應用於核酸電化學生物感測器與近場影像儀之讀出電路

Abstract

本論文分成兩大部分，分別是用於體外診斷之核酸電化學生物感測器與近場射頻感測影像儀。 核酸電化學生物感測器利用合成核酸適體檢測目標分子是否存在與其濃度，提供即時檢測，無須額外試劑，適用於長期分子感測。我們利用氧化還原標記分子其電子轉移的特性，提出一種方波伏庫倫法讀出電路，可將信號增強100倍以上。作者開發了專門用於此生物感測器的十位元位雙模式（同步/非同步）逐漸趨近式類比數位轉換器，並引領電路系統整合與量測。此生物感測系統採用180奈米互補式金氧半導體製程製作，並與酸鹼值和溫度感測器整合，總功耗為2.4 mW。類比數位轉換器量測結果顯示於同步模式下，可達到58.00 dB之訊號雜訊失真比，而非同步模式下可達到55.13 dB之訊號雜訊失真比。感測鏈在±300 nA差分輸入電流下，達到0.26% THD，並於3.3 nF輸入負載電容而積分範圍考慮到1 kHz下，電流雜訊為5.2 pArms。透過萬古霉素適體和常間回文重複序列叢集關聯蛋白相關酶展示了其分子濃度檢測的能力 在第二個部分，我們專注於研發用於乳癌手術中的邊緣評估影像儀，確保癌細胞有徹底摘除。為了提高診斷準確性與減小感測面積，我們提出一種以駐波震盪器作為配置之現場可編程差動傳輸線，實現51.2 μm × 50 μm解析度與64%填滿率。作者開發了專門用於此影像儀的讀出電路，包括一個最大工作頻率為18 GHz之除64除頻鏈、一個用於頻率偵測的32位元的計數器，以及一個系統串化器。此影像系統採用180奈米互補式金氧半導體製程製作，每個SWO感測鏈功率消耗為107.8 mW。計數器量測結果顯示，工作頻率範圍為1 MHz到500 MHz，與Agilent 53220a進行比對，頻率誤差低於8 kHz。透過浸泡於墨水中的三通道微流道以及浸泡於福馬林中的老鼠腫瘤切片展示了其成像能力。

This thesis is divided into two parts: an aptamer-based electrochemical biosensor for in vitro diagnostics and a near-field RF-sensing imager. An aptamer-based electrochemical biosensor employs synthetic nucleic acid aptamers for detecting the presence and the concentration of the target molecules in real-time without the need for reagents, making it suitable for long-term in vivo molecular sensing. We take advantage of the signaling property from the electron transfers of the redox reporters and present a square-wave volt-coulometry (SWVC) electrochemical readout circuit to achieve over 100 times signal enhancement. The author develops a 10-bit dual-mode (synchronous/asynchronous) SAR ADC dedicated to this biosensor system and leads both the system integration and testing. The biosensor system is implemented in 180-nm CMOS technology, integrated with pH and temperature sensors, and consumes a total power of 2.4 mW. The ADC measurement result shows an SNDR of 58.00 dB in the synchronous mode and 55.13 dB in the asynchronous mode. The sensor chain achieves 0.26% THD at ±300 nA differential input current and 5.2 pArms integrated up to 1 kHz with 3.3 nF input loading capacitors. We demonstrate the molecular concentration detection capability with vancomycin aptamer and CRISPR-associated enzymes (Cas). In the second part, we focus on intraoperative imaging for rapid margin assessment in breast tumor surgery to ensure the complete removal of cancer cells. To improve the diagnostic accuracy and reduce the sensing area, we propose a field-programmable differential trans-mission line (t-line) configured as a standing-wave oscillator (SWO) to achieve 51.2 μm × 50 μm spatial resolution at 64% filling-factor. The author develops a readout circuit dedicated to this imaging system, including a divide-by-64 frequency divider chain with a maximum operating frequency of 18 GHz, a timing-aware 32-bit counter for frequency detection, and a system serializer. The imaging system is implemented in 180-nm CMOS technology and each SWO sensing chain consumes a total power of 107.8 mW. The counter measurement result shows the operating frequency ranges from 1 MHz to 500 MHz with a frequency error lower than 8 kHz compared with Agilent 53220a. The imaging capability has been demonstrated with a three-channel microfluidics immersed in inked water and tumor tissues excised from mice immersed in formalin.