Optimization of CMOS-ISFET-Based Biomolecular Sensing: Analysis and Demonstration in DNA Detection

Ion-sensitive field-effect transistors (ISFETs) have been used to detect a variety of biomolecules whose charges alter the current or threshold voltage of the transistor. ISFETs can be built into large-scale arrays by CMOS compatible technology, offering the promise of highly parallel, all-electrical biomolecule sensing in a true chip-scale construct. Although CMOS-ISFET-based biomolecule detection has been amply demonstrated, a comprehensive optimization study of its sensitivity based on the device design, which would aid the development of large-scale arrays, remains lacking. Here, we present a systematic optimization strategy for CMOS-ISFET-based biomolecule sensing, using real-time DNA hybridization detection as an example. We analytically show that biasing the ISFETs close to the threshold is optimal, whereas minimizing the channel-to-sensing area ratio is beneficial but with limited sensitivity enhancement due to the double-layer capacitance of the sensing area. We then experimentally confirm our strategy with 26 ISFETs of varying sizes and biases from two CMOS chips, which detect the same 200-nM target DNA with different hybridization signals. The measured data correlate well to the presented theory. Our results are generally applicable to detecting other types of biomolecules, and may help in developing large-scale arrays of electrical biomolecular sensors.