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Page 4 of 44 Jung et al. Soft Sci 2024;4:15 https://dx.doi.org/10.20517/ss.2024.02
STRATEGIES FOR ELECTROCHEMICAL SENSING
Electrochemical biosensors assume a pivotal role in identifying biomarkers within biofluids, including
sweat, saliva, tears, and ISF, facilitating the delineation of risk stages in chronic diseases . Moreover, the
[97]
real-time monitoring of various DM-related parameters, such as glucose, lactate, uric acid, and electrolyte,
during daily life provides valuable data for assessing DM management of an individual [64,78] . The intricacies
of biomarker detection necessitate a systematic approach to sensor development, ensuring precision in
[98]
sensing and translating biomarker research into clinically applicable solutions . There are three different
types of electrochemical sensors: potentiometric [86-88] ; amperometric [89-91] ; voltametric [92-94] .

Conventionally, electrochemical sensors comprise three electrodes: the working electrode (WE), reference
electrode (RE), and counter electrode (CE) . Voltammetry, particularly cyclic voltammetry, is
[99]
acknowledged as a traditional electrochemical technique. This approach entails measuring the current
within controlled potential conditions. In contrast, amperometric sensors function as apparatuses dedicated
to quantifying the current resulting from the oxidation and reduction processes inherent in biochemical
reactions. Potentiometric electrochemical sensors are composed of two electrodes: the WE and RE . In
[100]
potentiometric measurements, these sensors assess the charge accumulation at the WE concerning the RE.
These types of electrochemical sensors comprise enzymatic and non-enzymatic sensors, and a wide range of
materials has been used in both enzymatic and non-enzymatic electrochemical biosensors such as enzymes,
antibodies, aptamers, molecular imprinted polymers (MIPs), and polymer-based ISM.

Enzymatic electrochemical sensing
Enzyme
Enzymes are crucial in constructing wearable electrochemical biosensors. Through simple enzymatic
reactions targeting biomarkers such as glucose, lactate, and uric acid, biosensors offer numerous advantages,
manifesting in cost-effectiveness, rapid result acquisition, and necessitating minimal sample volume for
measurement.

The fundamental concept of an enzyme-based biosensing electrode involves immobilizing enzyme
molecules in close proximity to an electrode surface. Among the enzyme families associated with
biomarkers for DM and its related complications, glucose oxidase (GO ) is commonly employed for glucose
X
monitoring in DM management . Similarly, lactate oxidase (LO ) and lactate dehydrogenase (LDH) are
[101]
X
[102]
[103]
used in developing lactate biosensors , while uricase is employed for uric detection . According to the
difference of electron transfer mechanisms, various architectural designs of enzyme-based electrochemical
biosensors measuring free electrons emitted from enzymatic reactions are illustrated in Figure 2A-C.
First-generation electrochemical biosensors utilize enzymes that catalyze reactions involving either the
consumption of electroactive reactants (e.g., O ) or the production of electroactive species (e.g., H O )
2
2
2
[Figure 2A]. The depletion of the target substrate (e.g., glucose, lactate, etc.) or the increase in the product
(electrochemically active H O ) is then monitored to determine the concentration of the target analyte. The
2
2
current, which is directly proportional to the concentration of biomarkers, arises from the oxidation of H O
2
2
at the WE. It is important to note that oxygen serves as the physiological electron acceptor in this oxidase-
based concept. First-generation biosensors have demonstrated remarkable sensitivity and are distinguished
by exceedingly short response times, typically on the order of one second [104] . Nevertheless, the
stoichiometric constraints of oxygen and the inherent fluctuations in its levels within biofluids may
introduce inaccuracies in this initial conceptualization . Additionally, the exigency of a high potential for
[105]