Real-time imaging of microparticles and living cells with CMOS nanocapacitor arrays

Massively parallel, label free biosensing platforms can in principle be realized by combining all-electrical detection with low-cost integrated circuits. Examples include field-effect transistor (FET) arrays used for mapping neuronal signals1,2 and DNA sequencing3,4. Despite these remarkable successes, however, bioelectronics has so far failed to deliver a broadly applicable biosensing platform, in no small part because DC or low-frequency signals do not allow probing beyond the electrical double layer (EDL) formed by screening salt ions5-8. This entails that, under physiological conditions, the sensing of target analytes located even a short distance from the sensor (~1 nm) is severely hampered. Here we demonstrate theoretically and experimentally the ability to detect and image microscale entities at long range under physiological salt conditions using high-frequency impedance spectroscopy with unprecedented spatial and temporal resolution. The assay employs a large-scale, high-density array of nanoelectrodes integrated with CMOS electronics on a single chip. The sensor response depends on the electrical properties of the analyte, allowing impedance-based fingerprinting. We also image the dynamic attachment and micromotion of BEAS, THP1 and MCF7 cancer cell lines in real time at submicron resolution in growth medium, demonstrating the potential of the platform for label/tracer-free high-throughput screening of anti-tumor drug candidates