key: cord-0916320-3xqwania
authors: Varghese, Ryan; Salvi, Sahil; Sood, Purab; Karsiya, Jainam; Kumar, Dileep
title: Carbon nanotubes in COVID-19: A critical review and prospects
date: 2021-11-10
journal: Colloid Interface Sci Commun
DOI: 10.1016/j.colcom.2021.100544
sha: f2735cd9100b77d1835cf8dfd3594470701c087b
doc_id: 916320
cord_uid: 3xqwania

The rapid spread of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) around the world has ravaged both global health and economy. This unprecedented situation has thus garnered attention globally. This further necessitated the deployment of an effective strategy for rapid and patient-compliant identification and isolation of patients tested positive for SARS-CoV-2. Following this, several companies and institutions across the globe are striving hard to develop real-time methods, like biosensors for the detection of various viral components including antibodies, antigens, ribonucleic acid (RNA), or the whole virus. This article attempts to review the various, mechanisms, advantages and limitations of the common biosensors currently being employed for detection. Additionally, it also summarizes recent advancements in various walks of fighting COVID-19, including its prevention, diagnosis and treatment.

inflammatory indicators that exert their influence in the COVID-19 infections. They also reported that the major hematological indicators in COVID-19 include the absolute and relative (ratios) counts of the circulating neutrophils and lymphocytes in the blood [9] .

Several studies also reported clinical incidences of lymphopenia in progressing and more severe cases of COVID-19 infections in patient populations [10] . Of the numerous biomarkers in the progression of COVID-19 infection, the most conspicuous ones include creatine kinase, D-dimer, and troponin. The evidence presented by Tersalvi et al. and Yao et al. underscores the direct relation of D-dimer levels with the severity of the COVID-19 conditions [11, 12] . However, Garg et al. state that the severity of the SARS-CoV-2 infection can be analyzed by measuring the elevated levels of inflammatory biomarkers like C-reactive protein (CRP), ferritin (FT), interleukin-6 (IL-6), and procalcitonin (PCT) [13] .

Nevertheless, there has not been a commercially available test kit that facilitates the evaluation of specific immune responses while eliciting a robust cellular response. Although antibodies targeted against the receptor-binding domain (RBD) of the S protein are highly specific for the SARS-CoV-2, their role against other proteins in the pathogenesis of COVID-19 still needs to be elucidated and studied further [6] .

( Furthermore, the factors such as the individual, test technique, and the data collection strategy can profoundly affect the test sensitivity, which may further introduce inconsistencies and errors between the tests. Additionally, a negative test report in a typical clinical setting does mortality statistics have produced a great demand for rapid, highly selective, and sensitive detection methods to ensure early diagnosis and to avail treatment, primarily in cases where there are limited prevention and mitigation strategies in place [24] .

Most diagnostic toolkits that employ antigen-based or human blood serum-based lateral-flow immunoassays usually suffer from low sensitivity issues. In addition, the performance is improved by advanced digital systems, but at the cost of speed and the requirement for massive equipment [25] .

Furthermore, the gold standard currently employed for detecting COVID-19 is the commonly utilized quantitative real-time polymerase chain reaction (qRT-PCR). Nevertheless, this method is arduous, cumbersome, require skilled labor, and might be of limited utility in distant and resource-constrained surroundings. Moreover, this method may also produce specific individual false-positive results. It could fail to meet the newer challenges (like rapid viral mutation) or the need for mass-producing methods for quicker and more direct detection of viral particles or proteins. In contrast, most biosensors work by detecting the viral internal genetic material or the viral surface proteins. Therefore, these shortcomings limit its utility while impeding the ability to produce accurate data on the infectivity and extent of COVID-19 infection in the community or population [24] .

In addition, the pandemic has strained the testing resources, further prompting the development of rapid point-of-care assays along with the deployment of isothermal DNA

With the evidence of recent pandemics and viral outbreaks, the viruses are considered a great peril to the health and well-being of humans, owing to the ravage that they cause on both health and the global economy alike. Additionally, their higher prevalence of these outbreaks can be attributed to the current improper detection tools employed for the detection of these infectious agents. Therefore, this demands a detection or diagnostic tool that is robust, rapid, selective, and accurate in its biosensing properties. The biosensors can be defined as analytical instruments that can assess very low concentrations of an analyte in biological samples (like the human serum, blood, tears, saliva, etc.) [26] . Compared to conventional qualitative and quantitative test kits, these biosensors are highly accurate, specific, and sensitive to the directed target. Generally, these biosensors comprise a biological element like a microorganism, cell organelle, cellular receptor, enzyme, antibodies, nucleic acids, proteins, or any other such biological element that could potentially generate signals (like thermal, electrical, or optical signals). These signals are produced on the interaction of these biological elements with a tested element and a transducer, which further aids in converting these signals into a quantifiable electrical parameter [27] . These measurement methods usually encompass special features for identifying and measuring these target analytes, owing to the utilization of distinct biological components. Several biosensors are currently being developed for a plethora of clinical and pharmaceutical applications. These utilities range In recent years, several novel biosensors have been employed in the detection of RNA viruses. The most prominent ones include aptamer-based biosensors, antigen Au/Ag-based electrochemical biosensors, CRISPR-Cas9-based paper strips, nucleic acid-based biosensors, optical biosensors, and surface plasmon resonance biosensors, to name a few. These biosensors could be potential instruments in providing a rapid, more accurate, compact, and much promising diagnostic tool in the light of the World Health Organization's (WHO) testtest-test theme. Furthermore, the newer technologies like aptamer-based bio-nanogate, DhITACT-TR chip-based biosensors, graphene-field-effect transistor (FET) basedbiosensors, nucleic acid hybridization, rapid-cum-portable RNA extraction preps, and surface plasmon-based [like quartz-crystal microbalance (QCM), surface-enhanced Raman scattering (SERS), and surface plasmon resonance (SPR) technologies] innovations could promote rapid, highly sensitive, and efficient solutions for better diagnosis and biosensing for COVID-19 or any further unprecedented outbreaks [24] .

Although numerous biosensors have been developed and commercialized for regular use, they pose several downsides. These shortcomings have been studied to be eliminated by employing nanotechnology-based interventions that perform the real-time direct detection of specific molecular targets. Thus, various nanomaterials like carbon nanotubes (CNTs), quantum dots (QDs), gold (Au), and other metallic-nanoparticles are being complemented with several biosensors owing to their characteristic features (physical, chemical, mechanical, electrical, magnetic, etc.) to accentuate the biosensing capability [26] .

( 

At the outset, the specific properties of the carbon nanotubes ( higher surface area to volume ratio, low density, fine pore size, flexibility, high mechanical strength, and the ability to transmit the generated physical or chemical interactions. These

CNTs are also resistant to most acids and bases, resistant to respiratory droplets, able to create reactive oxygen species (ROS), and biologically compatible with various drugs [33, 34] . The

CNTs also comprise covalent bonds (sp2+sp3 hybrid phases), accounting for exceptional electrical conductivity. The single-walled carbon nanotubes (SWCNTs) and multi-wall carbon nanotubes (MWCNTs) are studied to be folded graphene sheets with lengths ranging from ~50-1,000 nm and diameters of ~5-20 nm [35] . These factors thus deem SWCNTs as a favorable nanoparticle for detecting, filtering, and the inactivation of biological agents. Their use has been employed in diagnosis, viral protein detection, and drug delivery modalities for fighting viruses like influenza, SARS-CoV-1, SARS-CoV-2, and HIV [34] . [37] . This intratubular spacing between the MWCNTs was tailored between 17 nm to 325 nm for allowing size-based viral entrapment [34] . A study conducted by Wasik et al. manufactured and demonstrated the utility of a chemiresistive biosensor in the detection of dengue virus based on a heparin-functionalized SWCNT network [38] . Additionally, as the SARS-CoV-2 spike (S)-protein experiences a conformational shift around its receptor-binding domain on interaction with heparin [39] , which directs the utility of these heparin-functionalized CNTs in developing potent SARS-CoV-2 therapies. investigated that the pore size of the CNT network is smaller than the average size of a SARS-CoV-2, thereby filtering it without impeding the breathability that was found equivalent to a conventional polypropylene filter. The simplistic processability, feasibility, and light-weight of the aerosol-synthesized CNT filters underscore its practicality, especially in fighting against the COVID-19 pandemic [44] .

Furthermore, owing to the powerful oxidizing nature of hydrogen peroxide (H2O2), several living beings produce it for a multitude of reasons, including cellular signaling, self-defense J o u r n a l P r e -p r o o f Journal Pre-proof mechanism, or killing of pathogens. This has also extrapolated the utility of H2O2 in the cleaning and the disinfection of microbial pathogens. According to the density functional theory (DFT), the adsorption energy of a single H2O2 molecule onto the pristine SWCNT estimates to 0.25 eV, implying its modest interaction. Thus, for developing a filter with a long shelf life in a clinical setting, it is imperative to ensure the retainability of the H2O2 and the virus on the CNT filter. Thus, due to their catalytic activity, the transition metal atomconjugated SWCNTs aid in eliminating the virus and improve the association between the target molecule and the biosensing material [34] . constraints in the supply chains [50] .

In the context of alleviating the symptoms associated with COVID-19, the CNTs may demonstrate limitations due to the toxicity issues post their intranasal administration. On exposure to the lungs, the CNTs tend to activate the lower respiratory tract macrophages, which paves the way for pulmonary fibrosis and collagen creation in the lesions. These with antiretroviral drugs were also found to be potent in inhibiting the reverse transcriptase enzyme activity in the lymphocytes of patients who tested positive with HIV. These insights

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Figure 1: Classification and applications of various biosensors) (Figure 2: Models of using CNTs for the prevention and treatment of SARS-CoV-2 infection

Graphical Abstract (Figure 1: Graphical Abstract on the utility of Carbon nanotubes in the prevention, diagnosis and treatment of COVID-19)

This review encompasses the various biosensor and nanobiosensors employed in the prevention, diagnosis and treatment of SARS-CoV-2 infection

The authors declare that there is no conflict of interest.

The images have been created with the aid of BioRender.com

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ryan