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研究生:林上竣
研究生(外文):Shang-Jyun Lin
論文名稱:微流道抗生素濃度梯度產生器整合於表面增強拉曼散射平行進行細菌抗藥性檢測
論文名稱(外文):A Microfluidic Antibiotic Concentration Gradient Generator Integrating Surface enhanced Raman Spectroscopy for Multiparallel Antimicrobial Susceptibility Testing
指導教授:黃念祖黃念祖引用關係
指導教授(外文):Nien-Tsu Huang
口試委員:王玉麟王俊凱韓吟宜張祐嘉
口試委員(外文):Yuh-Lin WangJuen-Kai WangYin-Yi HanYou-Chia Chang
口試日期:2021-09-08
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生醫電子與資訊學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:英文
論文頁數:83
中文關鍵詞:微流道濃度梯度細菌抗藥性檢測表面增強拉曼散射
外文關鍵詞:microfluidicconcentration gradientbacteriaantimicrobial susceptibility testsurface-enhanced Raman spectroscopy
DOI:10.6342/NTU202104148
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  • 被引用被引用:0
  • 點閱點閱:101
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  • 下載下載:14
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為了提供適當的抗生素治療,臨床應用上的標準做法是將從病人檢體分離出來的菌株進行抗藥性檢測(antimicrobial susceptibility test,AST),來選擇合適的抗生素種類和劑量,同時也可以避免抗生素的濫用。然而,目前的AST方法仍有耗時、耗力、低準確性等缺點。為了提高準確性,具有高專一性和免標定等優點的表面增強拉曼散射(surface-enhanced Raman spectroscopy,SERS)開始被應用在細菌檢測和抗藥性檢測上。在本論文中,我們設計了一個微流道裝置,具有可用來建立抗生素濃度梯度的側流道(side channel),及在液體流動時,可將細菌保留在其中的微流井(microwell)。透過使用針筒幫浦同時注入細菌培養液與抗生素溶液,此裝置可以自動建立2、4、8、16、32、64 μg/mL等六個抗生素濃度。在螢光珠模擬細菌的實驗中,得知微流井可保留80%以上的螢光珠避免被沖走。接著,當細菌在建立好的各個抗生素濃度下培養三個小時後,即可整合SERS檢測技術進行AST(SERS-AST)。本論文研究共針對兩株細菌進行AST,分別為氨苄青黴素(ampicillin)非抗藥性與抗藥性的大腸桿菌(Escherichia coli)。所有微流井的SERS訊號皆會被量測,經分析即可測得最小抑菌濃度(minimum inhibitory concentration,MIC),且該結果與標準AST作法的結果一致。此SERS-AST方法不僅只需要少量(20 μL)細菌溶液與單一微流道裝置與即可測得MIC,更是將整個AST過程從一天大幅縮短至5小時,如此一來可以幫助醫生及早修正施用的抗生素種類和劑量,進一步提高病患存活率並減少抗生素的濫用。
To ensure appropriate antibiotic treatment, antimicrobial susceptibility test (AST) is a standard method in clinical therapies for selecting proper antibiotic treatment and preventing antibiotic misuse or overuse. However, current AST methods still suffer from time-consuming, label-intensive, and low accuracy issues. To address above issues, surface-enhanced Raman spectroscopy (SERS) technology has been used in bacterial detection and AST based on its high specificity and label-free features. In this thesis, we designed a microfluidic device with branch channels for antibiotic concentration gradient generation and microwells for trapping bacteria during the fluidic introduction, including reagent gradient generation and culture medium removal steps. Operated by the syringe pump, the bacteria culture medium and antibiotics are injected into the microfluidic device to automatically generate a wide range of antibiotic concentrations, from 2 to 64 μg/mL, which increased by the power of two. In the fluorescent beads experiments, over 80% of beads were trapped inside the microwells, which prevents the beads be washed away during gradient generation. Then, after 3-hour-incubation, the device is integrated with SERS substrate for SERS-AST. Finally, two Escherichia coli strains, susceptible and resistant to ampicillin, are applied in AST. The SERS signal of all microwells in each side channel was analyzed to obtain the minimum inhibitory concentration (MIC). The result is consistent with the gold standard method. With this microfluidic device in SERS-AST, only 20 μL of bacteria solution and a single chip are required to obtain MIC. Moreover, this SERS-AST process only requires 5 hours, much faster than the current gold standard methods. Therefore, the antibiotic treatment can be modified earlier, which can increase the survival rate and prevent antibiotic misuse or overuse.
口試委員會審定書 I
致謝 II
摘要 III
Abstract IV
Chapter 1 Introduction 1
1.1 Research Background 1
1.1.1 Antimicrobial resistance and AST 1
1.1.2 Clinical AST methods 2
1.1.3 Microfluidic AST 3
1.2 Literature Review 4
1.2.1 Bacteria incubation in the microfluidic chip 4
1.2.2 Bacteria quantification methods in microfluidic AST 5
1.2.3 Antibiotic concentration gradient generation in microfluidic AST 12
1.3 Research Motivation 17
Chapter 2 SERS Theory 18
2.1 Introduction of Raman Scattering 18
2.2 Surface-Enhanced Raman Scattering 19
2.3 Bacteria SERS signal source 20
Chapter 3 Materials and Methods 22
3.1 Bacteria Preparation 22
3.2 Device Design and Fabrication 22
3.2.1 Microfluidic device design 23
3.2.2 Microfluidic device fabrication 24
3.2.3 SERS-active substrate fabrication 28
3.3 The Bright-field and Fluorescent Optical Setup 28
3.4 SERS Measurement and Spectral Processing 29
3.5 On-chip MIC Measurement Protocol 29
3.6 Image Analysis 30
3.6.1 Fluorescent molecule quantification 31
3.6.2 Beads number quantification 31
3.6.3 SERS imaging 32
Chapter 4 Results and Discussion 33
4.1 Channel Design 33
4.1.1 260-side-channel-design 33
4.1.2 64-side-channel-design 35
4.2 COMSOL Simulation 38
4.2.1 Flow rate effect 38
4.2.2 Balancing time 41
4.3 Concentration of Gradient Generation 42
4.3.1 Flow rate optimization 42
4.3.2 Channel isolation optimization 44
4.3.3 Microwell isolation optimization 48
4.4 Beads Encapsulation with Microwell Array 51
4.4.1 Trapping efficacy of the side channel 51
4.4.2 Washing efficiency 53
4.5 Bacteria Incubation 55
4.5.1 The bacterial growth evaluation in the PDMS microfluidic chip 55
4.5.2 Evaporation and Rehydration 56
4.6 SERS-AST 59
4.6.1 Alignment 59
4.6.2 SERS-AST without antibiotic gradient 62
4.6.3 SERS-AST with antibiotic gradient 63
Chapter 5 Conclusion 68
Chapter 6 Future Work 69
References 72
Appendix 80
A. Python and ImageJ code 80
A.1 Python 80
A.2 ImageJ 81
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