cell-substrate impedance spectroscopy (ECIS) has been widely used to monitor cells in

real time and without the use of labels. The technique relies on the basic application of

Ohm’s law to a two-electrode system [27–29]. The cells in impedance sensors can be in

contact with the electrodes by adhering directly to the electrodes or they can be in sus­

pension. The presence or absence of a cell, the location of the cell, and the shape and size

of the cell all affect the electric field lines between two electrodes. The cells’ interactions

with the field lines are recorded as a change in current, and the relationship between this

change in current and the applied voltage is recorded as the impedance.

Although impedance sensing has a significant advantage of being label-free and af­

fording real-time monitoring, the technique lacks specificity. For example, cells moving

farther away in the vertical direction from an electrode may give a similar impedance

measurement compared to cells that are shrinking (smaller impedance) but are near the

electrode. Despite this, impedance sensing is useful for monitoring populations of cells

over time, and it provides another method for label-free imaging of cells. Furthermore,

since the internal cellular environment affects cell morphology, impedance sensing is

useful for monitoring, for example, the effects of external stimuli on cells and overall cell

viability. Cell types can also be differentiated, and this capability can be useful in ap­

plications such as differentiating cancer cells from healthy cells. Potentially, even iden­

tifying different stages of the disease, such as early-stage versus metastasized cancer cells

can be performed using impedance sensing.

6.4.4 Examples of Applications of CMOS ECIS Sensors

An example application of an impedance sensor was demonstrated by Jung et al. [30].

They showed a multi-modal array for simultaneous extracellular potential, impedance,

and optical sensing. The chip used a 4-point impedance measurement based on the

swept frequency approach over a 15 kHz to 500 kHz range. The design used SAR ADCs

and four pixels were selected from a bank of pixels for each differential mode mea­

surement of the complex impedance. The design was implemented in a 0.13 μm CMOS

process and contained 21,592 pixels with a 16 μm × 16 μm pitch and gold-plated

electrodes. The chip was able to produce an impedance image of neonatal rat ven­

tricular myocytes.

6.5 Image Sensors

CMOS image sensors are ubiquitous in consumer electronics products, notably in cell

phones. High-performance CMOS image sensors are now increasingly being considered

for biosensing applications. Compared to charge-coupled devices (CCDs), CMOS image

sensors have lower power consumption and can be implemented using a system-on-a-

chip framework. These features offer the possibility for integrating them in biosensing

platforms as a means for optical sensing via fluorescence sensing, direct contact imaging,

or luminescence imaging [31–40]. These imagers typically use active pixel sensors [41] as

the pixel configuration for intensity-based detection or single-photon avalanche diodes

for time-resolved detection [39], [40], [42–48]. In this section, we discuss the basic ar­

chitecture of CMOS image sensors and their design, and we discuss several example

applications.

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Bioelectronics