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Jung et al. Soft Sci 2024;4:15 https://dx.doi.org/10.20517/ss.2024.02 Page 21 of 44

platform combines wireless amperometric circuitry with a Bluetooth communication system to achieve
compactness and low-power operation [Figure 6E]. Featuring an isolated electrochemical detector to
prevent material leakage into the mouth, the device also includes a polymeric nipple equipped with a safety
rectifying channel for saliva sampling. As presented in Figure 6E, saliva measurements from diabetic
patients were conducted using the pacifier sensor 30 min post-meal. The signal observed in a fasting state
(b) was lower than after a meal (c). Furthermore, the ability of the device to detect glucose levels in diabetic
adults was examined and compared to their blood glucose levels, revealing a strong correlation and
affirming the effectiveness of the sensor.

ISF
In recent decades, a pronounced focus has been on developing wearable electrochemical sensors to monitor
ISF beneath the epidermal layer. This fluid, rich in essential ions, such as Na , K , and Cl , and metabolites,
-
+
+
including glucose and lactate, has emerged as a pivotal target for obtaining precise and rapid data on
glucose levels, rivaling blood as a primary source. ISF encapsulates the skin cells, facilitating nutrient supply
through direct diffusion from the capillary endothelium . This physiological mechanism establishes
[51]
reliable associations between the levels of various biomolecules in the blood and ISF, except for larger
molecules such as lipids . Given its ease of accessibility and robust correlation with the established gold
[237]
standard of blood sampling, a range of miniaturized wearable devices is designed for real-time sensing of
ISF [237-240] . Notably, commercially available options include Abbott’s FreeStyle Libre, DexCom G6,
TM
Guardian Sensor 3, A.Menarini Diagnostics GlucoMen Day CGM, and ISENS Caresens Air, specifically
designed for monitoring glucose levels in individuals managing diabetes [Table 6].

MNAs offer a minimally invasive approach for monitoring vital biomarkers in ISF. Sharma et al. developed
a glucose biosensor with a MNA electrode for continuous monitoring. The sensor devices were crafted
through casting structures in SU8 50, subsequent crosslinking, and metallization using platinum or silver for
the WE and RE, respectively. Functionalization included entrapping GO within an electropolymerized
X
polyphenol (PP) film. Scanning electron microscopy (SEM) images revealed MNAs with dimensions of
1,000 μm length, 600 μm base, 35 μm tip diameter, and 1,200 μm pitch. In Figure 7A, the sensor exhibited a
surge in current, reaching 4,500 nA in response to a glucose bolus (slice of cake) over 45 min, followed by a
decline. The figures demonstrated a correlation and time lag between capillary blood and dermal ISF.
Despite the focus on a minimally invasive design, in-vivo studies revealed operational challenges in securely
fixing the sensors in the sub-dermal space. Figure 7A on the right visually depicted artifacts from arm
[241]
movement, with a shorter duration than observed changes in glucose concentration .
Yang et al. developed a smartphone-controlled wearable continuous glucose monitoring (CGM) system
using microneedles . The system featuring a disposable glucose sensor and a reusable CGM device
[242]
employs a cost-effective fabrication method involving screen printing and laser cutting for double-sided
electrochemical three-electrode strips. The enzyme immobilization strategy uses a sandwich-type
configuration, including a protective biocompatible membrane and layers with carbon nanotubes (CNTs)
and Nafion. Glucose level fluctuations were monitored on day 1, day 7, and day 14 [Figure 7B], revealing a
rapid post-injection increase and return to normal levels within one hour in healthy rats. The CGM system
demonstrated similar profiles to a standard glucometer, with ISF glucose levels showing a typical delay of
approximately 10 min, attributed to dermal capillary density and slow epidermal metabolic activity.

Reverse iontophoresis (RI), recognized as another method for monitoring ISF nutrients, is an advanced
non-invasive technique involving extracting ISF to the skin surface using electrical currents through skin-
worn electrodes. This process induces an ion flux, primarily cations such as Na , across the skin, creating an
+
[243]
electroosmotic flow that transports neutral glucose molecules toward the cathode electrode .