# Advancements in Glucose Monitoring: From Traditional Methods to Wearable Sensors
## 3 Minimally Invasive Methods
### Microneedle Array  
The minimally invasive microneedle array became widely popular owing to its advantage of minimizing tissue trauma or fibrosis after implantation. These implantable microneedles have a diameter in the micrometer range and a length of under 1 mm [77]. The microneedle arrays, made up of several tiny, neatly arranged needles, typically penetrate the stratum corneum and reach the dermis without affecting blood vessels or nerves [77]. Over the last two decades, there has been extensive research into the design and fabrication of microneedles, leading to the exploration of various microneedle structures. For example, [PERSON] et al. designed the CGM device by integrating an ultra-miniaturized electrochemical-sensing probe inside the single hollow microneedle [49]. Their device reported a sensitivity of 1.5 nA/mM with a linearity of up to 14 mM of glucose concentration. The in vivo human test revealed reduced discomfort and high accuracy in real-time monitoring (Figure 8a) [49]. In another study, [PERSON] and his team introduced a wearable CGM system based on microneedles that can be controlled via a smartphone to monitor glucose concentration in real time [78]. The system uses hollow microneedles to access ISF and detect subcutaneous glucose levels. Flexible sensing electrodes, fabricated through screen printing and laser cutting, ensure good sensitivity and stability in glucose monitoring. This glucose sensor uses a sandwich-type enzyme immobilization strategy to detect the glucose level in vitro with a relative standard deviation (RSD) of 4.8%, indicating the accuracy of this sensor (Figure 8b) [78]. Figure 8: **(a)** (i) A cross-sectional illustration showing the developed CGM device inserted into the skin. The sensing probe is placed within a hollow microneedle lumen, with the sensing electrodes  
positioned towards the opening, facilitating the diffusion of substances to and from the dermal interstitial fluid. (**ii**) A closer view of the three sensing electrodes aligned with the lateral opening of the microneedle. Reprinted with permission from [49]. (**b**) (**i**) The illustration of CGM system combined with a customized smartphone app, a reusable CGM device, and an MN-based glucose sensor. The expanded view of the CGM device with its main components, including the cap, holders, PCB, battery, and cover. (**ii**) The schematic illustration of the CGM device combined with a glucose sensor for transdermal ISF glucose detection. Reprinted with permission from [78]. (**c**) Wireless glucose sensor. (**i**) The sensor patch is shown adhered to the arm of the wearer. (**ii**) A cross-sectional illustration displays the sensor patch with microneedles penetrating the skin to reach the epidermis, alongside a schematic of the microelectrode configuration used in the multiplexed sensor component. (**iii**) The back view of the microneedle sensor patch, with an exploded view highlighting the corresponding subcomponents. (**iv**) The front view of the sensor patch displays the two main parts--the disposable sensor array and the reusable electronics. Reprinted with permission from [79]. (**d**) The schematic illustration of glucose responsiveness for the self-regulated release of insulin and the real-time glycemia monitoring visible to the naked eye. (**i**) Insulin mineralization through Ca2+ ions. (**ii**) A bifunctional microneedle array patch fabricated using crosslinking and micro-molding techniques. Reprinted with permission from [80]. [PERSON] and his team further advanced the field by developing a fully integrated, wearable microneedle array for wireless, continuous, and real-time monitoring of two metabolites in ISF throughout daily life [79]. This system consists of two primary components, i.e., a \"disposable sensor\" and a \"reusable electronic device\", which can be disassembled into nine separate parts. When the sensor becomes worn out, the low-cost \"disposable sensor\" can be replaced, enabling continuous metabolic sensing.