側流免疫層析檢測（Lateral Flow Immunoassay，LFIA）是一種低成本、快速的診斷方法，且同時具有高特異性和敏感性。在COVID-19疫情爆發後，由於其便利性，使LFIA的應用更加普及。除此之外，利用金奈米粒子（AuNPs）做為載體的LFIA可以在無需專業實驗室設備或醫療專業人員的情況下進行。憑藉以上優勢，LFIA已被應用於病毒診斷、食品安全等領域。在本論文中，我們開發用於檢測喙和羽毛病毒（BFDV）和人類絨毛膜促性腺激素（hCG）蛋白的LFIA平台。通過物理吸附或隨機醯胺鍵形成的方式，將能夠識別病毒上抗原的抗體包覆在金奈米粒子上。在存在病毒或目標蛋白的情況下，抗體金奈米粒子、病毒、測試線上抗體會於測試線上形成「三明治」複合物結構，並產生兩條線之陽性訊號。為了確保測試線和控制線上的訊號品質，最終使用兩種不同的抗體AuNPs。未來可嘗試將本論文中所開發之LFIA系統應用至其他目標物的檢測當中。

Lateral flow immunoassay (LFIA) is a low-cost and rapid diagnosis, with high specificity and sensitivity. After the outbreak of COVID-19, LFIA became more widespread for its convenience. Additionally, AuNPs-based LFIA can be performed without specialized lab equipment or healthcare professionals. With these advantages, LFIA has been applied to virus diagnosis, food safety, etc. In this thesis, LFIA-based platforms were developed for the detection of beak and feather disease virus (BFDV) and human chorionic gonadotropin (hCG) protein. The antibodies which recognize the antigen on the virus were coated on AuNPs by either physical absorption or random amide bond formation. In the presence of virus or target protein, “sandwich” complex forms at the test line, indicating positive signal. Two different AuNPs were used for control line and test line, respectively, to ensure the bright signals on both lines. The LFIA system herein developed opens the application in various biological diagnosis.

摘要﹍﹍﹍II
Abstract﹍﹍﹍III
謝誌﹍﹍﹍IV
目錄﹍﹍﹍VII
圖目錄﹍﹍﹍XIV
表目錄﹍﹍﹍XX
流程圖目錄﹍﹍﹍XXI
縮寫對照表﹍﹍﹍XXIII
第一章、緒論﹍﹍﹍1
1.1金奈米粒子﹍﹍﹍1
1.1.1金奈米粒子之性質﹍﹍﹍1
1.1.1.1 物理性質﹍﹍﹍1
1.1.1.2 化學性質﹍﹍﹍3
1.1.2金奈米粒子之合成方法﹍﹍﹍6
1.1.3金奈米粒子於生化領域之應用﹍﹍﹍10
1.2抗體﹍﹍﹍12
1.2.1抗體的結構與分類﹍﹍﹍12
1.2.2抗體於生化領域之應用﹍﹍﹍14
1.3生物分子固化方式﹍﹍﹍15
1.3.1非共價鍵固化法﹍﹍﹍16
1.3.1.1 物理吸附法﹍﹍﹍16
1.3.1.2 親和標籤作用﹍﹍﹍17
1.3.2共價鍵固化法﹍﹍﹍20
1.3.2.1 胺基酸耦合法﹍﹍﹍20
1.3.1.2 點擊化學固化法﹍﹍﹍22
1.3.1.3硼酯鍵﹍﹍﹍24
1.4側流免疫層析檢測系統（LFIA）﹍﹍﹍25
1.4.1側流免疫層析檢測方式﹍﹍﹍27
1.4.1.1三明治型LFIA﹍﹍﹍27
1.4.1.2競爭型LFIA﹍﹍﹍28
1.4.2檢測所使用之載體﹍﹍﹍29
1.5鸚鵡喙羽症病毒（BFDV）﹍﹍﹍33
1.6人絨毛膜促性腺激素（Human chorionic gonadotropin, hCG）﹍﹍﹍34
1.7研究動機﹍﹍﹍35
第二章、結果與討論﹍﹍﹍37
2.1檸檬酸鈉包覆之金奈米粒子合成﹍﹍﹍37
2.2側流免疫層析試紙之組成及設計﹍﹍﹍39
2.3開發檢測鸚鵡喙羽症病毒之LFIA系統﹍﹍﹍40
2.3.1競爭型LFIA系統﹍﹍﹍40
2.3.1.1流程設計原理﹍﹍﹍40
2.3.1.2控制線辨認之Goat IgG@AuNP之合成﹍﹍﹍41
2.3.1.3抗原胜肽之合成﹍﹍﹍42
2.3.1.4連接子與兩性離子之合成﹍﹍﹍47
2.3.1.5 Peptide@AuNP之合成與定量﹍﹍﹍48
2.3.1.5.1醯胺鍵固化方法﹍﹍﹍48
2.3.1.5.2點擊反應固化方法﹍﹍﹍49
2.3.1.6 Peptide@AuNP之專一性及穩定度測試﹍﹍﹍51
2.3.1.7利用胜肽抗原競爭結果﹍﹍﹍54
2.3.1.8實際鳥隻樣品檢測結果﹍﹍﹍55
2.3.2三明治型LFIA系統﹍﹍﹍56
2.3.2.1流程設計原理﹍﹍﹍56
2.3.2.2測試線辨認之anti-BFDV Ab@AuNP合成﹍﹍﹍57
2.3.2.3實際鳥隻樣品檢測結果﹍﹍﹍58
2.3.2.4胜肽抗原與抗體之結合力測試﹍﹍﹍61
2.3.2.4.1微陣列晶片檢測﹍﹍﹍61
2.3.3斑點印跡法（Dot blot assay）﹍﹍﹍62
2.3.3.1競爭型BFDV﹍﹍﹍63
2.3.3.2三明治型BFDV﹍﹍﹍64
2.4開發檢測人絨毛膜促性腺激素之LFIA系統﹍﹍﹍67
2.4.1流程設計原理﹍﹍﹍67
2.4.2物理吸附型固化方法﹍﹍﹍68
2.4.2.1測試線辨認之Anti-hCG alpha Ab@AuNP合成﹍﹍﹍68
2.4.2.2優化合成Anti-hCG alpha Ab@AuNP的抗體使用量﹍﹍﹍69
2.4.2.3測試線辨認之Anti-hCG alpha Ab@AuNP之穩定度測試﹍﹍﹍70
2.4.2.4試紙條件優化﹍﹍﹍72
2.4.2.5 hCG檢測結果﹍﹍﹍75
2.4.2.6 探討使用兩種抗體奈米金之必要性﹍﹍﹍78
2.4.3隨機共價鍵固化方法﹍﹍﹍80
2.4.3.1測試線辨認之Anti-hCG alpha Ab@AuNP合成﹍﹍﹍80
2.4.3.2 hCG檢測結果﹍﹍﹍84
2.4.4位向性共價鍵固化方法﹍﹍﹍87
2.4.4.1測試線辨認之Ab@AuNP合成﹍﹍﹍87
2.4.4.2 hCG檢測結果﹍﹍﹍89
2.4.5實際尿液樣品檢測結果﹍﹍﹍90
第三章、結論與未來展望﹍﹍﹍93
第四章、實驗步驟﹍﹍﹍94
4.1 Materials and methods﹍﹍﹍94
4.2 Linkers synthesis﹍﹍﹍95
4.3 Citrate-AuNP synthesis﹍﹍﹍101
4.3.1 Synthesis of 13 nm AuNP﹍﹍﹍101
4.3.2 Synthesis of 30 nm AuNP﹍﹍﹍101
4.4 High-performance liquid chromatography (HPLC)﹍﹍﹍101
4.4.1 Analytical HPLC﹍﹍﹍101
4.4.2 Semi-preparative HPLC﹍﹍﹍102
4.5 Solid Phase Peptide Synthesis﹍﹍﹍102
4.5.1 General procedure for manual peptide synthesis﹍﹍﹍102
4.5.2 Final cleavage from resin﹍﹍﹍103
4.5.3 Peptide precipitation﹍﹍﹍103
4.5.4 Peptide purification and analysis﹍﹍﹍103
4.6 Protein analysis procedure﹍﹍﹍103
4.7 AuNP stability test﹍﹍﹍104
4.8 AuNP protein quantification via micro BCA assay﹍﹍﹍104
4.9 Transmission electron microscopy of citrate AuNP﹍﹍﹍104
4.10 Fabrication of Goat IgG coated AuNP (IgG@AuNP)﹍﹍﹍104
4.11 BFDV LFIA strip﹍﹍﹍105
4.11.1 Fabrication of BFDV peptide antigen@AuNP﹍﹍﹍105
4.11.1.1 Conjugation by random covalent formation﹍﹍﹍105
4.11.1.2 Conjugation by CuAAc﹍﹍﹍105
4.11.2 Evaluating the capability of BFDV peptide antigen@AuNP for Ab capture﹍﹍﹍106
4.11.3 BFDV Strip assembly﹍﹍﹍106
4.11.4 Non-specific test of BFDV strip﹍﹍﹍106
4.11.5 Competitive test of BFDV strip (Competitive LFIA)﹍﹍﹍107
4.11.6 Actual sample test of BFDV strip (Competitive LFIA)﹍﹍﹍107
4.11.7 Fabrication of Anti-BFDV Ab@AuNP﹍﹍﹍107
4.11.8 Actual sample test of BFDV strip (Sandwich LFIA)﹍﹍﹍108
4.12 hCG LFIA strip﹍﹍﹍108
4.12.1 Anti-hCG Ab@AuNP synthesis﹍﹍﹍108
4.12.1.1 Fabrication of anti-hCG Ab@AuNP by physical absorption﹍﹍﹍108
4.12.1.2 Fabrication of anti-hCG Ab@AuNP by random covalent bond﹍﹍﹍108
4.12.1.3 Fabrication of anti-hCG Ab@AuNP by oriented covalent bond﹍﹍﹍109
4.12.2 hCG Strip assembly﹍﹍﹍110
4.12.3 Non-specific test of hCG strip﹍﹍﹍110
4.12.4 Actual sample test of hCG strip﹍﹍﹍110
4.12.5 Optimization of hCG strip test condition﹍﹍﹍111
4.12.5.1 Running buffer﹍﹍﹍111
4.12.5.2 Surfactant effect﹍﹍﹍111
4.12.5.3 Membrane effect﹍﹍﹍112
4.12.5.4 Time effect on strip drying﹍﹍﹍112
4.12.5.5 Effect of using only anti-hCG Ab@AuNP﹍﹍﹍113
4.12.6 Detection of hCG in real urine sample﹍﹍﹍113
4.13 Dot blot assay﹍﹍﹍113
4.13.1 Using dot blot test to ensure competitive BFDV LFIA﹍﹍﹍113
4.13.2 Using dot blot test to ensure sandwich BFDV LFIA﹍﹍﹍114
第五章、參考文獻﹍﹍﹍115
附錄﹍﹍﹍124

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