# Advancements in Glucose Monitoring: From Traditional Methods to Wearable Sensors
## 4 Non-Invasive Methods
### Reverse iontophoresis  
Reverse iontophoresis is a transdermal technique, where glucose is extracted through intact skin by electro-osmotic flow (a process called \"reverse iontophoresis\"). In 1991, [PERSON]'s group proposed to use reverse iontophoresis to extract glucose through the skin for the diagnosis of diabetes, initiating the development of the technology [83]. A low electric current is applied across the skin between two electrodes. Since glucose is uncharged, its transportation occurs through electro-osmosis (Figure 9a) [84]. At the physiological pH, the skin carries a net negative charge, causing Na+ ions to be the primary charge carriers. The movement of these Na+ ions generates a convective solvent flow, which transports uncharged molecules like glucose towards the iontophoretic cathode [85]. The Cygnus GlucoWatch reverse iontophoresis sensor was the first transdermal glucose sensor licensed by the US Food and Drugs Administration (FDA) [85; 86]. In clinical trials, it showed an adequate precision for home blood glucose monitoring [87]. However, it was not useful for the detection of hypoglycemia with a sensitivity of 23% for glucose concentrations of \(\leq\)3.3 mmol/L and a 51% false alarm rate [88]. The device was withdrawn in 2008. With the advancements in flexible electronics, several transdermal miniaturized iontophoresis interfaces have been developed to monitor glucose through sweat, with im  
Figure 9: **(a)** The schematic illustration demonstrating the reverse iontophoresis process. Reprinted with permission from [84]. **(b)** (i) The depiction of the wearable glucose-sensing platform, containing the electrode array unit and wireless flexible printed circuit board (FPCB). **(ii)** The depiction of the electrodes used for iontophoresis and sweat sensing, designed to detect Na+ and Cl – concentrations. Reprinted with permission from [89]. **(c)** (i) The image of the smartphone-integrated Glucose Electrochemical Detection Platform (GEDP). **(ii)** The image of the wireless electrochemical detector linked with the touch-activated glucose sensor for reverse iontophoresis (RI) extraction and electrochemical glucose measurement. **(iii)** The schematic representation of the smartphone-based GEDP, comprising the touch-activated glucose sensor with integrated microneedle array (MA) and RI, wireless electrochemical detector, and Android-based app for transdermal glucose monitoring. Reprinted with permission from [90]. proved sensitivity [89; 90]. For example, the electrochemically enhanced iontophoresis interface developed by [PERSON] et al. can stimulate sweat secretion and measure various analytes present in the collected sweat (e.g., glucose, Na+, and Cl-) (Figure 9b(i)) [89]. The integration of sensing electrodes on the same substrate as the iontophoresis electrodes has helped to analyze sweat onsite and in real time. As illustrated in Figure 8b(ii), the sensing device consists of an array of electrodes designed for both sweat induction and sensing, which are integrated with a wireless, flexible printed circuit board (FPCB) [89]. The design ensures that the sweat sensing and sweat induction functions operate separately, allowing each to function independently without interfering with the other. Although the wearable sensing platform showed a promising way for non-invasive glucose monitoring, the sensitivity of this sensor was low (2.1 nA/uM). [PERSON] et al. developed touch-activated glucose biosensor for monitoring glucose levels in the interstitial fluid (ISF) with improved sensitivity [90]. The glucose sensor consists of a microneedles array (MA) for painless skin penetration, a reverse iontophoresis (RI) unit for extracting ISF, and a sensing unit for glucose detection (Figure 9c) [90]. The glucose-sensing unit was prepared by immobilizing glucose oxidase (GOD) in the agarose gel at the working electrode. This biosensor operates based on the process of skin penetration, RI extraction, and electrochemical detection [90]. The sensitivity of the glucose sensor was reported as 7.76 uA mM-1.