# Advancements in Glucose Monitoring: From Traditional Methods to Wearable Sensors
## 2 Invasive Methods
### Ion-Selective Field-Effect Transistor (ISFET)  
Invasive ISFET glucose sensors are used to measure blood glucose levels by inserting the sensors into the skin to measure interstitial fluid glucose levels. An ISFET-based glucose sensor uses the principle of hydrogen peroxide electrolysis, which is one of the by-products of glucose oxidation. The ISFET sensor typically consists of a transducer along with a sensing element. The sensing film is usually defined as the gate of ISFET. The gate materials on the sensing film determine the sensing performance of the ISFET. A preliminary design of common ISFET is shown at Figure 4a(i) [43]. In 1996, [PERSON] et al. developed an ISFET-based glucose sensor by crosslinking a mixture of glucose oxidase and bovine serum albumin in saturated glutaraldehyde vapor on the sensitive area of the transducer [44]. Recently, [PERSON] et al. reported a low-power, portable, real-time glucose-sensing device with dextran-capped silver nanoparticles (Dex-AgNPs) served as sensitive nanoprobes on the ISFET gate (Figure 4a(ii)) [43]. The have utilized the affinity between Con A and carbohydrates to capture Con A by ISFET/Dex-AgNPs system. Then, glucose can be indirectly detected by removing Con A from the ISFET/Dex-AgNPs/Con A unit via competition with dextran [43]. In a different approach, a silk fibroin-encapsulated graphene field-effect transistor (FET) enzymatic biosensor was developed for glucose detection [31]. It detects glucose levels by measuring the differential drain-source current and the Dirac point shift in the graphene transistor, as glucose is oxidized by glucose oxidase immobilized in the silk fibroin film on the graphene FET (Figure 4b(i-iv)). The glucose sensors has a linear detection range over 0.1-10 mM, with a detection limit of 0.1 mM [31]. To improve the sensitivity of this technique, [PERSON] et al. modified the sensing component, by immobilizing glucose oxidase-containing silk fibroin membrane on a TiO\({}_{2}\)/Ti surface as the bio-sensing component. This TiO\({}_{2}\)/Ti extended gate electrode field-effect transistor (EGFET) reported detection limit as 0.001 mg/mL [29]. [PERSON] et al. developed ZnO nano-array-based EGFETs for detecting pH and glucose levels [45]. Their sensor reported a very fast response time of approximately 6-7 s. The schematic illustration of ZnO nano-array and the incorporation of ZnO nano-array in EGFET circuit in shown in Figure 4c(i) and Figure 4c(ii), respectively [45]. With its high specific surface area, the ZnO nano-array EGFET sensor showed a sensitivity of \(-0.395\) mV/uM for glucose detection within a concentration range of 20 to 100 uM. These EGFET glucose biosensors exhibit good linearity and can detect glucose at low concentrations (as low as 20 uM), making them suitable for detecting glucose in saliva and tears at concentrations lower than those typically found in blood. To improve portability and reusability, [PERSON] et al. designed a polymer-functionalized graphene field-effect transistor (P-GFET) portable bio-sensing device for glucose monitoring. The polymer is synthesized using acrylamide/3-acryladipphenylboronic acid (AAPBA)/N and N-dimethylaminopropyl acrylamide [46]. The SEM and AFM image of graphene before and after functionalization is shown in Figure 4d(i). In the presence of glucose, the P-GFET exhibits shifts in the Dirac point and changes in current due to the formation of a covalent bond between glucose and AAPBA in the synthesized polymer on the graphene surface (Figure 4d(ii,iii)). The P-GFET demonstrates a high sensitivity of 822 uA\(\cdot\)cm\({}^{-2}\cdot\)mM\({}^{-1}\) and a detection limit of 1.9 uM for glucose monitoring in human urine. The sensor covers a detection range of 0.04-10 mM and exhibits excellent reusability, maintaining its per formance over 20 cycles. These advancements highlight the promise of ISFET sensors in providing highly sensitive, specific, and versatile glucose-monitoring solutions.