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Jung et al. Soft Sci 2024;4:15 https://dx.doi.org/10.20517/ss.2024.02 Page 27 of 44

[257]
detection limit of 50 μM in artificial ISF . Furthermore, Moon et al. from the same group reported a
touch-based sweat HB detection method, which relies on collecting fingertip sweat and transporting the
sweat to a biocatalytic layer through a porous poly(vinyl alcohol) (PVA) hydrogel [Figure 9F]. The response
on sweat HB was enhanced by mediating the oxidation reaction of NADH. A dual disposable biosensing
device, integrating with ketone and glucose sensors, was demonstrated within healthy human subjects by
simultaneously measuring the change of sweat HB and glucose levels during the intake of ketone
supplements and glucose drinks .
[258]

Insulin is another significant biomarker for diagnosing DM, but the detection of insulin using a non-
invasive wearable platform has some limitations due to extremely low concentrations in biofluids and
interference from constituents in blood. Moreover, for detecting glucose and insulin simultaneously to
improve the glycemic control and personalized health monitoring, a major challenge relies on integrating
enzymatic and immunosensing electrochemical detection methods into a single system. Vargas et al., from
the group led by Wang, addressed the different assay requirements by fabricating dual diabetes biomarker
chip [Figure 9G]. Glucose detection was performed amperometrically through the biocatalytic oxidation of
glucose, and insulin detection was conducted through the sandwich immunoreaction assay using
horseradish peroxidase (HRP) as an enzymatic label and 3,3’,5,5’-tetramethylbenzidine (TMB)/H O as the
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mediator/detection system. The glucose and insulin chip showed a considerable promise by accurately
measuring two biomarkers with large concentration differences in blood and saliva . Recently, Liu et al.
[259]
developed an electrochemical aptasensor on carbon electrode, which enables real-time detection of glucose
and insulin in saliva using two thiolated aptamers targeting glucose and insulin, respectively [Figure 9H].
The real-time detection was realized with a portable and wireless interface and demonstrated the sensing
performance of the linearity in the range of 0.1-50 mM for glucose [limit of detection (LOD), 0.08 mM] and
0.05-15 nM for insulin (LOD, 0.85 nM) .
[260]

Cortisol is a glucocorticoid hormone that is significant for regulating glucose metabolism. In order to keep
the glucose amounts in plasma, it increases the expression of glucogenesis-related enzymes. Moreover,
according to recent studies, insufficient pancreatic insulin secretion may result from the disturbance in the
[261]
circadian rhythm caused by cortisol . Therefore, the simultaneous monitoring of glucose and cortisol can
play an important role in better forecasting the onset of diabetes and/or stress-related symptoms. Munje
et al., from the group led by Prasad, developed a wearable electrochemical biosensor for the multi-
biomarker detection of glucose and cortisol in sweat [Figure 9I]. Ultrasensitive detection of low-volume
glucose and cortisol was realized with stacked metal/metal-oxide thin films within porous polyamide
substrates. Monoclonal GO and cortisol antibodies were used to bind to GO enzyme and cortisol antigen
X
X
molecules, respectively. Combinatorial detection of glucose and cortisol was demonstrated through
electrochemical impedance spectroscopy with LOD of 0.1mg/dL in human sweat . Very recently, Tian et
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al., from the group led by Zhang, engineered a fully integrated system for cortisol biosensing with an
antibody-oriented immunosensor in human sweat [Figure 9J]. This system was demonstrated with several
volunteers that it has a good linear range from 1 pg/mL to 1 μg/mL (LOD, 0.26 pg/mL). Furthermore, the
immunosensor showed relatively long-term stability with only 4.1% decay after nine days of storage .
[263]
Alcohol and many other nutrients, such as amino acids and vitamins, can be additional factors for DM
monitoring in terms of various food intake activities . Kim et al., from the group led by Wang, presented a
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wearable device capable of measuring sweat-alcohol and ISF-glucose in human subjects while intaking food
and drinking alcohol [Figure 9K]. This platform allowed on-demand sampling and analysis of two different
biofluids, sweat and ISF, through sweat stimulation at an anode and ISF extraction at a cathode. The dual
measurements of sweat-based alcohol and ISF-based glucose demonstrated good correlations of their blood