## 2 Latest Developed Biosensors for COVID-19
### Surface Plasmon Resonance (SPR)/Localised Surface Plasmon Resonance (LSPR) Biosensor
#### 2.2.1 SPR/LSPR Biosensor for COVID-19  
SPR and LSPR technologies have been explored for detecting the SARS-CoV-2 virus. Recent reports on these types of sensors show promising sensitivity with fast and reliable detection. In one of the recent works, a two-dimensional heterostructure, \(\text{PtSe}_{2}\)/Graphene, was attached to the gold film of the SPR sensor--the sensor configuration is shown in Figure 3A. The sensing region comprises three different ligand-analyte modes: (i) the monoclonal antibodies (mAbs) as ligand and the SARS-CoV-2 virus spike RBD as analyte, (ii) the virus spike RBD as ligand and the virus anti-spike protein (IgM, IgG) as the analyte and (iii) the specific RNA probe as ligand and the virus single-stranded RNA as analyte [35]. The sensor employed BK\({}_{7}\) type prism glass, which generates stronger surface plasmon waves at the metal-dielectric interface. The hetero-structure (\(\text{PtSe}_{2}\)/Graphene) provided an increased surface area for better adsorption of the target analyte, and hence enhanced sensitivity of the sensor. Graphene's high conductivity, large surface area and chemical stability improved interaction between the target analyte and the ligand [51]. It was observed that the sensitivity tend to increase by (1 + 0.55) \(\times\) L times for an increase of L number of graphene layers [35]. Using multiple graphene layers is promising in detecting different analytes such as virus spike RBD, antibodies (IgG or IgM) and viral RNA with a detection sensitivity of 183.33\({}^{\circ}\) RIU\({}^{-1}\), 153.85\({}^{\circ}\) RIU\({}^{-1}\) and 140.35\({}^{\circ}\) RIU\({}^{-1}\) in SPR angle, respectively. SPRi-based biosensors for detecting SARS-CoV-2 have also been developed. These sensors follow the principles of SPR and have been utilised to study binding kinetics between biomolecular species in the past [52; 53; 54]. SPRi assay was used for quantitative measurement of IgG, IgM and IgA antibodies binding to the RBD spike protein in serum sample [43]. RBD is an ideal target for blocking and neutralisation therapies. This is because viral infection occurs when the S protein on SARS-CoV-2 recognises and binds to the ACE2 receptor on the human host cell through its RBD [55]. Hence, this assay is ideally suited for monitoring the concentration of anti-RBD antibodies of both COVID-19 patients and healthy people who are vaccinated against SARS-CoV-2. Figure 2: (**A**) Typical Surface Plasmon Resonance (SPR) configuration, (**B**) Resonance angle after antibody immobilisation on sensor surface (\(\theta^{\prime}_{\text{SPR}}\)) and after analytes bind with immobilised antibodies (\(\theta^{\prime\prime}_{\text{SPR}}\)). The resonance angle shift is \(\theta^{\prime\prime}_{\text{SPR}}\)—\(\theta^{\prime}_{\text{SPR}}\). [PERSON] and co-workers [37; 38] demonstrated photothermal-assisted plasmonic sensing (PTAPS) for SARS-CoV-2 detection. Their biosensing device, as shown in Figure 3B, utilises LSPR for the detection of unamplified SARS-CoV-2 [37]. Two-dimensional gold nano-islands (AuNI) played the roles of nanoabsorber, nanoheater and nanotransducer. In this dual-functional system, AuNI functionalised with cDNA receptors were used to detect SARS-CoV-2 RNA through nucleic acid hybridisation. The entire AuNI sensing surface functionalised with a sufficient amount of thiol-cDNA receptor increased sensitivity and inhibit non-specific binding. Non-radiative decay of the resonantly-excited LSPs produces heat that is localised near the AuNI [56]. This plasmonic photothermal (PPT) effect aids the in-situ hybridisation of the RdRp-COVID sequence and its cDNA for SARS-CoV-2 detection. With the use of localised PPT heating, false positive is minimised as the imperfectly matched sequences have difficulty remaining attached to the probe. This LSPR sensor has a detection limit of 0.22 \(\pm\) 0.08 pM but is highly specific in discriminating the SARS-CoV-2 sequence from similar RdRp-SARS sequence. [PERSON] et al.