Biosensors for the detection of bacterial and viral clinical pathogens and covid-19 diagnosis v2.0

Abstract

Biosensors are measurement devices that can sense several biomolecules, and are widely used for the detection of relevant clinical pathogens such as bacteria and viruses, showing outstanding results. Because of the latent existing risk of facing another pandemic like the one we are living due to COVID-19, researchers are constantly looking forward to developing new technologies for diagnosis and treatment of infections caused by different bacteria and viruses. Regarding that, nanotechnology has improved biosensors design and performance through the development of materials and nanoparticles that enhance their affinity, selectivity, and efficacy in detecting these pathogens, such as employing nanoparticles, graphene quantum dots, and electrospun nanofibers. Therefore, this work aims to present a comprehensive review that exposes how biosensors work in terms of bacterial and viral detection, and the nanotechnological features that are contributing to achieving a faster yet still efficient COVID-19 diagnosis at the point-of-care.

Full text

Review
Biosensors for the Detection of Bacterial and Viral
Clinical Pathogens and COVID-19 Diagnosis
Luis Castillo-Henríquez1,2, Mariana Brenes-Acuña3, Arianna
Castro-Rojas3, Rolando Cordero-Salmerón3, Mary Lopretti4 and
José Roberto Vega-Baudrit 1,3,*
1National Laboratory of Nanotechnology (LANOTEC), National Center for High Technology
(CeNAT), 1174-1200, San José, Costa Rica; luis.castillohenriquez@ucr.ac.cr (L.C.H)
2Physical Chemistry Laboratory, Faculty of Pharmacy, University of Costa Rica, 11501-2060, San
José, Costa Rica
3Chemistry School, National University of Costa Rica, 86-3000, Heredia, Costa Rica;
mbrenesacua@gmail.com (M.B.A); ariannac.r9vi@gmail.com (A.C.R); rocordero105@gmail.com
(R.C.S)
4UDELAR University, 1140, Montevideo, Uruguay; mlopretti@gmail.com (M.L.C)
*Correspondence: jvegab@gmail.com
Received: date; Accepted: date; Published: date
Abstract: Biosensors are measurement devices that can sense several biomolecules, and are widely
used for the detection of relevant clinical pathogens such as bacteria and viruses, showing
outstanding results. Because of the latent existing risk of facing another pandemic like the one we
are living due to COVID-19, researchers are constantly looking forward to developing new
technologies for diagnosis and treatment of infections caused by different bacteria and viruses.
Regarding that, nanotechnology has improved biosensors design and performance through the
development of materials and nanoparticles that enhance their affinity, selectivity, and efficacy in
detecting these pathogens, such as employing nanoparticles, graphene quantum dots, and
electrospun nanofibers. Therefore, this work aims to present a comprehensive review that exposes
how biosensors work in terms of bacterial and viral detection, and the nanotechnological features
that are contributing to achieving a faster yet still efficient COVID-19 diagnosis at the point-of-care.
Keywords: Bacterial detection; Biosensors; Clinical pathogen; COVID-
19; Electrospun nanofibers; Nano-biosensors; Point-of-care; SARS-CoV-2;
Viral detection.
1. Introduction
Biosensor’s concept was firstly addressed by Clark and Lyons around 1962 when they
developed an oxidase enzyme electrode for glucose detection [1]. Since then, nanotechnological
development has promoted biosensors evolution and specialization for different purposes [2].
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Currently, nanotechnology is at the forefront of science, and its combination with biosensoring
applications involves different fields such as medicine, biology, environmental, drug delivery, food
safety, and others [3–7]. However, the detection of pathogens has become one of the most relevant
objectives for these devices since bacterial and viral diseases currently represent an important
thread for human health [8,9].
Virus and bacteria detection commonly involves the use of several molecular techniques
such as the reverse transcription-polymerase chain reaction (RT-PCR), which remains the gold
standard for pathogen detection [10]. The classical detection methods for these pathogens usually
require isolation, culturing, and then, biochemical tests [11]. Additionally, serological tests like
ELISA are used for the detection of antibodies and immunoglobulin needed for identification
purposes [12]. However, some of these techniques take a long time for obtaining results and are
usually laborious. Therefore, new approaches based on nanotechnological advances have emerged
as suitable and easier options for detecting pathogens in faster and efficient ways [11,13].
On one hand, nanoparticles (NPs) have demonstrated outstanding properties against
different pathogens used to develop novel devices and technologies that contribute to this public
health issue [14,15]. The interest is not limited to human diseases, but also considers the ones
affecting animals since zoonosis is an existent thread. Stringer et al. developed an optical biosensor
using gold NPs (AuNPs) and quantum dots (QDs) for the detection of porcine reproductive and
respiratory syndrome virus [16].
On the other hand, international scientific community’s interest in using DNA biosensors
or sequence-specific DNA detectors for clinical studies is increasingly growing. In 2007, Dell’Atti et
al. developed a combined DNA-based piezoelectric biosensor for simultaneous detection and
genotyping of high-risk Human Papilloma Virus (HPV) strains [17]. In addition to that, these
biosensors have been employed for DNA damage research and specific gene sequences detection
[18,19].
Biosensors and nano-biosensors have been extensively used for the detection of viral and
bacterial clinical pathogens. These devices are practical (e.g., enable point-of-care (POC) testing
through smartphone-based nano-biosensor), fast, and are considered as innovative technologies
that provide an alternative solution to the mentioned disadvantages presented by common
detection methods [20–22]. The aforementioned have been employed for studying viruses affecting
human health such as Ebola virus, Human Immunodeficiency Virus (HIV), and more recently the
newly discovered acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as bacteria like
Escherichia coli, Salmonella spp. and others [23–27].
Because of the latent existing risk of facing another pandemic like we are living due to
Coronavirus disease (COVID-19), researchers are constantly looking forward to developing new
technologies for diagnosis and treatment of infections caused by different bacteria and viruses.
Therefore, this review aims to expose how biosensors work in terms of bacterial and viral detection,
describing the nanotechnological features such as NPs, graphene QDs (GQDs), and electrospun
nanofibers, which enhance their affinity, selectivity, and efficacy in detecting these pathogens, as
well as highlighting current advances for the COVID-19 pandemic assessment at the POC.
2. Biosensors
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Biosensors can be defined as a measurement system for analyte detection that combines a
biological component with a physicochemical detector [28]. The analyte detection depends on the
biosensor design and purpose. Some commonly used devices such as smartphones can be
employed as a biosensor with the inclusion of simple accessories such as published by Soni et al.,
where they developed a non-invasive smartphone-based biosensor for urea using saliva as sample
[29,30]. This allows fast and low-cost preliminary detection [31].
Usually, biosensors detect biomolecules such as nucleic acids, proteins, and cells that are
associated with diseases. This is possible because of their three major components: the biologically
sensitive element, the detector element, and the reader device [32]. Enzymes, microorganisms,
organelles, antibodies, and nucleic acids are used to detect the biomolecules [33]. In order to obtain
a high-quality biosensor, researchers must identify the requirements to obtain a fully functional
device. Hence, multidisciplinary studies are fundamental to select the proper material, transducing
device, and biological element involved, before assembling the biosensor [34].
At a clinical level, biosensors are applied for detecting disease-associated biomolecules [32].
These devices can monitor several parameters like disease-causing bacteria, and several body fluids
such as saliva, blood, or urine [35,36]. Zhang et al. developed a non-invasive method for glucose
testing based on a disposable saliva nano-biosensor to improve patient compliance, reduce
complications, and costs derived from diabetes management. In the clinical trials, they obtained
outstanding results in terms of accuracy compared to the UV spectrophotometer. Thus, the
disposable device can be presented as an alternative for real-time salivary glucose tracking [37].
Biosensors can be applied for many other clinical diagnostic purposes, such as cholesterol,
markers related to cardiovascular diseases, biomarkers of cancer or tumors, allergic responses,
disease-causing bacteria, viruses, and fungi infections [38–41]. Aside from that, biosensors can be
employed for bacteria and virus detection in food and water, which are potential sources of
diseases [42,43]. Zhao et al. fabricated a low-cost, portable microfluidic chemiresistive biosensor
based on monolayer graphene, AuNPs, and streptavidin-antibody system for the rapid in-situ
detection of E. coli. In this case, the bacteria are captured on the biosensor’s surface and detection is
performed through electric readouts [44]. Another approach published by Samanman et al.
describes the development of a glutathione-S-transferase tag for white spot binding protein (GST-
WBP) immobilized onto a gold electrode through a self-assembled monolayer. This biosensor can
detect white spot syndrome virus (WSSV) in shrimp pond water due to binding between WSSV and
the immobilized GST-WBP [45].
2.1. Operating principles
Biosensors are constituted by three components (Figure 1) [38,46]. In the first place, these
devices have sensing elements, also called bioreceptor that emulates in vivo molecular recognition
phenomena [47]. There is a wide range of sensing elements such as cells, microbes, cell receptors,
antibodies, enzymes, or nucleic acids [48–52]. These biological sensitive elements recognize the
analyte and interact with it in different ways according to the type of biosensor [53]. One of the
main biorecognition strategies is based on bacterial or viral nucleic acid sequences [54,55]. Solanki
et al. developed a DNA bioelectrode to detect Vibrio cholerae, which is stable for at least 15 weeks
under 4°C storage. The biosensor consisted of O1 gene-based 24‐mer single-stranded DNA probe
immobilized onto sol‐gel derived nanostructured zirconium oxide (NanoZrO2) film [56].
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Figure 1. Biosensor’s basic design. Reprinted with permission from Huang, Y. et al. Disease-Related Detection
with Electrochemical Biosensors: A Review. Sensors 17(10). Copyright (2017) MDPI [46].
The second element is the transductor or detector, which works by sensing a signal related
to a physicochemical change caused by the interaction between the bioreceptor and the analyte. It
transforms the signal into another one that can be evaluated and quantified [57–61]. The last part of
a biosensor is the reader device. It usually involves a display that depends on software and
hardware to generate the results [62].
Some important attributes define the performance of a biosensor. In the first place,
selectivity is the capacity of a bioreceptor to detect a specific bio-entity when analyzing a sample
composed of other components. This is probably the main feature and determines the needed
bioreceptor. Second, reproducibility is the ability to produce the same response for a certain
experimental set-up that is performed multiple times. Reproducible signals provide high reliability
and robustness. Third, stability is the capacity to endure ambient disturbances around the system
that can affect the precision and accuracy of the device. Fourth, sensitivity also known as the limit
of detection (LOD) is the minimum amount of the analyte that can be detected by a biosensor. For
clinical applications, it is required to detect the analyte in samples of low concentrations (ng/ml or
fg/ml). Finally, linearity examines how accurate are the measurements within the analyte range of
concentrations (i.e. linear range), and in response to the smallest variation in terms of concentration
that can cause a change in the output (i.e. resolution) [63].
2.2. Types of biosensors
Biosensors can be classified by the way they transduce signals into optical, electrochemical,
and piezoelectric devices [57–61,64]. Optical biosensors are those that perform their analysis
through the measure of photons, using optic fibers as transduction elements [58,59,65]. Several optic
sensing mechanisms can be employed by this type of biosensor for analyte detection such as
absorption, colorimetry, fluorescence, or luminescence [66]. This kind of biosensor presents a lower
noise and immunity to electromagnetic interference, which gives it an advantage over
electrochemical and piezoelectric biosensors [67].
Vidal et al. developed a chromatic biosensor for quick bacterial detection based on
polyvinyl butyrate-polydiacetylene non-woven fiber composites. The device shows promising
potential to alert about possible infections caused by Staphylococcus aureus, Micrococcus luteus, and
E.coli [68]. In another study, Jeong et al. constructed a fluorescent supramolecular biosensor for
bacterial detection. The binding of these pathogens induces conformational changes in the
supramolecular state, which causes a fluorescence emission that can selectively detect E.coli over
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other microorganisms [69]. Regarding viral analysis, Ahmadi et al. evaluated single virus detection
through an optical biosensor, where viral particles attached to a microsphere optical resonator’s
surface caused a shift of resonance to longer wavelengths [70].
The second type, electrochemical biosensor, has been extensively applied to pathogen
detection. These devices sense the analyte through electrodes by measuring electrical signals
resulting from catalytic reactions or specific unions. The previous is derived from the capture of
electrons as a result of redox reactions between the analyte and the bio-element [71]. In addition to
that, the analysis of the desired element is determined by different readouts like potentiometry,
amperometry, and conductometry [72]. This type of biosensor has been subjected to improvements
due to bio-and nanomaterials development [72,73].
Recently, Mathelié et al. employed non-cytotoxic silica NPs-assisted electrochemical
biosensor for sensitive and specific detection of E. coli. The electrochemical immune-biosensor
detects the bacteria in five minutes by cyclic voltammetry measurements, and also represents a
potential device for targeting a variety of other microorganisms through little modifications within
its features [74]. In another study, Baek et al. developed an electrochemical biosensor composed of
eight novel peptides separately in a gold electrode for the detection of human norovirus. The
peptides exhibited a high binding affinity towards the viruses, and a decrease in current signals
explained by increasing concentration of the virus [75].
Finally, yet importantly, there are piezoelectric biosensors. Piezoelectricity refers to the
ability of a material to generate a voltage under mechanical stress [76]. These biosensors possess
crystals that vibrate under the influence of an electric field. Besides, certain materials vibrate at
characteristic resonant frequencies in response to interaction with other molecules. The relationship
between the resonant frequency changes and the mass from the molecules adsorbed or desorbed
from the crystal’s surface is conceived as the working principle of transduction in this type of
biosensor. Therefore, vibration provides information on the phenomenon that is being measured
[77,78].
Fu et al. discuss the advances in piezoelectric thin films acoustic wave devices for bacterial
and viral detection of pathogens adsorbed on surfaces through DNA interaction with
complementary strands. The previous allows early detection of clinical pathogens, and thus,
prevents the spreading of the infection [79]. In another approach, Guo et al. worked on sensitive E.
coli O157:H7 detection system using a piezoelectric biosensor-quartz crystal microbalance with
antibody-functionalized AuNPs to enhance changes in detection signals. It was demonstrated that
the developed device can be used as a suitable real-time monitoring method for the mentioned
pathogen [80].
3. Biosensors nanotechnological features for bacterial and viral detection
Over time, many techniques and methods have been developed for detecting pathogens
such as viruses and bacteria, including colorimetric methods, fluorescence polarization, and
electrochemical analysis [81]. However, those are very expensive and possess limitations related to
time-consumption, low precision of the results, poor stability, and short life span [82].
Bacterial and viral outbreaks have caused many issues in biomedical, food and
environmental context, making necessary the development of new strategies that allow faster
detection of these pathogens to effectively contain and control their impact on human health [83].
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The combination of nanotechnologies and biosensors’ characteristics is currently being considered
as a potential opportunity for speeding up the development of fast, highly sensitive, and specific
devices for genuine bacterial and viral detection. As a consequence, nano-biosensors make use of
chemical, electrical, optical, and magnetic properties of materials for detecting biomolecules and
pathogens [84,85].
In order to satisfy the previous, nanotechnology has greatly contributed to the development
of biosensors due to research in nanomaterials and nanostructures, such as carbon nanotubes,
GQDs, metal oxide NPs, metal nanoclusters, plasmonic nanomaterials, polymer nanocomposites,
nanogels, among others (Figure 2) [86–89]. These have been employed for modifying electrode
surfaces to improve critical features, such as reproducibility, selectivity, and sensitivity, due to their
biocompatible character, structural compatibility, and high adsorption capacity. Therefore,
nanomaterials have demonstrated to be suitable for biosensing applications, enhancing the
performance with increased sensitivities and lower detection limits [90].
Figure 2. Different nanomaterials and nanostructures used for the development of nano-biosensors. Reprinted
with permission from Pirzada, M. et al. Nanomaterials for Healthcare Biosensing Applications. Sensors 19(23):
5311. Copyright (2019) MDPI [91].
Additionally, nanomaterials have been used to increase the immobilized bioreceptor
loadings. However, the strategy for immobilizing the bio-specific entity onto the nanomaterial is
considered as the biggest challenge for developing high quality and reliable nano-biosensor. Non-
covalent approaches such as electrostatic interactions, polymers entrapment, or van der Waals
forces between the nanomaterial and the biomolecule do not alter their specific properties. On the
other hand, covalent binding provides more stability and reproducibility of surface
functionalization, as well as reducing the risk of unspecific physisorption. Although the previous
techniques represent good strategies for binding biological species to surfaces, supramolecular
interactions have recently been considered as superior since these are reversible, which enables the
regeneration of the transducer element [91,92].
Regarding other uses, nanomaterials can perform as nanocarriers for signaling elements, as
well as signal amplification. Depending on the chemical composition, nanomaterials can be subject
to direct functionalization during synthesis, or functionalized by coating using functional polymers
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[93]. Nanomaterials functionalization provides three important advantages: reproducible
immobilization of bioreceptor units, increase the biocompatibility, and the development of label-
free transduction techniques [92].
Moreover, nano-biosensor materials’ high surface area is considered a major advantage
compared to conventional devices and plays an important role in the sensitivity, and fast response
of the devices [94,95]. Therefore, these are conceived as excellent tools used for the detection,
function, and interaction of proteins and nucleic acids, which improve the quality and performance
of diagnosis for bacterial and viral diseases [96]. The following sections present an overview of
some promising nanotechnological features in biosensors.
3.1. NPs
NPs are a wide range of materials with dimensions below 100 nm that have been used in
various areas such as medical, pharmaceutical, manufacturing and materials, environmental,
electronics, and mechanical industries due to their multiple properties [97–100]. Among the mostly
employed are metal NPs such as AuNPs and silver NPs (AgNPs), which can be produced in
different sizes and shapes (e.g., nanospheres, nanocylinders, nanowires, and nanocages). These NPs
exhibit low toxicity, as well as multiple interesting chemical, biological, and physical properties,
such as photo-thermal, optical, electrochemical, and biocompatibility based on their inert nature in
biological fluids [101–103]. Additionally, these NPs can be synthesized with ease fulfilling relevant
roles for diagnostic probes, and functionalized due to the presence of functional groups for
achieving ligand-binding functions with a wide range of molecules, such as antibodies or genetic
material [104,105].
An important application of nano-biosensors composed of metal NPs is related to
waterborne diseases, where the infection is usually linked to microbial contamination due to several
pathogens, including bacteria, where nanotechnological detection systems with optical sensing
have been used for these pathogens [106]. Elahi et al. designed a highly sensitive fluorescence nano-
biosensor for the detection of Shigella species. To achieve a satisfactory design, two DNA probes as
sensing elements were immobilized on the surface of AuNPs synthesized for the development,
forming a DNA-probe AuNPs-fluorescence system. The research group also synthesized iron NPs
(MNPs) that were later modified with Sulfosuccinimidyl 4-Nmaleimidomethyl cyclohexane-1-
carboxylate (SMCC), and a second system constituted by a third DNA probe immobilized on MNPs
was formed for separating target DNA. The results exhibited an increasing fluorescence intensity
with an increase of target DNA concentration [107].
In another study, carried out by Takemura et al., an ultrasensitive, rapid, and specific
localized surface plasmon resonance (LSPR)-induced immunofluorescence nano-biosensor was
developed for detecting influenza virus. Researchers employed AuNPs-induced QD fluorescence
signal conjugated with antineuraminidase antibody (Anti-NA Ab) and conjugation of anti-
hemaglutinin antibody (anti-HA Ab) to the QDs. The device successfully detected influenza virus
H1N1. However, due to its versatility, it was also possible to detect clinically isolated influenza
virus H3N2 and norovirus-like particles [108].
3.2. GQDs
GQDs are among the most fascinating carbon-based nanomaterials employed for the
development of biosensors, mostly electrochemical. These materials present outstanding properties
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such as signal amplifying characteristics, biocompatibility, tunable size, electro-catalytic
performance, and capacity to detect multiple biomolecules. Additionally, their inertness, non-
toxicity, long-term chemical stability, and water stability make them very valuable for biomedical
applications [90,93].
GQDs obtained through different synthesis methods have been used for biosensing
applications since their large surface area can be functionalized, allowing them to directly detect
DNA, enzymes, proteins, antigens, antibodies, and other biomolecules by the oxide components
formed on their surface during the synthesis process [109]. Safardoust et al. synthesized GQDs from
citric acid and ethylene diamine for their use as a photoluminescence sensor for detecting S.aureus
and E.coli. This biosensor demonstrated a linear relationship between the fluorescence intensity and
the concentrations of the bacterias up to 9x107 CFU/ml [110].
In another approach, Hazani et al. fabricated a highly sensitive electrochemical peptide
nucleic acid (PNA) biosensor based on functionalized graphene oxide composited with cadmium
sulfide QDs (CdS QDs). The device was developed for detecting Mycobacterium tuberculosis and
showed a LOD of 8.948x10-13 M [111]. Furthermore, GQDs integration into a biosensor can improve
its performance in terms of reproducibility, selectivity, and sensitivity [112].
3.3. Electrospun nanofibers
Electrospinning is a nanotechnological method in which an electrostatic field force applied
to a polymer solution causes a charged liquid jet to moves downfield towards an oppositely
charged collector, where the fine fibers are deposited [113]. Electrospun nanofibers have been the
target of different applications like drug delivery systems or scaffolds for skin tissue engineering
due to their structure and physicochemical properties such as a large surface area to volume ratio,
small particle size, and high porosity, among others [113–116]. However, a novel application is their
use for developing nano-biosensors focused on detecting viral and bacterial pathogens [117–120].
Nano-biosensors development using these nanostructures can be achieved by two
approaches. On one hand, functional polymers are electrospun to obtain a nanofiber that is used
directly as an inducing element of the corresponding biosensor, which will present fast response
time, high sensitivity, and good biocompatibility. On the other hand, electrospun nanofibers are
used as templates to which a sensitive material is deposited on their surface, and later the system is
subjected to chemical modification in order to produce a composite film on an electrode, with
nanostructures that have the intended sensing characteristics [121,122].
Although the manufacturing process is simpler, keeping bio-receptor functionality is
considered a great challenge for the production of this type of device. The sensing element can be
immobilized through different strategies according to its physicochemical characteristics, as well as
the ones from the nanofiber scaffolds, and also, based on their interfacial interactions [123].
Moreover, this type of nano-biosensor is based on various sensing principles such as optics,
electric resistance, photoelectricity, vibration frequency, electric current, and others [124–128]. Luo
et al. developed a nitrocellulose electrospun nanofibrous capture membrane for detecting
E.coli O157:H7 and bovine viral diarrhea virus. The device’s design was based on capillary
separation, and conductometric immunoassay using a silver electrode. Nanofiber antibody’s
surface functionalization and sensor assembly process allowed retaining the unique fiber
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morphology, and displaying a linear response to both pathogens with a detection time of 8 minutes
[129].
Quiros et al. prepared electrospun membranes composed of polyacrylonitrile (PAN) and
poly(4-vinylphenylboronic acid-co-2-(dimethylamino)ethyl methacrylate-co-n-butyl methacrylate)
(pVDB) for fast sensing of bacteria. The pVDB@PAN membranes were used as fluorescent bacterial
biosensors, displaying maximum fluorescence intensity after 24 hours in contact with S. aureus or E.
coli. Meanwhile, the membranes became non-responsive within 8 hours in contact
with Pseudomonas putida due to the rapid formation of bacterial biofilm that blocked the membrane
surface, disrupting fluorescence readings. This development can be useful for the early
identification of pathogenic bacteria as an attempt to prevent their spreading [130].
Some research groups have designed nano-biosensors based on electrospun nanofibers for
viral detection as well. Tripathy et al. worked on an ultrasensitive electrochemical platform with
electrospun semi-conducting Manganese (III) Oxide (Mn2O3) nanofibers for DNA hybridization
detection. This biosensor makes use of electrochemical transduction techniques for zeptomolar (i.e.,
10-21 M) detection of Dengue primer, resulting in a limit of detection of 120×10–21 M [131].
Therefore, nanofiber-based biosensors present advantages over the conventional ones such
as polymer diversity for its manufacture, high specific surface area with high responsiveness, as
well as an outstanding sensibility [132–134].
4. Bacterial and viral pathogens detected through biosensors and nano-
biosensors
Conventional clinical analyses including an antibody or nucleic acid-based, biochemical,
and enzymatic methods, are very reliable but take a long time to obtain a result. Health disciplines
demand the acquisition of faster outcomes to speed up the appropriate treatment [135,136]. In this
sense, biosensors and nano-biosensors are useful tools that offer an accurate diagnosis in shorter
times due to their ability to provide real-time and faster clinical results [137]. Currently, there is an
increasing interest in their use to detect pathogens in the human body (Table 1) [136].
Table 1. Developed biosensors for detecting bacterial and viral pathogens in the human body.
Device Target pathogen LOD Response
time Ref
Long-period fiber grating using
bacteriophage T4 covalently
immobilized on optical fiber
surface.
E.coli 103 CFU/ml 20 min [138]
Label free polyaniline based
impedimetric. E.coli O157:H7 102 CFU/ml - [139]
Electrochemical biosensor using
antibody-modified NPs
(polymer-coated magnetic NPs
and carbohydrate-capped
AuNPs).
E.coli O157:H7 101 CFU/ml 45 min [140]
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Surface plasmon resonance (SPR)
biosensor based on ultra-low
fouling and poly(carboxibetaine
acrylamide).
Salmonella sp. 7.4x103 CFU/ml 80 min [141]
Graphene-based potentiometric. S. aureus 1 CFU/ml 10-15 min [142]
Aptamer based biosensor and
dual florescence resonance
energy transfer from QDs to
carbon NPs.
Vibrio
parahaemolyticus
and Salmonella
typhimurium
25 CFU/ml and 35
CFU/ml,
respectively
80 min [112]
Impedimetric biosensor based on
site specifically attached
engineered antimicrobial
peptides.
Pseudomona
aeruginosa 102 CFU/ml 30 min [143]
Electrochemical DNA biosensor
based on flower-like ZnO
nanostructures.
Neisseria
meningitides 5 ng/μl - [144]
Graphene-enabled biosensor
with a highly specific
immobilized monoclonal
antibody.
Zika virus 0.45 nM 4-8 min [145]
Giant magnetoresistance
biosensor. Influenza A virus 1.5x102 TCID50/mL - [146]
Electrochemical biosensor based
on DNA hybridization. Hepatitis A virus 6.94 fg/μl 15 min [147]
Impedimetric electrochemical
DNA biosensor for label free
detection.
Zika virus 25 nM 1.5 h [148]
Two-dimensional molybdenum
disulphide nanosheets based
disposable biosensor.
Chikungunya virus 3.4 nM 3 h [149]
Electrochemical DNA biosensor
using gold nanorods. Hepatitis B virus 2.0x10-12 mol/L 5 h [150]
Intensity-modulated surface
plasmon resonance (IM-SPR)
biosensor
Avian influenza A
H7N9 virus 144 copies/ml 10 min [151]
Silicon nanowire biosensor. Dengue virus 2.0 fM - [152]
E.coli: Escherichia coli; S.aureus: Staphylococcus aureus.
Molecular determination demands to improve the analytical performance of biosensors,
which have enhanced their unique features to develop POC devices in order to run a rapid and
cost-effective analysis of complex biological matrices [153]. Commercial versions of these devices
are available to detect diseases and pathogens such as E. coli, Helicobacter pylori, influenza A and B
viruses, HIV, tuberculosis, and malaria [154]. Advantages such as small samples and low energy
required to avoid complications in terms of transportation and processing, make them suitable for
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easy and fast use in the identification of bacterial and viral pathogens [137]. Needless to say,
nanomaterials advances have benefited biosensor performance to achieve the task [155].
4.1. Bacterial pathogen detection
Focusing on the human body, bacterial infections caused mainly by gram-negative
microorganisms represent a particular challenge in human health worldwide because of multidrug
resistance variants, greatly influenced by their indiscriminate exposure to antibiotics discharged in
water, addition to food or more commonly, due to improper use of these drugs from patients [156].
Since the previously mentioned is considered a major current health concern, different
kinds of nanomaterials and biorecognition elements have been employed to develop biosensors for
antibiotic detection, as well for bacteria [157]. Common pathogenic bacteria include E. coli,
Salmonella typhi, Clostridium perfringens, and Shigella spp., which can cause different kinds of diseases
in humans, animals, and plants [158]. However, S. aureus is recognized as one of the most fatal
bacteria that can cause rapid mortal infections and is often resistant to multiple antibacterial active
substances. Thus, it is necessary to develop new approaches for easier and faster detection since
conventional culture methods require 3-5 days to obtain results, and other nucleic acid-based
methods are expensive and imply trained personnel [159,160].
Suaifan et al. developed a biosensor able to detect S. aureus in a few minutes. The sensing
tool is based on the proteolytic activity of the pathogen proteases on a specific peptide substrate
placed in the middle of two magnetic nanobeads. In this case, the dissociation of magnetic
nanobeads-peptide moieties results in color change [161]. In another approach, Ahari et al.
constructed a potentiometric nano-biosensor able to detect the bacteria through the identification of
an exotoxin emitted by the microorganism. Particularly, the method is often used for contaminated
food, but it can also be applied for clinical detection [162].
Another important bacteria, V. cholerae, is a gram-negative facultative anaerobe that causes
Cholera disease. People would infect by consuming contaminated liquids or food, providing an
ideal platform for the disease, which also spreads quickly due to its secretory nature. Therefore, its
diagnosis plays an important role in the disease assessment because of its mortal rate rounds
between 50-60% [163]. Recently, Narmani et al. developed an ultrasensitive and selective
fluorescence DNA biosensor based on AuNPs and magnetic NPs for the determination of the
bacteria’s O1 OmpW gene [164].
The gram-negative bacteria, Shigella, belongs to the Enterobacteriaceae family. Infected
people develop diverse symptoms including diarrhea, cramps, fever, and vomit. According to the
World Health Organization (WHO), the annual number of Shigella cases worldwide is
approximately 164.7 million with 1.1 million of those resulting in death, and the majority of them
involve young children under the age of 5 years old [165]. Research performed by Elahi et al.
discovered an early detection method of infectious Shigella. In this study, AuNPs-DNA probes were
hybridized with Spa gene sequence in order to create an optical genosensing system. This biosensor
makes the sample solution turns to purple in the absence of the complementary target, whereas the
solution remains red in the presence of the specific gene sequence [166]. On the other hand, Xiao et
al. covalently immobilized a DNA probe onto fiber-optic biosensors able to hybridize with a
fluorescently labeled complementary DNA. The obtained results were comparable to the ones
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obtained by PCR, which suggests considering this method as an alternative for Shigella detection
[165].
The different approaches for biosensoring detection of pathogenic bacteria have been
successful and are currently being considered by many health governments and research
institutions, mainly because of their fast response, high-quality performance, and reliable results
[167–169].
4.2. Viral pathogen detection
Viral pathogen diagnosis is important for early and effective treatment in patients in order
to prevent outbreaks or pandemics. For that reason, biosensors are being widely employed for
making diagnosis easier, avoiding hard proteins or DNA identification techniques in specific virus
[170,171]. One of the most common and dangerous viral pathogens is the influenza virus because of
its ability to spread easily and constantly mutation. Hence, detection at early stages can be difficult
[172,173].
Hassanpour et al. developed a novel optical biosensor composed of pDNA bioconjugated
citrate capped AgNPs towards target sequences for ultrasensitive and selective Haemophilus
influenza detection in human biofluids [174]. This pathogen has also been detected through other
different biosensors, including the work reported by Jiang et al [148,174–176]. This paper describes
the development of a polydiacetylene sensitive biosensor using antibody detection for H5N1 (avian
influenza), in which the polydiacetylenes vesicles show a dramatic change in color from blue to red
upon the detection of the virus [176].
Other dangerous viruses that affect the population worldwide include ebolavirus, HIV, and
Hantavirus [177–179]. The first one is a negative strand-RNA virus that belongs to the Filoviridae
family and causes a deadly disease called Ebola. The infected people with this agent develop a
series of symptoms, where hemorrhagic fever is considered as fatal [180–182]. Currently, there is no
vaccine or specific treatment [183]. However, different studies have presented the development of
biosensors for detecting this pathogen [184]. Ilkhani et al. fabricated a novel electrochemical-based-
DNA biosensor through enzyme-amplified detection to improve the sensitivity and selectivity of
the device for the pathogen [185]. In addition to that, Baca et al. developed a biosensor that can
detect the virus within 10 minutes at the POC by using surface acoustic waves, showing potential to
detect it before symptoms onset [186].
On the other hand, HIV is a retrovirus that attacks a patient’s immune system, causing an
inability to resist many diseases, and culminating in death when the person is not under drug
control. Clinical treatments for HIV are crucial for reducing mortality, but early diagnosis saves
many lives as well and can decrease spread rates [187–189]. Shafiee et al. worked on a photonic
crystal biosensor to detect multiple HIV-1 subtypes (A, B, and D) upon binding of the biological
analyte with the biosensor [190]. In addition to that, Gong et al. prepared a nanocomposite of
polyaniline/graphene (PAN/GN) using reverse-phase polymerization for the development of an
electrical DNA-biosensor that showed great selectivity, and sensitivity for the detection of HIV-1
gene fragment [191].
Hantavirus is a cluster of viruses that are part of the Bunyaviridae family. The spread begins
through contact with liquids, food, or particles contaminated with rodent excreta. It causes
hemorrhagic fever, respiratory insufficiency, and heart failure within 2-7 days after getting infected
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[192,193]. Regarding its detection, Gogola et al. have performed important research for the
development of biosensors [194,195]. In a first approach, they prepared an electrochemical
immunosensor based on chemical modification of the gold surface with the virus antigen/protein
[194]. In a second study, the research group designed a quick electrochemical biosensor based on
biochar (BC) as a carbonaceous platform for immunoassay applications due to its highly
functionalized surface for covalent binding with biomolecules [195]. Both studies developed
devices as promising and suitable tools for hantavirus clinical detection [194,195].
Furthermore, several bio-elements can be incorporated into a biosensor for virus detection
including markers, RNA, structural proteins, and enzymes from the viral pathogens [196].
5. COVID-19 pandemic
Currently, many viruses are being considered to have the capacity of causing future
pandemics. Different factors such as fast dissemination, a high transmission rate of new variants,
difficulties to develop efficient and sensible diagnostic techniques, as well as the lack of specific
vaccines and safe drugs for treatment, make them one of the major threats for mankind [197,198].
The most recent case is the COVID-19 announced as pandemic on March 13th, which is an infectious
disease with rapid human-to-human transmission caused by SARS-CoV-2. This pathogen belongs
to the positive-strand RNA viruses [199,200].
Like any other viral outbreak, an early diagnosis is fundamental for preventing an
uncontrollable spread of the disease. However, this pandemic has the particularity that more than
30% of the confirmed cases are asymptomatic, thus making it harder to control [200–202]. RT-PCR is
the most used suitable and reliable method for detecting SARS-CoV-2 infections until now.
Nevertheless, the technique is time-consuming, labor-intensive, and unavailable in remote settings
[203,204]. Although several other methods can be employed for that purpose, such as
immunological assays, thoracic imaging, portable X-rays, or amplification techniques, the pandemic
spread of COVID-19 demands to develop POC devices for rapid detection (Figure 3) [205–208].
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Figure 3. POC for COVID-19.Reprinted with permission from Choi, J. et al. Development of Point-of-Care
Biosensors for COVID-19.Front Chem 8: 517. Copyright (2019) Frontiers in Chemistry [208].
Sheridan states that there are two types of rapid POC biosensors for COVID-19 detection.
In the first place, there is a nucleic acid test, which consists of detecting the virus in the patient’s
sputum, saliva, or nasal secretions [209,210]. The other type commonly employed is the antibody
test that is done through the analysis of collected blood samples five days after the initial infection,
which is when the immune response causes the production of IgM and IgG due to the presence of
the virus [211–213].
The industrial sector has developed some suitable POC biosensors for the qualitative
detection of SARS-CoV-2 IgM and IgG antibodies using samples as low as 10 µl of human serum,
whole blood, or finger prick, obtaining results within 10-15 minutes (Table 2) [214]. Many of these
rapid serological tests are paper-based biosensors that perform a colorimetric lateral flow
immunoassay. In this method, SARS-CoV-2 specific antigens are typically labeled with gold, and
bind the corresponding host antibodies, which migrate across an adhesive pad. As can be seen in
figure 4, anti-SARS-CoV-2 IgM antibodies interact with fixed anti-IgM secondary antibodies on the
M line, while IgG antibodies interact with anti-IgG antibodies on the G line. Therefore, M or G lines
only appear if the sample contains SARS-CoV-2 specific antibodies, otherwise, only the control line
(C) will be shown [215]. Although the use of serological tests to detect SARS-CoV-2 is still under
debate, these are foreseeing as crucial tools for the implementation or ceasing of lockdowns
established worldwide [216].
Table 2. FDA commercially authorized biosensors for SARS-CoV-2 detection [214].
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Manufacturer Device Target
Clinical
combined
specificity
Clinical
combined
sensitivity
Abbott
SARS-CoV-2 IgG
chemilumininescent
microparticle immunoassay
(CMIA)
Nucleocapsid 99.9% 100%
Access Bio, Inc. CareStart COVID-19
IgM/IgG
Spike and
Nucleocapsid 98.9% 98.4%
Beijing Wantai
Biological
Pharmacy
Enterprise Co. Ltd.
Wantai SARS-CoV-2 Ab
rapid test Spike 98.8% 100%
Biohit Healthcare
(Hefei)
Biohit SARS-CoV-2 IgM/IgG
antibody test kit Nucleocapsid 95.0% 96.7%
Cellex
Cellex Qsars-CoV-2 IgG/IgM
rapid test lateral flow
immunoassay
Spike and
nucleocapsid 96.0% 93.8%
DiaSorin LIAISON SARS-CoV-2 S1/S2
IgG CMIA Spike 99.3% 97.6%
Hangzhou Biotest
Biotech
COVID-19 IgG/IgM rapid
test cassette Spike 100% 100%
Hangzhou Laihe
Biotech
LYHER novel coronavirus
(2019-nCoV) IgM/IgG
antibody combo test kit
(colloidal gold)
Spike 98.8% 100%
Healgen COVID-19 IgG/IgM rapid
test cassette Spike 97.5% 100%
Megna Health, Inc. Rapid COVID-19 IgM/IgG
combo test kit Nucleocapsid 95% 100%
Salofa Oy
Siena-Clarity COVIBLOCK
COVID-19 IgG/IgM Rapid
test cassette
Spike 98.8% 93.3%
Xiamen Biotime
Biotechnology Co.,
Ltd.
BIOTIME SARS-CoV-2
IgG/IgM rapid qualitative
test
Spike 96.2% 100%
CMIA: chemilumininescent microparticle immunoassay; COVID-19: coronavirus disease 2019.
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Figure 4. COVID-19 rapid serological IgM/IgG test. Reprinted with permission from Ghaffari, A. et al.
COVID-19 Serological Test: How Well Do They Actually Perform? Diagnostics 10(7): 453. Copyright (2020)
MDPI [215].
Other research groups have developed Lab-on-a-Chip-based biosensors for SARS-CoV-2
detection [208,217]. This technology avoids the need for specialized personnel through the
integration of microfluidic components into a biosensor, allowing increasing their production, and
reducing the costs of the assay [218]. POC commercialized instruments based on this microfluidic
technology are having an important role in this pandemic, like ID NOW®, Filmarray®, GeneXpert®,
and RTisochip®[219].
Cell-based biosensors have also contributed to COVID-19 diagnosis. Mavrikou et al.
developed a biosensor based on membrane-engineered mammalian cells that possess the human
chimeric spike S1 antibody. The device can detect SARS-CoV-2 S1 spike protein selectively, where
the binding of the protein to the membrane-bound antibodies results in cellular bioelectric
properties modification measured by Bioelectric Recognition Assay. The LOD is 1 fg/ml and the
response time is about three minutes. In addition to that, the biosensor includes a portable read-out
device that can be operated by a smartphone [220].
Moreover, nano-biosensors have shown an outstanding potential to contribute to the fight
against COVID-19, providing holistic insights for developing ultrasensitive, cost-effective, and
rapid detection devices for mass production [221]. Advanced materials are the basis of nano-
enabled or integrated micro-and nano biosensing system technologies that can detect earlier the
virus, and even show good binding properties allowing them to inactive or destroy the pathogen
upon the application of an external stimulus [222].
Different research groups have developed carbon-based and graphene-based POC
biosensors [208,217]. Graphene is foreseeing to have a leading role in the attempt of fighting against
COVID-19. This low-cost material can be employed for virus detection since its sensitivity and
selectivity can be enhanced by modifying its hybrid structure (e.g., antibody-conjugated graphene
sheets) that allows tuning its optical and electrical features. Some graphene-based sensors that can
be explored for SARS-CoV-2 detection are photoluminescence, colorimetric, and SPR biosensors
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[223,224]. Seo et al. employed the material for the development of a field-effect transistor (FET)-
based biosensor for detecting SARS-CoV-2 (Figure 5). In this case, graphene sheets from the FET
were coated with a specific antibody against the virus spike protein, which was successfully
detected at concentrations of 1 fg/ml in a phosphate-buffered saline medium. In addition, the
device was able to detect the virus in clinical samples, exhibiting a LOD of 2.42 × 102 copies/ml. The
fabricated biosensor is considered as a promising immunological diagnostic alternative for the
disease [225].
Figure 5.Schematic diagram of COVID-19 FET sensor operation procedure. Reprinted with
permission from Seo, G. et al. Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human
Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor.ACS Nano 14(4): 5135-5142.
Copyright (2020) ACS [225].
Additionally to FET, a review published by Cui et al. considers potential electrochemical
biosensor and surface-enhanced Raman scattering (SERS)-based biosensor as other suitable options
for diagnosis of COVID-19 [226]. Also, Murugan et al. designed two field-deployable/portable
plasmonic fiber-optic absorbance biosensor (P-FAB) device for rapid detection of the virus’ N-
protein directly from saliva. One of them was a labeled immunoassay, and the other one was label-
free. Both bioanalytical approaches using the highly sensitive P-FAB platform can be considered as
ideal alternatives for COVID-19 diagnosis within 15 minutes [227]. More recently, Zhu et al.
reported another diagnosis approach based on the development of a multiplex reverse transcription
loop-mediated isothermal amplification combined with NP-based lateral flow biosensor. The
method allowed the multiplex detection of the open reading frame 1a/b (ORF1ab) and the N-
protein within an hour, ensuring the sufficient sensitivity for the virus [228].
In another approach, Qiu et al. developed a dual-functional plasmonic biosensor that
combines the plasmonic photothermal (PPT) effect and LSPR sensing transduction. The device is
constituted by a two-dimensional gold nano island functionalized with complementary DNA
receptors that can selectively detect specific sequences from SARS-CoV-2 through nucleic acid
hybridization. In addition to that, PPT can increase the in situ hybridization temperature, which
allows differentiating between two similar gene sequences. This biosensor showed high sensitivity
with a lower LOD at 0.22 pM (i.e., 10-12 M) [229].
Although we have discussed several options for COVID-19 diagnosis, researchers are
working on novel diagnostic techniques that combine different approaches based on
nanotechnology and nanoscience, in order to obtain faster, reliable, and more accurate results that
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allow accelerating life-saving decisions, and isolation of positive patients in an early stage to down-
regulate the virus spread [230,231].
6. Conclusions
Last few decades, viral and bacterial pathogens have become a real menace to human
safety. Their rapid identification must be considered as a priority task in order to prevent an
outbreak that represents a high risk of disruption of the healthcare system, and a disastrous socio-
economic impact. Scientists are performing intensive research for developing sensitive diagnostic
techniques and effective therapeutics. Although for many viruses and bacteria there is no vaccine or
pharmacological treatment, the development of a POC device for the rapid diagnosis of diseases
such as COVID-19, allows accelerating life-saving decisions, and isolation of positive patients in an
early stage. In this sense, biosensors and nano-biosensors are powerful measurement devices that
can make the detection process of important clinical bacteria and virus to be easy, quick, and
effective by sensing relevant parameter that can be related to infectious processes.
Author Contributions: Conceptualization, J.V.B. and R.C.S.; methodology, L.C.H., M.B.A., A.C.R., and J.V.B.;
investigation, L.C.H., M.B.A., and A.C.R.; resources, J.V.B.; writing—original draft preparation, L.C.H., M.B.A.,
A.C.R., and R.C.S.; writing—review and editing, L.C.H., and J.V.B.; visualization, M.B.A., A.C.R., and R.C.S.;
supervision, J.V.B.; project administration, J.V.B. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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