the drug release on the 4th day and the release rate is
0.0258 μg/ml．hr. The drug release of antibiotic nanocapsules reached 24.98
μg/ml on the 7th day.
The antibiotic biosensor platform using carbon nanotube electrodes for
preclinical evaluation of drug release profile of nanocapsules presented in this work
showed good performance in sensing of antibiotic Teoplanin drug samples. The
antibiotic biosensor platform could be further integrated with a micro fluidic platform
for controlled synthesis of nanocapsules to feedback the drug release profile for
optimization of the synthesis process. In addition, the developed biosensor can be
integrated with wireless passive transmission module to be an implantable biomedical
microsystem for health monitoring in future.

iv
目錄
摘要.................................................................................................................................i
ABSTRACT...................................................................................................................ii
目錄...............................................................................................................................iv
圖目錄...........................................................................................................................vi
表目錄........................................................................................................................ viii
第一章 緒論................................................................................................................1
1.1. 研究簡介........................................................................................................1
1.2. 傳統藥物開發與檢測程序............................................................................1
1.3. 奈米膠囊藥物................................................................................................3
1.4. 藥物釋放之臨床前試驗與臨床試驗............................................................4
1.5. 微全分析系統與生醫感測平台....................................................................4
1.6. 研究動機........................................................................................................6
1.7. 研究目的與方法............................................................................................6
1.8. 論文架構........................................................................................................7
第二章 電化學生醫感測平台開發............................................................................9
2.1. 電化學生醫感測介紹....................................................................................9
2.2. 傳統之電化學感測器及基本原理..............................................................10
2.2.1. 循環伏安法 ( Cyclic Voltammetry, CV )...................................................12
2.3. 電化學感測電極設計..................................................................................14
2.3.1. 電極幾何形狀..............................................................................................14
2.3.2. 電極材料......................................................................................................17
2.3.2.1. 電極強度......................................................................................................18
2.3.2.2. 電極訊號放大..............................................................................................18
2.3.2.3. 電極表面重生與生物相容性......................................................................19
2.3.2.4. 奈米碳管修飾電極......................................................................................19
2.3.2.4.1. 奈米碳管基本特性......................................................................................20
2.3.2.4.2. 奈米碳管於感測器之應用..........................................................................23
2.4. 電化學感測電極製程..................................................................................24
2.4.1. 電鍍..............................................................................................................26
2.5. 奈米碳管電極製程......................................................................................28
2.6. 微流體晶片整合..........................................................................................32
第三章 電化學生醫感測平台測試..........................................................................34
3.1. 感測電路及虛擬儀控設計..........................................................................34
3.2. 抗生素檢測藥物..........................................................................................37
3.3. 藥品準備與實驗步驟..................................................................................38 3.4. 電極測試結果..............................................................................................38
3.4.1. 電極訊號放大探討......................................................................................38
3.4.2. 電極強度探討..............................................................................................40
3.5. 奈米碳管修飾電極純藥測試......................................................................41
3.5.1. pH 變化對電化學感測之影響....................................................................41
3.5.2. 溫度變化對電化學感測之影響..................................................................44
3.5.3. 校正曲線( calibration )與靈敏度( sensitivity )...........................................45
3.6. 分析與討論..................................................................................................47
第四章 奈米碳管電極之電化學生醫感測器在奈米抗生素膠囊局部藥物釋放特
性評估之應用..............................................................................................................48
4.1. 骨髓炎臨床上醫療現況[70].......................................................................48
4.2. 奈米抗生素膠囊合成..................................................................................48
4.3. 奈米抗生素膠囊藥物釋放..........................................................................50
4.4. 以電化學生醫感測平台量測奈米抗生素膠囊藥物局部釋放..................51
4.4.1. 奈米抗生素膠囊藥物釋放觀察..................................................................52
4.4.2. 奈米抗生素膠囊藥物釋放濃度曲線..........................................................54
4.5. 分析與討論..................................................................................................56
第五章 總結與未來研究建議..................................................................................57
5.1. 討論與結論..................................................................................................57
5.2. 本論文研究之學術創新與價值..................................................................58
5.3. 未來研究建議..............................................................................................58
參考文獻......................................................................................................................61
附錄..............................................................................................................................69
A
抗生素感測專一性分析..............................................................................69
B
動物實驗之準備..........................................................................................70
C
裸金電極純藥測試及各項參數探討..........................................................72
發表著作......................................................................................................................76

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