Integrated Sensing: An Integrated Biosensor System for Cellular Studies

在生物学研究中，体外细胞功能的研究是临床诊断、治疗、药物筛选和环境监测等其他领域的基础。在我们的方案中，利用生物技术、硅微加工、微电子传感器和信号处理技术来实现集成低噪声信号处理的多用途生物传感器。我们研究硅芯片中生物细胞的培养、表征和操作。特别地，所提出的集成生物传感器系统结构可以用作平面膜片钳装置，用于实验测试和评估药物对制备离子通道的影响。所提出的装置还可以作为用于细胞培养和细胞群体特征的小型化平台，以及在培养室内计数和确定大小。基本的生物传感器是一个二维平面“膜片钳”，可用于感应离子通过离子通道的离子传输，生物颗粒的计数和大小，以及培养或分选细胞。我们相信所提出的生物传感器最终将通过测量单链DNA碱基序列通过纳米级孔时离子电流的变化来实现电子DNA测序，该孔是为了控制单链DNA而制造和大小的。我们提案的一个主要目标是开发一种生物电子界面，将生物离子通道集成到具有相关集成电子器件的“纳米井”中。该生物传感器将控制电子元件结合到低噪声、相关双采样（CDS）敏感信号读出器中，并配有开关电容“头级”前置放大器。片上电子器件将降低记录阻抗水平，最小化输出引线，防止串扰，并放大低电平离子通道信号。此外，生物传感器系统将能够快速、计算机辅助、自动测试和表征离子通道及其与药物的相互作用。该生物传感器还将能够对离子通道模型进行实验验证，并提供数据，这些数据可以用各种算法进行分析，以提取有关离子通道的时间和频率响应及其与药理药物研究的关系的信息。这项工作还将探索使用“片上”自适应信号处理，通过施加在细胞上的电压钳刺激实时电模拟生物细胞。

In biological research, the study of cellular functions in vitro is basic to other fields, such as clinical diagnostics, therapy, pharmacological drug screening, and environmental monitoring. In our proposal, biotechnology, silicon micromachining, microelectronics sensor and signal processing technology are used to realize a multi-purpose biological sensor with integrated lownoise signal processing. We research program to for culture, characterization and manipulation of biological cells in silicon chips. In particular, the proposed integrated biosensor system structure can be used as a planar patch-clamp setup for the experimental testing and evaluation of the effect of drugs on prepared ion channels. The proposed device can also act as a miniaturized platform for cell culture and characterization of a cell population together with counting and sizing within the culture chamber. The basic biosensor is a 2D planar 'patch-clamp', which can be employed for sensing the ion-transport through ion channels, the count and size of biological particles, and culturing or sorting cells. We believe the proposed biosensor will enable eventually electronic DNA sequencing through the measurement of ionic current changes as a sequence single-stranded DNA bases pass through a nanoscale pore, which is fabricated and sized to electrically control the single-stranded DNA. A major objective of our proposal is to develop a bio-electronic interface that integrates biological ion channels into a 'nanowell' with associated integrated electronics. The biosensor combines control electronics into a low noise, correlated-double-sampling (CDS)sensitive signal readout with a switched capacitor 'headstage' preamplifier. On-chip electronics will reduce the recording impedance levels, minimize the output leads, prevent crosstalk, and amplify the low-level ion-channel signals. In addition, the biosensor system will enable rapid, computer-aided, automated testing and characterization of ion-channels and their interaction with drugs. The biosensor will also enable experimental verification of ion channel models as well as provide data, which can be analyzed with various algorithms to extract information regarding time and frequency response of the ion channels and their relationship to pharmacological drug investigations. This effort will also explore the use of 'on-chip' adaptive signal processing to electrically model biological cells in real-time with voltage-clamp stimuli applied to the cells.