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Jung et al. Soft Sci 2024;4:15 https://dx.doi.org/10.20517/ss.2024.02 Page 11 of 44

exponential enrichment (SELEX) process, which involves selecting specific ligands. They are known for
their ability to fold into unique spatial configurations, granting them the specificity to bind to a wide array
of target molecules such as proteins, small molecules, and even cells. This binding capability is especially
valuable for targets that are challenging for antibodies to recognize due to their intricate structures or other
biochemical complexities . This high affinity and specificity make them particularly suitable for use in
[163]
sensors. A common mechanism associated with E-AB sensors is illustrated in Figure 3B. Initially, aptamers
are immobilized on the electrode surface, maintaining their ability to undergo conformational changes
upon binding to the target analyte. Upon introduction of the target molecule, the aptamer binds to it,
undergoing a conformational change that alters the spatial orientation or the distance between the electrode
surface and a reporter molecule, typically a redox-active compound, which is either part of the aptamer
structure or closely associated with it. This change in spatial configuration or distance affects the electron
transfer rate between the redox reporter and the electrode, a phenomenon meticulously captured by the
sensor. Specifically, the target binding event leads to either an increase or decrease in the electron transfer
rate, depending on the nature of the conformational change. This, in turn, causes a change in the
electrochemical signal, typically measured as a change in current, potential, or impedance. The
electrochemical signal is then recorded and quantified, correlating directly with the concentration of the
target analyte in the sample. The specificity of the aptamer for its target ensures that the sensor response is
highly selective, while the versatility of the aptamer structure allows for the detection of a wide range of
targets, from metal ions [164,165] to protein molecules [166,167] . Despite the impressive capabilities of E-AB sensors,
challenges such as the necessity for specific aptamer sequences for each target and potential for non-specific
binding do exist . However, ongoing advancements in aptamer selection [169-171] , strategies for preventing
[168]
non-specific binding , and immobilization strategies [173,174] are progressively refining these sensors,
[172]
enhancing their specificity, sensitivity, and practical applicability.

MIPs
MIPs are engineered as synthetic receptors, offering a high specificity for target molecules in
electrochemical biosensing applications. The synthesis of MIPs entails arranging monomers around a
preselected template molecule. Following polymerization and the subsequent removal of the template, the
process yields tailored cavities that correspond in shape and functional group orientation to the target
molecule. These cavities serve as binding sites for the analyte, causing a detectable electrochemical signal
shift that is directly proportional to the analyte concentration in the sample .
[175]
Figure 3C delineates the MIP synthesis stages. The process begins with the strategic assembly of functional
monomers around a template molecule. After polymerization, with a cross-linker to reinforce the structure,
the template is extracted, leaving behind cavities that are primed for the selective re-association with the
target analyte .
[176]

In the context of electrochemical biosensing, MIPs offer several advantages over biological receptors such as
antibodies and aptamers. Unlike these biological counterparts, MIPs are synthesized to be inherently more
stable across a broad spectrum of environmental conditions, including extreme pH, temperatures, and
solvent compositions . Their robust nature ensures longevity and reusability, which are significant
[177]
benefits for practical applications.

However, MIPs also exhibit certain limitations. Their inherent insulating nature can inhibit sensitivity due
to poor mass transfer, or challenges such as incomplete removal or saturation of the MIP matrix when
[178]
exposed to a sample containing the target . These issues not only affect the sensitivity of the sensor but
also its reusability, often necessitating design modifications to enhance performance.