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姓名 吳昱明(Yu-Ming Wu) 查詢紙本館藏 畢業系所 化學工程與材料工程學系 論文名稱 矽奈米線場效電晶體生物感測器進行不同化學表面改質並利用核酸適體或抗體探針檢測白細胞介素6之研究
(Ultrasensitive detection of Interleukin 6 by silicon nanowire field-effect transistors apta- or immuno- biosensors with different chemical surface modifications)相關論文 檔案 [Endnote RIS 格式]
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摘要(中) 嚴重急性呼吸道症候群冠狀病毒2型 (COVID-19)於2019年發現並在全球各地快速擴散，世界衛生組織 (WHO)於2020年3月將宣布大流行。當人體感染COVID-19病毒後會開始活化人體的免疫系統[1]，若免疫系統過度反應後會釋放過多的促發炎性物質 (Proinflammatory cytokine)，進而傷害正常功能的組織或細胞，此現象則稱為細胞激素風暴 (Cytokine storm)。而在眾多的促發炎性生物標誌物 (Biomarker)中[2]，白細胞介素6 (Interleukin 6, IL-6)與細胞激素風暴有著高度相關性，因此許多研究團隊致力於發展高靈敏度的IL-6檢測方法[3]。
目前臨床上主要診斷方式為抗原 (Antigen)或抗體 (Antibody)快篩試劑 (Rapid test kits)，其試劑雖檢測時間短，但目前只能定性 (Qualitative test)檢測，無法定量 (Quantitative test)觀察目標物 (Target)濃度變化與病程的關係，且檢測結果偽陰性 (False-negative)與偽陽性 (False-positive)機率高。此外，由臨床報告指出COVID-19病患體內IL-6濃度介於7 pg/mL-24.3 pg/mL (333 fM-1.2 pM)會開始由無症狀轉為輕症，高於1.2 pM轉為重症[4]。為了達到可定量目標物濃度範圍與快速精準的診斷方式，本研究使用具可定量目標物濃度、高靈敏度與即時檢測等特性之矽奈米線場效應電晶體 (Silicon nanowire field-effect transistors, SiNWFETs)作為檢測IL-6的平台。
本研究首先探討三種常見的矽烷化方式：APTES (3-aminopropyl triethoxysilane)、APS ((1-(3-Aminopropyl) silatrane)、Mixed-SAMs (silane-PEG-NH2：silane-PEG-OH =1：10 (mM/mM)以戊二醛 (Glutaraldehyde)與抗體探針 (Anti-IL-6 antibody)於SiNWFETs表面改質後進行IL-6檢量線(1 pM-10 nM)量測。同時藉由原子力顯微鏡 (Atomic force microscopy)分析不同矽烷化的表面形貌是否影響後續的表面化學接枝及IL-6檢量線檢測電訊號結果。
首先由不同矽烷化改質SiNWFETs後檢測IL-6檢量線之結果顯示，APTES/GA/抗體 (Anti-IL-6 antibody)表面隨IL-6濃度改變產生之電訊號呈現無序變化；APS/GA/抗體表面雖IL-6濃度變化與其產生之電訊號呈線性趨勢，但其值小於有效訊號，視為背景雜訊 (Noise)；Mixed-SAMs/GA/抗體表面隨IL-6濃度的改變產生之電訊號表現出線性變化且皆為有效訊號。接著由AFM結果顯示，APTES矽烷化會產生分子間縮和使表面形貌不均勻；APS雖有籠狀對稱結構可避免分子間縮和，較APTES表面較為均勻；Mixed-SAMs之AFM表面形貌均勻性與檢測IL-6之電訊號結果為最佳。總和上述結果，後續皆使用Mixed-SAMs表面矽烷化再進行後續GA/抗體或核酸適體表面改質實驗。
由SiNWFETs結果顯示，若是利用抗體當成探針之生物感測器來檢測IL-6之檢測極限 (Limit of detection)為210 pg/mL (10 pM)，線性範圍 (Linear range)為10 pM-1 nM。然而，若使用抗體作為探針的生物感測器進行IL-6之檢測僅能區分COVID-19重症患者，無法對無症狀與輕症患者進行診斷 (Diagnosis)，因此本研究除了使用抗體探針生物感測器之外，進一步使用核酸適體探針 (Anti-IL-6 aptamer)生物感測器進行IL-6檢量線檢測，嘗試解決抗體生物感測器對於COVID-19臨床IL-6檢測的不足。並透過原子力顯微鏡、X光光電子能譜儀 (X-ray photoelectron spectroscopy)確認抗體或核酸適體探針之表面改質的正確性，最後分析比較抗體或核酸適體探針之SiNWFETs進行IL-6檢量線之檢測。
由SiNWFETs結果顯示，核酸適體作為探針之生物感測器，其檢測IL-6檢量線之LOD為2.1 pg/mL (100 fM)，線性範圍100 fM-1 nM。由此研究結果顯示出，核酸適體生物感測器不但LOD比抗體生物感測器更低，並且增加了檢測 IL-6之線性範圍，滿足了COVID-19臨床上檢測的需求，也凸顯核酸適體生物感測器進行COVID-19病患之IL-6檢測具有較高靈敏度與準確定量IL-6濃度的優勢與潛力。
唯本研究未能進入組織樣品檢測，以及探討組織中其他複雜物質造成之檢測干擾，未來仍需進一步進行非專一性檢測及分析IL-6於人體組織或血清樣品中的檢測，以更符合實際檢測之需求。摘要(英) The severe acute respiratory syndrome coronavirus 2 (COVID-19) was discovered in 2019 and spread rapidly around the world, and the WHO declared a pandemic of COVID-19 in March 2020. When the human body is infected with the COVID-19 virus, it will start to activate the body′s immune system[1] If the immune system overreacts, it may release a large number of proinflammatory cytokines, which in turn damages normally functioning tissues or cells. This phenomenon is a so-called cytokine storm. Among many kinds of proinflammatory biomarkers[2], interleukin 6 (IL-6) is highly correlated with the cytokine storm. Therefore, many research groups are devoted to developing high-sensitivity IL-6 detection methods[3].
Currently, the main clinical diagnostic of COVID-19 methods is antigen or antibody rapid test kits. Although the detection time of these kits is short, they can only be qualitatively detected at present. Moreover, the relationship between the changes in the concentration of the target and the course of the disease cannot be clearly and quantitatively observed. More importantly, the probability of false-negative and false-positive test results is very high. In addition, the clinical reports indicate that IL-6 concentrations in COVID-19 patients ranging from 7 pg/mL to 24.3 pg/mL (333 fM to 1.2 pM) will begin to change from asymptomatic to mild, and those above 1.2 pM to severe [4]. To achieve a fast, accurate and diagnostic method that can quantify the target concentration range, this research used the silicon nanowire field-effect transistors (SiNWFETs) with the characteristics of qualitative target concentration, high sensitivity and real-time detection as the detection platform of IL-6.
In this research, three common silanization methods were first investigated: APTES (3-aminopropyl triethoxysilane), APS ((1-(3-Aminopropyl) silatrane), Mixed-SAMs (silane-PEG-NH2: silane-PEG-OH =1: 10 (mM/mM) was modified with GA (Glutaraldehyde) and antibody probe (Anti-IL-6 antibody) on the surface of SiNWFETs for IL-6 calibration curve (1 pM-10 nM) measurement. Whether the surface morphology of different silanization affects the subsequent surface chemical grafting and IL-6 calibration curve detection electrical signal results were analyzed by AFM (Atomic force microscopy).
First, the IL-6 calibration curve was detected by different silanization surfaces of SiNWFETs. The electrical signals on the surface of APTES/GA/Antibody (Anti-IL-6 antibody) showed disordered changes with the change of IL-6 concentration. Although the change of IL-6 concentration on the surface of APS/GA/antibody has a linear trend with the electrical signal generated, its value was regarded as background noise (Noise). The electrical signals generated on the surface of Mixed-SAMs/GA/antibody with the change of IL-6 concentration showed linear changes and were regarded as effective signals. Also, the AFM results revealed that the silanization surface of APTES will probably produce an intermolecular condensation reaction that makes the surface morphology non-uniform. Although the APS has a cage-like symmetric structure to avoid intermolecular condensation reaction, it is more uniform than the APTES silanization surface. Finally, the surface morphology of Mixed-SAMs showed the best uniformity and electrical signal detection of IL-6. To sum up the above results, the silanization surface of the Mixed-SAMs was used for subsequent surface modification experiments of GA/antibody or nucleic acid aptamer probes.
The SiNWFETs results showed that if the immunobiosensor using antibodies as probes was used, the limit of detection (LOD) of IL-6 was 210 pg/mL (10 pM) and the linear range was 10 pM-1 nM. However, the detection of IL-6 by the immunobiosensor can only distinguish patients with severe COVID-19, but cannot distinguish between asymptomatic and mild patients. To address the deficiencies of immunobiosensor for clinical IL-6 detection in COVID-19 patients. Therefore, not only used the antibody probe immunobiosensor but also used the aptamer probes (Anti-IL-6 aptamer) aptabiosensors for IL-6 calibration curve detection in this research. Simultaneously, confirm the correctness of the surface modification of the antibody or aptamer probes through AFM and X-ray photoelectron spectroscopy (XPS). Eventually, the SiNWFETs results showed that the LOD of the aptabiosensor was 2.1 pg/mL (100 fM), and the linear range was 100 fM-1 nM. In conclusion, The aptabiosensor not only has a lower LOD than the immunobiosensor but also increases the linear range of IL-6 detection, meeting the needs of clinical detection the IL-6 of in COVID-19 patients.關鍵字(中) ★ 矽奈米線場效電晶體
★ 生物感測器
★ 白細胞介素 6
★ 抗體與核酸適體關鍵字(英) 論文目次 摘要 I
Abstract IV
致謝 VII
目錄 IX
圖目錄 XII
表目錄 XV
第一章 緒論 1
第二章 文獻回顧 3
2.1 抗體分子 3
2.1.1 抗體分子概論 3
2.1.2 抗體結構 5
2.2 核酸適體 (Aptamer) 7
2.2.1 Systematic Evolution of Ligands by Exponential Enrichment (SELEX) 8
2.2.2 核酸適體 (Aptamer)與抗體 (Antibody)比較 10
2.3 白細胞介素6 12
2.3.1 嚴重急性呼吸道症候群冠狀病毒2型 (SARS-CoV-2) 12
2.3.2 細胞激素風暴 (Cytokine storm) 14
2.3.3 白細胞介素6 (Interleukin 6, IL-6) 16
2.3.4 白細胞介素6 (IL-6)於COVID-19中的臨床檢測 18
2.3.5 白細胞介素6 (IL-6)的檢測 18
2.4 矽奈米線場效應電晶體 23
2.5 晶片表面改質 26
2.5.1 自組裝單層膜 27
2.5.2 表面分子固定化 30
2.5.3 3-氨基丙基三乙氧基矽烷 (APTES)於自組裝單層膜之應用 31
2.5.4 氮矽三環類化合物 (APS)於自組裝單層膜之應用 34
2.5.5 矽氧烷-聚乙二醇 (Silane-PEG)於自組裝單層膜應用 35
第三章 實驗藥品、儀器設備及方法 38
3.1 實驗藥品 38
3.1.1 SiNWFETs晶片表面改質與檢測 38
3.2 儀器設備 40
3.3 晶片表面改質抗體探針 41
3.3.1 晶片表面清洗及氧電漿處理 41
3.3.2 修飾 Mixed-SAMs/APTES及APS 41
3.3.2 修飾 GA (Glutaraldehyde) 42
3.3.3 抗體探針固定化 42
3.4 晶片表面改質核酸適體探針 44
3.4.1 晶片表面清洗及氧電漿處理 44
3.4.2 修飾 Mixed-SAMs 44
3.4.3 修飾 GA (Glutaraldehyde) 45
3.4.4 核酸適體探針固定化 45
3.5 SiNWFETs 電性測量 47
3.6 原子力顯微鏡 (AFM)抗體改質之表面粗糙度分析 48
3.6.1 矽控片表面清洗及氧電漿處理 48
3.6.2 修飾 Mixed-SAMs/APTES及APS 48
3.6.3 修飾 GA (Glutaraldehyde) 49
3.6.4 抗體探針固定化 50
3.7 原子力顯微鏡 (AFM)核酸適體改質之表面粗糙度分析 51
3.7.1 矽控片表面清洗及氧電漿處理 51
3.7.2 修飾 Mixed-SAMs 51
3.7.3 修飾 GA (glutaraldehyde) 52
3.7.4 核酸適體探針固定化 52
3.8 光電子能譜儀 (XPS)抗體改質之表面元素分析 54
3.8.1 矽控片表面清洗及氧電漿處理 54
3.8.2 修飾 Mixed-SAMs 54
3.8.3 修飾 GA (Glutaraldehyde) 55
3.8.4 抗體探針固定化 55
3.9 光電子能譜儀 (XPS)核酸適體改質之表面元素分析 57
3.9.1 矽控片表面清洗及氧電漿處理 57
3.9.2 修飾 Mixed-SAMs 57
3.9.3 修飾 GA (Glutaraldehyde) 58
3.9.4 核酸適體探針固定化 58
第四章 結果與討論 60
4.1 不同Silanization表面於SiNWFETs檢測IL-6之影響 60
4.1.1 SiNWFETs之元件誤差 60
4.1.2 不同Silanization表面於SiNWFETs之IL-6檢測 60
4.2 原子力顯微鏡(AFM)表面粗糙度分析 64
4.2.1 不同Silanization之表面型態 65
4.2.2 抗體或核酸適體探針改質之表面型態 68
4.3 光電子能譜儀(XPS)表面元素分析 70
4.4 抗體或核酸適體探針於SiNWFETs檢測IL-6之影響 73
第五章 結論與未來展望 76
5.1 結論 76
5.2 未來展望 78
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