oa CMOS Integrated Circuits for DNA Sensing

Background

With the advance of semiconductor technologies, bio-technological application-specific integrated circuits (ASICs) have become a major trend of the industry. Examples include Microelectrode measurement array systems for in-vitro and in-vivo physiological research at the cellular level [1] [2]. Using DNA microarrays can lead to a high throughput, which finds wide applications in genome research and drug development [3].

Objective

This paper presents a DNA detection CMOS micro-array, which can help in detection of presence of specific DNA sequences. The array is comprised of 16 × 16 sensor sites (interdigitated electrodes), each with a dedicated readout circuit, which enables fast parallel measurements. The use of CMOS processes results in much more cost effective solution as opposed to the optical systems that are currently used in DNA detection. The proposed IC also utilizes a minimal number of electrical signals, and can be easily interfaced to the outside world.

Method

Figure 1 shows the proposed sensor and readout. The single stranded DNA probe molecules can be immobilized on the sensor sites, after target molecules are added to the chip, which causes hybridization in case of a match between the receptor and probe (Fig. 2). After the addition of a suitable substrate, a RedOx reaction can be initiated on the matching sites, by the application of a suitable potential [3]. The resultant current is then fed to a Current Mode Sigma Delta ADC for digital conversion.

Typical values of the current from the redox reaction range from a few pA to the nA range, which entails the use of a high resolution ADC. Sigma Delta ADCs are capable of achieving such resolution at the expense of smaller conversion frequency. However, even a conversion time of a few seconds (which is sufficient to obtain > 15 bit resolution) should be enough in this particular case.

A typical Sigma Delta Modulator is shown in Fig. 3. The input current from the Electrode array is integrated in a current mode integrator, which is enclosed in a feedback loop. The reference current (IREF) can be generated using an on-chip bandgap reference circuit [5].

Conclusion

The use of CMOS arrays and readout circuits for biotechnological applications is a very promising field. On chip A/D conversion provides a compact alternative to bulky expensive DNA detectors. Both the array as well as the sigma delta ADC consume very low power, and the whole system can be designed to achieve sub mW power consumption.

Moreover, the integration of frontend and detection on a single substrate with minimal post-processing presents a highly cost effective solution to the optical systems widely in use. CMOS sensors can also provide higher sensitivity and reliability than their optical counterparts.

References

[1] J. Guo, J. Yuan, J. Huang, J. K. Y. Law, C.K. Yeung, and M. Chan, “29.2nV/rt Hz -59.6dB THD dual-band micro-electrode array signal acquisition IC”, IEEE J. Solid-State Circuits (JSSC), Vol. 47, pp. 1209–1220, May, 2012.

[2] J. Guo, J. Yuan, and M. Chan, “Modeling of the cell-electrode interface noise for microelectrode array measurement”, IEEE Trans. Biomedical Circuits and Systems (TBCAS), Vol. 6, pp. 605–613, Nov. 2012.

[3] Stagni, C.; et al”CMOS DNA Sensor Array With Integrated A/D Conversion Based on Label-Free Capacitance Measurement,” in Solid-State Circuits, IEEE Journal of, vol.41, no.12, pp.2956–2964, Dec. 2006.

[4] Schienle, M.; Paulus, C.; Frey, A.; Hofmann, F.; Holzapfl, B.; Schindler-Bauer, P.; Thewes, R., “A fully electronic DNA sensor with 128 positions and in-pixel A/D conversion,” in Solid-State Circuits, IEEE Journal of, vol.39, no.12, pp.2438–2445, Dec. 2004.

[5] Bo Wang; Man Kay Law; Bermak, A., “A Precision CMOS Voltage Reference Exploiting Silicon Bandgap Narrowing Effect,” in Electron Devices, IEEE Transactions on, vol.62, no.7, pp.2128–2135, July 2015