隨著半導體產業的蓬勃發展，電路設計的技術已經相當成熟，使得跨領域的研究也開始多元發展。生物醫學感測晶片便是跨領域研究的其中之一，藉由將電路與微機電系統整合於同一晶片上，並透過表面改質與修飾方法，感測各式各樣的生物分子以利於進行生物醫學的多方面研究。
本論文提出利用離子感測場效電晶體(ion-sensitive field-effect transistors)在高離子濃度的溶液中，即時檢測低濃度的B型肝炎病毒DNA分子。離子感測場效電晶體是使用TSMC 0.18μm CMOS製程製作而成，並且藉由自組單層膜固定法將表面官能基與DNA分子修飾於感測器表面的感測層。在電路設計方面，設計8×8陣列式ISFET感測器，將ISFET作為MOS電容並將電路操作於高頻，觀察高離子強度下，微小德拜長度(Debye length)所造成的電荷遮蔽效應的影響。
此8×8陣列式ISFET感測器，在pH值感測方面，可得到44.04 mV/pH的感測度；在DNA分子感測方面，由於DNA分子於水溶液中帶負電荷，因此當target DNA與表面probe DNA進行雜交反應後，ISFET電容會上升，使得輸出頻率變化為下降趨勢，且高頻操作下在1X PBS的緩衝溶液下量測，可以感測到低濃度的target DNA。此外，量測到DNA雜交的反應時間約為11分鐘。

With the vigorous development of the semiconductor industry, the technology of circuit design has become quite mature, and cross-disciplinary research has become more diversified and biomedical sensors are one of them. By integrating readout circuits and MEMS sensors on the same chip with functionalized surface, a variety of biomolecules can be detected for various biomedical researches.
This paper proposes to use ion-sensitive field-effect transistors (ISFETs) to detect low-concentration hepatitis B virus DNA molecules in high ionic-strength solutions. The ISFETs are manufactured using TSMC 0.18 μm CMOS process. DNA molecules are immobilized on the functionalized SiO2 surface through self-assembled monolayer. An 8×8 ISFET sensor array is developed. The ISFET is implemented as a MOS capacitor in an oscillator readout operating at high frequency to observe the charge screening effect caused by the small Debye length under high ionic strength.
The sensors exhibit a pH sensitivity of 44.04 mV/pH in terms of the threshold voltage shift. Since DNA molecules are negatively charged in an aqueous solution, the ISFET MOS capacitance increases when the target DNAs hybridize with the probe DNAs, causing the output frequency to decrease. Under high-frequency operation, target DNA can be sensed in 1X PBS buffer solution with a reaction time near 11 minutes.

摘要----I
Abstract----II
致謝----III
目錄----IV
圖目錄----VI
表目錄----X
第1章 緒論----1
1-1 前言----1
1-2 文獻回顧----2
1-3 研究動機----6
第2章 設計與模擬----9
2-1 ISFET感測原理與設計----9
2-1-1 MOS電容原理----9
2-1-2 ISFET原理----17
2-1-3 ISFET等效電路模型----19
2-2 電路設計----23
2-2-1 電路架構----23
2-2-2 電路模擬----32
第3章 生物醫學實驗介紹----39
3-1 生物分子介紹—去氧核醣核酸(DNA)----39
3-2 表面修飾鍵結步驟----41
第4章 量測結果與分析----47
4-1 實驗與量測設備介紹----47
4-1-1 實驗設備介紹----47
4-1-2 量測設備介紹----49
4-2 晶片結構與PCB板封裝----52
4-3 量測結果----54
4-3-1 去離子水溶液中量測----54
4-3-2 ISFET元件之光感測實驗----56
4-3-3 pH值標準溶液中量測----57
4-3-4 不同離子強度的緩衝溶液中量測----59
4-3-5 DNA雜交(hybridization)的時間響應(time response)分析----61
4-3-6 DNA分子(HBV)量測實驗----63
第5章 結論與未來工作----77
參考文獻----78
附錄----86

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