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Received: 13 January 2022
-
Revised: 16 March 2022
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Accepted: 26 March 2022
DOI: 10.1002/rmv.2356
REVIEW
Biomarker based biosensors: An opportunity for diagnosis of
COVID‐19
Reza Khaksarinejad
1
|Zohreh Arabpour
2
|Leila RezaKhani
3,4
|
Farzad Parvizpour
2
|Yousef Rasmi
5,6
1
Department of Toxicology, Faculty of Medical
Sciences, Tarbiat Modares University, Tehran,
Iran
2
Iranian Tissue Bank and Research Center,
Tehran University of Medical Sciences, Tehran,
Iran
3
Fertility and Infertility Research Center,
Health Technology Institute, Kermanshah
University of Medical Sciences, Kermanshah,
Iran
4
Department of Tissue Engineering, School of
Medicine, Kermanshah University of Medical
Sciences, Kermanshah, Iran
5
Department of Biochemistry, Faculty of
Medicine, Urmia University of Medical
Sciences, Urmia, Iran
6
Cellular and Molecular Research Center,
Urmia University of Medical Sciences, Urmia,
Iran
Correspondence
Farzad Parvizpour, Iranian Tissue Bank and
Research Center, Tehran University of
Medical Sciences, Tehran, Iran.
Email: f-parvizpour@razi.tums.ac.ir
Yousef Rasmi, Department of Biochemistry,
Faculty of Medicine, Urmia University of
Medical Sciences, Urmia, Iran.
Email: Yrasmi@gmail.com
Abstract
Early diagnosis and treatment of diseases are crucial research areas of human
health. For early diagnosis, one method that has proven efficient is the detection of
biomarkers which can provide real‐time and accurate biological information. Most
biomarker detection is currently carried out at localised dedicated laboratories
using large and automated analysers, increasing waiting time and costs. Smaller,
faster, and cheaper devices could potentially replace these time‐consuming labo-
ratory analyses and make analytical results available as point‐of‐care diagnostics.
Innovative biosensor‐based strategies could allow biomarkers to be tested reliably
in a decentralised setting. Early diagnosis of COVID‐19 patients has a key role in
order to use quarantine and treatment strategies in a timely manner. Raised levels
of several biomarkers in COVID‐19 patients are associated with respiratory in-
fections or dysfunction of various organs. Through clinical studies of COVID‐19
patient biomarkers such as ferritin, Interleukins, albumin and …are found to re-
veals significant differences in their excretion ranges from healthy patients and
patients with SARS‐CoV‐2, in addition to the development of biomarkers based
biosensor such as stated biomarkers can be used and to investigate more specific
biomarkers further proteomic analysis can be performed. This review presents
several biomarker alterations in COVID‐19 patients such as salivary, circulatory,
coagulation, cardiovascular, renal, liver, C‐reactive protein (CRP), immunological
and inflammatory biomarkers. Also, biomarker sensors based on electrochemical,
optical, and lateral flow characteristics which have potential applications for SARS‐
COV‐2 in the recent COVID‐19 pandemic, will be discussed.
KEYWORDS
biosensors, COVID‐19, Corona virus, diagnosis
Abbreviations: ACE2, Angiotensin‐converting enzyme 2; α‐HBDH, Alpha‐Hydroxybutyrate Dehydrogenase; ALT, Aminotransferase Alanine; AST, Aspartate aminotransferase; BNP, B‐type
natriuretic peptide; BNU, Blood Urine Nitrogen; CK, Creatine kinase; CK‐MB, Creatinine kinase‐muscle/brain activity; COVID‐19, Coronavirus Disease 2019; CRP, C‐Reactive Protein; CTn‐I,
Cardiac Troponin I; EIS, Electrochemical impedance spectroscopy; ELISA, Enzyme‐Linked Immunosorbent Assay; ESR, Erythrocyte Sedimentation Rate; FGF, Fibroblast growth factors; G‐
CSF, Granulocyte Colony Stimulating Factor; GFR, Glomerular filtration rate; GM‐CSF, Granulocyte‐macrophage colony‐stimulating factor; GOT, Glutamic Oxaloacetic Transaminase; GPT,
Glutamic Pyruvic Transaminase; Gr‐FET, Graphene Field Effect Transistor; HBV, Hepatitis B virus; HEV, Hepatitis E virus; IgA, Immunoglobulin A; IL, Interleukin; INF, Interferon; IP,
Interferon gamma‐induced protein; LDH, Lactate Dehydrogenase; LFD, Lateral Flow Device; LSPCF, Localised Surface Plasmon Coupled Fluorescence; LSPR, Plasmonic Photothermal; Mb,
Myoglobin; MCP, Monocyte chemoattractant protein; MIP, Macrophage Inflammatory Protein; NLR, Neutrophil/Lymphocyte Ratio; NT‐proBNP, N‐terminal of the prohormone brain
natriuretic peptide; PDGF, Platelet‐Derived Growth Factor; PLR, Platelet/Lymphocyte Ratio; PPT, Receptor Binding Domain; QDs, Quantum Dots; RBD, Receptor Binding Domain; SARS‐
CoV‐2, Severe Acute Respiratory Syndrome Coronavirus; sHLH, Hemophagocytic Lymphohistiocytosis; TB, Total Bilirubin.
Zoherh Arabpour is co‐first author.
Rev Med Virol. 2022;e2356. wileyonlinelibrary.com/journal/rmv © 2022 John Wiley & Sons Ltd.
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https://doi.org/10.1002/rmv.2356
1
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INTRODUCTION
A novel human coronavirus, called severe acute respiratory syn-
drome coronavirus 2 (SARS‐CoV‐2), causing the disease COVID‐19
was identified in China in December 2019.
1
Severe acute respira-
tory syndrome coronavirus 2 has acquired the ability to establish
sustained human to‐human transmission. Its basic reproductive
number, the number of secondary infections generated from one
infected individual, is estimated to be between 1.4 and 6.49, with a
mean of 3.28.
2
The recent emergence of SARS‐CoV‐2 in the human
population has caused a dramatic and unprecedented impact of the
economy and prompted mobilisation of public health authorities
around the world to counter the rapid spread of the virus, and a wide
variety of methods have been developed for the purpose of the rapid
and accurate diagnosis of COVID‐19 virus.
3
Several studies have
reported haematologic and blood chemistry alterations in patients
infected by SARS‐CoV‐2.
1
Major laboratory findings in COVID‐19
patients identified by meta‐analysis include leucopenia, leucocy-
tosis, decreased albumin levels, increased levels of C‐reactive pro-
tein (CRP), lactate dehydrogenase (LDH), creatinine kinase, and
bilirubin, and a high erythrocyte sedimentation rate (ESR).
4
A
growing body of evidence suggests that SARS‐CoV‐2 infection can
trigger the overproduction of cytokines in some patients, known as a
cytokine storm, which is associated with poor outcomes.
5
As for
other severe viral infections, the exacerbated production of proin-
flammatory cytokines may be involved in some of the pathophysi-
ology of COVID‐19, including pulmonary oedema, lung failure, and
damage to the liver, heart, and kidneys. Compared to healthy adults,
COVID‐19 patients had higher levels of several biomarkers such as
IL‐1β, IL‐1RA, IL‐7, IL‐8, IL‐9, IL‐10, basic fibroblast growth factors,
granulocyte colony stimulating factor (G‐CSF), granulocyte‐
macrophage colony‐stimulating factor, IFN‐γ, IP‐10, MCP‐1, MIP‐
1A, MIP‐1B, platelet‐derived growth factor, and VEGF.
5
Serum bio-
markers associated with severe disease included IL‐2, IL‐7, IL‐10, G‐
CSF, IP‐10, MCP‐1, MIP‐1A, and TNF‐α.
5
A recent retrospective
study of 150 confirmed COVID‐19 cases (68 fatal and 82 discharged
cases) in Wuhan, China, identified several serological biomarkers
that were more elevated in lethal cases than in survivors: elevated
ferritin, IL‐6, myoglobin, CRP, and cardiac troponin.
6
Together, these
findings suggest that COVID‐19 makes alterations in biomarkers
compared to healthy individuals.
Since stricter requirements regarding human health have led to a
rising number of clinical tests, there is an increasing need to develop
highly sensitive, fast, and economic methods of analysis.
7
There are
several reported biosensors based on biomarkers that accurately
detect particular diseases such as non‐invasive biosensor developed
by Kumar et al.,
7
for oral cancer detection which used CYFRA‐21 as a
specific biomarker for oral cancer, same as these specific biomarkers
for COVID‐19 can also be used, and biosensor can be made.
8
The
development of biosensors is probably one of the most promising
ways to solve some of the problems concerning the increasing need
to develop highly sensitive, fast, and economic methods of analysis in
medical diagnostics.
7
In this review, some consideration will be given to biomarkers
levels in COVID‐19 patients as well as biomarkers based‐biosensors
and their application in medical diagnostics, taking into account
several crucial features. Researchers can break through bottlenecks
of existing biomarker sensors by reviewing previous works and finally
meet the various complex detection needs for the early diagnosis of
COVID‐19. The purpose of this review is to understand the present
by reviewing the past.
1.1
|
Types of biomarkers
Early identification and classification of COVID‐19 patients is very
important in order to use treatment strategies in a timely manner.
9
According to research, several biomarkers have been identified
to be increased in COVID‐19 patients that are associated with res-
piratory infections and dysfunction of various organs. Prognostica-
tion of intense diseases such as COVID‐19 can be possible by
Prognostic biomarkers.
10
According to research, markers of the
surface and sequence of the genome of the COVID‐19 virus have
been identified. This data is essential for identifying new biomarkers
that can be used to diagnose and predict pandemics.
11
1.1.1
|
Salivary biomarkers
Saliva is a hypotonic fluid secreted by the salivary glands, including
the parotid, submandibular, and sublingual glands. Since salivary
glands have high permeability and molecular exchange and are also
located in an environment rich in capillaries, blood, and acini, they
can be an appropriate source for evaluating circulating biomarkers.
12
Human salivary glands secrete 600 ml of serum and mucinous
saliva daily containing mucins, minerals, growth factors, cytokines,
buffers, electrolytes, enzymes and enzyme inhibitors, immunoglobu-
lins, and glycoproteins.
13
Saliva is currently being considered as a
potential diagnostic tool and as an alternative to other biological
fluids such as serum or urine for diagnosis. Saliva assessment is a
non‐invasive, self‐collecting method for detecting and monitoring
COVID‐19. Several salivary biomarkers, including salivary meta-
bolism, have the ability to better detect COVID‐19 and possibly
identify a disease with the ability to classify the severity of the dis-
ease and even identify asymptomatic carriers.
14
It is competitive with
nasopharyngeal swabs in terms of sensitivity and properties.
Human saliva is exuded about 600–1000 ml from the salivary
glands every day. Saliva, like a serum, contains growth factors, IgA,
cytokines, hormones, antibodies, enzymes, and microbes and has the
diagnostic ability. Therefore, saliva can be used as a fluid to assess
the physiological function of the body.
15
Although it is difficult to
evaluate some analytics in saliva due to their low concentration
compared to blood, highly sensitive molecular methods and nano-
technology have largely solved this problem. Saliva has been used to
diagnose several diseases, including malignancies, autoimmune and
hereditary diseases.
16
Saliva could be evaluated in terms of
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KHAKSARINEJAD
ET AL.
proteomics, transcriptomics, metabolomics, microRNA, micro-
biome.
17
The viral infections are detectable by evaluating of presence
viral RNA, DNA, microRNA, antigens, or antibodies in saliva, and
some kind of viral infections may be detected up to 29 days after
contamination.
18,19
The potential use of saliva for the diagnosis of SARS‐CoV‐2 by
expression of ACE2 as a SARS‐CoV‐2 major surface receptor
20
from
the salivary gland has been scientifically proven.
21
In addition, recent
studies by To et al. Have shown the presence of live SARS‐CoV‐2 in
saliva.
22
The diagnostic use of saliva for several viral infections such
as coronavirus has been shown >90% accordance between saliva and
pharyngeal swabs.
23
Recently, salivary biomarkers have been considered to use in
advanced technologies like electro‐mechanical systems, RNA‐
sequencing, fluorescent biosensors, photometric and electro-
chemical, and lab‐on‐chips.
24
Reduction or delayed generation of
interferon (IFN) after coronavirus infection leads to high inflamma-
tory reactions that lead to severe pulmonary disorders.
25
The inflammatory cytokines production is depends on infection
severity.
26
Increased expression of pro‐inflammatory chemokines
and cytokines, such as chemokine ligand (CC motifs; CCL) ‐2, CCL‐3,
Regulated on Activation, Normal T Cell Expressed and Secreted
(RANTES), interleukin (IL) ‐2 and IL‐8 have been shown during MERS‐
CoV infection.
26
According to recent studies in COVID‐19 patients
with increasing severity of infection, the amount of gamma‐induced
protein, interferon gamma 10 kDa, IL‐2, IL‐6, IL‐7, IL‐10, gran-
ulocyte colony‐stimulating factor, macrophage chemotactic protein 1,
macrophage inflammation of protein‐1A, and tumour necrosis factor‐
α(TNFα) in serum were increased to inflammatory response induced
of cytokine secretion.
5,25
Also, inflammatory markers like chemo-
kines and cytokines are present in saliva and this source is available
for diagnosis and prognosis of oral and systemic diseases such as
COVID‐19 infection.
16
Biomarkers such as lactate hydrogenase, CRP,
malic acid, platelet degranulation, guanosine monophosphate, and
macrophage‐related proteins could be detected in saliva as well as in
plasma.
Metabolism or the study of small molecules in cells, tissues, or
fluids that identify a phenotype. Metabolomics are used to identify
biomarkers and describe metabolic pathways in a variety of clinical
conditions, including viral pathogens, especially those that affect the
respiratory system, such as SARS and influenza.
27,28
There are studies that suggest the specific regulation of micro-
RNA is related to various infections, including respiratory virus
infection.
29
The previous study has been demonstrated the effect of
upregulation of miR‐574‐5p and miR214 expression and down-
regulation of miR‐223 and miR‐98 expression on pro‐inflammatory
cytokines generation in coronavirus (SARS‐CoV) infection.
30
Recently, the expression potential of microRNAs has been
considered as salivary biomarkers because microRNAs in extracel-
lular vesicles are protected from degradation. Therefore, micro-
RNAs in the biological fluid can be used to assess the condition of
cell infection.
18
SARS‐CoV‐2 infects the host respiratory tract cells
via ACE2 receptors.
31
Also previous studies the expression of
ACE2 receptor in epithelial cells of salivary glands, oral and the
tongue in humans.
32
So it can be an available source for the
detection of SARS‐CoV‐2 infection.
33
Furthermore, the salivary
glands may have hidden COVID‐19 infection that may be
activated.
34
According to the information obtained, the study of salivary
biomarkers is an opportunity to achieve a more complete molecular
view of the clinical relationship and risk assessment of COVID‐19, as
well as the evaluation of new antiviral therapies.
1.1.2
|
Blood biomarkers
Using of recovered COVID‐19 patients serum has been approved as
a safe and effective treatment in severe patients or to strengthen
instant immunity of high‐risk patients.
35,36
Boostels et al. have shown
that a new class of inflammatory dendritic cells (inf‐cDC 2) as a virus‐
specific antibody in serum can increase patient immunity.
37
In clinical
trials, collecting enough volunteers for testing is one of the most
important limitations.
In an interesting study, patients who recovered from acute res-
piratory syndrome induced by SARS‐CoV were evaluated by meta-
bolic assessment after 12 years. Phospholipids, organic acids, amino
acids, carnitine, and inositol in the serum of these patients were
different from healthy persons. Therefore, metabolism will be
considered to evaluate long‐term results.
28
The existence of IgM and IgG blood antibodies in the serum
versus COVID‐19 proteins (e.g., S and N protein) can show a history
of the previous infection regardless of any symptoms. Serum evalu-
ation methods like lateral flow assays and ELISAs, to tracing of IgM/
IgG antibodies or S and N proteins have been improved in human
plasma (Figure 1).
Primitive SARS‐COV‐2 infection could be diagnosed by increases
level of IgM antibodies 3–7 days after the viral attack and secondary
SARS‐COV‐2 infection can be determined by enhancement of IgG
level in serum that is mostly associated with increased IgM level.
Generally, the presence of IgG or IgM/IgG in the serum shows active
immunity.
38
According to research, the diagnosis of IgM was more
variable than IgG and the results of both should be analysed to more
precisely evaluate.
39
White blood cells
Evaluation of immune response in 450 COVID‐19 patients has been
reported that severe cases compared with mild cases had lower
lymphocyte counts, higher leucocyte, and lower percentages of eo-
sinophils, basophils, and monocytes.
40
Henry et al., in another study
of 3377 COVID‐19 patients with a severe and fatal disease, reported
that patients' WBCs increased significantly and the number of lym-
phocytes and platelets decreased compared with non‐severe dis-
ease.
41
In COVID‐19 patients with severe cases, the level of helper T
cells, memory helper T cells, and T regulatory cells were less than
normal levels while the percentage of naïve helper T cells and sup-
pressor T cells were increased.
42
KHAKSARINEJAD ET AL.
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To control viral infection, the role of cytotoxic lymphocytes, like
natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), are
essential, and decreased cytotoxic lymphocytes potency is associated
with exacerbation of the disease.
43
In some studies demonstrated that SARS‐CoV‐2 patients had a
lower amount of T cells, NK and, B cells.
44,45
According to the
research decreased specific subtypes of T lymphocytes such as
lymphocyte (<500/µL), B cell (<50/µL), CD3
+
T cell (<200/µL), CD4
+
T cell (<100/µL) and CD8
+
T cell (<100/µL) were observed in pa-
tients who died of COVID‐19 infection in hospital.
46
Analysis of eosinophil count in COVID‐19 patients showed that
although in most COVID‐19 patients eosinopenia was seen at
admission and returned to normal before discharge, in some cases
eosinopenia was not reported, so eosinopenia could not be a po-
tential predictor for COVID‐19 progression.
47–49
Neutrophil/
lymphocyte count ratio (NLR) is used as an inflammatory marker to
predict mortality in cardiovascular disease
50,51
Also, NLR is known as
a biomarker for severe diseases such as sepsis.
52
In studies in pa-
tients with severe COVID‐19 infection have been shown that NLR
amount was remarkably increased.
53
Platelet
Platelet counts are used as available biomarkers to assess disease
severity and mortality risk in intensive care units (ICUs).
54
In COVID‐
19 patients, platelet depletion has been reported to be significantly
associated with disease severity and risk of death.
55,56
Previous
studies have shown that COVID‐19 patients with higher platelets
and platelet/lymphocyte ratio (PLR) stayed longer in the hospital.
57
C‐reactive protein (CRP)
C‐reactive protein is a serum protein generated by the liver through
the stimulation of various inflammatory mediators such as IL‐6. This
biomarker is used to assess various inflammatory conditions and
prediction of disease severity.
58
C‐reactive protein is one of the first
biomarkers in serum that indicates the physiological condition. Ac-
cording to the studies, severe COVID‐19 patients had higher CRP
(>41.8 mg/L) levels.
59
C‐reactive protein levels were an important
indicator of the presence and severity of COVID‐19 infection.
Although the same study showed that in some COVID‐19 patients,
serum amyloid (SAA) levels were changed significantly instead of
CRP levels. However, with more evaluations, this biomarker can be
used to predict the progression of COVID‐19 infection.
60
This
biomarker in the beginning period of infection is more sensitive
versus ESR to indicate the severity of COVID‐19 infection.
61,62
D‐dimer
D‐dimer is derived from fibrin lysis and its increase indicates acti-
vation of coagulation and fibrinolysis.
63
Because COVID‐19 is asso-
ciated with haemostatic disorders, high levels of D‐dimer were
observed among patients.
64
D‐dimer levels were increased in
approximately 90% of patients admitted to pneumonia. It was
directly related to the mortality rate.
65
It can be an appropriate
marker for predicting severity and mortality in COVID‐19 patients.
62
1.1.3
|
Cardiovascular biomarkers
The most common clinical complications of COVID‐19 are acute
respiratory distress syndrome and lung disturbance. Also, the car-
diovascular disorder is another complication of this viral disease.
Evidence suggests the prediction of COVID‐19 severity and mortality
by cardiac biomarkers.
10
According to the researches, in COVID‐19 patients the number
of cardiac markers such as alpha‐hydroxybutyrate dehydrogenase (α‐
HBDH), Lactate dehydrogenase (LDH), creatine kinase (CK), aspar-
tate aminotransferase (AST), N‐terminal of the prohormone brain
natriuretic peptide (NT‐proBNP), creatinine kinase‐muscle/brain ac-
tivity (CK‐MB), myoglobin (Mb) and cardiac troponin I (cTnI) were
enhanced.
66
Increased in CTnI, NT‐proBNP, CK‐MB, and Mb
biomarker indicate the heart injury (Table 1) but an increase of LDH,
CK, α‐HBDH, and AST as cardiac enzymes, may not necessarily
indicate cardiac damage.
74
The most common clinical complications of COVID‐19 are acute
respiratory distress syndrome and lung disturbance. Also, the car-
diovascular disorder is another complication of this viral disease.
Evidence suggests the prediction of COVID‐19 severity and mortality
by cardiac biomarkers.
10
According to the researches, in COVID‐19 patients the number
of cardiac markers such as alpha‐hydroxybutyrate dehydrogenase (α‐
HBDH), Lactate dehydrogenase (LDH), creatine kinase (CK),
FIGURE 1 Schematic of serological
antibody testing by a lateral flow assay for
COVID‐19. Reprinted from
11
4 of 18
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KHAKSARINEJAD
ET AL.
aspartate aminotransferase (AST), N‐terminal of the prohormone
brain natriuretic peptide (NT‐proBNP), creatinine kinase‐muscle/
brain activity (CK‐MB), myoglobin (Mb), and cardiac troponin I (cTnI)
were enhanced.
66
Increased in CTnI, CK‐MB, NT‐proBNP and Mb
biomarker indicate heart injury but an increase of LDH, CK, α‐HBDH,
and AST as cardiac enzymes, may not necessarily indicate cardiac
damage.
74
The lungs and heart express the angiotensin‐converting enzyme
2 (ACE2).
74
Studies have shown that ACE2 receptor expression is
directly associated with SARS virus attack,
77
and SARS‐CoV infection
can cause ACE2‐dependent cardiomyocyte infection.
78
In addition,
some studies have confirmed that due to cardiac expression, SARS‐
CoV‐2 viruses easily attack cardiomyocytes and destroy car-
diomyocytes, thereby altering cardiac markers.
79
Troponin is a cardiac biomarker that can be used to predict and
assess the severity of heart damage. According to the studies,
COVID‐19 patients who died had a higher amount of troponin than
those who survive.
80
Heart injury is a complication of COVID‐19 patients, the severity
of infection is associated with increase B‐type natriuretic peptide
(BNP) levels as well as high‐sensitivity cardiac troponin I (hs‐TnI). So
the early detection and severity prediction of COVID‐19 can be
carried out by measuring Cardiac biomarkers BNP and hs‐TnI.
80
1.1.4
|
Immunological and inflammatory biomarkers
The most of severe COVID‐19 cases demonstrated elevated levels
of infection‐related biomarkers and inflammatory cytokines. Virus
particles spread through the respiratory mucosa, initially using the
ACE2 receptor at ciliated bronchial epithelial cells, and infect other
cells, induce a cytokine storm in the body, generate a series of
immune responses, and cause changes in peripheral white blood
cells and immune cells such as lymphocytes.
20,81,82
The total white
cell count was less consistently elevated among COVID‐19 pa-
tients who required ICU admission or died compared to patients
who did not.
61,83,84
The neutrophil to lymphocyte ratio (NLR) is a
well‐known marker of inflammation and appears to reflect the
severity of COVID‐19, particularly among patients older than
50 years of age.
85,86
Higher serum levels of pro‐inflammatory cy-
tokines (TNF‐α, IL‐1, and IL‐6) and chemokines (IL‐8) were found
in patients with severe COVID‐19. It demonstrated pronounced
lymphopenia and low counts of CD3+cells and CD4+cells in
COVID‐19 cases.
87
The frequency of lymphopenia found suggests
that COVID‐19 might act on lymphocytes, especially T lympho-
cytes.
25
Secondary hemophagocytic lymphohistiocytosis (sHLH) is
an under‐recognised, hyperinflammatory syndrome characterised
by a fulminant and fatal hypercytokinaemia with multiorgan failure.
In adults, it is most commonly triggered by viral infections.
88
A
cytokine profile resembling sHLH is associated with COVID‐19
disease severity, characterised by increased Interleukin (IL2‐IL7),
Granulocyte colony stimulating factor, Interferon‐γ, Inducible pro-
tein 10, Monocyte chemoattractant protein, macrophage inflam-
matory protein 1‐α and tumour necrosis factor‐α.
5
Immunoglobulin
G and M (IgG and IgM) were detected from the human serum of
COVID‐19 patients using an enzyme‐linked immunosorbent assay
(ELISA).
89
Many properties of IgM make this immunoglobulin
particularly well‐suited to its role in microbial immunity. But IgM
has a relatively short half‐life in the serum, approximately 28 h, in
normal mice in the absence of antigen. It is present in high con-
centrations in blood (in the range of 1.5 mg/ml), and is the first
antibody elicited in immune response following immunisation or
infection. IgG and IgM antibodies were detected in SARS‐CoV‐2
cases and increased to 81% and 100% at day five.
90
C‐reactive
proteins are another protein or cellular marker that can be used
for detection. Studies showed that infected patients had elevated
levels of CRP and D‐dimer as well as low levels of lymphocytes,
leucocytes, and blood platelets.
9
TABLE 1A table of prognostic valuable cardiac biomarkers in the coronavirus patients (COVID‐19)
Cardiac
biomarker Definition Dependence with COVID‐19
Prognostic
potential References
cTn cTnI and cTnT are specific biomarkers of myocardial necrosis,
regardless of injury mechanism
67
Increased cTnI/cTnT is
associated with
‐Acute myocardial damage
‐ICU admission
‐In hospital death
‐Severity COVID‐19
infection
+++
5,68
BNP BNP predicts the severity of acute myocardial injury. BNP levels rise
immediately after myocardial injury, this level is directly related to
the severity of the injury.
69
BNP raised by
‐Acute myocardial damage
‐ICU admission
‐In hospital death
++
70,71
CK‐MB CK‐MB is a biomarker of heart damage and blood flow. CK‐MB level is
directly related to the severity of the injury.
72,73
Increased CK‐MB is
associated with
‐Acute myocardial damage
‐ICU admission
‐In‐hospital death
+
74‐76
KHAKSARINEJAD ET AL.
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1.1.5
|
Renal biomarkers
There is also an indication that kidney injury is related to infection
with COVID‐19.
41
There are many biomarkers for kidney dysfunction
diagnosis which can be divided into urinalysis and blood indicators
related to kidney injury.
91
Biomarkers of renal impairment, including
an increase in creatinine, blood urine nitrogen (BUN), and the pres-
ence of AKI have been reported in most studies.
77
Furthermore, in-
dependent of age and sex, a higher baseline creatinine, underlying
proteinuria, and haematuria were associated with a higher risk of
mortality.
62,92
In patients with severe disease, creatinine and BUN
levels were consistently higher in men compared to women and older
males were more likely to have a higher baseline creatinine and
develop AKI,17.
92
Although studies have not investigated the effect of
sex on renal biomarkers and COVID‐19 severity. A woman's hormonal
environment, however, is thought to have a protective effect against
the development of AKI and females have been previously shown to
be at lower risk of AKI compared to males.
93
Similarly, smaller studies
of renal transplant patients have suggested that male sex may be a risk
factor for AKI in COVID‐19.
94
Table 2lists the types of biomarkers in
the diagnosis of Covid‐19 related to renal impairment.
1.1.6
|
Liver biomarker
Liver dysfunction caused by COVID‐19 has also been identified in
some cases, which may suggest a risk of liver damage caused by
COVID‐19.
95
Popular causes with different degrees of hepatic
damage are viral agents such as hepatitis C virus (HCV), hepatitis B
virus (HBV) and hepatitis E virus (HEV). In addition, some studies
have indicated that SARS‐infected patients and MERS‐infected pa-
tients have elevated liver enzyme levels and differing degrees of liver
damage.
96,97
In intense COVID‐19, hepatic dysfunction is followed by
relatively greater activation of coagulative and fibrinolytic pathways,
depressed counts of platelets, climbing counts of neutrophils and
neutrophils lymphocyte percentages, and elevated amounts of
ferritin.
66
Therefore, it is necessary to pay attention to the level of
liver tests in Covid‐19 patients. Aminotransferase aspartate (AST)
and aminotransferase alanine (ALT) are enzymes present in heart
cells, muscle tissue, red blood cells, and other tissues, such as the
pancreas and kidneys, are found primarily in the liver. AST and ALT
were previously referred to as serum glutamic oxaloacetic trans-
aminase (GOT) and serum glutamic pyruvic transaminase (GPT),
respectively.
98
In COVID‐19 patients, the prevalence of elevated ALT
and AST levels ranged from 14% to 53%.
99
However, liver dysfunc-
tion tests have concentrated mostly on improvements in the levels of
ALT, AST, and total bilirubin (TB). The role of prealbumin has been
underestimated as an important biomarker for assessing the liver's
protein synthesis function.
100
Increased TB and decreased albumin
were seen in patients with Covid‐19.
101
1.1.7
|
Coagulation biomarkers
COVID‐19 patients with thrombotic complications generally follow a
course of disease that is more aggressive. Moreover, evidence
consistently demonstrates the negative prognostic value of individual
coagulation parameters, including elevated D‐dimer
41,102
and
reduced platelet counts.
76,77
The underlying mechanism of coagul-
opathy in COVID‐19 patients is a disproportionate inflammatory
response resulting in endothelial cell dysfunction and a pro‐
thrombotic state.
103
Due to ACE2 receptor expression on endothe-
lial cells, the COVID‐19 virus may cause endotheliitis, which could
result in not only arterial and venous inflammation but also micro-
circulatory and lymphocytic endotheliitis. Patients with severe
COVID‐19 develop a hypercoagulable state.
78
Further demonstrated
by increased levels of factor VIII and von Willibrand factor, margin-
ally decreased anti‐thrombin III activity,
104
and inactivation of the
fibrinolytic system.
105
These derangements likely underlie venous
thromboses; arterial thromboses that may present as ischaemic
stroke, mesenteric ischaemia, and acute limb ischaemia, and the
phenomenon of free‐floating thrombi seen in COVID‐19 infection‐
related thrombotic events.
106
2
|
BIOSENSORS
During the last decade, electrochemical biosensors have emerged as
reliable analytical devices and represent a new promising tool for the
detection of different pathogenic viruses. Future research also looks
at the use of biosensors regarding a potential detection kit for the
rapid identification of the COVID‐19. Biosensors should offer quick
and efficient detection of viral diseases with high levels of specificity
and sensitivity.
107
These criteria are crucial in the success or failure
of the detection technology. As such, the choice of the targets of any
given pathogen can be a deciding factor. There are two strategies
followed: viral nucleic acid or specific proteins or biomarkers.
Nanotechnology‐based biosensors are known for their promising
results in addition to their advantage of being highly customisable
through immobilisation, labelling, and biofunctionalisation. In order
to find an efficient biomolecule immobilisation, a surface plasmon
resonance (SPR) biosensor was developed for SARS‐CoV based on
the use of gold binding polypeptide (GBP).
108
GBP was fused to
enhanced green fluorescent protein (GBP‐E) and to SARS‐CoV
membrane envelope (SCVme), the latter that can bind to anti‐
SCVme antibodies.
TABLE 2Biomarkers associated to blood test and urinalysis in
renal injury
Urinalysis Blood test
Proteinuria Creatinine (cr)
Haematuria Blood urea nitrogen (BUN)
Leukocyturia Estimated glomerular filtration rate (GFR)
Urine glucose Cystatin C
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Laboratory detection approaches for COVID‐19 in biological
samples demonstrate many pros and cons where the sequestration of
the virus could be obtained via cell culture, quick antibody kits, blood
samples, and other technologies such as CRISPR or biosensor‐based
methodologies. They are all assays actively utilised in epidemiological
studies and point of care applications.
109,110
2.1
|
Types of biosensors
2.1.1
|
Electrochemical biosensors
Electrochemical impedance spectroscopy (EIS) is considered as an
efficient technique, which even detects any tiny changes that occur at
the solution–electrode interface. However, considering highly sensi-
tive and selective, cost‐effective, simple, label‐free detection, POC
testing, antibody seroprevalence, nucleic acid amplification‐free, and
rapid diagnosis, electrochemical biosensors might be potential for the
detection of COVID‐19 (Figure 2).
112‐115
The development of elec-
trochemical biosensors for COVID‐19 detection is now in the early
stage. Therefore, thorough review of an electrochemical biosensor
for virus detection will help biosensing communities as soon as
to develop an effective electrochemical biosensor platform for
COVID‐19.
2.1.2
|
Electrochemical immunosensors
The application of immunosensors in clinical diagnosis and moni-
toring of diseases has been reported for the detection of bio-
markers,
114,116
and viruses.
117
In electrochemical immunosensors,
the biological signal is converted into an electrical signal when the
antigen‐antibody complex is formed.
84
Recently, an electrochemical
immunosensor has been developed for the detection of highly
pathogenic coronavirus associated with the MERS‐CoV.
77
Another
immunosensor based on ELISA have revealed to detect total anti-
bodies (Ab), IgM and IgG against COVID‐19 from human serum. IgM
and IgG detection methods were based on IgM μ‐chain capture
method (IgM‐ELISA) and recombinant nucleoprotein respectively.
86
A biosensor device (eCovSens) has built and compared with a com-
mercial potentiostat for the detection of nCovid‐19 spike antigen
(nCovid‐19Ag) in spiked saliva samples. A potentiostat based sensor
was fabricated using fluorine doped tin oxide electrode (FTO) with
gold nanoparticle (AuNPs) and immobilised with nCovid‐19 mono-
clonal antibody (nCovid‐19Ab) to measure change in the electrical
conductivity (Figure 3).
118
In order to facile and fast screening/
diagnosis of novel coronavirus, a sensitive graphene field effect
transistor (Gr‐FET) is combined with highly selective antibody‐
antigen interaction to develop a coronavirus immunosensor. The
Gr‐FET immunosensors can rapidly identify (about 2 min) and accu-
rately capture the COVID‐19 spike protein S1 (which contains a
receptor binding domain, RBD) at a limit of detection down to
0.2 pM, in a real‐time and label‐free manner.
25
This sensor was
constructed by conjugating the graphene of the FET with an antibody
against the spike protein of the COVID‐19 via 1‐pyrenebutyric acid
N‐hydroxysuccinimide ester. The platform was able to detect the S
protein as low as 1.0 fg/ml in PBS while in clinical transport medium it
reached 100 fg/mL.
119
2.1.3
|
Electrochemical nucleo‐sensors
COVID‐19 is an RNA virus and has single‐strand RNA instead of
ssDNA. By utilising the corresponding immobilisation of the single‐
stranded DNA probe nucleotide on to the biosensor, a specific viral
RNA sequence of COVID‐19 can be detected. A DNA probe is made
with functionalised gold nanoparticles as the transducing elements
(AuNP) chips to match specific viral RNA sequences through nucleic
acid hybridisation. This plasmonic photothermal biosensor is pro-
posed for highly sensitive and accurate COVID‐19 detection by
FIGURE 2 Coronavirus electrochemical biosensors arrangement
111
KHAKSARINEJAD ET AL.
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testing on SARS‐CoV (Figure 4).
120
However, the DNA‐hybridisation‐
based disease diagnosis requires the extraction of target DNA/RNA
from the infected host and the subsequent sample preparation.
In another attempt, label‐free electrochemical detection of DNA
hybridisation has been presented as a potential approach for COVID‐
19 diagnosis by using complementary thiolated probes (Figure 5).
121
The methods of electrochemical analysis to be used for data acqui-
sition and subsequent calibration, in relation to target analytic
detection. DNA hybridisation can be considered as a portable elec-
trochemical sensor for point mutation detection of COVID‐19‐
specific viral RNA/cDNA.
2.1.4
|
Electrochemical protein sensors
It is predicted that the whole virus SARS‐CoV‐2 have 28 proteins
with particle size in the ranges of 50–200 nm,
122–124
and their
structural proteins include the spike (S) glycoprotein, small envelope
(E) protein, matrix (M) protein, nucleocapsid (N) protein, and also
several accessory proteins can be used as antigens for COVID‐19
diagnosis. For example, N protein from SARS‐CoV is recognised by
using quantum dots‐conjugated RNA aptamer immobilised over a
designed chip
125
or the spike (S) glycoprotein was detected by the
Graphene FET technique (Figure 6).
The FET system has detected SARS‐CoV‐2 based on the
changes in channel surface potential and its effect on the electrical
response. The gate surface of FET is covered with a layer that can
be modified with biomolecules for selective detection of targets
(Figure 7).
127
Graphene FET was decorated with an antibody of
SARS‐CoV‐2 spike S1 subunit protein (CSAb) or angiotensin‐
converting enzyme 2 (ACE2) to detect SARS‐CoV‐2 spike protein
S1. The binding of the S1 protein that possesses a slightly positive
charge with the CSAb/ACE2 receptors on the graphene surface
changed the conductance/resistance in graphene‐FET which was
FIGURE 3 Plasmonic properties of Au nanoparticles in a potentiostat based sensor.
87
(a) A schematic diagram of nanostar synthesis.
(b) TEM images of 5 nm AuNP, enhanced 70 nm AuNP, and nanostars (scale bar: 100 nm). (c) Extinction spectra of 5 nm AuNP (black), 70 nm
AuNP (blue), and nanostars (red). The maximum absorbances of 5 nm AuNP, 70 nm AuNP, and nanostars occur at 519 nm, 543 nm, and
809 nm, respectively. (d) FDTD‐simulated scattering spectra of the corresponding nanoparticles. (e) Simulated local field distribution around a
70‐nm spherical AuNP at λ=532 nm, a Au nanostar at λ=532 nm, and a Au nanostar at λ=773 nm
8 of 18
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ET AL.
considered the basis of the detection. CSAb modified graphene‐FET
exhibited better sensitivity due to the higher affinity of this
antibody.
128
2.2
|
Optical biosensors
Optical biosensors focus on the measurement of a change in the
optical characteristics of the transducer surface when the analyte
and recognition element form a complex. These biosensors can be
divided into two groups. For example, signal generation depends on
the formation of a complex on the transducer surface in the direct
optical biosensor. The indirect optical biosensors are mostly
designed with various labels such as fluorophores or chromophores
to detect the binding events and amplify the signal.
129
A dual‐
functional plasmonic biosensor combining the plasmonic photo-
thermal (PPT) effect and localised surface plasmon resonance
(LSPR) sensing transduction provides an alternative and promising
solution for the clinical COVID‐19 diagnosis. The two‐dimensional
gold nanoislands (AuNPs) functionalised with complementary DNA
receptors can perform a sensitive detection of the selected se-
quences from SARS‐CoV‐2 through nucleic acid hybridisation. For
better sensing performance, the thermoplasmonics heat is gener-
ated on the same AuNPs chip when illuminated at their plasmonic
resonance frequency. The localised PPT heat is capable to elevate
the in situ hybridisation temperature and facilitate the accurate
discrimination of two similar gene sequences.
130,131
A tunable
biosensor using the localised surface plasmon resonance (LSPR),
controlling the distance between fluorescent CdZnSeS/ZnSeS
quantum dots (QDs) and gold nanoparticles (AuNPs) has been
developed for the detection of the virus. The distance between the
AuNPs and QDs has been controlled by a linkage with a peptide
chain of 18 amino acids. In the optimised condition, the fluorescent
properties of the QDs have been enhanced due to the surface
plasmon effect of the adjacent AuNPs.
132
Successive virus binding
on the peptide chain induces steric hindrance on the LSPR behav-
iour and the fluorescence of QDs has been quenched (Figure 8).
132
The nucleocapsid (N) protein of the severe acute respiratory
FIGURE 4 The surface‐functionalised AuNI chips in the LSPR systems for specific viral sequence detection.
120
(a) Schematic illustration of
the hybridisation of two complementary strands. (b) Realtime hybridisation of RdRp‐COVID and its cDNA sequence (RdRp‐COVID‐C) with or
without the thermoplasmonics enhancement. (c) PPT enhancement on RdRp‐COVID sequence detection at different concentrations. The error
bars refer to the standard deviations of LSPR responses after reaching the steady conditions following the buffer flushing. (d) Schematic
illustration of inhibited hybridisation of two partially matched sequences. The red arrows indicated the mismatch bases of RdRp‐SARS and
functionalised cDNA of RdRp‐COVID. (e) Discrimination of two similar sequences with PPT heat. The laser was applied at 200 s and switched
off at 700 s. (f) RdRp‐SARS sequence dissociation from the immobilised RdRp‐COVID‐C sequence. The original phase responses (red dots) and
the corresponding smoothed means (black curve) are shown
KHAKSARINEJAD ET AL.
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syndrome (SARS)‐associated coronavirus (SARS‐CoV) is an impor-
tant antigen for the early diagnosis of SARS and the detection of
diseases.
Here, a new quantum dots (QDs)‐conjugated RNA aptamer
with high sensitivity and rapidity is proposed for the detection of
SARS‐CoV N protein using an on‐chip system. It was demonstrated
that the QDs‐conjugated RNA aptamer could interact on a
designed chip specifically and sensitively. This device could form a
QDs‐conjugated biosensor prototype chip for SARS‐CoV N protein
diagnosis.
125
Based on the principle of localised surface plasmon resonance
(LSPR), an opto‐microfluidic sensing platform designed with gold
FIGURE 5 DNA immobilisation protocol
on to the gold sensing electrodes
121
FIGURE 6 Carbon quantum dots inhibit human corona virus interaction with its host receptor
126
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nanospikes, fabricated by electrodeposition, to detect the presence
and number of antibodies specific to the SARS‐CoV‐2 spike protein in
1μL of human plasma diluted in 1 ml of buffer solution, within
∼30 min. The target antibody concentration can be correlated with
the LSPR wavelength peak shift of gold nanoparticles caused by the
local refractive index change due to the antigen‐antibody binding.
This is performed in diluted human plasma without any labelling
agents, reaching a LOD of ≈0.08 ng/ml (≈0.5 pM), which falls under
the clinically relevant concentration range of specific antibodies
against bacteria or viruses responsible for the infection. This platform
shows great potential to complement the existing serological COVID‐
19 antibody tests.
133
Localised surface plasmon coupled fluorescence
(LSPCF) is another combined method of sandwich immunoassay that
a linear relationship between the fluorescence signal and the con-
centration of recombinant SARS‐CoV N (GST‐N) protein in buffer
solution could be observed from 0.1 pg/ml to 1 ng/ml. This level is
very suitable for application to the clinical diagnosis at the early stage
of SARS patients.
134
2.3
|
Lateral flow biosensors
A lateral flow device (LFD) is a particular type of biosensor, in which
the recognition layer is fabricated onto the surface of a porous
membrane. The membrane creates and sustains the flow of samples
and reagents by capillarity and holds specific recognition elements
that are confined in spatially defined zones or detection sites.
135
A
multiplex reverse transcription loop‐mediated isothermal amplifica-
tion (mRT‐LAMP) is designed that coupled with a nanoparticle‐based
lateral flow biosensor (LFB) assay (mRT‐LAMP‐LFB) for diagnosing
COVID‐19.
136
Using two LAMP primer sets, the ORF1ab (opening
reading frame 1a/b) and N (nucleoprotein) genes of SARS‐CoV‐2
were simultaneously amplified in a single‐tube reaction and detec-
ted with the diagnosis results easily interpreted by LFB. In presence
of FITC (fluorescein)‐/digoxin‐and biotin‐labelled primers, mRT‐
LAMP produced numerous FITC/digoxin and biotin‐attached duplex
amplicons, which were determined by LFB through immunoreactions
(FITC/digoxin on the duplex and anti‐FITC/digoxin on the test line of
FIGURE 7 A typical back‐gated (left) and solution‐gated (right) FET biosensors used in chemical and biological sensing applications
127
FIGURE 8 Preparation of CdZnSeS/ZnSeS
QD‐peptide‐AuNP 218 nanocomposite and
its detecting mechanism towards influenza
virus
132
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LFB) and biotin/streptavidin interaction (biotin on the duplex and
streptavidin on the polymerase nanoparticle; Figure 9).
136
3
|
FUTURE PROSPECTS AND CONCLUSION
Biosensors have been demonstrated as effective tools for early
diagnosis, on‐site, rapid, and ultrasensitive detection of SARS‐CoV‐2.
Clinical research on COVID‐19 patients shows that in addition to the
ability to assess the status of SARS‐CoV‐2 virus infection, some
biomarkers in the body also change and can be used in diagnosis,
treatment and disease monitoring. So, considering the urgent need
for fast detection of COVID‐19 the biomarkers‐based biosensors can
play an important role as it will decrease the detection time, will be
save cost, and also reduce the chance of virus transmission while
diagnosis.
COVID‐19 is a recent outbreak that occurred worldwide and
created an enormous dysfunction of various activities all around the
world.
137
The infection and spread of SARS‐CoV‐2 were firstly
observed in Wuhan city of China, has now affected nearly 200
countries worldwide.
138
In this review article, we have reviewed the significant bio-
markers which were reported in various papers after the clinical
studies in COVID‐19 patients. Biomarkers such as proinflammatory
FIGURE 9 Sensitivity of COVID‐19 mRT‐LAMP‐LFB assay. (a) LFB applied for reporting the results; (b) Real‐time turbidity applied for
reporting the results; (c) Visual detection reagent applied for reporting the results
136
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cytokines, ferritin, amyloid A and … are considerable biomarkers from
these studies which also shows a potential to detect specifically
COVID‐19 as there is a difference between secretion range and cut
off the range, and also haematological biomarkers which secreted in a
more substantial amount in COVID‐19 patient as compared to a
healthy patient.
5,139–141
COVID‐19 has become a substantial lethal disease worldwide,
and early diagnosis is a significant concern for this virus. Rapid and
early diagnosis of any disease is always a major concern for all
countries. Currently, the situation related to COVID‐19 is enormous,
as the globe does not have any rapid system for early and fast
detection of this virus.
142
Currently, RT‐PCR is being used for testing
the virus which is time taking and costly, moreover, some of the
research group has recently developed a biosensor for COVID‐19
detection through different approach but they all are invasive and
lead to virus particles exposers.
There are other techniques that can resolve this problem with a
more manageable approach and detect the virus rapidly. One of
these techniques is biomarker‐based on sensors, terming bio-
sensors.
142
The biomarker‐based biosensor can play a pivotal role,
as biomarkers are naturally occurring biomolecules specific to
particular diseases, such as CYFRA‐21 is a protein‐based biomarker
for oral cancer. Protein‐based biomarkers are easy to isolate as
compared to a nucleic acid (DNA/RNA) or cell‐based biomarker.
Moreover, the biomarkers isolation and sample preparation are
much more comfortable in protein‐based biomarker as compared
to a nucleic acid or other biomarkers. The current detection of
COVID‐19, which is RT‐PCR required RNA isolation, purification,
and processing step, which increases the time of detection and cost
of testing. It can locate out such biomarkers through proteomics
studies from COVID‐19 infected patients and find out specific
biomarkers for COVID‐19.
Furthermore, biosensors based on this approach will be non‐
invasive that can be user‐friendly in use so that the need for highly
qualified professional limits can be overcome, apart from these other
biomarkers which can also be considered in healthy patients and
COVID‐19 infected patients.
143
As well, the primary concern related
to this virus is early diagnosis, cost‐effectiveness and, reducing the
chance of spread so that working professionals also do not get
affected by human‐to‐human transmission while testing. Professional
working for the diagnosis is in a major threat to get into the contact
of this virus and get affected and to subdue this approach this bio-
markers based biosensor can be integrated with microfluidics system
which will restrict the sample amount as well as the chance of virus
transmission,
142
such as Singh et al., has tried to develop a
microfluidics‐based biosensor for influenza detection. Considering
the urgent need for rapid detection of COVID‐19 the biomarkers
based sensor can play a pivotal role as it will reduce the time to
detect, will be cost‐effective, and also reduce the chance of virus
transmission while diagnosis, we can look forward to the integration
of microfluidics system with this biosensor so that a minimal amount
of sample is used and the chance of virus transmission remains
insignificant.
142
In the other words, in recent years, the development of bio-
sensors for biomarkers of diseases has received a lot of attention.
However, the developments of biomarkers and the innovation of
diagnostic tools for early detection of COVOD‐19 are still in their
early stages. For future works, the development of another problem
is that owing to its low accuracy and reliability, few portable elec-
trochemical instruments are in clinical usage. Therefore, robust
biosensor‐based POCT devices are required of ultrasensitive elec-
trochemical label‐free methods will be of great potential. Re-
searchers must train the electrochemical biosensor to solve their
reliability problems with a significant number of clinical samples. The
development of wireless micro/nano electrochemical biosensors is an
ideal option for infection detection, as they can work in contaminated
environments. The approachable properties of electrochemical in-
struments improve the performance of infection diagnostics and
therapy monitoring. With further advancement and funding, these
handheld instruments are anticipated to improve COVID‐19 diag-
nosis, rendering diagnostic findings accessible in a matter of minutes
at the patient bedside or practitioner's office. Nonetheless, proposed
detection approaches for biomarker detection of COVID‐19 neces-
sarily require a standardisation of pre‐and post‐analytical protocols
such as sample preparation, storage, and optimisation of experi-
mental conditions for true validity of assays and more genuine output
of the biosensor produced. The production and progression of these
advanced COVID‐19 detection systems will aid in the early stages of
accelerated clinical SARS‐CoV‐2 diagnoses.
However, several challenges and limitations remain, which need
to be improved, in the design and application of biosensors for the
appropriate interpretation of the identified and quantified bio-
markers for COVID‐19. Researchers are continuing to conquer the
difficulties above and will eventually develop biomarker‐based de-
vices capable of clinical application.
ACKNOWLEDGEMENT
The authors would like to thank all staff who helped us to prepare
and publish this article.
CONFLICT OF INTEREST
All authors declare that there is no conflict of interest.
AUTHOR CONTRIBUTIONS
All authors equally contributed to this work.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were
created or analyzed in this study.
ORCID
Farzad Parvizpour
https://orcid.org/0000-0003-3711-9171
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How to cite this article: Khaksarinejad R, Arabpour Z,
RezaKhani L, Parvizpour F, Rasmi Y. Biomarker based
biosensors: an opportunity for diagnosis of COVID‐19. Rev
Med Virol. 2022;e2356. https://doi.org/10.1002/rmv.2356
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