MESA+ Institute for Nanotechnology, University of Twente , PO Box 217, 7500 AE Enschede, The Netherlands.
DPIA, University of Udine , Via delle Scienze 206, Udine 33100, Italy.
Acc Chem Res. 2016 Oct 18;49(10):2355-2362. doi: 10.1021/acs.accounts.6b00349. Epub 2016 Sep 19.
We have developed a measurement platform for performing high-frequency AC detection at nanoelectrodes. The system consists of 65 536 electrodes (diameter 180 nm) arranged in a sub-micrometer rectangular array. The electrodes are actuated at frequencies up to 50 MHz, and the resulting AC current response at each separately addressable electrode is measured in real time. These capabilities are made possible by fabricating the electrodes on a complementary metal-oxide-semiconductor (CMOS) chip together with the associated control and readout electronics, thus minimizing parasitic capacitance and maximizing the signal-to-noise ratio. This combination of features offers several advantages for a broad range of experiments. First, in contrast to alternative CMOS-based electrical systems based on field-effect detection, high-frequency operation is sensitive beyond the electrical double layer and can probe entities at a range of micrometers in electrolytes with high ionic strength such as water at physiological salt concentrations. Far from being limited to single- or few-channel recordings like conventional electrochemical impedance spectroscopy, the massively parallel design of the array permits electrically imaging micrometer-scale entities with each electrode serving as a separate pixel. This allows observation of complex kinetics in heterogeneous environments, for example, the motion of living cells on the surface of the array. This imaging aspect is further strengthened by the ability to distinguish between analyte species based on the sign and magnitude of their AC response. Finally, we show here that sensitivity down to the attofarad level combined with the small electrode size permits detection of individual 28 nm diameter particles as they land on the sensor surface. Interestingly, using finite-element methods, it is also possible to calculate accurately the full three-dimensional electric field and current distributions during operation at the level of the Poisson-Nernst-Planck formalism. This makes it possible to validate the interpretation of measurements and to optimize the design of future experiments. Indeed, the complex frequency and spatial dependence of the data suggests that experiments to date have only scratched the surface of the method's capabilities. Future iterations of the hardware will take advantage of the higher frequencies, higher electrode packing densities and smaller electrode sizes made available by continuing advances in CMOS manufacturing. Combined with targeted immobilization of targets at the electrodes, we anticipate that it will soon be possible to realize complex biosensors based on spatial- and time-resolved nanoscale impedance detection.
我们开发了一种用于在纳米电极上进行高频交流检测的测量平台。该系统由 65536 个（直径 180nm）电极组成，呈亚微米矩形阵列排列。这些电极可在高达 50MHz 的频率下工作，并且可实时测量每个单独寻址电极的交流电流响应。这些功能的实现得益于在互补金属氧化物半导体（CMOS）芯片上与相关控制和读出电子设备一起制造电极，从而最小化寄生电容并最大化信噪比。这种组合具有许多优点，适用于广泛的实验。首先，与基于场效应检测的替代 CMOS 基电气系统相比，高频操作不仅限于双电层，而且可以在高离子强度（如生理盐浓度的水）的电解质中探测到范围在几微米的实体。与传统电化学阻抗谱的单通道或少数通道记录不同，该阵列的大规模并行设计允许使用每个电极作为单独的像素对微米级实体进行电成像。这允许在复杂环境中观察复杂的动力学，例如，阵列表面上活细胞的运动。通过根据其交流响应的符号和幅度来区分分析物种类的能力，进一步增强了这种成像能力。最后，我们在这里展示了，灵敏度低至阿特法拉级，加上小电极尺寸，使得可以检测到单个 28nm 直径的颗粒在传感器表面上的着陆。有趣的是，使用有限元方法，也可以根据泊松-纳恩斯-普朗克公式的形式准确计算操作过程中的全三维电场和电流分布。这使得可以验证测量的解释，并优化未来实验的设计。事实上，数据的复杂频率和空间依赖性表明，迄今为止的实验仅触及了该方法能力的表面。硬件的未来迭代将利用 CMOS 制造持续进步带来的更高频率、更高电极填充密度和更小的电极尺寸。结合在电极上的目标的有针对性的固定化，我们预计很快就可以实现基于空间和时间分辨纳米级阻抗检测的复杂生物传感器。
