應用於檢測核酸及 CRISPR-Cas12a 酶之電化學生物感測器

Abstract

本論文提出了一種CMOS/微流道生物分析儀，專為即時醫療（PoC）應用設計，其中包含了兩代感測晶片系統（Gen.1 和 Gen.2）。 在 Gen.1中，我們實現了方波伏特庫侖測量（SWVC）進行電化學讀取，有效利用氧化還原標記分子的電子轉移特性，達成超過100倍的訊號增強。該系統在輸入負載為3.3 nF時，展現了5.2 pArms的輸入參考雜訊電流，使訊噪比（SNR）優於先前的研究。此外，Gen.1成功實現了：(1)利用適體（Aptamer）檢測萬古黴素（Vancomycin）和(2)透過DNA適體與CRISPR蛋白檢測細胞激素 TGF-β1。 在Gen.2中，我們將無線供電與通訊整合至CMOS晶片，並透過晶片上的線圈在700 MHz近場運作，這減少了組合CMOS與微流道所需的繁複步驟。此外，Gen.2整合了Amperometric、pH 及溫度感測器。其中，Amperometric感測器 採用訊號折疊技術（Signal-Folding），在100 Hz頻寬下實現0.24 pArms的輸入參考雜訊電流，並具備129.8 dB的動態範圍。該系統利用真空下PDMS自然的滲透現象以驅動流體流動，並已透過質子（Proton-Based）與氧化還原（Redox-Based）免疫分析檢測進行驗證。 Gen.1和Gen.2晶片皆採用TSMC 180-nm CMOS製程，功耗分別為2.4 mW 和2.5 mW。

This thesis presents a CMOS/microfluidics bio-analyzer designed for point-of-care (PoC) applications, including two generations of sensor SoCs (Gen.1 and Gen.2). In Gen.1, we implemented square-wave voltcoulometry (SWVC) for electrochemical readout, effectively leveraging the redox reporters’ electron transfer properties to achieve a >100× signal enhancement. The system demonstrates an input-referred noise current of 5.2 pArms with an input loading of 3.3 nF, resulting in a superior SNR compared to previous works. Additionally, Gen.1 successfully enabled: (1) vancomycin detection using aptamers and (2) cytokine (TGF-β1) detection using DNA aptamers and CRISPR-associated proteins. In Gen.2, we integrated fully wireless power and communication into the CMOS chip using an on-chip coil operating at 700 MHz in the near field. This design eliminates packaging complexity and the need for external fluidic actuation, while incorporating amperometric, pH, and temperature sensors. The amperometric front-end employs a signal-folding technique, achieving an input-referred noise current of 0.24 pArms at a 100 Hz bandwidth, along with a dynamic range of 129.8 dB. The system utilizes the natural permeability of PDMS under vacuum to drive fluid flow and has been validated using proton-based and redox-based immunoassay reagents. Both Gen.1 and Gen.2 SoCs are fabricated in TSMC 180-nm CMOS, consuming 2.4 mW and 2.5 mW, respectively.