In this article, we present the design and analysis of an electrochemical circuit for measuring the concentrations of therapeutic drugs using structure-switching aptamers. Aptamers are single-stranded nucleic acids, whose sequence is selected to exhibit high affinity and specificity toward a molecular target, and change its conformation upon binding. This property, when coupled with a redox reporter and electrochemical detection, enables reagent-free biosensing with a subminute temporal resolution for in vivo therapeutic drug monitoring. Especially, we design a chronoamperometry (CA)-based electrochemical circuit that measures the direct changes in the electron transfer (ET) kinetics of a methylene blue reporter conjugated at the distal end of the aptamer. To overcome the high-frequency noise amplification issue when interfacing with a large-size (> 0.25 mm2) implantable electrode, we present a sample-and-hold (S/H) circuit technique in which the desired electrode potentials are held onto noiseless capacitors during the recording of the redox currents. This allows disconnecting the feedback amplifiers to avoid its noise injection while reducing the total power consumption. A prototype circuit implemented in 65-nm CMOS demonstrates a cell-capacitance-insensitive input-referred noise (IRN) current of 15.2 pArms at a 2.5-kHz filtering bandwidth. We tested our system in human whole blood samples and measured the changes in the ET kinetics from the redox-labeled aptamers at different kanamycin concentrations. By employing principal component analysis (PCA) to compensate for the sampling errors, we report a molecular noise floor (at SNR = 1) of 3.1 μM\mu \text{M} with sub-1-s acquisition time at 0.22-mW power consumption.

中文翻译：

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用于基于适体的治疗药物监测的采样保持 CMOS 电化学传感器的设计和分析


在本文中，我们介绍了使用结构转换适体测量治疗药物浓度的电化学电路的设计和分析。适体是单链核酸，其序列经过选择以对分子靶标表现出高亲和力和特异性，并在结合时改变其构象。当与氧化还原报告分子和电化学检测相结合时，这种特性可以实现具有亚分钟时间分辨率的无试剂生物传感，用于体内治疗药物监测。特别是，我们设计了一种基于计时安培法（CA）的电化学电路，用于测量与适体远端缀合的亚甲基蓝报告基因的电子转移（ET）动力学的直接变化。为了克服与大尺寸 (> 0.25 mm2) 植入电极连接时的高频噪声放大问题，我们提出了一种采样保持 (S/H) 电路技术，其中所需的电极电位保持在无噪声上记录氧化还原电流期间的电容器。这允许断开反馈放大器以避免其噪声注入，同时降低总功耗。采用 65 nm CMOS 实现的原型电路展示了在 2.5 kHz 滤波带宽下对单元电容不敏感的输入参考噪声 (IRN) 电流为 15.2 pArms。我们在人类全血样本中测试了我们的系统，并测量了不同卡那霉素浓度下氧化还原标记适体的 ET 动力学变化。通过采用主成分分析 (PCA) 来补偿采样误差，我们报告了 3.1 μM\mu \text{M} 的分子本底噪声（SNR = 1 时），在 0.22 mW 功率下采集时间不到 1 秒消耗。