electrode and the working electrode create a potential difference in the solution, and a

current flows from the auxiliary electrode to the working electrode. In voltammetry, the

potential difference between the auxiliary and working electrodes is varied, and the current

between the two electrodes is examined. In impedance spectroscopy, the potential of the

working electrode is kept constant, and a sinusoidal voltage of fixed amplitude is applied to

the auxiliary electrode. The frequency of the sinusoidal signal is varied, and the output

signal frequency is examined rather than its amplitude. In potentiometric methods, the

electrochemical cell’s potential may be measured relative to a known reference potential,

with very little current flow. In amperometric methods, the intensity of the current flowing

through the electrochemical cell can be measured for a specific fixed potential.

An electrochemical biosensor consists of four functional components: an analyte, a

biorecognition element, a transducer, and an instrument. These components are needed,

independently of the method of analysis used. An analyte is a target of interest, such as a

protein or DNA. The biorecognition element is capable of selectively recognizing the

analyte. The transducer translates the interactions between the analyte and the bior­

ecognition element into an electrical signal. A typical transducer for electrochemical

biosensors is an electrode that converts an ionic current into an electrical current or a

voltage, depending on the method used. The instrument usually consists of electronic

circuitry that captures, amplifies, and records biorecognition signals from the transducer.

The analyte is typically in a liquid medium that consists of an electrolyte solution that

maintains the analyte’s biological activity and transports it to the transducer.

6.3.2 Miniaturization of Electrochemical Biosensors and Example CMOS

Electrochemical Biosensors

The miniaturization of electrochemical biosensors is slated to increase their role in the

diagnosis of various diseases, particularly in resource-limited settings. There are two

main approaches towards the miniaturization of electrochemical biosensors. A note­

worthy strategy is to use pre-existing hand-held instruments and modify them such that

they recognize biological components of interest that are different from those for which

they were originally intended. An example of such a biosensor is a glucometer that is

originally designed to detect blood glucose based on electrochemical signals generated by

redox reactions but that is retrofitted to recognize other analytes of interest. For instance,

the detection of non-glucose targets with a traditional miniaturized glucometer was

pioneered by Lu et al. [9]. They showed that by binding aptamers to targets with an

enzyme called invertase they could catalyze the hydrolysis of sucrose to glucose. Through

the generation of glucose catalyzed by invertase, a series of glucometer-based biosensors

were developed for a variety of analytical purposes such as the detection of disease

markers and the detection of DNA [10,11].

Another strategy, in scope with the present chapter, is to create miniature biosensor

systems based on CMOS sensors. Such an approach requires the integration of the in­

strumentation circuitry and the biorecognition element on the same CMOS chip.

Furthermore, an often overlooked but necessary component is the hardware necessary for

delivering the analyte to the sensor sites. Such hardware typically includes microfluidic

networks, and their integration with CMOS chips has been covered extensively, for ex­

ample by Huang et al. [12]. Below, we review a representative device that illustrates the

integration of electrochemical sensing into a CMOS platform.

The exemplary sensor was developed by Jafari et al. [13], and it was able to detect syn­

thetic DNA sequences consistent with biomarkers for prostate cancer (Figure 6.3). Unlike

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Bioelectronics