A Dual-Mode Large-Arrayed CMOS ISFET Sensor for Accurate and High-Throughput pH Sensing in Biomedical Diagnosis
A Dual-Mode Large-Arrayed CMOS ISFET Sensor for Accurate and High-Throughput pH Sensing in Biomedical Diagnosis
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DOI：
10.1109/tbme.2015.2419233
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发表时间：
2015-09-01
影响因子：
4.6
通讯作者：
Wu, Dongping
中科院分区：
文献类型：
--
作者：
Huang, Xiwei;Yu, Hao;Wu, Dongping
目的：现有的基于ISFET的DNA测序检测到DNA链在微珠上聚合时释放的氢离子，这些氢离子以未知的分布分散在ISFET传感器上方的微孔阵列中。然而，由于邻近微珠的串扰，在空微孔中会发生假pH检测。本文提出了一种双模CMOS ISFET传感器，用于DNA测序的精确pH检测。方法：通过集成CMOS图像传感器（CIS）和ISFET pH传感器实现光学和化学双模传感，并在标准的0.18 μ m CIS工艺中制造。通过接触成像，利用CIS像素精确确定微珠的物理位置，双模传感器可以在一个位置确定的微珠上关联一个DNA切片的局部pH，从而提高pH检测精度。此外，为了实现高通量DNA测序，还部署了支持两种模式的大阵列的相关双采样读出器，以减少像素到像素的不均匀性，例如阈值电压不匹配。结果：所提出的CMOS双模传感器经实验验证，pH值灵敏度为26.2 mV/pH，固定模式噪声（FPN）从4%降低到0.3%，读出速度为1200帧/秒，具有良好的pH图和微珠光学图像相关性。结论：提出了一种具有抑制FPN的双模CMOS ISFET传感器，用于精确的大阵列pH传感，并得到了最先进的测量结果，用于精确和高通量DNA测序。意义：所研制的双模CMOS ISFET传感器具有高精度、低成本的优点，在未来的个人基因组诊断中具有很大的潜力。
Goal: The existing ISFET-based DNA sequencing detects hydrogen ions released during the polymerization of DNA strands on microbeads, which are scattered into microwell array above the ISFET sensor with unknown distribution. However, false pH detection happens at empty microwells due to crosstalk from neighboring microbeads. In this paper, a dual-mode CMOS ISFET sensor is proposed to have accurate pH detection toward DNA sequencing. Methods: Dual-mode sensing, optical and chemical modes, is realized by integrating a CMOS image sensor (CIS) with ISFET pH sensor, and is fabricated in a standard 0.18-mu m CIS process. With accurate determination of microbead physical locations with CIS pixel by contact imaging, the dual-mode sensor can correlate local pH for one DNA slice at one location-determined microbead, which can result in improved pH detection accuracy. Moreover, toward a high-throughput DNA sequencing, a correlated-double-sampling readout that supports large array for both modes is deployed to reduce pixel-to-pixel nonuniformity such as threshold voltage mismatch. Results: The proposed CMOS dual-mode sensor is experimentally examined to show a well correlated pH map and optical image for microbeads with a pH sensitivity of 26.2 mV/pH, a fixed pattern noise (FPN) reduction from 4% to 0.3%, and a readout speed of 1200 frames/s. Conclusion: A dual-mode CMOS ISFET sensor with suppressed FPN for accurate large-arrayed pH sensing is proposed and demonstrated with state-of-the-art measured results toward accurate and high-throughput DNA sequencing. Significance: The developed dual-mode CMOS ISFET sensor has great potential for future personal genome diagnostics with high accuracy and low cost.