*2.3.5 Application of nanotechnology in electrochemical biosensors*

In electrochemical biosensors, nanomaterials are mainly applied for modifying the sensitive interface of the biosensors or immobilizing biomolecules. Because of its large specific surface area and high surface energy, nanomaterials can become an

#### **Figure 4.**

*Schematic diagram of rapid direct identification of SARS-CoV-2 using the PMO-functionalized G-FET nano-sensors.*

#### *Perspective Chapter: Novel Diagnostics Methods for SARS-CoV-2 DOI: http://dx.doi.org/10.5772/intechopen.105912*

active electron acceptor or electron donor. The electrode modified by nanomaterials can significantly improve the specific surface area of the electrode, improve the conductivity of the electrode, load more biomolecules, improve the sensitivity and stability of the biosensors, and speed up the response of the biosensor [49].

Nanomaterials commonly used in electrochemical biosensors include noble metal nanomaterials, carbon nanotubes, graphene, magnetic oxide nanoparticles, and so on. Noble metal nanoparticles represented by gold nanoparticles not only have large specific surface area and high surface energy, but also have high catalytic efficiency, strong adsorption, and excellent biocompatibility, which can effectively load and label target biomolecules. In addition, gold nanoparticles have excellent electrochemical activity and can effectively improve the electron transmission efficiency. Au nanoparticles can also form strong covalent binding through Au-S bond and Au-N bond, which is conducive to the coordination of biomolecules containing -SH and -NH2. Carbon-based materials such as carbon nanotubes and graphene have large specific surface area and strong electron conduction ability. The modification of this kind of carbon-based nanomaterials can greatly improve the electrochemical activity of the electrode, improve the detection sensitivity, increase the current signal, and improve the response time of the electrochemical biosensors [50]. Magnetic nanoparticles can be modified on the surface of the electrode to improve the specific surface area of the electrode, which can also be applied for immobilizing biomolecules to improve the selectivity and specificity of electrochemical detection and avoid the interference of other impurities in the biological environment to the target molecules.

#### **2.4 Magnetic biosensors**

Magnetic biosensors have attracted extensive attention of researchers in the past two decades. The biosensors can be divided into surface-based and volume-based magnetic biosensors, which are widely used in the detection of viruses, pathogens, and cancer biomarkers [51–53]. In magnetic biosensors, magnetic nanoparticles modified by suitable antibodies or DNA/RNA probes are usually used as magnetic nanotags, which can skillfully convert the concentration of analytes into magnetic signals [54]. Compared with optical, plasma, and electrochemical biosensors, magnetic biosensors have lower background noise. Because the biological environment of most biomolecules is non-magnetic, the magnetic biosensors will not be disturbed by the biological environment, so as to produce more accurate and reliable detection results [55]. Magnetic biosensors can be roughly divided into three categories: magnetoresistive (MR) biosensors, magnetic particle spectroscopy (MPS) platforms, and nuclear magnetic resonance (NMR) platforms.

#### *2.4.1 Magnetoresistive biosensor*

Magnetoresistive biosensor is a surface-based sensing technology, which is very sensitive to the stray field from generated by magnetic nanoparticles close to the sensor surface, so as to convert the binding of magnetic nanoparticles with analytes into readable electrical signals [56, 57]. Magnetic nanotags in magnetoresistive biosensors need to produce high magnetic moment without losing paramagnetic properties.

At present, there are few studies on magnetoresistive biosensors for the detection of SARS-CoV-2, and we infer main reason is that magnetic nanoparticles would inevitably reduce the magnetic moment when their size decreases. Jinhong Guo's team at the University of Electronic Science and technology of China [58] constructed

an LFIA detection platform based on superparamagnetic nanoparticles and giant magnetoresistive sensing system to detect the immunoglobulin IgM and IgG of SARS-CoV-2 at the same time. Among them, the giant magnetoresistive sensing platform can transmit medical data to smart phones through Bluetooth, which is convenient for medical personnel to obtain patient information. Superparamagnetic nanoparticles with an average size of 68 nm were synthesized by a simple and rapid coprecipitation method with excellent dispersion and magnetic properties. This sensing technique has the advantages of low cost, rapidity, easy operation, and high sensitivity, which can simultaneously detect two antibodies of SARS-CoV-2 within 10 min with the LOD of 10 ng/mL for IgM and the LOD of 5 ng/mL for IgG.

#### *2.4.2 Nuclear magnetic resonance (NMR) platform*

The nuclear magnetic resonance (NMR) platform uses magnetic nanoparticles as contrast enhancer, which causes the nonuniformity of local magnetic field and disturbs the precession frequency variations of surrounding water protons [59]. Therefore, the development of high-sensitivity NMR platform essentially depends on the application of appropriate magnetic nanoparticles with high transverse relaxation.

Siwei Yang's team of Shanghai Institute of Microsystems and Information Technology, Chinese Academy of Sciences [60] reported a rapid and highly sensitive detection of SARS-CoV-2 pathogens based on ultralow-field NMR relaxometry (**Figure 5a**). This method utilizes magnetic graphene quantum dots modified by SARS-CoV-2 antibody as a probe to construct a magnetic relaxation switch to specifically detect novel coronavirus. It is worth noting that closed-tube one-step strategy is safer for experimenters without samples preparation. This one-step detection method has the characteristics of excellent sensitivity and rapid detection with 248 particles/ mL within 2 min.

NMR spectroscopy, like infrared spectroscopy and Raman spectroscopy, can analyze the structure of the molecules to be measured. Different from infrared spectroscopy and Raman spectroscopy, which can directly reflect the molecular structure information, NMR spectroscopy obtains the skeleton structure of the molecules to be tested by analyzing the <sup>1</sup> H, 13C, and 15N NMR spectra. Nuclear magnetic resonance spectroscopy is also widely applied to the screening of antibodies of SARS-CoV-2 and the characterization of protein and nucleic acid structures. Magnetic nanoparticles can be used as a signal amplification tags in this technology to improve the sensitivity of detection. Schoenle et al. [61] reported the sequence-specific backbone assignment of the SARS-CoV-2 RBD and proved that biomolecular NMR spectroscopy chemical shift perturbation (CSP) mapping can quickly and successfully identify the molecular epitopes of RBD-specific antibodies. CSP mapping combined with other detection technology of biomolecules could help us accurately recognize the interaction between RBD and antibody, which is of great significance for antibody screening and further vaccine development.

#### *2.4.3 Magnetic particle spectroscopy platform*

Magnetic particle spectroscopy platform is a volume-based detection technology, which directly detects the dynamic magnetic responses of magnetic nanoparticles [62, 63]. Therefore, for this kind of biosensor, the properties of excitation magnetic field, saturation magnetization, and anisotropy should be considered. Rosch et al. [64] reported a novel SARS-CoV-2 nucleic acid detection platform based on

*Perspective Chapter: Novel Diagnostics Methods for SARS-CoV-2 DOI: http://dx.doi.org/10.5772/intechopen.105912*

#### **Figure 5.**

*a: The detection process of SARS-CoV-2 of the magnetic relaxation switches assay with ULF NMR. b: The schematic diagram of the detection of SARS-CoV-2 RNA based on magnetic particle spectroscopy biosensors.*

magnetic response changes of magnetic nanoparticles (**Figure 5b**). The specific modified magnetic nanoparticles and target molecules mediated assembling will lead to the increase of hydrodynamic radius, which can be measured by the magnetic particles spectrum in alternating magnetic field. This sensing technology has high sensitivity for the detection of SARS-CoV-2 RNA, with LOD of 0.28 nmol/L, and the biological environment such as saliva will not affect the performance of the detection platform.

Compared with optical biosensors, magnetic biosensors have simpler sample processing steps in the detection process, and magnetic tags are safer than electrochemical biosensors. Because of its high sensitivity, accuracy, and specificity, magnetic sensing technology is expected to be employed for on-site detection tools to restrain the spread of SARS-CoV-2.

#### *2.4.4 Application of nanotechnology in magnetic biosensors*

The unique magnetic relaxation properties and good biocompatibility of magnetic nanomaterials give many biosensors high sensitivity and selectivity. In the process of designing magnetic biosensors, which rely on magnetic nanoparticles tags, the size of magnetic nanotags is required to match that of analytes [65]. However, with the decrease of the size of magnetic nanoparticles, these magnetic nanotags often have low magnetic moment and uneven particle size distribution. In addition, the serious surface defects on the surface of nanoparticles and the unavoidable magnetocaloric effect will cause the fluctuation of magnetic signal in the detection of low-concentration analytes. Therefore, the development of magnetic biosensors should focus on how to prepare magnetic nanoparticles with uniform size and good dispersion and the point-of-care detection of magnetic biosensors.

## **3. Conclusions**

Up to now, SARS-CoV-2 has continued to diffuse and spread all over the world, and the epidemic of COVID-19 is facing the dilemma of globalization and time sustainability. Especially in view of the continuous variants of SARS-CoV-2 with

increasing transmission speed, concealment, and the proportion of immune escape, even new variants still pose a serious and death threat to people with low immunity and the elderly. Therefore, it is necessary to further improve the conventional detection methods and break through the limitations of the original detection methods and develop new methods as a supplement or substitute for future monitoring and detection tools. Especially in some developing countries with a shortage of medical resources, it is particularly important to develop rapid, simple, high-throughput, and intelligent detection methods.

The nanotechnology attached to the novel nano-biosensing technology has developed relatively mature, but the application of biomacromolecules detection still needs to be further improved, such as the biological toxicity of nanomaterials, the modification of biomolecules on the surface of nanomaterials, the large-scale manufacturing of nanomaterials, and so on. For the novel diagnostics methods, the following aspects need to be considered:


*Perspective Chapter: Novel Diagnostics Methods for SARS-CoV-2 DOI: http://dx.doi.org/10.5772/intechopen.105912*

with the existing nucleic acid, antibody, and pathogen detection methods and complementing their advantages, the combined use of them is expected to achieve the accurate and rapid detection of SARS-CoV-2. This method not only provides a powerful means for the current outbreak of COVID-19 and the detection of unknown pathogens in the future, but also has important practical significance for the future application in the fields of respiratory disease differential diagnosis, environmental monitoring, food safety assessment, etc.

7.Intelligent detection. Standardize the high-throughput screening results, instrument interpretation results, and analysis results for large population to avoid the lag and subjectivity of manual interpretation. The interpretation results are not only comparable, but also can be output in time for on-site or remote research and judgment.
