標題: 發展新穎側向閘極奈米線場效電晶體並應用於甲狀腺乳突癌的感測
Detection of the BRAFV599E Mutation Genes with a Novel Side-gated NWFET
作者: 吳奕儂
Yi-Nung Wu
Fu-Hsiang Ko
關鍵字: 奈米線;場效電晶體;DNA;生物感測器;Nanowire;FET;DNA;Biosensor
公開日期: 2006
摘要: 以半導體奈米線為基礎的元件裝置作為免標示、高度敏感且具選擇性的感測器,偵測的生物或化學物種包括低濃度離子,小分子、蛋白質、DNA和病毒。 然而,製作‘由下而上’的奈米線所需的流程,在未來的元件製作整合上具有非常大的阻礙。替代的‘由上而下’製程近幾年來已經被提出。然而,大多數此類的感測器裝置所製作的閘極是由背面閘極組成,限制了未來大規模的整合。在這篇論文中,使用了互補式金氧半場效電晶體的技術(包含矽的局部氧化製程及電子束直寫技術)來製作我們的新穎側向閘極矽奈米線場效電晶體。利用矽的局部氧化製程來製作線寬縮小的奈米線,此線可以達到較高的表面體積比以及獲得側向閘極以供未來整合的應用。我們的元件是由矽-絕緣體-矽的晶圓當做基材,可提供一個很好的二氧化矽介電層品質,進而達到一個較低的漏電流以及較優良的場效應性質。 關於疾病診斷的應用,我們想要偵測與甲狀腺乳突癌有關聯的BRAFV599E變異基因。甲狀腺乳突癌是一個人體中較常發生的內分泌腺惡性腫瘤。文獻報導指出,在BRAF這段基因序列產生變異,有66%的機會會導致嚴重的黑色素瘤,但對於人類的其他癌症,卻無法達到這麼高的比例。大部分發生突變的原因80%通常來自於激酶裡一個鹼基的變異,而造成胺基酸的改變。 我們藉由修飾奈米線表面進而偵測此疾病的DNA序列。矽奈米線表面修飾上APTES使其呈現含氨基的末端,然後將單股的捕捉DNA固定化上去,藉此來偵測另一股互補的DNA,也就是BRAFV599E變異基因。在控制實驗方面,我們在奈米線接上含螢光標示物的單股DNA,利用螢光顯微鏡來確認DNA確實接在我們的單晶奈米線元件。最後,我們使用一個半導體電性分析儀量測每個步驟的電性變化。 由矽的局部氧化製程製作的奈米通道被鳥嘴效應影響,其線寬縮小的程度可以達到八十奈米以下。此元件的電性達到十萬倍的開關電流比,可偵測到一千億分之一的莫耳濃度,其臨界電壓變化可達0.86伏特。結果顯示此元件可達到免標示、高靈敏度、高選擇性的生物感測器。此外,我們的製作方法提供了未來在多物種的偵測可能性、個別的閘極控制能力,以及在單一晶片上整合的可能性。
Devices based on semiconducting nanowires are functioning as highly sensitive and selective sensors for the label-free detection of biological and chemical species, including low concentrations of ions, small molecules, proteins, DNA and viruses. However, ‘bottom-up’ nanowires used for these demonstrations require hybrid fabrication schemes, which result in severe integration issues that have impeded widespread application. Alternative ‘Top-down’ fabrication methods of nanowire-like devices have been proposed in recent year. Nevertheless, most devices are composed of a back gate, which limits the application for the large-scale integration. In this thesis, a novel side-gated Si NWFET was fabricated by an approach that uses complementary metal oxide semiconductor (CMOS) field effect transistor compatible technology, including the conventional LOCOS isolation process and electron-beam writing. The shrinking nanowire with higher surface-to-volume ratio and individual side gate for integration are achieved by the LOCOS process. Our side-gated devices which fabricated using silicon-on-insulator (SOI) wafers provide a good quality of SiO2 gate dielectric, which exhibits lower leakage current and excellent field effect properties than those with air dielectric. Regarding to disease diagnosis, we want to detect the BRAFV599E mutation gene, which has been recently reported to be restricted to papillary thyroid carcinomas (PTCs). The PTC is well known to a common endocrine malignancy of human cancer. It is reported that BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Next, we modified the nanowires’ surfaces for the goal of using them for biosensing. The silicon nanowire surface was modified using APTES to present amino groups and then single-stranded DNA was immobilized through these groups to allow the detection of its complementary single-stranded gene sequence (BRAFV599E mutation gene). In a control experiment, we prepared a fluorescently labeled single-strand DNA so that we could observe, using fluorescence microscopy, that it did reside on the single crystal silicon nanowire. Finally, we used a semiconductor analyzer to measure the electrical properties of the nanowires at each step of the modification process. The width of shrinking nano-channel by the LOCOS “bird’s beak” can be 80 nm or thinner practically. The IDS-VG characteristic of the NWFETs exhibits about five orders of magnitude on Ion/Ioff, and the threshold voltage shifts positively to 0.86V after hybridization of 10 picomolar concentrations of BRAFV599E mutation gene. The results show that the nanowire-based device acts as a label-free, highly sensitive and selective biosensor for mutation gene sensing. In addition, our approach offers the possibility of highly parallel detection of multiple chemical and biological species with local control of individual elements in a single integrated chip.
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