應用於體外流式細胞儀之結合積體電路與微流道之細胞阻抗檢測系統

Abstract

本論文提出一個用於細胞阻抗檢測的體外流式細胞儀，該流式細胞儀結合採用180奈米CMOS (互補式金屬氧化物半導體)製程的阻抗感測晶片，以及採用具生物相容性質的PDMS (polydimethylsiloxane, 聚二甲基矽氧烷) 所製成的微流道結構，本論文設計之阻抗感測晶片，包含晶片上的刺激訊號生成電路結構，可藉由調整外部控制電壓調整生成的刺激訊號頻率，另外也包含了晶片上的阻抗感測電路架構，晶片設計包含晶片上的跨阻放大器 (TIA)，將待測物藉由微流道通道流過電極時的電流變化轉換為電壓變化，以及晶片上的差分放大器，用於扣除背景基線訊號，減少後端電路動態範圍的需求，並採用I/Q正交訊號進行阻抗解調變，取得待測物體之阻抗訊號。 本論文設計之晶片亦包含晶片上的感測電極，透過最小寬度為2微米寬度的晶片上電極，可以以小於細胞或模擬細胞之塑膠微珠直徑對細胞進行阻抗量測，提升對於目標物阻抗量測的空間解析度，能夠在一定程度上得知細胞的輪廓，本晶片也設計了包含多個電極尺寸以及多通道，以滿足不同需要量測的目標之需求，本論文提出之流式細胞儀主要刺激頻率操作在1 MHz，頻寬最高可至約3 MHz，用於I/Q解調的低通濾波頻率為100 kHz，跨阻放大器之回授電阻為200k歐姆，我們也提出了一套將微流道系統與CMOS晶片以及印刷電路(printed circuit board, PCB)板結合的方法，解決微流道系統與晶片結合的困難，本論文在模擬中對於懸浮在磷酸鹽緩衝生理鹽水(PBS) 1X 溶液中的10 μm 聚苯乙烯塑膠微珠，在刺激訊號 = 0.95 Vpp，1 MHz的情況下，在差動輸出的單端取得了~300 mV的訊號，訊雜比(SNR) ~ 43.5 dB. 對於懸浮在PBS 1X 溶液中的3 μm 聚苯乙烯塑膠微珠，在差動輸出的單端取得了~33 mV的訊號，SNR ~ 24.3 dB。

This paper presents an in vitro flow cytometry system for cell impedance detection. The system integrates an impedance sensing chip fabricated using a 180 nm CMOS (Complementary Metal-Oxide-Semiconductor) process with a microfluidic structure made of PDMS (polydimethylsiloxane), a material known for its biocompatibility. The proposed impedance sensing chip includes an on-chip excitation signal generation circuit, where the frequency of the generated signal can be adjusted by tuning an external control voltage. The chip also incorporates an on-chip impedance sensing circuit, including a transimpedance amplifier (TIA) that converts current changes—caused by target particles passing through the microfluidic channel—into voltage changes, and a differential amplifier that suppresses background baseline signals to reduce the dynamic range requirements of subsequent circuits. The system performs impedance demodulation using in-phase and quadrature-phase (I/Q) signals to extract the impedance information of the target. The chip also includes on-chip sensing electrodes, with minimum electrode widths of 2 μm, allowing impedance measurement of cells or polystyrene beads with diameters larger than the electrode width. This improves the spatial resolution of impedance detection, enabling partial profiling of the cell shape. Multiple electrode sizes and multi-channel structures are implemented to meet the measurement requirements of different targets. The proposed flow cytometry system operates mainly at an excitation frequency of 1 MHz, with a maximum bandwidth of approximately 3 MHz. The low-pass filter used in I/Q demodulation has a cutoff frequency of 100 kHz, and the feedback resistor of the TIA is 200 kΩ. Additionally, we propose a method for integrating the microfluidic system with the CMOS chip and a printed circuit board (PCB), addressing the challenges of aligning and bonding the microfluidic structure to the chip. In simulation, for a 10 μm polystyrene bead suspended in 1× phosphate-buffered saline (PBS), with an excitation signal of 0.95 Vpp at 1 MHz, a single-ended signal of approximately 300 mV was obtained from the differential output, with a signal-to-noise ratio (SNR) of approximately 43.5 dB. For a 3 μm polystyrene bead under the same conditions, a single-ended output of approximately 33 mV was observed, with an SNR of approximately 24.3 dB.